Download sulfamethoxazole/trimethoprim

DRUGDEX® Evaluations
SULFAMETHOXAZOLE/TRIMETHOPRIM
0.0 Overview
1) Class
a) This drug is a member of the following class(es):
Antibiotic
Sulfonamide Combination
2) Dosing Information
a) Adult
1) Acute infective exacerbation of chronic obstructive pulmonary disease
[1][2]
a) 1 double-strength tablet or 2 single strength tablets or 20 mL suspension ORALLY every 12 hr for 14 days
2) Granuloma inguinale
a) 1 double-strength (sulfamethoxazole 800 mg/trimethoprim 160 mg) tablet ORALLY twice daily for at least 3 weeks and until lesions
[12]
are healed completely
3) HIV infection - Pneumocystis pneumonia
a) moderate to severe, 75 to 100 mg/kg/day sulfamethoxazole and 15 to 20 mg/kg/day trimethoprim IV divided every 6 to 8 hr for 21
[13]
days; may switch to oral after clinical improvement (guideline dosing)
b) mild to moderate, 75 to 100 mg/kg/day sulfamethoxazole and 15 to 20 mg/kg/day trimethoprim ORALLY in 3 divided doses for 21
[13]
days, OR 1600 mg sulfamethoxazole and 320 mg trimethoprim ORALLY 3 times daily for 21 days (guideline dosing)
4) HIV infection - Pneumocystis pneumonia; Prophylaxis
a) primary and secondary prophylaxis, 800 mg sulfamethoxazole and 160 mg trimethoprim ORALLY once a day or 400 mg
sulfamethoxazole and 80 mg trimethoprim ORALLY once a day; alternative regimen, 800 mg sulfamethoxazole and 160 mg
[13]
trimethoprim ORALLY 3 times a week
5) HIV infection - Toxoplasma encephalitis
[13]
a) alternative therapy, sulfamethoxazole 25 mg/kg/trimethoprim 5 mg/kg ORALLY or IV twice daily for at least 6 wk
6) HIV infection - Toxoplasma encephalitis; Prophylaxis
a) primary prophylaxis, 1 double-strength tablet ORALLY daily (preferred); 1 double-strength tablet ORALLY three times weekly or 1
[13]
single-strength tablet ORALLY daily may be used as alternatively
7) Pneumocystis pneumonia
a) 75 to 100 mg/kg/day sulfamethoxazole and 15 to 20 mg/kg/day trimethoprim ORALLY in equally divided doses every 6 hr for 14 to
[2]
[17]
21 days OR 15 to 20 mg/kg/day trimethoprim component IV divided in 3 or 4 equal doses every 6 to 8 hr for up to 14 days
8) Pneumocystis pneumonia; Prophylaxis
[2]
a) 800 mg sulfamethoxazole and 160 mg trimethoprim ORALLY once a day
9) Shigellosis
[1][2]
a) 1 double-strength tablet or 2 single strength tablets or 20 mL suspension ORALLY every 12 hr for 5 days
b) 8 to 10 mg/kg trimethoprim component/day IV in 2 to 4 equally divided doses every 6, 8, or 12 hr for 5 days; max daily dose is 60
[3]
mL
10) Traveler's diarrhea
[1][2]
a) 1 double-strength tablet or 2 single-strength tablets or 20 mL suspension ORALLY every 12 hr for 5 days
11) Urinary tract infectious disease
a) sulfamethoxazole 800 mg/trimethoprim 160 mg (1 double-strength tablet) ORALLY twice daily for 3 days if uncomplicated cystitis
[30]
or 14 days if acute pyelonephritis (guideline dosing)
b) 1 double-strength tablet or 2 single-strength tablets or 20 mL suspension ORALLY every 12 hours for 10 to 14 days (manufacturer
[1][2]
dosing)
b) Pediatric
[3]
1) contraindicated in children younger than 2 months of age
a) Acute otitis media
1) 6 to 10 mg/kg trimethoprim component/day ORALLY divided every 12 hr for 5 to 7 days (6 yr and older) or 10 days (less than 6 yr
[36]
old or severe illness) (guideline dosing)
2) (2 months of age and older) 8 mg/kg trimethoprim component/day ORALLY divided every 12 hr for 10 days (manufacturer dosing)
[1][2]
b) HIV infection - Pneumocystis pneumonia
1) (2 months of age and older) 75 to 100 mg/kg/day sulfamethoxazole and 15 to 20 mg/kg/day trimethoprim IV in 3 or 4 divided doses
[14]
for 21 days; may switch to oral after clinical improvement
c) HIV infection - Pneumocystis pneumonia; Prophylaxis
1) (1 month of age and older) primary and secondary prophylaxis, 750 mg/m(2)/day sulfamethoxazole and 150 mg/m(2)/day
trimethoprim in 2 divided doses ORALLY 3 times a week on consecutive days (MAX 1600 mg/day sulfamethoxazole and 320 mg/day
trimethoprim); alternative regimens for the same dosage: given as a single dose ORALLY 3 times a week on consecutive days OR
given in 2 divided doses ORALLY every day OR given in 2 divided doses ORALLY 3 times a week on alternate days (guideline dosing)
[14]
d) HIV infection - Toxoplasma encephalitis; Prophylaxis
1) primary prophylaxis, sulfamethoxazole 750 mg/m(2) and trimethoprim 150 mg/m(2) ORALLY daily in 2 divided doses; alternative
regimens for the same dosage include a single dose ORALLY 3 times weekly on consecutive days OR 2 divided doses ORALLY 3
[14]
times weekly on alternate days
e) Pneumocystis pneumonia
1) (2 months of age and older) 75 to 100 mg/kg/day sulfamethoxazole AND 15 to 20 mg/kg/day trimethoprim ORALLY divided every 6
[2]
hr for 14 to 21 days OR 15 to 20 mg/kg/day trimethoprim component IV divided in 3 or 4 equal doses every 6 to 8 hr for up to 14 days
[17]
f) Pneumocystis pneumonia; Prophylaxis
1) (2 months of age and older) 750 mg/m(2)/day sulfamethoxazole (MAX 1600 mg/day) and 150 mg/m(2)/day trimethoprim (MAX 320
[2]
mg/day) in 2 divided doses ORALLY 3 times a week on consecutive days
g) Shigellosis
[1][2]
1) (2 months of age and older) 8 to 10 mg/kg trimethoprim component/day ORALLY in 2 divided doses every 12 hr for 5 days
2) (2 months of age and older) 8 to 10 mg/kg trimethoprim component/day IV in 2 to 4 equally divided doses every 6, 8, or 12 hr for 5
[3]
days
h) Urinary tract infectious disease
[1][2]
1) (2 months of age and older) 8 mg/kg trimethoprim component/day ORALLY divided every 12 hours for 10 days
3) Contraindications
[105]
a) history of sulfonamide- or trimethoprim-induced immune thrombocytopenia
[105]
b) hypersensitivity to sulfonamides or trimethoprim
[105]
c) infants less than 2 months of age
[105]
d) hepatic damage, marked
[105]
e) megaloblastic anemia due to folate deficiency
[105]
f) nursing mothers
[105]
g) pregnant patients
[105]
h) renal insufficiency, severe
4) Serious Adverse Effects
a) Agranulocytosis
b) Anaphylaxis
c) Aplastic anemia
d) Clostridium difficile diarrhea
e) Disorder of hematopoietic structure
f) Erythema multiforme
g) Hepatic necrosis, Fulminant
h) Neutropenia
i) Rhabdomyolysis
j) Stevens-Johnson syndrome
k) Thrombocytopenia
l) Toxic epidermal necrolysis
5) Clinical Applications
a) FDA Approved Indications
1) Acute infective exacerbation of chronic obstructive pulmonary disease
2) Acute otitis media
3) HIV infection - Pneumocystis pneumonia
4) HIV infection - Pneumocystis pneumonia; Prophylaxis
5) Pneumocystis pneumonia
6) Pneumocystis pneumonia; Prophylaxis
7) Shigellosis
8) Traveler's diarrhea
9) Urinary tract infectious disease
b) Non-FDA Approved Indications
1) Granuloma inguinale
2) HIV infection - Toxoplasma encephalitis
3) HIV infection - Toxoplasma encephalitis; Prophylaxis
1.0 Dosing Information
Drug Properties
Storage and Stability
Adult Dosage
Pediatric Dosage
1.1 Drug Properties
A) Information on specific products and dosage forms can be obtained by referring to the Tradename List (Product Index)
1.2 Storage and Stability
A) Preparation
1) General Information
a) Do not administer sulfamethoxazole/trimethoprim injection by intramuscular administration
2) Intravenous
a) Preparation and Rate of Intravenous Administration
[3]
1) Do not give sulfamethoxazole/trimethoprim injection by intravenous (IV) bolus or by rapid IV infusion. Dilute each 5 milliliters (mL)
in 125 mL of D5W and infuse intravenously over 60 to 90 minutes. For patients with fluid restriction, dilute each 5 mL in 75 mL of D5W.
[3]
If upon visual inspection, the solution is cloudy or has evidence of crystallization, the solution should be discarded .
b) Stability of Infusion Solution
1) Do not refrigerate the infusion solution. Use the solution within 2 hours of preparation if the total volume is 75 mL. Use within 4 hours
if the total volume is 100 mL, or use within 6 hours if the total volume is 125 mL. Use glass, unit-dose polyvinyl chloride, or polyolefin
[3]
containers for the infusion solutions .
[104]
2) Independent research substantiates the safe use of concentrated sulfamethoxazole/trimethoprim solutions
. Four separate
sulfamethoxazole/trimethoprim concentrations were evaluated for stability. The concentrations selected were 1:25, 1:20, 1:15 and
1:10 (ratio of volume of sulfamethoxazole/trimethoprim solution to volume of diluent fluid). The solution was visually examined for
precipitate and samples were assayed by HPLC over a 24-hour period at 23 to 25 degrees Centigrade. No precipitation nor significant
degradation occurred during the 24-hour study period.
B) Intravenous route
1) Solution
a) Store vials at room temperature, from 15 to 30 degrees C (59 to 86 degrees F); do not refrigerate. After initial entry into multidose
[498]
vial, use remaining contents within 48 hours
.
[498]
b) Use diluted concentrations of 5 mL of solution with 125 mL of D5W within 6 hours; do not refrigerate
.
[498]
c) Use diluted concentrations of 5 mL of solution in 100 mL D5W within 4 hours
.
[498]
d) Mix diluted concentrations of 5 mL of solution in 75 mL D5W just prior to use and complete administration within 2 hours
.
e) Cotrimoxazole injection (16 mg/80 mg per mL) in polypropylene syringes was stable for over 60 hours, with greater than 90% of the
[499]
initial concentration retained
.
f) Four separate cotrimoxazole concentrations were evaluated for stability. The concentrations selected were 1:25, 1:20, 1:15, and 1:10
(ratio of volume of cotrimoxazole solution to volume of diluent fluid). The solution was visually examined for precipitate and samples
were assayed by high performance liquid chromatography (HPLC) over a 24-hour period at 23 to 25 degrees C. No precipitation nor
significant degradation occurred during the 24-hour study period. Other investigators found that a 1:10 dilution (5 mL of cotrimoxazole in
50 mL IV fluid) was stable for only 1 hour in D5W or NS. They found a more dilute solution (1:25) to be stable for 48 hours in either
[500]
D5W or NS
.
C) Oral route
1) Suspension/Tablet
[105]
a) Store tablet at controlled room temperature, from 20 to 25 degrees C (68 to 77 degrees F)
.
[501]
b) Store suspension at controlled room temperature, from 20 to 25 degrees C (68 to 77 degrees F); protect from light
.
D) Extemporaneous Formulation - Ophthalmic route
[734]
[735][736]
1) Information about the use of cotrimoxazole eyedrops is limited to 4 case reports
; (Bucci et al, 1991)
. In each case, the
commercial intravenous solution was instilled directly into the affected eye. Stability and sterility of the intravenous solution when used
as an eyedrop were not tested. It should be stored at room temperature and inspected for cloudiness or precipitation. Further study is
necessary to address the issues of safety and efficacy.
1.3 Adult Dosage
Normal Dosage
Dosage in Renal Failure
Dosage in Geriatric Patients
Dosage Adjustment During Dialysis
Dosage in Other Disease States
1.3.1 Normal Dosage
Important Note
Intravenous route
Oral route
1.3.1.A Important Note
) Cotrimoxazole is a combination of sulfamethoxazole and trimethoprim. A single-strength (SS) tablet contains sulfamethoxazole
400 milligrams (mg)/trimethoprim 80 mg. A double-strength (DS) tablet contains sulfamethoxazole 800 mg/trimethoprim 160 mg. A 5milliliter (mL) vial of the intravenous form contains sulfamethoxazole 400 mg/trimethoprim 80 mg. Each 5 mL of the oral suspension
[1][2][3]
contains sulfamethoxazole 200 mg/trimethoprim 40 mg
.
1.3.1.B Intravenous route
Bacteremia associated with intravascular line
Bacterial meningitis
HIV infection - Pneumocystis pneumonia
HIV infection - Toxoplasma encephalitis
Pneumocystis pneumonia
Shigellosis
1.3.1.B.1 Bacteremia associated with intravascular line
a) The recommended dose of sulfamethoxazole/trimethoprim for the treatment of catheter-related bacteremia due to
Stenotrophomonas maltophilia, Burkholderia cepacia, and Ochrobacterium anthropi is 3 to 5 milligrams/kilogram of the trimethoprim
[4]
component intravenously every 8 hours .
1.3.1.B.2 Bacterial meningitis
a) The recommended dose of sulfamethoxazole/trimethoprim in adults with documented bacterial meningitis is 10 to 20
[53]
milligrams/kilogram trimethoprim component/day intravenously divided every 6 to 12 hours .
1.3.1.B.3 HIV infection - Pneumocystis pneumonia
a) The recommended dose of sulfamethoxazole/trimethoprim for the treatment of moderate to severe Pneumocystis jiroveci
pneumonia (PCP) infection in HIV-infected adults is 15 to 20 milligrams/kilogram of the trimethoprim component/day intravenously
[13]
divided every 6 to 8 hours for 21 days. A switch to oral therapy is appropriate after clinical improvement .
1.3.1.B.4 HIV infection - Toxoplasma encephalitis
a) The recommended dose of sulfamethoxazole/trimethoprim for treating toxoplasmic encephalitis in HIV-infected patients is
sulfamethoxazole 25 milligrams per kilogram (mg/kg)/trimethoprim 5 mg/kg intravenously twice daily for at least 6 weeks. Longer
[13]
duration may be necessary if clinical or radiologic disease is extensive or if response at 6 weeks is incomplete .
1.3.1.B.5 Pneumocystis pneumonia
a) The recommended dosage of sulfamethoxazole/trimethoprim for the treatment of Pneumocystis pneumonia in patients with human
immunodeficiency virus is 15 to 20 milligrams/kilogram/day of the trimethoprim component intravenously divided in 3 or 4 equal doses
[17]
every 6 to 8 hours for up to 14 days .
1.3.1.B.6 Shigellosis
a) The manufacturer recommends a dose of sulfamethoxazole 40 to 50 milligrams/kilograms/day (mg/kg/day)/trimethoprim 8 to 10
mg/kg/day in 2 to 4 equally divided doses every 6, 8, or 12 hours for up to 5 days. The maximum recommended total daily dose is 60
[3]
milliliters .
1.3.1.C Oral route
Acute exacerbation of pulmonary cystic fibrosis
Acute infective exacerbation of chronic obstructive pulmonary disease
Cyclosporiasis
Granuloma inguinale
HIV infection - Pneumocystis pneumonia
HIV infection - Pneumocystis pneumonia; Prophylaxis
HIV infection - Toxoplasma encephalitis
HIV infection - Toxoplasma encephalitis; Prophylaxis
Pneumocystis pneumonia
Pneumocystis pneumonia; Prophylaxis
Shigellosis
Sinusitis
Traveler's diarrhea
Urinary tract infectious disease
1.3.1.C.1 Acute exacerbation of pulmonary cystic fibrosis
a) The dose of sulfamethoxazole/trimethoprim recommended to treat cystic fibrosis patients with acute pulmonary exacerbations is
sulfamethoxazole 25 milligrams/kilogram (mg/kg)/trimethoprim 5 mg/kg every 6 hours. For the treatment of infections caused by
Burkholderia cepacia, sulfamethoxazole/trimethoprim may be administered alone or in combination with chloramphenicol. For the
treatment of mixed infections with Burkholderia cepacia and Pseudomonas aeruginosa ceftazidime with chloramphenicol or
[18]
sulfamethoxazole/trimethoprim is recommended .
b) Sulfamethoxazole 800 milligrams (mg)/trimethoprim 160 mg (1 double-strength tablet) every 12 hours has been given chronically
[18]
to patients with CYSTIC FIBROSIS to suppress the growth of Burkholderia cepacia .
1.3.1.C.2 Acute infective exacerbation of chronic obstructive pulmonary disease
a) The recommended oral dose is sulfamethoxazole 800 milligrams (mg)/trimethoprim 160 mg for exacerbations of chronic bronchitis
[1][2]
every 12 hours for 14 days
1.3.1.C.3 Cyclosporiasis
a) Sulfamethoxazole 800 milligrams (mg)/trimethoprim 160 mg four times daily for 10 days followed by prophylaxis with 1 tablet 3
[9]
times weekly, was effective for the treatment of 43 HIV Haitian patients with diarrhea & positive cyclospora in the stools .
1.3.1.C.4 Granuloma inguinale
a) As an alternative to doxycycline for the treatment of granuloma inguinale (donovanosis), the CDC recommends 1 double-strength
tablet (sulfamethoxazole 800 mg/trimethoprim 160 mg) orally twice daily for at least 3 weeks and until lesions are healed
[12]
completely .
1.3.1.C.5 HIV infection - Pneumocystis pneumonia
a) The recommended dose of sulfamethoxazole/trimethoprim for the treatment of mild to moderate Pneumocystis jiroveci Pneumonia
(PCP) infection in HIV-infected adults is 15 to 20 milligrams/kilogram (mg/kg) of the trimethoprim component/day orally in 3 divided
[13]
doses or 320 mg of the trimethoprim component orally 3 times daily for 21 days .
1.3.1.C.6 HIV infection - Pneumocystis pneumonia; Prophylaxis
a) The recommended dose of sulfamethoxazole/trimethoprim for primary and secondary prophylaxis of Pneumocystis jiroveci
pneumonia (PCP) in adults with human immunodeficiency virus (HIV) is 800 milligrams (mg) of sulfamethoxazole and 160 mg of
trimethoprim orally daily or 400 mg of sulfamethoxazole and 80 mg of trimethoprim orally daily . An alternative dosing regimen is 800
[13]
mg of sulfamethoxazole and 160 mg of trimethoprim orally 3 times weekly .
1.3.1.C.7 HIV infection - Toxoplasma encephalitis
a) The recommended dose of sulfamethoxazole/trimethoprim for treating toxoplasmic encephalitis in HIV-infected patients is
sulfamethoxazole 25 milligrams per kilogram (mg/kg)/trimethoprim 5 mg/kg orally twice daily for at least 6 weeks. Longer duration may
[13]
be necessary if clinical or radiologic disease is extensive or if response at 6 weeks is incomplete .
1.3.1.C.8 HIV infection - Toxoplasma encephalitis; Prophylaxis
a) The recommended dose of sulfamethoxazole/trimethoprim for the primary prophylaxis of toxoplasmic encephalitis in HIV-infected
patients is 1 double-strength tablet (sulfamethoxazole 800 milligrams (mg)/trimethoprim 160 mg) orally daily (preferred regimen).
Alternatively, 1 double-strength tablet orally three times weekly or 1 single-strength tablet (sulfamethoxazole 400 mg/trimethoprim 80
[13]
mg) orally daily is recommended .
b) Primary prophylaxis should be discontinued among patients who have responded to highly active antiretroviral therapy (HAART)
with an increase in CD4 T-lymphocyte counts to greater than 200 cells/microliter (mcL) for at least 3 months. Prophylaxis should be
[13]
reintroduced if the CD4 T-lymphocyte count decreases to less than 100 to 200 cells/mcL .
1.3.1.C.9 Pneumocystis pneumonia
a) The recommended dosage of sulfamethoxazole/trimethoprim for the treatment of Pneumocystis pneumonia in patients with human
immunodeficiency virus is 75 to 100 milligrams/kilogram (mg/kg) of sulfamethoxazole and 15 to 20 mg/kg of trimethoprim orally daily in
[2]
equally divided doses every 6 hours for 14 to 21 days .
1.3.1.C.10 Pneumocystis pneumonia; Prophylaxis
a) The recommended dose of sulfamethoxazole/trimethoprim for prophylaxis of Pneumocystis carinii pneumonia in
[2]
immunosuppressed patients is 800 milligrams (mg) of sulfamethoxazole and 160 mg of trimethoprim orally daily .
1.3.1.C.11 Shigellosis
a) The recommended adult dose is sulfamethoxazole 800 milligrams (mg)/trimethoprim 160 mg every 12 hours for 5 days
[1][2]
.
1.3.1.C.12 Sinusitis
a) Short course treatment, 1 double-strength tablet twice daily for three days, was as effective as standard therapy (1 double-strength
[24]
tablet twice daily for 10 days) for the treatment of acute maxillary sinusitis .
1.3.1.C.13 Traveler's diarrhea
a) The dose of sulfamethoxazole/trimethoprim for the treatment of travelers' diarrhea is 800 milligrams (mg)/160 mg every 12 hours
[1][2]
for 5 days
. An alternative regimen is a loading dose of sulfamethoxazole 1600 mg/trimethoprim 320 mg followed by
[29]
sulfamethoxazole 800 mg/trimethoprim 160 mg twice daily for 3 days .
1.3.1.C.14 Urinary tract infectious disease
a) Guideline Recommendations
1) For the treatment of acute uncomplicated cystitis in women, the recommended dosage is sulfamethoxazole 800 mg/trimethoprim
160 mg (1 double-strength tablet) orally twice daily for 3 days. For treatment of acute pyelonephritis, the same dose for a treatment
[30]
duration of 14 days is recommended .
b) Manufacturer Recommendation
1) The usual dose for the treatment of urinary tract infections is sulfamethoxazole 800 mg/trimethoprim 160 mg (1 double-strength
[1][2]
tablet) orally every 12 hours for 10 to 14 days
1.3.1.C.15 Desensitization
a) A six-hour graded challenge was safe and effective and enabled more patients to receive sulfamethoxazole/trimethoprim
prophylaxis in a study of 44 HIV-infected patients with documented sulfamethoxazole/trimethoprim hypersensitivity. The one-day, sixhour graded challenge protocol was initiated at least one month following the original sulfamethoxazole/trimethoprim hypersensitivity
reaction. Twelve doses were prepared from the pediatric suspension and administered orally at half-hour intervals. On day 2,
sulfamethoxazole 400 mg/trimethoprim 80 mg was administered orally once daily. Patients were advised to cautiously treat through
nonbullous cutaneous adverse reactions with cetirizine 10 mg daily and to discontinue sulfamethoxazole/trimethoprim if skin blistering
or mucosal involvement occurred. Following one month, the overall success rate was 91% or 40 of 44 patients. Following 10 months,
42 patients were receiving sulfamethoxazole/trimethoprim without adverse effect, resulting in an overall success rate of 95% (Demoly
et al, 1998):
Sulfamethoxazole/Trimethoprim
Dose
1
0.001 mg/0.0002 mg (1 mcg/0.2 mcg)
2
0.003 mg/0.0006 mg (3 mcg/0.6 mcg)
3
0.009 mg/0.0018 mg (9 mcg/1.8 mcg)
4
0.03 mg/0.006 mg (30 mcg/6 mcg)
5
0.09 mg/0.018 mg (90 mcg/18 mcg)
6
0.3 mg/0.06 mg (300 mcg/60 mcg)
7
1 mg/0.2 mg
8
3 mg/0.6 mg
9
9 mg/1.8 mg
10
30 mg/6 mg
11
90 mg/18 mg
12
300 mg/60 mg
1.3.1.C.16 A two day desensitization procedure with sulfamethoxazole/trimethoprim produced a 77% success rate in 48 previously
hypersensitive HIV-infected patients. Successful desensitization occurred more often in patients with lower CD4+ cell percentages and
CD4+/CD8+ ratios. Full dose sulfamethoxazole 400 mg/trimethoprim 80 mg was reached on the third day (Caumes et al, 1997):
Sulfamethoxazole/Trimethoprim (mg)
Day Hour
1
9 am
4/0.8
2
3
11 am
1 pm
5 pm
9 am
3 pm
9 pm
9 am
8/1.6
20/4
40/8
80/16
160/32
200/40
400/80
1.3.1.C.17 In patients with a history of hypersensitivity to sulfamethoxazole/trimethoprim (rash with or without fever), 23 of 28
[93]
patients were successfully desensitized :
Sulfamethoxazole/Trimethoprim (mg)
Day Daily Dose
1
1 mL of 1:20 pediatric suspension
2/0.4
2
2 mL of 1:20 pediatric suspension
4/0.8
3
4 mL of 1:20 pediatric suspension
8/1.6
4
8 mL of 1:20 pediatric suspension
16/3.2
5
1 mL of pediatric suspension
40/8
6
2 mL of pediatric suspension
80/16
7
4 mL of pediatric suspension
160/32
8
8 mL of pediatric suspension
320/64
9
1 single-strength tablet
400/80
10
1 double-strength tablet
800/160
1.3.2 Dosage in Renal Failure
A) Patients who receive sulfamethoxazole/trimethoprim intravenously or orally and have impaired renal function should be dosed
[1][2][3]
according to the following dosage schedule
:
Creatinine Clearance
Dosage
(mL/min)
Above 30
Standard regimen
15 to 30
1/2 standard regimen
Below 15
Not recommended
B) Centers for Disease Control and Prevention (CDC) recommendations for the administration of sulfamethoxazole/trimethoprim
[96][97]
(based on the trimethoprim component) among HIV-infected patients with renal dysfunction
:
Indication/Renal Function Dose (trimethoprim component)
PCP Treatment
CrCl greater than 30
15 to 20 mg/kg/day in 3 or 4 divided doses
mL/min
CrCl 15 to 30 mL/min
5 mg/kg/dose q6 to 8hr for 48hr then 3.5 to 5 mg/kg/dose q12hr
CrCl less than 15 mL/min 7 to 10 mg/kg/day in 1 or 2 divided doses
Hemodialysis
7 to 10 mg/kg after dialysis
PCP Prophylaxis
CrCl greater than 30
160 mg q24hr for 3 to 7 doses/week (or 80 mg q24hr for 7 doses/week)
mL/min
CrCl 15 to 30 mL/min
80 mg q24hr for 3 to 7 doses/week (or 40 mg q24hr for 7 doses/week)
CrCl less than 15 mL/min 80 mg q24hr for 3 to 7 doses/week (or 40 mg q24hr for 7 doses/week), or use alternative agent
80 mg q24hr for 3 to 7 doses/week (or 40 mg q24hr for 7 doses/week), administer scheduled dose after
Hemodialysis
each dialysis
C) Some specialists prefer to administer the standard dose of sulfamethoxazole/trimethoprim and monitor drug levels when treating
[96]
opportunistic infections in HIV-infected patients with renal insufficiency to prevent underdosing . A peak trimethoprim serum
concentration of 5 to 10 micrograms/milliliter (17.2 to 34.4 micromol/liter) has been advocated to achieve clinical efficacy and avoid
[98]
toxicity .
D) Guidelines for the administration of sulfamethoxazole/trimethoprim (based on the trimethoprim component) in patients with renal
[99][100]
dysfunctions
:
Indication/Renal Function
Dose (trimethoprim component)
PCP Treatment
CrCl greater than 30 mL/min
15 to 20 mg/kg/day divided q 6 to 8 hr
CrCl 15 to 30 mL/min
15 to 20 mg/kg/day divided q 6 to 8 hr for 48
hr then 7 to 10 mg/kg/day divided q 12 hr
CrCl less than 15 ml/min
15 to 20 mg/kg/dose q 48 hr (or 7 to 10
mg/kg/day divided q 12 to 24 hr)
Hemodialysis
PCP Prophylaxis
CrCl greater than 30 mL/min
CrCl 15 to 30 mL/min
CrCl less than 15 mL/min
Hemodialysis
Other Infections
CrCl greater than 30 mL/min
15 to 20 mg/kg/dose before dialysis and 7 to
10 mg/kg/dose after dialysis
5 mg/kg q 24 hr for 3 to 7 doses/week
5 mg/kg q 24 to 48 hr for 3 to 7 doses/week
5 mg/kg q 48 to 72 hr
5 mg/kg after dialysis
8 to 12 mg/kg/day divided q 12 hr for 14 days
then 4 to 6 mg/kg q 24 hr
CrCl 15 to 30 mL/min
8 to 12 mg/kg/day divided q 12 hr for 1 to 2
days then 4 to 6 mg/kg/day q 24 hr
CrCl less than 15 mL/min
8 to 12 mg/kg/dose q 48 hr (or 4 to 6
mg/kg/day divided q 12 to 24 hr)
Hemodialysis
8 to 12 mg/kg/dose before dialysis and 4 to 6
mg/kg/dose after dialysis
Use of sulfamethoxazole/trimethoprim in moderate-to-severe renal dysfunction have not been adequately studied. Therefore, these
recommendations should be interpreted along with the clinical status of the patient and therapeutic monitoring of drug levels are
[99]
recommended . A peak trimethoprim serum concentration of 5 to 10 micrograms/milliliter (17.2 to 34.4 micromol/liter) has been
[98]
advocated to achieve clinical efficacy and avoid toxicity .
1.3.4 Dosage in Geriatric Patients
A) The pharmacokinetics of sulfamethoxazole/trimethoprim and cotetroxazine used as partner drugs in elderly patients were found to
[101]
be comparable to younger patients, with the exception of reduced renal clearance of the sulfonamides
.
1.3.5 Dosage Adjustment During Dialysis
A) Hemodialysis
1) In hemodialysis patients, 50% of the maintenance dose of sulfamethoxazole/trimethoprim should be supplemented following each
dialysis session. These recommendations are based upon observations that 44% of administered trimethoprim and 57% of
[102]
administered sulfamethoxazole are removed during a 4-hour hemodialysis session
.
1.3.6 Dosage in Other Disease States
A) Cystic Fibrosis
1) Shorter elimination half-lives and enhanced plasma clearances of sulfamethoxazole/trimethoprim were reported in cystic fibrosis
[103]
patients, suggesting the need for increased doses or decreased dosing intervals in these patients
.
1.4 Pediatric Dosage
Normal Dosage
Dosage in Renal Failure
Dosage Adjustment During Dialysis
1.4.1 Normal Dosage
Important Note
Intravenous route
Oral route
1.4.1.A Important Note
) Cotrimoxazole is a combination of sulfamethoxazole and trimethoprim. A single-strength (SS) tablet contains sulfamethoxazole
400 milligrams (mg)/trimethoprim 80 mg. A double-strength (DS) tablet contains sulfamethoxazole 800 mg/trimethoprim 160 mg. A 5milliliter (mL) vial of the intravenous form contains sulfamethoxazole 400 mg/trimethoprim 80 mg. Each 5 mL of the oral suspension
[1][2][3]
contains sulfamethoxazole 200 mg/trimethoprim 40 mg
.
1.4.1.B Intravenous route
Bacterial meningitis
HIV infection - Pneumocystis pneumonia
Pneumocystis pneumonia
Shigellosis
Urinary tract infectious disease
1.4.1.B.1 Bacterial meningitis
a) The recommended dose of sulfamethoxazole/trimethoprim for the treatment of documented bacterial meningitis in infants and
children age greater than 28 days is 10 to 20 milligrams/kilogram trimethoprim component/day intravenously divided every 6 to 12
[53]
hours .
1.4.1.B.2 HIV infection - Pneumocystis pneumonia
a) The recommended dose of sulfamethoxazole/trimethoprim for the treatment of Pneumocystis pneumonia in children greater than 2
months of age with human immunodeficiency virus is 75 to 100 milligrams/kilogram (mg/kg) of sulfamethoxazole and 15 to 20 mg/kg
of trimethoprim administered intravenously in 3 to 4 divided doses for 21 days. After resolution of acute pneumonia, children with mild to
moderate disease can be switched to oral administration of sulfamethoxazole/trimethoprim if they do not have concurrent
malabsorption or diarrhea. The same dose should be administered in 3 to 4 divided doses to complete a 21-day course. Chronic
[14]
suppressive therapy with sulfamethoxazole/trimethoprim should be continued .
1.4.1.B.3 Pneumocystis pneumonia
a) The recommended dosage of sulfamethoxazole/trimethoprim for the treatment of Pneumocystis pneumonia in children 2 months
and older with human immunodeficiency virus is 15 to 20 milligrams/kilogram/day of the trimethoprim component intravenously divided
[17]
in 3 or 4 equal doses every 6 to 8 hours for up to 14 days .
1.4.1.B.4 Shigellosis
a) The recommended intravenous dose of sulfamethoxazole/trimethoprim in children 2 months and older is sulfamethoxazole 40 to
50 milligrams/kilograms/day (mg/kg/day)/ trimethoprim 8 to 10 mg/kg/day in 2 to 4 equally divided doses every 6, 8, or 12 hours for 5
[3]
days .
1.4.1.B.5 Urinary tract infectious disease
a) The recommended intravenous dose of sulfamethoxazole/trimethoprim for the treatment of urinary tract infections in children 2
months of age and older is sulfamethoxazole 40 to 50 milligrams per kilogram per day (mg/kg/day)/trimethoprim 8 to 10 mg/kg/day in
[3]
2 to 4 equally divided doses for up to 14 days .
1.4.1.B.6 Neonates
[3]
a) Sulfamethoxazole/trimethoprim use is contraindicated in children younger than 2 months of age .
1.4.1.C Oral route
Acute exacerbation of pulmonary cystic fibrosis
Acute otitis media
Cyclosporiasis
HIV infection - Pneumocystis pneumonia
HIV infection - Pneumocystis pneumonia; Prophylaxis
HIV infection - Toxoplasma encephalitis; Prophylaxis
Pneumocystis pneumonia
Pneumocystis pneumonia; Prophylaxis
Shigellosis
Urinary tract infectious disease
1.4.1.C.1 Acute exacerbation of pulmonary cystic fibrosis
a) The dose of sulfamethoxazole/trimethoprim recommended to treat cystic fibrosis patients with acute pulmonary exacerbations is
sulfamethoxazole 25 milligrams/kilogram (mg/kg)/trimethoprim 5 mg/kg every 6 hours. For the treatment of infections caused by
Burkholderia cepacia, sulfamethoxazole/trimethoprim may be administered alone or in combination with chloramphenicol. For the
treatment of mixed infections with Burkholderia cepacia and Pseudomonas aeruginosa ceftazidime with chloramphenicol or
[18]
sulfamethoxazole/trimethoprim is recommended .
b) Sulfamethoxazole 20 milligrams/kg (mg/kg)/trimethoprim 4 mg/kg every 12 hours has been given chronically to patients with
[18]
CYSTIC FIBROSIS to suppress the growth of Burkholderia cepacia .
1.4.1.C.2 Acute otitis media
a) Guideline Dosing
1) The recommended dose of sulfamethoxazole/trimethoprim for the treatment of acute otitis media is 6 to 10 milligrams/kilogram
(trimethoprim component) per day orally in 2 divided doses for 5 to 7 days (children 6 years of age and older) or 10 days (children less
[36]
than 6 years of age or severe illness) .
b) Manufacturer Dosing
1) The recommended dose for the treatment of acute otitis media in children 2 months of age and older is sulfamethoxazole 40 mg
[1][2]
per kilogram per day (mg/kg/day)/trimethoprim 8 mg/kg/day, given in divided doses every 12 hours for 10 days
.
[1][2]
2) The manufacturer provides the following table to attain the recommended dosage using oral suspension
:
Weight
Dose Q12H
Tablets(SS)
teaspoonful
lb
kg
22
10
1 (5 mL)
44
20
2 (10 mL)
1
66
30
3 (15 mL)
1 1/2
88
40
4 (20 mL)
2 (1 DS)
1.4.1.C.3 Cyclosporiasis
a) Sulfamethoxazole/trimethoprim has been used to treat Cyclospora enteric infection in 4 children. The dose was 5
[11]
milligrams/kilogram of trimethoprim daily for 3 days. Symptoms of diarrhea resolved in a mean of 3.8 days .
1.4.1.C.4 HIV infection - Pneumocystis pneumonia
a) The recommended dose of sulfamethoxazole/trimethoprim for the treatment of Pneumocystis pneumonia in children greater than 2
months of age with human immunodeficiency virus is 75 to 100 milligrams/kilogram (mg/kg) of sulfamethoxazole and 15 to 20 mg/kg
of trimethoprim administered intravenously in 3 to 4 divided doses for 21 days. After resolution of acute pneumonia, children with mild to
moderate disease can be switched to oral administration of sulfamethoxazole/trimethoprim if they do not have concurrent
malabsorption or diarrhea. The same dose should be administered in 3 to 4 divided doses to complete a 21-day course. Chronic
[14]
suppressive therapy with sulfamethoxazole/trimethoprim should be continued .
1.4.1.C.5 HIV infection - Pneumocystis pneumonia; Prophylaxis
a) The recommended dose of sulfamethoxazole/trimethoprim for primary and secondary prophylaxis of Pneumocystis jiroveci
pneumonia (PCP) in children with human immunodeficiency virus (HIV) older than 1 month of age is 750 milligrams/square meter
(mg/m(2)) per day of sulfamethoxazole and 150 mg/m(2)/day of trimethoprim in 2 divided doses orally 3 times a week on consecutive
days. The maximum daily doses are 1600 mg/day of sulfamethoxazole and 320 mg/day of trimethoprim. Alternative dosing regimens
consist of 750 mg/m(2)/day of sulfamethoxazole and 150 mg/m(2)/day of trimethoprim orally once daily 3 times a week on consecutive
days, or 750 mg/m(2)/day of sulfamethoxazole and 150 mg/m(2)/day of trimethoprim in 2 divided doses orally every day or 3 times a
week on alternate days. Infants should be continued on prophylaxis until at least 1 year of age, regardless of CD4+ counts. Parameters
[14]
for initiating primary prophylaxis and discontinuing both primary and secondary prophylaxis are listed in the following table :
Age
Initiating Primary Prophylaxis (CD4+
Count)
Discontinuing Primary and Secondary Prophylaxis (CD4+
Count)
1 to 5
years
less than 500/microliter or CD4+
percentages less than 15%
at least 500/microliter or CD4+ percentages at least 15% for
more than 3 consecutive months*
6 to 12
years
less than 200/microliter or CD4+
percentages less than 15%
at least 200/microliter or CD4+ percentages at least 15% for
more than 3 consecutive months
*only after at least 6 months of treatment with HAART
1.4.1.C.6 HIV infection - Toxoplasma encephalitis; Prophylaxis
a) The recommended treatment for primary prophylaxis against toxoplasmic encephalitis in children with human immunodeficiency
virus is sulfamethoxazole 750 milligrams/square meter (mg/m(2)) and trimethoprim 150 mg/m(2) orally daily in 2 divided doses.
Alternative regimens for the same dosage of sulfamethoxazole/trimethoprim are a single dose orally 3 times weekly on consecutive
days or 2 divided doses orally 3 times weekly on alternate days. Data in adults suggest discontinuing primary prophylaxis in children
once the CD4+ count rises to above 15% in children younger than 6 years or to above 100 cells/mm(3) in children 6 years and older,
[14]
but restarting prophylaxis if these parameters are met again .
1.4.1.C.7 Pneumocystis pneumonia
a) The recommended dosage of sulfamethoxazole/trimethoprim for the treatment of Pneumocystis pneumonia in children 2 months
and older with human immunodeficiency virus is 75 to 100 milligrams/kilogram (mg/kg) of sulfamethoxazole and 15 to 20 mg/kg of
[2]
trimethoprim orally daily in equally divided doses every 6 hours for 14 to 21 days .
1.4.1.C.8 Pneumocystis pneumonia; Prophylaxis
a) The recommended dose of sulfamethoxazole/trimethoprim for prophylaxis of Pneumocystis carinii pneumonia in
immunosuppressed children 2 months of age and older is 750 milligrams/square meter (mg/m(2)) per day of sulfamethoxazole
(maximum 1600 mg/day) and 150 mg/m(2)/day of trimethoprim (maximum 320 mg/day) in 2 divided doses orally 3 times a week on
[2]
consecutive days .
1.4.1.C.9 Shigellosis
a) The recommended oral dose of sulfamethoxazole/trimethoprim for the treatment of shigellosis in children 2 months and older is
sulfamethoxazole 40 milligrams/kilogram/day (mg/kg/day)/trimethoprim 8 mg/kg/day given in 2 divided doses every 12 hours for 5
[1][2]
days
.
b) The manufacturer provides the following table to attain the recommended dosage of oral sulfamethoxazole/trimethoprim using oral
[1][2]
suspension
:
Weight
Dose Q12H teaspoonful
Tablets(SS)
lb
kg
22
10
1 (5 mL)
44
20
2 (10 mL)
1
66
30
3 (15 mL)
1 1/2
88
40
4 (20 mL)
2 (1 DS)
1.4.1.C.10 Urinary tract infectious disease
a) The recommended oral dose for the treatment of urinary tract infections in children 2 months of age and older is sulfamethoxazole
[1][2]
40 milligrams per kilogram per day (mg/kg/day)/trimethoprim 8 mg/kg/day given every 12 hours for 10 days
.
[1][2]
b) The manufacturer provides the following table to attain the recommended dosage
.
Weight
Dose Q12H teaspoonful
Tablets (SS)
lb
kg
22
10
1 (5 mL)
44
20
2 (10 mL)
1
66
30
3 (15 mL)
1 1/2
88
40
4 (20 mL)
2 (1 DS)
c) Short-course therapy with sulfamethoxazole/trimethoprim (single dose or 3-day courses) was as effective as 5- to 10-day courses
according to a meta-analysis including 6 prospective, randomized studies evaluating sulfamethoxazole/trimethoprim for the treatment
of uncomplicated urinary tract infections in children (Tran et al, 2001).
d) For infants 8 weeks to 6 months of age sulfamethoxazole 200 milligrams (mg)/trimethoprim 40 mg per day orally or 5 milliliters
[35]
suspension daily in 2 equal divided doses has been recommended .
1.4.1.C.11 Desensitization
a) Procedures for successful desensitization to sulfamethoxazole/trimethoprim in 4 children (4 to 13 years) with AIDS have been
[94]
reported . Oral desensitization was performed with sulfamethoxazole 40 milligrams/milliliter (mg/mL)/trimethoprim 8 mg/mL
suspension (solution A); 1 mL of the suspension was diluted with 19 mL distilled water (solution B). The desensitization regimen was:
days 1 to 4 solution B (day 1=1 mL, day 2=2mL, day 3=4 mL, day 4=8 mL), day 5 to 9 solution A (day 5=0.6 mL, day 6=1.2 mL, day
7=2.5 mL, day 8=5 mL, day 9=10 mL). From day 10 to 17, sulfamethoxazole 200 mg/trimethoprim 40 mg was given daily. From day
18 the dose was raised every 3 days to 5 mg/kg (of the trimethoprim component) daily.
[95]
b) A more rapid desensitization has been utilized . Five infants or children were given doses of sulfamethoxazole/trimethoprim
suspension, diluted in sterile water, every 15 minutes. The following dilutions of suspension were used; 1:10000, 1:1000, 1:500, 1:250,
1:125, 1:62, 1:30, 1:15, 1:7.5, 1:5, 1:2.5 then full strength. Three of 5 patients were successfully desensitized using this desensitization
schedule.
1.4.1.C.12 Neonates
[1]
a) Sulfamethoxazole/trimethoprim use is contraindicated in children younger than 2 months of age .
1.4.2 Dosage in Renal Failure
A) Patients who receive sulfamethoxazole/trimethoprim intravenously or orally and have impaired renal function should be dosed
[1][2][3]
according to the following dosage schedule
Creatinine Clearance
Dosage
(mL/min)
Above 30
Standard regimen
15-30
1/2 standard regimen
Below 15
Not recommended
B) Guidelines for the administration of sulfamethoxazole/trimethoprim (based on the trimethoprim component) in patients with renal
[99][100]
dysfunctions
:
Indication/Renal Function
DOSE
PCP Treatment
CrCl greater than 30 ml/min
15-20 mg/kg/day divided q6-8h
CrCl 15 to 30 ml/min
15-20 mg/kg/day divided q6-8h for 48h then
7-10 mg/kg/day divided q12h
CrCl less than 15 ml/min
15-20 mg/kg/dose q48h (or 7-10 mg/kg/day
divided q12-24h)
Hemodialysis
15-20 mg/kg/dose before dialysis and 7-10
mg/kg/dose after dialysis
PCP Prophylaxis
CrCl greater than 30 ml/min
5 mg/kg q24h for 3 to 7 doses/week
CrCl 15 to 30 ml/min
5 mg/kg q24-48h for 3 to 7 doses/week
CrCl less than 15 ml/min
5 mg/kg q48-72h
Hemodialysis
5 mg/kg after dialysis
Other Infections
CrCl greater than 30 ml/min
8-12 mg/kg/day divided q12h for 14 days then
4-6 mg/kg q24h
CrCl 15 to 30 ml/min
8-12 mg/kg/day divided q12h for 1-2 days
then 4-6 mg/kg/day q24h
CrCl less than 15 ml/min
8-12 mg/kg/dose q48h (or 4-6 mg/kg/day
divided q12-24h)
Hemodialysis
8-12 mg/kg/dose before dialysis and 4-6
mg/kg/dose after dialysis
1.4.4 Dosage Adjustment During Dialysis
A) Hemodialysis
1) In hemodialysis patients, 50% of the maintenance dose of sulfamethoxazole/trimethoprim should be supplemented following each
dialysis session. These recommendations are based upon observations that 44% of administered trimethoprim and 57% of
[102]
administered sulfamethoxazole are removed during a 4-hour hemodialysis session
.
2.0 Pharmacokinetics
Drug Concentration Levels
ADME
2.2 Drug Concentration Levels
A) Time to Peak Concentration
[475]
1) Oral, 1 to 4 hours
.
B) Various infections, not well defined
1) Following administration of COTRIMOXAZOLE 160 mg/800 mg orally, in normal volunteers, peak levels of 30 to 50 mcg/mL of
[476][477]
SULFAMETHOXAZOLE with 0.9 to 1.9 mcg/mL of TRIMETHOPRIM occur about 2 to 4 hours after ingestion
.
2) Peak plasma concentrations of TRIMETHOPRIM and SULFAMETHOXAZOLE were 3.4 mcg/mL and 46.3 mcg/mL, respectively,
after a 1-hour intravenous infusion of COTRIMOXAZOLE 160 mg/800 mg. Following repeated administration (Q8H) the plasma
concentrations prior to and immediately after each infusion were 5.6 mcg/mL and 8.8 mcg/mL, respectively, for TRIMETHOPRIM and
[475]
70.6 mcg/mL and 105.6 mcg/mL, respectively, for SULFAMETHOXAZOLE
.
2.3 ADME
Absorption
Distribution
Metabolism
Excretion
Elimination Half-life
Extracorporeal Elimination
2.3.1 Absorption
A) Bioavailability
[478]
1) Oral, 90% to 100%
.
[479]
2) Peritoneal, 65% to 73%
.
2.3.2 Distribution
A) Distribution Sites
1) Protein Binding
[475][481]
a) Sulfamethoxazole, 70%; trimethoprim, 44% to 62%
.
2) OTHER DISTRIBUTION SITES
[482]
a) CEREBROSPINAL FLUID, good penetration
.
B) Distribution Kinetics
1) Volume of Distribution
[478]
a) Trimethoprim, 2.0 L/kg; Sulfamethoxazole, 360 mL/kg
.
2.3.3 Metabolism
A) Metabolism Sites and Kinetics
[483][484][485][476]
1) Liver, extensive (Sulfamethoxazole)
.
B) Metabolites
[476][484][485]
1) N4-acetylated and N4-glucuronidated derivatives
.
2.3.4 Excretion
A) Kidney
1) Renal Excretion (%)
a) Sulfamethoxazole, 10% to 30%; Trimethoprim, 50% to 75%
[475][484][485][476][477]
.
2.3.5 Elimination Half-life
A) Parent Compound
1) ELIMINATION HALF-LIFE
[475][477][476]
a) Trimethoprim, 6 to 17 hours; Sulfamethoxazole, 8 to 11 hours
.
1) After repeated IV administration (every 8 hours) in 11 adults, the plasma half-life of TRIMETHOPRIM was approximately 11 hours
[475]
and sulfamethoxazole was 12 hours. The half-life of TRIMETHOPRIM is reported to be age-dependent (increases with age)
.
2) The half-lives of TRIMETHOPRIM and SULFAMETHOXAZOLE are prolonged to 20 to 30 hours or more in patients with renal
[487]
failure
.
2.3.6 Extracorporeal Elimination
A) Hemodialysis
1) Dialyzable: YES
a) Hemodialysis removes moderate to significant amounts of both SULFAMETHOXAZOLE and TRIMETHOPRIM, which results in a
[475][486]
reduction of the half-lives of both drugs towards normal values during hemodialysis
.
B) Peritoneal
[475]
1) Dialyzable: NO
3.0 Cautions
Contraindications
Precautions
Adverse Reactions
Teratogenicity/Effects in Pregnancy/Breastfeeding
Drug Interactions
3.1 Contraindications
A) history of sulfonamide- or trimethoprim-induced immune thrombocytopenia
[105]
B) hypersensitivity to sulfonamides or trimethoprim
[105]
C) infants less than 2 months of age
[105]
D) hepatic damage, marked
[105]
E) megaloblastic anemia due to folate deficiency
[105]
F) nursing mothers
[105]
G) pregnant patients
[105]
H) renal insufficiency, severe
[105]
3.2 Precautions
A) agranulocytosis; has been reported, including fatalities; monitoring recommended; discontinue therapy at the first occurrence of skin
[105]
rash or any sign of adverse reaction, which may be early indicator of a more severe reaction
B) aplastic anemia; has been reported, including fatalities; monitoring recommended; discontinue therapy at the first occurrence of skin
[105]
rash or any sign of adverse reaction, which may be early indicator of a more severe reaction
C) blood dyscrasias; have been reported, including fatalities; monitoring recommended; discontinue therapy at the first occurrence of
[105]
skin rash or any sign of adverse reaction, which may be early indicator of a more severe reaction
D) dermatologic reactions, severe; have been reported, including fatalities (eg, Stevens-Johnson syndrome, toxic epidermal
necrolysis); discontinue therapy at the first occurrence of skin rash or any sign of adverse reaction, which may be early indicator of a
[105]
more severe reaction
E) fulminant hepatic necrosis; has been reported, including fatalities; discontinue therapy at the first occurrence of skin rash or any sign
[105]
of adverse reaction, which may be early indicator of a more severe reaction
[105]
F) hypersensitivity reactions of the respiratory tract (cough, shortness of breath, and pulmonary infiltrates); have been reported
[105]
G) thrombocytopenia; has been reported, including fatalities; monitoring recommended
H) AIDS patients; increased risk of side effects (rash, fever, leukopenia, elevated transaminase values, hyperkalemia); consider
[105]
discontinuing therapy if skin rash or any sign of adverse reaction
[105]
I) bronchial asthma, preexisting
[105]
J) crystalluria; may occur, especially in slow acetylators; manage with adequate fluid intake and urinary output
K) elderly; increased risk of side effects, especially thrombocytopenia, folic acid deficiency, hyperkalemia, severe skin reactions,
[105]
generalized bone marrow suppression
[105]
L) hepatic impairment, preexisting
M) folate deficiency, preexisting or new onset; cautious use especially in elderly, kidney failure, chronic alcoholics, severe allergies,
[105]
concomitant anticonvulsants, malabsorption syndrome, malnutrition
[105]
N) glucose-6-phosphate dehydrogenase deficiency; dose-related hemolysis may occur
O) hyperkalemia; may occur at recommended trimethoprim doses; increased risk with potassium metabolism disorders, renal
[105]
insufficiency, concomitant hyperkalemia-inducing agents; monitoring recommended
P) hypoglycemia; has been reported in nondiabetic patients; increased risk in renal dysfunction, liver disease, malnutrition, high doses
[105]
Q)
R)
S)
T)
U)
V)
Pneumocystis carinii pneumonia; high dose trimethoprim induces hyperkalemia; monitoring recommended
[105]
porphyria, preexisting
[105]
renal impairment, preexisting; monitoring recommended
[105]
severe allergies, preexisting
[105]
streptococcal infections, group A beta hemolytic; do not use; will not prevent rheumatic fever sequelae
[105]
thyroid dysfunction, preexisting
3.3 Adverse Reactions
Cardiovascular Effects
Dermatologic Effects
Endocrine/Metabolic Effects
Gastrointestinal Effects
[105]
Hematologic Effects
Hepatic Effects
Immunologic Effects
Musculoskeletal Effects
Neurologic Effects
Otic Effects
Psychiatric Effects
Renal Effects
Respiratory Effects
Other
3.3.1 Cardiovascular Effects
Cardiac dysrhythmia
Vasculitis
3.3.1.A Cardiac dysrhythmia
1) Prolongation of the QT interval occurred, on 2 occasions, in a 90-year-old female after a single dose of sulfamethoxazole 800
mg/trimethoprim 160 mg; on 1 occasion torsades de pointes resulted. After sulfamethoxazole/trimethoprim was discontinued, no
[120]
additional episodes of cardiac abnormalities occurred
.
3.3.1.B Vasculitis
1) A 69-year-old male treated with 4 days of sulfamethoxazole 1600 mg/trimethoprim 325 mg once daily for bronchitis developed a
non-itching rash on the ears, neck, face and extremities. Two days later, the patient developed a fever which required hospitalization
and was found to have necrotizing vasculitis affecting small blood vessels of the skin associated with erythema. Laboratory data
evaluation demonstrated an elevated ESR, thrombocytosis, leukocytosis, and reticulocytosis. The patient's fever and skin lesions
[121]
resolved spontaneously in 3 weeks with other clinical and laboratory findings resolved within 2 months
.
[122]
2) Thrombophlebitis migrans has been described during oral sulfamethoxazole/trimethoprim therapy
. Only the veins were
involved, without evidence of polyarteritis nodosa or underlying malignancy. Resolution of symptoms required intravenous
cyclophosphamide 200 mg on alternate days for 5 doses.
3.3.2 Dermatologic Effects
Drug-induced erythroderma
Erythema multiforme
Injection site pain
Nail finding, Loss of fingernail and toenail
Photosensitivity
Pruritus
Rash
Stevens-Johnson syndrome
Sweet's syndrome
Toxic epidermal necrolysis
Urticaria
3.3.2.A Drug-induced erythroderma
[105]
1) Exfoliative dermatitis has been reported with sulfamethoxazole/trimethoprim use
.
2) Approximately 1% to 4% of children receiving sulfamethoxazole/trimethoprim will develop a mild toxic erythema identical to the
dermal reactions observed with sulfonamides alone. The rate of severe reactions with the drug is unknown in children. Exfoliative
dermatitis has been reported as well as Stevens-Johnson syndrome, with some data suggesting an occurrence of these disorders in
[182]
1/200,000 courses of treatment
.
3) Exfoliative dermatitis occurred in a 6-year-old female after taking sulfamethoxazole/trimethoprim for less than 10 days. Three days
after sulfamethoxazole/trimethoprim was discontinued a generalized rash appeared, which then faded from the trunk, becoming
[183]
confined to the extremities. Desquamation occurred on the feet and not on any other part of the body
.
3.3.2.B Erythema multiforme
[105]
1) Erythema multiforme has been reported with sulfamethoxazole/trimethoprim use
.
2) Severe skin reactions is one of the most frequently reported severe adverse events reported in elderly patients
[105]
.
3.3.2.C Injection site pain
[151]
1) Pain on injection and slight irritation are infrequent effects of sulfamethoxazole/trimethoprim administration
.
3.3.2.D Nail finding, Loss of fingernail and toenail
1) A 3-year-old boy with a urinary tract infection had his fingernails and toenails slough off after receiving
sulfamethoxazole/trimethoprim. Following 2 weeks of prophylactic sulfamethoxazole/trimethoprim treatment (consisting of 1.3
milligrams trimethoprim/kilogram/day) for a urinary tract infection, 7 fingernails and 4 toenails became loose and fell off. There were no
other observed drug reactions such as fever or skin rash. Sulfamethoxazole/trimethoprim was discontinued, and his nails returned to a
[184]
normal appearance within 2 weeks
.
3.3.2.E Photosensitivity
[105]
1) Photosensitivity has been reported with sulfamethoxazole/trimethoprim use
.
3.3.2.F Pruritus
[105]
1) Pruritus has been reported with sulfamethoxazole/trimethoprim use
.
3.3.2.G Rash
[105]
1) Rash, including generalized skin eruptions, has been reported with sulfamethoxazole/trimethoprim use
.
[188]
2) In a report from the Boston Collaborative Drug Surveillance Program
, the incidence of drug-induced cutaneous reactions in
15,438 patients was reported. Overall, 358 cutaneous reactions occurred in 347 patients (reaction rate, 2.2%) with each patient
receiving a mean of 8 different drugs. Seventy-five percent of allergic cutaneous reactions were secondary to the use of antibiotic
therapy, blood products or inhaled mucolytics; the highest allergic reaction rate was attributed to amoxicillin (51.4 reactions/1000
exposed patients). The second and third highest reaction rates were due to sulfamethoxazole/trimethoprim (33.8/1000) and ampicillin
(33.2/1000), respectively.
3) Approximately 1% to 4% of children receiving sulfamethoxazole/trimethoprim will develop a mild toxic erythema identical to the
dermal reactions observed with sulfonamides alone. The rate of severe reactions with the drug is unknown in children. Exfoliative
dermatitis has been reported as well as Stevens-Johnson syndrome, with some data suggesting an occurrence of these disorders in
[182]
1/200,000 courses of treatment
.
4) Cutaneous reactions to sulfamethoxazole/trimethoprim prophylactically or therapeutically for P carinii pneumonia in patients with
AIDS (with or without Kaposi's sarcoma) has been reported up to 69% of the time. The rash generally occurred 4 days after initiation of
[189]
therapy (1 to 9 days) and consisted of maculopapular cutaneous eruptions
.
3.3.2.H Stevens-Johnson syndrome
1) Summary
a) Rare cases of fatalities due to severe reactions including Stevens-Johnson syndrome have been associated with sulfonamide use. A
skin rash may precede a more serious reaction and clinical signs (rash, sore throat, fever, arthralgia, pallor, purpura, jaundice) may be
early indicators of serious reactions. Sulfonamides should be discontinued at the first sign of skin rash or any sign of adverse reaction
[105]
.
2) Fatal Stevens-Johnson syndrome, although rare, has been reported with sulfonamide use, including
[105]
sulfamethoxazole/trimethoprim
.
[105]
3) Severe skin reactions is one of the most frequently reported severe adverse events reported in elderly patients
.
4) Approximately 1% to 4% of children receiving sulfamethoxazole/trimethoprim will develop a mild toxic erythema identical to the
dermal reactions observed with sulfonamides alone. The rate of severe reactions with the drug is unknown in children. Exfoliative
dermatitis has been reported as well as Stevens-Johnson syndrome, with some data suggesting an occurrence of these disorders in
[182]
1/200,000 courses of treatment
.
3.3.2.I Sweet's syndrome
1) Sweet's syndrome, also known as acute febrile neutrophilic dermatosis, is characterized by peripheral neutrophilia, high
sedimentation rate, fever, joint and muscle pains, painful plaques and pseudoblisters, and conjunctivitis. Other agents including
minocycline, filgrastim and tretinoin have been known to cause the adverse effect. Sweet's syndrome occurred 2 days after initiating
sulfamethoxazole/trimethoprim therapy for the treatment of diarrhea. Papulovesicles and plaques developed on sun exposed areas of
the skin. Biopsy proven Sweet's syndrome was diagnosed. Symptoms resolved rapidly upon discontinuation of
[181]
sulfamethoxazole/trimethoprim and topical administration of fluocinonide cream
.
3.3.2.J Toxic epidermal necrolysis
1) Summary
a) Rare cases of fatalities due to severe reactions including toxic epidermal necrolysis have been associated with sulfonamide use. A
skin rash may precede a more serious reaction and clinical signs (rash, sore throat, fever, arthralgia, pallor, purpura, jaundice) may be
early indicators of serious reactions. Sulfonamides should be discontinued at the first sign of skin rash or any sign of adverse reaction
[105]
.
2) Fatal toxic epidermal necrolysis, although rare, has been reported with sulfonamide use, including sulfamethoxazole/trimethoprim
[105]
.
[105]
3) Severe skin reactions is one of the most frequently reported severe adverse events reported in elderly patients
.
4) Toxic epidermal necrolysis (TEN) has been reported in isolated case reports in association with sulfamethoxazole/trimethoprim. In
these cases, TEN occurred 9 to 17 days after initiation of therapy and was often preceded by a generalized rash, fever, chills, and
muscle aches. Two of these cases have occurred in patients seropositive for HIV. Skin sloughing may continue after
sulfamethoxazole/trimethoprim is discontinued. Treatment with antihistamines and corticosteroids has been required (Oritz et al,
[185][186][187]
1982)
.
3.3.2.K Urticaria
[105]
1) Urticaria has commonly been reported with sulfamethoxazole/trimethoprim use
.
3.3.3 Endocrine/Metabolic Effects
Decreased uric acid level
Hyperkalemia
Hypoglycemia
Hyponatremia
Metabolic acidosis
3.3.3.A Decreased uric acid level
1) Trimethoprim has a uricosuric effect. Serum uric acid concentrations decreased from 5.6 mg/dL to 3.8 mg/dL (p less than 0.001) in 5
[148]
healthy volunteers after a 5 to 7 day course of trimethoprim 15 mg/kg/day
.
3.3.3.B Hyperkalemia
1) Hyperkalemia has been reported with sulfamethoxazole/trimethoprim use. Trimethoprim at recommended doses may cause
hyperkalemia in patients with renal insufficiency, with underlying disorders of potassium metabolism, or when receiving concomitant
hyperkalemia-inducing drugs. Monitoring is recommended. Patients with AIDS experience a much higher rate of adverse reactions to
sulfamethoxazole/trimethoprim therapy than in patients who do not have AIDS, including an increase in the incidence of hyperkalemia.
High sulfamethoxazole/trimethoprim doses used to treat Pneumocystis carinii pneumonia induces a progressive but reversible
[105]
increase of serum potassium levels
.
[105]
2) Hyperkalemia is one of the most frequently reported severe adverse events reported in elderly patients
.
[143][144][145][146]
3) Hyperkalemia has been noted in several case reports involving geriatric patients
. Trimethoprim is structurally related
to the potassium sparing diuretics amiloride and triamterene; it has been postulated that hyperkalemia is caused by the inhibition of
[147]
sodium channels in the distal tubules
.
4) Plasma potassium concentrations increased from 3.7 mEq/L to 4.5 mEq/L (p less than 0.005) in 5 healthy volunteers after a 5 to 7
[148]
day course of trimethoprim 15 mg/kg/day
.
5) In the study involving AIDS patients, serum potassium increased an average of 1.1 mmol/L after 9.8 days of treatment. Serum
[149]
potassium level decreased after sulfamethoxazole/trimethoprim was discontinued
. In the study involving patients with various
types of infection on standard doses of sulfamethoxazole/trimethoprim (1 double-strength tablet twice daily), serum potassium
increased an average of 1.21 mmol/L. The peak effect occurred after 4.6 days of treatment. A peak potassium concentration of greater
than 5.5 mmol/L was reported in 21.2% of patients. These investigators found that concurrent renal insufficiency was a risk factor for
[150]
developing hyperkalemia
.
3.3.3.C Hypoglycemia
1) Hypoglycemia has been reported rarely with sulfamethoxazole/trimethoprim use in nondiabetic patients, usually occurring after a
few days of therapy. Risk factors include high doses of sulfamethoxazole/trimethoprim, renal dysfunction, liver disease, and
[105]
malnutrition
.
2) Hypoglycemia associated with sulfamethoxazole/trimethoprim use is limited to case reports. In most cases, patients have
preexisting renal impairment or end stage renal failure, with no dosing adjustments to reflect this renal impairment. Hypoglycemia (as
low as 26 mg/dL) has occurred within 1.5 hours to 5 days of therapy. Following a dose reduction of sulfamethoxazole/trimethoprim
according to renal function and concomitant dextrose supplements, hypoglycemia generally has resolved with no further sequelae.
Because sulfonamides are chemically similar to sulfonylureas, the mechanism of this adverse effect is thought to be the same as that
for oral hypoglycemic agents. It is thought that the sulfamethoxazole portion of sulfamethoxazole/trimethoprim binds to receptors on
the pancreatic islet cells causing the release of insulin. Patients with a creatinine clearance less than 30 milliliters/minute should receive
[151][152][140][153]
adjusted doses of sulfamethoxazole/trimethoprim
.
3.3.3.D Hyponatremia
1) Hyponatremia has been observed with the use of sulfamethoxazole/trimethoprim. Hyponatremia has been attributed to a large
[141][142]
volume of fluid required for intravenous infusion or to diuretic action causing natriuresis
.
3.3.3.E Metabolic acidosis
1) Compensated metabolic acidosis has occurred in 6 HIV-infected patients receiving high-dose sulfamethoxazole/trimethoprim.
Onset of symptoms has generally occurred within 3 to 5 days of therapy (20 milligrams/kilograms trimethoprim component
[154]
intravenously), with symptoms resolving 2 to 3 days after discontinuation of therapy or bicarbonate administration
.
3.3.4 Gastrointestinal Effects
Abdominal pain
Clostridium difficile diarrhea
Diarrhea
Esophagitis
Loss of appetite
Nausea
Pancreatitis
Pseudomembranous enterocolitis
Stomatitis
Vomiting
3.3.4.A Abdominal pain
[105]
1) Abdominal pain has been reported with sulfamethoxazole/trimethoprim use
.
3.3.4.B Clostridium difficile diarrhea
1) Clostridium difficile associated diarrhea (CDAD) has been reported with antibiotic use, including sulfamethoxazole/trimethoprim.
Severity may range from mild diarrhea to fatal colitis. If CDAD is suspected or confirmed, discontinuation of therapy and medical
[105]
management may be necessary
.
3.3.4.C Diarrhea
[105]
1) Diarrhea has been reported with sulfamethoxazole/trimethoprim use
.
3.3.4.D Esophagitis
1) An esophageal ulcer occurred in a 63-year-old woman after swallowing a sulfamethoxazole/trimethoprim tablet without water.
[157]
Treatment with frequent antacids resolved the symptoms
.
3.3.4.E Loss of appetite
[105]
1) Anorexia has been commonly reported with sulfamethoxazole/trimethoprim use
.
3.3.4.F Nausea
[105]
1) Nausea has been commonly reported with sulfamethoxazole/trimethoprim use
.
3.3.4.G Pancreatitis
[105]
1) Pancreatitis has been reported with sulfamethoxazole/trimethoprim use
.
2) Acute pancreatitis was reported in a 50-year-old male who was being treated with sulfamethoxazole/trimethoprim. Six weeks after
sulfamethoxazole/trimethoprim was initiated headaches, nausea, fever, and upper abdominal pain developed. The serum amylase
level was 539 Units/L; the urine and serum lipase were 1550 units/L and 905 units/L, respectively. The symptoms resolved rapidly when
[158]
sulfamethoxazole/trimethoprim was discontinued; within 2 weeks laboratory values had returned normal
.
3) Pancreatitis occurred in a 33-year-old male following sulfamethoxazole/trimethoprim therapy for a Nocardia asteroides brain
abscess. Increases in serum amylase to 461 Units/L were observed on the 16th day of sulfamethoxazole/trimethoprim therapy
(normal 30 to 120 Units/L); amylase levels increased to over 1000 Units/L after approximately 20 more days of therapy. Withdrawal of
sulfamethoxazole/trimethoprim resulted in resolution of symptoms within 72 hours and normalization of amylase levels within 2 weeks.
Sulfamethoxazole/trimethoprim therapy was reinstituted resulting in recurrence of pancreatitis which again resolved after withdrawal
[159]
.
3.3.4.H Pseudomembranous enterocolitis
[105]
1) Pseudomembranous enterocolitis has been reported with sulfamethoxazole/trimethoprim use
.
2) Two HIV positive patients who were receiving sulfamethoxazole/trimethoprim for PCP prophylaxis developed C difficile-induced
colitis. At the time of diagnosis neither patient was being treated with any other antibiotics. Both patients were treated successfully with
[155]
oral vancomycin and both were able to continue sulfamethoxazole/trimethoprim therapy without recurrence of colitis
.
3) An 88-year-old female was treated with 2 tablets twice a day of sulfamethoxazole/trimethoprim for a urinary tract infection which
developed following an operation for a broken leg . Two weeks later, the patient developed diarrhea which did not respond to
symptomatic treatment. On the 20th day, sulfamethoxazole/trimethoprim was discontinued. A rectal examination on the 27th day
demonstrated large lumps of mucosa, and a barium enema demonstrated pancolitis suggestive of mucosal edema. Thirty-two days
[156]
postop the patient died with unremitting diarrhea. Autopsy demonstrated pseudomembranous colitis findings in the entire colon
.
3.3.4.I Stomatitis
[105]
1) Stomatitis has been reported with sulfamethoxazole/trimethoprim use
.
3.3.4.J Vomiting
[105]
1) Emesis has been commonly reported with sulfamethoxazole/trimethoprim use
.
3.3.5 Hematologic Effects
Acquired hypoprothrombinemia
Agranulocytosis
Aplastic anemia
Disorder of hematopoietic structure
Eosinophilia
Folic acid deficiency
Hemolytic anemia
Idiopathic thrombocytopenic purpura
Leukopenia
Megaloblastic anemia
Methemoglobinemia
Neutropenia
Thrombocytopenia
Thrombocytopenic purpura
3.3.5.A Acquired hypoprothrombinemia
[105]
1) Hypoprothrombinemia has been reported with sulfamethoxazole/trimethoprim use
.
3.3.5.B Agranulocytosis
1) Summary
a) Rare cases of fatalities due to severe reactions including agranulocytosis have been associated with sulfonamide use. Clinical signs
(rash, sore throat, fever, arthralgia, pallor, purpura, jaundice) may be early indicators of serious reactions. Sulfonamides should be
[105]
discontinued at the first sign of skin rash or any sign of adverse reaction
.
[105][119]
2) Fatal agranulocytosis, although rare, has been reported with sulfonamide use, including sulfamethoxazole/trimethoprim
.
3.3.5.C Aplastic anemia
1) Summary
a) Rare cases of fatalities due to severe reactions including aplastic anemia have been associated with sulfonamide use. Clinical signs
(rash, sore throat, fever, arthralgia, pallor, purpura, jaundice) may be early indicators of serious reactions. Sulfonamides should be
[105]
discontinued at the first sign of skin rash or any sign of adverse reaction
.
[105]
2) Fatal aplastic anemia, although rare, has been reported with sulfonamide use, including sulfamethoxazole/trimethoprim
.
3.3.5.D Disorder of hematopoietic structure
1) Summary
a) Rare cases of fatalities due to severe reactions including blood dyscrasias have been associated with sulfonamide use. Clinical
signs (rash, sore throat, fever, arthralgia, pallor, purpura, jaundice) may be early indicators of serious reactions. Sulfonamides should
[105]
be discontinued at the first sign of skin rash or any sign of adverse reaction
.
[105]
2) Fatal blood dyscrasias, although rare, have been reported with sulfonamide use, including sulfamethoxazole/trimethoprim
.
[105]
3) Bone marrow suppression is one of the most frequently reported severe adverse events reported in elderly patients
.
3.3.5.E Eosinophilia
[105]
1) Eosinophilia has been reported with sulfamethoxazole/trimethoprim use
.
3.3.5.F Folic acid deficiency
1) Hematologic changes indicative of folic acid deficiency may occur in geriatric patients, in patients with preexisting folic acid
[105]
deficiency, or kidney failure
.
3.3.5.G Hemolytic anemia
[105]
1) Hemolytic anemia has been reported with sulfamethoxazole/trimethoprim use
.
2) Sulfamethoxazole/trimethoprim has been associated with hemolytic anemia in a few case studies; most patients were deficient in
[112][113][114]
glucose-6-phosphate dehydrogenase (G6PD)
. Hemolytic anemia has been associated with the sulfamethoxazole
[115]
component
; (Chan et el, 1976). However, sulfamethoxazole/trimethoprim has been administered to G6PD-deficient patients
[116][117]
without causing an adverse effect
.
3.3.5.H Idiopathic thrombocytopenic purpura
1) Idiopathic thrombocytopenia purpura has been reported during postmarketing surveillance of sulfamethoxazole/trimethoprim;
[105]
causality and frequency cannot be established
.
3.3.5.I Leukopenia
1) Leukopenia has been reported with sulfamethoxazole/trimethoprim use. Patients with AIDS being treated for Pneumocystis carinii
pneumonia experience a much higher rate of adverse reactions to sulfamethoxazole/trimethoprim therapy than in patients who do not
[105]
have AIDS. This includes an increase in the incidence of leukopenia
.
2) Two trials evaluated the efficacy of leucovorin (folinic acid) for preventing hematologic toxicities caused by
sulfamethoxazole/trimethoprim use in patients with AIDS. In one trial with 92 patients who were receiving
sulfamethoxazole/trimethoprim for the treatment of pneumocystis carinii pneumonia (PCP), the incidence of neutropenia was lower in
the group which received leucovorin 7.5 milligrams daily. However, more importantly, the incidence of treatment failure and death were
significantly higher in the group that received leucovorin as compared to the group that received placebo (Sarin et al, 1994). In another
trial sulfamethoxazole/trimethoprim with or without leucovorin was administered for PCP prophylaxis in 107 HIV positive patients.
Patients were also divided into a low dose sulfamethoxazole/trimethoprim group (1 double strength tablet twice per day three times
weekly) or regular dose (1 double-strength tablet twice daily). There was no difference in the rate of discontinuation of therapy because
of toxicities between those taking leucovorin and those not. There was a higher rate of patients discontinuing treatment in the higher
dose group; indicating adverse effects are to sulfamethoxazole/trimethoprim are dose-related, but not related to leucovorin
[118]
administration
.
3.3.5.J Megaloblastic anemia
[105]
1) Megaloblastic anemia has been reported with sulfamethoxazole/trimethoprim use
.
3.3.5.K Methemoglobinemia
[105]
1) Methemoglobinemia has been reported with sulfamethoxazole/trimethoprim use
.
3.3.5.L Neutropenia
[105]
1) Neutropenia has been reported with sulfamethoxazole/trimethoprim use
.
3.3.5.M Thrombocytopenia
1) Severe, fatal, or life threatening cases of thrombocytopenia have been reported with sulfamethoxazole/trimethoprim use.
[105]
Thrombocytopenia usually resolved within a week of discontinuation of sulfamethoxazole/trimethoprim therapy
.
2) A decrease in platelets with or without purpura is one of the most frequently reported severe adverse events reported in elderly
[105]
patients
.
3) Sulfamethoxazole/trimethoprim has reportedly been associated with thrombocytopenia. The thrombocytopenia is often associated
with megaloblastic anemia and therefore the simultaneous administration of sulfamethoxazole/trimethoprim can lead to even more
severe thrombocytopenia. Sulfamethoxazole/trimethoprim appears to increase the severity of megaloblastic changes which in turn
lead to reduction in platelets. If at all possible, this drug combination should not be used in patients with megaloblastic anemia and until
more data becomes available, patients receiving sulfamethoxazole/trimethoprim should have blood counts done before and during
[106][107][108][109][110]
therapy
.
4) Two patients developed thrombocytopenic purpura and vaginal bleeding while receiving sulfamethoxazole/trimethoprim. The
platelet count was 2000/microliter in both patients. One patient responded to corticosteroids, and the other responded to a combination
[111]
of corticosteroids and intravenous immunoglobulin
.
3.3.5.N Thrombocytopenic purpura
1) Thrombotic thrombocytopenia purpura has been reported during postmarketing surveillance of sulfamethoxazole/trimethoprim;
[105]
causality and frequency cannot be established
.
2) A decrease in platelets with or without purpura is one of the most frequently reported severe adverse events reported in elderly
[105]
patients
.
3.3.6 Hepatic Effects
AST/SGOT level raised
Cholestatic jaundice syndrome
Hepatic necrosis
Hepatic necrosis, Fulminant
Hepatitis
Hepatotoxicity
Serum bilirubin raised
3.3.6.A AST/SGOT level raised
[105]
1) Elevated serum transaminase levels have been reported with sulfamethoxazole/trimethoprim use
.
3.3.6.B Cholestatic jaundice syndrome
1) Cholestatic jaundice has been reported with sulfamethoxazole/trimethoprim use
[105]
.
3.3.6.C Hepatic necrosis
1) Summary
a) Rare cases of fatalities due to severe reactions including fulminant hepatic necrosis have been associated with sulfonamide use.
Clinical signs (rash, sore throat, fever, arthralgia, pallor, purpura, jaundice) may be early indicators of serious reactions. Sulfonamides
[105]
should be discontinued at the first sign of skin rash or any sign of adverse reaction
.
[105]
2) Hepatic necrosis has been reported with sulfamethoxazole/trimethoprim use
.
3) Hepatic necrosis has been reported in an 80-year-old male treated for bilateral orchitis with sulfamethoxazole 20
mg/kg/trimethoprim 4 mg/kg. After a 10-day course of therapy, the drug was discontinued. However, 10 days after discontinuation of the
antibiotic therapy, hepatomegaly and jaundice associated with elevated liver function tests and urine containing moderate quantities of
bilirubin, urobilinogen, and protein were noted. Despite treatment, the patient's hepatomegaly and jaundice increased. The patient
developed ascites and stupor secondary to a hemorrhagic diathesis. On the twenty-fifth day after discontinuation of
sulfamethoxazole/trimethoprim, the patient died. Autopsy revealed massive centrilobular necrosis in a congested liver associated with
cholemic necrosis, ascites and hemorrhagic diathesis. The author concluded that this fatal hepatic necrosis was caused by the
sulfamethoxazole/trimethoprim combination as a result of the time course relationship between administration of the drug and onset of
[173]
the jaundice
.
4) A 70-year-old man developed a raised rash on his legs subsequent to two different exposures to sulfamethoxazole/trimethoprim.
After a third exposure consisting of 2 tablets, he developed the rash, became jaundiced and was admitted to the hospital. The patient's
condition progressively declined until his death on the 32nd day after the onset of jaundice. Autopsy revealed massive hepatic necrosis.
[174]
This hepatocellular type of injury is believed to be caused by acquired hypersensitivity to the sulfa drug and is not dose related
.
3.3.6.D Hepatic necrosis, Fulminant
1) Fatal fulminant hepatic necrosis, although rare, has been reported with sulfonamide use, including sulfamethoxazole/trimethoprim
[105]
.
3.3.6.E Hepatitis
[105]
1) Hepatitis has been reported with sulfamethoxazole/trimethoprim use
.
2) A 16-year-old paraplegic male given sulfamethoxazole/trimethoprim (2 to 4 tablets daily) as prophylaxis against urinary tract
infection developed fever, rash, eosinophilia and cholestatic hepatitis after 41 days of therapy. It was felt that the hepatic injury was of
the hypersensitivity type. The few previous case reports of jaundice and allergic cholestasis with this drug combination have been
[175]
associated with a history of infectious hepatitis, which was not the case with this patient
.
3) Jaundice occurred on two occasions in a 54-year-old male following sulfamethoxazole/trimethoprim administration for acute
prostatitis. Approximately two months after patient's first admission for hepatitis secondary to sulfamethoxazole/trimethoprim, he was
inadvertently treated again for the recurrence of prostatitis. Following three days of therapy, the patient was readmitted with jaundice
and aspiration biopsy of the liver demonstrated cholestatic hepatitis with nonspecific periportal inflammatory infiltrates compatible with
[176]
drug-induced liver disease. The patient recovered in five days
.
4) A 61-year-old male receiving sulfamethoxazole 800 mg/trimethoprim 160 mg twice a day for a chronic bladder infection developed
pruritus followed by jaundice within 1 month. Laboratory revealed a total bilirubin of 8.8 mg/dl, alkaline phosphatase of 225
milliunits/mL, and SGOT of 60 milliunits/mL. Upon hospitalization liver biopsy revealed centrilobular cholestasis with bile casts and
some hepatocyte degeneration. Ten days following discontinuation of sulfamethoxazole/trimethoprim, symptoms began to resolve and
[177]
liver-function tests returned to normal ranges
.
5) Intrahepatic cholestasis was described in a 65-year-old male following sulfamethoxazole/trimethoprim therapy (Septrin(R), 2
[178]
tablets twice daily) for approximately 4 weeks
. Hepatic biopsy demonstrated cholestasis, around and in the centrilobular
hepatocytes, with bile plugging. Withdrawal of the drug resulted in slow clinical improvement over the next several months; jaundice
persisted for 4 weeks after drug withdrawal.
6) A 22-year-old woman developed a rash and progressive jaundice after 2 weeks of treatment with sulfamethoxazole 800
[179]
mg/trimethoprim 160 mg daily
. SGPT and SGOT levels increased to 328 Units/L and 83 Units/L, respectively, and total bilirubin
increased to 5.9 mg/dL. A liver biopsy revealed central acinar cholestasis. A lymphocyte transformation test confirmed that the reaction
was allergic in nature. The patient recovered after 8 weeks without specific treatment.
3.3.6.F Hepatotoxicity
1) Sulfamethoxazole/trimethoprim rarely causes hepatotoxicity. Symptoms of hypersensitivity are commonly present in patients
experiencing sulfamethoxazole/trimethoprim-induced hepatotoxicity. For this reason it is thought that an immunologic mechanism may
be the cause of this reaction. In some cases, patients have been reported to recover spontaneously after
sulfamethoxazole/trimethoprim is discontinued; however, the degree of liver damage may be severe, requiring aggressive treatment
[170]
and deaths have been reported
.
2) Acute fulminant liver failure resulting in death occurred in a 32-year-old female who had taken a 12-day course of
sulfamethoxazole/trimethoprim for a urinary tract infection. The patient presented 5 days following completion of antibiotic therapy with
a full-body maculopapular pruritic rash, fever (spiking to 104 degrees Fahrenheit), and chills. The patient was found to have generalized
lymphadenopathy, severely elevated liver enzymes, elevated direct bilirubin, eosinophilia, and atypical lymphocytes. Diagnostic imaging
showed enlarged liver with ascites. She was treated with Solu-Medrol and showed improvement in liver function tests but died 3 days
[171]
after hospital admission awaiting a liver transplant
.
3) A 9-year-old male developed acute hepatotoxicity following treatment with sulfamethoxazole/trimethoprim for community-acquired
methicillin-resistant Staphylococcus aureus (CA-MRSA). On day 14 of treatment with sulfamethoxazole 160 mg/trimethoprim 800 mg
twice daily, he presented with a 3-day history of fever, headache, and neck pain. A diagnosis of viral syndrome was made and he was
discharged with acetaminophen for fever. He returned 3 days later with a fever of 102.8 degrees F and a 24-hour history of nausea,
vomiting, sharp, consistent abdominal pains, and decreased energy and appetite. Laboratory results revealed leukopenia and
significantly elevated ALT and AST values. Serological, virological, and CT of his abdomen and pelvis were normal, and
acetaminophen levels were within therapeutic range. Sulfamethoxazole/trimethoprim was thought to be the cause of his liver
dysfunction and was discontinued. Within 4 days, his symptoms had resolved and within a week, his white blood cell count and liver
function tests had returned to within normal range. Subsequent to discharge, the patient remained asymptomatic and had normal liver
[172]
function tests on follow-up
.
3.3.6.G Serum bilirubin raised
[105]
1) Elevated serum bilirubin levels have been reported with sulfamethoxazole/trimethoprim use
.
3.3.7 Immunologic Effects
Anaphylaxis
Henoch-Schönlein purpura
Immune hypersensitivity reaction
Myocarditis, Allergic
Polyarteritis nodosa
Systemic lupus erythematosus
3.3.7.A Anaphylaxis
[105]
1) Anaphylaxis has been reported with sulfamethoxazole/trimethoprim use
.
3.3.7.B Henoch-Schönlein purpura
[105]
1) Henoch-Schonlein purpura has been reported with sulfamethoxazole/trimethoprim use
.
3.3.7.C Immune hypersensitivity reaction
1) Hypersensitivity reactions have been reported following administration of sulfonamides, including sulfamethoxazole/trimethoprim,
[105]
with symptoms including cough, shortness of breath, and pulmonary infiltrates
.
2) In patients without AIDS, adverse reactions to sulfamethoxazole/trimethoprim are reported in 8% of patients and hypersensitivity
type reactions in 3.3%. In patients with AIDS, hypersensitivity reactions to sulfamethoxazole/trimethoprim, although usually mild, occur
commonly. Mild skin rashes occur in 24% to 50% of AIDS patients and severe skin rashes involving mucous membranes have been
reported in 0% to 20% of patients. In general, if the hypersensitivity reaction is considered mild, the patient may be rechallenged or
[191]
desensitized with sulfamethoxazole/trimethoprim and are able to tolerate further therapy
.
3) A 31-year-old homosexual male with P carinii pneumonia developed fever, a diffuse maculopapular rash and leukopenia 8 days
after initiation of therapy with sulfamethoxazole 1200 mg/trimethoprim 240 mg IV every 6 hours. The patient was treated successfully
with IM pentamidine. Rechallenge with one tablet of sulfamethoxazole/trimethoprim resulted in mild pruritus within 15 minutes,
followed by abdominal pain, rigor and fever. The patient subsequently developed diffuse erythema, diarrhea, tachycardia, and severe
[192]
hypotension
. The mechanism of action is hypothesized to be immune complex mediated vascular injury facilitated by B-cell
polyclonal activation.
4) The cause of the increased rate of adverse reactions to sulfamethoxazole/trimethoprim in patients with HIV infection is poorly
understood. Because they often occur after 8 to 12 days of therapy, an accumulation of toxic intermediate metabolites has been
proposed as a contributing factor. The hydroxylamine metabolite of sulfamethoxazole, which is reactive, may accumulate.
Accumulation of this metabolite, in combination with a deficiency of glutathione common in many AIDS patients, may increase the toxic
[193][194][195]
effects of sulfamethoxazole/trimethoprim
. As the total lymphocyte count decreases, the incidence of toxicity decreases in
AIDS patients. Infection of CD4 lymphocytes with HIV may increase the sensitivity of lymphocytes to sulfamethoxazole/trimethoprim or
[196]
metabolites
.
5) In adult patients with a history of hypersensitivity to sulfamethoxazole/trimethoprim, 23 of 28 patients were successfully
[93]
desensitized :
Day
Daily Dose
Milligrams
sulfamethoxazole/trimethoprim
1
1 mL of 1:20 pediatric suspension
0.4/2
2
2 mL of 1:20 pediatric suspension
0.8/4
3
4 mL of 1:20 pediatric suspension
1.6/8
4
8 mL of 1:20 pediatric suspension
3.2/16
5
1 mL of pediatric suspension
8/40
6
2 mL of pediatric suspension
16/80
7
8
9
10
4 mL of pediatric suspension
8 mL of pediatric suspension
1 single strength tablet
1 double strength tablet
32/160
64/320
80/400
160/800
6) Successful desensitization to sulfamethoxazole/trimethoprim in 4 pediatric patients (aged 4 to 13 years) with AIDS have been
reported. Oral desensitization was performed with sulfamethoxazole 40 mg/mL/trimethoprim suspension 8 mg/mL (solution A); 1 mL of
the suspension was diluted with 19 mL distilled water (solution B). The desensitization regimen was: days 1 through 4 solution B (day
1=1 mL, day 2=2 mL, day 3=4 mL, day 4=8 mL), day 5 through 9 solution A (day 5=0.6 mL, day 6=1.2 mL, day 7=2.5 mL, day 8=5 mL,
day 9=10 mL). From days 10 to 17, 40 mg sulfamethoxazole/trimethoprim was given daily. From day 18, the dose was raised every 3
days to 5 mg/kg daily. A desensitization regimen beginning with 1/10,000 of the desired dose, progressing through 1/5000, 1/1000,
[94][197]
1/500, 1/100, 1/50, and 1/10 of the desired dose, each given every 8 hours has also been used
.
[95]
7) A more rapid desensitization has been utilized . Five infants or children were given doses of sulfamethoxazole/trimethoprim
suspension, diluted in sterile water, every 15 minutes. The following dilutions of suspension were used; 1:10000, 1:1000, 1:500, 1:250,
1:125, 1:62, 1:30, 1:15, 1:7.5, 1:5, 1:2.5 then full strength. Three of 5 patients were successfully desensitized using this desensitization
schedule.
8) The sulfamethoxazole component of sulfamethoxazole/trimethoprim is often implicated in hypersensitivity reactions; however, the
trimethoprim component should also be considered. A patient experienced urticaria, facial angioedema, wheezing, dyspnea, and
dysphagia within 15 minutes of taking a double-strength sulfamethoxazole/trimethoprim tablet. The patient was treated with
corticosteroids and symptoms resolved. Skin prick test showed reactivity for trimethoprim but not sulfamethoxazole. IgE antibodies to
[198]
trimethoprim but not sulfamethoxazole were detected. An oral challenge with sulfamethoxazole was negative
.
3.3.7.D Myocarditis, Allergic
[105]
1) Allergic myocarditis has been reported with sulfamethoxazole/trimethoprim use
.
3.3.7.E Polyarteritis nodosa
[105]
1) Periarteritis nodosa has been reported with sulfamethoxazole/trimethoprim use
.
3.3.7.F Systemic lupus erythematosus
[105]
1) Systemic lupus erythematosus has been reported with sulfamethoxazole/trimethoprim use
.
See Drug Consult reference: DRUG-INDUCED SYSTEMIC LUPUS ERYTHEMATOSUS
3.3.8 Musculoskeletal Effects
Arthralgia
Myalgia
Rhabdomyolysis
3.3.8.A Arthralgia
[105]
1) Arthralgia has been reported with sulfamethoxazole/trimethoprim use
.
3.3.8.B Myalgia
[105]
1) Myalgia has been reported with sulfamethoxazole/trimethoprim use
.
3.3.8.C Rhabdomyolysis
[105]
1) Isolated cases of rhabdomyolysis have been reported with sulfamethoxazole/trimethoprim use, primarily in AIDS patients
.
2) A 28-year-old, obese, female leukemia patient developed rhabdomyolysis while receiving sulfamethoxazole/trimethoprim 550 mg
IV every 6 hours for the treatment of Pneumocystis jirovecii pneumonia (PCP) 167 days after undergoing an allogenic stem-cell
transplant. The patient presented with shortness of breath, chest pain, and cough with green sputum, and was initiated on
piperacillin/tazobactam, vancomycin, and methylprednisolone. On day 3 of admission, she developed a mixed respiratory and
metabolic acidosis and was intubated. Her condition progressed to pulmonary sepsis and multiorgan dysfunction. On day 4, continuous
renal replacement therapy was initiated due to acute renal insufficiency and continuing acidosis; additionally, she received
norepinephrine and drotrecogin alfa. A diagnosis of rhabdomyolysis was made subsequent to laboratory results showing a very
elevated serum CPK of 13,575 units/L. Sulfamethoxazole/trimethoprim was immediately discontinued and pentamidine was
substituted. Within 5 days, her CPK levels normalized and eventually the patient was discharged to a rehabilitation facility. According to
the Naranjo probability of adverse drug event scale, sulfamethoxazole/trimethoprim was the probable causative agent of
[190]
rhabdomyolysis in this case
.
3.3.9 Neurologic Effects
Aseptic meningitis
Asthenia
Ataxia
Headache
Insomnia
Parkinsonism
Peripheral neuritis
Seizure
Tremor
Vertigo
3.3.9.A Aseptic meningitis
[105]
1) Aseptic meningitis has been reported with sulfamethoxazole/trimethoprim use
.
2) Sulfamethoxazole/trimethoprim has caused aseptic meningitis in several case reports. Symptoms usually arise within 2 to 24 hours
after initiation of therapy, consisting of headache, confusion, nausea, vomiting, stiff neck, photophobia and weakness. Seizures,
abdominal pain, fever and rash have also been reported. In most cases, symptoms resolved within 48 hours of discontinuing
[124][125][126][127][128][129][130][131][132][133]
sulfamethoxazole/trimethoprim
.
3.3.9.B Asthenia
[105]
1) Weakness has been reported with sulfamethoxazole/trimethoprim use
.
3.3.9.C Ataxia
[105]
1) Ataxia has been reported with sulfamethoxazole/trimethoprim use
.
2) Ataxia associated with intravenous sulfamethoxazole/trimethoprim occurred in a 47-year-old male with AIDS and a 53-year-old
male with non-Hodgkin's lymphoma. In the first case the ataxia resolved 3 days after sulfamethoxazole/trimethoprim was discontinued.
In the second case the ataxia was associated with an elevated trimethoprim level of 36.4 mcg/mL. When the dose was reduced and the
[123]
trimethoprim level fell, the ataxia resolved
.
3.3.9.D Headache
[105]
1) Headache has been reported with sulfamethoxazole/trimethoprim use
.
3.3.9.E Insomnia
[105]
1) Insomnia has been reported with sulfamethoxazole/trimethoprim use
.
3.3.9.F Parkinsonism
1) Sulfamethoxazole/trimethoprim was reported to exacerbate symptoms of Parkinson's disease in a 48-month-old female with
dihydropteridine reductase deficiency. The patient had been stable while receiving therapy, including levodopa and carbidopa.
Symptoms of parkinsonism and central nervous system dopamine deficiency developed after receiving 7 doses of
sulfamethoxazole/trimethoprim. Trimethoprim is an inhibitor of dihydropteridine reductase. The symptoms resolved promptly after
[134]
sulfamethoxazole/trimethoprim was discontinued
.
3.3.9.G Peripheral neuritis
[105]
1) Peripheral neuritis has been reported with sulfamethoxazole/trimethoprim use
.
3.3.9.H Seizure
[105]
1) Convulsions have been reported with sulfamethoxazole/trimethoprim use
.
2) A patient on high dose sulfamethoxazole/trimethoprim (duration of therapy 8 days) for presumed PCP with 2 episodes of
[140]
hypoglycemia and seizures was described
. The patient was a renal transplant patient who had normal random serum glucoses
prior to sulfamethoxazole/trimethoprim administration. After the second hypoglycemic episode sulfamethoxazole/trimethoprim was
discontinued. The patient had elevated C-peptide serum levels which is consistent with the theory that sulfamethoxazole/trimethoprim
stimulates islet cells causing the release of excess insulin. The patient was treated with diazepam for seizure control and intravenous
glucose.
3.3.9.I Tremor
1) Tremor has been temporally related to sulfamethoxazole/trimethoprim therapy in patients being treated for Pneumocystis carinii
pneumonia in association with AIDS. Onset of tremors usually occurs within 3 to 6 days, with symptoms resolving 2 to 3 days after
[135][136][137]
sulfamethoxazole/trimethoprim was discontinued or the dose reduced
. In 1 similar case, rechallenge resulted in tremor that
resolved with discontinuation of the drug. Folic acid deficiency was proposed as the problem; however, serum folate concentrations
[138]
were not measured and the patient was not treated with folic acid
.
2) An immunocompetent 29-year-old male developed an action, postural tremor one day after initiation of intravenous
sulfamethoxazole 92.4 mg/kg/day/trimethoprim 18.5 mg/kg/day and oral ofloxacin 400 mg twice daily for Enterobacter aerogenes
meningitis. The tremor persisted and worsened to involve the tongue, trunk and extremities during the 14 days of
sulfamethoxazole/trimethoprim and ofloxacin therapy. Within 2 days of drug discontinuation, the tremor resolved and the patient
recovered fully. Possible mechanisms of tremor include decreased production of the dopamine precursor tyrosine and accumulation of
toxic hydroxylamine metabolites in glutathione-deficient patients. It was not determined if the drug which caused the tremor was the
[139]
ofloxacin or the sulfamethoxazole/trimethoprim
.
3.3.9.J Vertigo
[105]
1) Vertigo has been reported with sulfamethoxazole/trimethoprim use
.
3.3.11 Otic Effects
3.3.11.A Tinnitus
[105]
1) Tinnitus has been reported with sulfamethoxazole/trimethoprim use
.
3.3.12 Psychiatric Effects
Anxiety
Delirium
Depression
Feeling nervous
Hallucinations
Indifference
Psychotic disorder
3.3.12.A Anxiety
1) Sulfamethoxazole/trimethoprim was reported to exacerbate a panic disorder in a 48-year-old woman. The patient was being
treated for a panic disorder when sulfamethoxazole/trimethoprim was initiated, and she experienced an increase in anxiety, panic
[199]
attacks, and insomnia. The anxiety subsided 2 days after the sulfamethoxazole/trimethoprim was discontinued
.
3.3.12.B Delirium
1) Sulfamethoxazole/trimethoprim has been associated with delirium
[200]
.
3.3.12.C Depression
[105]
1) Depression has been reported with sulfamethoxazole/trimethoprim use
.
[201]
2) Severe depression has been described during sulfamethoxazole/trimethoprim therapy
.
3.3.12.D Feeling nervous
1) Nervousness has been reported with sulfamethoxazole/trimethoprim use
[105]
.
3.3.12.E Hallucinations
[105]
1) Hallucinations have been reported with sulfamethoxazole/trimethoprim use
.
3.3.12.F Indifference
[105]
1) Apathy has been reported with sulfamethoxazole/trimethoprim use
.
3.3.12.G Psychotic disorder
1) Isolated case reports have associated sulfamethoxazole/trimethoprim with acute psychosis. Psychosis was reported in a 55-year[202]
old man, occurring after receiving 6 doses of intravenous sulfamethoxazole/trimethoprim
. A 74-year-old woman became acutely
[203]
psychotic during 15 days of oral sulfamethoxazole/trimethoprim
. In these cases, the psychosis resolved within 24 to 60 hours after
sulfamethoxazole/trimethoprim was discontinued.
3.3.13 Renal Effects
Crystalluria
Diuresis
Interstitial nephritis
Nephrotoxicity
Renal failure
Serum blood urea nitrogen raised
Serum creatinine raised
Urolithiasis
3.3.13.A Crystalluria
1) During treatment with sulfamethoxazole/trimethoprim adequate fluid intake and urinary output should be ensured to prevents
[105]
crystalluria. Patients classified as slow acetylators may be more prone to idiosyncratic reactions to sulfonamides
.
3.3.13.B Diuresis
1) Diuresis has been rarely observed with sulfonamide use
[105]
.
3.3.13.C Interstitial nephritis
[105]
1) Interstitial nephritis has been reported with sulfamethoxazole/trimethoprim use
.
3.3.13.D Nephrotoxicity
[105]
1) Toxic nephrosis with oliguria and anuria has been reported with sulfamethoxazole/trimethoprim use
.
2) Sulfamethoxazole and trimethoprim have been implicated as nephrotoxic, especially in patients with preexisting renal impairment.
[160][161]
However, some data suggest this is not conclusive and their combined use is safe and effective in renal patients
.
3) Renal function declined in 16 patients in association with sulfamethoxazole/trimethoprim treatment. This was reversible in most,
but 3 patients showed permanent impairment of renal function. In 5 patients with impaired renal function in whom a modification of the
standard dose regimen was used, renal function further deteriorated. The authors suggest that sulfamethoxazole/trimethoprim should
[162]
not be used when the serum creatinine is above 2 mg per 100 mL
.
4) A significant rise in the mean plasma creatinine (17.6%) and a significant decrease in the mean creatinine clearance (26.3%), has
been reported in 10 healthy volunteers given 2 sulfamethoxazole/trimethoprim tablets twice daily for 7 days. Glomerular filtration rate
as calculated from 51CR-EDTA clearance did not show any significant change. They concluded that the effect of
sulfamethoxazole/trimethoprim on plasma creatinine and creatinine clearance was not due to a decrease in glomerular filtration rate
[163]
.
5) Long term administration of sulfamethoxazole/trimethoprim in children (3 to 6 months) with vesicoureteral reflux and/or recurrent
UTI did not adversely affect renal function in therapeutic doses. Renal function was normal at the beginning of treatment.
[164]
Sulfamethoxazole/trimethoprim also did not interfere with normal functional renal maturation
.
[165]
6) Acute granulomatous interstitial nephritis due to sulfamethoxazole/trimethoprim has been described in a 51-year-old man
. Five
days after starting oral sulfamethoxazole 800 mg/trimethoprim 160 mg two times daily, the patient developed a generalized pruritic
maculopapular rash, fever, and dark urine. Serum creatinine was elevated to 3.7 mg/dl. The patient had a history of diabetes mellitus
and mild hypertension and was receiving insulin and enalapril at the time sulfamethoxazole/trimethoprim was initiated. All medications
with the exception of the insulin were discontinued, however, the patient's condition continued to worsen. Percutaneous renal biopsy
revealed interstitial granulomas. The patient was treated with methylprednisolone 1 mg/kg/day for four days followed by a rapid taper;
symptoms resolved promptly followed by a gradual fall in serum creatinine.
3.3.13.E Renal failure
[105]
1) Renal failure has been reported with sulfamethoxazole/trimethoprim use
.
3.3.13.F Serum blood urea nitrogen raised
[105]
1) BUN and serum creatinine elevations have been reported with sulfamethoxazole/trimethoprim use
.
3.3.13.G Serum creatinine raised
[105]
1) BUN and serum creatinine elevations have been reported with sulfamethoxazole/trimethoprim use
.
3.3.13.H Urolithiasis
1) Although minimal, the possibility exists of renal stone formation due to sulfamethoxazole and the recommendations from several
authors to insure adequate hydration, fluid intake and maintain urine output in patients with normal renal function appear quite
[151][166][167][168]
reasonable
.
2) Two patients developed crystalluria when given intravenous sulfamethoxazole/trimethoprim, who were also septicemic and
[167]
hypoproteinemic
. Also, a 72-year-old male being treated for chronic prostatitis for 2 weeks with sulfamethoxazole/trimethoprim (no
[169]
dose given) developed oliguria and dramatic increases of BUN and serum creatinine
. After surgical removal of bilateral ureteral
obstructions, profound diuresis began. One obstruction was composed of pure sulfamethoxazole/trimethoprim metabolites.
3.3.15 Respiratory Effects
Acute respiratory distress syndrome
Cough
Dyspnea
Pulmonary eosinophilia
3.3.15.A Acute respiratory distress syndrome
[180]
1) The adult respiratory distress syndrome has been associated with sulfamethoxazole/trimethoprim therapy
. An 81-year-old
woman developed chills, cough and dyspnea within 5 to 6 hours after the ingestion of a single sulfamethoxazole 800 mg/trimethoprim
160 mg tablet on 3 separate occasions. Chest radiographs on each occasion demonstrated diffuse interstitial infiltrates. The patient had
been taking the drug for recurrent sinusitis. Following the third incident, a right lower lobe lobectomy was performed to remove a well
circumscribed squamous cell carcinoma. The patient had no further episodes and did not receive further
sulfamethoxazole/trimethoprim therapy.
3.3.15.B Cough
[105]
1) Cough has been reported with sulfamethoxazole/trimethoprim use .
3.3.15.C Dyspnea
[105]
1) Shortness of breath has been reported sulfamethoxazole/trimethoprim use
.
3.3.15.D Pulmonary eosinophilia
[105]
1) Pulmonary infiltrates have been reported with sulfamethoxazole/trimethoprim use
.
3.3.16 Other
Angioedema
Drug fever
Fatigue
Serum sickness due to drug
Shivering
3.3.16.A Angioedema
[105]
1) Angioedema has been reported with sulfamethoxazole/trimethoprim use
.
3.3.16.B Drug fever
[105]
1) Drug fever has been reported with sulfamethoxazole/trimethoprim use
.
2) Fever has occurred in 4 children while taking sulfamethoxazole/trimethoprim, mostly within a few hours from ingestion. All of these
patients had been treated with sulfamethoxazole/trimethoprim previously. In one patient, fever did not develop until the eighth day of
[204]
treatment; however, this patient had not received sulfamethoxazole/trimethoprim or other sulfonamides previously
.
3.3.16.C Fatigue
[105]
1) Fatigue has been reported with sulfamethoxazole/trimethoprim use
.
3.3.16.D Serum sickness due to drug
[105]
1) Serum-like sickness syndrome has been reported with sulfamethoxazole/trimethoprim use
.
2) During 1972 to 1985 there were 51 cases of sulfamethoxazole/trimethoprim-induced serum sickness reported to the Food and
[205]
Drug Administration
.
3.3.16.E Shivering
[105]
1) Chills have been reported with sulfamethoxazole/trimethoprim use
.
3.4 Teratogenicity/Effects in Pregnancy/Breastfeeding
A) Teratogenicity/Effects in Pregnancy
1) Sulfamethoxazole
a) U.S. Food and Drug Administration's Pregnancy Category: Category C (All Trimesters)
1) Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no
controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit
justifies the potential risk to the fetus.
b) Australian Drug Evaluation Committee's (ADEC) Category: C
1) Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing harmful effects on the human
fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further
details.
See Drug Consult reference: PREGNANCY RISK CATEGORIES
c) Crosses Placenta: Unknown
d) Clinical Management
1) There is insufficient data on the use of sulfamethoxazole in pregnant women. Although no teratogenic effects have been observed
with sulfonamides, sulfamethoxazole is contraindicated in pregnancy near term. The drug can compete with bilirubin for binding to
[458][459]
plasma albumin, and possibly result in kernicterus in the newborn
. Sulfonamides should not be used after the 32nd week of
[460]
pregnancy, as they displace bilirubin from its binding to albumin which can lead to jaundice and kernicterus
. Alternatives to sulfa
antibiotics are penicillins, cephalosporins, macrolides, and nitrofurantoin. Trimethoprim and sulfonamide combinations should not be
used during the first trimester. If used, folic acid 4 milligrams daily is recommended to prevent neural tube defects due to folic acid
[460]
antagonism from the drug
. If used, folic acid 4 milligrams daily is recommended to prevent neural tube defects due to folic acid
antagonism from the drug.
e) Literature Reports
1) Pregnant rats given oral doses of sulfamethoxazole 533 mg/kg or trimethoprim 200 mg/kg produced offspring with an increased
incidence of cleft palate. The highest dose which did not cause cleft palates in rats was sulfamethoxazole 512 mg/kg or trimethoprim
192 mg/kg. No teratogenic effects were seen when rats were given sulfamethoxazole 512 mg/kg in combination with trimethoprim 128
mg/kg. However, another study found an increase in cleft palate in one of nine litters of rats given sulfamethoxazole 355 mg/kg in
[456]
combination with trimethoprim 88 mg/kg
.
2) One retrospective study reporting the outcome of 186 pregnancies with the fetus exposed to trimethoprim, sulfamethoxazole, or
placebo found the incidence of congenital abnormalities at 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those
receiving trimethoprim and sulfamethoxazole. In mothers who took the drug during the first trimester, there were no adverse effects
seen in the infants. In another study, no congenital abnormalities were seen in 35 children whose mothers had received oral
[456]
trimethoprim and sulfamethoxazole around the time of conception or shortly thereafter
.
3) Two case reports describe HIV-positive women treated with combination antiretroviral therapy who unexpectedly conceived and
whose fetuses progressively developed spinal malformations. The first woman's regimen included zidovudine, zalcitabine, and
cotrimoxazole (sulfamethoxazole/trimethoprim) at the time of conception and throughout pregnancy. Folic acid 10 mg/day was added
in an attempt to lessen the antifolate activity of cotrimoxazole. At 32 weeks gestation, a fetal ultrasound revealed hemivertebrae in the
lumbar spine. A viable infant was delivered at term by Ceasarean section; a bony mass was present in the lumbar spine but no
neurological abnormalities were noted. The second woman's medications included didanosine, stavudine, nevirapine, and
cotrimoxazole at the time of conception and throughout pregnancy. A fetal ultrasound performed at 19 weeks gestation was significant
[457]
for spina bifida and ventriculomegaly. The pregnancy was electively terminated
. Fetal outcomes in HIV-infected patients with in
utero exposure to sulfamethaxazole should be interpreted with caution given the inherent risks of comorbid states, including serious
infection.
2) Trimethoprim
a) U.S. Food and Drug Administration's Pregnancy Category: Category C (All Trimesters)
1) Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no
controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit
justifies the potential risk to the fetus.
b) Australian Drug Evaluation Committee's (ADEC) Category: B3
1) Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in
the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals
have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.
See Drug Consult reference: PREGNANCY RISK CATEGORIES
c) Crosses Placenta: Yes
d) Clinical Management
1) Although trimethoprim is a folate antagonist and crosses the placenta, a causal relationship between the drug and an increase in
[469][470][471]
fetal abnormalities has not been proven
. Until more information is available, trimethoprim should only be used during
pregnancy if the maternal condition justifies the potential risk to the fetus.
e) Literature Reports
1) Two case reports describe HIV-positive women treated with combination antiretroviral therapy who unexpectedly conceived and
whose fetuses progressively developed spinal malformations. The first woman's regimen included zidovudine, zalcitabine, and
cotrimoxazole (trimethoprim/sulfamethoxisole) at the time of conception and throughout pregnancy. Folic acid 10 mg/day was added in
an attempt to lessen the antifolate activity of cotrimoxazole. At 32-weeks gestation, a fetal ultrasound revealed hemivertebrae in the
lumbar spine. A viable infant was delivered at term by Ceasarean section; a bony mass was present in the lumbar spine but no
neurological abnormalities were noted. The second woman's medications included didanosine, stavudine, nevirapine, and
cotrimoxazole at the time of conception and throughout pregnancy. A fetal ultrasound performed at 19-weeks gestation was significant
[467]
for spina bifida and ventriculomegaly. The pregnancy was electively terminated
.
2) Of 186 pregnancies during which the mother received either placebo or trimethoprim in combination with sulfamethoxazole, the
incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving
trimethoprim plus sulfamethoxazole. There were no abnormalities in the 10 children whose mothers received the drug during the first
[468]
trimester
.
B) Breastfeeding
1) Sulfamethoxazole
a) American Academy of Pediatrics Rating: Maternal medication usually compatible with breastfeeding.
b) World Health Organization Rating: Compatible with breastfeeding. Monitor infant for side effects.
c) Thomson Lactation Rating: Infant risk cannot be ruled out.
1) Available evidence and/or expert consensus is inconclusive or is inadequate for determining infant risk when used during
breastfeeding. Weigh the potential benefits of drug treatment against potential risks before prescribing this drug during breastfeeding.
d) Clinical Management
1) The combination product, sulfamethoxazole/trimethoprim is contraindicated in nursing mothers, because sulfonamides are
[464]
excreted in the milk and may cause kernicterus
. In addition, sulfamethoxazole/trimethoprim is contraindicated in pediatric patients
[464]
less than 2 months of age
. The World Health Organization recommends avoiding use in neonates, premature infants, and those
[462]
with G6PD deficiency
. If used during lactation, monitor infants for hemolysis and jaundice.
e) Literature Reports
[463]
1) Because a potential exists for harm to the infant (kernicterus), either nursing or sulfamethoxazole should be discontinued
.
2) Trimethoprim
a) American Academy of Pediatrics Rating: Maternal medication usually compatible with breastfeeding.
b) World Health Organization Rating: Compatible with breastfeeding. Monitor infant for side effects.
c) Thomson Lactation Rating: Infant risk is minimal.
1) The weight of an adequate body of evidence and/or expert consensus suggests this drug poses minimal risk to the infant when used
during breastfeeding.
d) Clinical Management
1) Although trimethoprim appears in breast milk, the dose received by a nursing infant has been estimated to be about 3 to 5% of the
[473]
maternal dose, and is not considered to be clinically important
.
e) Literature Reports
1) Concentrations of 1.2 to 5.5 mcg/mL in milk were reported in mothers taking 160 mg of trimethoprim 2 to 4 times a day. No effects in
[472]
the infants were noted
.
3.5 Drug Interactions
Drug-Drug Combinations
Drug-Food Combinations
Drug-Lab Modifications
Intravenous Admixtures
3.5.1 Drug-Drug Combinations
Acecainide
Acenocoumarol
Acetohexamide
Ajmaline
Amantadine
Aminobenzoic Acid
Amiodarone
Amisulpride
Amitriptyline
Amoxapine
Anisindione
Aprindine
Arsenic Trioxide
Astemizole
Azimilide
Benzocaine
Bepridil
Bretylium
Chloral Hydrate
Chloroprocaine
Chloroquine
Chlorpromazine
Chlorpropamide
Cisapride
Clarithromycin
Cyclosporine
Dapsone
Desipramine
Dibenzepin
Dicumarol
Didanosine
Didanosine
Digoxin
Disopyramide
Dofetilide
Dolasetron
Doxepin
Droperidol
Eltrombopag
Enalaprilat
Enalapril Maleate
Enflurane
Erythromycin
Flecainide
Fluconazole
Fluoxetine
Foscarnet
Fosphenytoin
Gemifloxacin
Glimepiride
Glipizide
Glyburide
Glyburide
Halofantrine
Haloperidol
Halothane
Hydroquinidine
Ibutilide
Imipramine
Isoflurane
Isradipine
Lamivudine
Leucovorin
Levomethadyl
Lidoflazine
L-Methylfolate
Lorcainide
Mefloquine
Mesoridazine
Metformin
Methotrexate
Nortriptyline
Octreotide
Pentamidine
Phenprocoumon
Phenytoin
Pimozide
Pirmenol
Porfimer
Prajmaline
Pralatrexate
Probucol
Procainamide
Procaine
Prochlorperazine
Propafenone
Pyrimethamine
Quetiapine
Quinapril
Quinidine
Repaglinide
Rifabutin
Risperidone
Rosiglitazone
Sematilide
Sertindole
Sotalol
Spiramycin
Sultopride
Tedisamil
Telithromycin
Terfenadine
Tetracaine
Thioridazine
Tolazamide
Tolbutamide
Tolbutamide
Trifluoperazine
Trimipramine
Typhoid Vaccine, Live
Vasopressin
Warfarin
Zidovudine
Zotepine
3.5.1.A Acecainide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Class III antiarrhythmics and cotrimoxazole have been shown to prolong the QTc interval at the recommended
[351]
therapeutic dose . The coadministration of Class III antiarrhythmic agents and other drugs known to prolong the QTc interval,
[352]
including cotrimoxazole, is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of Class III antiarrhythmic agents and agents that prolong the QT interval, such
as cotrimoxazole, is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.B Acenocoumarol
1) Interaction Effect: increased risk of bleeding
2) Summary: Some sulfonamides may impair the hepatic metabolism of oral anticoagulants resulting in enhanced
[384][385][386][387]
hypoprothrombinemic responses
.
3) Severity: major
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: In patients receiving oral anticoagulant therapy, the prothrombin time ratio or international normalized ratio
(INR) should be closely monitored with the addition and withdrawal of sulfamethoxazole, and should be reassessed periodically during
concurrent therapy. Downward adjustments of the acenocoumarol dose may be necessary in order to maintain the desired level of
anticoagulation.
7) Probable Mechanism: decreased acenocoumarol metabolism, displacement of acenocoumarol from protein binding sites
3.5.1.C Acetohexamide
1) Interaction Effect: enhanced hypoglycemic effects
2) Summary: There are several case reports related to combined use of sulfonamides and sulfonylureas resulting in profound
hypoglycemia requiring hospitalization. The proposed mechanism of action is displacement of the sulfonylurea from protein-binding
[272]
sites .
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Avoid the use of sulfonamide antibiotics in patients who are taking sulfonylureas. If concomitant therapy is
required, closely monitor blood glucose. Emergency treatment of a hypoglycemic episode may be required.
7) Probable Mechanism: potentiation of hypoglycemic effect of the sulfonylureas caused by displacement from protein-binding sites by
sulfonamides
8) Literature Reports
a) A brief review of some of the case reports relating to these interactions follows: (1) A 69-year-old black female who was stable on
cimetidine 300 mg orally at bedtime, docusate 200 mg daily, hydrochlorothiazide 50 mg daily, and chlorpropamide 500 mg daily orally,
was hospitalized two days after starting cotrimoxazole two tablets orally twice a day. Her laboratory results on admission were a blood
glucose of 48 mg/dL, blood pressure of 174/90, and serum sodium of 118 mEq/L; she was nauseous and vomiting. The patient was
[268]
discharged after seven days of hospitalization
. (2) A 67-year-old diabetic stable on chlorpropamide 250 mg daily was admitted to a
hospital two days after starting on sulfamethazine with a blood glucose of 10 mg/dL. She was semicomatose for a week and mentally
[269]
dull for a month
. (3) A 77-year-old man on chlorpropamide and phenformin was started on sulfisoxazole. The next day he was
[270]
[271]
hospitalized with hypoglycemia
. (4)
describe two patients on tolbutamide who were started on sulfisoxazole. They experienced
hypoglycemia and were hospitalized. One of the patients, a 47-year-old man, died with a blood glucose of 8 mg/dL.
3.5.1.D Ajmaline
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Even though no formal drug interaction studies have been done, the coadministration of Class IA antiarrhythmics and
[321]
other drugs known to prolong the QTc interval is not recommended
. Cotrimoxazole has demonstrated QT prolongation at
[322]
therapeutic doses
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: The concurrent administration of Class IA antiarrhythmic agents and agents that prolong the QT interval, such
as cotrimoxazole, is not recommended. Monitor serum procainamide and NAPA serum levels and for signs of procainamide toxicity
(cardiac arrhythmias, hypotension, CNS depression). Dosage adjustments may be made depending on serum levels and patient
response.
7) Probable Mechanism: additive effects on QT prolongation
8) Literature Reports
a) Eight healthy men received oral sustained-release procainamide 500 mg every six hours for three days, alone and with oral
trimethoprim 200 mg daily for four days. Trimethoprim coadministration increased the area under the concentration-time curve (AUC) of
procainamide from 19.9 mg/h/L to 32.5 mg/h/L, representing a 63% increase. Mean steady-state procainamide concentrations also
increased from 1.6 mcg/mL to 2.7 mcg/mL. Likewise, trimethoprim increased the AUC of N-acetylprocainamide (NAPA), the active
metabolite of procainamide, by 52% (14.1 mg/hr/L vs. 21.4 mg/hr/L). NAPA plasma concentrations increased from 1.2 mcg/mL to 1.8
mcg/mL. Renal clearance of procainamide and NAPA decreased by 47% and 13%, respectively. A small but significant increase in the
[319]
QTc interval was noted with procainamide administration, and this interval further increased with trimethoprim cotherapy
.
[320]
b) Ten healthy volunteers participated in an open, randomized, placebo-controlled, two-period crossover study by
to determine the
effects of trimethoprim and procainamide coadministration. Subjects received trimethoprim 100 mg or placebo twice daily on days 1
through 3 of each study period. On day 4, procainamide 1000 mg was administered orally as a single dose with trimethoprim 200 mg or
placebo, and another dose of trimethoprim 100 mg or placebo was given 12 hours later. Each treatment period was separated by at
least a one-week washout period. Trimethoprim decreased the renal clearance of procainamide by 45% (487 mL/min vs. 267 mL/min)
and also decreased the clearance of the active metabolite of procainamide, N-acetylprocainamide (NAPA), by 26% (275 mL/min vs.
192 mL/min) as compared to placebo. The area under the concentration-time curve (AUC) increased by 39% for procainamide (19.8
mg/h/L vs. 27.6 mg/h/L) and 27% for NAPA (9.1 mg/h/L vs. 11.4 mg/h/L). Procainamide and NAPA are weak bases and undergo
extensive renal tubular secretion. Trimethoprim is 50% to 60% excreted unchanged in the urine via glomerular filtration, tubular
secretion, and reabsorption. In the case of trimethoprim and procainamide coadministration, both drugs may be competing for tubular
secretion, causing a saturation of this route of elimination. This results in procainamide accumulation, and the potential for
procainamide toxicity.
3.5.1.E Amantadine
1) Interaction Effect: CNS toxicity (insomnia, confusion)
2) Summary: Coadministration of amantadine and trimethoprim (alone or in combination with sulfamethoxazole) may lead to reduced
[437]
tubular secretion of both amantadine and trimethoprim
.
3) Severity: minor
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Patients, especially the elderly, treated concurrently with amantadine and trimethoprim or cotrimoxazole
should be monitored for signs of central nervous system toxicity (insomnia, confusion, depression, hallucinations, anorexia, dizziness).
7) Probable Mechanism: decreased renal clearance
8) Literature Reports
a) Amantadine administered with trimethoprim alone or in combination with sulfamethoxazole may inhibit the renal tubular secretion
of both amantadine and trimethoprim. An 83-year-old Parkinson's patient taking amantadine 200 mg/day was administered
trimethoprim combined with sulfamethoxazole for the treatment of bronchitis. The patient became incoherent, confused, and
combative 3 days after starting the antibiotic. Both amantadine and the trimethoprim /sulfamethoxazole were discontinued and the
[436]
patient's behavior normalized within 1 day
.
3.5.1.F Aminobenzoic Acid
1) Interaction Effect: antagonism of the sulfonamide's antibacterial effect
2) Summary: Sulfonamides exert their antimicrobial effect through competitive inhibition of bacterial PABA. In sufficient doses,
concomitant para-aminobenzoic acid (PABA) therapy interferes with this competitive inhibition and antagonizes the antibacterial effects
[312][313][314]
of the sulfonamide
. Local anesthetics that are PABA derivatives (benzocaine, procaine, tetracaine) can also reportedly
antagonize the antibacterial activity of sulfonamides. It is suggested that local anesthetics that are not PABA derivatives (lidocaine,
[315]
dibucaine) be used in patients receiving antibacterial sulfonamides
.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Avoid use of para-aminobenzoic acid (PABA) or PABA derivatives in patients receiving sulfonamide
antimicrobials; consider alternative therapy.
7) Probable Mechanism: para-aminobenzoic acid (PABA) competition with bacterial PABA
3.5.1.G Amiodarone
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Class III antiarrhythmics and cotrimoxazole have been shown to prolong the QTc interval at the recommended
[351]
therapeutic dose . The coadministration of Class III antiarrhythmic agents and other drugs known to prolong the QTc interval,
[352]
including cotrimoxazole, is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of Class III antiarrhythmic agents and agents that prolong the QT interval, such
as cotrimoxazole, is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.H Amisulpride
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
[341]
2) Summary: Cotrimoxazole has been shown to prolong the QTc interval at the recommended therapeutic dose
. Even though no
formal drug interaction studies have been done, the coadministration of antipsychotics and other drugs known to prolong the QTc
interval, including cotrimoxazole, is not recommended. Several antipsychotic agents have demonstrated QT prolongation including
[342]
[343]
[344]
[345]
[346]
[347]
[348]
amisulpride
, haloperidol
, quetiapine
, risperidone
, sertindole
, sultopride
, and zotepine
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cotrimoxazole and antipsychotics is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.I Amitriptyline
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Tricyclic antidepressants (TCAs) and cotrimoxazole have been shown to prolong the QTc interval at the recommended
[330][331]
therapeutic dose
. Even though no formal drug interaction studies have been done, the coadministration of tricyclic
[332]
antidepressants and other drugs known to prolong the QTc interval, such as cotrimoxazole, is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: The concurrent administration of cotrimoxazole and tricyclic antidepressants is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.J Amoxapine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Tricyclic antidepressants (TCAs) and cotrimoxazole have been shown to prolong the QTc interval at the recommended
[330][331]
therapeutic dose
. Even though no formal drug interaction studies have been done, the coadministration of tricyclic
[332]
antidepressants and other drugs known to prolong the QTc interval, such as cotrimoxazole, is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: The concurrent administration of cotrimoxazole and tricyclic antidepressants is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.K Anisindione
1) Interaction Effect: increased risk of bleeding
2) Summary: Sulfonamides can impair the hepatic metabolism of oral anticoagulants resulting in enhanced hypoprothrombinemic
[366][367][368]
responses
.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: In patients receiving oral anticoagulant therapy, the prothrombin time ratio or INR (international normalized
ratio) should be closely monitored with the addition and withdrawal of treatment with cotrimoxazole, and should be reassessed
periodically during concurrent therapy. Adjustments of the anisindione dose may be necessary in order to maintain the desired level of
anticoagulation.
7) Probable Mechanism: decreased anisindione metabolism
3.5.1.L Aprindine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Even though no formal drug interaction studies have been done, the coadministration of Class I antiarrhythmics and other
[382]
drugs known to prolong the QTc interval is not recommended
. Cotrimoxazole has demonstrated QT prolongation at therapeutic
[383]
doses
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of Class I antiarrhythmic agents and agents that prolong the QT interval, such
as cotrimoxazole, is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.M Arsenic Trioxide
1) Interaction Effect: cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
[406]
2) Summary: Cotrimoxazole has been shown to prolong the QTc interval at the recommended therapeutic dose
. Even though no
formal drug interaction studies have been done, the coadministration of drugs known to prolong the QTc interval, including arsenic
[407]
trioxide and cotrimoxazole is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of arsenic trioxide and cotrimoxazole is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.N Astemizole
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Astemizole and cotrimoxazole have been shown to prolong the QTc interval at the recommended therapeutic
[281][282]
dose
. Even though no formal drug interaction studies have been done, the coadministration of astemizole and other drugs known
to prolong the QTc interval, including cotrimoxazole, is not recommended.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of astemizole and cotrimoxazole is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.O Azimilide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Class III antiarrhythmics and cotrimoxazole have been shown to prolong the QTc interval at the recommended
[351]
therapeutic dose . The coadministration of Class III antiarrhythmic agents and other drugs known to prolong the QTc interval,
[352]
including cotrimoxazole, is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of Class III antiarrhythmic agents and agents that prolong the QT interval, such
as cotrimoxazole, is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.P Benzocaine
1) Interaction Effect: antagonism of the sulfonamide's antibacterial effect
2) Summary: Sulfonamides exert their antimicrobial effect through competitive inhibition of bacterial PABA. In sufficient doses,
concomitant para-aminobenzoic acid (PABA) therapy interferes with this competitive inhibition and antagonizes the antibacterial effects
[312][313][314]
of the sulfonamide
. Local anesthetics that are PABA derivatives (benzocaine, procaine, tetracaine) can also reportedly
antagonize the antibacterial activity of sulfonamides. It is suggested that local anesthetics that are not PABA derivatives (lidocaine,
[315]
dibucaine) be used in patients receiving antibacterial sulfonamides
.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Avoid use of para-aminobenzoic acid (PABA) or PABA derivatives in patients receiving sulfonamide
antimicrobials; consider alternative therapy.
7) Probable Mechanism: para-aminobenzoic acid (PABA) competition with bacterial PABA
3.5.1.Q Bepridil
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
[363][364]
2) Summary: Bepridil and cotrimoxazole have been shown to prolong the QTc interval at the recommended therapeutic dose
.
Even though no formal drug interaction studies have been done, the coadministration of bepridil and other drugs known to prolong the
[363]
QTc interval, including cotrimoxazole, is contraindicated
.
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of bepridil and cotrimoxazole is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.R Bretylium
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Class III antiarrhythmics and cotrimoxazole have been shown to prolong the QTc interval at the recommended
[351]
therapeutic dose . The coadministration of Class III antiarrhythmic agents and other drugs known to prolong the QTc interval,
[352]
including cotrimoxazole, is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of Class III antiarrhythmic agents and agents that prolong the QT interval, such
as cotrimoxazole, is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.S Chloral Hydrate
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Chloral hydrate and cotrimoxazole (sulfamethoxazole/trimethoprim) have been shown to prolong the QTc interval at the
[260][261]
recommended therapeutic dose
. Even though no formal drug interaction studies have been done, the coadministration of drugs
known to prolong the QTc interval is not recommended.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of chloral hydrate and cotrimoxazole is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.T Chloroprocaine
1) Interaction Effect: antagonism of the sulfonamide's antibacterial effect
2) Summary: Sulfonamides exert their antimicrobial effect through competitive inhibition of bacterial PABA. In sufficient doses,
concomitant para-aminobenzoic acid (PABA) therapy interferes with this competitive inhibition and antagonizes the antibacterial effects
[312][313][314]
of the sulfonamide
. Local anesthetics that are PABA derivatives (benzocaine, procaine, tetracaine) can also reportedly
antagonize the antibacterial activity of sulfonamides. It is suggested that local anesthetics that are not PABA derivatives (lidocaine,
[315]
dibucaine) be used in patients receiving antibacterial sulfonamides
.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Avoid use of para-aminobenzoic acid (PABA) or PABA derivatives in patients receiving sulfonamide
antimicrobials; consider alternative therapy.
7) Probable Mechanism: para-aminobenzoic acid (PABA) competition with bacterial PABA
3.5.1.U Chloroquine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Cotrimoxazole and chloroquine have been shown to prolong the QTc interval at the recommended therapeutic
[357][358]
dose
. Even though no formal drug interaction studies have been done, the coadministration of drugs known to prolong the QTc
interval is not recommended.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cotrimoxazole and chloroquine is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.V Chlorpromazine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Although citing no data, the manufacturers of some phenothiazines state that concomitant use with other drugs which
[337][338][339]
prolong the QT interval is not recommended
. Q and T wave distortions have been observed in patients taking cotrimoxazole
[340]
. Other phenothiazines may have similar effects, though no reports are available.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cotrimoxazole and a phenothiazine is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.W Chlorpropamide
1) Interaction Effect: enhanced hypoglycemic effects
2) Summary: There are several case reports related to combined use of sulfonamides and sulfonylureas resulting in profound
hypoglycemia requiring hospitalization. The proposed mechanism of action is displacement of the sulfonylurea from protein-binding
[279][280]
sites
.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Avoid the use of sulfonamide antibiotics in patients who are taking sulfonylureas. If concomitant therapy is
required, closely monitor blood glucose. Emergency treatment of a hypoglycemic episode may be required.
7) Probable Mechanism: potentiation of hypoglycemic effect of the sulfonylureas caused by displacement from protein-binding sites by
sulfonamides
8) Literature Reports
a) A brief review of some of the case reports relating to these interactions follows: (1) A 69-year-old black female who was stable on
cimetidine 300 mg orally at bedtime, docusate 200 mg daily, hydrochlorothiazide 50 mg daily, and chlorpropamide 500 mg daily orally,
was hospitalized two days after starting cotrimoxazole two tablets orally twice a day. Her laboratory results on admission were a blood
glucose of 48 mg/dL, blood pressure of 174/90, and serum sodium of 118 mEq/L; she was nauseous and vomiting. The patient was
[275]
discharged after seven days of hospitalization
. (2) A 67-year-old diabetic stable on chlorpropamide 250 mg daily was admitted to a
hospital two days after starting on sulfamethazine with a blood glucose of 10 mg/dL. She was semicomatose for a week and mentally
[276]
dull for a month
. (3) A 77-year-old man on chlorpropamide and phenformin was started on sulfisoxazole. The next day he was
[277]
[278]
hospitalized with hypoglycemia
. (4)
describe two patients on tolbutamide who were started on sulfisoxazole. They experienced
hypoglycemia and were hospitalized. One of the patients, a 47-year-old man, died with a blood glucose of 8 mg/dL.
3.5.1.X Cisapride
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
[353]
2) Summary: Concomitant therapy of cisapride with any drug that prolongs the QT interval is contraindicated . Cotrimoxazole has
[354]
been shown to prolong the QTc interval at the recommended therapeutic dose
.
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cisapride with any drug that prolongs the QT interval, such as cotrimoxazole,
is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.Y Clarithromycin
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Cotrimoxazole and clarithromycin have been shown to prolong the QTc interval at the recommended therapeutic
[349][350]
dose
. Even though no formal drug interaction studies have been done, the coadministration of drugs known to prolong the QTc
interval is not recommended.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cotrimoxazole and clarithromycin is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.Z Cyclosporine
1) Interaction Effect: increased nephrotoxicity or reduced cyclosporine serum levels and potentially increased risk of organ rejection
2) Summary: In a case report, a patient stabilized on cyclosporine developed undetectable cyclosporine levels when placed on
trimethoprim and sulfamethazine. In other case reports involving renal transplant patients, the incidence of nephrotoxicity has been
[211][212][213][214]
reported to be greater or to have no change with concurrent trimethoprim use
.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Monitor circulating cyclosporine levels and adjust cyclosporine dosage as necessary. Monitor patients for
decreased response to cyclosporine therapy and for renal dysfunction.
7) Probable Mechanism: unknown synergism
8) Literature Reports
a) Although it has been suggested that concomitant administration of cotrimoxazole and cyclosporine may increase the nephrotoxicity
[209]
associated with cyclosporine
, a prospective, randomized, double-blind study of cotrimoxazole prophylaxis in 132 renal transplant
[210]
patients demonstrated no increase in nephrotoxicity or risk of rejection with cotrimoxazole relative to placebo
. A mild (15%)
increase in serum creatinine was noted in patients receiving both drugs; however, this was shown to be reversible.
3.5.1.AA Dapsone
1) Interaction Effect: an increased risk of dapsone toxicity (hemolytic anemia, methemoglobinemia, peripheral neuropathy) or
trimethoprim toxicity (bone marrow depression, thrombocytopenia, leukopenia, megaloblastic anemia)
2) Summary: In a randomized double-blind study, the concurrent use of trimethoprim and dapsone in AIDS patients with pneumocystic
[425]
carinii infection resulted in an increase in plasma concentration of both drugs by approximately 40%
. However, a later study found
[426]
no significant interaction between dapsone and trimethoprim in asymptomatic HIV-positive patients
. AIDS patients with acute illness
may be more susceptible to this drug interaction. Further studies are necessary to delineate the clinical implications of this drug
interaction in both groups of patients.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Monitor dapsone toxicity (hemolytic anemia especially in patients with G6PD deficiency, methemoglobinemia,
peripheral neuropathy) or trimethoprim toxicity (bone marrow depression, thrombocytopenia, leukopenia and/or megaloblastic anemia);
adjust dosages or discontinue one of the drugs if necessary. This interaction may be more pronounced in AIDS patients with acute
illness.
7) Probable Mechanism: altered clearance
8) Literature Reports
a) Trimethoprim increased dapsone levels by 40% in AIDS patients. In addition, trimethoprim levels were 48.4% higher in patients
receiving trimethoprim and dapsone than patients receiving trimethoprim and sulfamethoxazole. The patients taking trimethoprim and
dapsone had a decreased rate of therapeutic failure and an increased rate of toxicity when compared to the group that took dapsone
alone. It was theorized that the trimethoprim decreased the metabolism and excretion of dapsone. The mechanism by which dapsone
increased trimethoprim levels is unknown. Possibly, it was due to competitive inhibition for excretion pathways between dapsone or
[423]
monoacetyldapsone and trimethoprim
.
b) In a controlled study of eight HIV-positive patients, the pharmacokinetic interactions between zidovudine, trimethoprim, and dapsone
were assessed in two and three drug combinations. Patients received zidovudine 200 mg, trimethoprim 200 mg, or dapsone 100 mg
alone and with one or two of the other agents. In contrast to results from previous studies, no significant changes in dapsone or
trimethoprim pharmacokinetics were observed. In this study, the number of subjects may have been inadequate to detect any
interactions and the subjects were asymptomatic HIV-positive patients whereas the previous study examined AIDS patients being
treated for pneumocystis carinii pneumonia. The authors concluded that in most cases, zidovudine, trimethoprim, and dapsone can be
[424]
given concurrently without a clinically significant interaction
.
3.5.1.AB Desipramine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Tricyclic antidepressants (TCAs) and cotrimoxazole have been shown to prolong the QTc interval at the recommended
[330][331]
therapeutic dose
. Even though no formal drug interaction studies have been done, the coadministration of tricyclic
[332]
antidepressants and other drugs known to prolong the QTc interval, such as cotrimoxazole, is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: The concurrent administration of cotrimoxazole and tricyclic antidepressants is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.AC Dibenzepin
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Tricyclic antidepressants (TCAs) and cotrimoxazole have been shown to prolong the QTc interval at the recommended
[330][331]
therapeutic dose
. Even though no formal drug interaction studies have been done, the coadministration of tricyclic
[332]
antidepressants and other drugs known to prolong the QTc interval, such as cotrimoxazole, is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: The concurrent administration of cotrimoxazole and tricyclic antidepressants is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.AD Dicumarol
1) Interaction Effect: increased risk of bleeding
2) Summary: Some sulfonamides may impair the hepatic metabolism of oral anticoagulants resulting in enhanced
[215][216][217][218]
hypoprothrombinemic responses
.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: In patients receiving oral anticoagulant therapy, the prothrombin time ratio or international normalized ratio
(INR) should be closely monitored with the addition and withdrawal of sulfamethoxazole, and should be reassessed periodically during
concurrent therapy. Downward adjustments of the dicumarol dose may be necessary in order to maintain the desired level of
anticoagulation.
7) Probable Mechanism: decreased dicumarol metabolism, displacement of dicumarol from protein binding sites
3.5.1.AE Didanosine
1) Interaction Effect: reduced sulfamethoxazole exposure
2) Summary: In a drug interaction study of HIV-infected patients (n=8), sulfamethoxazole AUC and Cmax decreased by 11% (95%
confidence interval (CI), -17% to -4%) and 12% (95% CI, -28% to 8%), respectively, when a single 1000-mg dose of sulfamethoxazole
[309][309]
was coadministered with a single 200-mg dose of a buffered formulation of didanosine
. The clinical significance of this decrease
has not been determined. Consider monitoring the patient for reduced sulfamethoxazole efficacy didanosine and sulfamethoxazole
are coadministered.
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: Concomitant use of didanosine and sulfamethoxazole resulted in decreased sulfamethoxazole plasma
[309][309]
concentrations
. Therefore, consider monitoring for reduced efficacy of sulfamethoxazole when didanosine and
sulfamethoxazole are coadministered.
7) Probable Mechanism: unknown
3.5.1.AF Didanosine
1) Interaction Effect: increased didanosine plasma concentrations and potential for increased trimethoprim plasma concentrations
2) Summary: In a drug interaction study of HIV-infected patients (n=8) treated with a single 200-mg dose of trimethoprim that was
coadministered with a single 200-mg dose of a buffered formulation of didanosine, didanosine Cmax and trimethoprim AUC increased
by 17% (95% confidence interval (CI), -23% to 77%) and 10% (95% CI, -9% to 34%), respectively; however, trimethoprim Cmax
[309][309]
decreased by 22% (95% CI, -59% to 49%). The clinical implications of these results are not known
. Therefore, monitoring the
patient for didanosine and trimethoprim toxicity should be considered when didanosine and trimethoprim are coadministered.
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: Concomitant use of didanosine and trimethoprim resulted in increased didanosine plasma concentrations and
[309][309]
may result in increased trimethoprim plasma concentrations
. Therefore, consider monitoring for didanosine and trimethoprim
toxicity when didanosine and trimethoprim are coadministered.
7) Probable Mechanism: unknown
3.5.1.AG Digoxin
1) Interaction Effect: an increased risk of digoxin toxicity
2) Summary: Digoxin levels have been reported to increase during concurrent trimethoprim therapy, especially in elderly patients. This
effect may be due to decreased renal tubular secretion of digoxin. Trimethoprim administration did not affect the total body clearance of
digoxin or the glomerular filtration rate in young, healthy subjects. However, the renal clearance of digoxin decreased significantly in
[409]
elderly subjects, resulting in a 30% to 50% increase in digoxin concentrations
.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: In digitalized patients who receive trimethoprim therapy for seven days or longer, monitor digoxin serum
concentrations and monitor the patient for signs and symptoms of digoxin toxicity (nausea, vomiting, arrhythmias). A decrease in the
digoxin dose may be necessary.
7) Probable Mechanism: decreased renal tubular secretion of digoxin
8) Literature Reports
a) A study of nine elderly patients stabilized on digoxin therapy showed that the addition of trimethoprim 200 mg twice daily for two
weeks significantly altered the serum concentrations of digoxin. All patients had normal serum creatinine values, and no signs of
hepatic or cardiac disease existed. Immediately prior to the addition of trimethoprim, digoxin serum concentrations averaged 1.0
nmol/L. After seven days and 14 days of trimethoprim treatment, serum digoxin concentrations had risen to 1.3 nmol/L and 1.5 nmol/L,
[408]
respectively. Seven days after the discontinuation of trimethoprim, digoxin levels had decreased to 0.9 nmol/L
.
b) Six healthy young male subjects received a single intravenous infusion of digoxin 1 mg over 15 minutes, followed by four days of
intermittent venous blood samples. On the fifth day, participants were started on oral trimethoprim 200 mg twice daily. Another
intravenous dose of digoxin was given on day 10. Pharmacokinetic parameters for digoxin revealed that the renal clearance was
reduced by 17%, from an average of 1.93 mL/min/kg to 1.61 mL/min/kg. Digoxin total body clearance, extra renal clearance, and
[408]
glomerular filtration rate were not significantly affected by the administration of trimethoprim
.
3.5.1.AH Disopyramide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Even though no formal drug interaction studies have been done, the coadministration of Class IA antiarrhythmics and
[321]
other drugs known to prolong the QTc interval is not recommended
. Cotrimoxazole has demonstrated QT prolongation at
[322]
therapeutic doses
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: The concurrent administration of Class IA antiarrhythmic agents and agents that prolong the QT interval, such
as cotrimoxazole, is not recommended. Monitor serum procainamide and NAPA serum levels and for signs of procainamide toxicity
(cardiac arrhythmias, hypotension, CNS depression). Dosage adjustments may be made depending on serum levels and patient
response.
7) Probable Mechanism: additive effects on QT prolongation
8) Literature Reports
a) Eight healthy men received oral sustained-release procainamide 500 mg every six hours for three days, alone and with oral
trimethoprim 200 mg daily for four days. Trimethoprim coadministration increased the area under the concentration-time curve (AUC) of
procainamide from 19.9 mg/h/L to 32.5 mg/h/L, representing a 63% increase. Mean steady-state procainamide concentrations also
increased from 1.6 mcg/mL to 2.7 mcg/mL. Likewise, trimethoprim increased the AUC of N-acetylprocainamide (NAPA), the active
metabolite of procainamide, by 52% (14.1 mg/hr/L vs. 21.4 mg/hr/L). NAPA plasma concentrations increased from 1.2 mcg/mL to 1.8
mcg/mL. Renal clearance of procainamide and NAPA decreased by 47% and 13%, respectively. A small but significant increase in the
[319]
QTc interval was noted with procainamide administration, and this interval further increased with trimethoprim cotherapy
.
[320]
b) Ten healthy volunteers participated in an open, randomized, placebo-controlled, two-period crossover study by
to determine the
effects of trimethoprim and procainamide coadministration. Subjects received trimethoprim 100 mg or placebo twice daily on days 1
through 3 of each study period. On day 4, procainamide 1000 mg was administered orally as a single dose with trimethoprim 200 mg or
placebo, and another dose of trimethoprim 100 mg or placebo was given 12 hours later. Each treatment period was separated by at
least a one-week washout period. Trimethoprim decreased the renal clearance of procainamide by 45% (487 mL/min vs. 267 mL/min)
and also decreased the clearance of the active metabolite of procainamide, N-acetylprocainamide (NAPA), by 26% (275 mL/min vs.
192 mL/min) as compared to placebo. The area under the concentration-time curve (AUC) increased by 39% for procainamide (19.8
mg/h/L vs. 27.6 mg/h/L) and 27% for NAPA (9.1 mg/h/L vs. 11.4 mg/h/L). Procainamide and NAPA are weak bases and undergo
extensive renal tubular secretion. Trimethoprim is 50% to 60% excreted unchanged in the urine via glomerular filtration, tubular
secretion, and reabsorption. In the case of trimethoprim and procainamide coadministration, both drugs may be competing for tubular
secretion, causing a saturation of this route of elimination. This results in procainamide accumulation, and the potential for
procainamide toxicity.
3.5.1.AI Dofetilide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Trimethoprim inhibits the renal tubular secretion of dofetilide; concomitant use of trimethoprim and dofetilide is
[334][335][336]
contraindicated
.
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: The concurrent administration of dofetilide and trimethoprim with or without sulfamethoxazole is
contraindicated.
7) Probable Mechanism: additive effects on QT prolongation; inhibition of renal tubular secretion of dofetilide
8) Literature Reports
a) Trimethoprim 160 mg in combination with sulfamethoxazole 800 mg coadministered twice daily with dofetilide 500 mcg twice daily
for four days resulted in an increase in the dofetilide area under the concentration-time curve (AUC) by 103% and a 93% increase in the
maximum concentration (Cmax). Dofetilide can cause serious ventricular arrhythmias associated with QT interval prolongation,
including torsades de pointes, which are directly related to the dofetilide plasma concentration. The concurrent administration of
[333]
dofetilide and trimethoprim is contraindicated
.
3.5.1.AJ Dolasetron
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
[297]
2) Summary: Cotrimoxazole has been shown to prolong the QTc interval at the recommended therapeutic dose
. Though citing no
data, the manufacturer of dolasetron recommends caution if dolasetron is administered with another drug which can prolong the QTc
[298]
interval
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cotrimoxazole and dolasetron is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.AK Doxepin
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Tricyclic antidepressants (TCAs) and cotrimoxazole have been shown to prolong the QTc interval at the recommended
[330][331]
therapeutic dose
. Even though no formal drug interaction studies have been done, the coadministration of tricyclic
[332]
antidepressants and other drugs known to prolong the QTc interval, such as cotrimoxazole, is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: The concurrent administration of cotrimoxazole and tricyclic antidepressants is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.AL Droperidol
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Droperidol has been shown to prolong the QTc interval at the recommended therapeutic dose. Even though no formal
drug interaction studies have been done, the coadministration of droperidol and other drugs known to prolong the QTc interval,
[365]
including cotrimoxazole, is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of droperidol and cotrimoxazole is not recommended.
7) Probable Mechanism: additive cardiac effects
3.5.1.AM Eltrombopag
1) Interaction Effect: increased eltrombopag plasma concentrations
2) Summary: Concomitant use of eltrombopag and trimethoprim, a moderate CYP2C8 inhibitor, may result in elevated eltrombopag
plasma concentrations due to inhibition of CYP2C8-mediated eltrombopag metabolism. The patient should be monitored for excessive
[410]
eltrombopag exposure when eltrombopag and trimethoprim are coadministered
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Concomitant use of eltrombopag and trimethoprim, a moderate CYP2C8 inhibitor, may result in elevated
eltrombopag plasma concentrations. Monitor the patient for excessive eltrombopag exposure when eltrombopag and trimethoprim are
[410]
coadministered .
7) Probable Mechanism: inhibition of CYP2C8-mediated eltrombopag metabolism by trimethoprim
3.5.1.AN Enalaprilat
1) Interaction Effect: hyperkalemia
2) Summary: Severe hyperkalemia has been reported with the concurrent use of angiotensin-converting enzyme inhibitors and
[443][444]
trimethoprim
.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Avoid the concurrent use of ACE inhibitors and trimethoprim, especially in patients predisposed to renal
dysfunction, or ensure careful monitoring of serum potassium. Substitution of an alternative antihypertensive agent during acute
trimethoprim use should be considered. If the ACE inhibitor is being used for nephropathy, its temporary discontinuation during
trimethoprim use for an infective process should be satisfactory.
7) Probable Mechanism: additive effects of potassium secretion inhibition and aldosterone reduction
8) Literature Reports
a) Hyperkalemia to greater than 7 mEq/L associated with azotemia (BUN 33 mg/dL, serum creatinine 3.3 mg/dL) was noted 20 days
after addition of trimethoprim-sulfamethoxazole for mild acute pyelonephritis to a stable, 3-year regimen of quinapril 20 mg daily in a
74-year-old hypertensive male. The patient was asymptomatic; an EKG did not reflect classic signs of hyperkalemia. Drug withdrawal
and specific treatment for hyperkalemia including insulin, dextrose, sodium polystyrene sulfonate, and calcium was required, with
resolution over 36 hours. Nifedipine was substituted for blood pressure control. Caution is recommended when using this combination,
[442]
especially in the elderly or those with preexisting renal dysfunction
.
b) A 40-year-old woman with double lung transplantation developed a pneumocystis carinii infection one year post-transplant.
Medications she was stabilized on included enalapril 30 mg daily. High dose trimethoprim-sulfamethoxazole (TMP-SMX) therapy (20
mg/kg/day and 100 mg/kg/day) was instituted. After nine days of concurrent therapy with TMP-SMX and enalapril, the patient's
potassium level reached 6.8 mmol/L. Both medications were discontinued and the patient required treatment for her hyperkalemic
[439]
condition
.
3.5.1.AO Enalapril Maleate
1) Interaction Effect: hyperkalemia
2) Summary: Severe hyperkalemia has been reported with the concurrent use of angiotensin-converting enzyme inhibitors and
[443][444]
trimethoprim
.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Avoid the concurrent use of ACE inhibitors and trimethoprim, especially in patients predisposed to renal
dysfunction, or ensure careful monitoring of serum potassium. Substitution of an alternative antihypertensive agent during acute
trimethoprim use should be considered. If the ACE inhibitor is being used for nephropathy, its temporary discontinuation during
trimethoprim use for an infective process should be satisfactory.
7) Probable Mechanism: additive effects of potassium secretion inhibition and aldosterone reduction
8) Literature Reports
a) Hyperkalemia to greater than 7 mEq/L associated with azotemia (BUN 33 mg/dL, serum creatinine 3.3 mg/dL) was noted 20 days
after addition of trimethoprim-sulfamethoxazole for mild acute pyelonephritis to a stable, 3-year regimen of quinapril 20 mg daily in a
74-year-old hypertensive male. The patient was asymptomatic; an EKG did not reflect classic signs of hyperkalemia. Drug withdrawal
and specific treatment for hyperkalemia including insulin, dextrose, sodium polystyrene sulfonate, and calcium was required, with
resolution over 36 hours. Nifedipine was substituted for blood pressure control. Caution is recommended when using this combination,
[442]
especially in the elderly or those with preexisting renal dysfunction
.
b) A 40-year-old woman with double lung transplantation developed a pneumocystis carinii infection one year post-transplant.
Medications she was stabilized on included enalapril 30 mg daily. High dose trimethoprim-sulfamethoxazole (TMP-SMX) therapy (20
mg/kg/day and 100 mg/kg/day) was instituted. After nine days of concurrent therapy with TMP-SMX and enalapril, the patient's
potassium level reached 6.8 mmol/L. Both medications were discontinued and the patient required treatment for her hyperkalemic
[439]
condition
.
3.5.1.AP Enflurane
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Although no formal drug interaction studies have been done, cotrimoxazole should not be coadministered with other
[264][265]
drugs which may also prolong the QTc interval, including enflurane
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cotrimoxazole and agents that may prolong the QT interval, such as
enflurane, is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.AQ Erythromycin
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Erythromycin significantly increased the mean QTc interval versus baseline in a retrospective study of 49 patients. Of 16
[360]
patients receiving erythromycin and cotrimoxazole concomitantly, 8 developed a 15% or greater increase in the QTc interval
.
[361]
Erythromycin has demonstrated QTc prolongation in combination with other drugs that prolong the QT interval
. Cotrimoxazole has
[362]
been shown to prolong the QTc interval at the recommended therapeutic dose
. Caution is advised if erythromycin and
cotrimoxazole are administered concomitantly.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Caution is advised if erythromycin and cotrimoxazole are used concomitantly. Monitor QT interval at baseline
and periodically during treatment.
7) Probable Mechanism: additive cardiac effects
8) Literature Reports
a) Erythromycin significantly increased the QTc interval compared with baseline in a retrospective study of 49 patients. The
erythromycin dose was 500 milligrams or 1 gram four times daily, with a mean of 15 doses received. Patients (n equal to 9) who
received 60 mg/kg/day or more all developed increases in QT interval of 15% or greater. For all patients, the mean QTc interval
increased from 432 milliseconds (msec) at baseline to 483 msec (p less than 0.01). In patients with delayed repolarization at baseline
(n equal to 9), the QTc interval increased from 473 msec to 525 msec (p less than 0.01). In patients with heart disease (n equal to 30),
all experienced an increase in QTc interval (mean of 15%), compared with an increase of 8% in patients without heart disease (p less
than 0.05). In 5 patients (10%), the QTc interval was severely prolonged. One patient developed torsades de pointes attributed to
[359]
erythromycin. Of 16 patients receiving cotrimoxazole concomitantly, 8 developed QT prolongation of 15% or greater
.
3.5.1.AR Flecainide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Even though no formal drug interaction studies have been done, the coadministration of Class I antiarrhythmics and other
[382]
drugs known to prolong the QTc interval is not recommended
. Cotrimoxazole has demonstrated QT prolongation at therapeutic
[383]
doses
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of Class I antiarrhythmic agents and agents that prolong the QT interval, such
as cotrimoxazole, is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.AS Fluconazole
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
[251][252]
2) Summary: Case reports have described QT prolongation and torsades de points associated with fluconazole
. Cotrimoxazole
[253]
has been shown to prolong the QTc interval in one case report
. Even though no formal drug interaction studies have been done,
caution is advised if drugs known to prolong the QT interval are used concomitantly.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Caution is advised if fluconazole and cotrimoxazole are used concomitantly.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.AT Fluoxetine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
[254][255]
2) Summary: Cotrimoxazole and fluoxetine have been shown to prolong the QTc interval at the recommended therapeutic dose
.
Even though no formal drug interaction studies have been done, the coadministration of drugs known to prolong the QTc interval is not
recommended.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cotrimoxazole and fluoxetine is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.AU Foscarnet
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Foscarnet can prolong the QT interval in some patients, which may result in ventricular tachycardia, ventricular fibrillation,
and torsades de pointes. Because cotrimoxazole may also prolong the QT interval and increase the risk of arrhythmias, the concurrent
[206]
administration of foscarnet and cotrimoxazole is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of foscarnet and cotrimoxazole is not recommended.
7) Probable Mechanism: additive cardiac effects
3.5.1.AV Fosphenytoin
1) Interaction Effect: an increased risk of phenytoin toxicity (ataxia, nystagmus, hyperreflexia, lethargy)
2) Summary: Fosphenytoin is a prodrug of phenytoin and the same interactions that occur with phenytoin are expected to occur with
[420]
fosphenytoin . Concurrent treatment with cotrimoxazole or trimethoprim may result in decreased phenytoin clearance and possibly
[421][422]
phenytoin toxicity. Sulfamethoxazole alone has little effect on phenytoin pharmacokinetics
.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Monitor the patient for evidence of phenytoin toxicity such as nystagmus and ataxia if cotrimoxazole or
trimethoprim is added to therapy. If the patient exhibits signs of toxicity, a serum phenytoin level should be considered.
7) Probable Mechanism: inhibition by trimethoprim of phenytoin metabolism
8) Literature Reports
a) Phenytoin toxicity was described in a 4-year-old epileptic girl receiving phenytoin 200 mg daily following administration of
cotrimoxazole for a respiratory tract infection. It was suspected that cotrimoxazole caused competitive inhibition of phenytoin
metabolism resulting in toxicity; the patient also received sulthiame, an inhibitor of phenytoin metabolism, which may also have
[418]
contributed to toxicity
.
b) Concurrent treatment with trimethoprim-sulfamethoxazole or trimethoprim alone has resulted in a 27% to 30% reduction in
[419][418]
phenytoin clearance and a 39% to 51% increase in phenytoin half-life
.
c) The effect of sulfamethoxazole on phenytoin metabolism was studied. A single dose of intravenous phenytoin 100 mg was
administered after one week of sulfamethoxazole 1.6 g daily. A small but significant increase in mean phenytoin half-life (624 vs. 719
minutes, p less than 0.05) was seen in the nine study subjects following sulfamethoxazole administration. The corresponding
[419]
decrease in metabolic clearance was not significant
.
3.5.1.AW Gemifloxacin
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Gemifloxacin should be avoided in patients receiving cotrimoxazole. Gemifloxacin has the potential to prolong the QT
[428]
interval in some patients
. Additive effects on QT prolongation may occur with the concomitant use of cotrimoxazole and gemifloxacin
[429]
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: The concurrent administration of two drugs that prolong the QT interval, such as gemifloxacin and
cotrimoxazole, is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.AX Glimepiride
1) Interaction Effect: excessive hypoglycemia
2) Summary: The hypoglycemic potential of glimepiride may be increased with concomitant sulfonamide therapy. The mechanism of
this interaction is unknown. During concurrent therapy, monitor blood glucose levels closely and observe for signs and symptoms of
hypoglycemia (eg, fatigue, restlessness, malaise, irritability, weakness, increased perspiration). Lower doses of glimepiride may be
required to avoid excessive hypoglycemia. When sulfonamide therapy is withdrawn, careful monitoring of the patient is recommended
[318]
to observe for loss of glucose control .
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: During concurrent therapy, monitor blood glucose levels closely and observe for signs and symptoms of
hypoglycemia (eg, fatigue, restlessness, malaise, irritability, weakness, increased perspiration). Lower doses of glimepiride may be
required to avoid excessive hypoglycemia. When sulfonamide therapy is withdrawn, careful monitoring of the patient is recommended
[318]
to observe for loss of glucose control .
7) Probable Mechanism: unknown
3.5.1.AY Glipizide
1) Interaction Effect: enhanced hypoglycemic effects
2) Summary: There are several case reports related to combined use of sulfonamides and sulfonylureas resulting in profound
hypoglycemia requiring hospitalization. The proposed mechanism of action is displacement of the sulfonylurea from protein-binding
[290][291]
sites
.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Avoid the use of sulfonamide antibiotics in patients who are taking sulfonylureas. If concomitant therapy is
required, closely monitor blood glucose. Emergency treatment of a hypoglycemic episode may be required.
7) Probable Mechanism: potentiation of hypoglycemic effect of the sulfonylureas caused by displacement from protein-binding sites by
sulfonamides
8) Literature Reports
[288]
a) Symptomatic hypoglycemia developed in an 83-year-old man three days after cotrimoxazole was added to glipizide therapy
.
This patient may have been at increased risk for this drug interaction because of increased age and a history of alcohol abuse. This
type of interaction has also been reported with glyburide and cotrimoxazole, as well as chlorpropamide and cotrimoxazole. Monitor the
patient for hypoglycemia if cotrimoxazole is added to oral hypoglycemic therapy.
b) A 69-year-old black female who was stable on cimetidine 300 mg orally at bedtime, docusate 200 mg daily, hydrochlorothiazide 50
mg daily, and chlorpropamide 500 mg daily orally, was hospitalized two days after starting cotrimoxazole two tablets orally twice a day.
Her laboratory results on admission were a blood glucose of 48 mg/dL, blood pressure of 174/90, and serum sodium of 118 mEq/L; she
[237]
was nauseous and vomiting. The patient was discharged after seven days of hospitalization
.
c) A 77-year-old man on chlorpropamide and phenformin was started on sulfisoxazole. The next day he was hospitalized with
[239]
hypoglycemia
.
d) A 67-year-old diabetic stable on chlorpropamide 250 mg daily was admitted to a hospital two days after starting on sulfamethazine
[238]
with a blood glucose of 10 mg/dL. She was semicomatose for a week and mentally dull for a month
.
e) Two patients on tolbutamide who were started on sulfisoxazole experienced hypoglycemia and were hospitalized. One of the
[240]
patients, a 47-year-old man, died with a blood glucose of 8 mg/dL
.
f) In a randomized, crossover study, seven days of cotrimoxazole was found to have no significant effect on area under the
concentration-time curve (AUC) or clearance of glipizide after a single dose in healthy male volunteers. No effect on 24-hour glucose
[289]
AUC was observed. The half-life of glipizide was significantly increased, but this difference is of doubtful clinical significance
.
3.5.1.AZ Glyburide
1) Interaction Effect: excessive hypoglycemia
2) Summary: The hypoglycemic potential of glyburide may be increased with concomitant sulfonamide therapy. The mechanism of this
interaction is unknown. Blood glucose levels should be closely monitored when a sulfonamide is added in a patient receiving glyburide.
Lower doses of glyburide may be required to avoid excessive hypoglycemia. When sulfonamide therapy is withdrawn, careful
[223]
monitoring of the patient is recommended to observe for loss of glucose control
.
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The hypoglycemic potential of glyburide may be increased with concomitant sulfonamide therapy. Blood
glucose levels should be closely monitored when a sulfonamide is added in a patient receiving glyburide. Lower doses of glyburide may
be required to avoid excessive hypoglycemia. When sulfonamide therapy is withdrawn, careful monitoring of the patient is
recommended to observe for loss of glucose control
7) Probable Mechanism: unknown
[223]
.
3.5.1.BA Glyburide
1) Interaction Effect: enhanced hypoglycemic effects
2) Summary: There are several case reports related to combined use of sulfonamides and sulfonylureas resulting in profound
hypoglycemia requiring hospitalization. The proposed mechanism of action is displacement of the sulfonylurea from protein-binding
[229][230]
sites
. However, no pharmacokinetic interaction between cotrimoxazole and glyburide was detected in eight patients with type II
diabetes in an open label study. In addition, there was no significant change in plasma insulin or glucose levels caused by the addition
[231]
of cotrimoxazole to glyburide therapy
.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Avoid the use of sulfonamide antibiotics in patients who are taking sulfonylureas. If concomitant therapy is
required, closely monitor blood glucose. Emergency treatment of a hypoglycemic episode may be required.
7) Probable Mechanism: potentiation of hypoglycemic effect of the sulfonylureas caused by displacement from protein-binding sites by
sulfonamides
8) Literature Reports
a) A brief review of some of the case reports relating to these interactions follows: (1) A 69-year-old black female who was stable on
cimetidine 300 mg orally at bedtime, docusate 200 mg daily, hydrochlorothiazide 50 mg daily, and chlorpropamide 500 mg daily orally,
was hospitalized two days after starting cotrimoxazole two tablets orally twice a day. Her laboratory results on admission were a blood
glucose of 48 mg/dL, blood pressure of 174/90, and serum sodium of 118 mEq/L; she was nauseous and vomiting. The patient was
[225]
discharged after seven days of hospitalization
. (2) A 67-year-old diabetic stable on chlorpropamide 250 mg daily was admitted to a
hospital two days after starting on sulfamethazine with a blood glucose of 10 mg/dL. She was semicomatose for a week and mentally
[226]
dull for a month
. (3) A 77-year-old man on chlorpropamide and phenformin was started on sulfisoxazole. The next day he was
[227]
[228]
hospitalized with hypoglycemia
. (4)
describe two patients on tolbutamide who were started on sulfisoxazole. They experienced
hypoglycemia and were hospitalized. One of the patients, a 47-year-old man, died with a blood glucose of 8 mg/dL.
3.5.1.BB Halofantrine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Halofantrine can prolong the QT interval in some patients, which may result in ventricular tachycardia, ventricular
fibrillation, and torsades de pointes. Because cotrimoxazole may also prolong the QT interval and increase the risk of arrhythmias, the
[293][294]
concurrent administration of halofantrine with cotrimoxazole is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of halofantrine and cotrimoxazole is not recommended.
7) Probable Mechanism: additive cardiac effects
3.5.1.BC Haloperidol
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
[341]
2) Summary: Cotrimoxazole has been shown to prolong the QTc interval at the recommended therapeutic dose
. Even though no
formal drug interaction studies have been done, the coadministration of antipsychotics and other drugs known to prolong the QTc
interval, including cotrimoxazole, is not recommended. Several antipsychotic agents have demonstrated QT prolongation including
[342]
[343]
[344]
[345]
[346]
[347]
[348]
amisulpride
, haloperidol
, quetiapine
, risperidone
, sertindole
, sultopride
, and zotepine
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cotrimoxazole and antipsychotics is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.BD Halothane
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Although no formal drug interaction studies have been done, cotrimoxazole should not be administered with other drugs
[262][263]
which may also prolong the QTc interval, including halothane
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cotrimoxazole and agents that may prolong the QT interval, such as
halothane, is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.BE Hydroquinidine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Even though no formal drug interaction studies have been done, the coadministration of Class IA antiarrhythmics and
[321]
other drugs known to prolong the QTc interval is not recommended
. Cotrimoxazole has demonstrated QT prolongation at
[322]
therapeutic doses
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: The concurrent administration of Class IA antiarrhythmic agents and agents that prolong the QT interval, such
as cotrimoxazole, is not recommended. Monitor serum procainamide and NAPA serum levels and for signs of procainamide toxicity
(cardiac arrhythmias, hypotension, CNS depression). Dosage adjustments may be made depending on serum levels and patient
response.
7) Probable Mechanism: additive effects on QT prolongation
8) Literature Reports
a) Eight healthy men received oral sustained-release procainamide 500 mg every six hours for three days, alone and with oral
trimethoprim 200 mg daily for four days. Trimethoprim coadministration increased the area under the concentration-time curve (AUC) of
procainamide from 19.9 mg/h/L to 32.5 mg/h/L, representing a 63% increase. Mean steady-state procainamide concentrations also
increased from 1.6 mcg/mL to 2.7 mcg/mL. Likewise, trimethoprim increased the AUC of N-acetylprocainamide (NAPA), the active
metabolite of procainamide, by 52% (14.1 mg/hr/L vs. 21.4 mg/hr/L). NAPA plasma concentrations increased from 1.2 mcg/mL to 1.8
mcg/mL. Renal clearance of procainamide and NAPA decreased by 47% and 13%, respectively. A small but significant increase in the
[319]
QTc interval was noted with procainamide administration, and this interval further increased with trimethoprim cotherapy
.
[320]
b) Ten healthy volunteers participated in an open, randomized, placebo-controlled, two-period crossover study by
to determine the
effects of trimethoprim and procainamide coadministration. Subjects received trimethoprim 100 mg or placebo twice daily on days 1
through 3 of each study period. On day 4, procainamide 1000 mg was administered orally as a single dose with trimethoprim 200 mg or
placebo, and another dose of trimethoprim 100 mg or placebo was given 12 hours later. Each treatment period was separated by at
least a one-week washout period. Trimethoprim decreased the renal clearance of procainamide by 45% (487 mL/min vs. 267 mL/min)
and also decreased the clearance of the active metabolite of procainamide, N-acetylprocainamide (NAPA), by 26% (275 mL/min vs.
192 mL/min) as compared to placebo. The area under the concentration-time curve (AUC) increased by 39% for procainamide (19.8
mg/h/L vs. 27.6 mg/h/L) and 27% for NAPA (9.1 mg/h/L vs. 11.4 mg/h/L). Procainamide and NAPA are weak bases and undergo
extensive renal tubular secretion. Trimethoprim is 50% to 60% excreted unchanged in the urine via glomerular filtration, tubular
secretion, and reabsorption. In the case of trimethoprim and procainamide coadministration, both drugs may be competing for tubular
secretion, causing a saturation of this route of elimination. This results in procainamide accumulation, and the potential for
procainamide toxicity.
3.5.1.BF Ibutilide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Class III antiarrhythmics and cotrimoxazole have been shown to prolong the QTc interval at the recommended
[351]
therapeutic dose . The coadministration of Class III antiarrhythmic agents and other drugs known to prolong the QTc interval,
[352]
including cotrimoxazole, is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of Class III antiarrhythmic agents and agents that prolong the QT interval, such
as cotrimoxazole, is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.BG Imipramine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Tricyclic antidepressants (TCAs) and cotrimoxazole have been shown to prolong the QTc interval at the recommended
[330][331]
therapeutic dose
. Even though no formal drug interaction studies have been done, the coadministration of tricyclic
[332]
antidepressants and other drugs known to prolong the QTc interval, such as cotrimoxazole, is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: The concurrent administration of cotrimoxazole and tricyclic antidepressants is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.BH Isoflurane
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Although no formal drug interaction studies have been done, cotrimoxazole should not be administered with other drugs
[305][306]
which may also prolong the QTc interval, including isoflurane
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cotrimoxazole and agents that may prolong the QT interval, such as
isoflurane, is not recommended.
7) Probable Mechanism: additive effect on QT prolongation
3.5.1.BI Isradipine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Isradipine can prolong the QT interval in some patients, which may result in ventricular tachycardia, ventricular fibrillation,
and torsades de pointes. Because cotrimoxazole may also prolong the QT interval and increase the risk of arrhythmias
[208]
concurrent administration of isradipine with cotrimoxazole is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of isradipine and cotrimoxazole is not recommended.
7) Probable Mechanism: additive cardiac effects
[207]
, the
3.5.1.BJ Lamivudine
1) Interaction Effect: an increased risk of lamivudine adverse effects
2) Summary: A single-dose, controlled study of sulfamethoxazole/trimethoprim coadministered with lamivudine found increased
[234]
lamivudine serum concentrations
. The clinical significance of this finding was not explored. Sulfamethoxazole 800 mg/trimethoprim
160 mg once daily increases lamivudine exposure (AUC). The effect of higher doses of sulfamethoxazole/trimethoprim on lamivudine
[235]
pharmacokinetics has not been investigated
. At doses prescribed to prevent pneumocystis carinii pneumonia, it is unlikely that
sulfamethoxazole/trimethoprim will cause a significant increase in lamivudine concentrations. The effects on lamivudine
pharmacokinetics at higher doses of sulfamethoxazole/trimethoprim used to treat pneumocystis carinii pneumonia need to be
[236]
investigated
.
3) Severity: minor
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Clinicians should be aware that the combined use of sulfamethoxazole/trimethoprim (cotrimoxazole) and
lamivudine may cause elevated lamivudine serum concentrations. Patients who are given this combination of medications should be
followed for excessive adverse effects related to lamivudine (gastrointestinal disturbances, headache, fatigue, myalgia, and rarely
neutropenia). No change in dose of either drug is recommended.
7) Probable Mechanism: competition for renal excretion
8) Literature Reports
a) In a randomized, open-label, crossover study, 14 HIV-infected patients experienced a 43% increase in lamivudine AUC, a 30%
decrease in lamivudine oral clearance, and a 35% reduction in lamivudine renal clearance when this agent was coadministered with
sulfamethoxazole/trimethoprim. In the first arm of the study, each patient received one single 300 mg dose of lamivudine. The second
arm included 5 days of a once-daily dose of sulfamethoxazole 800 mg/trimethoprim 160 mg with a single dose of lamivudine 300 mg
[232]
on the fifth day. The pharmacokinetics of sulfamethoxazole and trimethoprim were unaffected by lamivudine
.
b) Trimethoprim increases the lamivudine AUC through competition for renal excretion in the organic cationic transport system of the
kidneys. Due to the high cost of antiviral therapy, it would seem tempting to consider lower doses of lamivudine when used in
combination with trimethoprim. However, this is not recommended because of the high interpatient variability of lamivudine
[233]
bioavailability when used alone or in combination with sulfamethoxazole/trimethoprim
.
3.5.1.BK Leucovorin
1) Interaction Effect: an increased rate of treatment failure
2) Summary: In a placebo-controlled study, the concurrent administration of leucovorin and trimethoprim-sulfamethoxazole to HIV[292]
infected patients with pneumocystis carnii pneumonia resulted in increased rates of treatment failure and morbidity
.
3) Severity: minor
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: If concomitant therapy is necessary, monitor patients for treatment efficacy.
7) Probable Mechanism: unknown
3.5.1.BL Levomethadyl
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Levomethadyl can prolong the QT interval in some patients, which may result in ventricular tachycardia, ventricular
fibrillation, and torsades de pointes. Because cotrimoxazole may also prolong the QT interval and increase the risk of arrhythmias, the
[256][257]
concurrent administration of levomethadyl with cotrimoxazole is contraindicated
.
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of levomethadyl and cotrimoxazole is contraindicated.
7) Probable Mechanism: additive cardiac effects
3.5.1.BM Lidoflazine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
[303][304]
2) Summary: Lidoflazine and cotrimoxazole have been shown to prolong the QTc interval at the recommended therapeutic dose
.
Even though no formal drug interaction studies have been done, the coadministration of drugs known to prolong the QTc interval is not
recommended.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of lidoflazine and cotrimoxazole is not recommended.
7) Probable Mechanism: additive effect on QT prolongation
3.5.1.BN L-Methylfolate
1) Interaction Effect: decreased l-methylfolate serum levels
2) Summary: L-methylfolate is the bioactive form of folic acid and is used as a medical food. Although no studies have been conducted,
coadministration of l-methylfolate with trimethoprim may decrease folate absorption, thereby reducing the amount of active folate
[427]
available .
3) Severity: minor
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Caution is advised if l-methylfolate is prescribed to patients receiving trimethoprim as concomitant use may
cause decreased plasma folate levels.
7) Probable Mechanism: decreased folate absorption
3.5.1.BO Lorcainide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Even though no formal drug interaction studies have been done, the coadministration of Class I antiarrhythmics and other
[382]
drugs known to prolong the QTc interval is not recommended
. Cotrimoxazole has demonstrated QT prolongation at therapeutic
[383]
doses
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of Class I antiarrhythmic agents and agents that prolong the QT interval, such
as cotrimoxazole, is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.BP Mefloquine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
[245]
2) Summary: Cotrimoxazole has been shown to prolong the QTc interval at the recommended therapeutic dose . Even though no
formal drug interaction studies have been done, the coadministration of mefloquine with other drugs which can prolong the QTc interval
[246]
is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cotrimoxazole and mefloquine is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.BQ Mesoridazine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Although citing no data, the manufacturer of mesoridazine states that concomitant use with other drugs which prolong the
[301]
[302]
QT interval is contraindicated . Q and T wave distortions have been observed in patients taking cotrimoxazole
. Other
phenothiazines may have similar effects, though no reports are available.
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Due to the potential for additive effects on the QT interval, the concurrent administration of cotrimoxazole and
mesoridazine is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.BR Metformin
1) Interaction Effect: an increase in metformin plasma concentrations
2) Summary: Caution is warranted if metformin is to be coadministered with cationic drugs. Elevated serum levels of metformin were
[414][415]
found when cimetidine, a cationic agent eliminated by renal tubular secretion, was given concomitantly with metformin
. Because
trimethoprim is also a cationic drug, it is possible that combined administration of trimethoprim with metformin could result in an
increase in peak metformin plasma and whole blood concentrations and plasma and whole blood metformin area under the
concentration-time curve (AUC).
3) Severity: moderate
4) Onset: rapid
5) Substantiation: theoretical
6) Clinical Management: Careful patient monitoring and dose adjustment of metformin and/or trimethoprim is recommended in patients
who are taking cationic medications that are excreted via the proximal renal tubular secretory system.
7) Probable Mechanism: reduced metformin clearance
8) Literature Reports
a) The cationic drug cimetidine was coadministered with metformin in single and multiple-dose studies in healthy volunteers. Effects on
metformin included a 60% increase in peak plasma and whole blood concentrations and a 40% increase in area under the
concentration-time curve (AUC). Metformin half-life was not affected. Cimetidine pharmacokinetics were unaltered. The postulated
mechanism of this interaction is competition between metformin and cimetidine for renal tubular secretion. Cationic drugs that are
eliminated by renal tubular secretion, such as trimethoprim, theoretically have the potential for interaction with metformin by competing
[412][413]
for common renal tubular transport systems
.
3.5.1.BS Methotrexate
1) Interaction Effect: an increased risk of methotrexate toxicity (myelotoxicity, pancytopenia, megaloblastic anemia)
2) Summary: Coadministered sulfamethoxazole/trimethoprim may increase methotrexate toxicity, often manifesting as myelotoxicity
and pancytopenia. The mechanism of this interaction is thought to be additive inhibition of dihydrofolate reductase by methotrexate and
trimethoprim. In addition, sulfamethoxazole may increase free serum levels of methotrexate by displacement of methotrexate from
[374][375][376][377][378][379][380][381]
plasma protein binding sites or decreased renal tubular elimination
.
3) Severity: major
4) Onset: delayed
5) Substantiation: established
6) Clinical Management: If possible, avoid concurrent administration of methotrexate and sulfamethoxazole/trimethoprim. Should it
become clinically necessary to coadminister these agents, aggressively monitor patients for hematologic abnormalities. Folinic acid has
been used to treat megaloblastic anemia.
7) Probable Mechanism: synergistic anti-folate effects, protein binding displacement, decreased renal tubular elimination
8) Literature Reports
[369]
a) A 70-year-old woman was taking long-term, low-dose methotrexate for psoriasis
. After diagnosing acute bronchitis, her general
practitioner prescribed sulfamethoxazole/trimethoprim for her. She developed severe pancytopenia with concurrent use of
methotrexate and sulfamethoxazole/trimethoprim.
b) A pharmacokinetic study found a 66% increase in systemic exposure to methotrexate when this agent was given concurrently with
sulfamethoxazole/trimethoprim. Methotrexate concentrations were measured in nine children with acute lymphoblastic leukemia
during methotrexate dosing alone and during coadministration with sulfamethoxazole/trimethoprim. The free methotrexate fraction
increased from 37.4% to 52.2% when sulfamethoxazole/trimethoprim was added to methotrexate therapy, and free methotrexate renal
clearance decreased from 12.1 to 5.6 mL/kg/min during multidrug administration. Serum concentrations of
[370]
sulfamethoxazole/trimethoprim and the percentage decrease in renal clearance of free methotrexate were closely correlated
.
c) An 81-year-old woman stabilized on methotrexate for rheumatoid arthritis was diagnosed with inoperable cancer of the bladder, and
was placed on trimethoprim 100 mg daily with an indwelling catheter. Two months later, she was readmitted with severe pancytopenia
after her general practitioner increased her trimethoprim dose to 200 mg daily for symptoms of a urinary tract infection. Despite
aggressive treatment with granulocyte colony stimulating factor, the patient's bone marrow did not recover and she died of
[371]
bronchopneumonia
.
d) An 80-year-old female was started on intramuscular methotrexate therapy for deteriorating psoriasis. Blood counts were normal
prior to the sixth injection of methotrexate, but five days later she presented with painful, ulcerated areas and contact bleeding over her
thighs, buttocks, back, and upper chest. Blood work revealed severe neutropenia (white cell count 0.9 x 10(9)/L, neutrophils 0.3 x
10(9)/L). Five days prior to the sixth injection of methotrexate, the patient had been started on trimethoprim 200 mg twice daily for a
[372]
urinary tract infection. Her skin ulcerations and leukopenia were attributed to an interaction between methotrexate and trimethoprim
.
e) A case report describes a patient who developed megaloblastic pancytopenia secondary to methotrexate and
sulfamethoxazole/trimethoprim. A 58-year-old male with a history of rheumatoid arthritis presented with symptoms of prostatitis. The
patient was started on a 6-week regimen of sulfamethoxazole/trimethoprim. Four weeks later symptoms of prostatisis resolved, but the
patient had hematuria, fatigue, decreased appetite, and orthostatic dizziness. A CBC demonstrated a hemoglobin of 72 g/L, a
hematocrit of 0.21, a leukocyte count of 2,000,000/L, and a platelet count of 50,000/L with macrocytic red cells, absence of
reticulocytes, and markedly hypersegmented neutrophils on a peripheral smear. All drugs were discontinued and the patient was
hospitalized for transfusion of platelets and packed red blood cells. The bone marrow revealed hypocellularity with megaloblastic redcell precursors and hypersegmented polyps. The patient was diagnosed with megaloblastic pancytopenia, secondary to methotrexate
and sulfamethoxazole/trimethoprim. The patient received leucovorin 25 mg every 6 hours and within 96 hours the patients complete
blood count showed a hemoglobin of 104 g/L, a hematocrit of 0.32, a leukocyte count of 7,100,000/L, and a platelet count of
218,000,000,000/L. Clinicians should be aware of the possibility of life-threatening pancytopenia when methotrexate is used
[373]
concomitantly with trimethoprim
.
3.5.1.BT Nortriptyline
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Tricyclic antidepressants (TCAs) and cotrimoxazole have been shown to prolong the QTc interval at the recommended
[330][331]
therapeutic dose
. Even though no formal drug interaction studies have been done, the coadministration of tricyclic
[332]
antidepressants and other drugs known to prolong the QTc interval, such as cotrimoxazole, is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: The concurrent administration of cotrimoxazole and tricyclic antidepressants is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.BU Octreotide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
[258][259]
2) Summary: Octreotide and cotrimoxazole have been shown to prolong the QTc interval at the recommended therapeutic dose
.
Even though no formal drug interaction studies have been done, the coadministration of drugs known to prolong the QTc interval is not
recommended.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of octreotide and cotrimoxazole is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.BV Pentamidine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Pentamidine and cotrimoxazole have been shown to prolong the QTc interval at the recommended therapeutic
[266][267]
dose
. Even though no formal drug interaction studies have been done, the coadministration of drugs known to prolong the QTc
interval is not recommended.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of pentamidine and cotrimoxazole is not recommended.
7) Probable Mechanism: additive effect on QT prolongation
3.5.1.BW Phenprocoumon
1) Interaction Effect: increased risk of bleeding
2) Summary: Some sulfonamides may impair the hepatic metabolism of oral anticoagulants resulting in enhanced
[219][220][221][222]
hypoprothrombinemic responses
.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: In patients receiving oral anticoagulant therapy, the prothrombin time ratio or international normalized ratio
(INR) should be closely monitored with the addition and withdrawal of sulfamethoxazole, and should be reassessed periodically during
concurrent therapy. Downward adjustments of the phenprocoumon dose may be necessary in order to maintain the desired level of
anticoagulation.
7) Probable Mechanism: decreased phenprocoumon metabolism, displacement of phenprocoumon from protein binding sites
3.5.1.BX Phenytoin
1) Interaction Effect: an increased risk of phenytoin toxicity (ataxia, hyperreflexia, nystagmus, tremors)
2) Summary: Concurrent treatment with sulfamethoxazole/trimethoprim or trimethoprim may result in decreased phenytoin clearance
[433][434]
and possibly phenytoin toxicity. Sulfamethoxazole alone has little effect on phenytoin pharmacokinetics
. Acute hepatic failure
[435]
following administration of phenytoin and sulfamethoxazole/trimethoprim was reported
.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Monitor the patient for evidence of phenytoin toxicity such as nystagmus and ataxia if
sulfamethoxazole/trimethoprim or trimethoprim is added to therapy. If the patient exhibits signs of toxicity, a serum phenytoin level
should be considered.
7) Probable Mechanism: inhibition by trimethoprim of phenytoin metabolism
8) Literature Reports
a) Phenytoin toxicity was described in a 4-year-old epileptic girl receiving phenytoin 200 mg/day following administration of
sulfamethoxazole/trimethoprim for a respiratory tract infection. It was suspected that sulfamethoxazole/trimethoprim caused
competitive inhibition of phenytoin metabolism resulting in toxicity; the patient also received sulthiame, an inhibitor of phenytoin
[430]
metabolism, which may also have contributed to toxicity
.
b) Concurrent treatment with sulfamethoxazole/trimethoprim or trimethoprim alone has resulted in a 27% to 30% reduction in
[431][430]
phenytoin clearance and a 39% to 51% increase in phenytoin half-life
.
c) The effect of sulfamethoxazole on phenytoin metabolism was studied. A single dose of phenytoin 100 mg IV was administered
after 1 week of sulfamethoxazole 1.6 g/day. A small but significant increase in mean phenytoin half-life (624 vs 719 minutes, p less
than 0.05) was seen in the 9 study subjects following sulfamethoxazole administration. The corresponding decrease in metabolic
[431]
clearance was not significant
.
d) A case report describes a 60-year-old patient who suffered massive hepatic necrosis following exposure to phenytoin and
sulfamethoxazole/trimethoprim. The patients medical history consisted of untreated hypertension and diabetes of unknown duration.
After inferior vena caval filter placement for deep venous thrombosis prophylaxis, treatment with phenytoin and cimetidine was initiated.
The patient was treated for a urinary tract infection with sulfamethoxazole 800 mg/trimethoprim 400 mg twice daily. On day 21, she
developed a spiking fever and change in mental status. Alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase,
total bilirubin, and gamma-glutamyl transferase levels were all markedly elevated. The patient was treated for possible urosepsis with
ceftriaxone. Sulfamethoxazole/trimethoprim, phenytoin and cimetidine were discontinued. On day 24, the patients temperature
increased. On day 26, the patients liver enzymes dramatically increased and the patient went into hypotensive shock. Ceftriaxone was
discontinued and imipenem/cilastatin and vancomycin were administered. The patient died after developing renal and hepatic
insufficiency. The author concludes that the temporal sequence of clinical symptoms, concurrent elevations in hepatic enzymes, as well
as a histologic picture of massive centriacinar necrosis suggest that phenytoin may have initiated the hepatic damage, but that
[432]
sulfamethoxazole/trimethoprim was responsible for the patient's fulminant hepatic failure
.
3.5.1.BY Pimozide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
[389]
2) Summary: Cotrimoxazole has been shown to prolong the QTc interval at the recommended therapeutic dose
. Even though no
formal drug interaction studies have been done, the manufacturer of pimozide warns against its administration with other drugs which
[390]
are also known to prolong the QTc interval, including cotrimoxazole
.
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of agents that prolong the QT interval, such as cotrimoxazole and pimozide, is
contraindicated.
7) Probable Mechanism: additive cardiac effects
8) Literature Reports
a) In experimental studies of conditions other than Tourette's Disorder, sudden, unexpected deaths have occurred. The patients were
receiving pimozide dosages of approximately 1 mg per kg. One possible mechanism for such deaths is prolongation of the QT interval
predisposing patients to ventricular arrhythmia. The manufacturer recommends that an electrocardiogram be performed before
[388]
pimozide treatment is initiated and periodically thereafter, especially during the period of dose adjustment
.
3.5.1.BZ Pirmenol
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Even though no formal drug interaction studies have been done, the coadministration of Class IA antiarrhythmics and
[321]
other drugs known to prolong the QTc interval is not recommended
. Cotrimoxazole has demonstrated QT prolongation at
[322]
therapeutic doses
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: The concurrent administration of Class IA antiarrhythmic agents and agents that prolong the QT interval, such
as cotrimoxazole, is not recommended. Monitor serum procainamide and NAPA serum levels and for signs of procainamide toxicity
(cardiac arrhythmias, hypotension, CNS depression). Dosage adjustments may be made depending on serum levels and patient
response.
7) Probable Mechanism: additive effects on QT prolongation
8) Literature Reports
a) Eight healthy men received oral sustained-release procainamide 500 mg every six hours for three days, alone and with oral
trimethoprim 200 mg daily for four days. Trimethoprim coadministration increased the area under the concentration-time curve (AUC) of
procainamide from 19.9 mg/h/L to 32.5 mg/h/L, representing a 63% increase. Mean steady-state procainamide concentrations also
increased from 1.6 mcg/mL to 2.7 mcg/mL. Likewise, trimethoprim increased the AUC of N-acetylprocainamide (NAPA), the active
metabolite of procainamide, by 52% (14.1 mg/hr/L vs. 21.4 mg/hr/L). NAPA plasma concentrations increased from 1.2 mcg/mL to 1.8
mcg/mL. Renal clearance of procainamide and NAPA decreased by 47% and 13%, respectively. A small but significant increase in the
[319]
QTc interval was noted with procainamide administration, and this interval further increased with trimethoprim cotherapy
.
[320]
b) Ten healthy volunteers participated in an open, randomized, placebo-controlled, two-period crossover study by
to determine the
effects of trimethoprim and procainamide coadministration. Subjects received trimethoprim 100 mg or placebo twice daily on days 1
through 3 of each study period. On day 4, procainamide 1000 mg was administered orally as a single dose with trimethoprim 200 mg or
placebo, and another dose of trimethoprim 100 mg or placebo was given 12 hours later. Each treatment period was separated by at
least a one-week washout period. Trimethoprim decreased the renal clearance of procainamide by 45% (487 mL/min vs. 267 mL/min)
and also decreased the clearance of the active metabolite of procainamide, N-acetylprocainamide (NAPA), by 26% (275 mL/min vs.
192 mL/min) as compared to placebo. The area under the concentration-time curve (AUC) increased by 39% for procainamide (19.8
mg/h/L vs. 27.6 mg/h/L) and 27% for NAPA (9.1 mg/h/L vs. 11.4 mg/h/L). Procainamide and NAPA are weak bases and undergo
extensive renal tubular secretion. Trimethoprim is 50% to 60% excreted unchanged in the urine via glomerular filtration, tubular
secretion, and reabsorption. In the case of trimethoprim and procainamide coadministration, both drugs may be competing for tubular
secretion, causing a saturation of this route of elimination. This results in procainamide accumulation, and the potential for
procainamide toxicity.
3.5.1.CA Porfimer
1) Interaction Effect: excessive intracellular damage in photosensitized tissues
2) Summary: Coadministration of porfimer with other photosensitizing agents, including sulfonamides, may increase the severity of
[224]
photosensitivity reactions and lead to excessive tissue damage
. Caution should be used if sulfamethoxazole is to be given to
patients receiving porfimer for photodynamic therapy.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Patients who are receiving sulfonamide therapy along with photodynamic therapy should be counseled to
avoid exposure of skin and eyes to direct sunlight or bright indoor light for 30 days after administration of porfimer. Application of
sunscreens does not protect against photosensitivity reactions.
7) Probable Mechanism: additive photosensitizing effects
3.5.1.CB Prajmaline
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Even though no formal drug interaction studies have been done, the coadministration of Class IA antiarrhythmics and
[321]
other drugs known to prolong the QTc interval is not recommended
. Cotrimoxazole has demonstrated QT prolongation at
[322]
therapeutic doses
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: The concurrent administration of Class IA antiarrhythmic agents and agents that prolong the QT interval, such
as cotrimoxazole, is not recommended. Monitor serum procainamide and NAPA serum levels and for signs of procainamide toxicity
(cardiac arrhythmias, hypotension, CNS depression). Dosage adjustments may be made depending on serum levels and patient
response.
7) Probable Mechanism: additive effects on QT prolongation
8) Literature Reports
a) Eight healthy men received oral sustained-release procainamide 500 mg every six hours for three days, alone and with oral
trimethoprim 200 mg daily for four days. Trimethoprim coadministration increased the area under the concentration-time curve (AUC) of
procainamide from 19.9 mg/h/L to 32.5 mg/h/L, representing a 63% increase. Mean steady-state procainamide concentrations also
increased from 1.6 mcg/mL to 2.7 mcg/mL. Likewise, trimethoprim increased the AUC of N-acetylprocainamide (NAPA), the active
metabolite of procainamide, by 52% (14.1 mg/hr/L vs. 21.4 mg/hr/L). NAPA plasma concentrations increased from 1.2 mcg/mL to 1.8
mcg/mL. Renal clearance of procainamide and NAPA decreased by 47% and 13%, respectively. A small but significant increase in the
[319]
QTc interval was noted with procainamide administration, and this interval further increased with trimethoprim cotherapy
.
[320]
b) Ten healthy volunteers participated in an open, randomized, placebo-controlled, two-period crossover study by
to determine the
effects of trimethoprim and procainamide coadministration. Subjects received trimethoprim 100 mg or placebo twice daily on days 1
through 3 of each study period. On day 4, procainamide 1000 mg was administered orally as a single dose with trimethoprim 200 mg or
placebo, and another dose of trimethoprim 100 mg or placebo was given 12 hours later. Each treatment period was separated by at
least a one-week washout period. Trimethoprim decreased the renal clearance of procainamide by 45% (487 mL/min vs. 267 mL/min)
and also decreased the clearance of the active metabolite of procainamide, N-acetylprocainamide (NAPA), by 26% (275 mL/min vs.
192 mL/min) as compared to placebo. The area under the concentration-time curve (AUC) increased by 39% for procainamide (19.8
mg/h/L vs. 27.6 mg/h/L) and 27% for NAPA (9.1 mg/h/L vs. 11.4 mg/h/L). Procainamide and NAPA are weak bases and undergo
extensive renal tubular secretion. Trimethoprim is 50% to 60% excreted unchanged in the urine via glomerular filtration, tubular
secretion, and reabsorption. In the case of trimethoprim and procainamide coadministration, both drugs may be competing for tubular
secretion, causing a saturation of this route of elimination. This results in procainamide accumulation, and the potential for
procainamide toxicity.
3.5.1.CC Pralatrexate
1) Interaction Effect: increased pralatrexate exposure
2) Summary: Sulfamethoxazole/trimethoprim may inhibit the renal elimination of pralatrexate, leading to increased serum
[307]
concentrations of pralatrexate
. If administered concomitantly, monitor the patient for systemic toxicity due to increased drug
exposure.
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Caution is warranted with the concomitant use of and sulfamethoxazole/trimethoprim and pralatrexate. The
combination of pralatrexate and sulfamethoxazole/trimethoprim may lead to increased serum concentrations of pralatrexate due to
[307]
decreased renal clearance . If administered concomitantly, monitor the patient for systemic toxicity due to increased drug exposure.
7) Probable Mechanism: decreased renal clearance
3.5.1.CD Probucol
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
[273][274]
2) Summary: Cotrimoxazole and probucol have been shown to prolong the QTc interval at the recommended therapeutic dose
.
Even though no formal drug interaction studies have been done, the coadministration of drugs known to prolong the QTc interval is not
recommended.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cotrimoxazole and probucol is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.CE Procainamide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Even though no formal drug interaction studies have been done, the coadministration of Class IA antiarrhythmics and
[321]
other drugs known to prolong the QTc interval is not recommended
. Cotrimoxazole has demonstrated QT prolongation at
[322]
therapeutic doses
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: The concurrent administration of Class IA antiarrhythmic agents and agents that prolong the QT interval, such
as cotrimoxazole, is not recommended. Monitor serum procainamide and NAPA serum levels and for signs of procainamide toxicity
(cardiac arrhythmias, hypotension, CNS depression). Dosage adjustments may be made depending on serum levels and patient
response.
7) Probable Mechanism: additive effects on QT prolongation
8) Literature Reports
a) Eight healthy men received oral sustained-release procainamide 500 mg every six hours for three days, alone and with oral
trimethoprim 200 mg daily for four days. Trimethoprim coadministration increased the area under the concentration-time curve (AUC) of
procainamide from 19.9 mg/h/L to 32.5 mg/h/L, representing a 63% increase. Mean steady-state procainamide concentrations also
increased from 1.6 mcg/mL to 2.7 mcg/mL. Likewise, trimethoprim increased the AUC of N-acetylprocainamide (NAPA), the active
metabolite of procainamide, by 52% (14.1 mg/hr/L vs. 21.4 mg/hr/L). NAPA plasma concentrations increased from 1.2 mcg/mL to 1.8
mcg/mL. Renal clearance of procainamide and NAPA decreased by 47% and 13%, respectively. A small but significant increase in the
[319]
QTc interval was noted with procainamide administration, and this interval further increased with trimethoprim cotherapy
.
[320]
b) Ten healthy volunteers participated in an open, randomized, placebo-controlled, two-period crossover study by
to determine the
effects of trimethoprim and procainamide coadministration. Subjects received trimethoprim 100 mg or placebo twice daily on days 1
through 3 of each study period. On day 4, procainamide 1000 mg was administered orally as a single dose with trimethoprim 200 mg or
placebo, and another dose of trimethoprim 100 mg or placebo was given 12 hours later. Each treatment period was separated by at
least a one-week washout period. Trimethoprim decreased the renal clearance of procainamide by 45% (487 mL/min vs. 267 mL/min)
and also decreased the clearance of the active metabolite of procainamide, N-acetylprocainamide (NAPA), by 26% (275 mL/min vs.
192 mL/min) as compared to placebo. The area under the concentration-time curve (AUC) increased by 39% for procainamide (19.8
mg/h/L vs. 27.6 mg/h/L) and 27% for NAPA (9.1 mg/h/L vs. 11.4 mg/h/L). Procainamide and NAPA are weak bases and undergo
extensive renal tubular secretion. Trimethoprim is 50% to 60% excreted unchanged in the urine via glomerular filtration, tubular
secretion, and reabsorption. In the case of trimethoprim and procainamide coadministration, both drugs may be competing for tubular
secretion, causing a saturation of this route of elimination. This results in procainamide accumulation, and the potential for
procainamide toxicity.
3.5.1.CF Procaine
1) Interaction Effect: antagonism of the sulfonamide's antibacterial effect
2) Summary: Sulfonamides exert their antimicrobial effect through competitive inhibition of bacterial PABA. In sufficient doses,
concomitant para-aminobenzoic acid (PABA) therapy interferes with this competitive inhibition and antagonizes the antibacterial effects
[312][313][314]
of the sulfonamide
. Local anesthetics that are PABA derivatives (benzocaine, procaine, tetracaine) can also reportedly
antagonize the antibacterial activity of sulfonamides. It is suggested that local anesthetics that are not PABA derivatives (lidocaine,
[315]
dibucaine) be used in patients receiving antibacterial sulfonamides
.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Avoid use of para-aminobenzoic acid (PABA) or PABA derivatives in patients receiving sulfonamide
antimicrobials; consider alternative therapy.
7) Probable Mechanism: para-aminobenzoic acid (PABA) competition with bacterial PABA
3.5.1.CG Prochlorperazine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Although citing no data, the manufacturers of some phenothiazines state that concomitant use with other drugs which
[337][338][339]
prolong the QT interval is not recommended
. Q and T wave distortions have been observed in patients taking cotrimoxazole
[340]
. Other phenothiazines may have similar effects, though no reports are available.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cotrimoxazole and a phenothiazine is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.CH Propafenone
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Even though no formal drug interaction studies have been done, the coadministration of Class I antiarrhythmics and other
[382]
drugs known to prolong the QTc interval is not recommended
. Cotrimoxazole has demonstrated QT prolongation at therapeutic
[383]
doses
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of Class I antiarrhythmic agents and agents that prolong the QT interval, such
as cotrimoxazole, is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.CI Pyrimethamine
1) Interaction Effect: an increased risk of megaloblastic anemia and pancytopenia
2) Summary: Coadministration of pyrimethamine with cotrimoxazole, an antifolic drug, may increase the risk of bone marrow
[326]
[327][328][329]
suppression . Coadministered cotrimoxazole and pyrimethamine may result in megaloblastic anemia or pancytopenia
. The
extent to which sulfamethoxazole and trimethoprim individually contribute to this interaction is unknown.
3) Severity: major
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Avoid giving cotrimoxazole (sulfamethoxazole/trimethoprim), an antifolic agent, and pyrimethamine
concomitantly. Should it become clinically necessary to coadminister these agents, aggressively monitor complete blood counts and
observe the patient for bruising and excessive bleeding. Consider adding leucovorin (folinic acid) to therapy.
7) Probable Mechanism: additive dihydrofolate reductase inhibition
8) Literature Reports
a) A 27-year-old female patient was receiving pyrimethamine 25 mg weekly plus cotrimoxazole for malaria prophylaxis. The patient
developed megaloblastic anemia which resolved with oral iron therapy and discontinuation of both drugs. The reaction was thought to
[323]
be due to the additive inhibition by both drugs of dihydrofolate reductase
.
b) A 43-year-old female was taking pyrimethamine 50 mg weekly for malaria prophylaxis. After signs of a urinary tract infection
developed, she self-treated with cotrimoxazole (trimethoprim 320 mg/sulfamethoxazole 800 mg per day) for ten days prior to
admission. On admission, the patient was found to have diffuse petechial hemorrhages and widespread bruising. Her hemoglobin level
was 9.4 g/dl, hematocrit 30%, platelets 28,000/mm(3), and white blood cell count 3100/mm(3); red blood cells exhibited anisocytosis,
some poikilocytosis, occasional multilobed polymorphs, and no macrocytes. Bone marrow aspiration showed grossly megaloblastic
erythropoiesis, numerous giant metamyelocytes, and scanty megakaryocytes. All medications were stopped except for chloroquine for
[324]
malaria prophylaxis. She responded rapidly to treatment with hydroxocobalamin and folic acid
.
[325]
c) An in vitro study using bone marrow was undertaken to determine the mechanism of pyrimethamine-induced megaloblastosis
.
Pyrimethamine was found to cause defective deoxyuridine conversion to thymidylate, thereby interfering with effective DNA synthesis.
3.5.1.CJ Quetiapine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
[341]
2) Summary: Cotrimoxazole has been shown to prolong the QTc interval at the recommended therapeutic dose
. Even though no
formal drug interaction studies have been done, the coadministration of antipsychotics and other drugs known to prolong the QTc
interval, including cotrimoxazole, is not recommended. Several antipsychotic agents have demonstrated QT prolongation including
[342]
[343]
[344]
[345]
[346]
[347]
[348]
amisulpride
, haloperidol
, quetiapine
, risperidone
, sertindole
, sultopride
, and zotepine
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cotrimoxazole and antipsychotics is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.CK Quinapril
1) Interaction Effect: hyperkalemia
2) Summary: Severe hyperkalemia has been reported with the concurrent use of angiotensin-converting enzyme inhibitors and
[440][441]
trimethoprim
.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Avoid the concurrent use of ACE inhibitors and trimethoprim, especially in patients predisposed to renal
dysfunction, or ensure careful monitoring of serum potassium. Substitution of an alternative antihypertensive agent during acute
trimethoprim use should be considered. If the ACE inhibitor is being used for nephropathy, its temporary discontinuation during
trimethoprim use for an infective process should be satisfactory.
7) Probable Mechanism: additive effects of potassium secretion inhibition and aldosterone reduction
8) Literature Reports
a) Hyperkalemia to greater than 7 mEq/L associated with azotemia (BUN 33 mg/dL, serum creatinine 3.3 mg/dL) was noted 20 days
after addition of trimethoprim-sulfamethoxazole for mild acute pyelonephritis to a stable, 3-year regimen of quinapril 20 mg daily in a
74-year-old hypertensive male. The patient was asymptomatic; an EKG did not reflect classic signs of hyperkalemia. Drug withdrawal
and specific treatment for hyperkalemia including insulin, dextrose, sodium polystyrene sulfonate, and calcium was required, with
resolution over 36 hours. Nifedipine was substituted for blood pressure control. Caution is recommended when using this combination,
[438]
especially in the elderly or those with preexisting renal dysfunction
.
b) A 40-year-old woman with double lung transplantation developed a pneumocystis carinii infection one year post-transplant.
Medications she was stabilized on included enalapril 30 mg daily. High dose trimethoprim-sulfamethoxazole (TMP-SMX) therapy (20
mg/kg/day and 100 mg/kg/day) was instituted. After nine days of concurrent therapy with TMP-SMX and enalapril, the patient's
potassium level reached 6.8 mmol/L. Both medications were discontinued and the patient required treatment for her hyperkalemic
[439]
condition
.
3.5.1.CL Quinidine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Even though no formal drug interaction studies have been done, the coadministration of Class IA antiarrhythmics and
[321]
other drugs known to prolong the QTc interval is not recommended
. Cotrimoxazole has demonstrated QT prolongation at
[322]
therapeutic doses
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: The concurrent administration of Class IA antiarrhythmic agents and agents that prolong the QT interval, such
as cotrimoxazole, is not recommended. Monitor serum procainamide and NAPA serum levels and for signs of procainamide toxicity
(cardiac arrhythmias, hypotension, CNS depression). Dosage adjustments may be made depending on serum levels and patient
response.
7) Probable Mechanism: additive effects on QT prolongation
8) Literature Reports
a) Eight healthy men received oral sustained-release procainamide 500 mg every six hours for three days, alone and with oral
trimethoprim 200 mg daily for four days. Trimethoprim coadministration increased the area under the concentration-time curve (AUC) of
procainamide from 19.9 mg/h/L to 32.5 mg/h/L, representing a 63% increase. Mean steady-state procainamide concentrations also
increased from 1.6 mcg/mL to 2.7 mcg/mL. Likewise, trimethoprim increased the AUC of N-acetylprocainamide (NAPA), the active
metabolite of procainamide, by 52% (14.1 mg/hr/L vs. 21.4 mg/hr/L). NAPA plasma concentrations increased from 1.2 mcg/mL to 1.8
mcg/mL. Renal clearance of procainamide and NAPA decreased by 47% and 13%, respectively. A small but significant increase in the
[319]
QTc interval was noted with procainamide administration, and this interval further increased with trimethoprim cotherapy
.
[320]
b) Ten healthy volunteers participated in an open, randomized, placebo-controlled, two-period crossover study by
to determine the
effects of trimethoprim and procainamide coadministration. Subjects received trimethoprim 100 mg or placebo twice daily on days 1
through 3 of each study period. On day 4, procainamide 1000 mg was administered orally as a single dose with trimethoprim 200 mg or
placebo, and another dose of trimethoprim 100 mg or placebo was given 12 hours later. Each treatment period was separated by at
least a one-week washout period. Trimethoprim decreased the renal clearance of procainamide by 45% (487 mL/min vs. 267 mL/min)
and also decreased the clearance of the active metabolite of procainamide, N-acetylprocainamide (NAPA), by 26% (275 mL/min vs.
192 mL/min) as compared to placebo. The area under the concentration-time curve (AUC) increased by 39% for procainamide (19.8
mg/h/L vs. 27.6 mg/h/L) and 27% for NAPA (9.1 mg/h/L vs. 11.4 mg/h/L). Procainamide and NAPA are weak bases and undergo
extensive renal tubular secretion. Trimethoprim is 50% to 60% excreted unchanged in the urine via glomerular filtration, tubular
secretion, and reabsorption. In the case of trimethoprim and procainamide coadministration, both drugs may be competing for tubular
secretion, causing a saturation of this route of elimination. This results in procainamide accumulation, and the potential for
procainamide toxicity.
3.5.1.CM Repaglinide
1) Interaction Effect: increased repaglinide exposure and plasma concentration
2) Summary: Repaglinide is metabolized by the CYP2C8 and CYP3A4 enzyme systems. Coadministration with trimethoprim, a
[416]
CYP2C8 inhibitor, has resulted in increased repaglinide exposure and plasma concentrations in a study of healthy volunteers
. In a
case report, symptomatic hypoglycemia was observed in a 76-year-old patient with diabetes and renal function impairment who
[417]
[416]
received concomitant repaglinide and sulfamethoxazole/trimethoprim
. Use caution if these agents are coadministered
. Dosage
adjustments to repaglinide may be necessary if repaglinide is coadministered with trimethoprim and monitoring of blood glucose
concentrations may also be warranted.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Caution is advised if repaglinide and trimethoprim are coadministered as this has resulted in increased
[416]
repaglinide exposure and plasma concentrations
. Therefore, repaglinide dosage adjustments may be necessary if these two drugs
are coadministered. Consider monitoring blood glucose concentrations carefully.
7) Probable Mechanism: inhibition of CYP2C8-mediated repaglinide metabolism by trimethoprim
8) Literature Reports
a) In healthy volunteers, coadministration of repaglinide and trimethoprim resulted in increases in repaglinide AUC and Cmax.
Following 2 days of twice-daily trimethoprim 160 mg dosing, a single 0.25 mg repaglinide dose was administered concomitantly with 1
dose of trimethoprim 160 mg on the third day. This resulted in a 61% increase in repaglinide AUC, from 5.9 to 9.6 nanogram (ng) x
[416]
hr/mL and a 41% increase in repaglinide Cmax, from 4.7 ng/mL to 6.6 ng/mL
.
b) Symptomatic hypoglycemia with an inability to speak was observed in a 76-year-old diabetic patient with impaired renal function
following coadministration of repaglinide and sulfamethoxazole/trimethoprim. When the patient was admitted for follow-up after a total
hip replacement, his diabetes was well-controlled with repaglinide 1 mg 3 times daily. Concomitant medications included amiodarone,
perindopril, furosemide, and esomeprazole. Medical history included atrial fibrillation and chronic heart failure. The patient was initiated
on sulfamethoxazole 800 mg/trimethoprim 160 mg once daily for a UTI 5 days after admission. This dose was lower than the usual
dose due to his microangiopathy-induced renal function impairment. Serum creatinine levels were stable 1.84 to 2 mg/dL and estimated
CrCl was 35 to 38 mL/min. However, 5 days after sulfamethoxazole/trimethoprim was started, the patient was unable to speak and
developed hypoglycemia (blood glucose level of 34 mg/dL). Subsequently, repaglinide and sulfamethoxazole/trimethoprim were
discontinued. The patient was administered 3 IV boluses of 30% D-glucose (total dose 90 g) along with a continuous 5% dextrose IV
infusion. His glycemia was in the normal range within the next 36 hours. Five days after the hypoglycemia occurred, the patient was
restarted on repaglinide with no further sequelae. In an assessment of causality, the interaction between repaglinide and
sulfamethoxazole/trimethoprim was rated as possible (Horn Drug Interaction Probability Scale) or probable (WHO-Uppsala Monitoring
Centre causality assessment system). There may have been a contributing effect of sulfamethoxazole lowering blood glucose effect
[417]
as well as trimethoprim induced CYP2C8 inhibition
.
3.5.1.CN Rifabutin
1) Interaction Effect: increased sulfamethoxazole hydroxylamine exposure
2) Summary: A pharmacokinetic study of cotrimoxazole and rifabutin cotreatment in subjects infected with HIV revealed significant
induction of sulfamethoxazole metabolism, resulting in increased serum concentrations of the potentially toxic sulfamethoxazole
[308]
hydroxylamine metabolite
.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Use cotrimoxazole or sulfamethoxazole and rifabutin concomitantly with caution or use therapeutic
alternative. Monitor the patient for the following sulfamethoxazole hydroxylamine-related adverse effects if these are used
concomitantly: rash, leukopenia, thrombocytopenia, and changes in liver transaminase levels.
7) Probable Mechanism: induction of CYP3A4 or CYP2C9-mediated sulfamethoxazole metabolism
8) Literature Reports
a) In a pharmacokinetic study of HIV-infected patients (n=9), the concurrent administration of rifabutin with cotrimoxazole significantly
induced sulfamethoxazole metabolism and increased the apparent formation of the sulfamethoxazole hydroxylamine metabolite.
Subjects infected with HIV received cotrimoxazole (sulfamethoxazole 800 milligrams (mg)/trimethoprim 160 mg daily) alone for 2
weeks. Each subject then received a 2-week regimen of rifabutin 300 mg daily given concurrently with cotrimoxazole. Serum and urine
analysis on day 14 of cotreatment revealed significantly increased area under the concentration-time curve (AUC) and urinary recovery
[308]
values for the sulfamethoxazole hydroxylamine metabolite (by 50% and 45%, respectively; p less than 0.05)
.
3.5.1.CO Risperidone
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
[341]
2) Summary: Cotrimoxazole has been shown to prolong the QTc interval at the recommended therapeutic dose
. Even though no
formal drug interaction studies have been done, the coadministration of antipsychotics and other drugs known to prolong the QTc
interval, including cotrimoxazole, is not recommended. Several antipsychotic agents have demonstrated QT prolongation including
[342]
[343]
[344]
[345]
[346]
[347]
[348]
amisulpride
, haloperidol
, quetiapine
, risperidone
, sertindole
, sultopride
, and zotepine
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cotrimoxazole and antipsychotics is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.CP Rosiglitazone
1) Interaction Effect: increased rosiglitazone serum concentrations and risk of hypoglycemia and toxicity (fluid retention, congestive
cardiac failure, CNS depression, seizures, diaphoresis, tachypnea, tachycardia, hypothermia)
2) Summary: In a study of healthy subjects, coadministration of rosiglitazone with trimethoprim significantly inhibited cytochrome P450
CYP2C8-mediated rosiglitazone metabolism, thereby reducing rosiglitazone bioavailability . The study authors observe that, since the
bioavailability of rosiglitazone appears to be directly proportional to trimethoprim exposure, the concomitant administration of
[411]
rosiglitazone and trimethoprim may increase the risk for developing concentration-dependent rosiglitazone adverse effects
.
3) Severity: moderate
4) Onset: rapid
5) Substantiation: established
6) Clinical Management: Caution is advised if rosiglitazone is coadministered with trimethoprim. Monitor patient closely for signs and
symptoms of hypoglycemia.
7) Probable Mechanism: competitive inhibition of rosiglitazone CYP2C8-mediated metabolism
8) Literature Reports
a) Coadministration of trimethoprim with rosiglitazone significantly increased rosiglitazone bioavailability by inhibition of cytochrome
P450 CYP2C8-mediated rosiglitazone metabolism. In a randomized, placebo-controlled cross-over study, healthy subjects (n=10)
received a 4-day oral regimen of placebo or trimethoprim 160 milligrams (mg) twice daily. On study day 3, each subject received a
single oral dose of rosiglitazone 4 mg. Serial blood analysis was performed over the following 48 hours. The presence of trimethoprim
evoked increases in rosiglitazone mean maximum serum concentration, area under the concentration-time curve (AUC 0-48 hours) and
elimination half-life (by 14%, 37%, and 24%, respectively; p=0.0014, p less than 0.0001, and p=0.0013, respectively). Concurrently, the
apparent formation rate for the metabolite N-desmethylrosiglitazone declined by 36% (p=0.0121) . The study authors observe that,
since the bioavailability of rosiglitazone appears to be directly proportional to trimethoprim exposure, the concomitant administration of
[411]
rosiglitazone and trimethoprim may increase the risk of occurrence of concentration-dependent rosiglitazone adverse effects
.
3.5.1.CQ Sematilide
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Class III antiarrhythmics and cotrimoxazole have been shown to prolong the QTc interval at the recommended
[351]
therapeutic dose . The coadministration of Class III antiarrhythmic agents and other drugs known to prolong the QTc interval,
[352]
including cotrimoxazole, is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of Class III antiarrhythmic agents and agents that prolong the QT interval, such
as cotrimoxazole, is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.CR Sertindole
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
[341]
2) Summary: Cotrimoxazole has been shown to prolong the QTc interval at the recommended therapeutic dose
. Even though no
formal drug interaction studies have been done, the coadministration of antipsychotics and other drugs known to prolong the QTc
interval, including cotrimoxazole, is not recommended. Several antipsychotic agents have demonstrated QT prolongation including
[342]
[343]
[344]
[345]
[346]
[347]
[348]
amisulpride
, haloperidol
, quetiapine
, risperidone
, sertindole
, sultopride
, and zotepine
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cotrimoxazole and antipsychotics is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.CS Sotalol
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Class III antiarrhythmics and cotrimoxazole have been shown to prolong the QTc interval at the recommended
[351]
therapeutic dose . The coadministration of Class III antiarrhythmic agents and other drugs known to prolong the QTc interval,
[352]
including cotrimoxazole, is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of Class III antiarrhythmic agents and agents that prolong the QT interval, such
as cotrimoxazole, is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.CT Spiramycin
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Spiramycin and cotrimoxazole have been shown to prolong the QTc interval at the recommended therapeutic
[355][356]
dose
. Even though no formal drug interaction studies have been done, the coadministration of drugs known to prolong the QTc
interval is not recommended.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of spiramycin and cotrimoxazole is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.CU Sultopride
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
[341]
2) Summary: Cotrimoxazole has been shown to prolong the QTc interval at the recommended therapeutic dose
. Even though no
formal drug interaction studies have been done, the coadministration of antipsychotics and other drugs known to prolong the QTc
interval, including cotrimoxazole, is not recommended. Several antipsychotic agents have demonstrated QT prolongation including
[342]
[343]
[344]
[345]
[346]
[347]
[348]
amisulpride
, haloperidol
, quetiapine
, risperidone
, sertindole
, sultopride
, and zotepine
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cotrimoxazole and antipsychotics is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.CV Tedisamil
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Class III antiarrhythmics and cotrimoxazole have been shown to prolong the QTc interval at the recommended
[351]
therapeutic dose . The coadministration of Class III antiarrhythmic agents and other drugs known to prolong the QTc interval,
[352]
including cotrimoxazole, is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of Class III antiarrhythmic agents and agents that prolong the QT interval, such
as cotrimoxazole, is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.CW Telithromycin
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Although no formal drug interaction studies have been done, cotrimoxazole should not be coadministered with other
[310][311]
drugs which may also prolong the QTc interval, including telithromycin
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cotrimoxazole and agents that may prolong the QT interval, such as
telithromycin, is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.CX Terfenadine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
[299]
2) Summary: Concomitant therapy of terfenadine with any drug that prolongs the QT interval is contraindicated
. Cotrimoxazole has
[300]
been shown to prolong the QTc interval at the recommended therapeutic dose
.
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of terfenadine with any drug that prolongs the QT interval, such as
cotrimoxazole, is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.CY Tetracaine
1) Interaction Effect: antagonism of the sulfonamide's antibacterial effect
2) Summary: Sulfonamides exert their antimicrobial effect through competitive inhibition of bacterial PABA. In sufficient doses,
concomitant para-aminobenzoic acid (PABA) therapy interferes with this competitive inhibition and antagonizes the antibacterial effects
[312][313][314]
of the sulfonamide
. Local anesthetics that are PABA derivatives (benzocaine, procaine, tetracaine) can also reportedly
antagonize the antibacterial activity of sulfonamides. It is suggested that local anesthetics that are not PABA derivatives (lidocaine,
[315]
dibucaine) be used in patients receiving antibacterial sulfonamides
.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Avoid use of para-aminobenzoic acid (PABA) or PABA derivatives in patients receiving sulfonamide
antimicrobials; consider alternative therapy.
7) Probable Mechanism: para-aminobenzoic acid (PABA) competition with bacterial PABA
3.5.1.CZ Thioridazine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Although citing no data, the manufacturer of thioridazine states that concomitant use with other drugs which prolong the
[316]
[317]
QT interval is contraindicated . Q and T wave distortions have been observed in patients taking cotrimoxazole
. Other
phenothiazines may have similar effects, though no reports are available.
3) Severity: contraindicated
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Due to the potential for additive effects on the QT interval, the concurrent administration of cotrimoxazole and
thioridazine is contraindicated.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.DA Tolazamide
1) Interaction Effect: enhanced hypoglycemic effects
2) Summary: There are several case reports related to combined use of sulfonamides and sulfonylureas resulting in profound
hypoglycemia requiring hospitalization. The proposed mechanism of action is displacement of the sulfonylurea from protein-binding
[287]
sites .
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Avoid the use of sulfonamide antibiotics in patients who are taking sulfonylureas. If concomitant therapy is
required, closely monitor blood glucose. Emergency treatment of a hypoglycemic episode may be required.
7) Probable Mechanism: potentiation of hypoglycemic effect of the sulfonylureas caused by displacement from protein-binding sites by
sulfonamides
8) Literature Reports
a) A brief review of some of the case reports relating to these interactions follows: (1) A 69-year-old black female who was stable on
cimetidine 300 mg orally at bedtime, docusate 200 mg daily, hydrochlorothiazide 50 mg daily, and chlorpropamide 500 mg daily orally,
was hospitalized two days after starting cotrimoxazole two tablets orally twice a day. Her laboratory results on admission were a blood
glucose of 48 mg/dL, blood pressure of 174/90, and serum sodium of 118 mEq/L; she was nauseous and vomiting. The patient was
[283]
discharged after seven days of hospitalization
. (2) A 67-year-old diabetic stable on chlorpropamide 250 mg daily was admitted to a
hospital with a blood glucose of 10 mg/dL two days after starting on sulfamethazine. She was semicomatose for a week and mentally
[284]
dull for a month
. (3) A 77-year-old man on chlorpropamide and phenformin was started on sulfisoxazole. The next day he was
[285]
[286]
hospitalized with hypoglycemia
. (4)
describe two patients on tolbutamide who were started on sulfisoxazole. They experienced
hypoglycemia and were hospitalized. One of the patients, a 47-year-old man, died with a blood glucose of 8 mg/dL.
3.5.1.DB Tolbutamide
1) Interaction Effect: enhanced hypoglycemic effects
2) Summary: It has been reported that cotrimoxazole may reduce the clearance of tolbutamide by 25% due to inhibition of tolbutamide
[242]
[243]
oxidation . In addition, sulfonamides may displace sulfonylureas from plasma protein binding sites
. There are several case
[244]
reports related to the combined use of sulfonamides and sulfonylureas resulting in profound hypoglycemia requiring hospitalization
.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Avoid the use of sulfonamide antibiotics in patients who are taking sulfonylureas. If concomitant therapy is
required, closely monitor blood glucose. Emergency treatment of a hypoglycemic episode may be required.
7) Probable Mechanism: displacement by sulfonamides of tolbutamide from protein-binding sites; inhibition of tolbutamide metabolism
8) Literature Reports
a) A brief review of some of the case reports relating to these interactions follows: (1) A 69-year-old black female who was stable on
cimetidine 300 mg orally at bedtime, docusate 200 mg daily, hydrochlorothiazide 50 mg daily, and chlorpropamide 500 mg daily orally,
was hospitalized two days after starting cotrimoxazole two tablets orally twice a day. Her laboratory results on admission were a blood
glucose of 48 mg/dL, blood pressure of 174/90, and serum sodium of 118 mEq/L; she was nauseous and vomiting. The patient was
[237]
discharged after seven days of hospitalization
. (2) A 67-year-old diabetic stable on chlorpropamide 250 mg daily was admitted to a
hospital two days after starting on sulfamethazine with a blood glucose of 10 mg/dL. She was semicomatose for a week and mentally
[238]
dull for a month
. (3) A 77-year-old man on chlorpropamide and phenformin was started on sulfisoxazole. The next day he was
[239]
hospitalized with hypoglycemia
. (4) Two patients on tolbutamide who were started on sulfisoxazole experienced hypoglycemia and
[240]
were hospitalized. One of the patients, a 47-year-old man, died with a blood glucose of 8 mg/dL
.
b) Tolbutamide metabolism was studied in seven healthy male volunteers to determine the effect of sulfamethoxazole and
[241]
trimethoprim, separately and combined, on tolbutamide disposition
. Tolbutamide undergoes oxidative metabolism by cytochrome P450 to hydroxytolbutamide (the rate-limiting step for tolbutamide clearance). Cotrimoxazole reduced tolbutamide total and unbound
plasma clearance, and prolonged the elimination half-life. The clearance of tolbutamide was inhibited by 25% with cotrimoxazole
(additive effects of sulfamethoxazole and trimethoprim). Both sulfamethoxazole and trimethoprim reduced tolbutamide clearance
alone, although more potently when used together. Sulfamethoxazole also displaced tolbutamide from plasma protein.
3.5.1.DC Tolbutamide
1) Interaction Effect: enhanced hypoglycemic effects
2) Summary: Trimethoprim has been shown to reduce tolbutamide total and unbound plasma clearance and prolong the elimination
half-life. However, the observed reduction in tolbutamide clearance was relatively small and a major change in the response to
[446]
tolbutamide is unlikely .
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Avoid the use of trimethoprim in patients who are taking tolbutamide. If concomitant therapy is required,
closely monitor blood glucose.
7) Probable Mechanism: inhibition of tolbutamide metabolism
8) Literature Reports
a) Tolbutamide metabolism was studied in seven healthy male volunteers to determine the effect of sulfamethoxazole and
[445]
trimethoprim, separately and combined, on tolbutamide disposition
. Tolbutamide undergoes oxidative metabolism by cytochrome P450 to hydroxytolbutamide (the rate-limiting step for tolbutamide clearance). Common clinical doses of either cotrimoxazole,
sulfamethoxazole, or trimethoprim reduced tolbutamide total and unbound plasma clearance and prolonged the elimination half-life.
The clearance of tolbutamide was inhibited by 25% with cotrimoxazole (additive effects of sulfamethoxazole and trimethoprim).
Although both sulfamethoxazole and trimethoprim reduced tolbutamide clearance, the greatest effect on clearance was observed with
the combination.
3.5.1.DD Trifluoperazine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Although citing no data, the manufacturers of some phenothiazines state that concomitant use with other drugs which
[337][338][339]
prolong the QT interval is not recommended
. Q and T wave distortions have been observed in patients taking cotrimoxazole
[340]
. Other phenothiazines may have similar effects, though no reports are available.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cotrimoxazole and a phenothiazine is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.DE Trimipramine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Tricyclic antidepressants (TCAs) and cotrimoxazole have been shown to prolong the QTc interval at the recommended
[330][331]
therapeutic dose
. Even though no formal drug interaction studies have been done, the coadministration of tricyclic
[332]
antidepressants and other drugs known to prolong the QTc interval, such as cotrimoxazole, is not recommended
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: The concurrent administration of cotrimoxazole and tricyclic antidepressants is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.DF Typhoid Vaccine, Live
1) Interaction Effect: a decreased immunological response to the typhoid vaccine
2) Summary: Antibiotics which possess bacterial activity against salmonella typhi organisms may interfere with the immunological
response to the live typhoid vaccine. Allow 24 hours or more to elapse between the administration of the last dose of the antibiotic and
[391][392]
the live typhoid vaccine
.
3) Severity: moderate
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Allow 24 hours or more to elapse between the last dose of antibiotic and the administration of oral live typhoid
vaccine.
7) Probable Mechanism: antimicrobial activity against the salmonella typhi organism
3.5.1.DG Vasopressin
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
2) Summary: Cotrimoxazole and vasopressin have been shown to prolong the QTc interval at the recommended therapeutic
[295][296]
dose
. Even though no formal drug interaction studies have been done, the coadministration of drugs known to prolong the QTc
interval is not recommended.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cotrimoxazole and vasopressin is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.1.DH Warfarin
1) Interaction Effect: an increased risk of bleeding
2) Summary: Concomitant administration of sulfamethoxazole (in cotrimoxazole) and warfarin has been reported to result in an
[399][400][401][402][403]
enhanced hypoprothrombinemic response to warfarin
. The mechanism appears to be related to impairment of the
hepatic metabolism of warfarin but may also involve displacement of warfarin from protein binding sites or alterations in intestinal flora
[400][404][405]
. There was an association between prior sulfamethoxazole/trimethoprim use and hospitalization for gastrointestinal bleed in
[394]
a nested case-control study using United States Medicaid data (n=308,100)
. If concomitant use is deemed necessary, a preemptive
[393]
warfarin dose reduction of 10 to 20% of the mean daily dose may be considered to prevent increased INR
.
3) Severity: major
4) Onset: delayed
5) Substantiation: established
6) Clinical Management: Use caution when prescribing sulfamethoxazole to patients who take warfarin. Concomitant use of
sulfamethoxazole and warfarin may result in significantly increased INR. Closely monitor the patient's prothrombin time and INR
during concomitant administration. Preemptive warfarin dose reductions of 10 to 20% of the mean daily dose may be considered to
[393]
prevent INR prolongation during coadministration of sulfamethoxazole .
7) Probable Mechanism: unknown
8) Literature Reports
a) There was an association between prior sulfamethoxazole/trimethoprim use and hospitalization for gastrointestinal bleed in a
nested case-control study using United States Medicaid data (n=308,100). The adjusted odds ratios (OR) for the time period (time
prescription was filled to the date of hospitalization) were 1.46 (95% CI 1.16 to 1.85) at 0 to 5 days; 2.54 (95% CI 2.08 to 3.1) at 6 to 10
days, 2.04 (95% 1.64 to 2.54) at 11 to 15 days, and 1.18 (95% CI 0.89 to 1.57) at 16 to 20 days. The OR were adjusted for age,
gender, race, state, prior gastrointestinal bleed, chronic renal disease, liver disease, and use of proton pump inhibitors, metronidazole,
[394]
acetaminophen, and prednisone. A case-crossover analysis of the data confirmed the association
.
b) Preemptive warfarin dose reduction (DR) prevented INR prolongation associated with concurrent trimethoprim-sulfamethoxazole
(TMP-SMX) administration, according to a cohort study of chronically anticoagulated patients. A mean preemptive warfarin DR of 16.3
+/- 2.8% was administered to 8 patients while 9 patients received no change in warfarin dose (control group). The two groups had
similar baseline INRs prior to initiation of TMP-SMX (2.53 +/- 0.12 vs 2.52 +/- 0.11; p=0.9), but after an average of 5 days, 25% (2 of 8)
of patients in the DR group had an INR greater than 4 compared with 88.9% (8 of 9) of patients in the control group (p less than 0.02).
[393]
Additionally, 0% of the DR group had an INR of 6 or greater compared with 44% (4 of 9) of the control group (p=0.08)
.
c) Potentiation of the hypoprothrombinemic effects of warfarin by cotrimoxazole was reported in six of 20 patients receiving
concomitant therapy. Prothrombin ratios increased after two to six days of the combination therapy in these patients. One patient
developed gastrointestinal hemorrhage. A decrease in the dosage of warfarin or discontinuation of therapy was required in all six
[395]
patients
.
d) An interaction was reported in a 71-year-old white female patient on cotrimoxazole two tablets twice daily for a urinary tract infection
pending culture and sensitivity. The duration of therapy was three days. The patient was also on warfarin 5 mg daily because of a
cerebral vascular accident. The prothrombin time increased from 23 to 32 seconds. Her next prothrombin time was 33 seconds, which
increased to 37 seconds. Ampicillin was instituted, cotrimoxazole discontinued, and warfarin stopped for two days. Prothrombin time
[396]
returned to 21 seconds. This interaction is clinically significant, and these two drugs should be avoided if possible
.
e) There are three possible mechanisms for the enhanced effect of warfarin caused by cotrimoxazole. Cotrimoxazole may decrease
the intestinal bacteria responsible for production of vitamin K, resulting in a decrease in vitamin K-dependent clotting factors. Warfarin
may be displaced from protein binding sites by cotrimoxazole. The third alternative is a stereoselective increase of serum levels of the
[397][398]
(S)-warfarin enantiomer of warfarin
.
3.5.1.DI Zidovudine
1) Interaction Effect: increased serum concentrations of zidovudine
2) Summary: In two controlled studies of HIV-positive patients, coadministration of zidovudine with trimethoprim resulted in decreased
renal excretion of zidovudine and its glucuronide metabolite. However, net clearance, metabolic clearance, and distribution were not
affected. This interaction may only be clinically important when hepatic glucuronidation is also impaired by liver disease or inhibited by
[249][250]
other drugs
.
3) Severity: minor
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Clinicians should be aware that the combined use of cotrimoxazole and zidovudine may cause elevated
zidovudine serum concentrations. Patients who are given this combination of medications should be followed for excessive adverse
effects related to zidovudine (GI disturbances, headache, fatigue).
7) Probable Mechanism: competitive inhibition of renal excretion of zidovudine
8) Literature Reports
a) In a randomized, three-phase crossover study of nine HIV-positive patients, the pharmacokinetic interactions of zidovudine with
trimethoprim and zidovudine with trimethoprim and sulfamethoxazole were studied. Patients were given either zidovudine at 3 mg per
kg alone, zidovudine plus 160 mg trimethoprim and 800 mg sulfamethoxazole, or zidovudine plus 150 mg trimethoprim. Renal
clearance of zidovudine was decreased by 58% and 48% after trimethoprim plus sulfamethoxazole and trimethoprim, respectively.
Clearance of the zidovudine glucuronide metabolite was decreased by 27% and 20%, respectively. The fraction of the zidovudine dose
excreted as the parent compound and metabolic ratio were also decreased in the presence of trimethoprim. However, net clearance,
metabolic clearance, and distribution were not affected during cotherapy. This suggested increased zidovudine elimination through an
extrarenal route, such as biliary excretion. The authors postulated that this interaction is unlikely to be clinically important unless hepatic
[247]
glucuronidation is also impaired by liver disease or inhibited by other drugs
.
b) In a controlled study of eight HIV-positive patients, pharmacokinetic interactions between zidovudine, trimethoprim, and dapsone
were assessed in two and three drug combinations. Patients received zidovudine 200 mg, trimethoprim 200 mg, or dapsone 100 mg
alone and with one or two of the other agents. Coadministration with trimethoprim resulted in an increase in the zidovudine area under
the concentration-time curve (AUC) from 1.11 to 1.46 mcg h/mL. In addition, zidovudine renal clearance decreased by 58%, which
coincided with a 54% decrease in the mean urinary recovery of zidovudine. The AUC from 0 to 6 hour ratio of the zidovudineglucuronide conjugate to zidovudine was unchanged. The proposed mechanism of the decreased clearance was trimethoprim
competition for renal secretion with zidovudine. No other significant pharmacokinetic interactions were noted with the other
combinations studied. In most cases, zidovudine can be administered with either trimethoprim or dapsone without a clinically significant
interaction. However, in AIDS patients with liver impairment and impaired glucuronidation, zidovudine dosage adjustment may be
[248]
necessary
.
3.5.1.DJ Zotepine
1) Interaction Effect: an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
[341]
2) Summary: Cotrimoxazole has been shown to prolong the QTc interval at the recommended therapeutic dose
. Even though no
formal drug interaction studies have been done, the coadministration of antipsychotics and other drugs known to prolong the QTc
interval, including cotrimoxazole, is not recommended. Several antipsychotic agents have demonstrated QT prolongation including
[342]
[343]
[344]
[345]
[346]
[347]
[348]
amisulpride
, haloperidol
, quetiapine
, risperidone
, sertindole
, sultopride
, and zotepine
.
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concurrent administration of cotrimoxazole and antipsychotics is not recommended.
7) Probable Mechanism: additive effects on QT prolongation
3.5.2 Drug-Food Combinations
3.5.2.A Ethanol
1) Interaction Effect: a disulfiram-like reaction (flushing, sweating, palpitations, drowsiness)
2) Summary: Two patients receiving cotrimoxazole double-strength experienced a disulfiram-type reaction after the ingestion of 24 to
36 ounces of beer. One of the patients had a similar reaction on rechallenge the next day after the ingestion of 6 ounces of beer.
Although the exact mechanism of this interaction is not known, it is possible that cotrimoxazole may inhibit aldehyde dehydrogenase or
[448]
may inhibit the elimination of acetaldehyde via the cytochrome P450 hepatic pathway
.
3) Severity: major
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Patients receiving sulfamethoxazole/trimethoprim should be warned that a disulfiram-type reaction may
occur if ethanol is ingested.
7) Probable Mechanism: unknown
8) Literature Reports
a) Two health care professionals receiving cotrimoxazole double-strength twice daily for three days as pertussis prophylaxis
experienced a disulfiram-like reaction after the ingestion of ethanol. The first patient, a 31-year-old male, drank 24 ounces of beer and
10-20 minutes elapsed before symptoms of flushing, heart palpitations, dyspnea, nausea, and headache occurred. He became drowsy
and fell asleep, and woke the next morning with no symptoms. When he consumed 6 ounces of beer the next day, the same type of
symptoms reoccurred. His average ethanol intake was 36 to 48 ounces of beer a week. The second patient, a 39-year-old male, also
experienced heart palpitations, flushing, dyspnea, nausea, and headache after the consumption of 36 ounces of beer. He also fell
asleep and woke the next morning with no symptoms. His average beer consumption was 24 to 36 ounces daily. Neither of these
patients had medical conditions before or after the disulfiram-like reaction, and neither was receiving any prescription or nonprescription
[447]
products
.
3.5.3 Drug-Lab Modifications
Creatinine measurement
Methotrexate measurement
Theophylline measurement
3.5.3.A Creatinine measurement
1) Interaction Effect: falsely elevated creatinine levels
2) Summary: Administration of trimethoprim may interfere with the Jaffe alkaline picrate reaction assay for creatinine resulting in
[451][452][453]
overestimations of about 10% in the range of normal values
. Use caution when interpreting results of creatinine assays using
the Jaffe alkaline picrate reaction in patients receiving trimethoprim or consider using alternative testing methods.
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: In patients receiving trimethoprimn, an overestimation of about 10% in the range of normal creatinine values
[451][452][453]
may occur due to interference with the Jaffe alkaline picrate reaction assay
. Therefore, interpret results of such tests with
caution in patients receiving trimethoprim concomitantly. Consider using alternative testing methods.
7) Probable Mechanism: interference with the Jaffe alkaline picrate reaction
3.5.3.B Methotrexate measurement
1) Interaction Effect: interference with serum methotrexate assay using the competitive binding protein technique
2) Summary: Concurrent trimethoprim use can interfere with serum methotrexate assays performed using the competitive binding
protein technique (CBPA). This test has a bacterial dihydrofolate reductase as the binding protein. However, as there is no interference
with the radioimmunoassay (RIA) method, it is recommended for serum methotrexate measurements in patients receiving trimethoprim
[451][452]
concomitantly
.
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: probable
6) Clinical Management: Trimethoprim can interfere with the serum methotrexate assay when the competitive binding protein technique
(CBPA) using bacterial dihydrofolate reductase is employed. Clinicians should use the radioimmunoassay (RIA) method for
[451][452]
methotrexate measurements when patients are also taking trimethoprim, as no interference occurs with this method
.
7) Probable Mechanism: assay interference
3.5.3.C Theophylline measurement
1) Interaction Effect: false increases in theophylline levels
[449][450]
2) Summary: Sulfamethoxazole has been reported to interfere with theophylline assay by some HPLC methods
. One method
which involved extraction with a solvent containing 10% glacial acetic acid, 40% chloroform, and 50% isopropanol resulted in coelution
[449]
of sulfamethoxazole and theophylline
. A C18 column was used with 4% isopropanol for the mobile phase for chromatographic
separation. Four patients demonstrated overlapping peaks, suggesting the interaction has potential clinical significance. However, the
report was vague regarding which peak was affected (theophylline or 8-chlorotheophylline, the internal standard). Sulfamethoxazole
overlap with theophylline has also been reported. This method used equivolume chloroform/isopropanol extraction, evaporation,
redissolution in methanol, and chromatographic separation using C18 column with acetonitrile mobile phase; 8-chlorotheophylline was
[450]
the internal standard
. Alternatively, extraction with equivolume chloroform/isopropanol, followed by evaporation and redissolution in
acetonitrile successfully differentiated retention times for theophylline, 8-chlorotheophylline, and sulfamethoxazole (3.22, 4.2, and 7.37
minutes, respectively). A Lichrosorb(R) column was used with acetonitrile for the mobile phase for chromatographic separation. All
HPLC theophylline assays should be evaluated for sulfamethoxazole interference.
3) Severity: minor
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Investigation of all HPLC theophylline assay methods for sulfamethoxazole interference is needed.
Fluorescence polarization immunoassay of theophylline using the Abbott TDx(R) system does not appear to be subject to interference
by sulfamethoxazole.
7) Probable Mechanism: theophylline assay interference
3.5.5 Intravenous Admixtures
Drugs
Solutions
3.5.5.1 Drugs
Acyclovir
Allopurinol Sodium
Amifostine
Amikacin
Aminophylline
Amphotericin B
Atracurium
Aztreonam
Cefamandole
Cefazolin
Cefotaxime
Cefoxitin
Cephalothin
Cephapirin
Cyclosporine
Enalaprilat
Esmolol
Fenoldopam Mesylate
Filgrastim
Fluconazole
Fludarabine
Folic Acid
Foscarnet
Gallium Nitrate
Gentamicin
Granisetron Hydrochloride
Heparin
Hydromorphone
Labetalol
Linezolid
Magnesium Sulfate
Meperidine
Morphine
Moxalactam
Nicardipine Hydrochloride
Pancuronium
Perphenazine
Piperacillin Sodium/Tazobactam Sodium
Sargramostim
Tacrolimus
Tetracycline
Tobramycin
Vancomycin
Vecuronium
Verapamil
Vinorelbine
Zidovudine
3.5.5.1.A Acyclovir
1) Compatible
a) Acyclovir 5 mg/mL in Dextrose 5% in water with cotrimoxazole (trimethoprim 0.8 mg/mL and sulfamethoxazole 4 mg/mL) in
[508]
Dextrose 5% in water visually compatible for 24 hours at 25 degrees C under fluorescent light
3.5.5.1.B Allopurinol Sodium
1) Compatible
a) Allopurinol sodium 3 mg/mL in Sodium chloride 0.9% injection with trimethoprim/sulfamethoxazole 0.8/4 mg/mL in Sodium chloride
[510]
0.9% injection, compatible for up to 4 hours at 22 degrees C
3.5.5.1.C Amifostine
1) Compatible
a) Amifostine 10 mg/mL in Dextrose 5% in water with trimethoprim-sulfamethoxazole 0.8/4 mg/mL in 5% Dextrose injection,
[527]
compatible during simulated Y-site administration
3.5.5.1.D Amikacin
1) Incompatible
a) Amikacin incompatible with cotrimoxazole; conditions not specified
[526]
3.5.5.1.E Aminophylline
1) Incompatible
a) Aminophylline (incompatible with cotrimoxazole; conditions not specified)
[506]
3.5.5.1.F Amphotericin B
1) Incompatible
[506]
a) Amphotericin B (incompatible with cotrimoxazole; conditions not specified)
[507]
b) Cotrimoxazole (incompatible with amphotericin B; conditions not specified)
3.5.5.1.G Atracurium
1) Compatible
a) Atracurium (500 mcg/mL with cotrimoxazole - trimethoprim 640 mcg/mL and sulfamethoxazole 3.2 mg/mL - visually compatible for
[518]
24 hours at 28 degrees C in Dextrose 5% in water under fluorescent light)
3.5.5.1.H Aztreonam
1) Compatible
a) Aztreonam 40 mg/mL in 5% Dextrose in water with trimethoprim- sulfamethoxazole 0.8/4 mg/mL in Dextrose 5% in water,
[511]
compatible for up to 4 hours at 23 degrees C
3.5.5.1.I Cefamandole
1) Incompatible
a) Cefamandole incompatible with cotrimoxazole; conditions not specified
3.5.5.1.J Cefazolin
1) Incompatible
a) Cefazolin (incompatible with cotrimoxazole; conditions not specified)
[525]
[506]
3.5.5.1.K Cefotaxime
1) Incompatible
[523]
a) Cotrimoxazole (incompatible with cefotaxime; conditions not specified)
[506]
b) Cefotaxime (incompatible with cotrimoxazole; conditions not specified)
3.5.5.1.L Cefoxitin
1) Incompatible
a) Cefoxitin (incompatible with cotrimoxazole; conditions not specified)
[506]
3.5.5.1.M Cephalothin
1) Incompatible
a) Cephalothin (incompatible with cotrimoxazole; conditions not specified)
3.5.5.1.N Cephapirin
1) Incompatible
a) Cephapirin (incompatible with cotrimoxazole; conditions not specified)
[506]
[506]
3.5.5.1.O Cyclosporine
1) Compatible
a) Cotrimoxazole (trimethoprim 0.8 mg/mL and sulfamethoxazole 4 mg/mL) with cyclosporine 2.5 mg/mL all in Dextrose 5% in water
visually compatible for a 4-hour study period at 25 degrees C under fluorescent light (Fanikos et al, 1987)
3.5.5.1.P Enalaprilat
1) Compatible
a) Cotrimoxazole (sulfamethoxazole 1.6 mg/mL and trimethoprim 800 mcg/mL) in Dextrose 5% in water with enalaprilat 50 mcg/mL in
[519]
Sodium chloride 0.9%, visually compatible for 24 hours at room temperature under fluorescent light
3.5.5.1.Q Esmolol
1) Compatible
a) Cotrimoxazole (trimethoprim 0.64 mg/mL and sulfamethoxazole 3.2 mg/mL with esmolol 10 mg/mL visually compatible for 24 hours
[536]
at 22 degrees C in Dextrose 5% in water under fluorescent light)
3.5.5.1.R Fenoldopam Mesylate
1) Compatible
a) Fenoldopam mesylate 80 mcg/mL in Sodium chloride 0.9% injection with trimethoprim-sulfamethoxazole 4/0.8 mg/mL in Sodium
chloride 0.9% injection, visually and physically compatible for up to 4 hours at 23 degrees C in a clear glass tube under constant
[530]
fluorescent light during simulated Y-site administration
.
3.5.5.1.S Filgrastim
1) Compatible
a) Trimethoprim-sulfamethoxazole 0.8 mg/4 mL in Dextrose 5% in water with filgrastim 30 mcg/mL in Dextrose 5% in water,
[531]
compatible for up to 4 hours at 22 degrees C
3.5.5.1.T Fluconazole
1) Incompatible
a) Fluconazole 2 milligrams/milliliter (mg/mL) with cotrimoxazole (trimethoprim/sulfamethoxazole 16 mg/mL), visually incompatible,
[542]
gel-like substance reported
3.5.5.1.U Fludarabine
1) Compatible
a) Cotrimoxazole (trimethoprim 0.8 mg/mL and sulfamethoxazole 4 mg/mL) with fludarabine 1 mg/mL, both in Dextrose 5% in water,
[517]
visually compatible for a 4-hour study period at room temperature under fluorescent light
3.5.5.1.V Folic Acid
1) Incompatible
a) Cotrimoxazole (sulfonamides with folic acid, precipitate formation reported; conditions not specified)
[538]
b) Folic acid (with sulfonamides, precipitate formation reported; conditions not specified)
[537]
3.5.5.1.W Foscarnet
1) Conflicting Data
a) Incompatible
1) Foscarnet 24 mg/mL with cotrimoxazole 16 mg/mL, immediate precipitate formation with gas production reported; individual
[543]
trimethoprim and sulfamethoxazole concentrations not stated
b) Compatible
1) Cotrimoxazole (trimethoprim 0.53 mg/mL and sulfamethoxazole 2.6 mg/mL) with foscarnet 24 mg/mL, visually compatible,
macroscopically and microscopically, in Dextrose 5% in water or Sodium chloride 0.9% for 24 hours at 25 degrees C under fluorescent
[540]
light
3.5.5.1.X Gallium Nitrate
1) Compatible
a) Gallium nitrate (Ganite(R)) 1 mg/mL admixed from a plastic syringe in a 1:1 ratio simulating Y-site administration with trimethoprim
0.8 mg/mL and sulfamethoxazole 4 mg/mL, all solutions in Sodium chloride 0.9%, visually compatible for up to 24 hours stored at
[521]
room temperature under fluorescent light in a glass container; chemical stability not tested
3.5.5.1.Y Gentamicin
1) Incompatible
a) Gentamicin (incompatible with cotrimoxazole; conditions not specified)
[506]
3.5.5.1.Z Granisetron Hydrochloride
1) Compatible
a) Granisetron hydrochloride diluted with 5% dextrose injection to a concentration of 50 mcg/mL is compatible with
trimethoprim/sulfamethoxazole at a concentration of 0.8/4 mg/mL (D5W) during simulated Y-site injection. Compatibility was
measured using visual examinations in fluorescent light and in high-intensity monodirectional light. Turbidity, particle size and particle
counts were completed for certain solutions. The mixtures were assessed at 1 and 4 hours (Trissel, 1997).
3.5.5.1.AA Heparin
1) Compatible
a) Cotrimoxazole (trimethoprim 80 mg/5 mL and sulfamethoxazole 400 mg/5 mL) with heparin 2500 U/1 mL, physically compatible for
[535]
at least 5 minutes in direct admixture in syringe
3.5.5.1.AB Hydromorphone
1) Compatible
a) Cotrimoxazole (trimethoprim 0.8 mg/mL and sulfamethoxazole 4 mg/mL with hydromorphone 0.2 mg/mL visually compatible for a
[512]
4-hour study period at 25 degrees C in Dextrose 5% in water under fluorescent light)
3.5.5.1.AC Labetalol
1) Compatible
a) Cotrimoxazole (trimethoprim 0.8 mg/mL and sulfamethoxazole 4 mg/mL) with labetalol 1 mg/mL, visually compatible for 24 hours
[520]
at 18 degrees C in Dextrose 5% in water under fluorescent light
.
3.5.5.1.AD Linezolid
1) Conflicting Data
a) Incompatible
[532]
1) Trimethoprim/sulfamethoxazole was physically incompatible with linezolid in simulated Y-site administration
; however, another
[533]
source describes conditions under which these drugs were found to be compatible
.
b) Compatible
1) Linezolid 2 mg/mL (tested undiluted) with sulfamethoxazole 4 mg/mL plus trimethoprim 0.8 mg/mL (diluted in 5% dextrose for
injection) is physically compatible for 4 hours at room temperature (approximately 23 degrees C) under fluorescent light during
[533]
[532]
simulated Y-site administration
; however, another source describes these drugs as incompatible
.
3.5.5.1.AE Magnesium Sulfate
1) Compatible
a) Magnesium sulfate (16.7, 33.3, 66.7 or 100 g/L with cotrimoxazole - trimethoprim 800 mg/L and sulfamethoxazole 4 g/L - visually
[515]
compatible for a 4-hour study period at 32 degrees C in Dextrose 5% in water under fluorescent lights)
3.5.5.1.AF Meperidine
1) Compatible
a) Cotrimoxazole - trimethoprim 800 mg/L and sulfamethoxazole 4 g/L - with meperidine 10 g/L, visually compatible for a 4-hour study
[522]
period at 25 degrees C in Dextrose 5% in water under fluorescent light
3.5.5.1.AG Morphine
1) Compatible
a) Cotrimoxazole (trimethoprim 0.8 mg/mL and sulfamethoxazole 4 mg/mL with morphine 1 mg/mL visually compatible for 4 hour
[546]
study period at 25 degrees C in Dextrose 5% in water under fluorescent light)
3.5.5.1.AH Moxalactam
1) Incompatible
[506]
a) Moxalactam (incompatible with cotrimoxazole; conditions not specified)
.
3.5.5.1.AI Nicardipine Hydrochloride
1) Compatible
a) Cotrimoxazole (trimethoprim 160 mcg/mL and sulfamethoxazole 800 mcg/mL) with nicardipine hydrochloride 100 mcg/mL, visually
[539]
compatible for 24 hours at room temperature in dextrose 5% in water under fluorescent light
3.5.5.1.AJ Pancuronium
1) Compatible
a) Cotrimoxazole (trimethoprim 0.64 mg/mL and sulfamethoxazole 3.2 mg/mL) with pancuronium 0.05 mg/mL, visually compatible for
[528]
24 hours at 28 degrees C in Dextrose 5% in water under fluorescent light
3.5.5.1.AK Perphenazine
1) Compatible
a) Cotrimoxazole (trimethoprim 0.8 mg/mL and sulfamethoxazole 4 mg/mL) with perphenazine 20 mg/L, visually compatible for a 4[545]
hour study period in Dextrose 5% in water at 25 degrees C under fluorescent light
3.5.5.1.AL Piperacillin Sodium/Tazobactam Sodium
1) Compatible
a) Piperacillin sodium 40 mg/mL plus tazobactam 5 mg/mL in Dextrose 5% in water with trimethoprim/sulfamethoxazole 0.8/4 mg/mL
[541]
in Dextrose 5% in water, compatible for 4 hours at 22 degrees C
3.5.5.1.AM Sargramostim
1) Compatible
a) Trimethoprim 0.8 mg/mL and sulfamethoxazole 4 mg/mL with sargramostim 10 mcg/mL, both in sodium chloride 0.9%, visually
[514]
compatible for a 4-hour study period at 22 degrees C under fluorescent light
3.5.5.1.AN Tacrolimus
1) Compatible
a) Cotrimoxazole (trimethoprim 16 mg/mL with sulfamethoxazole 8 mg/mL) in 5% Dextrose injection with tacrolimus 1 mg/mL in 0.9%
[544]
Sodium chloride injection, visually compatible for 24 hours at room temperature under fluorescent light
3.5.5.1.AO Tetracycline
1) Incompatible
a) Tetracycline (incompatible with cotrimoxazole; conditions not specified)
[506]
3.5.5.1.AP Tobramycin
1) Incompatible
a) Cotrimoxazole (incompatible with tobramycin in Dextrose 5% in water; drug concentrations not specified)
[506]
b) Tobramycin (incompatible with cotrimoxazole; conditions not specified)
3.5.5.1.AQ Vancomycin
1) Incompatible
a) Cotrimoxazole (incompatible with vancomycin; conditions not specified)
b) Vancomycin (incompatible with cotrimoxazole; conditions not specified)
[513]
[524]
[506]
3.5.5.1.AR Vecuronium
1) Compatible
a) Cotrimoxazole (trimethoprim 0.64 mg/mL and sulfamethoxazole 3.2 mg/mL) with vecuronium 0.1 mg/mL, visually compatible for 24
[534]
hours at 28 degrees C in Dextrose 5% in water under fluorescent light
3.5.5.1.AS Verapamil
1) Incompatible
a) Cotrimoxazole (trimethoprim 160 mg/L and sulfamethoxazole 800 mg/L) with verapamil 80 mg/L, visually incompatible due to
[509]
formation of a transient precipitate
3.5.5.1.AT Vinorelbine
1) Incompatible
a) Cotrimoxazole (trimethoprim 0.8 mg/mL and sulfamethoxazole 4 mg/mL) in Sodium chloride 0.9% with vinorelbine tartrate 1 mg/mL
[529]
in Sodium chloride 0.9%, heavy white turbidity formed immediately, developing into particles in 1 hour
3.5.5.1.AU Zidovudine
1) Compatible
a) Cotrimoxazole (trimethoprim 530 mg/L and sulfamethoxazole 2.6 g/L) with zidovudine 4 g/L in Dextrose 5% in water, visually
compatible, macroscopically and microscopically, for a 4-hour study period at 25 degrees C under fluorescent light in a polyolefin
[516]
container
3.5.5.2 Solutions
Dextrose 5% in sodium chloride 0.45%
Dextrose 5% in water
LACTATED RINGER'S INJECTION
SODIUM CHLORIDE 0.45%
Sodium chloride 0.9%
SODIUM CHLORIDE 0.9%
TOTAL PARENTERAL NUTRITION
3.5.5.2.A Dextrose 5% in sodium chloride 0.45%
1) Compatible
a) Dextrose 5% in sodium chloride 0.45% (with cotrimoxazole physically compatible for 24 hours at 24 degrees C with no
[104]
sulfamethoxazole decomposition and 6% or less trimethoprim decomposition; specific drug concentrations listed below)
:
trimethoprim 640 mg/L and sulfamethoxazole 3.2 g/L
trimethoprim 800 mg/L and sulfamethoxazole 4 g/L
trimethoprim 1.07 g/L and sulfamethoxazole 5.33 g/L
trimethoprim 1.6 g/L and sulfamethoxazole 8 g/L
b) Cotrimoxazole in DEXTROSE 5% IN SODIUM CHLORIDE 0.45%, physically compatible for 24 hours at 24 degrees C with no
[547]
sulfamethoxazole decomposition and 6% or less trimethoprim decomposition; specific drug concentrations listed below
:
Trimethoprim 642 mg/L and sulfamethoxazole 3.2 g/L
Trimethoprim 800 mg/L and sulfamethoxazole 4 g/L
Trimethoprim 1.07 g/L and sulfamethoxazole 5.33 g/L
Trimethoprim 1.6 g/L and sulfamethoxazole 8 g/L
3.5.5.2.B Dextrose 5% in water
1) Conflicting Data
a) Incompatible
1) Dextrose 5% in water (with cotrimoxazole - trimethoprim 640 mg and sulfamethoxazole 3.2 g/L or trimethoprim 1.6 g/L and
sulfamethoxazole 8 g/L - visually compatible and 5% trimethoprim decomposition in 2 hours at 22 degrees C, but turbidity and
precipitation appear after this time and trimethoprim decomposition increases to 28% to 64% in 24 hours; 1% to 3% sulfamethoxazole
decomposition in 24 hours; with cotrimoxazole - trimethoprim 3.2 g/L and sulfamethoxazole 16 g/L, precipitation formation reported
within 30 minutes and 32% trimethoprim decomposition reported within 1 hour, but only 9% sulfamethoxazole decomposition in 24
[548]
hours at 22 degrees C)
; (another source, however, describes the 2 lower concentrations as compatible with Dextrose 5% in water
[104]
at 24 degrees C)
2) Dextrose 5% in water (with cotrimoxazole 5 mL - trimethoprim 80 mg/5 mL and sulfamethoxazole 400 mg/5 mL - in a 1:20 v/v
dilution - trimethoprim 800 mg/L and sulfamethoxazole 4 g/L - 0% to 5% trimethoprim decomposition and no sulfamethoxazole
decomposition in 48 hours at 24 degrees C, but precipitate was detected at this time in one sample (Septra(R)); in a 1:15 v/v dilution trimethoprim 1.07 g/L and sulfamethoxazole 5.33 g/L - precipitate formation reported within 8 to 14 hours at 24 degrees C; in a 1:10
[500]
v/v dilution - trimethoprim 1.6 g/L and sulfamethoxazole 8 g/L - precipitate formation reported within 2 to 4 hours at 24 degrees C)
b) Compatible
1) Dextrose 5% in water (with cotrimoxazole physically compatible for 24 hours at 24 degrees C with no sulfamethoxazole
[104]
decomposition and 4% or less trimethoprim decomposition; specific drug concentrations listed below)
:
trimethoprim 640 mg/L and sulfamethoxazole 3.2 g/L
trimethoprim 800 mg/L and sulfamethoxazole 4 g/L
trimethoprim 1.07 g/L and sulfamethoxazole 5.33 g/L
trimethoprim 1.6 g/L and sulfamethoxazole 8 g/L
2) (another source, however, describes significant decomposition of trimethoprim in the 3 lower concentrations in Dextrose 5% in water
[548]
at 22 degrees C)
3) Dextrose 5% in water (with cotrimoxazole 5 mL - trimethoprim 80 mg/5 mL and sulfamethoxazole 400 mg/5 mL - in a 1:25 v/v
dilution - trimethoprim 640 mg/L and sulfamethoxazole 3.2 g/L - both drugs stable for 48 hours at 24 degrees C; in a 1:20 v/v dilution trimethoprim 800 mg/L and sulfamethoxazole 4 g/L - 0% to 5% trimethoprim decomposition and no sulfamethoxazole decomposition
in 48 hours at 24 degrees C, but precipitate was detected at this time in one sample (Septra(R)); in a 1:15 v/v dilution - trimethoprim
1.07 g/L and sulfamethoxazole 5.33 g/L - visually compatible for 4 hours at 24 degrees C without significant decomposition of either
drug; in a 1:10 v/v dilution - trimethoprim 1.6 g/L and sulfamethoxazole 8 g/L - visually compatible for 1 hour at 24 degrees C without
[500]
significant decomposition of either drug)
3.5.5.2.C LACTATED RINGER'S INJECTION
1) Conflicting Data
a) Incompatible
1) Lactated Ringer's injection (with cotrimoxazole - trimethoprim 1.6 g/L and sulfamethoxazole 8 g/L - visually compatible and both
drugs chemically stable for 12 hours at 24 degrees C, but precipitate formation was reported with a 26% decrease in trimethoprim
[104]
concentration at 24 hours in 1 of 4 samples; no sulfamethoxazole decomposition observed in 24 hours)
b) Compatible
1) Lactated Ringer's injection (with cotrimoxazole physically compatible for 24 hours at 24 degrees C with no sulfamethoxazole
[104]
decomposition and 4% trimethoprim decomposition; specific drug concentrations listed below)
:
trimethoprim 640 mg/L and sulfamethoxazole 3.2 g/L
trimethoprim 800 mg/L and sulfamethoxazole 4 g/L
trimethoprim 1.07 g/L and sulfamethoxazole 5.33 g/L
3.5.5.2.D SODIUM CHLORIDE 0.45%
1) Compatible
a) Cotrimoxazole in SODIUM CHLORIDE 0.45%, physically compatible for 24 hours at 24 degrees C with no sulfamethoxazole
[547]
decomposition and 4% trimethoprim decomposition; specific drug concentrations listed below
:
Trimethoprim 640 mg/L and sulfamethoxazole 3.2 g/L
Trimethoprim 800 mg/L and sulfamethoxazole 4 g/L
Trimethoprim 1.07 g/L and sulfamethoxazole 5.33 g/L
Trimethoprim 1.6 g/L and sulfamethoxazole 8 g/L
3.5.5.2.E Sodium chloride 0.9%
1) Incompatible
a) Cotrimoxazole (trimethoprim 640 mg and sulfamethoxazole 3.2 g/L) in Sodium chloride 0.9%, visually compatible and 1%
trimethoprim decomposition in 4 hours at 22 degrees C, but turbidity and precipitation appear after 4 hours and trimethoprim
[551]
decomposition increases to 36% in 24 hours; no sulfamethoxazole decomposition in 24 hours
b) Cotrimoxazole (trimethoprim 1.6 g/L and sulfamethoxazole 8 g/L) in Sodium chloride 0.9%, visually compatible but 15%
trimethoprim decomposition in 2 hours at 22 degrees C and turbidity appears after this time and trimethoprim decomposition increases
[551]
to 76% in 24 hours; 5% sulfamethoxazole decomposition in 24 hours
c) Cotrimoxazole (trimethoprim 3.2 g/L and sulfamethoxazole 16 g/L) in Sodium chloride 0.9%, precipitation formation reported within
30 minutes and 74% trimethoprim decomposition reported within 1 hour, but only 6% sulfamethoxazole decomposition in 24 hours at
[551]
22 degrees C
d) Cotrimoxazole 5 mL (trimethoprim 80 mg/5 mL and sulfamethoxazole 400 mg/5 mL) in a 1:20 v/v dilution in Sodium chloride 0.9% yielding final concentrations of trimethoprim 800 mg/L and sulfamethoxazole 4 g/L, 2% to 10% trimethoprim decomposition and no
sulfamethoxazole decomposition in 24 hours at 24 degrees C, but precipitate was detected at this time in one sample (Bactrim(R))and
[552]
precipitate developed within 48 hours in another sample (Septra(R))
e) Cotrimoxazole 5 mL (trimethoprim 80 mg/5 mL and sulfamethoxazole 400 mg/5 mL) in a 1:15 v/v dilution in Sodium chloride 0.9% yielding final concentrations of trimethoprim 1.07 g/L and sulfamethoxazole 5.33 g/L, precipitate formation reported within 4 to 8 hours
[552]
at 24 degrees C
3.5.5.2.F SODIUM CHLORIDE 0.9%
1) Compatible
a) Cotrimoxazole in SODIUM CHLORIDE 0.9%, physically compatible for 24 hours at 24 degrees C with no sulfamethoxazole
[547]
decomposition and 7% or less trimethoprim decomposition; specific drug concentrations listed below
:
Trimethoprim 640 mg/L and sulfamethoxazole 3.2 g/L
Trimethoprim 800 mg/L and sulfamethoxazole 4 g/L
Trimethoprim 1.07 mg/L and sulfamethoxazole 5.33 g/L
Trimethoprim 1.6 mg/L and sulfamethoxazole 8 g/L
b) Another source, however, describes significant decomposition of trimethoprim in the 3 lower concentrations in sodium chloride 0.9%
[549]
at 22 degrees C
c) Cotrimoxazole in sodium chloride 0.9% - trimethoprim 80 mg/5 mL and sulfamethoxazole 400 mg/5 mL - in a 1:25 v/v dilution [550]
trimethoprim 640 mg/L and sulfamethoxazole 3.2 g/L - both drugs stable for 48 hours at 24 degrees C
d) Cotrimoxazole in a 1:20 v/v dilution in sodium chloride 0.9% - trimethoprim 800 mg/L and sulfamethoxazole 4 g/L - 2% to 10%
trimethoprim decomposition and no sulfamethoxazole decomposition in 24 hours at 24 degrees C, but precipitate was detected at this
[550]
time in one sample (Bactrim(R))
e) Cotrimoxazole in a 1:15 v/v dilution in sodium chloride 0.9% - trimethoprim 1.07 g/L and sulfamethoxazole 5.33 g/L - visually
[550]
compatible for 2 hours at 24 degrees C without significant decomposition of either drug
f) Cotrimoxazole in a 1:10 v/v dilution in sodium chloride 0.9% - trimethoprim 1.6 g/L and sulfamethoxazole 8 g/L - visually compatible
[550]
for 1 hour at 24 degrees C without significant decomposition of either drug
3.5.5.2.G TOTAL PARENTERAL NUTRITION
1) Conflicting Data
a) Incompatible
[554]
1) Cotrimoxazole incompatible with total parenteral nutrition; conditions and composition of TPN not specified
b) Compatible
1) Trimethoprim 0.8 mg/mL and sulfamethoxazole 4 mg/mL in Dextrose 5% in water added to total parenteral nutrition solution
compatible in simulated Y-site administration for 4 hours at 23 degrees C; specific composition of total parenteral nutrition solution listed
[553]
below
:
Amino acids 10% (Aminosyn(R) II) 3.5%
Dextrose
5%
Sterile water for injection
516.8 mL
Potassium phosphates
3.5 mM
Sodium chloride
25 mEq
Potassium chloride
35 mEq
Magnesium sulfate
8 mEq
Multivitamins
10 mL
Trace elements
1 mL
Calcium gluconate
9.3 mEq
2) Trimethoprim 0.8 mg/mL and sulfamethoxazole 4 mg/mL in Dextrose 5% in water added to total parenteral nutrition solution
compatible in simulated Y-site administration for 4 hours at 23 degrees C; specific composition of total parenteral nutrition solution listed
[553]
below
:
Amino acids 10% (FreAmine(R) III) 3.5%
Dextrose
5%
Sterile water for injection
516.75 mL
Sodium chloride
37.5 mEq
Potassium chloride
40 mEq
Magnesium sulfate
8 mEq
Multivitamins
10 mL
Trace elements
1 mL
Calcium gluconate
5 mEq
3) Trimethoprim 0.8 mg/mL and sulfamethoxazole 4 mg/mL in Dextrose 5% in water added to total parenteral nutrition solution
compatible in simulated Y-site administration for 4 hours at 23 degrees C; specific composition of total parenteral nutrition solution listed
[553]
below
:
Amino acids 10% (Aminosyn(R) II) 4.25%
Dextrose
25%
Sterile water for injection
161 mL
Potassium phosphates
15 mM
Sodium chloride
25 mEq
Potassium chloride
18 mEq
Magnesium sulfate
8 mEq
Multivitamins
10 mL
Trace elements
1 mL
Calcium gluconate
9.15 mEq
4) Trimethoprim 0.8 mg/mL and sulfamethoxazole 4 mg/mL in Dextrose 5% in water added to total parenteral nutrition solution
compatible in simulated Y-site administration for 4 hours at 23 degrees C; specific composition of total parenteral nutrition solution listed
[553]
below
:
Amino acids 10% (FreAmine(R) III) 4.25%
Dextrose
25%
Sterile water for injection
158.6 mL
Potassium phosphates
5.75 mM
Sodium chloride
40 mEq
Potassium chloride
25 mEq
Magnesium sulfate
8 mEq
Multivitamins
Trace elements
Calcium gluconate
10 mL
1 mL
7.5 mEq
4.0 Clinical Applications
Monitoring Parameters
Patient Instructions
Place In Therapy
Mechanism of Action / Pharmacology
Therapeutic Uses
Comparative Efficacy / Evaluation With Other Therapies
4.1 Monitoring Parameters
A) Therapeutic
1) Laboratory Parameters
a) Monitor white blood cell count; repeat culture and sensitivities if necessary
2) Physical Findings
a) Monitor signs and symptoms of infection.
B) Toxic
1) Laboratory Parameters
a) Monitor renal and liver function tests, serum potassium. When COTRIMOXAZOLE is used in children for prophylaxis of P carinii
pneumonia a complete blood count with differential and platelet count should be performed when therapy is initiated and then at
[496]
monthly intervals
.
4.2 Patient Instructions
A) Sulfamethoxazole/Trimethoprim (By mouth)
Sulfamethoxazole/Trimethoprim
Treats or prevents infections. This medicine is a "sulfa drug" (sulfonamide).
When This Medicine Should Not Be Used:
You should not use this medicine if you have had an allergic reaction to trimethoprim, sulfamethoxazole, or any sulfa drug. Do not use
this medicine if you are pregnant or breastfeeding, or in some situations if you have severe liver or kidney problems. You should not
use this medicine if you have anemia (a problem with your blood) caused by not having enough folic acid in your body. You should not
use this medicine if you have a history of drug-induced thrombocytopenia (low platelets in the blood). This medicine should not be given
to infants younger than 2 months of age.
How to Use This Medicine:
Liquid, Tablet
Your doctor will tell you how much of this medicine to use and how often. Do not use more medicine or use it more often than your
doctor tells you to.
Measure the oral liquid medicine with a marked measuring spoon, oral syringe, or medicine cup.
Drink extra fluids so you will pass more urine while you are using this medicine. This will keep your kidneys working well and help
prevent kidney problems.
Keep using this medicine for the full treatment time, even if you feel better after the first few doses. Your infection may not clear up if
you stop using the medicine too soon.
If a Dose is Missed:
If you miss a dose or forget to use your medicine, use it as soon as you can. If it is almost time for your next dose, wait until then to use
the medicine and skip the missed dose. Do not use extra medicine to make up for a missed dose.
How to Store and Dispose of This Medicine:
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Do not freeze the oral liquid.
Ask your pharmacist, doctor, or health caregiver about the best way to dispose of any leftover medicine after you have finished your
treatment. You will also need to throw away old medicine after the expiration date has passed.
Keep all medicine away from children and never share your medicine with anyone.
Drugs and Foods to Avoid:
Ask your doctor or pharmacist before using any other medicine, including over-the-counter medicines, vitamins, and herbal products.
Make sure your doctor knows if you are also using a diuretic or "water pill" (such as hydrochlorothiazide, spironolactone, triamterene,
Aldactazide®, Aldactone®, Dyazide®, Hyzaar®, Maxzide®, or Moduretic®), certain blood pressure medicine (such as enalapril,
lisinopril, Accupril®, Lotrel®, or Zestril®), digoxin (Lanoxin®), indomethacin (Indocin®), or a blood thinner (such as warfarin,
Coumadin®).
Make sure your doctor knows if you are also using medicines to treat depression (such as amitriptyline, nortriptyline, Norpramin®, or
Vivactil®), amantadine (Symmetrel®), cyclosporine (Gengraf®, Neoral®, Sandimmune®), methotrexate (Rheumatrex®, Trexall®),
phenytoin (Dilantin®), diabetes medicine that you take by mouth (such as glipizide, glyburide, metformin, Actos®, Avandia®,
Glucotrol®, Glucophage®, or Glucovance®), or medicine to prevent malaria (such as pyrimethamine, Daraprim®).
Warnings While Using This Medicine:
Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting
pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.
Make sure your doctor knows if you have kidney disease, liver disease, diabetes, malabsorption syndrome (difficulty of absorbing food
in the body), malnutrition state (nutrition disorder), folate (vitamin B9) deficiency, high potassium in the blood, porphyria, thyroid
problems, a history of alcoholism, or if you are taking medicines to prevent seizures. Tell your doctor if you have asthma or severe
allergies, especially if you are allergic to any medicines. It is important for your doctor to know if you have HIV or AIDS, because this
medicine might work differently. Tell your doctor if you have a rare condition called glucose-6-phosphate dehydrogenase (G6PD)
deficiency.
Very rarely, this medicine has caused severe side effects. If you or your child start to have a skin rash, or if you think you are having a
severe reaction, stop taking this medicine and call your doctor right away. Symptoms of a severe reaction include a sore throat, fever,
muscle pain, cough, and trouble breathing. Other symptoms are a skin rash, or the color of your skin turning very pale or yellow, or
having purple spots.
This medicine, especially if you are receiving high doses or for a long period of time, may lower the number of platelets in your body,
which are necessary for proper blood clotting. Because of this, you may bleed or get infections more easily. Talk with your doctor if you
have concerns about this.
If you have severe diarrhea, ask your doctor before taking any medicine to stop the diarrhea. Check with your doctor right away if the
diarrhea continues. Diarrhea may occur 2 months or more after you stop taking this medicine.
This medicine may make your skin more sensitive to sunlight. Use a sunscreen when you are outdoors. Avoid sunlamps and tanning
beds.
Your doctor will need to check your progress at regular visits while you are using this medicine. Be sure to keep all appointments. Blood
and urine tests may be needed to check for unwanted effects.
Make sure any doctor or dentist who treats you knows that you are using this medicine. This medicine may affect the results of certain
medical tests.
Possible Side Effects While Using This Medicine:
Call your doctor right away if you notice any of these side effects:
Allergic reaction: Itching or hives, swelling in your face or hands, swelling or tingling in your mouth or throat, chest tightness, trouble
breathing
Blistering, peeling, or red skin rash.
Chest pain, cough, or shortness of breath.
Confusion, weakness, uneven heartbeat, shortness of breath, or numbness or tingling in your hands, feet, or lips.
Diarrhea that may contain blood.
Muscle twitching.
Severe nausea, vomiting, dizziness, or headache.
Severe stomach pain, cramps, or bloating.
Unusual bleeding or bruising.
Unusual tiredness or weakness.
Yellowing of your skin or the whites of your eyes.
If you notice these less serious side effects, talk with your doctor:
Mild nausea, vomiting, or loss of appetite.
If you notice other side effects that you think are caused by this medicine, tell your doctor.
B) Sulfamethoxazole/Trimethoprim (Injection)
Sulfamethoxazole/Trimethoprim
Treats severe infections caused by bacteria (germs). This medicine is a "sulfa drug" (sulfonamide).
When This Medicine Should Not Be Used:
You should not use this medicine if you have had an allergic reaction to trimethoprim, sulfamethoxazole, or any sulfa drug. Do not use
this medicine if you are pregnant or breast feeding. You should not use this medicine if you have anemia (a problem with your blood)
caused by not having enough folic acid in your body. This medicine should not be given to infants under 2 months of age.
How to Use This Medicine:
Injectable
Your doctor will prescribe your exact dose and tell you how often it should be given. This medicine is given through a needle placed in
one of your veins.
A nurse or other trained health professional will give you this medicine.
You may be taught how to give your medicine at home. Make sure you understand all instructions before giving yourself an injection.
Do not use more medicine or use it more often than your doctor tells you to.
Use a new needle and syringe each time you inject your medicine.
Drink extra fluids so you will pass more urine while you are using this medicine. This will keep your kidneys working well and help
prevent kidney problems.
Keep using this medicine for the full treatment time, even if you feel better after the first few doses. Your infection may not clear up if
you stop using the medicine too soon.
If a Dose is Missed:
This medicine needs to be given on a fixed schedule. If you miss a dose or forget to use your medicine, call your doctor or pharmacist
for instructions.
How to Store and Dispose of This Medicine:
If you store this medicine at home, keep it at room temperature, away from heat and direct light.
Throw away used needles in a hard, closed container that the needles cannot poke through. Keep this container away from children
and pets.
Ask your pharmacist, doctor, or health caregiver about the best way to dispose of any leftover medicine, containers, and other supplies.
You will also need to throw away old medicine after the expiration date has passed.
Keep all medicine away from children and never share your medicine with anyone.
Drugs and Foods to Avoid:
Ask your doctor or pharmacist before using any other medicine, including over-the-counter medicines, vitamins, and herbal products.
Make sure your doctor knows if you are also using methotrexate (Rheumatrex®), diuretics or "water pills" (such as hydrochlorothiazide,
Aldactazide®, Diuril®, Dyazide®, Enduron®, Maxzide®, Zaroxolyn®).
Tell your doctor if you are also using medicine for seizures (such as Depakote®, Dilantin®, Keppra™, Luminal®, Tegretol®).
Warnings While Using This Medicine:
Make sure your doctor knows if you have HIV or AIDS, liver disease, kidney disease, asthma, epilepsy (seizures), or G6PD (glucose 6phosphate dehydrogenase deficiency), or if you drink large amounts of alcohol.
Your doctor will need to check your blood or urine at regular visits while you are using this medicine. Be sure to keep all appointments.
If you have severe diarrhea, ask your doctor before taking any medicine to stop the diarrhea.
Very rarely, this medicine has caused severe side effects. If you start to have a skin rash, or if you think you are having a severe
reaction, stop taking this medicine and call your doctor right away. Symptoms of a severe reaction include a sore throat, fever, muscle
pain, cough, and trouble breathing. Other symptoms are a skin rash, or the color of your skin turning very pale or yellow, or having
purple spots.
Make sure any doctor or dentist who treats you knows that you are using this medicine. This medicine may affect the results of certain
medical tests.
Possible Side Effects While Using This Medicine:
Call your doctor right away if you notice any of these side effects:
Allergic reaction: Itching or hives, swelling in your face or hands, swelling or tingling in your mouth or throat, chest tightness, trouble
breathing
Blistering, peeling, red skin rash.
Dark-colored urine or pale stools.
Diarrhea.
Fever, sore throat, pale skin, body aches.
Loss of appetite, pain in your upper stomach.
Nausea, vomiting, dizziness, confusion.
Unusual bleeding, bruising, or weakness.
Yellowing of your skin or the whites of your eyes.
If you notice these less serious side effects, talk with your doctor:
Depression, nervousness.
Headache.
Irritation or swelling of your skin where the needle is placed.
Trouble sleeping.
If you notice other side effects that you think are caused by this medicine, tell your doctor.
4.3 Place In Therapy
A) SUMMARY: Oral cotrimoxazole is used in the treatment acute uncomplicated or chronic urinary tract infections (primarily
pyelonephritis, pyelitis and cystitis) due to susceptible organisms (E coli, Klebsiella-Enterobacter, Proteus mirabilis, indole-positive
proteus species). Cotrimoxazole has also been clinically investigated in the treatment gonorrhea and infections caused by Salmonella
typhi. Cotrimoxazole is used routinely for the treatment of travelers' diarrhea and shigellosis. It is also effective for the treatment of otitis
media. Parenteral and oral cotrimoxazole is used for the treatment of Pneumocystis carinii pneumonia (PCP) in children and adults, and
oral cotrimoxazole is considered the drug of choice for PCP prophylaxis in HIV-infected patients. It has also been used for prophylaxis
in other immunocompromised patients such as transplant patients.
B) SINUSITIS: The recommendation for the management of mild sinusitis is symptomatic treatment and reassurance. Antibiotic
therapy should be reserved for patients with moderately severe symptoms who meet the criteria for the clinical diagnosis of acute
bacterial sinusitis (rhinosinusitis) (symptoms that last greater than 7 days and include maxillary pain in the face or teeth and purulent
nasal secretions) and for those with severe rhinosinusitis symptoms, regardless of duration of illness. In patients with acute bacterial
sinusitis, the use of first-line agents (amoxicillin, trimethoprim-sulfamethoxazole) is associated with similar clinical benefits and
significant cost savings when compared to second-line agents (fluoroquinolones, azithromycin, clarithromycin, second- and thirdgeneration cephalosporins). Appropriate choice of narrow-spectrum antibiotics will also decrease the risk for emergence and spread of
[502][503][504]
antibiotic-resistant bacteria
. Quinolones may have a role for treating highly resistant or multidrug-resistant strains (Brooks et
al, 2000).
C) URINARY TRACT INFECTIONS: Cotrimoxazole is the recommended standard therapy for uncomplicated urinary tract infections in
women. Trimethoprim and fluoroquinolones have similar efficacy. Fluoroquinolones are not recommended as initial empirical therapy
due to issues of cost, as well as restricting use to prevent the development of resistance. Single-dose therapy for the treatment of
uncomplicated urinary tract infections is not recommended due to lower eradication rates; however, 3-day therapy with cotrimoxazole
[505]
has been shown to be as effective as 7-day therapy
.
4.4 Mechanism of Action / Pharmacology
A) MECHANISM OF ACTION
1) Trimethoprim-sulfamethoxazole (cotrimoxazole) is a synthetic antibacterial fixed-ratio combination product containing 1 part of
trimethoprim to 5 parts of sulfamethoxazole. Trimethoprim is 2,4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine. Sulfamethoxazole is
[488]
N-1-(5-methyl-3-isexazolyl) sulfanilamide. The combination demonstrates in vitro synergism and is often bactericidal
.
2) The sulfonamide, sulfamethoxazole, inhibits bacterial synthesis of dihydrofolic acid by competition with para-amino benzoic acid.
Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by reversibly inhibiting the required enzyme,
dihydrofolate reductase, thus blocking 2 consecutive steps necessary for the biosynthesis of nucleic acids and proteins essential to
[475]
many bacteria
.
3) A diuretic action may be observed, particularly when cotrimoxazole is used in patients where an infection is accompanied by an
[489]
edematous state. This effect is due to the sulfonamide, sulfamethoxazole, and its proven inhibition of carbonic anhydrase
.
B) RESISTANCE
1) In the Alexander Project, an international antimicrobial susceptibility surveillance study, 63.3% of Streptococcus pneumonia isolates
(n=8882) were susceptible to sulfamethoxazole/trimethoprim. Out of 26 countries, none had an isolate susceptibility rate greater than
90%. Of the penicillin resistant strains, 89.6% were also resistant to sulfamethoxazole/trimethoprim (range 52.2 - 100%). Of 8523
Haemophilus influenzae isolates, 78.3% were susceptible to sulfamethoxazole/trimethoprim. Resistance, however, did vary between
8.5% in Belgium to 55.2% in Kenya. Of the Moraxella catarrhalis isolates (n=874), 72% were susceptible to
sulfamethoxazole/trimethoprim. Isolates from 26 countries were obtained from blood and sputum samples collected between 1998 to
[490]
2000 and susceptibilities were interpreted using pharmacokinetic/pharmacodynamic breakpoints
.
2) Based on a serial cross-sectional study conducted at San Francisco General Hospital, investigators determined that cotrimoxazole
resistance increased substantially from 1988 to 1995, coincident with growing widespread use of cotrimoxazole prophylaxis in the
human immunodeficiency virus (HIV) population. Among the clinical isolates evaluated (Staphylococcus aureus, Citrobacter,
Escherichia coli, Enterobacter, Klebsiella, Morganella, Proteus, and Serratia), overall resistance rose from less than 5.5% prior to 1987
to 20.4% in 1995. In the subset of HIV hospital units, the corresponding elevation in resistance was even higher (from 6.3% to 53%). In
a breakdown of individual bacterial species, each exhibited significantly greater resistance in the HIV as opposed to non-HIV units, with
the exception of Serratia. For example, 36%, 48% and 74% of Klebsiella, S. aureus and E. coli isolates from HIV-infected patients were
cotrimoxazole-resistant in 1995, versus 0%, 0%, and 24%, respectively, in 1988. Cotrimoxazole-resistant strains of E. coli and S.
aureus in HIV-infected patients were significantly more likely to be resistant to other antibiotics as well. The authors conclude that the
[491]
benefits of long-term cotrimoxazole prophylaxis must be weighed against the public health risks of expanding resistance
.
C) REVIEW ARTICLES
1) A comprehensive review of cotrimoxazole, including antibacterial activity and antiprotozoal activity, pharmacokinetics, dose
[492]
recommendations, therapeutic efficacy, and adverse reactions, is presented
.
[493]
2) A comprehensive review of cotrimoxazole use in children is presented
.
[494]
3) A review on mechanisms of resistance to trimethoprim/sulfonamide combinations is presented
.
[495]
4) A review of the treatment of Pneumocystis carinii infections is presented
.
4.5 Therapeutic Uses
Actinomycotic infection
Acute exacerbation of pulmonary cystic fibrosis
Acute infective exacerbation of chronic obstructive pulmonary disease
Acute otitis media
Aeromonas infection
Bacteremia associated with intravascular line
Bacterial endocarditis
Bacterial gastrointestinal infectious disease - HIV infection
Bacterial keratitis, due to nocardia
Bacterial meningitis
Bacterial respiratory infection; Prophylaxis - HIV infection
Cholera
Chronic purulent otitis media
Crohn's disease
Cyclosporiasis
Diverticulitis
Febrile neutropenia; Prophylaxis
Granuloma inguinale
Hemopoietic stem cell transplant - Pertussis; Prophylaxis
Hemopoietic stem cell transplant - Pneumocystis pneumonia; Prophylaxis
Hemopoietic stem cell transplant - Toxoplasmosis; Prophylaxis
Hemopoietic stem cell transplant - Traveler's diarrhea; Prophylaxis
HIV infection - Opportunistic infection; Prophylaxis
HIV infection - Pneumocystis pneumonia
HIV infection - Pneumocystis pneumonia; Prophylaxis
HIV infection - Toxoplasma encephalitis
HIV infection - Toxoplasma encephalitis; Prophylaxis
Infection by Yersinia enterocolitica
Methicillin resistant Staphylococcus aureus infection; Prophylaxis - Staphylococcal pneumonia; Prophylaxis
Neutropenia - Selective decontamination of the digestive tract
Peritonitis
Pneumocystis pneumonia
Pneumocystis pneumonia; Prophylaxis
Prostatitis
Salmonella infection
Shigellosis
Sinusitis
Stenotrophomonas maltophilia infection
Traveler's diarrhea
Urinary tract infectious disease
Urinary tract infectious disease; Prophylaxis
Urinary tract infectious disease; Prophylaxis - Vesicoureteric reflux, Grades 1 to 4
Wegener's granulomatosis
Whipple's disease
4.5.A Actinomycotic infection
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIa
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
As part of two-phase combination therapy, effectively treated actinomycotic mycetomas
3) Adult:
a) A two-phase schedule with a combination of 3 drugs was effective in treating ACTINOMYCOTIC MYCETOMAS in 7 patients. In the
first phase, patients were hospitalized and treated with intravenous crystalline penicillin 1 million units every 6 hours, intravenous
gentamicin 80 milligrams (mg) twice daily, and oral sulfamethoxazole 400 mg/trimethoprim 80 mg 2 tablets twice a day for 5 to 7
weeks. The patients were then discharged and treated at home with amoxicillin 500 mg 3 times per day and
sulfamethoxazole/trimethoprim at the previous dose for 2 to 5 months after lesions became completely inactive. Discharge of pus from
lesions stopped 7 to 10 days after initiation of treatment and swelling decreased perceptibly within 2 weeks. In the 5 patients who
completed treatment, total duration of maintenance therapy was 6 to 16 months (mean 10.7 months). After stopping therapy, all 5
patients continued to be well during follow-up (up to 16 months). The other 2 patients responded significantly and were continuing
[38]
therapy. Two patients developed adverse reactions to gentamicin; discontinuation of gentamicin reversed the adverse effects .
4.5.B Acute exacerbation of pulmonary cystic fibrosis
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy; Pediatric, Evidence favors efficacy
Recommendation: Adult, Class IIb; Pediatric, Class IIb
Strength of Evidence: Adult, Category C; Pediatric, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
For the treatment of mixed infections with Burkholderia cepacia and Pseudomonas aeruginosa, ceftazidime with chloramphenicol or
[18]
sulfamethoxazole/trimethoprim is recommended
3) Adult:
a) Sulfamethoxazole/trimethoprim has been given chronically (alone or in combination with chloramphenicol) to patients with CYSTIC
FIBROSIS to suppress the growth of Burkholderia cepacia in the respiratory tract. This practice is controversial given that chronic
administration of antibiotics may increase the incidence of antibiotic-resistant bacteria. Further study is necessary to evaluate the
[18]
efficacy of cefuroxime for this use .
b) Sulfamethoxazole/trimethoprim is considered the drug of choice for the treatment of infections caused by Burkholderia
[19]
(Pseudomonas) cepacia .
4) Pediatric:
a) The dose of sulfamethoxazole/trimethoprim recommended to treat cystic fibrosis patients with acute pulmonary exacerbations is
sulfamethoxazole 25 milligrams/kilogram (mg/kg)/trimethoprim 5 mg/kg every 6 hours. For the treatment of infections caused by
Burkholderia cepacia, sulfamethoxazole/trimethoprim may be administered alone or in combination with chloramphenicol. For the
treatment of mixed infections with Burkholderia cepacia and Pseudomonas aeruginosa ceftazidime with chloramphenicol or
[18]
sulfamethoxazole/trimethoprim is recommended .
4.5.C Acute infective exacerbation of chronic obstructive pulmonary disease
FDA Labeled Indication
1) Overview
FDA Approval: Adult, yes; Pediatric, no
Efficacy: Adult, Effective; Pediatric, Effective
Recommendation: Adult, Class IIa; Pediatric, Class IIa
Strength of Evidence: Adult, Category B; Pediatric, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Indicated for treating acute exacerbations of chronic bronchitis due to susceptible strains of Haemophilus influenzae or S pneumonia in
[1][2]
adults
4.5.D Acute otitis media
FDA Labeled Indication
1) Overview
FDA Approval: Adult, no; Pediatric, yes (2 months of age and older)
Efficacy: Pediatric, Effective
Recommendation: Pediatric, Class IIb
Strength of Evidence: Pediatric, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Although not a drug of choice, sulfamethoxazole/trimethoprim is an option for the treatment of acute otitis media in patients with a type
[36]
1 penicillin allergy .
Sulfamethoxazole/trimethoprim is not recommended in patients who fail initial treatment with antibiotics
[36]
.
3) Pediatric:
a) Amoxicillin is the drug of choice for initial treatment of mild to moderate acute otitis media. However, in type 1 penicillin-allergic
children, sulfamethoxazole/trimethoprim is recommended is alternative initial therapy. Use of sulfamethoxazole/trimethoprim is not
[36]
recommended in patients who fail initial treatment with antibiotics .
b) An uncontrolled trial demonstrated clinical success in 46 out of 54 (85%) children, although 10 of the children relapsed between 1 to
3 weeks after completion of therapy, with culture-positive acute otitis media treated with sulfamethoxazole/trimethoprim. Before
beginning therapy, 67 isolates were recovered with 55% susceptible, 7.5% intermediately resistant, and 37% fully resistant to
sulfamethoxazole/trimethoprim. Each child (mean age 9 months) was administered sulfamethoxazole 40 milligrams per kilogram per
day (mg/kg/day)/trimethoprim 8 mg/kg/day, orally in divided doses every 12 hours for 10 days. The majority of
sulfamethoxazole/trimethoprim-resistant organisms were not eradicated. Bacteriologic failure was experienced by 54% (29 out of 54)
patients. Eight out of 54 (15%) children experienced clinical failure during therapy. Seven of the 8 children with clinical failure, also
demonstrated bacteriological failure. Nine new organisms emerged during sulfamethoxazole/trimethoprim therapy with 78% (7 out of
the 9) of those resistant to sulfamethoxazole/trimethoprim. Clinical failure was most likely due to bacteriological failure which is
[37]
associated with sulfamethoxazole/trimethoprim resistance .
4.5.E Aeromonas infection
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIa
Strength of Evidence: Adult, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Sulfamethoxazole/trimethoprim is considered the drug of choice for the treatment of infections caused by Aeromonas
[39]
4.5.F Bacteremia associated with intravascular line
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Sulfamethoxazole/trimethoprim is the preferred therapy for treating catheter-related bacteremia due to Stenotrophomonas maltophilia,
[4]
Burkholderia cepacia, and Ochrobacterium anthropi .
4.5.G Bacterial endocarditis
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive; Pediatric, Evidence is inconclusive
Recommendation: Adult, Class IIb; Pediatric, Class IIb
Strength of Evidence: Adult, Category C; Pediatric, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Limited to case reports
3) Adult:
a) Sulfamethoxazole/trimethoprim has been shown to be effective in the treatment of gram-negative bacterial endocarditis,
unresponsive to conventional treatment. A 60-year-old male with stenosis of the aortic valve developed endocarditis following
abdominal surgery. Klebsiella pneumoniae and Acinetobacter calcoaceticus were cultured and the patient was treated intravenously
with GENTAMICIN and CEPHALOTHIN. The organism cultured was found to be sensitive to GENTAMICIN and CEPHALOTHIN in
vitro, however the patients clinical course did not improve. The treatment regimen was changed to IV GENTAMICIN and oral
sulfamethoxazole 400 milligrams (mg)/trimethoprim 80 mg, 2 tablets every eight hours. Over the next three weeks the patient became
afebrile, the white blood cell count gradually returned to normal, and all subsequent blood culture were negative.
Sulfamethoxazole/trimethoprim therapy was continued after the patient underwent aortic valve replacement and right coronary artery
bypass. The patient was gradually tapered off of sulfamethoxazole/trimethoprim therapy and has remained free of infection for 5 years
[42]
.
b) The synergistic combination of intravenous sulfamethoxazole/trimethoprim (240 milligrams every 6 hours) and ticarcillin/clavulanic
acid (4 grams every 4 hours) successfully treated a case of Stenotrophomonas maltophilia endocarditis associated with a
ventriculoatrial cerebrospinal fluid shunt of 18 years duration in a 60-year-old female. Attempts to completely remove the extracranial
catheter initially failed. The organism was susceptible only to sulfamethoxazole/trimethoprim and ticarcillin/clavulanic acid, which
produced resolution of signs and symptoms within 2 weeks. However, the tricuspid valve vegetation remained until a final catheter
fragment was removed from the ventricular cavity, necessitating a total of 7 weeks of the antibiotic combination. Follow-up in 15 months
[43]
revealed no sequelae .
4) Pediatric:
a) Multiple antibiotic-resistant staphylococcal endocarditis and meningitis in an 11-month-old infant was treated with oral
[44]
sulfamethoxazole 100 milligrams per kilograms per day (mg/kg/day)/TRIMETHOPRIM 20 mg/kg/day in 4 daily divided doses .
4.5.H Bacterial gastrointestinal infectious disease - HIV infection
See Drug Consult reference: PREVENTION AND TREATMENT OF BACTERIAL ENTERIC INFECTIONS IN HIV-INFECTED
PERSONS - NIH/CDC/IDSA GUIDELINES
4.5.I Bacterial keratitis, due to nocardia
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
[50]
[51][52]
Four case reports include topical sulfamethoxazole/trimethoprim successful treatment nocardia keratitis ; (Bucci et al, 1991)
Sulfamethoxazole/trimethoprim is considered the drug of choice for the treatment of infections caused by Nocardia (Anon, 1996)
3) Adult:
[50]
a) GENERAL: Information about the use of sulfamethoxazole/trimethoprim eyedrops is limited to 4 case reports ; (Bucci et al,
[51][52]
1991)
. In each case, the commercial intravenous solution was instilled directly into the affected eye. Keratitis resolved in these
patients with no adverse reactions noted.
b) Ophthalmic sulfamethoxazole/trimethoprim successfully treated NOCARDIA ASTEROIDES KERATITIS in a patient. Treatment
with various courses of other topical antibiotics over 6 weeks was unsuccessful. Oral sulfamethoxazole/trimethoprim was started, then
7 days later all topicals were discontinued and topical sulfamethoxazole/trimethoprim (undiluted intravenous formulation) every hour
was started. Over the next 2 weeks significant improvement was noted and at 6 months, the patient had no complaints, visual acuity
[50]
returned to baseline, and a healed corneal scar with slight thinning remained .
c) An 82-year-old female with a Flavobacterium meningosepticum keratitis resistant to multiple antibiotics was successfully treated with
topical sulfamethoxazole/trimethoprim. Eyedrops prepared directly from the commercial intravenous solution were administered every
30 minutes while awake and every hour while asleep for the first 3 days. The frequency was reduced to every 2 hours while awake and
every 4 hours while asleep for the following 12 days, then 4 times daily to begin a 2-week tapering course of therapy (Bucci et al, 1991).
d) A 68-year-old male presented with an epithelial defect of 3 months duration refractory to various antibiotics, antivirals,
corticosteroids, and bandage lenses. Nocardia asteroides keratitis was subsequently diagnosed and treated with topical
sulfamethoxazole/trimethoprim. The patient applied the commercial intravenous solution (Septra(R): sulfamethoxazole 80
milligrams/milliliter (mg/mL)/ trimethoprim 16 mg/mL) hourly for 48 hours, then 4 times daily for 7 days. Complete resolution of
[51]
inflammation and restoration of visual acuity resulted .
e) One article was found that dealt with use of sulfamethoxazole/trimethoprim in the treatment of NOCARDIA KERATITIS in one
patient. The authors used sulfamethoxazole 80 milligrams/milliliter (mg/mL)/ trimethoprim 16 mg/mL eyedrops every 30 minutes in this
patient. The eyedrops were prepared fresh daily from unaltered sulfamethoxazole/trimethoprim intravenous solution, and were shaken
vigorously before instillation. After 5 days of treatment, the patient was discharged on a regimen that included these eyedrops every
hour, for more than one month's duration. The authors state that the eyedrops were well tolerated and there was no evidence of corneal
toxicity. These eyedrops, along with sulfacetamide ointment at bedtime, atropine 1% eyedrops once a day and one sulfamethoxazole
[52]
800 mg/trimethoprim 160 mg tablet twice a day were effective in treating the patient .
4.5.J Bacterial meningitis
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy; Pediatric, Evidence favors efficacy
Recommendation: Adult, Class IIb; Pediatric, Class IIb
Strength of Evidence: Adult, Category C; Pediatric, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
[54][55]
Effective against susceptible organisms
Recommended as alternative therapy for the treatment of bacterial meningitis caused by laboratory-isolated, susceptible pathogens of
[53]
Listeria monocytogenes, Escherichia coli, or methicillin-resistant Staphylococcus aureus .
Recommended as alternate therapy in adults for the treatment of presumptive infections due to Listeria monocytogenes or Escherichia
[53]
coli meningitis .
3) Adult:
a) Intravenous sulfamethoxazole/trimethoprim was successfully used in the treatment of Klebsiella pneumoniae meningitis. A 24year-old woman presented with confirmed K pneumoniae meningitis. Parenteral therapy with chloramphenicol, nafcillin sodium, and
gentamicin sulfate resulted in a return to normal mental status. Blood and CSF cultures yielded chloramphenicol-sensitive K
pneumoniae. After 10 days of therapy, an excellent clinical recovery and a suspected toxic reaction to the drug led to the decision to
discontinue treatment. Nine days later meningeal signs recurred and a need for prolonged therapy was demonstrated. Blood sensitivity
studies proved the K pneumoniae to have a low MIC and MBC to sulfamethoxazole/trimethoprim combination as compared to
chloramphenicol. Hoffmann-La Roche protocol 1028 recommended IV sulfamethoxazole/trimethoprim at a dosage of 10
milligrams/kilogram/day of trimethoprim in divided doses which continued into a 25-day course of therapy. No adverse hematologic or
[55]
allergic reactions were noted .
[54]
b) A comprehensive review of the use of sulfamethoxazole/trimethoprim in the treatment of bacterial meningitis was presented .
The drug appears to be as effective as penicillin G or chloramphenicol in the treatment of pneumococcal and meningococcal meningitis
and is beneficial in the treatment of gram-negative bacillary meningitis secondary to E cloacae, Serratia marcescens, Pseudomonas
cepacia, and Acinetobacter. The drug has been successfully used in patients with S aureus meningitis and Listeria monocytogenes
meningitis.
c) Listeria bacteremia in a 32-year-old woman and listeria meningitis in a 53-year-old woman were successfully treated with
[56]
sulfamethoxazole/trimethoprim . The patient with meningitis was treated with sulfamethoxazole 400 mg/trimethoprim 80 mg 3
times daily every 8 hours for weeks, resulting in cure and no recurrence of infection in 6 months. The patient with bacteremia was
treated similarly for 2 weeks resulting in sterile blood cultures for listeria monocytogenes.
4.5.K Bacterial respiratory infection; Prophylaxis - HIV infection
See Drug Consult reference: PREVENTION AND TREATMENT OF BACTERIAL RESPIRATORY INFECTION IN HIV-INFECTED
PERSONS - CDC/NIH/IDSA GUIDELINES
4.5.L Cholera
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Pediatric, Evidence favors efficacy
Recommendation: Pediatric, Class IIa
Strength of Evidence: Pediatric, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
[40]
May be beneficial for treatment of cholera .
3) Pediatric:
a) Sulfamethoxazole/trimethoprim may be useful as an adjunct to fluid and electrolyte replacement in the treatment of cholera in
children. The recommended dose is sulfamethoxazole 25 milligrams/kilogram (mg/kg)/trimethoprim 5 mg/kg 2 times daily for 3 days.
Antibiotic therapy in cholera may decrease the duration of diarrhea, decrease bacterial shedding, and decrease the volume of fluid
[40]
replacement needed .
4.5.M Chronic purulent otitis media
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Pediatric, Evidence favors efficacy
Recommendation: Pediatric, Class IIb
Strength of Evidence: Pediatric, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
In addition to the use of steroid/antibiotic eardrops, a 6- to 12-week oral course of high-dose sulfamethoxazole/trimethoprim led to
modest short-term benefit in children with chronic active otitis media refractory to conventional topical or short-term systemic antibiotic
[8]
therapy in a randomized, placebo-controlled study (n=101)
3) Pediatric:
a) In a randomized, placebo-controlled study (n=101), a 6- to 12-week oral course of high-dose sulfamethoxazole/trimethoprim was
more effective in reducing otorrhea at 12 weeks compared to placebo in children with chronic active otitis media refractory to
conventional topical or short-term systemic antibiotic therapy; however, there were no differences between the groups in improvements
in hearing loss and health-related quality of life. Children, aged 1 to 12 years (median age, 50 months), with a documented history of 3
or more months of continuous otorrhea through either a tympanic membrane perforation or a tympanostomy tube were included.
Blinded investigators randomly assigned either oral sulfamethoxazole/trimethoprim 18 milligrams/kilogram twice daily (n=50) or
placebo (n=51) for 6 weeks, or for 12 weeks if otorrhea was present in either ear at the end of week 6. Additionally, use of a 7 to 10 day
course of steroid/antibiotic eardrops and other medications, including antibiotics, was allowed during the study. At the 12-week visit,
treatment was discontinued if otorrhea was absent, and following treatment unblinding, if otorrhea was present, patients were treated
according to regular practice. The primary endpoint was otomicroscopic signs of otorrhea in the presence of a tympanostomy tube or
tympanic membrane perforation at the 6 weeks, 12 weeks, and 1 year. An intention-to-treat analysis revealed that 28% of children in
the sulfamethoxazole/trimethoprim group had otorrhea compared to 53% in the placebo group at the 6-week visit (difference, -25%;
95% confidence interval (CI), -44% to -6%). At 12 weeks, otorrhea was present in 32% and 47% of the sulfamethoxazole/trimethoprim
and placebo groups, respectively (difference, -15%; 95% CI, -34% to 4%). However, there was no difference between the
sulfamethoxazole/trimethoprim and placebo groups at the 1-year follow-up visit (25% vs 20%, respectively; difference, 5%; 95% CI, 12% to 22%). The number needed to treat at 6 weeks and 12 weeks was 4 children and 7 children, respectively. Compared to placebo,
treatment effect at 12 weeks was more pronounced among children with otorrhea for more than 6 months (difference, -38%; 95% CI, 64% to -12%) versus those with 3 to 6 months of otorrhea (difference, -17%; 95% CI, -44% to 10%). Among secondary endpoints, use
of antibiotic eardrops was extensive and similar between the sulfamethoxazole/trimethoprim group (83%) and the placebo group
(77%) during the first 6 weeks but more frequent in the placebo group (67% vs 55%) between weeks 6 to 12. Use of other systemic
antibiotics (mostly amoxicillin) did not differ substantially between the sulfamethoxazole/trimethoprim (11%) and placebo (18%) groups
during the 12 weeks of therapy (difference, 7% ; 95% CI, -23% to 9%). Proportions of culture-positive otorrhea samples were similar in
both groups, with Pseudomonas aeruginosa being the more frequently isolated microorganism. Rates of ear/nose/throat surgery
between 12 weeks and 1 year were also similar in both groups (30% for sulfamethoxazole/trimethoprim, 24% for placebo). Although
pure-tone hearing levels and health-related quality of life generally improved during the study, there were no differences between the 2
groups. Adverse events (vomiting or diarrhea) occurred in 9% of the sulfamethoxazole/trimethoprim group compared to 2% of the
[8]
placebo group .
4.5.N Crohn's disease
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class III
Strength of Evidence: Adult, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
[41]
Benefits limited to 1 case report
3) Adult:
a) Sulfamethoxazole/trimethoprim administered twice daily was effective in treating Crohn's disease in a 40-year-old woman.
Sulfamethoxazole/trimethoprim rapidly controlled the disease at the initial presentation and during the first relapse. After 1 week
sulfamethoxazole/trimethoprim was discontinued and SULFASALAZINE was started. The second relapse did not respond to
[41]
sulfamethoxazole/trimethoprim .
4.5.O Cyclosporiasis
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy; Pediatric, Evidence favors efficacy
Recommendation: Adult, Class IIa; Pediatric, Class IIa
Strength of Evidence: Adult, Category C; Pediatric, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Sulfamethoxazole/trimethoprim is the drug of choice for Cyclospora in adults and children
3) Adult:
a) Cyclospora is a coccidial parasite that has caused enteric infection, resulting in diarrhea, in both immunocompromised and
immunocompetent patients. This infection is most commonly present in countries such as Haiti, Mexico, Nepal, Morocco, Pakistan,
India, and Peru. As with other opportunistic infections, Cyclospora infection can be self limiting in immunocompetent patients; however,
in AIDS patients it can be severe. Sulfamethoxazole 800 milligrams (mg)/trimethoprim 160 mg four times daily for 10 days followed by
prophylaxis with 1 tablet 3 times weekly, was effective for the treatment of 43 HIV Haitian patients with diarrhea and positive Cyclospora
[9]
in the stools .
[10]
b) The Medical Letter recommends sulfamethoxazole 800 milligrams (mg)/trimethoprim 160 mg orally twice daily for 7 to 10 days .
4) Pediatric:
a) Sulfamethoxazole/trimethoprim (5 milligrams (mg)/kg of trimethoprim daily for 3 days) resolved diarrhea in a mean of 3.8 days in 4
[11]
children with Cyclospora infection .
4.5.P Diverticulitis
See Drug Consult reference: ANTIBIOTIC THERAPY OF DIVERTICULITIS
4.5.Q Febrile neutropenia; Prophylaxis
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class III
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Clinical data regarding the use of sulfamethoxazole/trimethoprim as prophylaxis in neutropenic patients are inconclusive
3) Adult:
a) Oral sulfamethoxazole/trimethoprim prophylaxis successfully reduced episodes of bacteremia and microbiologically confirmed
infections in granulocytopenic cancer patients. In a placebo-controlled study, acute leukemia was the primary cause of cancer in 46 of
58 evaluated granulocytopenic episodes in 47 patients. However, the incidence of candidiasis, candidemia, and esophagitis was
significantly greater in sulfamethoxazole/trimethoprim-treated patients. These data indicate that sulfamethoxazole/trimethoprim can
reduce the incidence of microbiologically documented infections during episodes of granulocytopenia. However, the emergence of
[45]
resistant organisms and fungal infections may limit its usefulness .
b) Oral sulfamethoxazole/trimethoprim (Bactrim(R)) plus erythromycin compared to placebo has been evaluated in a controlled study
of adult cancer patients with fever. The patients were receiving cytotoxic chemotherapy and were expected to develop significant
neutropenia. The incidence of fever was not significantly different between treatment groups. The interval between the onset of
neutropenia and the onset of fever was also similar between the drug and placebo groups, as was the incidence of mortality. The
incidence of adverse effects was greater in the treatment group (skin reactions, GI toxicity). Sulfamethoxazole/trimethoprim plus
erythromycin prophylaxis in granulocytopenic cancer patients appears to be unnecessary. This study has demonstrated that the
combination may mask the cause of infection in febrile neutropenic cancer patients and can produce substantial toxicity. Fourteen of 18
fevers in the sulfamethoxazole/trimethoprim plus erythromycin group were without a documented infectious source, as compared with
[46]
only 6 of 17 in placebo treated patients .
c) Sulfamethoxazole/trimethoprim does not show any beneficial effects over placebo in the prophylactic treatment of neutropenic
[47][24]
patients undergoing consolidation chemotherapy
. In 1 study, sulfamethoxazole/trimethoprim therapy was evaluated in a
[47]
prospective, controlled, randomized trial of 29 acute leukemia patients receiving consolidation chemotherapy . A total of 67
granulocytopenic episodes (less then 1000 granulocytes per mm(3)) were treated with chemotherapy in conjunction with oral
sulfamethoxazole 800 mg/trimethoprim 160 mg twice daily until the granulocyte count returned to 1000 cells/cubic millimeter (mm(3)).
Results showed no significant difference between the two groups in the incidence of febrile episodes (13 in the treatment group versus
14 in the control group), hospitalizations to treat fever of infection (10 versus 12), number of documented infections (8 versus 10),
number of septicemias (1 versus 2), or mean duration of hospital stay to treat fever or infection (8.9 versus 9.2 days).
d) Prophylactic sulfamethoxazole/trimethoprim was not effective in two patients with acute LEUKEMIA and GRANULOCYTOPENIA.
Both patients developed sepsis with Enterobacteriaceae resistant to sulfamethoxazole/trimethoprim, and resulted in death. In one
patient, a transferable plasmid encoding resistance to trimethoprim was observed in two bacterial species. A transferable sulfonamide
resistant plasmid was found in the other patient. These data indicate that resistance to Enterobacteriaceae may occur in leukemic
[48]
patients with oral prophylaxis. Results also indicate that in vivo transfer can occur and resistance may be likely .
e) Prophylactic therapy with sulfamethoxazole 1600 milligrams (mg)/trimethoprim 320 mg daily was evaluated against placebo as
infection prophylaxis in patients with small cell lung carcinoma in a controlled study. The incidence of infection was significantly lower in
the sulfamethoxazole/trimethoprim group, without an increase in bone marrow suppression. The need for prolonged hospitalization
[49]
and treatment with parenteral broad spectrum antibiotics was decreased .
4.5.R Granuloma inguinale
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Sulfamethoxazole/trimethoprim is recommended by the CDC for the treatment of granuloma inguinale as an alternative to doxycycline
[12]
.
3) Adult:
a) For the treatment of granuloma inguinale (donovanosis), the CDC recommends sulfamethoxazole/trimethoprim as an alternative to
doxycycline (preferred agent); other alternatives are azithromycin, ciprofloxacin, and erythromycin. Since pregnancy is a relative
contraindication to the use of sulfonamides, pregnant and lactating women should be treated with the recommended alternative
[12]
regimen of erythromycin .
4.5.S Hemopoietic stem cell transplant - Pertussis; Prophylaxis
See Drug Consult reference: PREVENTION OF BORDETELLA PERTUSSIS INFECTION IN HEMATOPOIETIC CELL TRANSPLANT
4.5.T Hemopoietic stem cell transplant - Pneumocystis pneumonia; Prophylaxis
See Drug Consult reference: PREVENTION OF PNEUMOCYSTIS CARINII PNEUMONIA INFECTION IN HEMATOPOIETIC CELL
TRANSPLANTATION
4.5.U Hemopoietic stem cell transplant - Toxoplasmosis; Prophylaxis
See Drug Consult reference: PREVENTION OF TOXOPLASMA GONDII INFECTION IN HEMATOPOIETIC CELL
TRANSPLANTATION
4.5.V Hemopoietic stem cell transplant - Traveler's diarrhea; Prophylaxis
See Drug Consult reference: PREVENTION OF TRAVELER'S DIARRHEA IN HEMATOPOIETIC CELL TRANSPLANTATION
4.5.W HIV infection - Opportunistic infection; Prophylaxis
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
In a randomized, double-blind, placebo-controlled trial in sub-Saharan Africa, chemoprophylaxis with sulfamethoxazole 800 milligrams
(mg)/trimethoprim 160 mg daily at early stages of HIV-1 infection resulted in significantly fewer severe clinical events from various
[58]
bacterial and parasitic pathogens (other than Pneumocystis carinii) compared with placebo .
Daily sulfamethoxazole/trimethoprim was well tolerated and significantly decreased mortality and morbidity in HIV-1 infected patients
[59]
with tuberculosis in a randomized, placebo-controlled trial (n=771) in sub-Saharan Africa .
In a double blind, placebo-controlled trial (n=1003) in sub-Saharan Africa, prophylaxis with oral sulfamethoxazole/trimethoprim
[60]
reduced mortality in HIV-infected patients being treated for pulmonary tuberculosis .
In a prospective, open-label, non-randomized cohort study (n=1160) in HIV infected persons in sub-Saharan Africa, daily
sulfamethoxazole/trimethoprim prevented malaria and reduced the incidence of antifolate-resistant Plasmodium falciparum, but was
[61]
associated with increased pneumococcus and commensal Escherichia coli resistance .
3) Adult:
a) In a randomized, double-blind, placebo-controlled trial in sub-Saharan Africa, chemoprophylaxis with sulfamethoxazole 800
milligrams (mg)/trimethoprim 160 mg daily at early stages of HIV-1 infection resulted in significantly fewer severe clinical events from
various bacterial and parasitic pathogens (other than Pneumocystis carinii) compared with placebo. A total of 545 patients with HIV-1 or
HIV-1 and HIV-2 dual seropositivity at stages 2 or 3 of the World Health Organization (WHO) staging received
sulfamethoxazole/trimethoprim or placebo daily. The primary study outcome was the occurrence of severe clinical events, determined
as death or hospital admission for any cause. Secondary outcomes were morbidity, specifically morbidity potentially preventable by
sulfamethoxazole/trimethoprim (including infections with bacteria, toxoplasma, Isospora, nocardia, Pneumocystis carinii, and malaria)
and adverse drug reactions. A total of 318 severe events were documented, 120 in the sulfamethoxazole/trimethoprim group and 198
in the placebo group. Death occurred in 87 cases (27%) and hospital admission without death was documented in 231 cases (73%).
Significantly fewer sulfamethoxazole/trimethoprim-treated patients experienced at least one severe event compared with the placebo
group (84 versus 124, p equal 0.0001). At the 12 month follow-up, the probability of remaining free of severe clinical events was 63.7%
in the sulfamethoxazole/trimethoprim group and 45.8% in the placebo group (p=0.0001). The overall survival between the
sulfamethoxazole/trimethoprim and placebo groups was not clinically significant (41 versus 46 deaths, respectively). In patients with at
least one severe event, the most significant differences between the sulfamethoxazole/trimethoprim and placebo groups were in the
rates of bacterial pneumonia (p equal 0.0009), malaria (p=0.007), and acute unexplained fever (p equal 0.005). Pulmonary
pneumocystosis was not diagnosed in any study participant. Patients treated with sulfamethoxazole/trimethoprim experienced a
higher incidence of neutropenia compared with placebo (62 versus 26 patients, p equal 0.0001). Early administration of
[58]
sulfamethoxazole/trimethoprim prophylaxis may alleviate the burden of opportunistic infections in HIV-1 infected patients .
b) Daily sulfamethoxazole/trimethoprim was well tolerated and significantly decreased mortality and morbidity in HIV-1 infected
patients with tuberculosis in a randomized, placebo-controlled trial in sub-Saharan Africa. A total of 771 HIV-1 seropositive and HIV-1
and HIV-2 dual seropositive patients with sputum-smear-positive pulmonary tuberculosis were randomized to receive
sulfamethoxazole 800 milligrams (mg)/trimethoprim 160 mg daily or placebo daily beginning one month after the start of a standard 6month tuberculosis regimen. Median follow-up periods were 10.1 months in the placebo group and 10.8 months in the
sulfamethoxazole/trimethoprim group. Death was recorded in 86 placebo group patients and 51 sulfamethoxazole/trimethoprim
group patients. Estimated death rates per 100 person-years were 25.4 in the placebo group and 13.8 in the
sulfamethoxazole/trimethoprim group, resulting in a 46% decrease in mortality risk (p less than 0.001). Hospital admissions were
required in 29 sulfamethoxazole/trimethoprim-treated patients and 47 placebo patients, producing a 43% decrease in hospital
admission risk (p equal 0.02). The most frequent causes of hospital admissions were tuberculosis, enteritis, and septicemia. Significant
decreases in hospital admissions among patients in the sulfamethoxazole/trimethoprim group were recorded for septicemia (p equal
0.01) and enteritis due to isosporiasis and non-typhoid salmonellosis (p equal 0.02 and 0.04, respectively). Hospital admissions for all
potentially preventable diseases by sulfamethoxazole/trimethoprim prophylaxis (including septicemia, enteritis, chest infection, urinary
tract infection, and toxoplasmosis) were significantly lower for the sulfamethoxazole/trimethoprim patients compared with placebo
patients (p equal 0.001). Clinical and laboratory adverse events were similar among the two study groups, with lower rates of
respiratory and gastrointestinal adverse events occurring in the sulfamethoxazole/trimethoprim patients than the placebo patients (p
[59]
equal 0.02 and 0.003, respectively) .
1) Mortality
a) In a double blind, placebo-controlled trial (n=1003) in sub-Saharan Africa, prophylaxis with oral sulfamethoxazole/trimethoprim
reduced mortality in HIV-infected patients being treated for pulmonary tuberculosis. Two groups of antiretroviral-naive adults with HIV
infection (patients with newly diagnosed tuberculosis and receiving tuberculosis treatment for the first time or for re-treatment after
relapse (n=835); and clinically healthy patients previously treated for tuberculosis but not receiving any treatment (n=168)) were
randomized in a 1:1 ratio to receive daily 2 tablets of sulfamethoxazole 400 milligrams (mg)/trimethoprim 80 mg per tablet (n=416) or
placebo (n=419). The primary study outcomes were all cause mortality and adverse events resulting in an interruption of study drug.
For the patients receiving tuberculosis treatment, follow-up data was available for 757 patients, with a total of 1012.6 person years of
follow-up. A total of 310 patients died during the study (147 sulfamethoxazole/trimethoprim, 163 placebo) with death rates of 27.3 and
34.4 per 100 person years in the sulfamethoxazole/trimethoprim and placebo groups, respectively. There was a 21% reduction in all
cause mortality (hazard ratio, 0.79; 95% confidence interval (CI), 0.63 to 0.99; p=0.04) associated with sulfamethoxazole/trimethoprim.
To prevent one death, the number needed to treat was 141.8 (95% CI, 71.7 to 588.7). Retrospective exploratory analysis showed a
delay before any benefit of sulfamethoxazole/trimethoprim was seen (6 months) and a weaning of effect over time (after 18 months).
Analysis also showed benefit in both newly diagnosed, previously untreated patients and in those being treated for relapse; there was
no difference in benefit by CD4 count, age, or sex. Adverse events leading to study drug interruption occurred in 18 patients (12
sulfamethoxazole/trimethoprim, 6 placebo), with 6 patients (all sulfamethoxazole/trimethoprim) discontinuing the study drug
permanently. Adverse events resulting in permanent discontinuation included Stevens-Johnson syndrome and anemia, itchy rash,
swollen face and lips, peripheral neuropathy, and 2 cases of anemia. Mortality rates in the 168 patients not receiving tuberculosis
treatment at baseline were 14.7 per 100 person-years (95% CI, 10.5 to 20.6 per 100 person-years) and 14.5 per 100 person years
[60]
(95% CI, 10.3 to 20.5 per 100 person-years) in the sulfamethoxazole/trimethoprim and placebo groups, respectively .
2) Development of Resistance
a) In a prospective, open-label, non-randomized cohort study (n=1160) in HIV-infected persons in sub-Saharan Africa, daily
sulfamethoxazole/trimethoprim prevented malaria and reduced the incidence of antifolate-resistant Plasmodium falciparum (P
falciparum), but was associated with increased pneumococcus and commensal Escherichia coli (E coli) resistance. Patients were
assigned to 1 of 3 study groups according to HIV status and CD4 cell count: HIV-infected persons with CD4 cell count less than 350
cells/microliter (lower-CD4; n=692) received daily sulfamethoxazole 800 milligrams (mg)/trimethoprim 160 mg as a single tablet per
day, HIV-infected persons with CD4 cell count of 350 cells/microliter or greater (higher-CD4; n=336), and HIV-negative persons (n=132)
received a daily multivitamin. Median and mean follow-up was 24 and 20 weeks, respectively, for all patients. There was a 90%
reduction in incidence density of first or only infection with P falciparum parasitemia in lower-CD4 patients compared with higher-CD4
patients, and a similar decrease in incidence density for all episodes of P falciparum (16 and 156/100 person-years in lower-CD4 and
higher-CD4, respectively; adjusted rate ratio=0.09; 95% confidence interval (CI), 0.06 to 0.14; p less than 0.025). There was a
significant reduction (38%) in all episodes of P falciparum parasitemia in HIV-negative patients compared with higher-CD4 patients
(p=0.018). The number of pneumococcus isolates that were sulfamethoxazole/trimethoprim-resistant was high in all groups at
baseline, and increased significantly in lower-CD4 patients (93% (n=223/241)) isolates resistant at baseline compared with 100%
(n=196/196) resistant 2 weeks later; p=0.005); resistance remained high through month 6 (99% of 164 isolates). Prevalence of
sulfamethoxazole/trimethoprim-resistant E coli was high among all groups at baseline, but only significantly increased in the lowerCD4 group, going from 79% (n=542/688) to 98% (n=172/176) by week 2 (p less than 0.0001); resistance remained high through month
6 (96% of 290 isolates). The study was underpowered to measure the efficacy of sulfadoxine pyrimethamine (SP) for patients with
[61]
clinical malaria, but a trend of increased SP failure among lower-CD4 patients was seen .
4.5.X HIV infection - Pneumocystis pneumonia
FDA Labeled Indication
1) Overview
FDA Approval: Adult, yes; Pediatric, yes (2 months of age and older)
Efficacy: Adult, Effective; Pediatric, Effective
Recommendation: Adult, Class IIa; Pediatric, Class IIa
Strength of Evidence: Adult, Category B; Pediatric, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Sulfamethoxazole/trimethoprim is considered the drug of choice for treatment of Pneumocystis jiroveci Pneumonia (PCP) infection in
[13][14]
HIV-infected adults and children
.
3) Adult:
a) Guideline Recommendations
1) The agent of choice to treat Pneumocystis jiroveci Pneumonia (PCP) infection in HIV-infected adults is
sulfamethoxazole/trimethoprim. Multiple randomized trials have demonstrated that sulfamethoxazole/trimethoprim has been as
effective as intravenous pentamidine and more effective than other regimens. In patients with mild-to-moderate disease, oral
administration of sulfamethoxazole/trimethoprim has been highly effective in the outpatient setting. Patients who develop PCP despite
prophylaxis with sulfamethoxazole/trimethoprim may still be treated effectively with standard doses of
sulfamethoxazole/trimethoprim. Alternative therapeutic regimens for mild-to-moderate PCP include dapsone plus trimethoprim,
primaquine plus clindamycin, or atovaquone suspension. Intravenous pentamidine or clindamycin plus primaquine is an alternative in
patients with moderate to severe PCP. The recommended duration of therapy is 21 days. Patients with documented, moderate-tosevere PCP should also receive corticosteroid therapy as early as possible (at least within 72 hours after initiation of a specific PCP
regimen). It is appropriate to switch to another regimen in cases of treatment-related toxicity or lack of clinical improvement; however, it
is important to wait 4 to 8 days before switching regimens in cases where there is lack of clinical improvement.
sulfamethoxazole/trimethoprim is also the preferred initial therapy in pregnant women; however, the alternative therapies may also be
[13]
used in cases of intolerance or clinical unresponsiveness .
b) Clinical Trials
1) Sulfamethoxazole/trimethoprim was reported superior to pentamidine in the treatment of Pneumocystis jiroveci pneumonia for 70
AIDS patients in a prospective, randomized study. Sulfamethoxazole/trimethoprim was initially administered intravenously as 15 to 20
mg/kg/day (trimethoprim) followed by oral therapy. Sulfamethoxazole/trimethoprim doses were adjusted to maintain serum
trimethoprim levels at 5 to 8 mcg/mL. Intravenous pentamidine was given in doses of 4 mg/kg/day and followed by intramuscular
therapy after clinical improvement. The pentamidine dose was reduced by 30% to 50% for absolute rises in serum creatinine of greater
than 88 mmol/L (1 mg%). All patients were randomly assigned to receive 1 regimen for 17 to 21 days. The number of patients surviving
without the need for respiratory support at the completion of therapy was greater in the sulfamethoxazole/trimethoprim group (86%) as
compared to pentamidine (61%). In addition, oxygenation improved 8 days earlier in sulfamethoxazole/trimethoprim-treated patients
[15]
.
4) Pediatric:
a) Guideline Recommendations
1) The agent of choice to treat Pneumocystis jiroveci pneumonia (PCP) in children with human immunodeficiency virus (HIV) is
intravenous sulfamethoxazole/trimethoprim. After resolution of acute pneumonia, children with mild to moderate disease can be
switched to oral administration of sulfamethoxazole/trimethoprim if they do not have concurrent malabsorption or diarrhea. In cases of
intolerance or clinical failure (after 5 to 7 days) to sulfamethoxazole/trimethoprim, patients should be switched to intravenous
pentamidine. Pentamidine combined with sulfamethoxazole/trimethoprim is not recommended. If clinical improvement is noted after 7
to 10 days of intravenous pentamidine therapy, an oral regimen, such as atovaquone, might be considered to complete a 21-day course
of therapy. Other alternatives to sulfamethoxazole/trimethoprim in cases of mild to moderate PCP include clindamycin plus primaquine
or dapsone plus trimethoprim, although data on using these regimens in children are lacking. Patients with moderate-to-severe PCP (ie,
partial arterial pressure of oxygen (PaO2) of less than 70 millimeters of mercury (mmHg) at room air or alveolar-arterial oxygen gradient
greater than 35 mmHg) should also receive a short course of corticosteroid therapy within 72 hours of diagnosis, as studies have found
that early use of corticosteroids reduce acute respiratory failure, decrease the need for ventilation, and decrease mortality. Following
initial therapy, patients should receive chronic suppressive therapy (ie, secondary prophylaxis) with sulfamethoxazole/trimethoprim.
Discontinuation may be considered in children who have received highly active antiretroviral therapy for at least 6 months and who
have at least 3 consecutive months of CD4+ counts of 15% or greater or at least 200 cells/cubic millimeter (mm(3)) in patients older
than 6 years, or CD4+ counts of 15% or greater or at least 500 cells/mm(3) in patients ages 1 to 5 years. Secondary prophylaxis should
[14]
not be discontinued in infants with HIV younger than 1 year of age .
b) Clinical Trials
1) Sulfamethoxazole/trimethoprim has been utilized in 18 immunosuppressed children with mild to moderately severe Pneumocystis
jiroveci pneumonia. Of 6 patients treated with trimethoprim 4 to 7 milligrams/kilogram/day (mg/kg/day) and sulfamethoxazole 20 to 35
mg/kg/day, 4 recovered and 2 died. Of 14 patients treated with sulfamethoxazole 100 mg/kg/day and trimethoprim 20 mg/kg/day, 12
recovered and 2 died. In the 4 fatal cases and in 2 of the patients who recovered concomitant treatment was instituted with pentamidine
when the initial response to sulfamethoxazole/trimethoprim was inadequate. Patients became afebrile after 1 to 6 days, chest
radiographs were normal in 3 to 15 days and PaO2 at room air was greater than 85 mmHg by 1 to 9 days after initiation of
[16]
sulfamethoxazole/trimethoprim .
4.5.Y HIV infection - Pneumocystis pneumonia; Prophylaxis
FDA Labeled Indication
1) Overview
FDA Approval: Adult, yes; Pediatric, yes (2 months of age and older)
Efficacy: Adult, Effective; Pediatric, Effective
Recommendation: Adult, Class IIa; Pediatric, Class IIa
Strength of Evidence: Adult, Category B; Pediatric, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Sulfamethoxazole/trimethoprim is considered the drug of choice for prophylaxis of Pneumocystis jiroveci pneumonia (PCP) in adults
[13][14]
and children with human immunodeficiency virus
.
3) Adult:
a) Guideline Recommendations
1) To prevent a first episode of Pneumocystis jiroveci pneumonia (PCP) in adults and adolescents with human immunodeficiency virus
(HIV), including pregnant women and those on highly active antiretroviral therapies (HAART), it is recommended that all HIV-positive
patients with a CD4+ cell count less than 200/microliter (mcL) or a history of oropharyngeal candidiasis receive primary prophylaxis.
Primary prophylaxis should also be considered for patients with a CD4+ percentage of less than 14%, a history of an AIDS-defining
illness, or possibly for those with CD4+ counts of greater than 200 but less than 250 cells/mcL. Sulfamethoxazole/trimethoprim is the
prophylactic drug of choice. If sulfamethoxazole/trimethoprim cannot be tolerated, alternative prophylactic regimens include dapsone,
dapsone plus pyrimethamine plus leucovorin, aerosolized pentamidine, or atovaquone. The recommended prophylactic agent in
pregnant women is sulfamethoxazole/trimethoprim. Pneumocystis primary prophylaxis should be discontinued in individuals who have
responded to HAART with a CD4+ count greater than 200 for 3 months or more. Reintroduction of prophylaxis is recommended when
CD4+ cell counts drop below 200 cells/mcL. The prophylactic agent of choice to prevent recurrence of PCP (secondary prophylaxis) is
sulfamethoxazole/trimethoprim. Alternatives include dapsone, dapsone plus pyrimethamine plus leucovorin, aerosolized pentamidine,
[13][64]
atovaquone, or atovaquone plus pyrimethamine plus leucovorin
.
b) Discontinuing Primary Prophylaxis
1) Current CDC guidelines recommend that patients with a history of PCP disease should remain on chemoprophylaxis for life unless
they have responded to combination antiretroviral therapy (cART) with a CD4+ count greater than 200 cells/mcL for 3 months or more.
Secondary prophylaxis should be reinitiated if the CD4+ cell counts drop below 200 cells/mcL or if PCP recurred at a CD4+ count of
[13]
greater than 200 cells/mcL . However, the Opportunistic Infections Project Team of the Collaboration of Observational HIV
Epidemiological Research in Europe (COHERE) found a low incidence of primary PCP following discontinuation of primary prophylaxis
in patients with a CD4+ cell count of 101 to 200 cells/mcL, who were receiving combined antiretroviral therapy (cART), and were
virologically-suppressed. The analysis used prospective data from 12 cohorts (n=23,412 adults) including patients who began taking
cART after 1997; median duration of follow-up was 4.7 years. Primary prophylaxis with sulfamethoxazole/trimethoprim prophylaxis
was used in 86.9% of patients (n=4263). Overall, during 107,016 person-years of follow-up (PYFU), there were 253 cases of PCP. The
incidence of PCP in patients receiving primary prophylaxis was significantly reduced compared to those not receiving prophylaxis for
patients with a CD4+ count of 100 cells/mcL or less (adjusted incidence rate ratio (IRR), 0.41; 95% confidence interval (CI), 0.27 to 0.6;
p less than 0.001), but not for patients with CD4+ cell counts of 101 to 200 cells/mcL (adjusted IRR, 0.63; 95% CI, 0.34 to 1.17;
p=0.15); however, the study may have been underpowered. Among patients who had virologically suppressed HIV infection (viral load
less than 400 copies/mL) and who had CD4+ cell counts of 100 to 200 cells/mcL, the incidence of PCP was 2.1 cases per 1000 PYFU
(95% CI, 0.8 to 4.3 cases per 1000 PYFU; 7 events during 3363 PYFU) in patient receiving prophylaxis compared with 1.2 cases per
1000 PYFU (95% CI, 0.2 to 4.5 cases per 1000 PYFU; 2 events during 1614 PYFU) in patients not receiving prophylaxis (adjusted IRR,
1.65; 95% CI, 0.33 to 8.15; p=0.54). In contrast, receipt of prophylaxis significantly decreased the incidence of primary PCP (adjusted
IRR, 0.47; 95% CI, 0.23 to 0.97; p=0.041) in patients with a viral load of 400 copies/mL or greater compared with those who did not
receive prophylaxis. Among patients with a CD4+ cell count of 101 to 200 cells/mcL who were receiving cART, there were 0 PCP cases
[65]
per 1000 PYFU (95% CI, 0 to 2.7 cases per 1000 PYFU) after discontinuation of primary prophylaxis, regardless of viral load .
c) Clinical Trials
1) In a retrospective review, the administration of sulfamethoxazole/trimethoprim prophylaxis significantly reduced the risks of death
and of Pneumocystis jiroveci pneumonia (PCP) and associated with a trend toward reduced risk of major bacterial infections in patients
with AIDS. A medical record review of 1078 patients with HIV infection receiving PCP prophylaxis regimens who were observed an
average of 36 months was conducted. PCP occurred in 9% of sulfamethoxazole/trimethoprim-treated patients compared with 21% of
other prophylaxis regimen patients, resulting in a decreased risk of PCP of approximately 77% and an adjusted relative risk of 0.23
(95% confidence interval (CI), 0.14 to 0.36). At the conclusion of the review, death was recorded in 42% of
sulfamethoxazole/trimethoprim users and 57% of others, with an adjusted relative risk of death for sulfamethoxazole/trimethoprim
users of 0.58 (95% CI, 0.47 to 0.71). A significantly reduced risk of death continued to be evident when evaluating deaths not
attributable to PCP, with an adjusted relative risk for sulfamethoxazole/trimethoprim users of 0.59 (95% CI, 0.47 to 0.73).
Sulfamethoxazole/trimethoprim users demonstrated a borderline significant risk reduction of developing major bacterial infections.
Following inclusion of major infections of unknown etiology in addition to major bacterial infections, 36% of
sulfamethoxazole/trimethoprim users compared with 40% of others developed major infections, resulting in an adjusted relative risk of
0.77 (95% CI, 0.61 to 0.97) or an approximate 23% risk reduction. Analysis of bacterial pneumonia and pneumonia of unknown etiology
demonstrated a trend toward a sulfamethoxazole/trimethoprim prophylaxis protective effect with at least one episode of pneumonia in
[66]
28% of sulfamethoxazole/trimethoprim patients versus 29% of others .
2) Administration of sulfamethoxazole 800 milligrams (mg)/trimethoprim 160 mg twice daily orally for 24 months) was reported
effective in preventing P jiroveci pneumonia in patients with newly diagnosed Kaposi's sarcoma associated with AIDS. All 60 patients
treated had no history of opportunistic infections, and were randomized to receive either sulfamethoxazole/trimethoprim or no therapy;
Pneumocystis jiroveci pneumonia was observed in none of the 30 patients receiving sulfamethoxazole/trimethoprim but occurred in 16
of 30 receiving no suppressive therapy. In the control group, P jiroveci pneumonia development was associated with advanced stages
of Kaposi's sarcoma, B subtype disease, and the presence of fewer pretreatment CD4 cells (0.2 X 10(9)/L or fewer). The number of
patients surviving, and the mean length of survival, were greater in the treatment group compared to the control group. Adverse
reactions were high, however, occurring in 50% of patients receiving sulfamethoxazole/trimethoprim. The most common adverse
[67]
effects were erythroderma, pruritus and nausea .
4) Pediatric:
a) Guideline Recommendations
1) Sulfamethoxazole/trimethoprim is the agent of choice for Pneumocystis jiroveci pneumonia (PCP) prophylaxis in children with
human immunodeficiency virus (HIV) and children born to mothers with HIV. Prophylaxis should be initiated at 4 to 6 weeks of age in
children born to mothers with HIV and in any infant with HIV, regardless of CD4+ count. Alternatives to sulfamethoxazole/trimethoprim
include dapsone or atovaquone. Dapsone is tolerated in approximately two-thirds of patients who are intolerant to
sulfamethoxazole/trimethoprim. For children 5 years of age and older who cannot take sulfamethoxazole/trimethoprim, dapsone, or
atovaquone, aerosolized pentamidine is recommended. Prophylaxis should be discontinued in children who are subsequently
determined not to be HIV-infected. Prophylaxis should continue for the first year of life in children who are HIV-infected or whose
infection status is unknown, regardless of CD4+ counts. Subsequent prophylaxis beyond 1 year of age in HIV-infected children is
determined based on age-specific CD4+ count thresholds as indicated in the following table:
Age
Initiating Primary Prophylaxis (CD4+
Count)
Discontinuing Primary and Secondary Prophylaxis (CD4+
Count)
1 to 5
years
less than 500/microliter or CD4+
percentages less than 15%
at least 500/microliter or CD4+ percentages at least 15% for
more than 3 consecutive months*
6 to 12
years
less than 200/microliter or CD4+
percentages less than 15%
at least 200/microliter or CD4+ percentages at least 15% for
more than 3 consecutive months
*only after at least 6 months of treatment with HAART
Children who have had PCP should be treated with secondary prophylaxis after treatment is completed. For secondary prophylaxis,
sulfamethoxazole-trimethoprim is the drug of choice, and dapsone, atovaquone, and aerosolized pentamidine (in children 5 years of
age and older) are alternatives. The same parameters used to guide discontinuing primary prophylaxis are recommended for
[14]
discontinuing secondary prophylaxis .
4.5.Z HIV infection - Toxoplasma encephalitis
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Sulfamethoxazole/trimethoprim is recommended as an alternative for the treatment of Toxoplasma gondii encephalitis in adults and
[13]
children with HIV-infection; pyrimethamine, in combination with leucovorin and sulfadiazine, is the preferred regimen .
3) Adult:
a) Initial preferred therapy for treatment of toxoplasmic encephalitis (TE) is with a combination of pyrimethamine, sulfadiazine, and
leucovorin. Sulfamethoxazole/trimethoprim is recommended as an alternative. Other regimens include pyrimethamine (plus
leucovorin) in combination with either clindamycin, atovaquone, or azithromycin. Duration of acute therapy is at least 6 weeks, if clinical
and radiological improvement is observed. Longer duration may be necessary if clinical or radiologic disease is extensive or if response
at 6 weeks is incomplete. Patients who have completed initial therapy for TE should be administered lifelong suppressive therapy (ie,
[13]
secondary prophylaxis or chronic maintenance therapy), unless immune reconstitution occurs as a consequence of HAART .
b) Sulfamethoxazole/trimethoprim was effective in treating toxoplasmic encephalitis (TE), when compared with
pyrimethamine/sulfadiazine (PS), in patients with AIDS. In a prospective, multicenter, randomized, pilot study, patients with signs,
symptoms and imaging scans compatible with a diagnosis of TE were randomized to receive pyrimethamine/sulfadiazine (n=37;
pyrimethamine 50 milligrams/day and sulfadiazine 60 milligrams/kilogram (mg/kg) orally or by nasogastric tube daily) or
sulfamethoxazole/trimethoprim (n=40; 10 to 50 mg/kg/day orally or intravenously in divided doses every 12 hours) for 30 days as
acute therapy. Maintenance therapy was then continued at 50% of the original dose for another 3 months. Folinic acid, 10 mg/day, was
given to the pyrimethamine/sulfadiazine group for the entire course of therapy. Patients were crossed-over to the opposite therapy if
there was no response within 15 days. The majority of patients in both groups received dexamethasone therapy, and patients were not
receiving antiretroviral therapy for their HIV infection. Prior to the primary evaluation, 3 patients receiving
sulfamethoxazole/trimethoprim and 4 patients receiving pyrimethamine/sulfadiazine required therapy cross-over due to treatment
nonresponse. After 30 days of acute therapy, 65.7% and 62.1% of patients achieved a complete clinical response (resolution of signs
and symptoms) in the pyrimethamine/sulfadiazine and sulfamethoxazole/trimethoprim groups, respectively; partial clinical response
was noted in 20% and 21.6%, respectively. A lack of response or disease progression occurred in 14.2% and 16.2% of the
pyrimethamine/sulfadiazine and sulfamethoxazole/trimethoprim groups, respectively. Complete resolution of radiologic lesions
occurred in 39.3% of pyrimethamine/sulfadiazine patients and 62.1% of sulfamethoxazole/trimethoprim patients (p=0.048); partial
resolution was observed in 30.3% and 10.8%, respectively. A lack of resolution was noted in 30.3% and 27% of
pyrimethamine/sulfadiazine and sulfamethoxazole/trimethoprim patients, respectively. One relapse of disease was reported in the
sulfamethoxazole/trimethoprim group during maintenance therapy; no relapse was reported in the pyrimethamine/sulfadiazine group.
Adverse reactions to drug therapy were reported more frequently in patients receiving pyrimethamine/sulfadiazine (37.8%) when
[73]
compared with patients receiving sulfamethoxazole/trimethoprim (12.5%; p=0.016) .
4.5.AA HIV infection - Toxoplasma encephalitis; Prophylaxis
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy; Pediatric, Evidence favors efficacy
Recommendation: Adult, Class IIa; Pediatric, Class IIa
Strength of Evidence: Adult, Category B; Pediatric, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Sulfamethoxazole/trimethoprim is the preferred agent for primary prophylaxis of Toxoplasma gondii encephalitis in adults and children
[13][14]
with human immunodeficiency virus
.
3) Adult:
a) Guideline Recommendations
1) Adults and adolescents who have HIV infection and are Toxoplasma-seropositive should receive chemoprophylaxis against
toxoplasmic encephalitis (TE) if they have a CD4 T-lymphocyte count of less than 100 cells/microliter (mcL). A daily dose of 1
sulfamethoxazole/trimethoprim double-strength tablet is the preferred regimen; a three-times weekly dose of the double-strength tablet
is recommended as an alternative. For patients who cannot tolerate sulfamethoxazole/trimethoprim, the recommended alternatives
are dapsone/pyrimethamine plus leucovorin, or atovaquone with or without pyrimethamine. Primary prophylaxis against TE should be
discontinued among patients who have responded to highly active antiretroviral therapy (HAART) with an increase in CD4 Tlymphocyte counts to greater than 200 cells/mcL for at least 3 months. This recommendation is supported by multiple observational
studies and two randomized trials where the majority of patients were on antiretroviral regimens that included a protease inhibitor and
had a CD4 cell count of greater than 200 cells/mcL for at least 3 months before discontinuing prophylaxis. The median CD4 cell count
at the time prophylaxis was discontinued was greater than 300 cells/mcL; the median follow-up ranged from 7 to 22 months.
[13]
Prophylaxis should be reintroduced if the CD4 T-lymphocyte count decreases to less than 100 to 200 cells/mcL .
b) Clinical Trials
1) A case-control study determined that higher doses of sulfamethoxazole/trimethoprim (more than 4 double-strength (DS) tablets
weekly) were more effective than lower doses (less than 4 DS tablets weekly) in preventing toxoplasmic encephalitis in patients with
human immunodeficiency virus (HIV). Cases (n=32) and controls (n=64) were matched for toxoplasmosis risk factors, including CD4
cell count and Toxoplasma gondii serum status, as well as timing of diagnostic neuroimaging studies. After adjustment for possible
confounders including compliance, the odds ratio for developing toxoplasmosis with low versus high sulfamethoxazole/trimethoprim
doses was 9.36 (95% confidence interval (CI), 2.05 to 42.75). The protective efficacy of high doses was 89% (95% CI, 49% to 98%).
Rifampin exposure was more common among cases than controls (47% versus 25%, p=0.03), with an adjusted odds ratio of 3.38 (95%
CI, 1.08 to 10.61). It is recommended that HIV-positive patients with low CD4 counts and Toxoplasma antibodies should receive
[25]
prophylaxis with more than 4 sulfamethoxazole/trimethoprim DS tablets weekly, particularly with concomitant rifampin .
2) In a retrospective review, sulfamethoxazole/trimethoprim was compared to pentamidine for the prophylaxis of toxoplasmic
encephalitis (TE) in patients with AIDS. Approximately 40% of patients in each group were seropositive for toxoplasma gondii specific
IgG before treatment. No cases of toxoplasmic encephalitis were reported in patients receiving sulfamethoxazole/trimethoprim (dose 1
double-strength tablet twice daily on Mondays and Wednesdays). Of those receiving pentamidine 33% were diagnosed with TE. All
cases of TE were diagnosed in patients who were seropositive prior to prophylaxis indicating reactivation of infection, rather than
[26]
primary infection .
4) Pediatric:
a) Guideline Recommendations
1) Children with human immunodeficiency virus who are Toxoplasma-seropositive should receive primary prophylaxis for Toxoplasma
gondii if their CD4+ count is less than 15% and they are younger than 6 years of age, or if their CD4+ count is below 100 cells/cubic
millimeter (mm(3)) and they are 6 years or older. Sulfamethoxazole/trimethoprim is the treatment of choice. Dapsone plus
pyrimethamine (plus leucovorin) is recommended in children who are unable to tolerate sulfamethoxazole/trimethoprim. Alternatively,
atovaquone with or without pyrimethamine (plus leucovorin) may be considered. Data in adults suggest that primary prophylaxis may be
discontinued once the CD4+ count rises to above 15% in children younger than 6 years or to above 100 cells/mm(3) in children 6 years
[14]
and older. Prophylaxis should be restarted if CD4+ counts fall below these parameters .
4.5.AB Infection by Yersinia enterocolitica
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Sulfamethoxazole/trimethoprim is considered the drug of choice for the treatment of infections caused by Yersinia enterocolitica
(Anon, 1996).
3) Adult:
a) One study reported no effect of Sulfamethoxazole/trimethoprim in shortening the clinical or bacteriologic course of Yersinia
enterocolitica gastroenteritis in infants and children. Sulfamethoxazole 50 milligrams per kilogram (mg/kg)/trimethoprim 10 mg/kg was
given twice daily for 7 days, and compared with placebo in double-blind fashion. The drug had no effect on the course of the disease or
in reducing the frequency of intrafamilial spread. However, the authors admit limitations of the study, due to the small number of
patients treated (34) and initiation of treatment late in the course of illness. It is possible that earlier treatment (in the first few days of
[92]
illness) might be more effective .
4.5.AC Methicillin resistant Staphylococcus aureus infection; Prophylaxis - Staphylococcal pneumonia; Prophylaxis
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
[57]
Benefits limited to one small study for MRSA prophylaxis
3) Adult:
a) When administered by nasogastric tube to intubated patients with burns covering at least 20% of body surface area,
sulfamethoxazole 400 milligrams (mg)/trimethoprim 80 mg three times daily for 10 days successfully decreased the incidence of
pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA). This Japanese study (n=40) found that only 5% of the
sulfamethoxazole/trimethoprim-treated group contracted MRSA pneumonia as compared with 37% of the placebo-treated group
(p=0.017). Pneumonia due to any pathogen was also less common with sulfamethoxazole/trimethoprim prophylaxis (10% versus 53%,
[57]
p=0.005). The groups did not differ statistically with respect to airway flora, mortality rates, or adverse effects .
4.5.AD Neutropenia - Selective decontamination of the digestive tract
See Drug Consult reference: SELECTIVE DECONTAMINATION OF THE DIGESTIVE TRACT
4.5.AE Peritonitis
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Benefits limited to case reports
3) Adult:
a) Sulfamethoxazole/trimethoprim appears effective, safe, and cost-effective for the prevention of SPONTANEOUS BACTERIAL
PERITONITIS (SBE). In this randomized trial, 60 patients with cirrhosis and ascites received either sulfamethoxazole/trimethoprim, 1
double strength tablet daily Monday through Friday, or no prophylaxis. After a median follow-up of 90 days, SBE and extraperitoneal
peritonitis developed in 9 patients (30%) not receiving prophylaxis, and SBE occurred in 1 patient (3%) receiving
sulfamethoxazole/trimethoprim (p less than 0.05). Although not statistically significant, the overall mortality rate was lower in patients
[62]
receiving sulfamethoxazole/trimethoprim (7% versus 21%) .
b) When peritonitis was suspected in 45 continuous ambulatory peritoneal dialysis patients, sulfamethoxazole 400 mg, trimethoprim
80 mg, and heparin 1000 units was added to each of the 4 daily dialysate bags. If the organism was found to be sensitive and/or the
patient responded well to therapy, treatment was continued at that dose for 2 weeks, and at half the dose (drug added to every other
bag) for an additional 2 weeks. If the organism was resistant, with an unsatisfactory clinical response, the patient was treated with
antibiotics specific for the organism. A total of 45 cases of peritonitis were treated in these patients, mostly Staphylococcus epidermidis
and Staphylococcus aureus. Gram negative infections were seen in only 3 cases (E coli, Proteus, and Pseudomonas). Overall, 38 of 45
cases were successfully treated. The only side effects were nausea and intestinal discomfort in 5 patients. Resistance was not found to
[63]
be a problem in patients that had multiple episodes of peritonitis over the course of the study .
4.5.AF Pneumocystis pneumonia
FDA Labeled Indication
1) Overview
FDA Approval: Adult, yes; Pediatric, yes (2 months of age and older)
Efficacy: Adult, Effective; Pediatric, Effective
Recommendation: Adult, Class IIa; Pediatric, Class IIa
Strength of Evidence: Adult, Category B; Pediatric, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Sulfamethoxazole/trimethoprim is indicated for the treatment of Pneumocystis pneumonia in adults and children 2 months and older
[2][17]
.
3) Adult:
a) Sulfamethoxazole/trimethoprim was reported superior to pentamidine in the treatment of Pneumocystis jiroveci pneumonia for 70
[15]
AIDS patients in a prospective, randomized study . Sulfamethoxazole/trimethoprim was initially administered intravenously as 15 to
20 mg/kg/day (trimethoprim) followed by oral therapy. Sulfamethoxazole/trimethoprim doses were adjusted to maintain serum
trimethoprim levels at 5 to 8 mcg/mL. Intravenous pentamidine was given in doses of 4 mg/kg/day and followed by intramuscular
therapy after clinical improvement. The pentamidine dose was reduced by 30% to 50% for absolute rises in serum creatinine of greater
than 88 mmol/L (1 mg%). All patients were randomly assigned to receive 1 regimen for 17 to 21 days. The number of patients surviving
without the need for respiratory support at the completion of therapy was greater in the sulfamethoxazole/trimethoprim group (86%) as
compared to pentamidine (61%). In addition, oxygenation improved 8 days earlier in sulfamethoxazole/trimethoprim-treated patients.
4) Pediatric:
a) Sulfamethoxazole/trimethoprim has been utilized in 18 immunosuppressed children with mild to moderately severe Pneumocystis
jiroveci pneumonia. Of 6 patients treated with trimethoprim 4 to 7 milligrams/kilogram/day (mg/kg/day) and sulfamethoxazole 20 to 35
mg/kg/day, 4 recovered and 2 died. Of 14 patients treated with sulfamethoxazole 100 mg/kg/day and trimethoprim 20 mg/kg/day, 12
recovered and 2 died. In the 4 fatal cases and in 2 of the patients who recovered concomitant treatment was instituted with pentamidine
when the initial response to sulfamethoxazole/trimethoprim was inadequate. Patients became afebrile after 1 to 6 days, chest
radiographs were normal in 3 to 15 days and PaO2 at room air was greater than 85 mmHg by 1 to 9 days after initiation of
[16]
sulfamethoxazole/trimethoprim .
4.5.AG Pneumocystis pneumonia; Prophylaxis
FDA Labeled Indication
1) Overview
FDA Approval: Adult, yes; Pediatric, yes (2 months of age and older)
Efficacy: Adult, Effective; Pediatric, Effective
Recommendation: Adult, Class IIa; Pediatric, Class IIa
Strength of Evidence: Adult, Category B; Pediatric, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Sulfamethoxazole/trimethoprim is indicated as prophylaxis in immunosuppressed patients who are at an increased risk of developing
[2]
Pneumocystis carinii pneumonia .
3) Adult:
a) In a retrospective review, the administration of sulfamethoxazole/trimethoprim prophylaxis significantly reduced the risks of death
and of Pneumocystis jiroveci pneumonia (PCP) and associated with a trend toward reduced risk of major bacterial infections in patients
with AIDS. A medical record review of 1078 patients with HIV infection receiving PCP prophylaxis regimens who were observed an
average of 36 months was conducted. PCP occurred in 9% of sulfamethoxazole/trimethoprim-treated patients compared with 21% of
other prophylaxis regimen patients, resulting in a decreased risk of PCP of approximately 77% and an adjusted relative risk of 0.23
(95% confidence interval (CI), 0.14 to 0.36). At the conclusion of the review, death was recorded in 42% of
sulfamethoxazole/trimethoprim users and 57% of others, with an adjusted relative risk of death for sulfamethoxazole/trimethoprim
users of 0.58 (95% CI, 0.47 to 0.71). A significantly reduced risk of death continued to be evident when evaluating deaths not
attributable to PCP, with an adjusted relative risk for sulfamethoxazole/trimethoprim users of 0.59 (95% CI, 0.47 to 0.73).
Sulfamethoxazole/trimethoprim users demonstrated a borderline significant risk reduction of developing major bacterial infections.
Following inclusion of major infections of unknown etiology in addition to major bacterial infections, 36% of
sulfamethoxazole/trimethoprim users compared with 40% of others developed major infections, resulting in an adjusted relative risk of
0.77 (95% CI, 0.61 to 0.97) or an approximate 23% risk reduction. Analysis of bacterial pneumonia and pneumonia of unknown etiology
demonstrated a trend toward a sulfamethoxazole/trimethoprim prophylaxis protective effect with at least one episode of pneumonia in
[66]
28% of sulfamethoxazole/trimethoprim patients versus 29% of others .
b) Administration of sulfamethoxazole 800 milligrams (mg)/trimethoprim 160 mg twice daily orally for 24 months) was reported
effective in preventing P jiroveci pneumonia in patients with newly diagnosed Kaposi's sarcoma associated with AIDS. All 60 patients
treated had no history of opportunistic infections, and were randomized to receive either sulfamethoxazole/trimethoprim or no therapy;
Pneumocystis jiroveci pneumonia was observed in none of the 30 patients receiving sulfamethoxazole/trimethoprim but occurred in 16
of 30 receiving no suppressive therapy. In the control group, P jiroveci pneumonia development was associated with advanced stages
of Kaposi's sarcoma, B subtype disease, and the presence of fewer pretreatment CD4 cells (0.2 X 10(9)/L or fewer). The number of
patients surviving, and the mean length of survival, were greater in the treatment group compared to the control group. Adverse
reactions were high, however, occurring in 50% of patients receiving sulfamethoxazole/trimethoprim. The most common adverse
[67]
effects were erythroderma, pruritus and nausea .
4) Pediatric:
a) Intermittent therapy with sulfamethoxazole/trimethoprim (3 consecutive days per week) was reported as effective as daily
administration for prophylaxis against Pneumocystis jiroveci pneumonitis in children with acute lymphocytic leukemia. Patients were
randomly assigned to sulfamethoxazole 750 milligrams/squared meter (mg/m(2))/trimethoprim 150 mg/m(2), in 2 divided doses, either
on 3 consecutive days weekly (Monday, Tuesday and Wednesday) or daily; maximal daily doses were sulfamethoxazole 1.6 gram/
trimethoprim 320 mg. Pneumocystis pneumonitis did not occur in any of the 74 and 92 patients receiving the drug 3 days weekly or
daily, respectively. The incidence of P jiroveci pneumonitis with no prophylaxis is approximately 21%. Systemic mycoses were reduced
significantly in patients receiving the 3 days/week regimen as opposed to once daily in this study. Due to cost advantages and a lower
frequency of fungal infections, a 3 times weekly regimen is preferable to a once daily sulfamethoxazole/trimethoprim as prophylaxis for
[68]
P jiroveci pneumonitis .
b) Intermittent therapy (2 non-consecutive days per week) with oral sulfamethoxazole/trimethoprim was effective for prophylaxis of
Pneumocystis jiroveci pneumonia (PCP) in pediatric patients receiving chemotherapy or hematopoietic stem cell transplantation
(HSCT) in a retrospective analysis (n=181). The sulfamethoxazole/trimethoprim dose was 8 milligrams/kilogram (mg/kg) per day of the
trimethoprim component given orally on 2 non-consecutive days per week (eg, Tuesday and Friday) to 147 patients.
Sulfamethoxazole/trimethoprim was temporarily withheld during high-dose methotrexate therapy and subsequent myelosuppression
(neutrophil count less than 500 cells/microliter), and between preconditioning and day +28 in patients undergoing HSCT. For those
patients unable to tolerate sulfamethoxazole/trimethoprim (n=34), inhaled pentamidine 5 to 10 mg/kg or intravenous pentamidine 4
mg/kg every month was administered. No breakthrough cases of PCP developed during the total duration of prophylaxis (29,063
patient-days for sulfamethoxazole/trimethoprim and 11,294 patient-days for pentamidine). In 59% (n=20) of patients receiving
pentamidine, the reason for switching to pentamidine was intolerability (nausea, mucositis, or dysphagia for the majority of patients).
Other reasons included allergy (rash) (6%), myelosuppression (3%), and renal insufficiency (3%); reasons for switching were not
[69]
documented in 29% of the cases .
4.5.AH Prostatitis
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class III
Strength of Evidence: Adult, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Effective for treating prostatitis
3) Adult:
a) In chronic bacterial prostatitis, most antibiotics are ineffective because adequate levels cannot be reached in prostatic fluid. In 24
patients with prostatitis receiving two standard tablets twice daily for 28 days, 4 patients experienced mild side effects, and of 18
patients with sufficient data for analysis, 78% had one or more pathogens killed by therapy. Long term cure occurred only in 6 patients,
[70]
suggesting the possible need for therapy of a longer duration .
4.5.AI Salmonella infection
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive; Pediatric, Evidence is inconclusive
Recommendation: Adult, Class IIb; Pediatric, Class IIb
Strength of Evidence: Adult, Category C; Pediatric, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Limited to case reports
3) Adult:
a) The incidence of salmonellosis in patients with inflammatory bowel disease is enhanced. If properly diagnosed, salmonellosis
complicating ulcerative colitis is easily treated. A 22-year-old female diagnosed 4 years earlier with ulcerative colitis was chronically
treated with sulfasalazine 3 grams (g)/day. Five weeks before admission the patient experienced bloody diarrhea and severe abdominal
pain. Sulfasalazine dosage was increased to 4 g/day and prednisone 40 milligrams (mg)/day was added to her regimen. On admission
the patient had diffuse abdominal tenderness and guarding, and underwent intensive therapy with total parenteral nutrition,
hydrocortisone sodium succinate, and sulfasalazine, 4 g/day. The condition failed to respond and the patient was being considered for
total colectomy. On the 8th day however stool culture was positive for Salmonella type B. The patient was subsequently treated with
sulfamethoxazole 800 mg/trimethoprim 160 mg (2 tablets twice daily). Within two days there was a marked improvement of the
patient's condition and the patient was discharged within six days and instructed to complete a two week course of
sulfamethoxazole/trimethoprim. The patient was also maintained on sulfasalazine 4 g/day, prednisone 30 mg/day and iron
[71]
supplements. At a nine month follow-up, the patient remained asymptomatic on sulfasalazine 3 g/day .
4) Pediatric:
a) Oral or intravenous sulfamethoxazole/trimethoprim (10 to 20 milligrams trimethoprim/kilogram/day) has been effective in relapses
[72]
of salmonella meningitis in infants unresponsive to other antibiotic therapy (chloramphenicol, ampicillin) . The authors suggest that
sulfamethoxazole/trimethoprim might be preferred when ampicillin and chloramphenicol, alone or in combination, are not bactericidal
for the infecting Salmonella strain.
4.5.AJ Shigellosis
FDA Labeled Indication
1) Overview
FDA Approval: Adult, yes; Pediatric, yes (2 months of age and older)
Efficacy: Adult, Effective
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Effective for the treatment of Infections caused by Shigella
[1][2][3]
4.5.AK Sinusitis
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIa
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
[20]
Has been used to treat acute maxillary sinusitis
3) Adult:
a) The recommendation for the management of mild sinusitis is symptomatic treatment and reassurance. Antibiotic therapy should be
reserved for patients with moderately severe symptoms who meet the criteria for the clinical diagnosis of acute bacterial sinusitis
(rhinosinusitis) (symptoms that last greater than 7 days and include maxillary pain in the face or teeth and purulent nasal secretions)
and for those with severe rhinosinusitis symptoms, regardless of duration of illness. In patients with acute bacterial sinusitis, the use of
first-line agents (amoxicillin, sulfamethoxazole/trimethoprim) is associated with similar clinical benefits and significant cost savings
when compared to second-line agents (fluoroquinolones, azithromycin, clarithromycin, second- and third-generation cephalosporins).
Appropriate choice of narrow-spectrum antibiotics will also decrease the risk for emergence and spread of antibiotic-resistant bacteria
[21][22][23]
. Quinolones may have a role for treating highly resistant or multidrug-resistant strains (Brooks et al, 2000).
b) A trial comparing a 3 day course versus the standard 10-day course of sulfamethoxazole/trimethoprim for acute, uncomplicated
MAXILLARY SINUSITIS found no difference between treatment groups. Eighty patients were randomized to receive 1
sulfamethoxazole/trimethoprim double-strength tablet twice daily for 10 days or 3 days of sulfamethoxazole/trimethoprim plus 7 days
of placebo. There was no difference in cure rates at 2 weeks, 1 month or 2 months after treatment. The cure rate was 77% in the three
[20]
day group and 76% in the group receiving 10 days of treatment .
4.5.AL Stenotrophomonas maltophilia infection
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIa
Strength of Evidence: Adult, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Sulfamethoxazole/trimethoprim is the drug of choice for the treatment of infections caused by stenotrophomonas (Pseudomonas)
maltophilia (Anon, 1996)
3) Adult:
a) The synergistic combination of intravenous sulfamethoxazole/trimethoprim (240 milligrams every 6 hours) and ticarcillin/clavulanic
acid (4 grams every 4 hours) successfully treated a case of Stenotrophomonas maltophilia endocarditis associated with a
ventriculoatrial cerebrospinal fluid shunt of 18 years duration in a 60-year-old female. Attempts to completely remove the extracranial
catheter initially failed. The organism was susceptible only to sulfamethoxazole/trimethoprim and ticarcillin/clavulanic acid, which
produced resolution of signs and symptoms within 2 weeks. However, the tricuspid valve vegetation remained until a final catheter
fragment was removed from the ventricular cavity, necessitating a total of 7 weeks of the antibiotic combination. Follow-up in 15 months
[43]
revealed no sequelae .
4.5.AM Traveler's diarrhea
FDA Labeled Indication
1) Overview
FDA Approval: Adult, yes; Pediatric, no
Efficacy: Adult, Effective; Pediatric, Effective
Recommendation: Adult, Class IIa; Pediatric, Class IIa
Strength of Evidence: Adult, Category B; Pediatric, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
[1][2]
Effective for the treatment of travelers' diarrhea
3) Adult:
a) Sulfamethoxazole/trimethoprim or trimethoprim alone may be an alternative for early treatment of travelers' diarrhea in a controlled
study involving 110 adults traveling to Mexico. Patients were randomized to either sulfamethoxazole 800 mg/trimethoprim 160 mg,
trimethoprim alone 200 mg or a placebo, 2 times daily for 5 days. After a period of 24 hours, patients receiving
sulfamethoxazole/trimethoprim or trimethoprim alone passed fewer unformed stools and experienced a greater reduction in abdominal
pain than patients administered placebo. Treatment failures occurred in 5% of sulfamethoxazole/trimethoprim treated patients, 8% of
[27]
TRIMETHOPRIM treated patients and 49% of placebo treated patients .
b) Sulfamethoxazole/trimethoprim in combination with loperamide was found to be more effective than either agent used alone for the
treatment of travelers' diarrhea in 227 adults. sulfamethoxazole 1600 milligrams (mg)/trimethoprim 320 mg as a single dose plus
loperamide 4 mg initially, then 2 mg after each loose stool for 3 days reduced the duration of diarrhea to 1 hour.
Sulfamethoxazole/trimethoprim alone was associated with diarrhea for 28 hours. Loperamide alone did not significantly reduce the
[28]
duration of diarrhea .
[29]
c) Three different dosing regimens of sulfamethoxazole/trimethoprim were studied for the treatment of travelers' diarrhea .
Loperamide use was permitted in all groups. Group A patients received 1 double-strength (DS) tablet every 12 hours for 6 doses; group
B patients received a single dose of 2 DS tablets and, group C received a loading dose of 2 DS tablets followed by 1 DS tablet twice
daily for 5 doses. Patients in group C responded to treatment significantly faster than patients in the other 2 groups, and significantly
less loperamide was used in these patients.
4.5.AN Urinary tract infectious disease
FDA Labeled Indication
1) Overview
FDA Approval: Adult, yes; Pediatric, yes (greater than 2 months old)
Efficacy: Adult, Effective; Pediatric, Effective
Recommendation: Adult, Class IIa; Pediatric, Class IIa
Strength of Evidence: Adult, Category B; Pediatric, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Sulfamethoxazole/trimethoprim is indicated for the treatment of urinary tract infections caused by Escherichia coli, Klebsiella species,
[1][2]
Enterobacter species, Morganella morganii, Proteus mirabilis, and Proteus vulgaris
.
Sulfamethoxazole/trimethoprim is recommended for the treatment of acute uncomplicated cystitis in women if local resistance rates for
[30]
urinary pathogens are not greater than 20% or if the organism is known to be susceptible .
Sulfamethoxazole/trimethoprim is recommended for the treatment of acute pyelonephritis if the urinary pathogen is known to be
[30]
susceptible .
Short-course (single-dose or 3-day courses) therapy was as effective as traditional dosing (5- or 10-day courses) in children with
[31]
uncomplicated urinary tract infections .
3) Adult:
a) Guideline Recommendations
1) Sulfamethoxazole/trimethoprim is recommended for the treatment of acute uncomplicated cystitis in women if local resistance rates
for urinary pathogens are not greater than 20% or if the organism is known to be susceptible. In clinical studies with
sulfamethoxazole/trimethoprim with resistance rates less than 20%, early clinical and bacterial cure rates have ranged from 90% to
100% with late clinical cure rates ranging from 80% to 90%. A treatment duration of 3 days is recommended for acute uncomplicated
cystitis. For acute pyelonephritis, sulfamethoxazole/trimethoprim may be used if the urinary pathogen is known to be susceptible. If
sulfamethoxazole/trimethoprim is used empirically (ie, unknown susceptibility), an intravenous dose of a long-acting antimicrobial
(ceftriaxone or consolidated 24-hour dose of aminoglycoside) should be used initially to improve clinical and bacterial success. For
[30]
acute pyelonephritis, a treatment duration of 14 days is recommended .
b) Clinical Studies
1) Three-day treatment of urinary tract infections with sulfamethoxazole/trimethoprim has been found to be as effective as 7-day
[32][33]
treatment in adult females
.
2) In elderly patients with urinary tract infections, 3 days of treatment with sulfamethoxazole/trimethoprim will eradicate urinary
[34]
bacteria in approximately 70% of patients, but after 6 months only about 25% will remain free of infection .
4) Pediatric:
a) In a meta-analysis including 6 prospective, randomized studies evaluation sulfamethoxazole/trimethoprim for the treatment of
uncomplicated urinary tract infections in pediatric patients, short-course therapy with sulfamethoxazole/trimethoprim (single-dose or 3day courses) was as effective as 5- to 10-day courses. The overall difference in cure rate between short-course and conventional
therapy was not significant (difference in cure rate 6.2%; 95% confidence interval, -3.7% to 16.2%) (Tran et al, 2001).
[31]
b) In children, 3 days of sulfamethoxazole/trimethoprim is as effective as 14 days of treatment .
4.5.AO Urinary tract infectious disease; Prophylaxis
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Effective; Pediatric, Evidence is inconclusive
Recommendation: Adult, Class IIa; Pediatric, Class III
Strength of Evidence: Adult, Category B; Pediatric, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Effective prophylaxis in adults for urinary tract infections in women with 2 or more urinary tract infections in one year and in men with
[74]
[75]
[76]
chronic bacterial prostatitis , in renal transplant patients , and as postcoital therapy
Prophylaxis of recurrent urinary tract infection in children with low-dose sulfamethoxazole/trimethoprim provided modest benefit, but
[77]
increased the risk of developing bacterial resistance, in a randomized, placebo-controlled trial (n=576) .
Following an initial febrile urinary tract infection (UTI), prophylaxis with sulfamethoxazole/trimethoprim or amoxicillin/clavulanate
continued after 40 days offered no benefit for the prevention of recurrent febrile UTI infection in a 12-month, randomized, open-label,
[78]
noninferiority trial in 338 children .
3) Adult:
a) Sulfamethoxazole/trimethoprim has been reported effective in prophylaxis of urinary tract infections in renal transplant recipients.
Administration of 1 sulfamethoxazole 800 mg/trimethoprim 160 mg tablet daily for a period of 4 months (beginning with removal of
Foley catheter) resulted in the occurrence of urinary tract infections in only 2 of 26 patients (8%), as compared to 10 of 26 patients
(38%) not receiving the drug (control group). Oral mycostatin was administered throughout prophylaxis since 3 of the first 5 patients
treated with sulfamethoxazole/trimethoprim developed oral candidiasis. These data indicate the efficacy of long-term
[75]
sulfamethoxazole/trimethoprim treatment in the prophylaxis of UTIs in renal transplant recipients .
b) The prophylactic use of sulfamethoxazole/trimethoprim is recommended for women with 2 or more urinary tract infections in one
[79][80][74][81]
year and in men with chronic bacterial prostatitis
. For women with 3 or more infections in the past 12 months, the
recommended length of prophylactic therapy is at least one year. In women with less than 3 infections per year, 6 months of therapy is
[74][81]
recommended
. For women, the recommended dosage is sulfamethoxazole 200 milligrams (mg)/trimethoprim 40 mg every night
[82]
or 400 mg/80 mg every other night . For men with chronic bacterial prostatitis, the recommended continuous therapy is
[80][74][81]
sulfamethoxazole 200 milligrams (mg)/trimethoprim 40 mg or 400 mg/80 mg every night or 400 mg/80 mg 3 times a week
.
c) Sulfamethoxazole 200 milligrams (mg)/trimethoprim 40 mg 3 times weekly has been administered for up to 5 years to 11 women
previously experiencing recurrent urinary tract infections. In this study 7 urinary tract infections occurred. No evidence of emerging
[83]
bacterial resistance was observed .
d) Postcoital prophylaxis for recurrent urinary tract infections (UTI) was studied in a randomized, double-blind, placebo-controlled trial
[76]
. Sixteen patients were randomized to receive postcoital sulfamethoxazole 200 milligrams (mg)/trimethoprim 40 mg, while 11
patients received postcoital placebo. In the next 6 months, 9 of the 11 patients on postcoital placebo developed a UTI, while only 2 of
the 16 patients on postcoital sulfamethoxazole/trimethoprim developed a UTI. Postcoital sulfamethoxazole/trimethoprim prophylaxis
is a safe, effective, and inexpensive approach for the prevention of recurrent UTI in young women.
4) Pediatric:
a) Prophylaxis of recurrent urinary tract infection (UTI) in children with low-dose sulfamethoxazole/trimethoprim provided modest
benefit, but with a significant risk of developing bacterial resistance, in a multicenter, randomized, placebo-controlled trial (n=576).
Children with a history of at least 1 symptomatic UTI were recruited and those with all grades of vesicoureteral reflux or recurrent
infection were potentially eligible. Urinary tract imaging was not required for inclusion; however, enrolled patients (median age, 14
months; 64% female) had completed short-term treatment and were clinically asymptomatic prior to randomization. All patients received
sulfamethoxazole/trimethoprim for a 2-week, single-blind, run-in period. Patients were then randomized to receive sulfamethoxazole
10 milligrams (mg)/trimethoprim 2 mg/kg (n=288) or matching placebo (n=288) daily for 12 months. The primary outcome was
occurrence of microbiologically-confirmed symptomatic UTI within the 12-month period. If infection recurred during the study period,
treatment was discontinued. At study entry, 42% of patients had known vesicoureteral reflux and approximately 87% of the infections
were due to Escherichia coli. During the 12-month study period, UTI recurred in 13% (n=36/288) compared with 19% (n=55/288) of
patients in the sulfamethoxazole/trimethoprim and placebo groups, respectively, yielding an absolute difference of 6% (95%
confidence interval (CI), 1% to 13%) and a hazard ratio in the active treatment group of 0.61 (95% CI, 0.4 to 0.93; p=0.02). Thus, the
number of patients needed to treat to prevent 1 UTI was 14 (95% CI, 9 to 86). The modest benefit of long-term prophylaxis with lowdose sulfamethoxazole/trimethoprim did not vary significantly across subgroups stratified by age, gender, reflux status, UTI history or
causative microorganism (p greater than or equal to 0.2). However, significantly more patients in the active treatment group had a UTI
with bacterial resistance to sulfamethoxazole/trimethoprim compared with the placebo group (67% vs 25%; difference, -42%; 95% CI,
[77]
-61% to -22%; p less than 0.001) .
b) Following an initial febrile urinary tract infection (UTI), with or without degree 1 to 3 vesicoureteral reflux,
sulfamethoxazole/trimethoprim or amoxicillin/clavulanate prophylaxis continued after 40 days offered no benefit for the prevention of
recurrent infection compared with no prophylaxis in a 12-month, randomized, open-label, noninferiority trial in 338 children. Included in
the study were children 2 months to 7 years of age, with normal renal function, and a first febrile UTI defined as fever 38 degrees
Celsius or higher, pyuria, and 2 positive urine cultures. Patients included also had raised inflammatory indices in the first 48 hours
(erythrocyte sedimentation rate 30 millimeters or greater in the first hour, or C-reactive protein 3 or more times the upper limit of normal,
or both) or an elevated neutrophil count. Treatment of the initial febrile UTI was with either intravenous ceftriaxone for 3 days followed
by oral amoxicillin/clavulanate for 7 days, or oral amoxicillin/clavulanate for 10 days. All children were treated prophylactically with
amoxicillin/clavulanate for a median of 40 days (range, 33 to 55 days) until a voiding cystourethrography was done. Patients were then
randomized to receive either no prophylaxis (n=127), or prophylaxis with amoxicillin/clavulanate (n=113) or
sulfamethoxazole/trimethoprim (n=98) both dosed at 15 milligrams/kilogram/day for a median duration of 40 days. The primary
endpoint was the first recurrence of febrile UTI in 12 months after randomization and noninferiority was defined as an upper confidence
limit of 30% for the no-prophylaxis arm. In an intent-to-treat analysis, the incidence of recurrent febrile UTIs was not significantly
different between the 2 groups: 9.45% (12/127) in the no-prophylaxis group and 7.11% (15/211) in the prophylaxis group for a risk
difference of 2.34% (95% confidence interval (CI), 3.8% to 8.4%). An on-treatment analysis that assumed recurrence of febrile UTI in
patients lost to follow-up revealed similar results (no-prophylaxis, 10.2% (12/117) vs prophylaxis, 7.6% (15/195); difference, 2.6% (95%
confidence interval (CI), -4% to 9.2%)). Among secondary endpoints, rates of new renal scar formation (in a difference site from the
initial pyelonephritis site) were also no different between the no-prophylaxis and prophylaxis groups (1.9% (2/108) vs 1.1% (2/187);
difference, 0.8% (95% CI, -2.1% to -3.7%)). In a multivariate analysis, grade III reflux was identified as a risk factor for recurrence but
not receiving prophylaxis was not a risk factor. There were 9 recurrences of infection that were attributed to resistant bacteria, 8 in the
prophylaxis group and one in a patient switched from no-prophylaxis to prophylaxis. The study did not evaluate a complete prophylaxis[78]
free protocol since all children were treated prophylactically for a median of 40 days prior to randomization .
4.5.AP Urinary tract infectious disease; Prophylaxis - Vesicoureteric reflux, Grades 1 to 4
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Pediatric, Ineffective
Recommendation: Pediatric, Class III
Strength of Evidence: Pediatric, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
In 3 open-label, randomized trials, long-term prophylaxis (1 to 2 years) with sulfamethoxazole/trimethoprim failed to reduce the
incidence of pyelonephritis and urinary tract infection, and to prevent renal damage and development of renal scars in children with
[5][6][7]
vesicoureteral reflux, grades l to IV
In a sub-analysis, prophylaxis significantly reduced UTI in boys (ages 1 month to 3 years) with vesicoureteral reflux grade III but not
[7]
grades I and II, in an open-label, randomized, multicenter, study (n=225)
3) Pediatric:
a) Sulfamethoxazole/trimethoprim prophylaxis for 2 years was ineffective in preventing pyelonephritis recurrences and renal damage
in children (younger than 30 months) with vesicoureteral reflux (VUR) (grade II to IV), in an open-label, multicenter, randomized, control
trial (n=100). Children with grade II, III, or IV VUR, monolateral or bilateral, were randomized to an intervention group
sulfamethoxazole/trimethoprim (n=50) or control group (no antibiotic) (n=50). The doses of sulfamethoxazole/trimethoprim were
sulfamethoxazole 5 to 10 milligrams/kilograms (mg/kg)/trimethoprim 1 to 2 mg/kg once daily for 2 years. Infections were treated with
oral ceftibuten, cefaclor, or amoxicillin/clavulanate for 10 days and changed as necessary based on antibiogram. The primary outcome
was the recurrence of pyelonephritis with secondary outcomes of progression of renal damage. Patients were followed for an additional
2 years (without prophylaxis) after the initial 2-year intervention phase. Renal damage was defined as the appearance of new scars
measured by renal ultrasound and cystourethrography and worsening dimercaptosuccinic acid (DMSA) uptake measured by renal
scan. Rates of pyelonephritis were not significantly different between the 2 groups during the first year, second year, and the 2 years
combined. In the first 2 years of prophylaxis, the incidence of pyelonephritis recurrence was 36% for the
sulfamethoxazole/trimethoprim group and 30% for the control group with a corresponding relative risk (RR) of 1.2 (95% confidence
interval (CI), 0.68 to 2.11) for at least 1 recurrence with prophylaxis. In the first year, the incidence of pyelonephritis recurrence was
44% for the sulfamethoxazole/trimethoprim group and 34% for the control group with a corresponding RR of 1.42 (95% CI, 0.76 to
2.65). In the second year, the incidence of pyelonephritis recurrence was 18% for the sulfamethoxazole/trimethoprim group and 16%
for the control group with a corresponding RR of 1.25 (95% CI, 0.54 to 2.9). There was no significant difference between the
prophylaxis group and control group with respect to DMSA uptake (p=0.6 right kidney and p=0.7 left kidney) and renal scar presence
(40% vs 36%, respectively, p=0.4). The RR for renal scars was 1.22 (95% CI, 0.75 to 1.98). Pyelonephritis developed in 1 patient on
prophylaxis and 2 in the control group, in the second phase, 2-year, follow-up without antibiotics. Of note, all recurrences in the control
group were caused by E coli sensitive organisms. However, in the prophylaxis arm, recurrences were caused by multiresistant bacteria.
[5]
The following table provides resistance patterns for pathogens responsible for recurrences in the prophylaxis group :
Resistance Patterns For Recurrences in the Prophylaxis Group
Organisms
Resistant
Sensitive-sulfamethoxazole/trimethoprim
Escherichia coli (n=37)
37- sulfamethoxazole/trimethoprim
12- amoxicillin
37- cephalosporins
37- ciprofloxacin
Pseudomonas aeruginosa (n=3)
3-sulfamethoxazole/trimethoprim
3-amoxicillin3-ampicillin
3-ciprofloxacin
3-aminoglycosides
3- ceftazidime
Enterococcus fecalis (n=2)
2- sulfamethoxazole/trimethoprim
2-amoxicillin
2-ampicillin
Morganella moorganii (n=1)
1- sulfamethoxazole/trimethoprim
1-amoxicillin1- amoxicillin/clavulanate
1- ampicillin
1-ciprofloxacin
1-aminoglycosides
b) Antibiotic prophylaxis with either sulfamethoxazole/trimethoprim or nitrofurantoin for 1 year in children with an episode of acute
pyelonephritis with or without vesicoureteral reflux (VUR) failed to reduce the frequency of urinary tract infection (UTI) and to prevent
the development of renal scars, in an open-label, randomized, multicenter, controlled study (n=236). Patients (3 months to 18 years)
with acute pyelonephritis diagnosed by dimercaptosuccinic acid (DMSA) scintigraphic scan were randomized to no prophylaxis or
prophylaxis of either sulfamethoxazole/trimethoprim or nitrofurantoin. The prophylactic agent used was chosen at the discretion of the
participating center. The dosages were sulfamethoxazole 5 to 10 milligrams/kilogram (mg/kg)/trimethoprim 1 to 2 mg/kg once daily
and nitrofurantoin 1.5 mg/kg once daily for 1 year. Patients were stratified into those with VUR and those without VUR. Patients with
VUR grade IV or V were excluded. Focal or diffuse areas of decreased DMSA uptake without evidence of cortical loss was the
definition for acute pyelonephritis. Decreased uptake associated with loss of the contours of the kidney or cortical thinning with
decreased volume was the definition of renal scar. The primary outcome was the occurrence of UTI, pyelonephritis, and renal scars, in
[6]
the on-treatment analysis. The following table provides outcomes for patients with VUR and without VUR, respectively :
Outcomes in Patients with VUR
Outcomes
Prophylaxis
No Prophylaxis
Asymptomatic UTI*
0%
5.1%
Cystitis*
9.2%
15.5%
Acute pyelonephritis**
12.9%
1.7%
No UTI*
79.6%
75.6%
Renal Scars*
9%
3.4%
Key: UTI = urinary tract infection; * = no difference in outcomes between the 2 groups; ** p=0.0291
Outcomes in Patients Without VUR *
Outcomes
Prophylaxis
No Prophylaxis
Asymptomatic UTI
2.2%
6.6%
Cystitis
2.2%
13.8%
Acute pyelonephritis
4.5%
3.3%
None
9.1%
76.7%
Renal Scars
4.5%
6.6%
Key: UTI = urinary tract infection; * = no difference in outcomes between the 2 groups
Among those not receiving prophylaxis, the incidence of UTI was 22.4% and 23.3% (p=0.9999) for patients with VUR and without VUR,
respectively. Among those receiving prophylaxis, the incidence was 23.6% and 8.8% (p=0.063) for patients with VUR and for patients
without VUR, respectively. Of note, each of the 7 individuals with VUR who developed acute pyelonephritis while on prophylactic
[6]
therapy demonstrated resistance to the prophylactic agent .
c) There was no significant difference between prophylaxis with sulfamethoxazole/trimethoprim and no prophylaxis in the recurrence
of urinary tract infections (UTI) or febrile UTI in children with grade I to III vesicoureteral reflux (VUR), in an open-label, randomized,
multicenter, study (n=225). Children (ages 1 month to 3 years) were randomized to sulfamethoxazole 10 milligrams/kilogram
(mg/kg)/trimethoprim 2 mg/kg once daily or no prophylaxis and followed for 18 months. Renal ultrasounds and clinical examinations
were performed at 9 and 10 months and urine dipsticks monthly. A UTI was defined as greater than 10(5) bacterial/mL in the urine. The
combined recurrence rate for UTI and febrile UTI was 17% for the prophylaxis group and 26% for the control group (p=0.15). The
recurrence rate of febrile UTI was 13% for the prophylaxis group and 16% for the control group (p=0.52). In a sub-analysis, prophylaxis
[7]
significantly reduced UTI in boys with VUR grade III (p=0.04) but not grades I and II VUR (p=0.36 and p=0.41, respectively) .
4.5.AQ Wegener's granulomatosis
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Sulfamethoxazole/trimethoprim has been used to treat Wegener's granulomatosis
Exact mechanism unknown; may be related to an antiinflammatory or antioxidant effect rather than an antimicrobial effect
3) Adult:
a) The dose most commonly used has been sulfamethoxazole 800 milligrams (mg)/trimethoprim 160 mg 2 times daily for 2 to 8
[84][85][86][87]
weeks, then the dose may be reduced to 800 mg/160 mg once daily
. Patients that are unresponsive to
CYCLOPHOSPHAMIDE and corticosteroids, or need large doses of these agents, may respond to sulfamethoxazole/trimethoprim
[88][89]
.
b) Sulfamethoxazole/trimethoprim significantly reduced the incidence of relapses in patients with Wegener's granulomatosis. A 2-year
trial compared sulfamethoxazole/trimethoprim 1 double strength tablet twice daily to placebo in 81 patient with Wegener's
granulomatosis. Patients were enrolled when their disease was in remission. Patients in the sulfamethoxazole/trimethoprim group
[90]
(81%) were more likely to remain in remission as compared to patients in the placebo group (60%) .
4.5.AR Whipple's disease
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Sulfamethoxazole/trimethoprim is often used as first-line therapy in the treatment of Whipple's disease because of its ability to
penetrate the central nervous system
3) Adult:
a) A patient who initially responded to treatment with sulfamethoxazole/trimethoprim, relapsed, and was then successfully treated with
cefixime. The dose of sulfamethoxazole/trimethoprim given was a double-strength tablet twice daily. At the time the patient was taking
sulfamethoxazole/trimethoprim he was also receiving low dose methotrexate for the treatment of psoriasis. The authors felt that the
[91]
methotrexate may have impaired the patients cell mediated immunity attributing to the relapse .
4.6 Comparative Efficacy / Evaluation With Other Therapies
Amdinocillin
Amdinocillin Pivoxil
Amoxicillin
Amoxicillin/Clavulanic Acid
Ampicillin
Atovaquone
Brodimoprim
Carbinoxamine
Cefaclor
Cefadroxil
Cefixime
Cefotaxime
Cefpodoxime Proxetil
Ceftibuten
Ceftriaxone
Cephalexin
Chloroquine
Cinoxacin
Ciprofloxacin
Clindamycin
Cyclacillin
Dapsone
Doxycycline
Enoxacin
Erythromycin
Erythromycin Ethylsuccinate/Sulfisoxazole Acetyl
Fosfomycin
Framycetin
Furazolidone
Methenamine
Methotrexate
Metronidazole
Mupirocin
Nalidixic Acid
Nitrofurantoin
Nitrofurantoin, Macrocrystals/Nitrofurantoin Monohydrate
Norfloxacin
Ofloxacin
Oxytetracycline
Pefloxacin
Penicillin G
Penicillin G Procaine
Pentamidine
Prednisolone
Primaquine
Pyrimethamine
Spectinomycin
Streptomycin
Sulfamethoxazole
Sulfisoxazole
Temafloxacin
Trimethoprim
Trimethoprim/Sulfadiazine
Vancomycin
4.6.A Amdinocillin
Enteropathogenic Escherichia coli gastrointestinal tract infection
Typhoid and paratyphoid fevers
Typhoid fever
4.6.A.1 Enteropathogenic Escherichia coli gastrointestinal tract infection
a) Some studies have reported the comparable efficacy of cotrimoxazole and amdinocillin in diarrhea caused by enteropathogenic
[726][727]
Escherichia coli
.
4.6.A.2 Typhoid and paratyphoid fevers
a) Some studies have reported the comparable efficacy of cotrimoxazole and amdinocillin in enteric fever
appear that amdinocillin will replace standard therapy for enteric fever.
[728]
. However, it does not
4.6.A.3 Typhoid fever
a) Amdinocillin was compared to cotrimoxazole for the treatment of typhoid fever in children. Ten children received amdinocillin 40
mg/kg 4 times daily and 10 children received cotrimoxazole 6 mg/24 mg per kg 2 times daily. The total duration of illness was not
significantly different for the 2 treatment groups; however, the total duration of illness was significantly shorter for the cotrimoxazole
group (4.2 days, compared to 7.9 days for the amdinocillin group). Addition of amoxicillin 100 mg/kg 3 times daily to amdinocillin did not
[729]
significantly increase its effectiveness
.
4.6.B Amdinocillin Pivoxil
4.6.B.1 Typhoid and paratyphoid fevers
a) Some studies have reported the comparable efficacy of cotrimoxazole and amdinocillin in enteric fever
appear that amdinocillin will replace standard therapy for enteric fever.
[720]
. However, it does not
4.6.C Amoxicillin
Cystitis
Otitis media
Typhoid fever
4.6.C.1 Cystitis
a) Single dose regimens of cotrimoxazole (320 mg trimethoprim/1.6 g sulfamethoxazole), appears to be more effective than
amoxicillin (3 g) or cyclacillin (3 g) in the treatment of acute cystitis in 38 women. Clinical cure occurred all of 13 cotrimoxazole treated
patients two days after treatment, as compared to persistent bacteriuria remaining in 4 of 13 given amoxicillin (31%) and 4 of 12 given
cyclacillin (33%). At a two week follow-up, 11 of 13 cotrimoxazole treated patients (85%) were cured, as compared to 3 of 10 (30%)
given cyclacillin and 6 of 12 (50%) given amoxicillin. Acute pyelonephritis developed 3 days after cyclacillin treatment in one patient
who had positive results of antibody-coated bacteria testing. Two patients treated with amoxicillin and one with cotrimoxazole converted
antibody-coated bacteria test results from negative to positive after treatment. These data do not support the use of cyclacillin and
[692]
amoxicillin in unselective women with cystitis; progression to pyelonephritis may recur after ineffective single-dose therapy
.
4.6.C.2 Otitis media
a) Cotrimoxazole suspension (5 to 20 mL every 12 hours for 10 days) was found to be as effective as amoxicillin (40 mg/kg/day in
[693]
three divided doses for 10 days) in the treatment of acute otitis media in a study involving 221 children
.
b) Cotrimoxazole proved as effective as amoxicillin in otitis media in one clinical trial involving 61 patients (age 6 months to 12 years)
[694]
.
4.6.C.3 Typhoid fever
a) The combination of amoxicillin and mecillinam was compared to cotrimoxazole for the treatment of typhoid fever in children. Ten
children received amoxicillin 100 mg/kg 3 times daily and mecillinam 40 mg/kg 4 times daily; cotrimoxazole 6 mg/24 mg per kg 2 times
daily was administered to other 10 children. The total duration of illness was significantly shorter for the cotrimoxazole group (4.2 days,
[695]
compared to 6.1 days for the amoxicillin and mecillinam group)
.
4.6.D Amoxicillin/Clavulanic Acid
Bacterial infectious disease
Urinary tract infectious disease
4.6.D.1 Bacterial infectious disease
a) Cotrimoxazole (trimethoprim 160 mg and sulfamethoxazole 800 mg) every 12 hours for 1 week was compared with amoxicillin 250
mg plus clavulanic acid 125 mg every eight hours for 1 week in adult infections (lower or upper respiratory tract infections, urinary tract
infections, skin and soft tissue infections). A total of 694 patients were treated (347 with amoxicillin-clavulanic acid and 347 with
cotrimoxazole). A good clinical response was observed in 68% of the patients receiving amoxicillin/clavulanate and 67.6% of
[591]
cotrimoxazole patients, resulting in elimination of organisms in 80% and 64% of patients, respectively
.
4.6.D.2 Urinary tract infectious disease
a) One study reported the slight superiority of cotrimoxazole (960 mg every 12 hours) over amoxicillin 250 mg plus clavulanic acid 125
[592]
mg every eight hours in patients with uncomplicated urinary tract infections. Patients were treated for a period of 5 days
. All 28
cotrimoxazole patients were cured as compared to 20 of 24 patients treated with the combination. Of the 4 treatment failures with the
amoxicillin-clavulanic acid regimen, resistant organisms were observed on follow-up in 2 patients.
b) In another single-blind study, amoxicillin/clavulanate was similarly effective as cotrimoxazole in urinary tract infections, with a more
[593]
rapid cure occurring in amoxicillin/clavulanate patients: 3.2 days versus 4.7 days
. However, this is of doubtful clinical significance.
c) Amoxicillin 250 mg plus clavulanic acid 125 mg (one tablet three times daily) was reported superior to cotrimoxazole (Septra-DS(R))
[594]
twice daily, each given for 7 days, in the treatment of urinary tract infections in the elderly
. Of 27 patients treated with
amoxicillin/clavulanic acid, the cumulative number of patients with sterile urines were 22, 25, and 26 on days 2, 5, and 7 of therapy,
respectively; of 28 patients treated with cotrimoxazole, sterile urines were observed in 13, 17, and 18 on days 2, 5, and 7 of therapy,
respectively.
4.6.E Ampicillin
Otitis media
Pneumonia
Pyelonephritis, acute
4.6.E.1 Otitis media
a) Cotrimoxazole is as effective as ampicillin in the treatment of acute otitis media either as initial therapy or when resistance of
[601][602][603][604]
Haemophilus influenzae to ampicillin is suspected
. The dosage recommended by the manufacturer is 8 mg/kg of
trimethoprim and 40 mg/kg of sulfamethoxazole per 24 hours in a twice a day dosage regimen for 10 days. One disadvantage of
cotrimoxazole may be that the taste is less pleasant than that of ampicillin; however, several studies indicate cotrimoxazole is as
[605][604]
acceptable by children as ampicillin and generally causes much less diarrhea
. The overall cost of this therapy seems to be
about the same as that of ampicillin.
b) A study in 132 children with acute otitis media that used either ampicillin or cotrimoxazole showed that both drugs had comparable
efficacy. Seventy-seven patients were treated with a combination of trimethoprim 10 mg/kg/day and sulfamethoxazole 50 mg/kg/day.
[604]
Fifty-five patients were treated with ampicillin 70 mg/kg/day. There was no significant difference in the efficacy of the 2 regimens
.
c) Additional authors have data to indicate that cotrimoxazole has produced similar clinical results to ampicillin in pediatric otitis media
[606]
, but presently this drug offers no significant advantage over ampicillin as the initial drug of choice. Cotrimoxazole should be
[607]
considered in ampicillin-resistant Haemophilus influenzae otitis media or for patients with penicillin hypersensitivity
.
4.6.E.2 Pneumonia
a) A 5-day course of oral cotrimoxazole was as effective as combination therapy with a single intramuscular dose of procaine penicillin
G plus benzyl penicillin G and a 5-day course of oral ampicillin in the treatment of severe community-acquired pneumonia in young
Gambian children. All drugs were given in doses according to the current WHO recommendations (not provided). It is suggested that
[608]
cotrimoxazole is the antibiotic of first choice for outpatient therapy of pneumonia in young children in developing countries
.
4.6.E.3 Pyelonephritis, acute
a) A combination of cotrimoxazole plus gentamicin was associated with significantly less antimicrobial resistance than ampicillin plus
[609]
gentamicin in a study involving 85 women with acute uncomplicated pyelonephritis
. All patients were initially treated with
intravenous antibiotics and later switched to the oral route of the assigned study drug. Cotrimoxazole combined therapy was also
reported to be less costly than ampicillin combined therapy. Adverse effects were similar in both groups.
4.6.F Atovaquone
Infection by Pneumocystis jiroveci
Pneumocystis pneumonia
4.6.F.1 Infection by Pneumocystis jiroveci
a) Atovaquone was effective and better tolerated than sulfamethoxazole/trimethoprim in the prophylaxis of Pneumocystis carinii
pneumonia (PCP) after autologous stem cell transplantation. In an open-label, randomized, prospective, clinical trial, patients were
treated with a regimen comprising 5 pre-transplant days of once-daily prophylactic antimicrobial therapy until 1 day prior to
transplantation, followed by 100 days of 3 times per week antimicrobial prophylaxis therapy after resolution of post-transplant
neutropenia. Patients received either oral atovaquone 1.5 grams (n=20) or oral sulfamethoxazole 800 milligrams (mg)/trimethoprim
160 mg (n=19), administered once daily 3 times per week. All patients were treated in HEPA-filtered rooms. No patient in either group
developed PCP, nor were other bacterial infections observed. There were no toxicity-related patient study withdrawals from the
atovaquone group compared with 8 patients withdrawn from the sulfamethoxazole/trimethoprim group due to side effects (p=0.003)
[639]
.
b) Atovaquone was effective and better tolerated than sulfamethoxazole/trimethoprim in the prophylaxis of pneumocystis carinii
pneumonia (PCP) after autologous stem cell transplantation. In an open-label, randomized, prospective, clinical trial, patients were
treated with a regimen comprising 5 pre-transplant days of once-daily prophylactic antimicrobial therapy until 1 day prior to
transplantation, followed by 100 days of 3 times per week antimicrobial prophylaxis therapy after resolution of post-transplant
neutropenia. Patients received either oral atovaquone 1.5 grams (n=20) or oral sulfamethoxazole/trimethoprim (800 milligrams/160
milligrams; n=19), administered once daily 3 times per week. All patients were treated in HEPA-filtered rooms. No patient in either
group developed PCP, nor were other bacterial infections observed. There were no toxicity-related patient study withdrawals from the
atovaquone group compared with 8 patients withdrawn from the sulfamethoxazole/trimethoprim group due to side effects (p=0.003)
[713]
.
4.6.F.2 Pneumocystis pneumonia
a) Atovaquone is comparable to cotrimoxazole in the treatment of mild or moderately severe Pneumocystis carinii pneumonia (PCP). In
a randomized, double-blind trial, 322 AIDS patients with PCP received either 750 mg atovaquone (n=160) or cotrimoxazole 320
mg/1600 mg (n=162) 3 times a day for 21 days. Four weeks after the end of therapy, 62% of atovaquone patients and 64% of
cotrimoxazole patients demonstrated a successful outcome. Although there was a lower response rate with atovaquone (80% vs
cotrimoxazole 93%), treatment-limiting adverse effects were greater with cotrimoxazole (20% vs atovaquone 7%), resulting in a similar
[624]
overall rate of efficacy
.
4.6.G Brodimoprim
Bronchitis
Tonsillitis
4.6.G.1 Bronchitis
a) In a randomized study of 96 adult patients with acute bronchitis and exacerbation of chronic bronchitis, brodimoprim (400 milligram
(mg) loading dose on day 1 followed by 200 mg daily) and cotrimoxazole (960 mg twice daily) achieved similar rates of clinical success.
Treatment continued until five days after the disappearance of fever. Clinical evaluation included signs and symptoms. Both therapeutic
regimens demonstrated similar efficacy. Incidence of adverse effects was 13.1% in the brodimoprim group and 21.3% in the
[636]
cotrimoxazole group. Four patients in each group withdrew from treatment due to the severity of adverse effects
.
4.6.G.2 Tonsillitis
a) In an open study of 75 pediatric patients with acute bacterial tonsillitis, brodimoprim in a dosage of 10 milligrams/kilogram (mg/kg)
on day 1 followed by 5 mg/kg/day and cotrimoxazole (6 mg/kg/twice daily trimethoprim) produced similar rates of success or
improvement (92.3% and 88.9%, respectively). Treatment continued until 5 days after the disappearance of fever. Efficacy was
according to the evolution of the symptoms (pharynx pain, dysphonia, pharyngotonsillar exudate, dysphagia) and the results of bacterial
cultures. Thirty-two patients in the brodimoprim group (82.0%) and 25 (69.5%) in the cotrimoxazole group were defined as successful.
Four brodimoprim patients and 7 cotrimoxazole patients were defined as improved. Adverse effects were mild (6 brodimoprim patients,
[637]
9 cotrimoxazole patients)
.
4.6.H Carbinoxamine
4.6.H.1 Sinusitis, chronic
a) Carbinoxamine maleate (in the combination product Rondec(R)) was found to be less effective than cotrimoxazole in treatment of
[555]
chronic sinusitis in a controlled double-blind study on 84 children
. The mean duration of symptoms prior to treatment was 18 weeks;
the treatment period consisted of 14 days. Improvement was assessed based on reduction of sinus opacification in radiographs and
diminution of respiratory symptoms.
4.6.I Cefaclor
Otitis media
Pyelonephritis
4.6.I.1 Otitis media
a) Cefaclor and cotrimoxazole were equivalent in efficacy in the treatment of acute otitis media for 100 pediatric patients in a controlled
[582]
study
. Patients were assigned to 2 treatment groups in a double-blind, randomized fashion and treated for 10 days with either oral
cotrimoxazole 8 mg/kg/day (trimethoprim) given in 2 equally divided doses or cefaclor 40 mg/kg/day in 3 divided doses. Both drugs
were found to be of similar efficacy, with 4 of 50 in the cefaclor group and 2 of 50 in the cotrimoxazole group considered treatment
failures. Either of these agents would be acceptable as ampicillin substitutes for acute otitis media.
4.6.I.2 Pyelonephritis
a) SUMMARY: Cefaclor may offer an advantage over cotrimoxazole in the treatment of pyelonephritis by virtue of the lower
gastrointestinal toxicity; efficacy is similar.
[583]
b) Cefaclor has been compared with cotrimoxazole in the treatment of pyelonephritis and cystitis
. Fourteen women were evaluated
with cefaclor and 15 with cotrimoxazole. In randomized fashion, patients were given oral cefaclor in doses of 250 mg every 8 hours for
10 days or Septra(R) (trimethoprim 80 mg and sulfamethoxazole 400 mg) 2 tablets by mouth twice a day for 10 days. Most infections
were caused by E coli. The results suggest that these 2 agents are equally effective in the treatment of urinary tract infections, as all
patients had sterile urine cultures during therapy and immediately after treatment. There were 2 recurrences in each group. However,
there was a higher predominance of older patients with pyelonephritis in the cotrimoxazole group and more data are required to
determine the benefits of each drug in the treatment of patients with different types of infections. There was a slight trend towards a
lower number of recurrences in patients with pyelonephritis receiving cotrimoxazole. In addition, more severe side effects occurred in
patients receiving cotrimoxazole (gastrointestinal distress).
4.6.I.3 Adverse Effects
a) Data obtained from the FDA's computer-based spontaneous report system has indicated a significantly higher incidence of serum
sickness-like reactions and arthralgias with cefaclor as opposed to other commonly used antibiotics (amoxicillin, cephalexin,
cotrimoxazole). In this study, there were 638 case reports of serum sickness, arthritis, or arthralgia attributed to cefaclor, with 51, 28,
and 10 cases being attributed to cotrimoxazole, cephalexin, and amoxicillin, respectively. These data suggest an excess risk of serum
[581]
sickness with cefaclor
.
4.6.J Cefadroxil
4.6.J.1 Respiratory tract infection
a) Cefadroxil 1 g by mouth twice daily and cotrimoxazole 160 to 800 mg by mouth twice daily were comparable in the treatment of
[566]
lower respiratory tract infections in an open, randomized study
.
4.6.K Cefixime
Shigellosis
Urinary tract infectious disease
4.6.K.1 Shigellosis
a) The clinical and bacteriologic response to either cefixime or cotrimoxazole was compared in the treatment of pediatric shigellosis
[590]
. Currently, cotrimoxizole is the recommended empiric agent for treatment of suspected shigellosis; however, a good deal of
resistance to this agent has been demonstrated worldwide. Patients were randomized to receive either cefixime 8 mg/kg/day or
cotrimoxazole 10-50 mg/kg/day for 5 days. The authors reported the following results with respect to cure, improvement, and failure: for
the cefixime group, 89%, 8%, and 3%, respectively; for the cotrimoxazole group, 25%, 44%, and 31%, respectively. The authors
concluded that in areas where it has been demonstrated that Shigella strains have a high degree of resistance to cotrimoxazole,
cefixime appears to be a highly effective, suitable alternative.
4.6.K.2 Urinary tract infectious disease
a) SUMMARY: Cefixime appears to be as effective as cotrimoxazole for the treatment of urinary tract infections. Trials have been done
in adults as well as pediatric patients.
b) Acute uncomplicated urinary tract infections were effectively treated with cefixime and cotrimoxazole in a poorly designed,
[587]
randomized, double-blind clinical trial with 528 patients
. Patients received oral cefixime 400 mg/day as a single dose or divided
twice a day or cotrimoxazole 160 mg/800 mg twice a day for 10 days. After all evaluation criteria were considered, 146 patients (28%)
remained in the clinical efficacy analysis. All treatment regimens demonstrated a 98% to 100% cure rate; however, patients were
eliminated if resistant pathogens were detected or if no pathogens were isolated on initial cultures and the clinical cure rate is thus
difficult to interpret. Adverse effects were related primarily to gastrointestinal complaints with cefixime and central nervous system
complaints with cotrimoxazole. Cefixime may ultimately prove to be an appropriate alternative to cotrimoxazole in this setting, but this
study does not confirm this recommendation.
c) The efficacy of cefixime was compared to cotrimoxazole for the treatment of urinary tract infections in a randomized study. Patients
received either cefixime 400 mg once daily or cotrimoxazole 160 mg/800 mg twice daily, each for 10 to 11 days. Four to 6 weeks after
therapy, clinical cure was obtained in 87% of patients in the cefixime group and 83% of patients in the cotrimoxazole group; bacterial
[588]
eradication was obtained in 90% and 93% of patients, respectively
.
d) Cefixime 8 mg/kg/d was compared to cotrimoxazole 8-40 mg/kg/d for 7 to 10 days to treat PEDIATRIC patients with urinary tract
[589]
infections
. The most common organism isolated was E coli (85%). Both groups did very well with all patients being cured. One
patient in the cotrimoxazole group and two patients in the cefixime group had a relapse of the infection.
4.6.L Cefotaxime
4.6.L.1 Surgical procedure; Prophylaxis
a) Cefotaxime and cotrimoxazole (trimethoprim/sulfamethoxazole) were equally effective for preventing infection after neurosurgery.
In a large, randomized, open trial, patients (n=613) undergoing elective craniotomy, shunt surgery, or sterotactic surgery were given
either intravenous cefotaxime 1 gram or intravnous trimethoprim/sulfamethoxazole 160 milligrams/800 mg just before the start of
surgery. A second dose was administered if the surgery lasted longer than 4 hours and/or if there was a delay of 3 hours or more
between the administration of the first dose of antibiotic and the commencement of surgery. Neurosurgical infections occurred in 2.5%
of patients in the cefotaxime group and in 2.3% of patients in the cotrimoxazole group (p=0.91). The rate of postsurgical infection with
both treatments was lower than that derived from historical data from surgeries without prophylaxis. Adverse clinical events that could
be related to study medications occurred in 7.6% of patients in the cefotaxime group and 6.4% of those in the cotrimoxazole group (not
[638]
significantly different)
.
4.6.M Cefpodoxime Proxetil
4.6.M.1 Cystitis, Uncomplicated
a) Short-term cefpodoxime-proxetil and sulfamethoxazole/trimethoprim (SMX-TMP) therapies were equally effective in treating
uncomplicated acute cystitis in women. In a randomized, multicenter, open-label study, patients received either cefpodoxime-proxetil
100 milligrams (mg) (n=63) or SMX-TMP 160/800 mg (n=70) orally twice daily for 3 days. Patients were followed at baseline, 4-7 days
post therapy and 28 days post therapy. By the first follow-up visit, 98.4% of cefpodoxime-proxetil patients and 100% of SMX-TMP
patients no longer exhibited symptoms of cystitis. Bacterial eradication had occurred in 98.4% of cefpodoxime-proxetil patients and
100% of SMX-TMP patients. By the second follow-up visit, 87.3% of cefpodoxime-proxetil patients and 85% of SMX-TMP patients
remained symptom free. In addition, the urine samples of 86% of cefpodoxime-proxetil patients and 84% of SMX-TMP patients
remained bacteria-free. The differences in clinical and bacteriological efficacy were not statistically significant between the two
treatment arms(p=0.54). Adverse events associated with cefpodoxime-proxetil were 1 case of mild gastrointestinal pain and 1 case of
allergic maculopapular rash. One case of intense epigastric pain and vomiting led to treatment discontinuation in the SMX-TMP arm
[725]
.
4.6.N Ceftibuten
Cystitis, Uncomplicated
Dysentery
4.6.N.1 Cystitis, Uncomplicated
a) A 3 day course but not a 1 day course of ceftibuten was as effective as a 7 day course of cotrimoxazole for UNCOMPLICATED
CYSTITIS. Sixty women were randomized to receive either a single dose of oral ceftibuten 400 milligrams (mg); 3 days of oral
ceftibuten 400 mg daily; or 7 days of oral cotrimoxazole 160/800 mg twice daily. The cure (absence of the clinical symptoms of cystitis
and microbiologic eradication) rate was 70%, 95%, and 90% for the single dose ceftibuten; 3 days of ceftibuten; and 7 days of
cotrimoxazole, respectively. Cotrimoxazole and 3 days of ceftibuten were significantly (p less than 0.05) superior to a single dose of
[730]
ceftibuten
.
4.6.N.2 Dysentery
a) The effectiveness of ceftibuten and cotrimoxazole were compared for the treatment of dysentery, caused by Shigella or
[731]
enteroinvasive Escherichia coli, in children
. Nine children were treated with cotrimoxazole 5 mg/25 mg per kg 2 times daily and 13
children received ceftibuten 4.5 mg/kg 2 times daily; both treatments were given for 5 days. All of the strains isolated were sensitive to
ceftibuten, but 6 of 20 strains of Shigella and 4 of 5 strains of Escherichia coli were resistant to cotrimoxazole. The clinical response to
treatment was not significantly different, unless the bacterial isolate was resistant to cotrimoxazole. In children with cotrimoxazoleresistant strains, significantly more stools were observed on days 3, 4, and 5 and significantly more watery consistency on these days.
4.6.O Ceftriaxone
Acute otitis media
Cystitis
Urinary tract infectious disease
4.6.O.1 Acute otitis media
a) A single intramuscular dose of ceftriaxone was as effective as a ten-day oral regimen of sulfamethoxazole/trimethoprim in treating
acute otitis media (AOM) in children ages 3 months to 3 years. Fourteen days after the initiation of therapy, 409 children were
evaluated. Ceftriaxone cured 80.2% (158/197) and sulfamethoxazole/trimethoprim cured 82.1% (174/212) of patients treated. Twentyeight days after beginning therapy, cure rates were 79.4% and 80% for ceftriaxone and sulfamethoxazole/trimethoprim, respectively. A
cure was defined as having clinical signs of AOM subside and the child behave in a normal, healthy manner. Middle-ear fluid (MEF)
was not considered failure to therapy, and the occurrence of MEF at day 14 or 28 was not significantly different (p=0.16 and 0.48,
respectively), between the two agents. Significant differences in the occurrence of adverse reactions included new-onset diarrhea (p
less than 0.001), and skin rash (p=0.245) with ceftriaxone. Lidocaine was used, according to manufacturer's instructions, for injecting
ceftriaxone. Less than 10% of patients had pain with injection. The dose of ceftriaxone was 50 milligram/kilogram (mg/kg) and the dose
of sulfamethoxazole/trimethoprim was 40 milligrams (mg)/kilogram (kg)/day/8 mg/kg/day given in two divided doses for 10 days.
Ceftriaxone may be a valuable alternative for treating AOM in children unable or unwilling to take oral sulfamethoxazole/trimethoprim
[721]
.
4.6.O.2 Cystitis
a) Single-dose intramuscular ceftriaxone was as effective as a 10-day regimen of oral sulfamethoxazole/trimethoprim in children and
adolescents for the treatment of uncomplicated cystitis. Patients (1 to 19 years of age) were given either a single-dose of ceftriaxone 25
to 50 milligrams/kilograms (mg/kg) (maximum of 250 or 500 mg, respectively) or oral sulfamethoxazole/trimethoprim at a dose of 4 to
5 mg/kg trimethoprim for 10 days. Patients in the sulfamethoxazole/trimethoprim group weighing over 40 kg were given an adult dose.
Treatment cure (bacteriologic and clinical cure) was noted as early (less than days), short-term (10 to 30 days), interim (31 to 41 days)
and long-term (42 days or longer). The study states that there were no significant differences at any time point between treatment
groups; however, results reported were not clear. This study suggest that IM ceftriaxone was not superior to
sulfamethoxazole/trimethoprim (in terms of efficacy and safety) and is more costly in drug acquisition costs. This study had a limited
number of patients and may have been underpowered. Additional trials, including a pharmacoeconomic analysis, would be helpful in
[722]
establishing the place in therapy of ceftriaxone for this indication
.
4.6.O.3 Urinary tract infectious disease
a) One study reported the similar efficacy of sulfamethoxazole 0.16 grams/trimethoprim 0.8 grams (g) orally two times daily for 7 days
[723]
and a single-dose of ceftriaxone (0.5 g IM) in the treatment of acute, uncomplicated urinary tract infections
. Cure rates were over
80% for each at follow-up (28 days).
b) Ceftriaxone 500 milligrams (mg) IM as a single dose was compared with sulfamethoxazole 800 mg/trimethoprim 160 mg orally two
times daily for 7 days in the treatment of acute urinary tract infections in 54 college women. Both regimens were similarly effective, with
92% and 96% being cured after 1 week of treatment, respectively. Diarrhea and malaise occurred in 16% of ceftriaxone-treated
patients, whereas leukopenia was observed in 14% of sulfamethoxazole/trimethoprim treated patients. It appears that a single IM
dose of ceftriaxone is as effective as a 7 day course of sulfamethoxazole/trimethoprim in uncomplicated urinary tract infections in
young women. Single-dose ceftriaxone treatment should be monitored with repeat urine cultures at 1 and 4 weeks to assure eradication
[724]
of the infection
.
4.6.P Cephalexin
4.6.P.1 Respiratory tract infection
a) Cotrimoxazole and cephalexin were equally effective in treating severe respiratory tract infections in a randomized study. Patients
were randomized to receive either cephalexin 500 mg every 6 hours orally or cotrimoxazole 160 mg/800 mg every 12 hours, both for 15
days; 25 patients were treated with each drug. Cephalexin was slightly superior to cotrimoxazole after 10 days of treatment. However,
[625]
after 15 days of treatment there was no significant difference between treatment groups
.
4.6.Q Chloroquine
4.6.Q.1 Malaria
a) Chloroquine was significantly faster in clearing parasitemia than cotrimoxazole. This study measured the responses of parasitemia
[628]
and fever in vivax malaria to standard doses of chloroquine and different dosage schedules of cotrimoxazole in 165 children
.
4.6.R Cinoxacin
4.6.R.1 Cystitis
a) Cinoxacin appears to be as effective and possibly less toxic than cotrimoxazole when used to treat cystitis. This was demonstrated
[732]
in a comparative trial of cinoxacin and cotrimoxazole used to treat 64 patients with cystitis
. Patients were either given oral cinoxacin
500 milligrams (mg) two times a day or oral cotrimoxazole (trimethoprim 80 mg/sulfamethoxazole 400 mg) 2 tablets twice daily for 14
days. Of the 50 evaluable patients, 96% in each group had a satisfactory clinical response. Two patients in the group became
reinfected with a new pathogen and 1 patient had a recurrence. One patient in the cotrimoxazole group also became reinfected with a
new organism. Adverse reactions were noted in 19% and 56% of cinoxacin- and cotrimoxazole-treated patients, respectively, requiring
5 patients in the cotrimoxazole group to withdraw.
4.6.R.2 Adverse Effects
a) The toxicity of cinoxacin in 2801 patients receiving the drug was described in single-blind and double-blind studies prior to
marketing. Adverse drug reactions to cinoxacin occurred in approximately 5% of patients. In comparative studies, cinoxacin-treated
[733]
patients had fewer adverse drug reactions than patients receiving cotrimoxazole
.
4.6.S Ciprofloxacin
Diarrhea
Neutropenic disorder
Pyelonephritis, Uncomplicated
Salmonella infection
Traveler's diarrhea
Urinary tract infectious disease
4.6.S.1 Diarrhea
a) Empiric antimicrobial therapy was evaluated for the treatment of acute diarrhea in a randomized, double-blind, placebo-controlled
study with 202 patients. The patients were treated on the day of presentation with oral ciprofloxacin 500 milligrams,
sulfamethoxazole/trimethoprim double-strength (DS), or placebo every 12 hours for 5 days. Bacterial isolates included Campylobacter
(35), Shigella (18), and Salmonella (15). One hundred seventy-five patients were evaluable for efficacy. Other pathogens were
Blastocystis hominis (7), Clostridium difficile (2), and Entamoeba histolytica (2). Ciprofloxacin did shorten the duration of diarrhea, 2.4
versus 3.4 days, when compared to placebo and 82% percent of patients were better after 3 days of therapy. Not unexpectedly
[556]
sulfamethoxazole/trimethoprim DS did not do as well because Campylobacter, the most common isolate was not susceptible
.
4.6.S.2 Neutropenic disorder
a) Ciprofloxacin 500 milligrams (mg) orally twice a day was superior to a combination of oral sulfamethoxazole 800 mg/trimethoprim
[557]
160 mg and colistin 200 mg every 8 hours in the prevention of infection for leukemia patients with granulocytopenia
. A total of 56
patients received either ciprofloxacin or the sulfamethoxazole/trimethoprim plus colistin regimen, and all patients received oral
amphotericin B 200 mg four times a day as antifungal prophylaxis. The regimens were initiated 1 to 2 days prior to the initiation of
chemotherapy and continued until the granulocyte counts exceeded 500/mcL. Bacteriologically documented infections occurred in 5
ciprofloxacin-treated patients as compared to 14 in the sulfamethoxazole/trimethoprim plus colistin group; 6 major infections (4
bacteremias) were observed with ciprofloxacin as opposed to 11 in the combination group (10 bacteremias). Ciprofloxacin was superior
to the combination in preventing infections caused by gram-negative bacilli with no infections in the ciprofloxacin patients and 7 in the
patients receiving the combination. Colonization with resistant gram-negative bacilli was prevented with ciprofloxacin, but resistant
strains were observed in 10 patients who were treated with the combination.
4.6.S.3 Pyelonephritis, Uncomplicated
a) A 7-day course of oral ciprofloxacin was significantly more effective than a 14-day course of oral sulfamethoxazole/trimethoprim
when used in the treatment of acute, uncomplicated pyelonephritis in women. In a randomized, double-blind, comparative trial,
premenopausal women with culture-confirmed, acute bacterial pyelonephritis were assigned to receive outpatient, oral regimens of
either sulfamethoxazole 800 milligram (mg)/trimethoprim 160 mg twice daily (n=187) for 14 days, or ciprofloxacin 500 mg twice daily
for 7 days followed by 7 days of placebo (n=191). Bacteriological and clinical cure was assessed during office visits on posttreatment
days 4 to 11. Escherichia (E) coli was the uropathogen most frequently isolated from efficacy-valid patients receiving either
sulfamethoxazole/trimethoprim or ciprofloxacin (94% and 91%, respectively); 47 (18.4%) of all uropathogens were resistant to
sulfamethoxazole/trimethoprim, compared with 1 pathogen (0.1%) found resistant to ciprofloxacin (p less than 0.001). Within the
efficacy-valid population, 112 (99%) of 113 patients receiving ciprofloxacin for 7 days had persistent bacteriologic cure at the 4- to 11day posttherapy assessment, compared with 90 (89%) of 101 patients receiving sulfamethoxazole/trimethoprim for 14 days (95%
confidence interval (CI), 0.04 to 0.16; p=0.004); 94 (85%) of 111 patients treated with ciprofloxacin, and 80 (74%) of 108 patients
treated with sulfamethoxazole/trimethoprim experienced continued bacteriologic cure through the 22- to 48 day posttreatment
assessment period. Persistent clinical cure at posttreatment days 4 to 11 was experienced by 109 (96%) of 113 patients treated with 7
days of ciprofloxacin, compared with 92 (83%) of 111 patients treated with 14 days of sulfamethoxazole/trimethoprim (95% CI, 0.06 to
0.22; p=0.002). Clinical cure rates for the 22- to 48-day posttreatment follow-up assessment were 91% and 77% for patients treated
with ciprofloxacin and sulfamethoxazole/trimethoprim, respectively (95% CI, 0.03 to 0.23; p=0.02). Gastrointestinal events, headache,
and rash occurred more frequently in patients receiving sulfamethoxazole/trimethoprim compared with patients receiving ciprofloxacin,
[558]
and more sulfamethoxazole/trimethoprim patients withdrew from study participation due to adverse events
.
b) Ciprofloxacin 750 milligrams twice daily was equally as effective as sulfamethoxazole/trimethoprim 1 double-strength tablet twice
daily for prophylaxis of infection in 146 bone marrow transplant patients. The incidence of febrile neutropenia and overall infection rate
was similar between groups; however there was a higher incidence of Clostridium difficile enterocolitis in the group that received
[559]
sulfamethoxazole/trimethoprim
.
c) Previous studies have speculated on the potential advantage of ciprofloxacin compared with sulfamethoxazole/trimethoprim in the
prophylaxis of patients following autologous bone marrow transplantation (ABMT). Ciprofloxacin was previously found to result in faster
neutrophil recovery compared with sulfamethoxazole/trimethoprim.
4.6.S.4 Salmonella infection
a) Ciprofloxacin 500 milligrams (mg) orally twice daily for 10 days was comparable to a 14-day course of sulfamethoxazole 800
mg/trimethoprim 160 mg orally twice daily in the treatment of uncomplicated typhoid or paratyphoid fever during a randomized, non[560]
blinded study
. Ciprofloxacin appears to be an effective alternative for salmonella infections.
4.6.S.5 Traveler's diarrhea
a) A 5-day course of oral sulfamethoxazole 800 milligrams (mg)/trimethoprim 160 mg three times a day appears to be equal in
efficacy to oral ciprofloxacin 500 mg three times a day in the treatment of acute traveler's diarrhea. This controlled study included 181
adults who developed diarrhea within 5 weeks of arrival to Mexico. Both drug regimens were more effective than placebo in treating
diarrhea secondary to enterotoxigenic Escherichia coli, invasive enteropathogens, and unknown pathogens. Ciprofloxacin is a
reasonable alternative to sulfamethoxazole/trimethoprim for patients with an allergy to sulfamethoxazole/trimethoprim or for patients
traveling to areas where resistance to sulfamethoxazole/trimethoprim has been observed
[561]
.
4.6.S.6 Urinary tract infectious disease
a) Ciprofloxacin, ofloxacin and sulfamethoxazole/trimethoprim given for 3 days have similar efficacy in treating acute, uncomplicated,
lower urinary tract infections in women. A randomized, double-blind, three-arm study evaluated the safety and efficacy of 3-day courses
of the above medications in 688 women, 81% of whom were infected with Escherichia coli, of which 100% were susceptible to
ciprofloxacin and ofloxacin and 94% to sulfamethoxazole/trimethoprim. Doses were ciprofloxacin 100 milligrams (mg) twice daily,
ofloxacin 200 mg twice daily and sulfamethoxazole 800 mg/trimethoprim 160 mg twice daily. Bacterial eradication rates at the end of
therapy were not significantly different among the 3 groups and were as follows: 94% for ciprofloxacin, 97% for ofloxacin, and 92% for
sulfamethoxazole/trimethoprim. Recurrence at the end of 4 to 6 weeks occurred in 61 patients. Discontinuation of therapy due to drugrelated adverse events occurred most frequently with sulfamethoxazole/trimethoprim. Although the bacterial eradication rates were
similar for the 3 drugs in this study, it should be noted that the rate of resistance of E. coli to sulfamethoxazole/trimethoprim in the
[562]
United States has since increased to approximately 17% in 1996
.
b) Ciprofloxacin 250 milligrams (mg) orally twice a day was superior to oral sulfamethoxazole 800 mg/trimethoprim 160 mg every 12
hours each for 7 days, in the treatment of complicated urinary tract infections in a controlled study involving 45 patients who were
[563]
primarily elderly men
. Bacteriologic cure was achieved in 18 of 22 (82%) ciprofloxacin-treated patients and in 12 of 23 (52%)
sulfamethoxazole/trimethoprim-treated patients during and 5 to 9 days following therapy. Relapse and reinfection rates were similar in
both groups at 4 to 6 weeks following treatment. Side effects occurred in 6 of 23 sulfamethoxazole/trimethoprim-treated patients and
included increased serum creatinine levels in 4; only 1 of 22 ciprofloxacin-treated patients developed an adverse effect (increase in
hepatic function tests). These data suggest that ciprofloxacin is a safe alternative to sulfamethoxazole/trimethoprim for the treatment
of complicated urinary tract infections.
c) A randomized, double-blind study compared sulfamethoxazole/trimethoprim and ciprofloxacin in the treatment of uncomplicated
[564]
urinary tract infections
. Treatment with oral ciprofloxacin 250 milligrams (mg) twice a day for 10 days resulted in bacteriologic and
clinical cures for 100% of 31 patients as compared to a bacteriologic cure rate of 94% and a clinical cure rate of 91% (n=34) with oral
sulfamethoxazole/trimethoprim DS (800 mg/160 mg) twice a day. The differences were not statistically significant.
4.6.T Clindamycin
4.6.T.1 Pneumocystis pneumonia
a) The combination of clindamycin (900 mg orally 4 times daily) plus primaquine (30 mg orally daily) appeared to be an equally
effective alternative to cotrimoxazole in the treatment mild to moderately severe Pneumocystis carinii pneumonia in patients with AIDS
[585]
[586]
. The results of this trial were confirmed by
. There was no significant difference in efficacy or incidence of adverse effects
between cotrimoxazole or the combination of clindamycin and primaquine, for the treatment of mild to moderate Pneumocystis carinii
pneumonia in 181 patients with AIDS.
4.6.U Cyclacillin
4.6.U.1 Cystitis
a) Single-dose regimens of cotrimoxazole (320 mg trimethoprim/1.6 g sulfamethoxazole), amoxicillin (3 g), and cyclacillin (3 g) were
[619]
compared in the treatment of acute cystitis in 38 women
. Clinical cure occurred in all of 13 cotrimoxazole-treated patients two days
after treatment, as compared to persistent bacteriuria remaining in 4 of 13 given amoxicillin (31%) and 4 of 12 given cyclacillin (33%). At
a two-week follow-up, 11 of 13 cotrimoxazole-treated patients (85%) were cured, as compared to 3 of 10 (30%) given cyclacillin and 6
of 12 (50%) given amoxicillin. Acute pyelonephritis developed three days after cyclacillin treatment in one patient who had positive
results of antibody-coated bacteria testing. Two patients treated with amoxicillin and one with cotrimoxazole converted antibody-coated
bacteria test results from negative to positive after treatment. These data do not support the use of cyclacillin and amoxicillin in
unselected women with cystitis; progression to pyelonephritis may occur after ineffective single-dose therapy.
4.6.V Dapsone
Pneumocystis pneumonia
Pneumocystis pneumonia, Primary; Prophylaxis
Toxoplasmosis; Prophylaxis
4.6.V.1 Pneumocystis pneumonia
a) The combination of dapsone and trimethoprim was as effective as sulfamethoxazole/trimethoprim for the treatment of mild to
moderate Pneumocystis carinii pneumonia in a trial involving 181 patients with AIDS. There was no statistical difference between
[614]
groups in incidence of dose limiting toxicities
.
b) Compared to historical controls, oral dapsone appeared to be less effective than the combination of dapsone and trimethoprim,
sulfamethoxazole/trimethoprim, or pentamidine for the treatment of Pneumocystis carinii infections in AIDS patients. Dapsone is not
considered first-line therapy for Pneumocystis carinii pneumonia; however, it may provide an alternative regimen for patients exhibiting
[615]
major toxicity with other forms of therapy
.
4.6.V.2 Pneumocystis pneumonia, Primary; Prophylaxis
a) SUMMARY: Following allogeneic blood or marrow transplantation for the treatment of malignancies, Pneumocystis carinii
pneumonia (PCP) prophylaxis with dapsone 50 milligrams (mg) twice daily 3 times/week has been associated with a higher incidence of
[616]
PCP than prophylaxis with sulfamethoxazole 800 mg/trimethoprim 160 mg twice daily 2 times/week
. Prophylaxis with dapsone for
prevention of PCP among HIV-infected patients has been used with variable success as an alternative to
sulfamethoxazole/trimethoprim. In some studies, dapsone alone or in combination with pyrimethamine was found to be a good
[617]
alternative for the primary prevention of PCP in HIV positive patients (Bozzette et al, 1995)
. However, in one study (n=166) lowdose, once a week dapsone (100 mg) and pyrimethamine (25 mg) was inferior to sulfamethoxazole 800 mg/trimethoprim 160 mg
[618]
twice daily 3 times/week
. In contrast, twice weekly dapsone (100 mg) with pyrimethamine (50 mg) was as effective as the above
[617]
mentioned sulfamethoxazole/trimethoprim regimen
. Studies have suggested that only daily dosing of dapsone provides protection
[616]
similar to that provided by sulfamethoxazole/trimethoprim
.
b) Following allogeneic blood or marrow transplantation for the treatment of malignancies, Pneumocystis carinii pneumonia (PCP)
prophylaxis with dapsone has been associated with a higher incidence of PCP than prophylaxis with sulfamethoxazole/trimethoprim.
In this retrospective cohort, 111 patients received dapsone (n=111) 50 milligrams (mg) twice daily 3 times/week and 535 patients
received sulfamethoxazole 800 mg/trimethoprim 160 mg twice daily 2 times/week. The incidence of PCP was significantly higher in
the dapsone cohort than in the sulfamethoxazole/trimethoprim cohort (7.2% vs 0.37%, respectively). The relative risk for developing
PCP in the dapsone cohort was 18.8 (p less than 0.001). Studies have suggested that only daily dosing of dapsone provides protection
[616]
similar to that provided by sulfamethoxazole/trimethoprim
.
c) In a large trial involving 843 HIV positive patients, dapsone was as effective as sulfamethoxazole/trimethoprim for the prevention of
PCP. Patients were assigned to one of three treatment groups (1) sulfamethoxazole/trimethoprim, starting dose of 1 double-strength
(DS) tablet twice daily, (2) dapsone, starting dose 50 milligrams twice daily, or (3) aerosolized pentamidine 300 mg every 4 weeks.
Dosage reductions of dapsone and sulfamethoxazole/trimethoprim were permitted if the patient experienced adverse effects. Overall
efficacy was similar between the three groups except in patients with a CD4 count less than 100. In these patients dapsone and
sulfamethoxazole/trimethoprim were more effective than aerosolized pentamidine. When doses of dapsone were decreased to 50 mg
daily there was a significantly higher rate of failure compared to the dose of 50 mg twice daily. Conversely, when comparing
sulfamethoxazole/trimethoprim doses of 1 DS tablet twice daily to 1 DS tablet daily there appeared to be little advantage to using the
larger dose (Bozzette et al, 1995).
d) In the analysis of patients receiving treatment, oral dapsone 100 mg plus oral pyrimethamine 50 mg (n=96) twice weekly was as
effective as sulfamethoxazole 800 mg/trimethoprim 160 mg (n=104) twice a day 3 times per week in preventing primary Pneumocystis
carinii pneumonia (PCP). Effectiveness was evaluated 12 and 24 months after starting therapy. Patients were HIV positive with CD4
counts less than 200/cubic millimeter and were receiving antiretroviral therapy. In the intent to treat analysis,
sulfamethoxazole/trimethoprim was statistically more effective than dapsone plus pyrimethamine in preventing PCP. However, 5 of the
6 patients in the dapsone plus pyrimethamine group had voluntarily stopped taking the drug at least 2 months before the episode of
[617]
PCP
.
e) In 166 HIV-infected patients (CD4 less than 200 per cubic millimeter), dapsone 100 mg plus pyrimethamine 25 mg administered
once a week was inferior to sulfamethoxazole 800 mg/trimethoprim 160 mg twice a day three times a week in preventing primary
Pneumocystis carinii pneumonia (PCP). Over a 2 year period a significant increase in the rate of developing PCP occurred in the
dapsone/pyrimethamine group (42%) compared to the sulfamethoxazole/trimethoprim group (10%). There was no significant
[618]
difference in the number of deaths in each group. This study was based on an intention-to-treat analysis
.
4.6.V.3 Toxoplasmosis; Prophylaxis
a) In 166 HIV-infected patients (CD4 less than 200 per cubic millimeter), dapsone 100 mg plus pyrimethamine 25 mg administered
once a week was not significantly different in preventing toxoplasmosis than sulfamethoxazole 800 mg/trimethoprim 160 mg twice a
day three times a week. There was no significant difference in the number of deaths in each group. This study was based on an
[618]
intention-to-treat analysis
. In a follow-up study of HIV infected patients, oral dapsone 100 mg plus oral pyrimethamine 50 mg (n=96)
twice weekly was not statistically different than sulfamethoxazole 800 mg/trimethoprim 160 mg (n=104) twice a day 3 times per week
in preventing toxoplasmosis. The effectiveness of both regimens were evaluated at 12 and 24 months after starting therapy. The
[617]
toxoplasmosis rate was 0.11 to 0.12 per 100 patient-months in patients receiving either regimen
.
4.6.W Doxycycline
4.6.W.1 Urinary tract infectious disease
a) Single doses of doxycycline 300 mg PO, given for 5 days to 45 patients with bacterial cystitis, produced an 84% cure rate in
[611]
comparison to a 98% cure rate with cotrimoxazole DS
. Each patient was randomly assigned to receive either cotrimoxazole DS
every 12 hours or doxycycline QD and adequacy of therapy was determined at 1 week following completion of medication with urine
cultures. Among the patients treated with single dose doxycycline therapy, 6 experienced relapses and 1 experienced a reinfection
compared to 1 reinfection in the cotrimoxazole group. This doxycycline regimen was well tolerated with only 3 complaints of adverse
effects: anorexia 1, vomiting 1, muscle aches 1. Doxycycline was effective in eradicating urinary tract infection although not to the
extent of cotrimoxazole, however the authors accepted 84% as an adequate response for single dose therapy when susceptible
[611]
pathogens are involved
.
4.6.X Enoxacin
Chancroid
Urinary tract infectious disease
4.6.X.1 Chancroid
a) In a review of clinical trials, oral enoxacin was as effective as oral sulfamethoxazole/trimethoprim in the treatment of chancroid
caused by Haemophilus ducreyi. Patients were either treated with oral enoxacin 400 milligrams (mg) (a total of 3 doses at 12-hour
intervals) or a single dose of sulfamethoxazole 3200 mg/trimethoprim 640 mg. Within 72 hours post-treatment, H ducreyi was
[613]
eradicated from ulcers of 94% of men treated with enoxacin and 91% of those treated with sulfamethoxazole/trimethoprim
.
4.6.X.2 Urinary tract infectious disease
a) Fifty-six patients with complicated, recurrent, urinary tract infections were randomized to receive either 400 milligrams (mg) enoxacin
every 12 hours or sulfamethoxazole 800 mg/trimethoprim 160 mg every 12 hours for 14 days. Microbiologic cure was obtained in
[612]
100% of sulfamethoxazole/trimethoprim-treated patients and 87% (20 of 23) of enoxacin-treated patients
.
b) In a review of clinical trials, enoxacin was as effective as cotrimoxazole in the treatment of complicated urinary tract infections (UTI).
Patients were randomized to enoxacin 400 milligrams (mg) twice daily or sulfamethoxazole 800 mg/trimethoprim 160 mg twice daily
for 14 days. Both treatment regimens produce similar eradication rates (range, 95 to 97%). Long-term therapy (4 to 6 weeks) tend to
favor enoxacin in terms of maintaining bacteriologic eradication; however, differences between sulfamethoxazole/trimethoprim and
[613]
enoxacin were not statistically significant
.
4.6.Y Erythromycin
Pertussis
Respiratory tract infection
4.6.Y.1 Pertussis
a) Cotrimoxazole and erythromycin were studied to compare their ability in clearing Bordetella pertussis from the nasopharynx of 22
children admitted to the hospital with whooping cough. Both agents appeared effective. Nevertheless, 10 of 22 patients gave positive
[597]
cultures 4 or more days after antimicrobial administration was begun
.
b) Cotrimoxazole has been compared to erythromycin for the treatment of pertussis in 55 children. Both drugs eradicated Bordetella
pertussis from the nasopharynx, except in 1 patient treated with cotrimoxazole. In the treatment failure, vomiting may have effected the
[598]
absorption of cotrimoxazole. Erythromycin and cotrimoxazole were both effective in treating pertussis in children
.
4.6.Y.2 Respiratory tract infection
a) Erythromycin, amoxicillin, and cotrimoxazole were comparatively studied for treating respiratory tract infections in 56 pediatric
patients (25 months to 148 months). Dosage schedules for each drug was based on child's age, weight, severity of disease, and
manufacturer's recommendations. All 3 were equally effective against acute upper and lower respiratory diseases in the 7 to 10 day
[599]
treatment. No side effects were reported
.
4.6.Z Erythromycin Ethylsuccinate/Sulfisoxazole Acetyl
Haemophilus influenzae infection
Otitis media
4.6.Z.1 Haemophilus influenzae infection
a) Excellent in vitro activity was reported against Haemophilus influenzae with cotrimoxazole, whereas
[667]
erythromycin/sulfamethoxazole displayed little activity. No isolates were resistant to trimethoprim/sulfamethoxazole
.
4.6.Z.2 Otitis media
a) Erythromycin/sulfisoxazole did not penetrate the middle ear fluid (MEF) as efficiently as amoxicillin, cefaclor, or cotrimoxazole in a
study of 83 children (mean, 4.6 years) with chronic otitis media. Patients were administered a single dose of either amoxicillin 15 mg/kg
(19 patients), cefaclor 15 mg/kg (26 patients), erythromycin 12.5 mg/kg plus sulfisoxazole 37.5 mg/kg (15 patients), or trimethoprim 4
mg/kg plus sulfamethoxazole 20 mg/kg (23 patients) after an overnight fast. Samples from the MEF were examined 15 to 240 minutes
after drug administration. Amoxicillin demonstrated the highest mean peak concentration in MEF to minimal inhibitory concentration
(MIC) ratio for the three most common pathogens of otitis media (Streptococcus pneumonia, Haemophilus influenzae, and
Streptococcus pyogenes). Trimethoprim-sulfamethoxazole achieved the highest ratio of mean peak concentration in MEF to MIC for
ampicillin-resistant Haemophilus influenzae. None of the 15 patients administered erythromycin/sulfisoxazole exhibited detectable
concentrations of erythromycin (less than 0.20 mcg/mL) in the MEF samples, but sulfisoxazole reached 20% of the peak serum
[668]
concentration (20.9 mcg/mL)
.
4.6.AA Fosfomycin
4.6.AA.1 Urinary tract infectious disease
a) Fosfomycin tromethamine (3 grams orally as a single dose) is at least as effective as cotrimoxazole 960 milligrams orally daily for 3
days in uncomplicated urinary tract infections (Crocchiolo et al, 1990). In a larger study, single oral doses of fosfomycin tromethamine
[610]
(3 grams) and cotrimoxazole (1.92 grams) were similarly effective in treating female uncomplicated urinary tract infections
. In both
studies, the overall incidence and severity of adverse effects were similar with each agent, although diarrhea was observed more often
[610]
with fosfomycin
.
4.6.AB Framycetin
4.6.AB.1 Neutropenic disorder
a) SUMMARY: Oral cotrimoxazole and a lactobacillus preparation was reported as effective but better tolerated than combined oral
use of framycetin, colistin, nystatin, and metronidazole in neutropenic children with cancer.
b) A combination of oral framycetin 50 mg/kg/day, colistin sulfate 150,000 units/kg/day, nystatin 2 x 19(6) units/day, plus metronidazole
150 to 600 mg/day (modified FRACON regimen) appeared similarly as effective as cotrimoxazole (80 to 160/400 to 800 milligrams
[596]
daily) plus a lactobacillus preparation (Synerlac(R)) in neutropenic children with leukemia and solid tumors or leukemia
. Compared
to an historical control group, a significant decrease in pyrexial episodes was observed with both regimens, with a trend toward a
reduction in positive blood cultures. The cotrimoxazole/lactobacilli combination may offer an advantage over FRACON regimens by
virtue of better tolerability and reduced cost. In particular, nausea and vomiting were significantly more frequent with the FRACON
regimen in this study. However, the use of an historical control group in this trial precludes adequate assessment of the efficacy of
either modified FRACON or cotrimoxazole. A prospective, blinded study of these regimens incorporating a placebo is needed.
4.6.AC Furazolidone
4.6.AC.1 Diarrhea, Invasive
a) Acute invasive diarrhea, caused predominately by Shigella sp and Escherichia coli, in 101 Mexican children was treated with either
[600]
furazolidone or cotrimoxazole
. Forty-nine children were given 7.5 mg/kg/day furazolidone for 5 days. The other 52 children were
given 8 mg/40 mg/kg/daily of cotrimoxazole for 5 days. By day three, 82.7% of the furazolidone group had improved compared to
45.5% of the cotrimoxazole group. On day six, 63% of the furazolidone patients were classified as having a clinical and bacteriologic
success compared to 69% in the cotrimoxazole group and 23% in an untreated control group of 22 patients.
4.6.AD Methenamine
4.6.AD.1 Urinary tract infectious disease
a) Methenamine salts are less effective than cotrimoxazole in the prophylactic treatment of recurrent urinary tract infections (UTI)
[696][697]
.
4.6.AE Methotrexate
4.6.AE.1 Wegener's granulomatosis
a) As compared to an historical group (n=32) treated with co-trimoxazole between 1986 and 1993, significantly more patients who
received low-dose methotrexate (n=33) between 1992 and 1995 sustained remission of generalized Wegener's granulomatosis. Prior to
study entry, all patients had received the Fauci scheme (cyclophosphamide and prednisone) and/or pulse cyclophosphamide as the
induction regimen. Intravenous methotrexate was administered as 0.3 milligram/kilogram (mg/kg) once weekly with or without
prednisone (median dose 3 mg/day). The co-trimoxazole regimen consisted of trimethoprim 160 mg plus sulfamethoxazole 800 mg
orally twice daily with or without prednisone (median dose 10 mg/day). In the methotrexate only and methotrexate plus prednisone
groups, 86% and 91% maintained remission for a median 16 and 22 months of treatment, respectively. In the co-trimoxazole only
group, 58% maintained remission for a median 37 months of treatment, while the entire co-trimoxazole plus prednisone group relapsed
after a median 15 months of treatment. These data are statistically significant (p less than 0.05) in favor of methotrexate. The authors
conclude that co-trimoxazole is not recommended to maintain remission of generalized Wegener's granulomatosis. A prospective,
[620]
controlled trial is needed to determine the optimal maintenance treatment
.
4.6.AF Metronidazole
4.6.AF.1 Appendicitis
[565]
a) Cotrimoxazole (Bactrim(R)) was compared with metronidazole suppositories as surgical prophylaxis following appendectomy
.
Cotrimoxazole was given in intramuscular doses of 2 mL (exact dose not specified) prior to surgery then twice a day for 3 days
postoperatively. Metronidazole suppositories were given in doses of 1 gram prior to surgery, then 1 g every 8 hours for 3 days. Followup at 2 weeks and 1 month indicated that sepsis rates were 8.3% for the cotrimoxazole group and 9% for the metronidazole group, as
compared to 27% for the untreated group. However, combined therapy with this regimen resulted in a sepsis rate of only 2.7%.
Combination therapy appears to be more effective than either agent alone in prophylaxis against wound infections following
appendectomy.
4.6.AG Mupirocin
4.6.AG.1 Staphylococcus carrier, Nasal
a) A five course of intranasal mupirocin calcium is as effective as oral trimethoprim-sulfamethoxazole (TMP-SMX) plus intranasal
fusidic acid. The dosage regimen included the following: Mupirocin, intranasal 3 times daily; TMP-SMX, 160 milligrams/800 milligrams
twice daily; Fusidic acid, intranasal 3 times daily. Methicillin-resistant Staphylococcus aureus nasal cultures were negative in both
[627]
treatment groups at the end of the 5-day treatment period; 90% remain negative after one month
.
4.6.AH Nalidixic Acid
Cystitis
Urinary tract infectious disease
4.6.AH.1 Cystitis
a) Nalidixic acid and cotrimoxazole were effective in the treatment of acute cystitis due to E coli. Staphylococcus saprophyticus was
[633]
resistant to nalidixic acid but responded to cotrimoxazole
.
b) Mictral(R) (a citrated form of nalidixic acid) was compared to amoxicillin, trimethoprim, and nitrofurantoin in the treatment of acute
cystitis in three open, randomized, multi-center studies. A 3-day course of therapy with Mictral(R) was compared with amoxicillin 250
mg three times a day, trimethoprim 200 mg two times daily and nitrofurantoin 100 mg daily. Dysuria and frequency were relieved
[634]
significantly faster with Mictral(R)
.
4.6.AH.2 Urinary tract infectious disease
a) One hundred thirty-five college age women are reported in a comparison of trimethoprim-sulfamethoxazole and nalidixic acid.
[631]
Results showed similar cure rates and similar incidences of drug reactions
.
b) One hundred ten females took part in a comparison of cotrimoxazole and nalidixic acid (Mictral(R)). The results were equal for 3-day
nalidixic acid therapy and 7-day cotrimoxazole therapy in eradicating lower urinary tract infection. Nalidixic acid had an advantage of
[632]
76.9% of the patients being asymptomatic by day 4 as compared with 44.9% of those on cotrimoxazole
.
4.6.AI Nitrofurantoin
4.6.AI.1 Urinary tract infectious disease
a) Cotrimoxazole (40/200 mg), trimethoprim (100 mg), and nitrofurantoin (100 mg once daily) were equally effective in the prophylaxis
[622]
of recurrent urinary tract infections in a double-blind, controlled, six-month study of 60 women
. None of the three drug regimens
caused emergence of resistant E coli. Side effects were minimal.
b) Nitrofurantoin modified-release 100 mg twice a day was as effective as co-trimoxazole DS twice a day and trimethoprim 200 mg
twice a day in a seven-day regimen for treatment of uncomplicated urinary tract infections in 538 patients from 45 different general
[623]
practice centers across the UK
.
4.6.AJ Nitrofurantoin, Macrocrystals/Nitrofurantoin Monohydrate
4.6.AJ.1 Urinary tract infectious disease, Uncomplicated
a) A 5-day course of therapy with nitrofurantoin was as effective as a 3-day course of sulfamethoxazole/trimethoprim for the treatment
of acute uncomplicated cystitis in women according to a randomized, open-label study (n=308). Women (median age, 21 years; range,
18 to 41) with symptoms of acute cystitis and a urine culture displaying at least 10(2) colony forming units (CFU)/mL of uropathogen
were randomized to receive open-label treatment with either sulfamethoxazole 800 mg/trimethoprim 160 mg orally twice daily for 3
days (n=148) or nitrofurantoin 100 mg orally twice daily for 5 days (n=160). At baseline, 26% of patients in the
sulfamethoxazole/trimethoprim group and 24% in the nitrofurantoin group had experienced 3 or more lifetime urinary tract infections
(UTI). The primary endpoint was clinical cure, which was defined as the resolution of initial UTI symptoms or of new UTI symptoms of
dysuria, frequency, and/or urgency, or signs of pyelonephritis (costovertebral angle tenderness, with or without fever) during the period
including 30 days following therapy. Equivalence of nitrofurantoin treatment compared with trimethoprim/sulfamethoxazole could be
established if the upper bound value of the 95% confidence interval (CI) for the treatment difference (primary endpoint) was less than
10%. At enrollment, 82% of the UTIs were caused by Escherichia coli and 4% by E coli in combination with another uropathogen;
overall, 14% of isolates were determined to have intermediate susceptibility or were resistant to sulfamethoxazole/trimethoprim.
Clinical cure was achieved in 79% (n=117/148) of sulfamethoxazole/trimethoprim-treated patients and 84% (n=134/160) of
nitrofurantoin-treated patients, yielding a treatment difference of -5% (95% CI, -13% to 4%), thereby establishing equivalence. An early
microbiological cure assessed 5 to 9 days after therapy was achieved in 91% (n=131/144) of sulfamethoxazole/trimethoprim-treated
patients and 92% (n=141/154) of nitrofurantoin-treated patients, for a treatment difference of -1% (95% CI, -7% to 6%). Discontinuation
from the study due to adverse events occurred in 1% and 2% of patients in the sulfamethoxazole/trimethoprim and nitrofurantoin
[635]
groups, respectively
.
b) Nitrofurantoin modified-release 100 mg twice a day was as effective as co-trimoxazole DS twice a day and trimethoprim 200 mg
twice a day in a seven-day regimen for treatment of uncomplicated urinary tract infections in 538 patients from 45 different general
[623]
practice centers across the UK
.
4.6.AK Norfloxacin
Diarrhea
Neutropenic disorder
Urinary tract infectious disease
4.6.AK.1 Diarrhea
a) A single dose of norfloxacin 800 mg was as effective as cotrimoxazole 160 mg/800 mg 2 times daily for 5 days for treating bacillary
dysentery caused by shigellosis, in a study of 55 patients. There was no significant difference in the number of days of illness, number
[652]
of unformed stools after initiation of treatment, or the number of treatment failures between the 2 groups
. Similar results have been
[653]
reported
. Short-course treatment regimens using norfloxacin (800 mg as a single dose or 400 mg twice daily for three days) and
cotrimoxazole were effective in the treatment of Shigellosis. However, these treatments did not consistently eliminate Salmonella spp
infection.
b) Norfloxacin 400 mg 2 times daily was shown to be more effective than cotrimoxazole 160 mg/800 mg in the treatment of bacterial
diarrhea. Norfloxacin provided a significantly shorter time to bacterial elimination, a higher rate of bacterial cure, and a shorter time to
normalization of bowel movements than cotrimoxazole. In addition, bacterial resistance increased from 2% to 65% in the cotrimoxazole
[654]
group; no bacterial resistance was observed in the norfloxacin group
.
4.6.AK.2 Neutropenic disorder
a) Cotrimoxazole has been compared to norfloxacin for prevention of infections in neutropenic adults and children, undergoing
chemotherapy for leukemia or other malignancies. Norfloxacin was more effective than cotrimoxazole for preventing gram-negative
anaerobic infections. However, norfloxacin was less effective than cotrimoxazole for preventing gram-positive infections. The overall
rate of infection has been similar for both drugs. Emergence of resistant strains of bacteria occurs more commonly with cotrimoxazole
[655][656]
.
4.6.AK.3 Urinary tract infectious disease
a) SUMMARY: Several clinical studies have reported that norfloxacin is at least as effective as cotrimoxazole in the treatment of
urinary tract infections, with comparable doses in most studies being 400 mg norfloxacin twice a day and cotrimoxazole 160/800 mg
[640][641][642][643][644][645][646][647][648]
twice a day for 7 to 10 days
. Norfloxacin is more effective than cotrimoxazole in recurrent urinary tract
[649]
[641][648]
infections
. Norfloxacin may cause a lower incidence of gastrointestinal and allergic adverse effects
.
b) Norfloxacin in oral doses of 200 or 400 mg twice a day for 7 days was as effective as cotrimoxazole (160 trimethoprim/800 mg
sulfamethoxazole) twice a day for 7 days in the treatment of symptomatic urinary tract infections in a double-blind study involving 2255
[647]
consecutive patients
. Following treatment, bacteriologic efficacy was 97.6%, 97.5%, and 98.6% in patients receiving norfloxacin
200 mg, norfloxacin 400 mg, and cotrimoxazole, respectively. Corresponding rates of reinfection were 0%, 5%, and 0%, respectively.
Norfloxacin 400 mg was no more effective than 200 mg in women with sporadic or recurrent urinary tract infections. In men and patients
with complicated urinary tract infections, the 200 mg regimen was less effective than the 400 mg regimen. In addition, in patients with
recurrent urinary tract infections, cotrimoxazole was more effective than norfloxacin. However, in all of these subgroups, statistical
analyses were not meaningful due to the small numbers of patients. Adverse effects occurred to a lesser extent in norfloxacin patients
as opposed to cotrimoxazole, and the lower-dose regimen was associated with less toxicity than the higher dose.
c) Norfloxacin was superior to cotrimoxazole in the treatment of complicated and uncomplicated urinary tract infections during a
[650]
controlled study involving 80 patients
. In uncomplicated urinary tract infections, patients were administered either cotrimoxazole
160/800 mg orally twice daily or norfloxacin 200 mg orally twice daily for 7 days. The dose of norfloxacin was doubled in patients with
complicated infections; the dose of cotrimoxazole in these patients was not specified, but was presumed to be the same as for
uncomplicated infections. Clinical cure was observed in 93% and 70% of patients treated with norfloxacin and cotrimoxazole,
respectively; this difference was attributed to a higher incidence of bacterial resistance to cotrimoxazole, particularly with Escherichia
coli and Klebsiella. Adverse effects were minimal with both regimens.
d) A study treated 40 patients with bacteriologically-confirmed complicated urinary tract infections in random fashion with oral
norfloxacin 400 mg twice a day or oral cotrimoxazole 160/800 mg twice a day for 10 days. Reinfections 1 to 6 weeks after the end of
treatment occurred in 3 of 19 patients receiving norfloxacin and 1 of 15 receiving cotrimoxazole. A 3-day course of norfloxacin 400 mg
[643]
twice a day was as effective as a 7-day course of cotrimoxazole in simple urinary tract infections
.
e) One study involved the treatment of 43 women with acute urinary tract infections (upper or lower) with either oral norfloxacin 400 mg
twice a day or oral cotrimoxazole 160/800 mg twice a day for 10 days in a randomized study. Seven patients (16%) had low-count
bacteriuria and pyuria and were included in the evaluation. Escherichia coli was the primary infecting pathogen and was isolated in 72%
of infections; coagulase-negative staphylococci were isolated in 14%. Clinical cure after 10 days of treatment was similar with
norfloxacin and cotrimoxazole: 95% and 90%, respectively. Eradication of the infecting organism from fecal flora was demonstrated in
93% of norfloxacin patients, but in only 57% of cotrimoxazole patients. Early reinfections occurred more frequently in cotrimoxazole
patients, with resistant organisms appearing in urine, periurethral, and fecal flora in all cases. Adverse effects were of similar incidence
in each group (3 patients), but were considered more severe in cotrimoxazole patients. Both drugs are comparable in the treatment of
[640]
uncomplicated upper and lower urinary tract infections, but norfloxacin appears to offer some advantages over cotrimoxazole
.
f) Norfloxacin 400 mg orally twice a day was superior to cotrimoxazole 160/800 mg orally twice a day in the treatment of men with
[651]
recurrent urinary tract infections in a randomized study
. Patients with recurrent urinary tract infections (UTI) were selected if they
had a history of at least 1 prior UTI within the last year with or without a history of prostatitis. Each drug was given for 4 to 6 weeks.
Bacteriologic eradication was observed in 56 of 60 norfloxacin patients (93%) and in 39 of 49 (67%) cotrimoxazole patients, a
statistically significant difference. Although norfloxacin was superior in this study, the trial was an open, randomized, controlled study
without blinding techniques. It is unclear whether the randomization techniques allowed unbiased allocation of treatments.
4.6.AL Ofloxacin
Bronchitis
Neutropenic disorder
Urinary tract infectious disease
4.6.AL.1 Bronchitis
a) In a double-blind study of 137 patients with exacerbations of chronic bronchitis and chronic obstructive lung disease, ofloxacin 200
milligrams orally twice a day was more effective than sulfamethoxazole/trimethoprim (2 tablets twice daily). The failure rate for
[657]
sulfamethoxazole/trimethoprim was 13.8% compared to 3.2% for ofloxacin
.
4.6.AL.2 Neutropenic disorder
a) Oral ofloxacin 300 milligrams (mg) twice daily was superior to oral sulfamethoxazole 800 mg/trimethoprim 160 mg in preventing
[658]
infections in 102 neutropenic patients following cytotoxic chemotherapy
.
4.6.AL.3 Urinary tract infectious disease
a) Oral ofloxacin 100 milligrams (mg) twice daily was reported as effective as oral sulfamethoxazole 800 mg/trimethoprim 160 mg
[659]
twice daily in the treatment of acute uncomplicated lower urinary tract infections in a controlled study involving 250 female patients
.
Side effects occurred in 22% and 19% of patients receiving sulfamethoxazole/trimethoprim and ofloxacin, respectively.
b) Ofloxacin 200 milligrams (mg) orally 2 times daily was reported superior to oral sulfamethoxazole 800 mg/trimethoprim 160 mg
[660]
twice daily in the treatment of complicated urinary tract infections in an open, randomized study involving 40 patients
.
c) Ciprofloxacin, ofloxacin and sulfamethoxazole/trimethoprim given for 3 days have similar efficacy in treating acute, uncomplicated,
lower urinary tract infections in women. A randomized, double-blind, three-arm study evaluated the safety and efficacy of 3-day courses
of the above medications in 688 women, 81% of whom were infected with Escherichia coli, of which 100% were susceptible to
ciprofloxacin and ofloxacin and 94% to sulfamethoxazole/trimethoprim. Doses were ciprofloxacin 100 milligrams (mg) twice daily,
ofloxacin 200 mg twice daily and sulfamethoxazole 800 mg/trimethoprim 160 mg twice daily. Bacterial eradication rates at the end of
therapy were not significantly different among the 3 groups and were as follows: 94% for ciprofloxacin, 97% for ofloxacin, and 92% for
sulfamethoxazole/trimethoprim. Recurrence at the end of 4 to 6 weeks occurred in 61 patients. Discontinuation of therapy due to drugrelated adverse events occurred most frequently with sulfamethoxazole/trimethoprim. Although the bacterial eradication rates were
similar for the 3 drugs in this study, it should be noted that the rate of resistance of E. coli to sulfamethoxazole/trimethoprim in the
[661]
United States has since increased to approximately 17% in 1996
.
d) Ofloxacin 100 milligrams (mg) twice daily was as effective as sulfamethoxazole 400 mg/trimethoprim 80 mg twice daily for three
days during a double-blind trial involving 250 women with acute uncomplicated urinary tract infection. Bacteriologic cure was achieved
in 92% of patients receiving ofloxacin as compared with 88% of those receiving sulfamethoxazole/trimethoprim. Another trial, using
dosages twice as high for 7 days reported ofloxacin to be superior to sulfamethoxazole/trimethoprim in 42 patients with upper urinary
[662]
tract infections
. In both uncomplicated and complicated urinary tract infections, another study reports cure rates between 97% and
[663]
100% with either ofloxacin or sulfamethoxazole/trimethoprim
.
e) Ofloxacin 200 milligrams (mg) twice daily for 7 days was reported superior to oral sulfamethoxazole 800 mg/trimethoprim 160 mg
[664]
twice daily in the treatment of upper urinary tract infections in a controlled study involving 42 patients
. Clinical cure was observed in
19 of 23 ofloxacin patients (82%) and in 11 of 19 sulfamethoxazole/trimethoprim patients (58%); bacterial eradication was observed in
85% and 69% of patients treated, respectively.
f) Once daily ofloxacin 200 milligrams (mg) orally for 3 days was equally effective as oral sulfamethoxazole 800 mg/trimethoprim 160
[665]
mg every 12 hours for 7 days) in the treatment of uncomplicated urinary tract infections
.
g) Single 400 milligrams (mg) doses of ofloxacin are less effective than 7 days of therapy with sulfamethoxazole 800 mg/trimethoprim
160 mg twice daily for acute cystitis in women. However, ofloxacin 200 mg once daily for 3 days was similar in efficacy to the 7-day
[666]
sulfamethoxazole/trimethoprim regimen
.
4.6.AM Oxytetracycline
4.6.AM.1 Acne vulgaris
a) Sulfamethoxazole/trimethoprim was equally effective and safe as oxytetracycline in a study of 30 patients with a 1- to 9-year history
of acne vulgaris. In the double-blind trial, each patient received either sulfamethoxazole 400 milligrams (mg)/trimethoprim 80 mg or
oxytetracycline 250 mg daily for 8 weeks. After 3 months, all patients had responded well with much improved or completely cleared
[718]
lesions. No adverse reactions were noted
.
4.6.AN Pefloxacin
Typhoid fever
Urinary tract infectious disease
4.6.AN.1 Typhoid fever
a) Pefloxacin was compared to cotrimoxazole in the treatment of typhoid fever in a prospective, randomized study involving 42 adult
patients. The patients received either pefloxacin 400 mg orally twice daily or cotrimoxazole 160/800 mg orally twice daily for 14 days.
Clinical and bacteriologic cure rates were 100% in each treatment group and no patient experienced relapse or became a Salmonella
carrier. However, pefloxacin therapy was associated with a more rapid onset of apyrexia and resolution of gastrointestinal and
neurological symptoms as compared to cotrimoxazole; apyrexia occurred in a mean of 4.37 days with pefloxacin as compared to 7.75
[714]
days with cotrimoxazole
.
4.6.AN.2 Urinary tract infectious disease
a) In an unblinded study, pefloxacin 400 mg twice daily was as effective as cotrimoxazole 160/800 mg twice daily, each administered
[715]
for 10 days, in the treatment of uncomplicated urinary tract infections
.
b) A single oral dose of pefloxacin 800 mg was compared to cotrimoxazole 160 mg/800 mg orally 2 times daily for 5 days for the
treatment of uncomplicated cystitis. In the 140 patients treated with pefloxacin, 97.1% had a bacteriological cure after 7 to 10 days;
95.2% of the cotrimoxazole were cured. After 28 to 42 days, the urine culture was negative in 95% of the pefloxacin group and 90.3% of
[716]
cotrimoxazole group
.
4.6.AO Penicillin G
4.6.AO.1 Pneumonia
a) A 5-day course of oral cotrimoxazole was as effective as combination therapy with a single IM dose of fortified procaine penicillin G
(procaine penicillin G plus benzyl penicillin G) plus a 5-day course of oral ampicillin in the treatment of severe community-acquired
[621]
pneumonia in young Gambian children
. All drugs were given in doses according to the current WHO recommendations (not
provided). It is suggested that cotrimoxazole is the antibiotic of first choice for outpatient therapy of pneumonia in young children in
developing countries.
4.6.AP Penicillin G Procaine
4.6.AP.1 Pneumonia
a) The efficacy of cotrimoxazole for the treatment of pneumonia was compared to procaine penicillin G, in 614 children, aged 3 months
to 12 years. Procaine penicillin G 150 to 600 mg intramuscularly once daily was administered to 311 children; cotrimoxazole 20 mg/100
mg to 80 mg/400 mg was given 2 times daily to 303 children. The doses were determined by age and each treatment was given for 5
[567]
days. The 2 treatments were equally effective for treating pneumonia in children
.
4.6.AQ Pentamidine
Pneumocystis pneumonia
Pneumocystis pneumonia; Prophylaxis
Toxoplasmosis; Prophylaxis
4.6.AQ.1 Pneumocystis pneumonia
a) SUMMARY: Sulfamethoxazole/trimethoprim is the drug of first choice for Pneumocystis carinii pneumonia due to its superior
[669][670][671][672][673]
efficacy when compared to pentamidine
. The drug also has the advantage of oral administration. Pentamidine may be
favored for use in some patients with AIDS since this population has a higher incidence of adverse reactions to
sulfamethoxazole/trimethoprim.
b) Although sulfamethoxazole/trimethoprim remains the agent of choice for P carinii pneumonia, recent studies have suggested a
high incidence of adverse reactions to this drug in AIDS patients, primarily leukopenia, hepatotoxicity, rash, fever and hypersensitivity
[674][675][676]
reactions, which generally occur during the second week of treatment
. The number of AIDS patients completing a course of
treatment with sulfamethoxazole/trimethoprim has been significantly less as compared to those receiving pentamidine in some reports
[677]
. In addition, recent studies have demonstrated that as many as 50% of AIDS patients receiving sulfamethoxazole/trimethoprim
[678]
initially were switched to pentamidine therapy due to toxicity or lack of efficacy of sulfamethoxazole/trimethoprim
. Pentamidine
[677][672]
has; however, not been associated with a higher incidence of toxicity in AIDS patients, in available studies
. For the present time,
sulfamethoxazole/trimethoprim should remain the agent of choice, with pentamidine being reserved for those patients who are unable
[672]
to tolerate sulfamethoxazole/trimethoprim
.
c) The combination of pentamidine and sulfamethoxazole/trimethoprim appears to be no more effective than
[672]
sulfamethoxazole/trimethoprim alone, and may be associated with a greater degree of toxicity
.
d) In a randomized crossover design trial of 50 children, pentamidine isothionate was as effective as sulfamethoxazole/trimethoprim
in the treatment of Pneumocystis carinii pneumonia, although sulfamethoxazole/trimethoprim has fewer side effects. Those patients
not responding favorably within 3 or more days of therapy were switched to the other drug. Twenty-six patients initially received oral
sulfamethoxazole/trimethoprim (20 mg/kg of trimethoprim) every 6 hours. Twenty recovered without switching drugs. Of the 9 patients
switched to pentamidine for 14 days, three recovered. All but one of these 9 patients were switched because of progressive infection,
one was switched because of severe urticarial rash despite improvement of the pneumonia. Of the 24 patients initially receiving
pentamidine (4 mg/kg IM daily), 18 recovered; 14 after pentamidine alone and 4 of 9 who were crossed over
sulfamethoxazole/trimethoprim. All nine were switched because of progressive infection. Side effects encountered were much more
severe from pentamidine and included nephrotoxicity. The only side effect from sulfamethoxazole/trimethoprim was one case of
[670]
severe rash
.
e) Only 5 of 37 patients who initially received sulfamethoxazole/trimethoprim for treatment of Pneumocystis carinii pneumonia
associated with AIDS were able to complete therapy due to toxicity. Two patients died within 7 days, 19 had
sulfamethoxazole/trimethoprim discontinued because of toxicity and 11 were switched to pentamidine because of therapeutic failure
after 8 days of treatment. Toxicity occurred in 29 patients, consisting of a rash, generally involving the whole body and associated with
fever, which usually developed within 8 to 12 days after initiation of treatment. Neutropenia or thrombocytopenia occurred in more than
half of patients but resolved with withdrawal of treatment. Hepatitis occurred in 11 patients, as evidenced by elevations in alanine
transaminase or alkaline phosphatase elevations. Pentamidine (rash, neutropenia, transaminase elevations, azotemia and
[677]
hypoglycemia) also produced toxicity, however to a lesser extent than sulfamethoxazole/trimethoprim
.
f) In a prospective randomized study involving 40 patients, efficacy was comparable for pentamidine isothionate and
sulfamethoxazole/trimethoprim in the treatment of first episodes of P carinii pneumonia in patients with AIDS. Patients were randomly
assigned to receive sulfamethoxazole/trimethoprim 100 milligrams/kilograms/day (mg/kg/day)/20 mg/kg/day IV, given at 6 hour
intervals or pentamidine isothionate (4 mg/kg/day IV or IM) as a single daily dose; duration of treatment was 21 days. Overall mortality
during therapy was 15% (6 of 40 patients). Five patients receiving sulfamethoxazole/trimethoprim initially, and one patient receiving
pentamidine initially, died during the 21 day treatment period, these differences not being significantly different. Three months after the
completion of treatment, 7 patients (35%) initially allocated to receive sulfamethoxazole/trimethoprim and 6 patients (30%) initially
assigned to receive pentamidine had died; these differences also did not reach statistical significance. Adverse effects requiring
changing from the initial drug occurred in 10 sulfamethoxazole/trimethoprim-treated patients and 11 pentamidine-treated patients. It
appears that pentamidine and sulfamethoxazole/trimethoprim are equally effective in the treatment of pneumonia secondary to P
[679]
carinii in AIDS patients
.
g) Sulfamethoxazole/trimethoprim was reported superior to pentamidine in the treatment of Pneumocystis carinii pneumonia for 70
[680]
AIDS patients in a prospective, randomized study
. Sulfamethoxazole/trimethoprim (trimethoprim) was initially administered
intravenously as 15 to 20 mg/kg/day (trimethoprim); this was followed by oral therapy when improvement occurred.
Sulfamethoxazole/trimethoprim doses were adjusted to maintain serum trimethoprim levels at 5 to 8 mcg/mL. Intravenous pentamidine
was given in doses of 4 mg/kg/day and followed by intramuscular therapy after clinical improvement. The pentamidine dose was
reduced by 30% to 50% for absolute rises in serum creatinine of greater than 88 mmol/L (1 mg%). All patients were randomly assigned
to receive 1 regimen for 17 to 21 days. The number of patients surviving without the need for respiratory support at the completion of
therapy was greater in the sulfamethoxazole/trimethoprim group (86%) as compared to pentamidine (61%). In addition, oxygenation
improved 8 days earlier in sulfamethoxazole/trimethoprim-treated patients.
4.6.AQ.2 Pneumocystis pneumonia; Prophylaxis
a) SUMMARY: Sulfamethoxazole/trimethoprim is considered the drug of choice for prophylaxis of PCP in HIV positive adults and
[681]
children
; (Anon, 1991b, Gallant et al, 1994). In clinical trials sulfamethoxazole/trimethoprim has been either as effective or more
[673][682][683]
effective than aerosolized pentamidine
. Even though pentamidine is usually associated with less adverse reactions than
sulfamethoxazole/trimethoprim; it is much more expensive, possibly less effective, and is therefore, considered to be second line
therapy.
b) Sulfamethoxazole/trimethoprim single strength and double strength tablets once daily for 264 days were more effective in the
primary prophylaxis of pneumocystis carinii pneumonia (PCP) than aerosolized pentamidine 300 mg given every month. Significantly
more HIV patients with a CD4 count below 200 per cubic millimeter receiving pentamidine developed primary PCP (6/71) while 0/142
[673]
HIV patients with CD4 counts below 200 per cubic millimeter receiving sulfamethoxazole/trimethoprim developed PCP
.
c) Oral sulfamethoxazole/trimethoprim double strength was more effective than aerosolized pentamidine (150 mg every 2 weeks for 1
year then 300 mg every 4 weeks for 1 year) in preventing recurrent pneumocystis carinii pneumonia (PCP). At 18 months of treatment,
significantly more AIDS patients receiving aerosolized pentamidine developed recurrent PCP (36/156) 27.6% compared to AIDS
patients receiving sulfamethoxazole/trimethoprim (14/154) 11.4%. The 1 year rate of recurrence was estimated to be 3.5% in the
sulfamethoxazole/trimethoprim group and 18.5% in the pentamidine group. Forty-two patients crossed over from
sulfamethoxazole/trimethoprim to pentamidine, primarily due to adverse effects and 4 patients crossed over from pentamidine to
[682]
sulfamethoxazole/trimethoprim. In addition, all patients were receiving zidovudine
.
d) In a larger trial involving 843 HIV positive patients, pentamidine was as effective or less effective than
sulfamethoxazole/trimethoprim or dapsone depending on the patients CD4 cell count. Patients were assigned to one of three
treatment groups (1) sulfamethoxazole/trimethoprim, starting dose of 1 double-strength (DS) tablet twice daily, (2) dapsone, starting
dose 50 milligrams twice daily, or (3) aerosolized pentamidine 300 mg every 4 weeks. Dosage reductions of dapsone and
sulfamethoxazole/trimethoprim were permitted if the patient experienced adverse effects. Overall efficacy was similar between the
three groups except in patients with a CD4 count less than 100. In these patients, dapsone and sulfamethoxazole/trimethoprim were
more effective than aerosolized pentamidine. Pentamidine was better tolerated than the other 2 agents with fewer patients having to be
[683]
switched to an alternate therapy
.
4.6.AQ.3 Toxoplasmosis; Prophylaxis
a) In a retrospective review, sulfamethoxazole/trimethoprim was compared to pentamidine for the prophylaxis of toxoplasmic
encephalitis (TE) in patients with AIDS. Approximately 40% of patients in each group were seropositive for toxoplasma gondii specific
IgG before treatment. No cases of toxoplasmic encephalitis were reported in patients receiving sulfamethoxazole/trimethoprim (dose 1
double-strength tablet twice daily on Mondays and Wednesdays). Pentamidine was administered by aerosol in 78 patients and
intravenously in 17; the dose was 300 milligrams every 4 weeks whether given intravenously or aerosolized. Of those receiving
pentamidine 33% were diagnosed with TE. All cases of TE were diagnosed in patients who were seropositive prior to prophylaxis
[684]
indicating reactivation of infection, rather than primary infection
.
4.6.AR Prednisolone
4.6.AR.1 Otitis media with effusion, chronic
a) Resolution rates of otitis media with effusion(OME) which had persisted for more than 8 weeks, were compared to controls in a
randomized trial of 76 children (age 10 to 95 months) utilizing trimethoprim-sulfamethoxazole (8 milligrams of trimethoprim, 40
milligrams of sulfamethoxazole/kilogram/daily in 2 divided doses) for 4 weeks, prednisone 1 milligram/kilogram/daily in 2 divided doses
(prednisolone equivalent) for 2 weeks, and aluminum ibuprofen suspension (24 milligrams/kilogram/daily in 4 divided doses) for 2
[717]
weeks
. All other medications, antihistamines or over the counter combinations, were withheld during the 12 month follow up period.
Patients were evaluated at 2 and 4 weeks, then monthly until protocol completion. Following two-thirds of the patients being admitted to
the protocol, animal data suggesting that ibuprofen(IBP) treatment delayed resolution of middle ear inflammation resulted in the
discontinuation of patients being assigned to the IBP treatment arm. After 2 weeks of treatment resolution rates of OME in the
prednisone and trimethoprim-sulfamethoxazole(TMS) groups were significantly greater than controls or the IBP group. A similar
percentage of patients in all groups eventually resolved their OME, 67% IBP and prednisone, 75% TMS, and 79% of controls; 34/72
failed treatment and required tympanostomy tube placement. Differences in hearing sensitivity among groups were not statistically
significant after 12 months, unfortunately short-term antiinflammatory or antibiotic treatment failed to produce a long lasting effect on
OME.
4.6.AS Primaquine
4.6.AS.1 Pneumocystis pneumonia
a) The combination of clindamycin (900 mg orally 4 times daily) plus primaquine (30 mg orally daily) appeared to be an equally
effective alternative to cotrimoxazole in the treatment of mild to moderately severe Pneumocystis carinii pneumonia in patients with
[689]
[690]
AIDS (acquired immunodeficiency virus)
. The results of this trial were confirmed
. There was no significant difference in efficacy
or incidence of adverse effect between cotrimoxazole or the combination of clindamycin and primaquine, for the treatment of mild to
moderate Pneumocystis carinii pneumonia in 181 patients with AIDS.
b) Similar efficacy has been reported between clindamycin/primaquine and Co-trimoxazole as primary treatment for AIDS-related
[691]
Pneumocystis carinii pneumonia from a pilot trial
. There were no differences with regards to outcome, duration of survival, relapse
rate or mortality. Their results show a trend towards less toxicity with clindamycin/primaquine; overall incidence and severity of adverse
[691]
effects were lower but the differences were not statistically significant
.
4.6.AT Pyrimethamine
Pneumocystis pneumonia; Prophylaxis
Toxoplasmosis; Prophylaxis
4.6.AT.1 Pneumocystis pneumonia; Prophylaxis
a) In 166 HIV-infected patients dapsone 100 mg plus pyrimethamine 25 mg administered once a week was inferior to trimethoprim 160
mg/sulfamethoxazole 800 mg BID three times a week in preventing primary pneumocystis carinii pneumonia (PCP). Over a 2 year
period a significant increase in the rate of developing PCP occurred in the dapsone/pyrimethamine group (42%) compared to the
trimethoprim/sulfamethoxazole group (10%). There was no significant difference in the mortality rates between groups
[719]
.
4.6.AT.2 Toxoplasmosis; Prophylaxis
a) In 166 HIV-infected patients dapsone 100 mg plus pyrimethamine 25 mg administered once a week was not significantly different in
preventing toxoplasmosis than trimethoprim 160 mg/sulfamethoxazole 800 mg BID three times a week. There was no significant
[719]
difference in mortality rates between groups
.
4.6.AU Spectinomycin
4.6.AU.1 Chancroid
a) A single dose of spectinomycin 2 g intramuscularly was significantly superior to cotrimoxazole 160 mg/800 mg orally 2 times daily for
7 days in a randomized study. The ulcers were healed in 93.7% of patients receiving spectinomycin and in 48.2% of patients treated
with cotrimoxazole. In addition, the in vitro sensitivity of Haemophilus ducreyi was significantly superior for spectinomycin compared to
[595]
cotrimoxazole
.
4.6.AV Streptomycin
4.6.AV.1 Chancroid
a) Cotrimoxazole was found to be as efficacious as streptomycin and probably superior to sulfisoxazole and tetracycline in the
[626]
treatment of chancroid
.
4.6.AW Sulfamethoxazole
Chancroid
Urinary tract infectious disease
4.6.AW.1 Chancroid
a) Oral cotrimoxazole (160/800 mg twice daily) was superior to sulfamethoxazole alone (1 g twice daily) in the treatment of chancroid
[685]
in a randomized study involving 109 patients
.
4.6.AW.2 Urinary tract infectious disease
a) Despite some studies suggesting the similar efficacy of sulfamethoxazole and cotrimoxazole in the treatment of urinary tract
[686][687]
[688]
infections
, cotrimoxazole is often preferred over a single sulfonamide
. Cotrimoxazole is considered the agent of choice for
single-dose therapy of acute urinary tract infections in nonpregnant women who have no renal parenchymal involvement. For
conventional therapy of cystitis (7 to 14 days) in women not qualifying for single-dose therapy, cotrimoxazole or the more soluble
sulfisoxazole are preferred over sulfamethoxazole.
4.6.AX Sulfisoxazole
4.6.AX.1 Urinary tract infectious disease
[629]
a) Single-dose therapy with a short-acting antimicrobial agent has been advocated for the treatment of acute cystitis
. Four different
single-dose regimens were compared in a group of 117 women with symptoms of acute cystitis. Patients were randomized into one of
four groups: 1) 1 gram of sulfisoxazole, 2) 2 grams of sulfisoxazole, 3) a combination of trimethoprim 160 mg and sulfamethoxazole
800 mg, and 4) a combination of trimethoprim 320 mg and sulfamethoxazole 1600 mg. Although the antibacterial activity was
significantly greater in urine collected from patients receiving trimethoprim/sulfamethoxazole, overall cure rate was not significantly
different among the 4 regimens (range 85% to 95%). In the 13 patients with possible renal infection there was a cure rate of 69% which
was significantly lower than that (95%) seen in women without evidence of renal infection. With an overall cure rate of 85% to 95% it
appears that single-dose therapy may be sufficient for the treatment of acute cystitis. Further study is required.
b) In a double-blind study of patients with urinary tract infections 9 of 10 patients taking a single 1-g sulfisoxazole dose were "cured"
with 1 recurrence, while 6 of 7 patients who took a single 2-g dose were "cured" with 1 recurrence. All 9 patients taking a single 160mg/800 mg trimethoprim/sulfamethoxazole dose and all 13 patients taking twice this much in a single dose were "cured" with no
[630]
recurrences
.
4.6.AY Temafloxacin
4.6.AY.1 Urinary tract infectious disease
a) Temafloxacin is at least as effective as cotrimoxazole for uncomplicated urinary tract infections. Studies have compared
temafloxacin 400 mg once daily for 7 days with trimethoprim/sulfamethoxazole 160/800 mg twice a day for 10 days. Clinical cure rates
of 93% and 95% in the temafloxacin and cotrimoxazole groups, respectively, have been reported. Bacteriologic cure rates of up to
100% for both drugs have been observed. The primary pathogens reported in these studies were Escherichia coli, Klebsiella
[698]
pneumoniae, and Proteus mirabilis (Tech Info temafloxacin, 1990)
.
4.6.AY.2 Adverse Effects
a) In clinical trials comparing temafloxacin and cotrimoxazole a higher incidence of side effects have been reported with cotrimoxazole
(Tech Info temafloxacin, 1990). In a study of 400 women, adverse effects, which included nausea, vomiting, rash, headache, and
dizziness, occurred in 19.6% and 23.5% of patients receiving temafloxacin and cotrimoxazole, respectively. The temafloxacin and
[698]
cotrimoxazole groups experienced transient leukopenia at rates of 0.5% and 4.1%, respectively
.
4.6.AZ Trimethoprim
Neutropenic disorder
Pneumocystis pneumonia
Respiratory tract infection
Traveler's diarrhea
Urinary tract infectious disease
4.6.AZ.1 Neutropenic disorder
a) The clinical and microbiologic efficacy of trimethoprim alone has been compared to cotrimoxazole in febrile granulocytopenic
patients. Trimethoprim was given in doses of 150 mg orally 2 times daily and cotrimoxazole in doses of 160/800 mg orally 2 times daily.
Infection occurred more frequently in the trimethoprim group (50%) as compared to cotrimoxazole (39%), however this was not
considered statistically significant. However, trimethoprim was not as protective as cotrimoxazole when the granulocyte count was
below 100/mm(3). In addition, cotrimoxazole-treated patients acquired fewer new aerobic gram-negative bacilli than in those receiving
trimethoprim alone and aerobic gram-negative bacilli were cleared from fecal surveillance cultures more often with the combination.
Trimethoprim does not appear to be optimal for the prevention of colonization and infection in this group of patients, and the
[700]
combination therapy is preferred to increase the spectrum of activity. However, myelosuppression was greater with cotrimoxazole
.
b) In a randomized, double blind study, cotrimoxazole was as effective as trimethoprim for the treatment of bacterial pneumonia.
Trimethoprim 160 mg 2 times daily was given to 16 patients; cotrimoxazole 160/800 mg was given to 15 patients. Therapy was given
for 10 to 14 days. Fifteen (94%) of patients given trimethoprim improved, compared to 12 (80%) of patients given cotrimoxazole (not
significant). There was no difference between the groups in symptom duration or severity. Side effects were observed in 1 patient
taking trimethoprim and in 4 patients taking cotrimoxazole. Trimethoprim was evaluated as being superior because of the lower
[701]
incidence of side effects
.
4.6.AZ.2 Pneumocystis pneumonia
a) The combination of trimethoprim and dapsone was as effective as cotrimoxazole for the treatment of mild to moderate Pneumocystis
carinii pneumonia in a trial involving 181 patients with AIDS. There was no statistical difference between groups in incidence of dose
[702]
limiting toxicities
.
4.6.AZ.3 Respiratory tract infection
a) Trimethoprim 200 mg orally 2 times daily was as effective as cotrimoxazole 160/800 mg orally 2 times daily, each for 7 days, in the
[703]
treatment of acute bronchitis in a single-blind study involving 74 patients
. Better eradication of Haemophilus species was observed
with trimethoprim alone, and resistance appeared to be greater with the combination.
4.6.AZ.4 Traveler's diarrhea
a) Cotrimoxazole 160/800 mg was superior to trimethoprim 200 mg alone in the prevention of travelers' diarrhea. Each preparation was
taken once daily for 14 days in male and female students from the USA who had been in Mexico for more than 3 days. Both drugs were
[704]
superior to placebo. Cotrimoxazole appears to be effective prophylaxis for travelers' diarrhea
.
4.6.AZ.5 Urinary tract infectious disease
a) SUMMARY: Cotrimoxazole and trimethoprim are equally effective as therapy for acute urinary tract infections or as prophylaxis;
however, cotrimoxazole is superior in the treatment of complicated urine infections.
b) Sulfamethoxazole, trimethoprim, and cotrimoxazole have been compared in the treatment of acute urinary tract infections after
major gynecological operations. No difference was found between trimethoprim and cotrimoxazole. Treatment with trimethoprim alone
[705]
is superior to cotrimoxazole due to smaller incidence of side effects
.
c) Efficacy was not different with trimethoprim alone or cotrimoxazole in the treatment of acute urinary tract infections. In the
trimethoprim group only 2 of 139 and in the combined preparations 4 of 129 patients withdrew from the study because of side effects. It
can be concluded that, at least in ambulatory treatment, trimethoprim alone is a suitable drug in the treatment of acute urinary tract
[706]
infections
.
d) In a prospective randomized double-blind trial 279 patients were treated with either 100 mg of trimethoprim or cotrimoxazole
100/500 mg twice daily for 5 days. The efficacy of each regimen was similar for patients being treated for chest infections. However,
patients experienced more side effects with cotrimoxazole than with trimethoprim. In patients being treated for urinary tract infections
the cure rate between the 2 regimens was also similar. The authors conclude that most chest and urinary infections previously treated
[707]
with cotrimoxazole should be treated with trimethoprim alone
.
e) Trimethoprim has been compared to ampicillin, cephalexin, and cotrimoxazole for the treatment of urinary tract infections in hospital
patients, bacteriuria in pregnancy and patients in general practice. The overall results show that trimethoprim and the combination
cotrimoxazole gave a similar and highly acceptable cure rate of 83%. Ampicillin cured 73% and cephalexin 69%. In general practice,
highly satisfactory cure rates were obtained with trimethoprim (96%), ampicillin (89%), and cotrimoxazole (81%), but cephalexin cured
only 62% of the patients treated. In the hospital patients, the relatively small numbers suggested that cotrimoxazole was superior to
trimethoprim, ampicillin, and cephalexin, although the difference did not reach the conventional level for statistical significance. In
pregnancy, the results with cotrimoxazole (85% cure) and trimethoprim were equally good. Ampicillin (65%) and cephalexin (78%) were
[708]
less satisfactory
.
f) Trimethoprim alone (300 mg daily), cotrimoxazole (160 mg trimethoprim; 2 tablets Q12H), or sulfamethizole (1 g Q8H) for 5 days, in
[709]
the treatment of uncomplicated urinary tract infections have achieved similar cure rates
. The cure rates were 90%, 95%, and 90%,
respectively. The investigators recommend the use of trimethoprim over cotrimoxazole for uncomplicated urinary tract infections.
g) Trimethoprim 250 mg twice daily was less effective than cotrimoxazole 2 tablets twice daily in the treatment of complicated urinary
[710]
tract infections; however, there were no statistically significant differences between treatment groups
.
h) Cotrimoxazole (40/200 mg), trimethoprim (100 mg) and nitrofurantoin (100 mg) once daily were equally effective in the prophylaxis
of recurrent urinary tract infections in a double-blind controlled study of 60 women over 6 months. None of the 3 drug regimens resulted
[711]
in emergence of resistant E coli. Side effects were minimal
.
i) Oral cotrimoxazole 1 to 2 mg/kg (trimethoprim) once daily was reported as effective as trimethoprim alone (1 to 2 mg/kg/day) as
[712]
prophylaxis of recurrent urinary tract infections in the unobstructed urinary tract for 334 children in a prospective study
.
4.6.AZ.6 Adverse Effects
a) A 23-year-old male developed fever, vasculitic rash, granulomatous hepatitis, elevated serum amylase, and splenomegaly following
2 days therapy with cotrimoxazole. This syndrome reappeared following rechallenge with cotrimoxazole but not following trimethoprim
[699]
challenge
.
4.6.BA Trimethoprim/Sulfadiazine
Respiratory tract infection
Urinary tract infectious disease
4.6.BA.1 Respiratory tract infection
a) SUMMARY: Available studies indicate that cotrimazine is as effective as cotrimoxazole in treating respiratory tract infections
[568][569]
(maxillary sinusitis, pneumonia, bronchitis, and tonsillitis)
.
b) Fifty-four patients with ACUTE MAXILLARY SINUSITIS were treated with a 10-day course of either cotrimazine 1 tablet daily (820
mg sulfadiazine plus 180 mg trimethoprim) or cotrimoxazole (sulfamethoxazole 800 mg plus trimethoprim 160 mg), 1 tablet in the
[569]
morning and at bedtime in a controlled study
. A faster clinical response was observed in cotrimazine patients; however, by the end
of treatment, both drugs were equally effective, with improvement in 19 of 28 cotrimazine-treated patients and in 18 of 26
cotrimoxazole-treated patients. The double-blind technique utilized in this study was not described adequately.
c) Cotrimazine (225 mg sulfadiazine and 75 mg trimethoprim/tablet; two tablets 2 times daily) was deemed superior to cotrimoxazole
(400 mg sulfamethoxazole and 80 mg trimethoprim tablet; two tablets 2 times daily), each for 7 to 14 days, in the treatment of acute
[568]
respiratory tract infections in adults
. Eighty-eight of one hundred patients receiving cotrimazine were cured, as compared to sixtynine of one hundred patients receiving cotrimoxazole; however, the only statistically significant difference was in the cure rate in
pneumonia (32 of 37 cotrimazine-treated patients and 17 of 34 cotrimoxazole-treated patients). In addition, the dose utilized in this
study for cotrimazine was slightly higher than in other studies comparing the two drugs in urinary tract infections and other indications.
However, a slight superiority of cotrimazine is evident in this report, possibly related to higher tissue levels of the drug due to its lower
degree of protein binding.
4.6.BA.2 Urinary tract infectious disease
a) SUMMARY: Most controlled studies have indicated the comparable efficacy of cotrimoxazole and cotrimazine in treating acute
[570][571][572][573][574][575][576]
uncomplicated urinary tract infections in adults and children
. Comparable doses appear to be 1 tablet of
cotrimazine 500 mg (410 mg sulfamethoxazole and 90 mg trimethoprim) orally 2 times daily and cotrimoxazole 2 tablets (400 mg
sulfamethoxazole and 80 mg trimethoprim per tablet) orally 2 times daily.
b) Some studies have indicated a lower incidence of adverse reactions with cotrimazine as compared to cotrimoxazole, primarily skin
[570][573]
rash and gastrointestinal disturbances
. However, available data are not convincingly in favor of cotrimazine in this regard.
c) Cotrimazine appears to have more favorable pharmacokinetic parameters than cotrimoxazole, which constitutes the primary
difference between the two drugs. Cotrimazine is eliminated as intact drug in the urine to a greater extent than sulfamethoxazole,
[577][578][579]
which is the reason for the lower dose of cotrimazine administered
. With lower doses of sulfonamide in cotrimazine, it is
postulated that a lower incidence of sulfonamide-related toxicity will appear. Similarly, accumulation of potentially toxic metabolites is
more likely to occur with sulfamethoxazole as compared to sulfadiazine in patients with renal failure, suggesting increased safety of
cotrimazine in these patients; more active, unchanged sulfadiazine is excreted in the urine than is unchanged sulfamethoxazole in
[580][579][577]
patients with either normal or reduced renal function
. However, there are no adequate studies to determine significant
differences of the 2 agents in patients with renal insufficiency. The lower doses of sulfonamide given with cotrimazine have not been
demonstrated to be superior to cotrimoxazole administration as to side effects.
d) Cotrimoxazole and cotrimazine were compared in 127 patients with acute uncomplicated urinary tract infections in a double-blind
[570]
study
. Cotrimazine 500 mg or cotrimoxazole 960 mg were administered to randomized patients every 12 hours for 14 days,
resulting in a cure rate of 97.7% with cotrimazine and of 97.6% with cotrimoxazole. Side effects occurred in 15.1% of cotrimazinetreated patients, compared to 23.7% of patients treated with cotrimoxazole; however, these differences were not statistically significant.
e) Cotrimazine, one tablet (410 mg sulfadiazine and 90 mg trimethoprim) every 12 hours, was as effective as cotrimoxazole (160 mg
[573]
trimethoprim and 800 mg sulfamethoxazole) every 12 hours, each for one week, in treating acute urinary tract infections
. Side
effects were less in cotrimazine-treated patients; however, these effects were mild and significant differences are questionable.
4.6.BB Vancomycin
4.6.BB.1 Staphylococcal infectious disease
a) Vancomycin was significantly superior to cotrimoxazole for the treatment of infections caused by Staphylococcus aureus in 101
intravenous drug users. The dose of vancomycin was 1 g intravenously every 12 hours and the dose of cotrimoxazole was 320
mg/1600 mg intravenously every 12 hours. Overall, the average duration of bacteremia was 6.7 days in the cotrimoxazole group and
4.3 days in the vancomycin group. In the subgroup of patients with methicillin-resistant Staphylococcus aureus infections, the duration
of bacteremia was 7.3 days in the cotrimoxazole group and 3.5 days in the vancomycin group. In addition, the average duration of
[584]
hospitalization was significantly shorter for the vancomycin group (22.1 days) compared to the cotrimoxazole group (29.8 days)
.
6.0 References
1. Product Information: sulfamethoxazole, trimethoprim oral suspension, sulfamethoxazole, trimethoprim oral suspension. Teva
Pharmaceuticals USA, Sellersville, PA, 2006.
2. Product Information: sulfamethoxazole, trimethoprim oral tablets, oral double-strength tablets, sulfamethoxazole, trimethoprim oral
tablets, oral double-strength tablets. Lannett Company,Inc, Philadelphia, PA, 2005.
3. Product Information: sulfamethoxazole/trimethoprim intravenous solution, sulfamethoxazole/trimethoprim intravenous solution.
Sicor Pharmaceuticals, Inc, Irvine , CA, 2003.
4. Mermel LA , Allon M , Bouza E , et al: Clinical Practice Guidelines for the Diagnosis and Management of Intravascular CatheterRelated Infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis 2009; 49:1-45.PubMed Abstract:
http://www.ncbi.nlm.nih.gov/...PubMed Article: http://www.ncbi.nlm.nih.gov/...
5. Pennesi M, Travan L, Peratoner L, et al: Is antibiotic prophylaxis in children with vesicoureteral reflux effective in preventing
pyelonephritis and renal scars? A randomized, controlled trial. Pediatrics 2008; 121(6):e1489-e1494.PubMed Abstract:
http://www.ncbi.nlm.nih.gov/...PubMed Article: http://www.ncbi.nlm.nih.gov/...
6. Garin EH, Olavarria F, Garcia Nieto,V, et al: Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis
after acute pyelonephritis: a multicenter, randomized, controlled study. Pediatrics 2006; 117(3):626-632.PubMed Abstract:
http://www.ncbi.nlm.nih.gov/...PubMed Article: http://www.ncbi.nlm.nih.gov/...
7. Roussey-Kesler G, Gadjos V, Idres N, et al: Antibiotic prophylaxis for the prevention of recurrent urinary tract infection in children with
low grade vesicoureteral reflux: results from a prospective randomized study. J Urol 2008; 179(2):674-679.PubMed Abstract:
http://www.ncbi.nlm.nih.gov/...PubMed Article: http://www.ncbi.nlm.nih.gov/...
8. vanderVeen EL, Rovers MM, Albers FW, et al: Effectiveness of trimethoprim/sulfamethoxazole for children with chronic active otitis
media: a randomized, placebo-controlled trial. Pediatrics 2007; 119(5):897-904.PubMed Abstract:
http://www.ncbi.nlm.nih.gov/...PubMed Article: http://www.ncbi.nlm.nih.gov/...
9. Pape JW, Verdier RI, Boncy M, et al: Cyclospora infection in adults infected with HIV: clinical manifestations, treatment, and
prophylaxis. Ann Intern Med 1994; 121:654-657.
10. Anon: The Medical Letter of Drugs and Therapeutics. Drugs for parasitic infections. April 2002, April 2002.
11. Madico G, Gilman RH, Miranda E, et al: Treatment of cyclospora infections with co-trimoxazole. Lancet 1993; 342:122-123.
12. Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines, 2010. Centers for Disease Control
and Prevention. Atlanta, GA. 2010. Available from URL: . As accessed 2010-12-16.
13. Centers for Disease Control and Prevention, National Institutes of Health, HIV Medicine Association of the Infectious Diseases
Society of America, et al: Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents:
Recommendations from the CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society
of America. MMWR Recomm Rep 2009; 58 (RR4):1-207.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...PubMed Article:
http://www.ncbi.nlm.nih.gov/...
14. Centers for Disease Control and Prevention, National Institutes of Health, HIV Medicine Association of the Infectious Diseases
Society of America, et al: Guidelines for the prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected
children. Recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases
Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. MMWR Recomm Rep 2009;
58(RR11):1-166.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...PubMed Article: http://www.ncbi.nlm.nih.gov/...
15. Sattler FR, Cowan R, Nielsen DM, et al: Trimethoprim-sulfamethoxazole compared with pentamidine for treatment of
Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Ann Intern Med 1988; 109:280-287.
16. Hughes WT, Feldman S, & Sanyal SK: Treatment of pneumocystis carinii pneumonitis with trimethoprim-sulfamethoxazole. Can
Med Assoc J 1975; 112:47-50.
17. Product Information: sulfamethoxazole, trimethoprim IV injection, sulfamethoxazole, trimethoprim IV injection. Sicor
Pharmaceuticals,Inc, Irvine, CA, 2003.
18. Ramsey BW: Management of pulmonary disease in patients with cystic fibrosis. N Engl J Med 1996; 335:179-188.
19. Anon: The choice of antibacterial drugs. Med Lett Drugs Ther 1996; 38:25-34.
20. Williams JW Jr, Holleman DR Jr, Samsa GP, et al: Randomized controlled trial of 3 vs 10 days of trimethoprim/sulfamethoxazole
for acute maxillary sinusitis. JAMA 1995; 273:1015-1021.
21. Snow V, Mottur-Pilson C, & Hickner JM: Principles of appropriate antibiotic use for acute sinusitis in adults. Ann Intern Med 2001;
134:495-497.
22. Hickner JM, Bartlett JG, Besser RE, et al: Principles of appropriate antibiotic use for acute rhinosinusitis in adults: background. Ann
Intern Med 2001; 134:489-505.
23. Piccirillo JF, Mager DE, Frisse ME, et al: Impact of first-line vs second-line antibiotics for the treatment of acute uncomplicated
sinusitis. JAMA 2001; 286(15):1849-1856.
24. Ward TT, Thomas RG, Fye CL, et al: Trimethoprim-Sulfamethoxazole prophylaxis in granulocytopenic patients with acute
leukemia: evaluation of serum antibiotic levels in a randomized, double-blind, placebo-controlled Department of Veterans Affairs
Cooperative Study. Clin Infect Dis 1993; 17(3):323-332.
25. Ribera E, Fernandex-Sola A, Juste C, et al: Comparison of high and low doses of trimethoprim-sulfamethoxazole for primary
prevention of toxoplasmic encephalitis in human immunodeficiency virus-infected patients. Clin Infect Dis 1999; 29:1461-1466.
26. Carr A, Tindall B, Brew BJ, et al: Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with
AIDS. Ann Intern Med 1992; 117:106-111.
27. DuPont HL, Reves RR, Galindo ET, et al: Treatment of travelers' diarrhea with trimethoprim/sulfamethoxazole and with
trimethoprim alone. N Engl J Med 1982; 307:841-844.
28. Ericsson CD, DuPont HL, Mathewson JJ, et al: Treatment of traveler's diarrhea with sulfamethoxazole and trimethoprim and
loperamide. JAMA 1990; 263:257-261.
29. Ericsson CD, Nicholls-Vasquez I, DuPont HL, et al: Optimal dosing of trimethoprim-sulfamethoxazole when used with loperamide
to treat traveler's diarrhea. Antimicrob Agents Chemother 1992; 36:2821-2824.
30. Gupta K, Hooton TM, Naber KG, et al: International clinical practice guidelines for the treatment of acute uncomplicated cystitis and
pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and
Infectious Diseases. Clin Infect Dis 2011; 52(5):e103-e120.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...PubMed Article:
http://www.ncbi.nlm.nih.gov/...
31. Jojart G: Comparison of 3-day versus 14-day treatment of lower urinary tract infection in children. Int Urol Nephrol 1991; 23:129134.
32. Trienekens T: Cotrimoxazole in acute uncomplicated urinary tract infections in women. Biomed Pharmacother 1990; 44:439.
33. Trienekens TAM, Stobberingh EE, Winkens RAG, et al: Different lengths of treatment with co-trimoxazole for acute uncomplicated
urinary tract infections in women. Br Med J 1989; 299:1319-1322.
34. Tzias V, Dontas AS, Petrikkos G, et al: Three-day antibiotic therapy in bacteriuria of old age. J Antimicrob Chemother 1990; 26:705711.
35. Fowle ASE, Bye A, Hariri F, et al: The dosage of co-trimoxazole in childhood. Eur J Clin Pharmacol 1975; 8:217.
36. Subcommittee on Management of Acute Otitis Media: Diagnosis and management of acute otitis media. Pediatrics 2004; 113:1451-
1465.
37. Leiberman A, Leibovitz E, Piglansky L, et al: Bacteriologic and clinical efficacy of trimethoprim-sulfamethoxazole for treatment of
acute otitis media. Pediatr Infect Dis J 2001; 20(3):260-264.
38. Ramam M, Garg T, D'Souza P, et al: A two-step schedule for the treatment of actinomycotic mycetomas. Acta Derm Venereol 2000;
80:378-380.
39. Anon: The choice of antibacterial drugs. Med Lett Drug Ther 1996; 38:25-33.
40. CDC: Centers for Disease Control and Prevention. Cholera diagnosis and treatment-1991 CDC recommendations. MMWR 1991;
40:562-565.
41. Gradon JD & Zimbalist EH: Is trimethoprim-Sulfamethoxazole helpful in Crohn's disease (letter)?. J Clin Gastroenterol 1990;
12:598-607.
42. Noble RC, Cooper RM, Jarvis AL, et al: Trimethoprim-sulfamethoxazole therapy for infective endocarditis. South Med J 1981;
74:1299-1303.
43. Gutierrez Rodero F, del Mar Masia M, Cortes J, et al: Endocarditis caused by Stenotrophomonas maltophilia: case report and
review. Clin Infect Dis 1996; 23:1261-1265.
44. Tamer MA & Bray JD: Trimethoprim-sulfamethoxazole treatment of multiantibiotic-resistant staphylococcal endocarditis and
meningitis. Clin Pediatr 1982; 21:125-126.
45. Gualtieri RJ, Donowitz GR, Kaiser DL, et al: Double-blind randomized study of prophylactic trimethoprim/sulfamethoxazole in
granulocytopenic patients with hematologic malignancies. Am J Med 1983; 74:934-940.
46. Kramer BS, Carr DJ, Rand KH, et al: Prophylaxis of fever and infection in adult cancer patients: a placebo-controlled trial of oral
trimethoprim-sulfamethoxazole plus erythromycin. Cancer 1984; 53:329-335.
47. Weiser B, Lange M, Fialk MA, et al: Prophylactic trimethoprim-sulfamethoxazole during consolidation chemotherapy for acute
leukemia: a controlled trial. Ann Intern Med 1981; 95:436-438.
48. Wilson JM & Guiney DG: Failure of oral trimethoprim-sulfamethoxazole prophylaxis in acute leukemia. N Engl J Med 1982;
306:16-20.
49. de Jongh CA, Wade JC, Finley RS, et al: Trimethoprim/sulfamethoxazole versus placebo: a double-blind comparison of infection
prophylaxis in patients with small cell carcinoma of the lung. J Clin Oncol 1983; 1:302-307.
50. Lee LH, Zaidman GW, & Van Horn K: Topical Bactrim versus trimethoprim and sulfonamide against Nocardia keratitis. Cornea
2001; 20(2):179-182.
51. Perry HD, Nauheim JS, Donnenfeld ED, et al: Nocardia asteroides keratitis presenting as a persistent epithelial defect. Cornea
1989; 8:41-44.
52. Donnenfeld ED, Cohen EJ, Barza M, et al: Treatment of nocardia keratitis with topical trimethoprim-sulfamethoxazole. Am J
Ophthalmol 1985; 99(5):601-602.
53. Tunkel AR, Hartman BJ, Kaplan SL, et al: Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004;
39(9):1267-1284.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...PubMed Article: http://www.ncbi.nlm.nih.gov/...
54. Levitz RE & Quintiliani R: Trimethoprim-sulfamethoxazole for bacterial meningitis. Ann Intern Med 1984; 100:881-890.
55. Hickstein DD & Dillon JT: Klebsiella pneumoniae meningitis intravenous trimethoprim-sulfamethoxazole treatment. JAMA 1982;
248:1212-1213.
56. Scheer MS & Hirschman SZ: Oral and ambulatory therapy of listeria bacteremia and meningitis with trimethoprimsulfamethoxazole. Mt Sinai J Med 1982; 49:411-414.
57. Kimura A, Mochizuki T, Nishizawa K, et al: Trimethoprim-sulfamethoxazole for the prevention of methicillin-resistant
Staphylococcus aureus pneumonia in severely burned patients. J Trauma, Inj, Infect Crit Care 1998; 45(2):383-387.
58. Anglaret X, Chene G, Attia A, et al: Early chemoprophylaxis with trimethoprim-sulphamethoxazole for HIV-1-infected adults in
Abidjan, Cote d'Ivoire: a randomised trial. Lancet 1999; 353(9163):1463-1468.
59. Wiktor SZ, Sassan-Morokro M, Grant AD, et al: Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and
mortality in HIV-1-infected patients with tuberculosis in Abidjan, Cote d'Ivoire: arandomised controlled trial. Lancet 1999;
353(9163):1469-1475.
60. Nunn AJ, Mwaba P, Chintu C, et al: Role of co-trimoxazole prophylaxis in reducing mortality in HIV infected adults being treated for
tuberculosis: randomised clinical trial. BMJ 2008; 337:a257-.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...PubMed Article:
http://www.ncbi.nlm.nih.gov/...
61. Hamel MJ, Greene C, Chiller T, et al: Does cotrimoxazole prophylaxis for the prevention of HIV-associated opportunistic infections
select for resistant pathogens in Kenyan adults?. Am J Trop Med Hyg 2008; 79(3):320-330.PubMed Abstract:
http://www.ncbi.nlm.nih.gov/...PubMed Article: http://www.ncbi.nlm.nih.gov/...
62. Singh N, Gayowski T, Yu VL, et al: Trimethoprim-Sulfamethoxazole for the prevention of spontaneous bacterial peritonitis in
cirrhosis: a randomized trial. Ann Intern Med 1995; 122:595-598.
63. Glasson P & Favre H: Treatment of peritonitis in continuous ambulatory dialysis patients with co-trimoxazole. Nephron 1984; 36:6567.
64. Mussini C, Pezzotti P, Antinori A, et al: Discontinuation of secondary prophylaxis for Pneumocystis carinii pneumonia in human
immunodeficiency virus-infected patients: a randomized trial by the CIOP Study Group. Clin Infect Dis 2003; 36:645-651.
65. Opportunistic Infections Project Team of the Collaboration of Observational HIV Epidemiological Research: Is it safe to discontinue
primary Pneumocystis jiroveci pneumonia prophylaxis in patients with virologically suppressed HIV infection and a CD4 cell count <200
cells/microL?. Clin Infect Dis 2010; 51(5):611-619.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...PubMed Article:
http://www.ncbi.nlm.nih.gov/...
66. Buskin SE, Newcomer LM, Koutsky LA, et al: Effect of trimethoprim-sulfamethoxazole as Pneumocystis carinii pneumonia
prophylaxis on bacterial illness, Pneumocystis carinii pneumonia, and death in persons with AIDS. J Acquir Immune Defic Syndr Hum
Retrovirol 1999; 20(2):201-206.
67. Fischl MA, Dickinson GM, & La Voie L: Safety and efficacy of sulfamethoxazole and trimethoprim chemoprophylaxis of
Pneumocystis carinii pneumonia in AIDS. JAMA 1988; 259:1185-1189.
68. Hughes WT, Rivera GK, Schell MJ, et al: Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J
Med 1987; 316:1627-1632.
69. Ohata Y, Ohta H, Hashii Y, et al: Intermittent oral trimethoprim/sulfamethoxazole on two non-consecutive days per week is
effective as Pneumocystis jiroveci pneumonia prophylaxis in pediatric patients receiving chemotherapy or hematopoietic stem cell
transplantation. Pediatr Blood Cancer 2008; Epub:--.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...PubMed Article:
http://www.ncbi.nlm.nih.gov/...
70. Drach GW: Trimethoprim/sulfamethoxazole therapy of chronic bacterial prostatitis. J Urol 1974; 111:637-639.
71. Kressner MS, Williams SE, Biempica L, et al: Salmonellosis complicating ulcerative colitis: treatment with trimethoprimsulfamethoxazole. JAMA 1982; 248:584-585.
72. Murphy TF & Fernald GW: Trimethoprim-sulfamethoxazole therapy for relapses of salmonella meningitis. Pediatr Infect Dis 1983;
2:465-468.
73. Torre D, Casari S, Speranza F, et al: Randomized trial of trimethoprim-sulfamethoxazole versus pyrimethamine-sulfadiazine for
therapy of toxoplasmic encephalitis in patients with AIDS. Antimicrob Agents Chemother 1998; 42(6):1346-1349.
74. Fendler KJ: Urinary tract infections, in Young LY & Koda-Kimble MA (eds): Applied Therapeutics The Clinical Use of Drugs (), 4th.
Applied Therapeutics, Inc, Vancouver, WA, 1988.
75. Tolkoff-Rubin NE, Cosimi AB, Russell PS, et al: A controlled study of trimethoprim-sulfamethoxazole prophylaxis of urinary tract
infection in renal transplant recipients. Rev Infect Dis 1982; 4:614-618.
76. Stapleton A, Latham RH, Johnson C, et al: Postcoital antimicrobial prophylaxis for recurrent urinary tract infection. JAMA 1990;
264:703-706.
77. Craig JC, Simpson JM, Williams GJ, et al: Antibiotic prophylaxis and recurrent urinary tract infection in children. N Engl J Med 2009;
361(18):1748-1759.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...PubMed Article: http://www.ncbi.nlm.nih.gov/...
78. Montini G, Rigon L, Zucchetta P, et al: Prophylaxis after first febrile urinary tract infection in children? A multicenter, randomized,
controlled, noninferiority trial. Pediatrics 2008; 122(5):1064-1071.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...PubMed Article:
http://www.ncbi.nlm.nih.gov/...
79. Stamm WE: Prevention of urinary tract infections. Am J Med 1984; 76:148-151.
80. Bell GP & Frentz GD: Urinary tract infections in the elderly. Geriatrics 1983; 38:42-47.
81. Walsh PC & Andriole VT: Cecil Textbook of Medicine, 17th. WB Saunders, Philadelphia, PA, 1985.
82. Harding GKM, Buckwold FJ, Marrie TJ, et al: Prophylaxis of recurrent urinary tract infection in female patients. JAMA 1979;
242:1975-1977.
83. Nicolle LE, Harding GKM, Thomson M, et al: Efficacy of five years of continuous, low-dose trimethoprim-sulfamethoxazole
prophylaxis for urinary tract infection. J Infect Dis 1988; 157:1239-1242.
84. West BC, Todd JR, & King JW: Wegener granulomatosis and trimethoprim-sulfamethoxazole. Complete remission after a twentyyear course. Ann Intern Med 1987; 106:840-842.
85. Axelson JA, Clark RH, & Ancerewicz S: Wegener granulomatosis and trimethoprim-sulfamethoxazole. Ann Intern Med 1987;
107:600-601.
86. Spiera H, Lawson W, & Weinrauch H: Wegener's granulomatosis treated with sulfamethoxazole-trimethoprim: report of a case.
Arch Intern Med 1988; 148:2065-2066.
87. Fukuda K, Yuasa K, Uchizono A, et al: Three cases of Wegener's granulomatosis treated with an antimicrobial agent. Arch
Otolaryngol Head Neck Surg 1989; 115:515-518.
88. Israel HL: Sulfamethoxazole-trimethoprim therapy for Wegener's Granulomatosis. Arch Intern Med 1988; 148:2293-2295.
89. Roberts DS & Curd JG: Sulfonamides as antiinflammatory agents in the treatment of wegener's granulomatosis. Arthritis Rheum
1990; 33:1590-1593.
90. Stegeman CA, Tervaert JWC, De Jong PE, et al: Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of
Wegener's granulomatosis. N Engl J Med 1996; 335:16-20.
91. Cooper GS, Blades EW, Remler BF, et al: Central nervous system whipple's disease: relapse during therapy with trimethoprimsulfamethoxazole and remission with cefixime. Gastroenterol 1994; 106:782-786.
92. Pai CH, Gillis F, Tuomanen E, et al: Placebo-controlled double-blind evaluation of trimethoprim-sulfamethoxazole treatment of
Yersinia enterocolitica gastroenteritis. J Pediatr 1984; 104:308-311.
93. Absar N, Daneshvar H, & Beall G: Desensitization to trimethoprim-sulfamethoxazole in HIV-infected patients. J Allergy Clin
Immunol 1994; 93:1001-1005.
94. Kreuz W, Gungor T, Lotz CHR, et al: "Treating through" hypersensitivity to cotrimoxazole in children with HIV infection. Lancet
1990; 336:508-509.
95. Palusci VJ, Kaul A, Lawrence RM, et al: Rapid oral desensitization to trimethoprim-sulfamethoxazole in infants and children.
Pediatr Infect Dis J 1996; 15:456-460.
96. Mofenson LM, Oleske J, Serchuck L, et al: Treating opportunistic infections among HIV-exposed and infected children:
recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. MMWR Recomm Rep
2004; 53(RR-14):1-92.
97. CDC: USPHS/IDSA guidelines for preventing opportunistic infections among HIV-infected persons - 2002. MMWR 2002; 51(RR8):1-48.
98. Rivey MP, Taylor JW, & Mullenix TA: TMP/SMX in renally impaired patients with P. carinii pneumonia. DICP 1989; 23(9):687689.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...PubMed Article: http://www.ncbi.nlm.nih.gov/...
99. Paap CM & Nahata MC: Trimethoprim/sulfamethoxazole dosing during renal dysfunction. Ann Pharmacother 1995; 29:1300.
100. Paap CM & Nahata MC: Clinical use of trimethoprim/sulfamethoxazole during renal dysfunction. DICP 1989; 23:646-654.
101. Naber K, Vergin H, & Weigand W: Pharmacokinetics of cotrimoxazole and co-tetroxazine in geriatric patients. Infection 1981;
9(5):239-243.
102. Nissenson AR, Wilson C, & Holazo A: Pharmacokinetics of intravenous trimethoprim-sulfamethoxazole during hemodialysis. Am
J Nephrol 1987; 7:270-274.
103. Reed MD, Stern RC, Bertino JS, et al: Dosing implications of rapid elimination of trimethoprim-sulfamethoxazole in patients with
cystic fibrosis. J Pediatr 1984; 104:303-307.
104. Deans KW, Lang JR, & Smith DE: Stability of trimethoprim-sulfamethoxazole injection in five infusion fluids. Am J Hosp Pharm
1982; 39:1681-1684.
105. Product Information: BACTRIM(TM) double strength tablets, oral tablets, sulfamethoxazole and trimethoprim double strength
tablets, oral tablets. AR Scientific, Inc., Philadelphia, PA, 2010.
106. Mohan P: Thrombocytopenia and agranulocytosis following septrin. Practitioner 1969; 202:553.
107. McPherson VJ: Thrombocytopenia following administration of septrin. Med J Aust 1970; 2:754.
108. Anon: Co-trimoxazole and blood (editorial). Lancet 1973a; 2:950.
109. Hammett JF: Thrombocytopenia following administration of bactrim. Med J Aust 1970; 2:200.
110. Rickard KA & Uhr E: Acute thrombocytopenic purpura associated with "septrin". Med J Aust 1971; 1(14):769-770.
111. Herrington A, Mahmood A, & Berger R: Treatment options in sulfamethoxazole-trimethoprim-induced thrombocytopenic purpura.
South Med J 1994; 87:948-950.
112. Owusu SK: Acute hemolysis complicating co-trimoxazole therapy for typhoid fever in a patient with G6PD deficiency. Lancet 1972;
2:81.
113. Chan TK & McFadzean AJS: Hemolytic effect of trimethoprim-sulphamethoxazole in G-6-PD deficiency. Trans R Trop Med Hyg
1974; 68:61-62.
114. Taraszewski R, Harvey R, & Rosman P: Death from drug-induced hemolytic anemia. Postgrad Med 1989; 85:79-80.
115. Chan TK, Todd D, & Tso SC: Drug-induced hemolysis in glucose-6-phosphate dehydrogenase deficiency. Br Med J 1976; 2:12271229.
116. Chan MCK & Wong HB: Glucose 6 phosphate dehydrogenase deficiency and co-trimoxazole. Lancet 1975; 1:410.
117. Markowitz N & Saravolatz LD: Use of trimethoprim-sulfamethoxazole in a glucose-6-phosphate dehydrogenase-deficient
population. Rev Infect Dis 1987; 9(suppl 2):S218-S225.
118. Bozzette SA, Finkelstein DM, Spector SA, et al: A randomized trial of three antipneumocystis agents in patients with advanced
human immunodeficiency virus infection. N Engl J Med 1995; 332:693-699.
119. Tapp H & Savarirayan R: Megaloblastic anaemia and pancytopenia secondary to prophylactic cotrimoxazole therapy. J Paediatr
Child Health 1997; 33:166-167.
120. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
121. Wahlin A & Rosman N: Skin manifestations with vasculitis due to co-trimoxazole. Lancet 1976; 2:1415.
122. Verne-Pignatelli J, Spickett GP, Dalgleish AG, et al: Thrombophlebitis migrans following co-trimoxazole therapy. Postgrad Med J
1989; 65:51-52.
123. Liu LX, Seward SJ, & Crumpacker CS: Intravenous trimethoprim-sulfamethoxazole and ataxia (letter). Ann Intern Med 1986;
104:448.
124. Andrade A & Walter C: A rare occurrence of trimethoprim/sulfamethoxazole (TMP/SMX)-induced aseptic meningitis in an older
woman (letter). J Am Geriatr Soc 2000; 48(11):1537-1538.
125. Jurado R, Carpenter SL, & Rimland D: Case reports: trimethoprim-sulfamethoxazole-induced meningitis in patients with HIV
infection. Am J Med Sci 1996; 312:27-29.
126. Blumenfeld H, Cha JH, & Cudkowicz ME: Trimethoprim and sulfonamide-associated meningoencephalitis with MRI correlates.
Neurology 1996; 46:556-558.
127. Wong JG, Hathaway SC, Paat JJ, et al: Drug-induced meningitis: a case involving trimethoprim-sulfamethoxazole. Postgrad Med
1994; 96:117-124.
128. Tunkel AR & Starr K: Trimethoprim-sulfamethoxazole-associated aseptic meningitis (letter). Am J Med 1990; 88:696.
129. Birndorf LB & Kaufman DI: Aseptic meningitis with retinal ischemia due to trimethoprim-sulfamethoxazole. Neuroophthalmology
1991; 11:215-222.
130. Davis BJ, Thompson J, Peimann A, et al: Drug-induced aseptic meningitis caused by two medications. Neurol 1994; 44:984-985.
131. Joffe MA, Farley JD, Linden D, et al: Trimethoprim-sulfamethoxazole-associated aseptic meningitis: case reports and review of
the literature. Am J Med 1989; 87:332-338.
132. Kremer I, Ritz R, & Brunner F: Aseptic meningitis as an adverse effect of co-trimoxazole (letter). N Engl J Med 1983; 308:1481.
133. Hass EJ: Trimethoprim-sulfamethoxazole: another cause of recurrent meningitis. JAMA 1984; 252:343.
134. Woody RC & Brewster MA: Adverse effects of trimethoprim-sulfamethoxazole in a child with dihydropteridine reductase
deficiency. Dev Med Child Neurol 1990; 32:633-644.
135. Slavik RS, Rybak MJ, & Lerner SA: Trimethoprim/sulfamethoxazole-induced tremor in a patient with AIDS. Ann Pharmacother
1998; 32:189-192.
136. Van Gerpen JA: Tremor caused by trimethoprim-sulfamethoxazole in a patient with AIDS. Neurology 1997; 48:537-538.
137. Borucki MJ, Matzke DS, & Pollard RB: Tremor induced by trimethoprim-sulfamethoxazole in patients with the acquired
immunodeficiency syndrome (AIDS). Ann Intern Med 1988; 109:77-78.
138. Aboulafia DM: Tremors associated with trimethoprim-sulfamethoxazole therapy in a patient with AIDS: case report and review.
Clin Infect Dis 1996; 22:598-600.
139. Patterson RG & Couchenour RL: Trimethoprim-sulfamethoxazole-induced tremor in an immunocompetent patient.
Pharmacotherapy 1999; 19(12):1456-1458.
140. Johnson JA, Kappel JE, & Sharif MN: Hypoglycemia secondary to trimethoprim-sulfamethoxazole administration in a renal
transplant patient. Ann Pharmacother 1993; 27:304-306.
141. Kaufman AM, Hellman G, & Abramson RG: Renal salt wasting and metabolic acidosis with trimethoprim-sulfamethoxazole
therapy. Mt Sinai J Med 1983; 50:238-239.
142. Ahn YH & Goldman JM: Trimethoprim-sulfamethoxazole and hyponatremia (letter). Ann Intern Med 1985; 103:161-162.
143. Modest GA, Price B, & Mascoli N: Hyperkalemia in elderly patients receiving standard doses of trimethoprim-sulfamethoxazole.
Ann Intern Med 1994; 120:437-438.
144. Pennypacker LC, Mintzer J, & Pitner J: Hyperkalemia in elderly patients receiving standard doses of trimethoprimsulfamethoxazole (letter). Ann Intern Med 1994; 120:437.
145. Canaday DH & Johnson JR: Hyperkalemia in elderly patients receiving standard doses of trimethoprim-sulfamethoxazole (letter).
Ann Intern Med 1994; 120:437-438.
146. Funai N, Shimamoto Y, Matsuzaki M, et al: Hyperkalaemia with renal tubular dysfunction by sulfamethoxazole-trimethoprim for
pneumocystis carinii pneumonia in patients with lymphoid malignancy. Haematologia 1993; 25:137-141.
147. Hsu I & Wordell CJ: Hyperkalemia and high-dose trimethoprim/sulfamethoxazole. Ann Pharmacother 1995; 29:427-429.
148. Don BR: The effect of trimethoprim on potassium and uric acid metabolism in normal human subjects. Clin Nephrol 2001;
55(1):45-52.
149. Greenberg S, Reiser IW, Chou SY, et al: Trimethoprim-sulfamethoxazole induces reversible hyperkalemia. Ann Intern Med 1993;
119:291-295.
150. Alappan R, Perazella MA, & Buller GK: Hyperkalemia in hospitalized patients treated with trimethoprim-sulfamethoxazole. Ann
Intern Med 1996; 124:316-320.
151. Product Information: Septra(R), trimethoprim and sulfamethoxazole. Burroughs Wellcome, Research Triangle Park, NC, 1998.
152. Lee AJ & Maddix DS: Trimethoprim/sulfamethoxazole-induced hypoglycemia in a patient with acute renal failure. Ann
Pharmacother 1997; 31:727-732.
153. Frankel MC, Leslie BR, Sax FL, et al: Trimethoprim-sulfamethoxazole-related hypoglycemia in patients with renal failure. N Y
State J Med 1984; 84:30-31.
154. Porras MC, Lecumberri JN, & Castrillon JLP: Case reports: trimethoprim/sulfamethoxazole and metabolic acidosis in HIVinfected patients. Ann Pharmacother 1998; 32:185-189.
155. Gordin F, Gilbert C, & Schmidt ME: Clostridium difficile colitis associated with trimethoprim-sulfamethoxazole given as
prophylaxis for pneumocystis carinii pneumonia. Am J Med 1994; 96:94-95.
156. Cameron A & Thomas M: Pseudomembranous colitis and co-trimoxazole. Br Med J 1977; 1:1321.
157. Bjarnason I & Bjornsson S: Oesophageal ulcers: an adverse reaction to co-trimoxazole. Acta Med Scand 1981; 209:431-432.
158. Bartels RH, van der Spek JA, & Oosten HR: Acute pancreatitis due to sulfamethoxazole-trimethoprim. South Med J 1992;
85:1006-1007.
159. Antonow DR: Acute pancreatitis associated with trimethoprim-sulfamethoxazole. Ann Intern Med 1986; 104:363-365.
160. Rosenfeld JB, Najenson T, & Grosswater Z: Effect of long-term co-trimoxazole therapy on renal function. Med J Aust 1975; 2:546.
161. Bennett WM & Craven R: Urinary tract infections in patients with severe renal disease: treatment with ampicillin and trimethoprimsulfamethoxazole. JAMA 1976; 236:946.
162. Kalowski S, Nanra NS, Mathew TH, et al: Deterioration in renal function in association with co-trimoxazole therapy. Lancet 1973;
1:394.
163. Kainer G & Rosenberg AR: Effect of co-trimoxazole on the glomerular filtration rate of healthy adults. Chemotherapy 1981; 27:229232.
164. Guignard JP, Tabin R, Vienny H, et al: Effect of trimethoprim-sulfamethoxazole on renal function. Curr Ther Res 1983; 34:801806.
165. Cryst C & Hammar SP: Acute granulomatous interstitial nephritis due to co-trimoxazole. Am J Nephrol 1988; 8:483-488.
166. Appel GB & Neu HC: The nephrotoxicity of antimicrobial agents (third of three parts). N Engl J Med 1977; 296:784-787.
167. Buchanan N: Sulfamethoxazole, hypoalbuminemia, crystalluria, and renal failure. Br Med J 1978; 2:172.
168. Roxe DM: Toxic nephropathy due to drugs. Ration Drug Ther 1975; 9:1-5.
169. Siegal WH: Unusual complication of therapy with sulfamethoxazole-trimethoprim. J Urol 1977; 117:397.
170. Berg PA & Daniel PT: Co-trimoxazole-induced hepatic injury - an analysis of cases with hypersensitivity-like reactions. Infection
1987; 15(suppl 5):S259-S264.
171. Tse W, Singer C, & Dominick D: Acute fulminant hepatic failure caused by trimethoprim-sulfamethoxazole. Infect Dis Clin Pract
2000; 9(7):302-303.
172. Bell TAL, Foster JN, & Townsend ML: Trimethoprim-sulfamethoxazole-induced hepatotoxicity in a pediatric patient.
Pharmacotherapy 2010; 30(5):539.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...PubMed Article: http://www.ncbi.nlm.nih.gov/...
173. Colucci CF & Cicero ML: Hepatic necrosis and trimethoprim-sulfamethoxazole. JAMA 1975; 233:952.
174. Ransohoff DF & Jacobs G: Terminal hepatic failure following a small dose of sulfamethoxazole-trimethoprim. Gastroenterology
1981; 80:816-819.
175. Stevenson DK, Christie DL, & Haas JE: Hepatic injury in a child caused by trimethoprim-sulfamethoxazole. Pediatrics 1978;
61:864-866.
176. Thies PW & Dull WL: Trimethoprim-sulfamethoxazole-induced cholestatic hepatitis. Arch Intern Med 1984; 144:1691-1692.
177. Nair SS, Kaplan JM, Levine LH, et al: Trimethoprim-sulfamethoxazole-induced intrahepatic cholestasis. Ann Intern Med 1980;
92:511-512.
178. Oliver RM, Rickenbach MA, Thomas MR, et al: Intrahepatic cholestasis associated with co-trimoxazole. Br J Clin Pract 1987;
41:975-976.
179. Cario E, Ruenzi M, Becker EW, et al: Trimethoprim-Sulfamethoxazol-induzierte cholestatische Hepatitis. Dtsch Med Wochenschr
1996; 121:129-132.
180. Cass RM: Adult respiratory distress syndrome and trimethoprim-sulfamethoxazole. Ann Intern Med 1987; 106:331.
181. Walker DC & Cohen PR: Trimethoprim-sulfamethoxazole-associated acute febrile neutrophilic dermatosis: case report and
review of drug-induced Sweet's syndrome. J Am Acad Dermatol 1996; 34:918-923.
182. Gutman LT: The use of trimethoprim-sulfamethoxazole in children: a review of adverse reactions and indications. Pediatr Infect
Dis 1984; 3:349-357.
183. Ponte CD, Arbogast JG, & Dattola RK: A suspected case of trimethoprim/sulfonamide-induced localized exfoliation. DICP 1990;
24:140-142.
184. Slaughenhoupt BL, Adeagbo S, & Van Savage JG: A suspected case of trimethoprim-sulfamethoxazole- induced loss of
fingernails and toenails. Pediatr Infect Dis J 1999; 18(1):76-77.
185. Senneville E, Lecocq P, Ajana F, et al: Co-trimoxazole for toxic epidermal necrolysis in AIDS (letter). Lancet 1991; 337:919.
186. Romeu J, Clotet B, Tural C, et al: Therapeutic challenge for Isospora belli enteritis in an AIDS patient who developed Lyell
syndrome after co-trimoxazole therapy (letter). Am J Gastroenterol 1989; 84:207-209.
187. Whittington RM: Toxic epidermal necrolysis and co-trimoxazole (letter). Lancet 1989; 2:574.
188. Bigby M, Jick S, Jick H, et al: Drug-induced cutaneous reactions: a report from the Boston Collaborative Drug Surveillance
Program on 15,438 consecutive inpatients, 1975 to 1982. JAMA 1986; 256:3358-3363.
189. Mitsuyasu R & Groopman J: Cutaneous reaction to trimethoprim-sulfamethoxazole in patients with AIDS and Kaposi's sarcoma.
N Engl J Med 1983; 308:1535.
190. Kiel PJ, Dickmeyer N, & Schwartz JE: Trimethoprim-sulfamethoxazole-induced rhabdomyolysis in an allogeneic stem cell
transplant patient. Transpl Infect Dis 2010; 12(5):451-454.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...PubMed Article:
http://www.ncbi.nlm.nih.gov/...
191. Jung AC & Paauw DS: Management of adverse reactions to trimethoprim-sulfamethoxazole in human immunodeficiency virusinfected patients. Arch Intern Med 1994; 154:2402-2406.
192. Cohn DL, Penley KA, Judson FN, et al: The acquired immunodeficiency syndrome and a trimthoprim-sulfamethoxazole adverse
reaction. Ann Intern Med 1984; 100:311.
193. van der Ven AJ, Vree TB, Koopmans PP, et al: Adverse reactions to co-trimoxazole in HIV infection: a reappraisal of the
glutathione-hydroxylamine hypothesis. J Antimicrob Chemother 1996; 37(suppl B):55-60.
194. Johnson MP, Goodwin SD, & Shands JW Jr: Trimethoprim-sulfamethoxazole anaphylactoid reactions in patients with AIDS: case
reports and literature review. Pharmacother 1990; 10:413-416.
195. van der Ven AJ, Koopmans PP, Vree TB, et al: Adverse reactions to co-trimoxazole in HIV infection. Lancet 1991; 338:431-433.
196. Carr A, Swanson C, Penny R, et al: Clinical and laboratory markers of hypersensitivity to trimethoprim-sulfamethoxazole in
patients with pneumocystis carinii and AIDS. J Infect Dis 1993; 167:180-185.
197. Kletzel M, Beck S, Elser J, et al: Trimethoprim-sulfamethoxazole oral desensitization in hemophiliacs infected with human
immunodeficiency virus with a history of hypersensitivity reactions. Am J Dis Child 1991; 145:1428-1429.
198. Cabanas R, Caballero MT, Vega A, et al: Anaphylaxis to trimethoprim (correspondence). J Allergy Clin Immunol 1996; 97:137-138.
199. Zealberg, JJ, & Lydiard RB: Exacerbation of panic disorder in a woman treated with trimethoprim-sulfamethoxazole (letter). J Clin
Psychopharmacol 1991; 11:144-145.
200. McCue JD & Zandt JR: Acute psychoses associated with the use of ciprofloxacin and trimethoprim-sulfamethoxazole. Am J Med
1991; 90:528-529.
201. Saxe TG: Severe depression from TMP-SMX. Drug Intell Clin Pharm 1988; 22:267.
202. Mermel LA, Doro JM, & Kabadi UM: Acute psychosis in a patient receiving trimethoprim-sulfamethoxazole intravenously. J Clin
Psych 1986; 47:269-270.
203. Gregor JC, Zilli CA, & Gotlib IH: Acute psychosis associated with oral trimethoprim-sulfamethoxazole therapy. Can J Psychiatry
1993; 38:56-58.
204. Boyce TG, Smidt RG, & Edmonson MB: Fever as an adverse reaction to oral trimethoprim-sulfamethoxazole therapy. Pediatr
Infect Dis J 1992; 11:772-773.
205. Platt R, Dreis MW, Kennedy DL, et al: Serum sickness-like reactions to amoxicillin, cefaclor, cephalexin, and trimethoprimsulfamethoxazole. J Infect Dis 1988; 158:474-477.
206. Product Information: Foscavir(R), foscarnet. AstraZeneca, Inc., Alexandria, VA, 1998.
207. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
208. Product Information: DynaCirc(R), isradipine. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2000.
209. Thompson JF, Chalmers DH, Hunnisett AG, et al: Nephrotoxicity of trimethoprim and cotrimoxazole in renal allograft recipients
treated with cyclosporine. Transplantation 1983; 36:204-206.
210. Maki DG, Fox BC, Kuntz J, et al: A prospective, randomized, double-blind study of trimethoprim-sulfamethoxazole for prophylaxis
of infection in renal transplantation. Side effects of trimethoprim-sulfamethoxazole, interaction with cyclosporine. J Lab Clin Med 1992;
119:11-24.
211. Wallwork J, McGregor CG, Wells FC, et al: Cyclosporin and intravenous sulphadimidine and trimethoprim therapy (letter). Lancet
1983; 1:366-367.
212. Thompson JF, Chalmers DH, Hunnisett AG, et al: Nephrotoxicity of trimethoprim and cotrimoxazole in renal allograft recipients
treated with cyclosporine. Transplantation 1983; 36:204-206.
213. Ringden O, Myrenfors P, Klintmalm G, et al: Nephrotoxicity by co-trimoxazole and cyclosporin in transplanted patients (letter).
Lancet 1984; 1:1016-1017.
214. Jones DK, Hakim M, Wallwork J, et al: Serious interaction between cyclosporin A and sulphadimidine. Br Med J (Clin Res Ed)
1986; 292:728-729.
215. Anton AH: Increasing activity of sulfonamides with displacing agents: a review. Ann N Y Acad Sci 1973; 226:273.
216. Hassall C, Feetam CL, Leach RH, et al: Potentiation of warfarin by co-trimoxazole (letter). Lancet 1975; 2:1155.
217. Tilstone WJ, Gray JM, Nimmo-Smith RH, et al: Interaction between warfarin and sulphamethoxazole. Postgrad Med J 1977;
53:388-390.
218. Kaufman JM & Fauver HE Jr: Potentiation of warfarin by trimethoprim-sulfamethoxazole. Urology 1980; 16:601-603.
219. Anton AH: Increasing activity of sulfonamides with displacing agents: a review. Ann N Y Acad Sci 1973; 226:273.
220. Hassall C, Feetam CL, Leach RH, et al: Potentiation of warfarin by co-trimoxazole (letter). Lancet 1975; 2:1155.
221. Tilstone WJ, Gray JM, Nimmo-Smith RH, et al: Interaction between warfarin and sulphamethoxazole. Postgrad Med J 1977;
53:388-390.
222. Kaufman JM & Fauver HE Jr: Potentiation of warfarin by trimethoprim-sulfamethoxazole. Urology 1980; 16:601-603.
223. Product Information: DiaBeta(R) oral tablets, glyburide oral tablets. Sanofi-Aventis, Bridgewater, NJ, 2009.
224. Product Information: Photofrin(R), porfimer sodium for injection. Lederle Parenterals Inc, Carolina, Puerto Rico, 1995.
225. Baciewicz A & Swafford W: Hypoglycemia induced by the interaction of chlorpropamide and co-trimoxazole. Drug Intell Clin Pharm
1984; 18:309-310.
226. Dall JL, Conway H, & McAlpine SG: Hypoglycaemia due to chlorpropamide. Scott Med J 1967; 12:403-404.
227. Tucker HS Jr & Hirsch JI: Sulfonamide-sulfonylurea interaction (letter). N Engl J Med 1972; 286:110-111.
228. Soeldner JS & Streinke J: Hypoglycemia in tolbutamide-treated diabetes. JAMA 1965; 193:398-399.
229. Product Information: Diabeta(R), glyburide. Hoechst-Roussel Pharmaceuticals, Inc., Somerville, NJ, 1994.
230. Christensen L, Hansen J, & Kristensen M: Sulphaphenazole-induced hypoglycaemic attacks in tolbutamide-treated diabetics.
Lancet 1963; 2:1298-1301.
231. Sjoberg S, Wiholm BE, Gunnarsson R, et al: Lack of pharmacokinetic interaction between glibenclamide and trimethoprimsulphamethoxazole. Diabet Med 1987; 4:245-247.
232. Moore KHP, Yuen GJ, Raasch RH, et al: Pharmacokinetics of lamivudine administered alone and with trimethoprimsulfamethoxazole. Clin Pharmacol Ther 1996; 59:550-558.
233. Katlama C: Effect of trimethoprim on lamivudine bioavailability (letter). JAMA 1996; 276:1140.
234. Product Information: Epivir HBV(R), lamivudine. GlaxoSmithKline, Research Triangle Park, NC, 2003.
235. Product Information: Trizivir(R), abacavir sulfate, lamivudine, and zidovudine. GlaxoSmithKline, Research Triangle Park, NC,
2002.
236. Moore KHP, Yuen GJ, Raasch RH, et al: Pharmacokinetics of lamivudine administered alone and with trimethoprimsulfamethoxazole. Clin Pharmacol Ther 1996; 59:550-558.
237. Baciewicz A & Swafford W: Hypoglycemia induced by the interaction of chlorpropamide and co-trimoxazole. Drug Intell Clin Pharm
1984; 18:309-310.
238. Dall JL, Conway H, & McAlpine SG: Hypoglycaemia due to chlorpropamide. Scott Med J 1967; 12:403-404.
239. Tucker HS Jr & Hirsch JI: Sulfonamide-sulfonylurea interaction (letter). N Engl J Med 1972; 286:110-111.
240. Soeldner JS & Streinke J: Hypoglycemia in tolbutamide-treated diabetes. JAMA 1965; 193:398-399.
241. Wing LMH & Miners JO: Cotrimoxazole as an inhibitor of oxidative drug metabolism: effects of trimethoprim and
sulphamethoxazole separately and combined on tolbutamide disposition. Br J Clin Pharmacol 1985; 20:482-485.
242. Wing LMH & Miners JO: Cotrimoxazole as an inhibitor of oxidative drug metabolism: effects of trimethoprim and
sulphamethoxazole separately and combined on tolbutamide disposition. Br J Clin Pharmacol 1985; 20:482-485.
243. Christensen L, Hansen J, & Kristensen M: Sulphaphenazole-induced hypoglycaemic attacks in tolbutamide-treated diabetics.
Lancet 1963; 2:1298-1301.
244. Soeldner JS & Streinke J: Hypoglycemia in tolbutamide-treated diabetes. JAMA 1965; 193:398-399.
245. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
246. Product Information: Lariam(R), mefloquine. Roche Laboratories, Nutley, NJ, 1999.
247. Chatton JY, Munafo A, Chave JP, et al: Trimethoprim, alone or in combination with sulphamethoxazole, decreases the renal
excretion of zidovudine and its glucuronide. Br J Clin Pharmacol 1992; 34:551-554.
248. Lee BL, Safrin S, Makrides V, et al: Zidovudine, trimethoprim and dapsone pharmacokinetic interactions in patients with human
immunodeficiency virus infection. Antimicrob Agents Chemother 1996; 40:1231-1236.
249. Chatton JY, Munafo A, Chave JP, et al: Trimethoprim, alone or in combination with sulphamethoxazole, decreases the renal
excretion of zidovudine and its glucuronide. Br J Clin Pharmacol 1992; 34:551-554.
250. Lee BL, Safrin S, Makrides V, et al: Zidovudine, trimethoprim and dapsone pharmacokinetic interactions in patients with human
immunodeficiency virus infection. Antimicrob Agents Chemother 1996; 40:1231-1236.
251. Khazan M & Mathis AS: Probable cause of torsades de pointes induced by fluconazole. Pharmacotherapy 2002; 22(12):16321637.
252. Wassmann S, Nickenig G, & Bohm M: Long QT syndrome and torsade de pointes in a patient receiving fluconazole. Ann Intern
Med 1999; 131(10):797.
253. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
254. Product Information: Prozac(R), fluoxetine. Eli Lilly and Company, Indianapolis, IN, 2001.
255. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
256. Product Information: Orlaam(R), levomethadyl acetate. Roxane Laboratories, Columbus, OH, 2001.
257. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
258. Product Information: Sandostatin(R), octreotide. Novartis Pharmaceuticals, East Hanover, NJ, 1999.
259. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
260. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
261. Young JB, Vandermolen LA, & Pratt CM: Torsade de pointes: an unusual mainfestation of chloral hydrate poisoning. Am Heart J
1986; 112:181-184.
262. Owens R: Risk assessment for antimicrobial agent-induced QTc prolongation and torsades de pointes. Pharmacother 2001;
21(3):310-319.
263. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
264. Owens R: Risk assessment for antimicrobial agent-induced QTc prolongation and torsades de pointes. Pharmacother 2001;
21(3):310-319.
265. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
266. Lindsay J Jr, Smith MA, & Light JA: Torsades de pointes associated with antimicrobial therapy for pneumonia. Chest 1990;
98:222-223.
267. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprim-
sulfamethoxazole. Am J Cardiol 1987; 59:376-377.
268. Baciewicz A & Swafford W: Hypoglycemia induced by the interaction of chlorpropamide and co-trimoxazole. Drug Intell Clin Pharm
1984; 18:309-310.
269. Dall JL, Conway H, & McAlpine SG: Hypoglycaemia due to chlorpropamide. Scott Med J 1967; 12:403-404.
270. Tucker HS Jr & Hirsch JI: Sulfonamide-sulfonylurea interaction (letter). N Engl J Med 1972; 286:110-111.
271. Soeldner JS & Streinke J: Hypoglycemia in tolbutamide-treated diabetes. JAMA 1965; 193:398-399.
272. Christensen L, Hansen J, & Kristensen M: Sulphaphenazole-induced hypoglycaemic attacks in tolbutamide-treated diabetics.
Lancet 1963; 2:1298-1301.
273. Gohn DC & Simmons TW: Polymorphic ventricular tachycardia (torsade de pointes) associated with the use of probucol (letter).
New Eng J Med 1992; 326:1435-1436.
274. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
275. Baciewicz A & Swafford W: Hypoglycemia induced by the interaction of chlorpropamide and co-trimoxazole. Drug Intell Clin Pharm
1984; 18:309-310.
276. Dall JL, Conway H, & McAlpine SG: Hypoglycaemia due to chlorpropamide. Scott Med J 1967; 12:403-404.
277. Tucker HS Jr & Hirsch JI: Sulfonamide-sulfonylurea interaction (letter). N Engl J Med 1972; 286:110-111.
278. Soeldner JS & Streinke J: Hypoglycemia in tolbutamide-treated diabetes. JAMA 1965; 193:398-399.
279. Product Information: Diabinese(R), chlorpropamide. Pfizer Inc, New York, NY, 1995.
280. Christensen L, Hansen J, & Kristensen M: Sulphaphenazole-induced hypoglycaemic attacks in tolbutamide-treated diabetics.
Lancet 1963; 2:1298-1301.
281. Product Information: Hismanal(R), astemizole. Janssen Pharmaceutica, Inc., Titusville, NJ, 1996.
282. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
283. Baciewicz A & Swafford W: Hypoglycemia induced by the interaction of chlorpropamide and co-trimoxazole. Drug Intell Clin Pharm
1984; 18:309-310.
284. Dall JL, Conway H, & McAlpine SG: Hypoglycaemia due to chlorpropamide. Scott Med J 1967; 12:403-404.
285. Tucker HS Jr & Hirsch JI: Sulfonamide-sulfonylurea interaction (letter). N Engl J Med 1972; 286:110-111.
286. Soeldner JS & Streinke J: Hypoglycemia in tolbutamide-treated diabetes. JAMA 1965; 193:398-399.
287. Christensen L, Hansen J, & Kristensen M: Sulphaphenazole-induced hypoglycaemic attacks in tolbutamide-treated diabetics.
Lancet 1963; 2:1298-1301.
288. Johnson JF & Dobmeier ME: Symptomatic hypoglycemia secondary to a glipizide-trimethoprim/sulfamethoxazole drug
interaction. DICP 1990; 24:250-251.
289. Kradjan WA, Witt DM, Opheim KE, et al: Lack of interaction between glipizide and co-trimoxazole. J Clin Pharmacol 1994; 34:9971002.
290. Product Information: Glucotrol XL(R), glipizide. Pfizer Inc, New York, NY, 1999.
291. Christensen L, Hansen J, & Kristensen M: Sulphaphenazole-induced hypoglycaemic attacks in tolbutamide-treated diabetics.
Lancet 1963; 2:1298-1301.
292. Product Information: Leucovorin calcium for injection. Immunex, US, 97.
293. Product Information: Halfan(R), halofantrine hydrochloride. Research Triangle Park, NC, 1998.
294. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
295. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
296. Jacoby AG & Wiegman MV: Cardiovascular complications of intravenous vasopressin therapy. Focus Crit Care 1990; 17:63-66.
297. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
298. Product Information: Anzemet(R), dolasetron. Hoechst Marion Roussel, Inc., Kansas City, MO, 1997.
299. Anon: Hoescht Marion Roussel, Inc, Dear Pharmacist letter. Food and Drug Administration. Rockville, MD. 1997. Available from
URL: . As accessed 09/22/1997.
300. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
301. Product Information: Serentil(R), mesoridazine. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2000.
302. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
303. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
304. Hanley SP & Hampton JR: Ventricular arrhythmias associated with lidoflazine: side effects observed in a randomized trial. Eur
Heart J 1983; 4:889-893.
305. Owens R: Risk assessment for antimicrobial agent-induced QTc prolongation and torsades de pointes. Pharmacother 2001;
21(3):310-319.
306. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
307. Product Information: FOLOTYN(TM) solution for IV injection, pralatrexate solution for IV injection. Allos Therapeutics, Inc.,
Westminister, CO, 2009.
308. Winter HR, Trapnell CB, Slattery JT, et al: The effect of clarithromycin, fluconazole, and rifabutin on sulfamethoxazole
hydroxylamine formation in individuals with human immunodeficiency virus infection (AACTG 283).. Clin Pharmacol Ther 2004; 76:313322.
309. Product Information: VIDEX(R) pediatric powder for oral solution, didanosine pediatric powder for oral solution. Bristol-Myers
Squibb Company, Princeton, NJ, 2009.
310. Owens R: Risk assessment for antimicrobial agent-induced QTc prolongation and torsades de pointes. Pharmacother 2001;
21(3):310-319.
311. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
312. Avery GS: Check-list to potential clinically important interactions. Drugs 1973; 5:187-211.
313. AnonAnon: Evaluation of Drug Interactions, 2nd. American Pharmaceutical Association, Washington, DC, 1976.
314. Cohen SN & Armstrong MFCohen SN & Armstrong MF: Drug Interactions, Williams & Wilkins, Baltimore, MD, 1974.
315. Sveen OB, Yaekel M, & Adair SM: Efficacy of using benzocaine for temporary relief of toothache. Oral Surg Oral Med Oral Pathol
1982; 53:574-576.
316. Product Information: Mellaril(R), thioridazine. Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, 2000.
317. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
318. Product Information: AMARYL(R) oral tablets, glimepiride oral tablets. Sanofi-Aventis U.S. LLC, Bridgewater, NJ, 2009.
319. Kosoglou T, Rocci ML Jr., & Vlasses PH: Trimethoprim alters the disposition of procainamide and N-acetylprocainamide. Clin
Pharmacol Ther 1988; 44:467-477.
320. Vlasses PH, Kosoglou T, Chase SL, et al: Trimethoprim inhibition of the renal clearance of procainamide and Nacetylprocainamide. Arch Intern Med 1989; 149:1350-1353.
321. Product Information: Quinaglute Dura-tabs(R), quinidine gluconate. Berlex Laboratories, Wayne, NJ, 1999.
322. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
323. Ansdell VE, Wright SG, & Hutchinson DB: Megaloblastic anaemia associated with combined pyrimethamine and co-trimoxazole
administration (letter). Lancet 1976; 2:1257.
324. Fleming AF, Warrell DA, & Dickmeiss H: Co-trimoxazole and the blood (letter). Lancet 1974; 2:284.
325. Waxman S & Herbert V: Mechanism of pyrimethamine-induced megaloblastosis in human bone marrow. N Engl J Med 1969;
280:1316-1319.
326. Product Information: Daraprim(R), pyrimethamine. GlaxoSmithKline, Research Triangle Park, NC, 2003.
327. Ansdell VE, Wright SG, & Hutchinson DB: Megaloblastic anaemia associated with combined pyrimethamine and co-trimoxazole
administration (letter). Lancet 1976; 2:1257.
328. Fleming AF, Warrell DA, & Dickmeiss H: Co-trimoxazole and the blood (letter). Lancet 1974; 2:284.
329. Borgstein A & Tozer RA: Infectious mononucleosis and megaloblastic anemia associated with Daraprim and Bactrim. Cent Afr J
Med 1974; 20:185-187.
330. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
331. Marshall JB & Forker AD: Cardiovascular effects of tricyclic antidepressant drugs: therapeutic usage, overdose, and management
of complications. Am Heart J 1982; 103:401-414.
332. Product Information: Elavil(R), amitriptyline. Merck & Co, Inc, West Point, PA, 1999.
333. Product Information: Tikosyn(TM), dofetilide capsules. Pfizer Inc, New York, NY, 1999.
334. Yamreudeewong W, DeBisschop M, Martin LG, et al: Potentially significant drug interactions of class III antiarrhythmic drugs. Drug
Safety 2003; 26(6):421-438.
335. Allen MJ, Nichols DJ, & Oliver SD: The pharmacokinetics and pharmacodynamics of oral dofetilide after twice daily and three
times daily dosing. Br J Clin Pharmacol 2000; 50:247-253.
336. Product Information: Tikosyn(TM), dofetilide. Pfizer Inc, New York, NY, 1999.
337. Product Information: Compazine(R), prochlorperazine maleate spansule. GlaxoSmithKline, Research Triangle Park, NC, 2002.
338. Product Information: Stelazine(R), trifluoperazine hydrochloride. GlaxoSmithKline, Research Triangle Park, NC, 2002.
339. Product Information: Thorazine(R), chlorpromazine. Smithkline Beecham Pharmaceuticals, Philadelphia, PA, 2002.
340. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
341. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
342. Product Information: Solian(R), amisulpride tablets. Lorex Synthelabo, Maidenhead, Berkshire, UK, 1999.
343. O'Brien JM, Rockwood RP, & Suh KI: Haloperidol-induced torsade de pointes. Ann Pharmacother 1999; 33:1046-1050.
344. Owens R: Risk assessment for antimicrobial agent-induced QTc prolongation and torsades de pointes. Pharmacother 2001;
21(3):310-319.
345. Duenas-Laita A, Castro-Villamor MA, Martin-Escudero JC, et al: New clinical manifestations of acute risperidone poisoning (letter).
Clin Toxicol 1999; 37(7):893-894.
346. Agelink MW, Zeit T, Baumann B, et al: In vivo cardiovascular effects of the new atypical neuroleptic sertindole. Int J Psychiatry Clin
Pract 2001; 5:33-40.
347. Lande G, Drouin E, Gauthier C, et al: Arrhythmogenic effects of sultopride chlorhydrate: clinical and cellular electrophysiological
correlation. Ann Fr Anesth Reanim 1992; 11:629-635.
348. Sweetman S (Ed): Martindale: The Complete Drug Reference. London: Pharmaceutical Press. Electronic version, MICROMEDEX,
Greenwood Village, Colorado, Edition expires 06/2003.
349. Product Information: Biaxin(R), clarithromycin. Abbott Laboratories, North Chicago, IL, 2002.
350. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
351. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
352. Yamreudeewong W, DeBisschop M, Martin LG, et al: Potentially significant drug interactions of class III antiarrhythmic drugs. Drug
Safety 2003; 26(6):421-438.
353. Product Information: Propulsid(R), cisapride. Janssen Pharmaceutica Inc., Toronto, Ontario, 2000.
354. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
355. Stramba-Badiale M, Nador F, Porta N, et al: QT interval prolongation and risk of life-threatening arrhythmias during toxoplasmosis
prophylaxis with spiramycin in neonates. Am Heart J 1997; 133:108-111.
356. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
357. Product Information: Aralen(R), chloroquine phosphate (oral), chloroquine hydrochloride (intravenous). Sanofi Pharmaceuticals,
New York, NY, 1999.
358. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
359. Oberg KC & Bauman JL: QT interval prolongation and torsades de pointes due to erythromycin lactobionate. Pharmacotherapy
1995; 15(6):687-692.
360. Oberg KC & Bauman JL: QT interval prolongation and torsades de pointes due to erythromycin lactobionate. Pharmacotherapy
1995; 15(6):687-692.
361. Product Information: PCE(R), erythromycin particles in tablets. Abbot Laboratories, North Chicago, IL, 1997.
362. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
363. Product Information: Vascor(R), bepridil. Ortho-McNeil Pharmaceuticals, Raritan, NJ, 2000.
364. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
365. Product Information: Inapsine(R), droperidol. Akorn, Inc., Decatur, IL, 2002.
366. O'Reilly RA & Motley CH: Racemic warfarin and trimethoprim-sulfamethoxazole in interction in humans. Ann Intern Med 1979;
91:34.
367. O'Reilly RA: Stereoselective interaction of trimethoprim-sulfamethoxazole with the separated enantiomorphs of racemic warfarin
in man. N Engl J Med 1980; 302:33-35.
368. Sioris LJ, Weibert RT, & Pentel PR: Potentiation of warfarin anticoagulation by sulfisoxazole. Arch Intern Med 1980; 140:546-547.
369. Liddle BJ: Methotrexate interactions (letter). Clin Exp Dermatol 1991; 16:311-312.
370. Ferrazzini G, Klein J, Sulh H, et al: Interaction between trimethoprim-sulfamethoxazole and methotrexate in children with
leukemia. J Pediatr 1990; 117:823-826.
371. Steuer A & Gumpel JM: Methotrexate and trimethoprim: a fatal interaction (letter). Br J Rheumatol 1998; 37:105-106.
372. Ng HW, Macfarlane AW, Graham RM, et al: Near fatal drug interactions with methotrexate given for psoriasis. Br J Med 1987;
295:752-753.
373. Mungall D & White R: Pancytopenia from using trimethoprim and methotrexate. Ann Intern Med 1992; 117(10):877-878.
374. Chevrel G, Brantus J, Sainte-Laudy J, et al: Allergic pancytopenia to trimethoprim-sulphamethoxazole for Pneumocyctis carinii
pneumonia following methotrexate treatment for rheumatoid arthritis (Letter). Rheumatology (Oxford) 1999; 38(5):475-476.
375. Product Information: Methotrexate LPF(R), methotrexate. Xanodyne Pharmacal, Inc., Florence, KY, 2003.
376. Ferrazzini G, Klein J, Sulh H, et al: Interaction between trimethoprim-sulfamethoxazole and methotrexate in children with
leukemia. J Pediatr 1990; 117:823-826.
377. Groenendal H & Rampen FHJ: Methotrexate and trimethoprim-sulphamethoxazole-a potentially hazardous combination. Clin Exp
Dermatol 1990; 15:358-360.
378. Jeurissen ME, Boerbooms AM, & van de Putte LB: Pancytopenia and methotrexate with trimethoprim-sulfamethoxazole (letter).
Ann Intern Med 1989; 111:261.
379. Maricic M, Davis M, & Gall EP: Megaloblastic pancytopenia in a patient receiving concurrent methotrexate and trimethoprimsulfamethoxazole treatment. Arthritis Rheum 1986; 29:133-135.
380. Thomas DR, Dover JS, & Camp RDR: Pancytopenia induced by the interaction between methotrexate and trimethoprimsulfamethoxazole. J Am Acad Dermatol 1987; 17:1055-1056.
381. Thomas MH & Gutterman LA: Methotrexate toxicity in a patient receiving trimethoprim-sulfamethoxazole. J Rheumatol 1986;
13:440-441.
382. Product Information: Tambocor(R) flecainide acetate. 3M Pharmaceuticals, Northridge, CA, 1998.
383. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
384. Anton AH: Increasing activity of sulfonamides with displacing agents: a review. Ann N Y Acad Sci 1973; 226:273.
385. Hassall C, Feetam CL, Leach RH, et al: Potentiation of warfarin by co-trimoxazole (letter). Lancet 1975; 2:1155.
386. Tilstone WJ, Gray JM, Nimmo-Smith RH, et al: Interaction between warfarin and sulphamethoxazole. Postgrad Med J 1977;
53:388-390.
387. Kaufman JM & Fauver HE Jr: Potentiation of warfarin by trimethoprim-sulfamethoxazole. Urology 1980; 16:601-603.
388. Product Information: Orap(R) pimozide. TEVA Pharmaceuticals, Sellersville, PA, 1999.
389. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
390. Product Information: Orap(R), pimozide. TEVA Pharmaceuticals, Sellersville, PA, 1999.
391. Product Information: Vivotif Berna(R) Vaccine, typhoid vaccine live oral ty21a. Berna Products, Corp., Coral Gables, FL, 1997.
392. CDC: Typhoid immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1994;
43(RR14):1-7.
393. Ahmed A, Stephens JC, Kaus CA, et al: Impact of preemptive warfarin dose reduction on anticoagulation after initiation of
trimethoprim-sulfamethoxazole or levofloxacin. J Thromb Thrombolysis 2008; 26(1):44-48.PubMed Abstract:
http://www.ncbi.nlm.nih.gov/...PubMed Article: http://www.ncbi.nlm.nih.gov/...
394. Schelleman H, Bilker WB, Brensinger CM, et al: Warfarin with fluoroquinolones, sulfonamides, or azole antifungals: interactions
and the risk of hospitalization for gastrointestinal bleeding. Clin Pharmacol Ther 2008; 84(5):581-588.PubMed Abstract:
http://www.ncbi.nlm.nih.gov/...PubMed Article: http://www.ncbi.nlm.nih.gov/...
395. Hassall C, Feetam CL, Leach RH, et al: Potentiation of warfarin by co-trimoxazole (letter). Lancet 1975; 2:1155.
396. Greenlaw CW: Drug interaction between co-trimoxazole and warfarin (letter). Am J Hosp Pharm 1979; 36:1155-1156.
397. Fredriks DA: Comment: TMP/SMX-warfarin interaction (letter). DICP 1989; 23:619-620.
398. Richmond RG, Sawyer WT, Aiello PD, et al: Extreme warfarin intoxication secondary to possible covert drug ingestion. Drug Intell
Clin Pharm 1988; 22:696-699.
399. Kaufman JM & Fauver HE Jr: Potentiation of warfarin by trimethoprim-sulfamethoxazole. Urology 1980; 16:601-603.
400. O'Reilly RA: Stereoselective interaction of trimethoprim-sulfamethoxazole with the separated enantiomorphs of racemic warfarin
in man. N Engl J Med 1980; 302:33-35.
401. Greenlaw CW: Drug interaction between co-trimoxazole and warfarin (letter). Am J Hosp Pharm 1979; 36:1155-1156.
402. Errick JK & Keyes PW: Co-trimoxazole and warfarin: a case report of an interaction. Am J Hosp Pharm 1978; 35:1399-1401.
403. Tilstone WJ, Gray JM, Nimmo-Smith RH, et al: Interaction between warfarin and sulphamethoxazole. Postgrad Med J 1977;
53:388-390.
404. Fredriks DA: Comment: TMP/SMX-warfarin interaction (letter). DICP 1989; 23:619-620.
405. Richmond RG, Sawyer WT, Aiello PD, et al: Extreme warfarin intoxication secondary to possible covert drug ingestion. Drug Intell
Clin Pharm 1988; 22:696-699.
406. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
407. Product Information: Trisenox(R), arsenic trioxide. Cell Therapeutics, Inc., Seattle, WA, 2001.
408. Petersen P, Kastrup J, Bartram R, et al: Digoxin-trimethoprim interaction. Acta Med Scand 1985; 217:423-427.
409. Petersen P, Kastrup J, Bartram R, et al: Digoxin-trimethoprim interaction. Acta Med Scand 1985; 217:423-427.
410. Product Information: PROMACTA(R) oral tablets, eltrombopag oral tablets. Glaxo Smith Kline, Research Triangle Park,, NC, 2008.
411. Niemi M, Backman JT, & Neuvonen PJ: Effects of trimethoprim and rifampin on the pharmacokinetics of the cytochrome P450 2C8
substrate rosiglitazone.. Clin Pharmacol Ther 2004; 76(3):239-249.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...PubMed Article:
http://www.ncbi.nlm.nih.gov/...
412. Product Information: Avandamet(TM), rosiglitazone maleate and metformin hydrochloride. GlaxoSmithKline, Research Triangle
Park, NC, 2003.
413. Product Information: Glucophage(R), metformin hydrochloride. Bristol-Myers Squibb Company, Princeton, NJ, 1999.
414. Product Information: Avandamet(TM), rosiglitazone maleate and metformin hydrochloride. GlaxoSmithKline, Research Triangle
Park, NC, 2003.
415. Product Information: Glucophage(R), metformin hydrochloride. Bristol-Myers Squibb Company, Princeton, NJ, 1999.
416. Product Information: PRANDIN(R) oral tablets, repaglinide oral tablets. Novo Nordisk Inc, Princeton, NJ, 2010.
417. Roustit M, Blondel E, Villier C, et al: Symptomatic hypoglycemia associated with trimethoprim/sulfamethoxazole and repaglinide
in a diabetic patient. Ann Pharmacother 2010; 44(4):764-767.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...PubMed Article:
http://www.ncbi.nlm.nih.gov/...
418. Gillman MA & Sandyk R: Phenytoin toxicity and co-trimoxazole (letter). Ann Intern Med 1985; 102:559.
419. Hansen JM, Kampmann JP, Siersbaek-Nielsen K, et al: The effect of different sulfonamides on phenytoin metabolism in man. Acta
Med Scand Suppl 1979; 624:106-110.
420. Product Information: Cerebyx(R), fosphenytoin sodium injection. Parke-Davis, Division of Warner-Lambert, Morris Plains, NJ,
1999.
421. Gillman MA & Sandyk R: Phenytoin toxicity and co-trimoxazole (letter). Ann Intern Med 1985; 102:559.
422. Hansen JM, Kampmann JP, Siersbaek-Nielsen K, et al: The effect of different sulfonamides on phenytoin metabolism in man. Acta
Med Scand Suppl 1979; 624:106-110.
423. Lee BL, Medina I, Benowitz NL, et al: Dapsone, trimethoprim, and sulfamethoxazole plasma levels during treatment of
pneumocystis pneumonia in patients with the acquired immunodeficiency syndrome (AIDS): evidence of drug interactions. Ann Intern
Med 1989; 110:606-611.
424. Lee BL, Safrin S, Makrides V, et al: Zidovudine, trimethoprim and dapsone pharmacokinetic interactions in patients with human
immunodeficiency virus infection. Antimicrob Agents Chemother 1996; 40:1231-1236.
425. Lee BL, Medina I, Benowitz NL, et al: Dapsone, trimethoprim, and sulfamethoxazole plasma levels during treatment of
pneumocystis pneumonia in patients with the acquired immunodeficiency syndrome (AIDS): evidence of drug interactions. Ann Intern
Med 1989; 110:606-611.
426. Lee BL, Safrin S, Makrides V, et al: Zidovudine, trimethoprim and dapsone pharmacokinetic interactions in patients with human
immunodeficiency virus infection. Antimicrob Agents Chemother 1996; 40:1231-1236.
427. Product Information: Zervalx(R) oral tablets, l-methylfolate oral tablets. Pamlab,LLC, Covington, LA, 2008.
428. Product Information: Factive(R), gemifloxacin. Genesoft Pharmaceuticals, Seoul, Korea, 2003.
429. Lopez JA, Harold JG, Rosenthal MC, et al: QT prolongation and torsades de pointes after administration of trimethoprimsulfamethoxazole. Am J Cardiol 1987; 59:376-377.
430. Gillman MA & Sandyk R: Phenytoin toxicity and co-trimoxazole (letter). Ann Intern Med 1985; 102:559.
431. Hansen JM, Kampmann JP, Siersbaek-Nielsen K, et al: The effect of different sulfonamides on phenytoin metabolism in man. Acta
Med Scand Suppl 1979; 624:106-110.
432. Ilario M, Ruiz J, & Axiotis C: Acute fulminant hepatic failure ina a woman treated wtih phenytoin and trimethoprimsulfamethoxazole. Arch Pathol Lab Med 2000; 124:1800-1803.
433. Gillman MA & Sandyk R: Phenytoin toxicity and co-trimoxazole (letter). Ann Intern Med 1985; 102:559.
434. Hansen JM, Kampmann JP, Siersbaek-Nielsen K, et al: The effect of different sulfonamides on phenytoin metabolism in man. Acta
Med Scand Suppl 1979; 624:106-110.
435. Ilario M, Ruiz J, & Axiotis C: Acute fulminant hepatic failure ina a woman treated wtih phenytoin and trimethoprimsulfamethoxazole. Arch Pathol Lab Med 2000; 124:1800-1803.
436. Speeg KV, Leighton JA, & Maldonado AL: Toxic delirium in a patient taking amantadine and trimethoprim-sulfamethoxazole. Am
J Med Sci 1989; 298:410-412.
437. Speeg KV, Leighton JA, & Maldonado AL: Toxic delirium in a patient taking amantadine and trimethoprim-sulfamethoxazole. Am
J Med Sci 1989; 298:410-412.
438. Thomas RJ: Severe hyperkalemia with trimethoprim-quinapril. Ann Pharmacother 1996; 30:413-414.
439. Bugge JF: Severe hyperkalaemia induced by trimethoprim in combination with an angiotensin-converting enzyme inhibitor in a
patient with transplanted lungs. J Intern Med 1996; 240:249-251.
440. Thomas RJ: Severe hyperkalemia with trimethoprim-quinapril. Ann Pharmacother 1996; 30:413-414.
441. Bugge JF: Severe hyperkalaemia induced by trimethoprim in combination with an angiotensin-converting enzyme inhibitor in a
patient with transplanted lungs. J Intern Med 1996; 240:249-251.
442. Thomas RJ: Severe hyperkalemia with trimethoprim-quinapril. Ann Pharmacother 1996; 30:413-414.
443. Thomas RJ: Severe hyperkalemia with trimethoprim-quinapril. Ann Pharmacother 1996; 30:413-414.
444. Bugge JF: Severe hyperkalaemia induced by trimethoprim in combination with an angiotensin-converting enzyme inhibitor in a
patient with transplanted lungs. J Intern Med 1996; 240:249-251.
445. Wing LMH & Miners JO: Cotrimoxazole as an inhibitor of oxidative drug metabolism: effects of trimethoprim and
sulphamethoxazole separately and combined on tolbutamide disposition. Br J Clin Pharmacol 1985; 20:482-485.
446. Wing LMH & Miners JO: Cotrimoxazole as an inhibitor of oxidative drug metabolism: effects of trimethoprim and
sulphamethoxazole separately and combined on tolbutamide disposition. Br J Clin Pharmacol 1985; 20:482-485.
447. Heelon MW & White M: Disulfiram-cotrimoxazole reaction. Pharmacotherapy 1998; 18:869-870.
448. Heelon MW & White M: Disulfiram-cotrimoxazole reaction. Pharmacotherapy 1998; 18:869-870.
449. Weidner N, Dietzler DN, & Ladenson JH: A clinically applicable high-pressure liquid chromatographic method for measurement of
serum theophylline, with detailed evaluation of interferences. Am J Clin Pathol 1980; 73:79-86.
450. Bowman DB, Aravind MK, Kauffman RE, et al: Sulfamethoxazole interferes with liquid-chromatographic analysis for theophylline
in serum. Clin Chem 1980; 26:1622.
451. Product Information: PRIMSOL(R) oral solution, trimethoprim hcl oral solution. FSC Laboratories,Inc, Charlotte, NC, 2005.
452. Product Information: PROLOPRIM(R) oral tablets, trimethoprim oral tablets. Monarch Pharmaceutical, Bristol, TN, 2003.
453. Product Information: SEPTRA(R) DS oral tablets, trimethoprim, sulfamethoxazole double-strength oral tablets. Monarch
Pharmaceuticals,Inc, Bristol, TN, 2005.
454. Product Information: Gantanol(R), sulfamethoxazole. Roche Laboratories, Nutley, NJ, 1998.
455. Batagol RBatagol R (Ed): Australian Drug Evaluation Committee: Medicines in Pregnancy-An Australian categorisation of risk of
drug use in pregnancy, 3rd. Australian Government Publishing Service, Canberra, Australia, 1996.
456. Product Information: Septra(R), trimethoprim and sulfamethoxazole suspension. King Pharmaceuticals, Inc., Bristol, TN, 2000.
457. Richardson M, Osrin D, Donaghy S, et al: Spinal malformations in the fetuses of HIV infected women receiving combination
antiretroviral therapy and co-trimoxazole. Eu J Obstet Gynecol Reprod Biol 2000; 93:215-217.
458. Hensleigh PA & Kauffman RE: Maternal absorption and placental transfer of sulfasalazine. Am J Obstet Gynecol 1977; 127:443444.
459. Heinonen OP, Slone D, & Shapiro SHeinonen OP, Slone D, & Shapiro S: Birth Defects and Drugs in Pregnancy, Publishing
Sciences Group, Inc., Littleton, MA, 1977.
460. Sivojelezova A, Einarson A, Shuhaiber S, et al: Trimethoprim-sulfonamide combination therapy in early pregnancy. Can Fam
Physician 2003; 19:1085-1086.
461. Anon: American academy of pediatrics committee on drugs: transfer of drugs and other chemicals into human milk. Pediatrics
2001; 108(3):776-789.
462. Anon: Breastfeeding and Maternal Medication. World Health Organization, Geneva, Switzerland, 2002.
463. Product Information: Gantanol(R), sulfamethoxazole. Roche Laboratories, Nutley, NJ, 1998.
464. Product Information: Septra(R), sulfamethoxazole/trimethoprim suspension. King Pharmaceuticals, Inc., Bristol, TN, 2000.
465. Product Information: Proloprim(R), trimethoprim tablets. Monarch Pharmaceuticals, Bristol, TN, 2002.
466. Batagol RBatagol R (Ed): Australian Drug Evaluation Committee: Medicines in Pregnancy-An Australian categorisation of risk of
drug use in pregnancy, 3rd. Australian Government Publishing Service, Canberra, Australia, 1996.
467. Richardson M, Osrin D, Donaghy S, et al: Spinal malformations in the fetuses of HIV infected women receiving combination
antiretroviral therapy and co-trimoxazole. Eu J Obstet Gynecol Reprod Biol 2000; 93:215-217.
468. Brumfitt W & Pursell R: Trimethoprim/sulfamethoxazole in the treatment of bacteriuria in women. J Infect Dis 1973;
128(suppl):S657.
469. Bailey RR: Single-dose antibacterial treatment for bacteriuria in pregnancy. Drugs 1984; 27:182-186.
470. Azad Khan AK & Truelove SC: Placental and mammary transfer of sulphasalazine. Br Med J 1979; 2:1553.
471. Hensleigh PA & Kauffman RE: Maternal absorption and placental transfer of sulfasalazine. Am J Obstet Gynecol 1977; 127:443444.
472. Pagliaro LA & Levin RHPagliaro LA & Levin RH: Problems in Pediatric Drug Therapy, Drug Intell Publications, Hamilton, IL, 1979.
473. Anon: Committee on Drugs & American Academy of Pediatrics: The transfer of drugs and other chemicals into human milk.
Pediatrics 1994; 93:137-150.
474. Trimpex (Roche).. PDR 1991, pp 1858-9., .
475. Product Information: Septra(R), trimethoprim and sulfamethoxazole. Burroughs Wellcome, Research Triangle Park, NC, 1998.
476. Nolte H & Buttner H: Investigations on plasma levels of sulfamethoxazole in man after single and chronic oral administration
alone and in combination with trimethoprim. Chemotherapy 1974; 20:321.
477. Nolte H & Buttner H: Pharmacokinetics of trimethoprim and its combination with sulfamethoxazole in man after single and chronic
oral administration. Chemotherapy 1973; 18:274.
478. Chow MSS & Ronfeld RA: Pharmacokinetic data and drug monitoring: I. Antibiotics and antiarrhythmias. J Clin Pharmacol 1975;
15:405.
479. O'Brien MA & Mason NA: Systemic absorption of intraperitoneal antimicrobials in continuous ambulatory peritoneal dialysis. Clin
Pharm 1992; 11:246-254.
480. Product Information: SEPTRA(R) oral grape suspension, suspension, double strength tablet, tablet,
sulfamethoxazole/trimethoprim oral grape suspension, suspension, double strength tablet, tablet. Monarch Pharmaceuticals, Inc ,
Bristol, TN, 2000.
481. Jusko WJ & Gretch M: Plasma and tissue protein binding of drugs in pharmacokinetics. Drug Metab Rev 1976; 5:43-140.
482. Siber GR, Gorham CC, Ericson JF, et al: Pharmacokinetics of intravenous trimethoprim-sulfamethoxazole in children and adults
with normal and impaired renal function. Rev Infect Dis 1982; 4(2):566-578.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...PubMed
Article: http://www.ncbi.nlm.nih.gov/...
483. Vree TB, Hekster YA, Damsma JE, et al: Renal excretion of sulphamethoxazole and its metabolite N4-acetyl sulphamethoxazole
in patients with impaired kidney function. Ther Drug Monit 1981; 3:129-135.
484. Ball AP, Gray JA, & Murdoch JM: Antibacterial drugs today. Drugs 1975; 10(2 part 1):1-55.
485. Ball AP, Gray JA, & Murdoch JM: Antibacterial drugs today. Drugs 1975a; 10(2 part 2):81-111.
486. Craig WA & Kunin CM: Trimethoprim-sulfamethoxazole: pharmacodynamic effects of urinary pH and impaired renal function. Ann
Intern Med 1973; 78:491.
487. Welling PG, Craig WA, Amidon GL, et al: Pharmacokinetics of trimethoprim and sulfamethoxazole in normal subjects and in
patients with renal failure. J Infect Dis 1973; 128(suppl):S556.
488. Reeves DS, Faiers MC, Pursell RE, et al: Trimethoprim/sulfamethoxazole: comparative study in urinary infection in hospital. Br
Med J 1969; 1:541.
489. Tobin MJ, O'Connor P, & Fitzgerald MX: Co-trimoxazole induced diuresis. Ir J Med Sci 1982; 151:181.
490. Jacobs M, Felmingham D, Appelbaum P, et al: The Alexander Project 1998-2000: susceptibility of pathogens isolated from
community-acquired respiratory tract infection to commonly used antimicrobial agents. J Antimicrob Chemother 2003; 52:229-246.
491. Martin JN, Rose DA, & Hadley WK: Emergence of trimethoprim-sulfamethoxazole resistance in the AIDS era. J Infect Dis 1999;
180:1809-1818.
492. Cockerill FR III & Edson RS: Trimethoprim-Sulfamethoxazole. Mayo Clin Proc 1991; 66:1260-1269.
493. Gutman LT: The use of trimethoprim-sulfamethoxazole in children: a review of adverse reactions and indications. Pediatr Infect
Dis 1984; 3:349-357.
494. Huovinen P, Sundstrom L, Swedberg G, et al: Trimethoprim and sulfonamide resistance. Antimicrob Agents Chemother 1995;
39:279-289.
495. Miller RF, Noury JL, Corbett EL, et al: Pneumocystis carinii infection: current treatment and prevention. J Antimicrob Chemother
1996; 37(suppl B):33-53.
496. CDC: Centers for Disease Control and Prevention. Cholera diagnosis and treatment-1991 CDC recommendations. MMWR 1991;
40:562-565.
497. Product Information: SEPTRA(R) DS oral tablets, sulfamethoxazole and trimethoprim DS oral tablets. Monarch Pharmaceutical,
Bristol, TN, 2005.
498. Product Information: sulfamethoxazole and trimethoprim IV injection, sulfamethoxazole and trimethoprim IV injection. Teva
Parenteral Medicines, Inc (per DailyMed), Irvine, CA, 2009.
499. Kaufman MB, Scavone JM, & Foley JJ: Stability of undiluted trimethoprim-sulfamethoxazole for injection in plastic syringes. Am J
Hosp Pharm 1992; 49:2782-2783.
500. Jarosinski PF, Kennedy PE, & Gallelli JF: Stability of concentrated trimethoprim-sulfamethoxazole admixtures. Am J Hosp Pharm
1989; 46:732-737.
501. Product Information: sulfamethoxazole and trimethoprim oral suspension, sulfamethoxazole and trimethoprim oral suspension.
Hi-Tech Pharmacal Co., Inc (per DailyMed), Amityville, NY, 2010.
502. Snow V, Mottur-Pilson C, & Hickner JM: Principles of appropriate antibiotic use for acute sinusitis in adults. Ann Intern Med 2001;
134:495-497.
503. Hickner JM, Bartlett JG, Besser RE, et al: Principles of appropriate antibiotic use for acute rhinosinusitis in adults: background.
Ann Intern Med 2001; 134:489-505.
504. Piccirillo JF, Mager DE, Frisse ME, et al: Impact of first-line vs second-line antibiotics for the treatment of acute uncomplicated
sinusitis. JAMA 2001; 286(15):1849-1856.
505. Warren JW, Abrutyn E, Hebel JR, et al: Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute
pyelonephritis in women. Guidelines from the Infectious Diseases Society of America. Clin Infect Dis 1999; 29:745-758.
506. Vohra S, Aggarwal P, & O'Donnell J: Guidelines for compatibility of IV additives. Infusion 1984; 8:102-109.
507. Vohra S, Aggarwal P, & O'Donnell J: Guidelines for compatibility of IV additives. Infusion 1984; 8:102-109.
508. Forman JK, Lachs JR, & Souney PF: Visual compatibility of acyclovir sodium with commonly used intravenous drugs during
simulated Y-site injection. Am J Hosp Pharm 1987; 44:1408-1409.
509. Cutie MR: Compatibility of verapamil hydrochloride injection with commonly used additives. Am J Hosp Pharm 1983; 40:12051207.
510. Trissel LA & Martinez JF: Compatibility of allopurinol sodium with selected drugs during simulated Y-site administration. Am J
Hosp Pharm 1994; 51:1792-1799.
511. Trissel LA & Martinez JF: Compatibility of aztreonam with selected drugs during simulated Y-site administration. Am J Health Syst
Pharm 1995; 52:1086-1090.
512. Nieves-Cordero AL, Luciw HM, & Souney PF: Compatibility of narcotic analgesic solutions with various antibiotics during simulated
Y-site injection. Am J Hosp Pharm 1985; 42:1108-1109.
513. Vohra S, Aggarwal P, & O'Donnell J: Guidelines for compatibility of IV additives. Infusion 1984; 8:102-109.
514. Trissel LA, Bready BB, Kwan JW, et al: Visual compatibility of sargramostim with selected antineoplastic agents, anti-infectives, or
other drugs during simulated Y-site injection. Am J Hosp Pharm 1992; 49:402-406.
515. Souney PF, Colucci RD, Mariani G, et al: Compatibility of magnesium sulfate solutions with various antibiotics during simulated Ysite injection. Am J Hosp Pharm 1984; 41:323-324.
516. Bashaw ED, Amantea MA, Minor JR, et al: Visual compatibility of zidovudine with other injectable drugs during simulated Y-site
administration. Am J Hosp Pharm 1988; 45:2532-2533.
517. Trissel LA, Parks NPT, & Santiago NM: Visual compatibility of fludarabine phosphate with antineoplastic drugs, anti-infectives, and
other selected drugs during simulated Y-site injection. Am J Hosp Pharm 1991a; 48:2186-2189.
518. Savitsky ME: Visual compatibility of neuromuscular blocking agents with various injectable drugs during simulated Y-site injection.
Am J Hosp Pharm 1990; 47:820-821.
519. Halpern NA, Colucci RD, Alicea M, et al: Visual compatibility of enalaprilat with commonly used critical care medications during
simulated Y-site injection. Int J Clin Pharmacol Ther Toxicol 1989a; 27:294-297.
520. Colucci RD, Cobuzzi LE, & Halpern NA: Visual compatibility of labetalol hydrochloride injection with various injectable drugs during
simulated Y-site injection. Am J Hosp Pharm 1988a; 45:1357-1358.
521. Lober CA & Dollard PA: Visual compatibility of gallium nitrate with selected drugs during simulated Y-site injection. Am J Hosp
Pharm 1993; 50:1208-1210.
522. Nieves-Cordero AL, Luciw HM, & Souney PF: Compatibility of narcotic analgesic solutions with various antibiotics during simulated
Y-site injection. Am J Hosp Pharm 1985; 42:1108-1109.
523. Vohra S, Aggarwal P, & O'Donnell J: Guidelines for compatibility of IV additives. Infusion 1984; 8:102-109.
524. Vohra S, Aggarwal P, & O'Donnell J: Guidelines for compatibility of IV additives. Infusion 1984; 8:102-109.
525. Vohra S, Aggarwal P, & O'Donnell J: Guidelines for compatibility of IV additives. Infusion 1984; 8:102-109.
526. Vohra S, Aggarwal P, & O'Donnell J: Guidelines for compatibility of IV additives. Infusion 1984; 8:102-109.
527. Trissel LA & Martinez JF: Compatibility of amifostine with selected drugs during simulated Y-site administration. Am J Health Syst
Pharm 1995; 52:2208-2212.
528. Savitsky ME: Visual compatibility of neuromuscular blocking agents with various injectable drugs during simulated Y-site injection.
Am J Hosp Pharm 1990; 47:820-821.
529. Trissel LA & Martinez JF: Visual, turbidimetric, and particle-content assessment of compatibility of vinorelbine tartrate with selected
drugs during simulated Y-site injection. Am J Hosp Pharm 1994a; 51:495-499.
530. Trissel LA, Saenz CA, Ogundele OB, et al: Compatibility of fenoldopam mesylate with other drugs during simulated Y-site
administration. Am J Health-Syst Pharm 2003; 60:80-85.
531. Trissel LA & Martinez JF: Compatibility of filgrastim with selected drugs during simulated Y-site administration. Am J Hosp Pharm
1994; 51:1907-1913.
532. Product Information: ZYVOX(R) IV injection, oral tablets, oral suspension, linezolid IV injection, oral tablets, oral suspension.
Pharmacia and Upjohn Company, New York, NY, 2008.
533. Trissel LA, Williams KY, & Gilbert DL: Compatibility screening of linezolid injection during simulated Y-site administration with other
drugs and infusion solutions. J Am Pharm Assoc (Wash) 2000; 40(4):515-519.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...PubMed
Article: http://www.ncbi.nlm.nih.gov/...
534. Savitsky ME: Visual compatibility of neuromuscular blocking agents with various injectable drugs during simulated Y-site injection.
Am J Hosp Pharm 1990; 47:820-821.
535. Trissel LA: Handbook on Injectable Drugs, 5th. American Society of Hospital Pharmacists, Bethesda, MD, 1988.
536. Colucci RD, Cobuzzi LE, & Halpern NA: Visual compatibility of esmolol hydrochloride and various injectable drugs during
simulated Y-site injection. Am J Hosp Pharm 1988; 45:630-632.
537. Kramer W, Inglott A, & Cluxton R: Some physical and chemical incompatibilities of drugs for IV administration. Drug Intell Clin
Pharm 1971; 5:211-228.
538. Kramer W, Inglott A, & Cluxton R: Some physical and chemical incompatibilities of drugs for IV administration. Drug Intell Clin
Pharm 1971; 5:211-228.
539. Halpern NA, Colucci RD, Alicea M, et al: The compatibility of nicardipine hydrochloride injection with various ICU medications
during simulated Y-site injection. Int J Clin Pharmacol Ther Toxicol 1989; 27:250-254.
540. Baltz JK, Kennedy P, Minor JR, et al: Visual compatibility of foscarnet with other injectable drugs during simulated Y-site
administration. Am J Hosp Pharm 1990; 47:2075-2077.
541. Trissel LA & Martinez JF: Compatibility of piperacillin sodium plus tazobactam with selected drugs during simulated Y-site
injection. Am J Hosp Pharm 1994; 51:672-678.
542. Lor E, Sheybani T, & Takagi J: Visual compatibility of fluconazole with commonly used injectable drugs during simulated Y-site
administration. Am J Hosp Pharm 1991; 48:744-746.
543. Lor E & Takagi J: Visual compatibility of foscarnet with other injectable drugs. Am J Hosp Pharm 1990; 47:157-159.
544. Min DI, Brown T, & Hwang GC: Visual compatibility of tacrolimus with commonly used drugs during simulated Y-site injection. Am
J Hosp Pharm 1992; 49:2964-2966.
545. Gasca M, Fanikos J, & Souney PF: Visual compatibility of perphenazine with various antimicrobials during simulated Y-site
injection. Am J Hosp Pharm 1987; 44:574-575.
546. Nieves-Cordero AL, Luciw HM, & Souney PF: Compatibility of narcotic analgesic solutions with various antibiotics during simulated
Y-site injection. Am J Hosp Pharm 1985; 42:1108-1109.
547. Deans KW, Lang JR, & Smith DE: Stability of trimethoprim-sulfamethoxazole injection in five infusion fluids. Am J Hosp Pharm
1982; 39:1681-1684.
548. Lesko LJ, Marion A, Ericson J, et al: Stability of trimethoprim-sulfamethoxazole injection in two infusion fluids. Am J Hosp Pharm
1981; 38:1004-1006.
549. Lesko LJ, Marion A, Ericson J, et al: Stability of trimethoprim-sulfamethoxazole injection in two infusion fluids. Am J Hosp Pharm
1981; 38:1004-1006.
550. Jarosinski PF, Kennedy PE, & Gallelli JF: Stability of concentrated trimethoprim-sulfamethoxazole admixtures. Am J Hosp Pharm
1989; 46:732-737.
551. Lesko LJ, Marion A, Ericson J, et al: Stability of trimethoprim-sulfamethoxazole injection in two infusion fluids. Am J Hosp Pharm
1981; 38:1004-1006.
552. Jarosinski PF, Kennedy PE, & Gallelli JF: Stability of concentrated trimethoprim-sulfamethoxazole admixtures. Am J Hosp Pharm
1989; 46:732-737.
553. Trissel LA, Gilbert DL, Martinez JF, et al: Compatibility of parenteral nutrition solutions with selected drugs during simulated Y-site
administration. Am J Health Syst Pharm 1997; 54:1295-1300.
554. Vohra S, Aggarwal P, & O'Donnell J: Guidelines for compatibility of IV additives. Infusion 1984; 8:102-109.
555. Rachelefsky GS, Katz RM, & Siegel SC: Chronic sinusitis in children with respiratory allergy: the role of antimicrobials. J Allergy
Clin Immunol 1982; 69:382-387.
556. Goodman LJ, Trenholme GM, Kaplan RL, et al: Empiric antimicrobial therapy of domestically acquired acute diarrhea in urban
adults. Arch Intern Med 1990; 150:541-546.
557. Dekker AW, Rozenberg-Arska M, & Verhoef J: Infection prophylaxis in acute leukemia: a comparison of ciprofloxacin with
trimethoprim-sulfamethoxazole and colistin. Ann Intern Med 1987; 106:7-12.
558. Talan DA, Stamm WE, Hooton TM, et al: Comparison of ciprofloxacin (7 days) and trimethoprim-sulfamethoxazole (14 days) for
acute unclomplicated pyelonephritis in women. JAMA 2000; 283(12):1583-1590.
559. Lew MA, Kehoe K, Ritz J, et al: Ciprofloxacin versus trimethoprim/sulfamethoxazole for prophylaxis of bacterial infections in bone
marrow transplant recipients: a randomized, controlled trial. J Clin Oncol 1995; 13:239-250.
560. Limson BM & Littaua RT: Comparative study of ciprofloxacin versus co-trimoxazole in the treatment of salmonella enteric fever
(letter). Infection 1989; 17:105-106.
561. Ericsson CD, Johnson PC, Herbert PC, et al: Ciprofloxacin or trimethoprim-sulfamethoxazole as initial therapy for traveler's
diarrhea. Ann Intern Med 1987; 106:216-220.
562. McCarty JM, Richard G, Huck W, et al: A randomized trial of short-course ciprofloxacin, ofloxacin, or trimethoprim/
sulfamethoxazole for the treatment of acute urinary tract infection in women. Am J Med 1999; 106:292-299.
563. Allais JM, Preheim LC, Cuevas TA, et al: Randomized, double-blind comparison of ciprofloxacin and trimethoprimsulfamethoxazole for complicated urinary tract infections. Antimicrob Agents Chemother 1988; 32:1327-1330.
564. Henry NK, Schultz HJ, Grubbs NC, et al: Comparison of ciprofloxacin and co-trimoxazole in the treatment of uncomplicated urinary
tract infection in women. J Antimicrob Chemother 1986; 18(suppl D):103-106.
565. Chiam HL, Chee CP, Cheah KC, et al: The prevention of postappendicectomy sepsis by metronidazole and co-trimoxazole: a
controlled double blind trial. Aust N Z J Surg 1983; 53:421-425.
566. Castro M: A comparative study of cefadroxil and co-trimoxazole in patients with lower respiratory tract infections. Drugs 1986;
32(suppl 3):50-56.
567. Keeley DJ, Nkrumah FK, & Kapuyanyika C: Randomized trial of sulfamethoxazole + trimethoprim versus procaine penicillin for
the outpatient treatment of childhood pneumonia in Zimbabwe. Bull World Health Organ 1990; 68:185-192.
568. Salmi HA: Comparison of sulphadiazine-trimethoprim and sulphamethoxazole-trimethoprim in the treatment of acute respiratory
tract infections. Chemotherapy 1980; 26:297-300.
569. Federspil P & Bamberg P: Sulphadiazine/trimethoprim once daily in maxillary sinusitis: a randomized double-blind comparison with
sulphamethoxazole/trimethoprim BID. J Int Med Res 1981; 9:478-481.
570. Skjerven O & Bergan T: Double-blind comparison of sulphonamide-trimethoprim combinations in acute uncomplicated urinary tract
infections. Infection 1979; 7(suppl 4):S398-S399.
571. Bailey RR & Pearson S: Comparative trial of sulphadiazine-trimethoprim (co-trimazine), co-trimoxazole and sulphamethizole in the
treatment of uncomplicated urinary tract infections. NZ Med J 1980; 91:43-44.
572. Lovestad A, Gastrin B, & Lundstrom R: A clinical study of co-trimazine in comparison with co-trimoxazole and sulphalene in urinary
tract infections. Infection 1979; 7(suppl 4):S401-S403.
573. Chapman ST, Reeves DS, Morris RW, et al: Co-trimazine versus co-trimoxazole as therapy for acute symptomatic urinary
infection In: Periti P & Grassi GG (Eds): Current Chemotherapy and Immunotherapy: Proceedings of the 12th International Congress of
Chemotherapy, The American Society for Microbiology, Washington, DC, 1981.
574. Adam D, Hager C, Dorn G, et al: A comparison of co-trimazine once daily and co-trimoxazole twice daily in treatment of urinary
tract infections in children. J Antimicrob Chemother 1982; 10:453-458.
575. Allgulander S, Holm S, & Lundgren C: The use of co-trimazine and co-trimoxazole in elderly patients with urinary tract infections.
Infection 1979; 7(suppl 4):404S-407S.
576. Bergfors PG: Clinical studies on co-trimazine in children. Infection 1979a; 7(suppl 4):408-410.
577. Anon: Coptin (sulphadiazine + trimethoprim). Drug and Therapeutics Bull 1979; 17(25):97-99.
578. Ortengren B, Magni L, & Bergan T: Development of sulphonamide-trimethoprim combinations for urinary tract infections. Part 3:
Pharmacokinetic characterization of sulphadiazine and sulphamethoxazole given with trimethoprim. Infection 1979; 7(suppl 4):S371S387.
579. Mannisto PT, Mantyla R, Mattila J, et al: Comparison of pharmacokinetics of sulphadiazine and sulphamethoxazole after
intravenous infusion. J Antimicrob Chemother 1982; 9:461-470.
580. Bergan T, Brodwall EK, Vik-Mo H, et al: Pharmacokinetics of sulphadiazine, sulphamethoxazole and trimethoprim in patients with
varying renal function. Infection 1979; 7(suppl 4):S382-S386.
581. Platt R, Dreis MW, Kennedy DL, et al: Serum sickness-like reactions to amoxicillin, cefaclor, cephalexin, and trimethoprimsulfamethoxazole. J Infect Dis 1988; 158:474-477.
582. Blumer JL, Bertino JS, & Husak MP: Comparison of cefaclor and trimethoprim-sulfamethoxazole in the treatment of acute otitis
media. Pediatr Infect Dis 1984; 3:25.
583. Trager GM, White GW, Porembski PE, et al: A comparison of cefaclor and trimethoprim/sulfamethoxazole in the treatment of
urinary tract infections. Curr Ther Res 1980; 28:419-423.
584. Markowitz N, Quinn EL, & Saravolatz LD: Trimethoprim-sulfamethoxazole compared with vancomycin for the treatment of
Staphylococcus aureus infection. Ann Intern Med 1992; 117:390-398.
585. Ruf B, Rohde I, & Pohle HD: Efficacy of clindamycin primaquine versus trimethoprim/sulfamethoxazole in primary treatment of
pneumocystis carinii pneumonia. Eur J Clin Microbiol Infect Dis 1991; 10:207-210.
586. Safrin S, Finkelstein DM, Feinberg J, et al: Comparison of three regimens for treatment of mild to moderate pneumocystis carinii
pneumonia in patients with AIDS: a double-blind, randomized trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and
clindamycin-primaquine. Ann Intern Med 1996; 124:792-802.
587. Levenstein J, Summerfield PJF, Fourie S, et al: Comparison of cefixime and co-trimoxazole in acute uncomplicated urinary tract
infection. A double-blind general practice study. S Afr Med J 1986; 70:455-460.
588. Cox CE: Cefixime versus trimethoprim/sulfamethoxazole in treatment of patients with acute, uncomplicated lower urinary tract
infections. Urology 1989; 34:322-326.
589. Dagan R, Einhorn M, Lang R, et al: Once daily cefixime compared with twice daily trimethoprim/sulfamethoxazole for treatment of
urinary tract infection in infants and children. Pediatr Infect Dis J 1992; 11:198-203.
590. Ashkenazi S, Amir J, Waisman Y, et al: A randomized, double-blind study comparing cefixime and trimethoprimsulfamethoxazole in the treatment of childhood shigellosis. J Pediatr 1993; 123:817-821.
591. Davies JG, Rose AJ, & Walker GD: A comparison of Augmentin and co-trimoxazole in the treatment of adult infections in general
practice. Br J Clin Pract 1983; 126:387-393.
592. Bailey RR, Bishop V, Peddie B, et al: Comparison of Augmentin with co-trimoxazole for the treatment of uncomplicated urinary
tract infection. N Z Med J 1983; 96:970-972.
593. Fancourt GJ, Matts SGF, & Mitchell CJ: Augmentin (amoxycillin-clavulanic acid) compared with co-trimoxazole in urinary tract
infections. Br Med J 1984; 289:82-83.
594. Ancill RJ, Ballard JH, & Capewell MA: Urinary tract infections in geriatric inpatients: a comparative study of amoxicillin-clavulanic
acid and cotrimoxazole. Curr Ther Res 1987; 41:444-448.
595. Traisupa A, Ariyarit C, Metheeprapha C, et al: Treatment of chancroid with spectinomycin or co-trimoxazole. Clin Ther 1990;
12:200-205.
596. Ekert H, Jurk IH, Waters KD, et al: Prophylactic co-trimoxazole and lactobacilli preparation in neutropenic patients. Med Pediatr
Oncol 1980; 8:47-51.
597. Henry RL, Dorman DC, Skinner JA, et al: Antimicrobial therapy in whooping cough. Med J Aust 1981; 2:27-28.
598. Hoppe JE, Halm U, Hagedorn HJ, et al: Comparison of erythromycin ethylsuccinate and co-trimoxazole for treatment of pertussis.
Infection 1989; 17:227-231.
599. Bottone E, Baldini G, Macchia P, et al: Evaluation of the clinical efficacy of erythromycin, amoxicillin, and co-trimoxazole in the
treatment of acute respiratory tract infections in paediatric patients. Curr Med Res Opin 1982; 8:67-74.
600. Rodriguez RS, Chaez AZ, & Galindo E: A randomized, controlled, single-blind study comparing furazolidone with trimethoprimsulfamethoxazole in the empirical treatment of acute invasive diarrhea. Scand J Gastroenterol 1989; 24(suppl 169):47-53.
601. Klein JO: Microbiology and antimicrobial treatment of otitis media. Ann Otol Rhinol Laryngol 1981; 90(suppl):30-36.
602. McCracken GH: Antimicrobial therapy for acute otitis media. Pediatr Infect Dis 1984; 3:383-386.
603. Schwartz RH: New concepts in otitis media. Am Fam Physician 1979; 19:91-98.
604. Shurin PA, Pelton SI, Donner A, et al: Trimethoprim-sulfamethoxazole compared with ampicillin in the treatment of acute otitis
media. J Pediatr 1980; 96:1081-1087.
605. Feder HM: Comparative tolerability of ampicillin, amoxicillin, and trimethoprim-sulfamethoxazole suspensions in children with
otitis media. Antimicrob Agents Chemother 1982; 21:426-427.
606. Cameron GC, Pomahac AC, Johnston MT, et al: Comparative efficacy of ampicillin and trimethoprim-sulfamethoxazole in otitis
media. Can Med Assoc J 1975; 112:87-88.
607. Shurin PA, Pelton SI, Scheifele D, et al: Otitis media caused by non-typable, ampicillin resistant strains of Haemophilus influenza.
J Pediatr 1976; 88:646-649.
608. Campbell H, Byass P, Forgie IM, et al: Trial of co-trimoxazole versus procaine penicillin with ampicillin in treatment of communityacquired pneumonia in young Gambian children. Lancet 1988; 2:1182-1184.
609. Johnson JR, Lyons MF II, Pearce W, et al: Therapy for women hospitalized with acute pyelonephritis: a randomized trial of
ampicillin versus trimethoprim-sulfamethoxazole for 14 days. J Infect Dis 1991; 163:325-330.
610. Naber KG & Thyroff-Friesinger U: Fosfomycin trometamol versus ofloxacin/co-trimoxazole as single dose therapy of acute
uncomplicated urinary tract infection in females: a multicentre study. Infection 1990; 18(suppl 2):S70-S76.
611. Bailey RR, Peddie B, Chambers PFM, et al: Single dose doxycycline, cefuroxime and pivmecillinam for treatment of bacterial
cystitis. N Z Med J 1982; 95:699-700.
612. Cox CE: A comparison of enoxacin and co-trimoxazole in the treatment of patients with complicated urinary tract infections. J
Antimicrob Chemother 1988; 21(suppl B):113-118.
613. Patel SS & Spencer CM: Enoxacin: a reappraisal of its clinical efficacy in the treatment of genitourinary tract infections. Drugs
1996; 51:137-160.
614. Safrin S, Finkelstein DM, Feinberg J, et al: Comparison of three regimens for treatment of mild to moderate pneumocystis carinii
pneumonia in patients with AIDS: a double-blind, randomized trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and
clindamycin-primaquine. Ann Intern Med 1996; 124:792-802.
615. Mills J, Leoung G, Medina I, et al: Dapsone treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency
syndrome. Antimicrob Agents Chemother 1988; 32:1057-1060.
616. Souza JP, Boeckh M, Gooley TA, et al: High rates of Pneumocystis carinii pneumonia in allogeneic blood and marrow transplant
recipients receiving dapsone prophylaxis. Clin Infect Dis 1999; 29:1467-1471.
617. Podzamczer D, Salazar A, Jimenez J, et al: Intermittent trimethroprim-sulfamethoxazole compared with dapsone-pyrimethamine
for the simultaneous primary prophylaxis of pneumocystis pneumonia and toxoplasmosis in patients infected with HIV. Ann Intern Med
1995; 122:755-761.
618. Podzamczer D, Santin M, Jimenez J, et al: Thrice-weekly cotrimoxazole is better than weekly dapsone-pyrimethamine for the
primary prevention of Pneumocystis-carinii pneumonia in HIV-infected patients. AIDS 1993; 7:501-506.
619. Hooton TM, Running K, & Stamm WE: Single-dose therapy for cystitis in women. JAMA 1985; 253:387-390.
620. de Groot K, Reinhold-Keller E, Tatsis E, et al: Therapy for the maintenance of remission in sixty-five patients with generalized
Wegener's granulomatosis: methotrexate vs trimethoprim/sulfamethoxazole. Arthritis Rheum 1996; 39(12):2052-2061.
621. Campbell H, Byass P, Forgie IM, et al: Trial of co-trimoxazole versus procaine penicillin with ampicillin in treatment of communityacquired pneumonia in young Gambian children. Lancet 1988; 2:1182-1184.
622. Stamm WE, Counts GW, Wagner KF, et al: Antimicrobial prophylaxis of recurrent urinary tract infections: a double-blind, placebocontrolled trial. Ann Intern Med 1980; 92:770-775.
623. Spencer RC, Moseley DJ, & Greensmith MJ: Nitrofurantoin modified release versus trimethoprim or co-trimoxazole in the
treatment of uncomplicated urinary tract infection in general practice. J Antimicrob Chemother 1994; 33(suppl):121-129.
624. Hughes W, Leoung G, Kramer F, et al: Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat
pneumocystis carinii pneumonia in patients with AIDS. N Engl J Med 1993; 328:1521-1527.
625. Phadtare JM & Rangnekar RY: Comparative study of the efficacy of co-trimoxazole and cephalexin in respiratory infections.
Pharmatherapeutica 1988; 5:183-188.
626. Fitzpatrick JE, Tyler H, & Gramstad NG: Treatment of chancroid: comparison of sulfamethoxazole-trimethoprim with
recommended therapies. JAMA 1981; 246:1804-1805.
627. Parras F, Guerrero MC, Bouza, et al: Comparative study of mupirocin and oral cotrimoxazole plus topical fusidic acid in eradication
of nasal carriage of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 1995; 39:175-179.
628. Lal H: A comparative trial of oral chloroquine and oral co-trimoxazole in vivax malaria in children. Am J Top Med Hyg 1982;
31:438-440.
629. Buckwold FJ, Ludwig P, Harding GKM, et al: Therapy for acute cystitis in adult women. JAMA 1982; 247:1839-1842.
630. Anon: Single-dose treatment of urinary tract infections. JAMA 1979; 241:1226.
631. Iravani A, Richard GA, Baer H, et al: Comparative efficacy and safety of nalidixic acid verses trimethoprim/sulfamethoxazole in
treatment of acute urinary tract infections in college age women. Antimicrob Agents Chemother 1981; 19:598-604.
632. Vogel R, Deaney NB, Round EM, et al: Norfloxacin, amoxicillin, cotrimoxazole and nalidixic acid: a summary of 3-day and 7-day
therapy studies in the treatment of urinary tract infections. J Antimicrob Chemother 1984; 13(suppl B):113-120.
633. Butler AVJ, Cullen MJ, Parry MOL, et al: Acute cystitis in young women: treatment with citrated nalidixic acid compared with cotrimoxazole. Practitioner 1983; 227:833-835.
634. Lightstone BL, Greaves WE, & Humphries JM: Comparison of mictral with amoxycillin, trimethoprim and nitrofurantoin in the
treatment of acute cystitis. Br J Clin Pract 1988; 42:283-288.
635. Gupta K, Hooton TM, Roberts PL, et al: Short-course nitrofurantoin for the treatment of acute uncomplicated cystitis in women.
Arch Intern Med 2007; 167(20):2207-2212.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...PubMed Article:
http://www.ncbi.nlm.nih.gov/...
636. Moretti M, Marchioni CF, & Bisetti A: Efficacy and tolerability of brodimoprim in respiratory tract infections. J Chemother 1993;
5:517-520.
637. Galetti G & Dallari S: Efficacy and tolerability of brodimoprim in pharyngotonsillitis in children. J Chemother 1993; 5:548-550.
638. Whitby M, Johnson BC, Atkinson RL, et al: The comparative efficacy of intravenous cefotaxime and
trimethoprim/sulfamethoxazole in preventing infection after neurosurgery: a prospective, randomized study. Br J Neurosurgery 2000;
14(1):13-18.
639. Colby C, McAfee SL, Sackstein R, et al: A prospective randomized trial comparing the toxicity and safety of atovaquone with
trimethoprim/sulfamethoxazole as Pneumocystis carinii pneumonia prophylaxis following autologous peripheral blood stem cell
transplantation. Bone Marrow Transplant 1999; 24:897-902.
640. Haase DA, Harding GKM, Thomson MJ, et al: Comparative trial of norfloxacin and trimethoprim-sulfamethazole in the treatment of
women with localized, acute, symptomatic urinary tract infections and antimicrobial effect on periurethral and fecal microflora.
Antimicrob Agents Chemother 1984; 26:481-484.
641. Watt B, Chait I, Kelsey MC, et al: Norfloxacin versus cotrimoxazole in the treatment of uncomplicated urinary tract infections--a
multi-centre trial. J Antimicrob Chemother 1984; 13(suppl B):89-94.
642. Panichi G, Pantosti A, & Testore GP: Norfloxacin (MK-0366) treatment of urinary tract infections in hospitalized patients. J
Antimicrob Chemother 1983; 11:589-592.
643. Vogel R, Deaney NB, Round EM, et al: Norfloxacin, amoxicillin, cotrimoxazole and nalidixic acid: a summary of 3-day and 7-day
therapy studies in the treatment of urinary tract infections. J Antimicrob Chemother 1984; 13(suppl B):113-120.
644. Giamarellou H, Tsagarakis J, Petrikkos G, et al: Norfloxacin versus cotrimoxazole in the treatment of lower urinary tract infections.
Eur J Clin Microbiol 1983; 2:266-269.
645. Goldstein EJC, Alpert ML, & Ginsberg BP: Norfloxacin versus trimethoprim-sulfamethoxazole in the therapy of uncomplicated,
community-acquired urinary tract infections. Antimicrob Agents Chemother 1985; 2:422-423.
646. Sabbaj J, Hoagland VL, & Shih WJ: Multiclinic comparative study of norfloxacin and trimethoprim-sulfamethoxazole for treatment
of urinary tract infections. Antimicrob Agents Chemother 1985; 27(3):297-301.
647. Anon: Urinary Tract Infection Study Group: Coordinated multicenter study of norfloxacin versus trimethoprim-sulfamethoxazole
treatment of symptomatic urinary tract infections. J Infect Dis 1987; 155:170-177.
648. Corrado ML, Hesney M, Struble WE, et al: Norfloxacin versus trimethoprim-sulfamethoxazole in the treatment of urinary tract
infections. Eur Urol 1990; 17(suppl 1):34-39.
649. Seidmon EJ, Krisch EB, Truant AL, et al: Treatment of recurrent urinary tract infection with norfloxacin versus trimethoprimsulfamethoxazole. Urology 1990; 35:187-193.
650. Chan MK, Wong WT, Yin PD, et al: A double-blind controlled trial of norfloxacin versus cotrimoxazole in the treatment of urinary
tract infections. Br J Clin Pract 1989; 43:61-63.
651. Sabbaj J, Hoagland VL, & Cook T: Norfloxacin versus co-trimoxazole in the treatment of recurring urinary tract infections in men.
Scand J Infect Dis 1986; 48(suppl):48-53.
652. Gotuzzo E, Oberhelman RA, Maguina C, et al: Comparison of single-dose treatment with norfloxacin and standard 5-day treatment
with trimethoprim-sulfamethoxazole for acute shigellosis in adults. Antimicrob Agents Chemother 1989; 33:1101-1104.
653. Bassily S, Hyams KC, El-Masry A, et al: Short-course norfloxacin and trimethoprim-sulfamethoxazole treatment of shigellosis and
salmonellosis in Egypt. Am J Trop Med Hyg 1994; 51:219-233.
654. Lolekha S, Patanachareon S, Thanangkul B, et al: Norfloxacin versus co-trimoxazole in the treatment of acute bacterial diarrhoea:
a placebo controlled study. Scand J Infect Dis 1988; 56(suppl):35-45.
655. Cruciani M, Concia E, Navarra A, et al: Prophylactic co-trimoxazole versus norfloxacin in neutropenic children - perspective
randomized study. Infection 1989; 17:65-69.
656. Bow EJ, Rayner E, & Louie TJ: Comparison of norfloxazin with cotrimoxazole for infection prophylaxis in acute leukemia: the
trade-off for reduced gram-negative sepsis. Am J Med 1988; 84:847-854.
657. Boye NP & Gaustad P: Double-blind comparative study of ofloxacin (Hoe 280) and trimethoprim-sulfamethoxazole in the
treatment of patients with acute exacerbations of chronic bronchitis and chronic obstructive lung disease. Infection 1991; 19(suppl
7):S388-S390.
658. Liang RH, Yung RWH, Chan TK, et al: Ofloxacin versus co-trimoxazole for prevention of infection in neutropenic patients following
cytotoxic chemotherapy. Antimicrob Agents Chemother 1990; 34:215-218.
659. Block JM, Walstad RA, Bjertnaes A, et al: Ofloxacin versus trimethoprim-sulphamethoxazole in acute cystitis. Drugs 1987;
34(suppl 1):100-106.
660. Vellucci A, Bernardini G, Battaglia AM, et al: Ofloxacin vs cotrimoxazole in patients with complicated urinary tract infections. Int J
Clin Pharmacol Ther Toxicol 1987; 25:279-281.
661. McCarty JM, Richard G, Huck W, et al: A randomized trial of short-course ciprofloxacin, ofloxacin, or trimethoprim/
sulfamethoxazole for the treatment of acute urinary tract infection in women. Am J Med 1999; 106:292-299.
662. Monk JP & Campoli-Richards DM: Ofloxacin: a review of its antibacterial activity, pharmacokinetic properties and therapeutic use.
Drugs 1987; 33:346-391.
663. Cox CE, Callery SV, & Tack KJ: Clinical experience with ofloxacin in urinary tract infection. Infection 1986; 14(suppl 4):S303-S304.
664. Ludwig G & Pauthner H: Clinical experience with ofloxacin in upper and lower urinary tract infections: a comparison with cotrimoxazole and nitrofurantoin. Drugs 1987; 34(suppl 1):95-99.
665. Basista MP: Randomized study to evaluate efficacy and safety of ofloxacin vs trimethoprim and sulfamethoxazole in treatment of
uncomplicated urinary tract infection. Urology 1991; 37(suppl 3):21-27.
666. Hooton TM, Johnson C, Winter C, et al: Single-dose and three-day regimens of ofloxacin versus trimethoprim-sulfamethoxazole
for acute cystitis in women. Antimicrob Agents Chemother 1991; 35:1479-1483.
667. Simon HB: Haemophilus influenza in hospitalized adults: current perspectives. Am J Med 1980; 69:219-225.
668. Krause PJ, Owens NJ, Nightingale CH, et al: Penetration of amoxicillin, cefaclor, erythromycin/sulfisoxazole, and trimethoprimsulfamethoxazole into the middle ear fluid of patients with chronic serous otitis media. J Infect Dis 1982; 145:815-821.
669. Lane HC, Laughon BE, Falloon J, et al: Recent advances in the management of AIDS-related opportunistic infections. Ann Intern
Med 1994; 120:945-955.
670. Hughes WT, Feldman S, Chaudhary SC, et al: Comparison of pentamidine isethionate and trimethoprim-sulfamethoxazole in the
treatment of pneumocystis carinii pneumonia. J Pediatr 1978; 92:285-291.
671. Siegel SE, Wolff LJ, Baehner RL, et al: The diagnosis and management of Pneumocystis carinii pneumonia. Ann Thorac Surg
1984; 14:335-346.
672. Drake S, Lampasona V, Nicks HL, et al: Pentamidine isethionate in the treatment of pneumocystis carinii pneumonia. Clin Pharm
1985; 4:507-516.
673. Schneider MME, Hoepelman AIM, Schattenkerk JKM, et al: A controlled trial of aerosolized pentamidine or trimethoprimsulfamethoxazole as primary prophylaxis against pneumocystis carinii pneumonia in patients with human immunodeficiency virus
infection. N Engl J Med 1992; 327:1836-1841.
674. Kovacs JA, Heimenz JW, Macher AM, et al: Pneumocystis carinii pneumonia: a comparison between patients with the acquired
immunodeficiency syndrome and patients with other immunodeficiencies. Ann Intern Med 1984; 100:495-499.
675. Small CB, Harris CA, Friedland GH, et al: The treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency
syndrome. Arch Intern Med 1985; 145:837-840.
676. Engelberg LA, Lerner CW, & Tapper ML: Clinical features of Pneumocystis pneumonia in the acquired immune deficiency
syndrome. Am Rev Respir Dis 1984; 130:689-694.
677. Gordin FM, Simon GL, Wofsy CB, et al: Adverse reactions to trimethoprim-sulfamethoxazole in patients with the acquired
immunodeficiency syndrome. Ann Intern Med 1984; 100:495-499.
678. Haverkos HW: Assessment of therapy for Pneumocystis carinii pneumonia. Am J Med 1984; 76:501-508.
679. Wharton JM, Coleman DL, Wofsy CB, et al: Trimethoprim-sulfamethoxazole or pentamidine for Pneumocystis carinii pneumonia
in the acquired immunodeficiency syndrome. Ann Intern Med 1986; 105:37-44.
680. Sattler FR, Cowan R, Nielsen DM, et al: Trimethoprim-sulfamethoxazole compared with pentamidine for treatment of
Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Ann Intern Med 1988; 109:280-287.
681. Anon: Recommendations for prophylaxis against pneumocystis carinii pneumonia for adults and adolescents infected with HIV.
JAMA 1992; 267:2294-2299.
682. Hardy WD, Feinberg J, Finkelstein DM, et al: A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamide for
secondary prophylaxis of pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. N Engl J Med
1992; 327:1842-1848.
683. Bozzette SA, Finkelstein DM, Spector SA, et al: A randomized trial of three antipneumocystis agents in patients with advanced
human immunodeficiency virus infection. N Engl J Med 1995; 332:693-699.
684. Carr A, Tindall B, Brew BJ, et al: Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients
with AIDS. Ann Intern Med 1992; 117:106-111.
685. Fast MV, Nsanze H, Plummer FA, et al: Treatment of chancroid: a comparison of sulphamethoxazole and trimethoprimsulphamethoxazole. Br J Vener Dis 1983; 59:320-324.
686. Howard JB & Howard JE Sr: Trimethoprim-sulfamethoxazole vs sulfamethoxazole for acute urinary tract infections in children.
Am J Dis Child 1978; 132:1085-1087.
687. Bergan T & Skjerven O: Comparison of sulfamethoxazole alone and combined with trimethoprim in urinary tract infections.
Infection 1979a; 7:14-16.
688. AMA Department of Drugs: AMA Drug Evaluations, 6th. American Medical Association, Chicago, IL, 1986.
689. Ruf B, Rohde I, & Pohle HD: Efficacy of clindamycin primaquine versus trimethoprim/sulfamethoxazole in primary treatment of
Pneumocystis carinii pneumonia. Eur J Clin Microbiol Infect Dis 1991; 10:207-210.
690. Safrin S, Finkelstein DM, Feinberg J, et al: Comparison of three regimens for treatment of mild to moderate pneumocystis carinii
pneumonia in patients with AIDS: a double-blind, randomized trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and
clindamycin-primaquine. Ann Intern Med 1996; 124:792-802.
691. Toma E, Fournier S, Dumont M, et al: Clindamycin/primaquine versus trimethoprim/sulfamethoxazole as primary therapy for
Pneumocystis carinii pneumonia in AIDS: a randomized, double-blind, pilot trial. Clin Infect Dis 1993; 17:178-184.
692. Hooton TM, Running K, & Stamm WE: Single-dose therapy for cystitis in women. JAMA 1985; 253:387-390.
693. Feldman W, Momy J, & Dulberg C: Trimethoprim-sulfamethoxazole v amoxicillin in the treatment of acute otitis media. Can Med
Assoc J 1988; 139:961-964.
694. Cooper J, Inman JS, & Dawson AF: A comparison between co-trimoxazole and amoxicillin in the treatment of acute otitis media in
general practice. Practitioner 1976; 217:804-809.
695. Thisyakorn U & Mansuwan P: Comparative efficacy of mecillinam, mecillinam/amoxicillin and trimethoprim-sulfamethoxazole for
treatment of typhoid fever in children. Pediatr Infect Dis J 1992; 11:979-980.
696. Harding GK & Ronald AR: A controlled study of antimicrobial prophylaxis of recurrent urinary infection in women. N Engl J Med
1974; 291:599.
697. Kalowski S, Nanra RS, Friedman A, et al: Controlled trial comparing co-trimoxazole and methenamine hippurate in the prevention
of recurrent urinary tract infections. Med J Aust 1975; 1:585.
698. Iravani A: Comparative, double-blind, prospective, multicenter trial of temafloxacin versus trimethoprim-sulfamethoxazole in
uncomplicated urinary tract infections in women. Antimicrob Agents Chemother 1991; 35:1777-1781.
699. Clark AJL, Mauchizadeh J, Faunch R, et al: Trimethoprim alone. Lancet 1980; 1:1030.
700. Bow EJ, Louie TJ, Riben PD, et al: Randomized controlled trial comparing trimethoprim/sulfamethoxazole and trimethoprim for
infection prophylaxis in hospitalized granulocytopenic patients. Am J Med 1984; 76:223-233.
701. Haataja M, Hanninen P, Platin LH, et al: Trimethoprim or cotrimoxazole in pneumonia. Curr Ther Res 1985; 37:191-196.
702. Safrin S, Finkelstein DM, Feinberg J, et al: Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii
pneumonia in patients with AIDS: a double-blind, randomized trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and
clindamycin-primaquine. Ann Intern Med 1996; 124:792-802.
703. Amyes SGB, Doherty CJ, & Wonnacott S: Trimethoprim and co-trimoxazole: a comparison of their use in respiratory tract
infections. Scand J Infect Dis 1986; 18:561-566.
704. DuPont HL, Galindo E, Evens DG, et al: Prevention of traveler's diarrhea with trimethoprim-sulfamethoxazole and trimethoprim
alone. Gastroenterology 1983; 84:75-80.
705. Koch UJ, Schumann KP, Kuchler R, et al: Efficacy of trimethoprim, sulfamethoxazole and the combination in acute urinary tract
infection. Chemotherapy 1973; 19:314-321.
706. Kasanen A, Sundquist H, & Junnila SYT: Trimethoprim in the treatment of acute urinary tract infection. Curr Ther Res Clin Exp
1979; 25:202-209.
707. Lacey RW, Lord VL, Gunasekera HKW, et al: Comparison of trimethoprim alone with trimethoprim sulphamethoxazole in the
treatment of respiratory and urinary infections with particular reference to selection of trimethoprim resistance. Lancet 1980; 1:12701273.
708. Brumfitt W & Pursell R: Double-blind trial to compare ampicillin, cephalexin, co-trimoxazole, and trimethoprim in treatment of
urinary infection. Br Med J 1972; 2:673.
709. Keenan TD, Eliott JC, Bishop V, et al: Comparison of trimethoprim alone with cotrimoxazole and sulphamethizole for treatment of
urinary tract infections. N Z Med J 1983; 96:341-342.
710. Rundle JS & Scott R: Co-trimoxazole and trimethoprim in complicated urinary tract infection. Urology 1983; 11:645-647.
711. Stamm WE, Counts GW, Wagner KF, et al: Antimicrobial prophylaxis of recurrent urinary tract infections: a double-blind placebocontrolled trial. Ann Intern Med 1980; 92:770-775.
712. Smellie JM, Gruneberg RN, Bantock HM, et al: Prophylactic co-trimoxazole and trimethoprim in the management of urinary tract
infection in children. Pediatr Nephrol 1988; 2:12-17.
713. Colby C, McAfee SL, Sackstein R, et al: A prospective randomized trial comparing the toxicity and safety of atovaquone with
trimethoprim/sulfamethoxazole as Pneumocystis carinii pneumonia prophylaxis following autologous peripheral blood stem cell
transplantation. Bone Marrow Transplant 1999; 24:897-902.
714. Hajji M, El Mdaghri N, Benbachir M, et al: Prospective randomized comparative trial of pefloxacin versus cotrimoxazole in the
treatment of typhoid fever in adults. Eur J Clin Microbiol Infect Dis 1988; 7:361-363.
715. Gonzalez JP & Henwood JM: Pefloxacin: a review of its antibacterial activity, pharmacokinetic properties, and therapeutic use.
Drugs 1989; 37:628-668.
716. Petersen EE, Wingen F, Fairchild KL, et al: Single dose pefloxacin compared with multiple dose co-trimoxazole in cystitis. J
Antimicrob Chemother 1990; 26(suppl B):147-152.
717. Giebink GS, Batalden PB, Le CT, et al: A controlled trial comparing three treatments for chronic otitis media with effusion. Pediatr
Infect Dis J 1990; 9:33-40.
718. Jen I: A comparison of low dosage trimethoprim/sulfamethoxazole with oxytetracycline in acne vulgaris. Cutis 1980; 26:106-108.
719. Podzamczer D, Santin M, Jimenez J, et al: Thrice-weekly cotrimoxazole is better than weekly dapsone-pyrimethamine for the
primary prevention of Pneumocystis carinii pneumonia in HIV-infected patients. AIDS 1993; 7:501-506.
720. Ball AP & Geddes AM: Management of enteric fever with amdinocillin. Am J Med 1983; 75(suppl 2A):130-133.
721. Barnett E, Teele D, Klein J, et al: Comparison of ceftriaxone and trimethoprim-sulfamethoxazole for acute otitis media. Pediatrics
1997; 99:23-28.
722. Komoroski EM, Lensing SY, Portilla MG, et al: Single-dose intramuscular ceftriaxone for the treatment of uncomplicated cystitis in
children and adolescents. Curr Ther Res 1999; 60(11):580-594.
723. Iravani A & Richard GA: Single-dose ceftriaxone (Ro 13-9904) vs seven-day trimethoprim/sulfamethoxizole in treatment of acute
urinary tract infections (abstr 521), 23rd Intersci Conferance on Antimicrobial Agents Chemotherapy, Las Vegas, 1983.
724. Iravani A & Richard GA: Single-dose ceftriaxone versus multiple-dose trimethoprim-sulfamethoxazole in the treatment of acute
urinary tract infections. Antimicrob Agents Chemother 1985; 27:158-161.
725. Kavatha D, Giamarellou H, Alexiou Z, et al: Cefpodoxime-proxetil versus trimethoprim-sulfamethoxazole for short-term therapy of
uncomplicated acute cystitis in women. Antimicrob Agents Chemother 2003; 47(3):897-900.
726. Stintzing G & Moelby R: Colonization of the upper jejunum by enteropathogenic and enterotoxigenic Escherichia coli in pediatric
diarrhea. Acta Pediatr Scand 1982; 1:457-465.
727. Thoren A, Wolde-Mariam T, Stintzing G, et al: Antibiotics in the treatment of gastroenteritis caused by enteropathogenic
Escherichia coli. J Infect Dis 1980; 141:27-31.
728. Ball AP & Geddes AM: Management of enteric fever with amdinocillin. Am J Med 1983; 75(suppl 2A):130-133.
729. Thisyakorn U & Mansuwan P: Comparative efficacy of mecillinam, mecillinam/amoxicillin and trimethoprim-sulfamethoxazole for
treatment of typhoid fever in children. Pediatr Infect Dis J 1992; 11:979-980.
730. Figueroa-Damian R & Arredondo-Garcia A: Comparison of the clinical and microbiologic efficacy of single-dose ceftibuen, 3-dose
ceftibuten, and 7-day trimethoprim/sulfamethoxazole in the treatment of uncomplicated cystitis. Curr Ther Res 1999; 60(7):371-78.
731. Prado D, Lopez E, Liu H, et al: Ceftibuten and trimethoprim-sulfamethoxazole for treatment of Shigella and enteroinvasive
Escherichia coli disease. Pediatr Infect Dis J 1992; 11:644-647.
732. Schneider RE: A comparison of cinoxacin and co-trimoxazole in the treatment of cystitis. Clin Ther 1982; 5:510-514.
733. Burt RAP: Review of adverse reactions associated with cinoxacin and other drugs used to treat urinary tract infections. Urology
1984; 23:101-107.
734. Lee LH, Zaidman GW, & Van Horn K: Topical Bactrim versus trimethoprim and sulfonamide against Nocardia keratitis. Cornea
2001; 20(2):179-182.
735. Perry HD, Nauheim JS, Donnenfeld ED, et al: Nocardia asteroides keratitis presenting as a persistent epithelial defect. Cornea
1989; 8:41-44.
736. Donnenfeld ED, Cohen EJ, Barza M, et al: Treatment of nocardia keratitis with topical trimethoprim-sulfamethoxazole. Am J
Ophthalmol 1985; 99(5):601-602.
737. None Listed: Choice of antibacterial drugs. Treat Guidel Med Lett 2007; 5(57):33-50.PubMed Abstract:
http://www.ncbi.nlm.nih.gov/...PubMed Article: http://www.ncbi.nlm.nih.gov/...
738. Gross PA, Barrett Tl, Dellinger EP, et al: Purpose of quality standards for infectious diseases. Clin Infect Dis 1994; 18(3):421.
739. Gross PA, Barrett TL, Dellinger EP, et al: Purpose of quality standards for infectious diseases. Clin Infect Dis 1994; 18(3):421.
740. Gross PA, Barrett Tl, Dellinger EP, et al: Purpose of quality standards for infectious diseases. Clin Infect Dis 1994; 18(3):421.
741. CDC: USPHS/IDSA guidelines for the preventing opportunistic infections among HIV-infected persons. MMWR 2002; 51(RR-8):148.
742. Tursi A: Acute diverticulitis of the colon - current medical therapeutic management. Expert Opin Pharmacother 2004; 5(1):55-59.
743. Guernsey JM: Antibiotics in acute abdominal infections. Drug Ther 1976; 6:99.
744. Diner WC & Barnhart HJ: Acute diverticulitis. Semin Roentgenol 1973; 8:415-431.
745. Griffen WO: Management of the acute complications of diverticular disease: acute perforation of colonic diverticula. Dis Colon
Rectum 1976; 19:293-295.
746. Spiro HM (Ed): Clinical Gastroenterology, MacMillan Publishing Co, London, 1970, pp 555.
747. Rege RV & Nahrwold DL: Diverticular disease. Curr Probl Surg 1989; 26:133-189.
748. Barbezat GO: Rational treatment of diverticular disease. Drugs 1980; 19:63-69.
749. Pohlman T: Diverticulitis. Gastroenterol Clin North Am 1988; 17:357-385.
750. Finegold SM: Appendicitis and diverticulitis In: Hoeprich PD (Ed): Infectious Diseases, Harper & Row, Maryland, 1972, pp 697.
751. Condon RE: Management of the acute complications of diverticular disease: peritonitis and septicemia. Dis Colon Rectum 1976;
19:296-300.
752. Chappuis CW & Cohn I: Acute colonic diverticulitis. Surg Clin North Am 1988; 68:301-313.
753. Donnelly JP: Selective decontamination of the digestive tract and its role in antimicrobial prophylaxis. J Antimicrob Chemother
1993; 31:813-829.
754. Boom SJ & Ramsay G: Selective decontamination of the digestive tract in intensive care. Epidemiol Infect 1992; 109:337-347.
755. Craven DE: Use of selective decontamination of the digestive tract (editorial). Ann Intern Med 1992; 117:609-611.
756. Tetteroo GWM, Wagenvoort JHT, Mulder PGH, et al: Decreased mortality rate and length of hospital stay in surgical intensive care
unit patients with successful selective decontamination of the gut. Crit Care Med 1994; 21:1692-1698.
757. Van Saene HK, Stoutenbeek CC, & Stoller JK: Selective decontamination of the digestive tract in the intensive care unit: current
status and future prospects. Crit Care Med 1992; 20:691-703.
758. Occhipinti DJ, Itokazu G, & Danziger LH: Selective decontamination of the digestive tract as an infection-control measure in
intensive care unit patients. Pharmacotherapy 1992; 12:50S-63S.
759. Hathorn JW: Critical appraisal of antimicrobials for prevention of infections in immunocompromised hosts. Hematol/Oncol Clin N
Am 1993; 7:1051-1099.
760. Boom S & Ramsay G: Selective decontamination of the digestive tract. Drugs 1991; 42:541-550.
761. Gomez EC, Markowsky SJ, & Rotschafer JC: Selective decontamination of the digestive tract in intensive care patients: review
and commentary. Ann Pharmacother 1992; 26:963-976.
762. Kurrle E, Schmeiser T, & Kern W: Selective decontamination in neutropenic patients. Epidemiol Infect 1992; 109:327-335.
763. Kaufhold A, Behrendt W, Krauss T, et al: Selective decontamination of the digestive tract and methicillin-resistant staphylococcus
aureus (letter). Lancet 1992; 339:1411-1412.
764. Pizzo PA: Considerations for the prevention of infectious complications in patients with cancer. Rev Infect Dis 1989; 2:S1551S1563.
765. Wiesner RH: The incidence of gram-negative bacterial and fungal infections in liver transplant patients treated with selective
decontamination. Infection 1990; 18:S19-S21.
766. Korinek AM, Laisne MJ, Nicolas MH, et al: Selective decontamination of the digestive tract in neurosurgical intensive care unit
patients: a double-blind, randomized, placebo-controlled study. Crit Care Med 1993; 21:1466-1473.
767. Dummer JS, Hardy A, Poorsattar A, et al: Early infections in kidney, heart, and liver transplant recipients on cyclosporine.
Transplantation 1983; 36:259-267.
768. Wajszczuk CP, Dummer JS, Ho M, et al: Fugal infections in liver transplant recipients. Transplantation 1985; 40:347-353.
769. Mackie DP, van Hertum WAJ, Schumburg T, et al: Prevention of infection of burns: preliminary experience with selective
decontamination of the digestive tract in patients with extensive injuries. J Trauma 1992; 32:570-575.
770. McCaig LF, Besser RE, & Hughes JM: Trends in antimicrobial prescribing rates for children and adolescents. JAMA 2002;
287(23):3096-3102.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...PubMed Article: http://www.ncbi.nlm.nih.gov/...
771. Blumer JL: Fundamental basis for rational therapeutics in acute otitis media. Pediatr Infect Dis J 1999; 18(12):1130-1140.
772. Takata GS, Chan LS, Shekelle P, et al: Evidence assessment of management of acute otitis media: 1. The role of antibiotics in
treatment of uncomplicated acute otitis media.. Pediatrics 2001; 108:239-247.
773. Rovers MM, Glasziou P, Appelman CL, et al: Antibiotics for acute otitis media: a meta-analysis with individual patient data. Lancet
2006; 368(9545):1429-1435.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...PubMed Article: http://www.ncbi.nlm.nih.gov/...
774. Rubin LG & Papsin B: Policy Statement--Cochlear Implants in Children: Surgical Site Infections and Prevention and Treatment of
Acute Otitis Media and Meningitis. Pediatrics 2010; Epub:Epub.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...PubMed Article:
http://www.ncbi.nlm.nih.gov/...
775. American Academy of Family Physicians, American Academy of Otolaryngology-Head and Neck Surgery, & American Academy of
Pediatrics Subcommittee on Otitis Media With Effusion: Otitis media with effusion. Pediatrics 2004; 113(5):1412-1429.PubMed
Abstract: http://www.ncbi.nlm.nih.gov/...PubMed Article: http://www.ncbi.nlm.nih.gov/...
776. Dowell SF, Butler JC, Giebink GS, et al: Acute otitis media: management and surveillance in an era of pneumococcal resistance a report from the Drug-resistant Streptococcus Pneumoniae Therapeutic Working Group.. Pediatr Infect Dis J 1999; 18:1-9.
777. Alarcon-Segona: Lupus diathesis and hydralazine syndrome. N Engl J Med 1965; 272, 9, 462, 1965.
778. Pisetsky DS: Systemic lupus erythematosus. Med Clin North Am 1986; 70:337-353.
779. Carter JD, Valeriano-Marcet J, Kanik KS, et al: Antinuclear antibody-negative, drug-induced lupus caused by lisinopril. So Med J
2001; 94(11):1122-1123.
780. Stratton MA: Drug-induced systemic lupus erythematosus. Clin Pharm 1985; 4:657-663.
781. Cush JJ & Goldings EA: Drug induced lupus: clinical spectrum and pathogenesis. Am J Med Sci 1985; 290:36-45.
782. Alarcon-Segona: Drug induced lupus syndromes. Mayo Clin Proc 1969; 44:664.
783. Weinstein A: Drug-induced systemic lupus erythematosus. Prog Clin Immunol 1980; 4:1-21.
784. Hahn BH, Sharp GC, Irvin WS, et al: Immune response to hydralazine in SLE. Ann Intern Med 1972; 76:365.
785. Utsinger PD, Zvaifler NJ, & Bluestern HG: Hypocomplementemia in procainamide-associated systemic lupus erythematosus
(letter). Ann Intern Med 1976; 84:293.
786. Kale SA: Drug-induced systemic lupus erythematosus: differentiating it from the real thing. Postgrad Med 1985; 77:231-235, 238239, 242.
787. Reidenberg MM: The chemical induction of systemic lupus erythematosus and lupus-like illnesses. Arthritis Rheum 1981; 24:10041009.
788. Anon: Drug induced lupus syndrome. Med Lett Drug Ther 1974; 16,1,34, 1974.
789. Gross PA, Barrett TL, Dellinger EP, et al: Purpose of quality standards for infectious diseases. Clin Infect Dis 1994; 18:421.
790. Benson CA, Kaplan JE, & et al: Treating opportunistic infections among HIV-exposed and infected adults and adolescents:
recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. Clin Infect Dis 2005;
40(Suppl):S131-S235.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...PubMed Article: http://www.ncbi.nlm.nih.gov/...
791. Tomblyn M, Chiller T, Einsele H, et al: Guidelines for preventing infectious complications among hematopoietic cell transplantation
recipients: a global perspective. Biol Blood Marrow Transplant 2009; 15(10):1143-1238.PubMed Abstract:
http://www.ncbi.nlm.nih.gov/...PubMed Article: http://www.ncbi.nlm.nih.gov/...
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