Download Urinary Tract Infections: From Simple to Complex Learning

10/12/2014
Urinary Tract Infections:
From Simple to Complex
Adriane N Irwin, MS, PharmD, BCACP
Clinical Assistant Professor – Ambulatory Care
October 25, 2014
Learning Objectives
• Develop empiric antimicrobial treatment regimens for
acute uncomplicated and complicated urinary tract
infections (UTIs)
• Develop antimicrobial treatment regimens for UTIs in
response to specific culture and susceptibility testing
• Assess treatment options for complex patient cases
1
Urinary Tract Infections
Introduction
• Presence of microorganisms
in the urinary tract that
cannot be accounted for by
contamination
• Two types of urinary tract
infection
• Cystitis: Involves the lower
urinary tract (bladder)
• Pyelonephritis: Involves the
upper urinary tract (kidney)
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10/12/2014
Uncomplicated
Complicated
- Cystitis
- Pyelonephritis
- Patient characteristics
- Patient characteristics
- Women of child bearing age
- Men
- No structural and/or
functional abnormalities
- Structural and/or function
abnormalities (catheters,
obstructions, neurologic
deficits, transplant)
- Pathogens
- Pathogens
Primary: Escherichia coli
(80%)
Other: Enterobacteriaceae
(Klebsiella & Proteus species)
Primary: Escherichia coli
(50%)
Other: Enterococcus species,
miscellaneous gram negatives
(Pseudomonas aeruginosa)
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Diagnosis
Introduction
• Symptoms suggestive of cystitis:
• Dysuria
• Possibly with any of the following: frequency, urgency, suprapubic
pain or heaviness, hematuria
• Symptoms suggestive of pyelonephritis:
• Any indication of upper tract or systemic disease: nausea/vomiting,
fever, flank pain, costovertebral angle tenderness, fatigue
• Dysuria or other classic symptoms of cystitis may not be present
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Diagnosis
Introduction
• Patient populations that can present with asymptomatic
bacteriuria:
•
•
•
•
Elderly
Children
Pregnant women
Patients with indwelling catheters
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Goals of Treatment
Introduction
1. Eradicate the invading organism
2. Prevent (and treat) systemic consequences of
infection
3. Prevent recurrence
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Antibiotic Selection
Treatment
• Choice of agent should be individualized based on:
•
•
•
•
•
•
•
Allergies
Patient compliance history
Most likely organism(s)
Local susceptibility
Cost
Availability
Provider threshold for failure
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Terminology
Treatment
• Empiric therapy:
• Treatment prior to a firm diagnosis
• Antibiotic treatment given before specific microorganism and
susceptibilities are known
• Culture driven therapy:
• Antibiotic treatment tailored to the microorganism
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Uncomplicated Cystitis
Treatment
• Woman with…
• Absence of symptoms suggestive of pyelonephritis
• Able to take oral medication
Empiric Treatment Recommendations
nitrofurantoin
100 mg BID x 5 days
trimethoprim/sulfamethoxazole
(TMP/SMX)
160/800 mg BID x 3
days
fosfomycin
3 g as a single dose
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Gu tp a K e t a l . Cl i n In fe ct Di s. 2 0 11 ;5 2:e 1 0 3-2 0 .
Empiric Agents:
nitrofurantoin
TMP/SMX
fosfomycin
Nitrofurantoin:
- Avoid if
pyelonephritis is
suspected
- CrCl < 60
mL/min
TMP/SMX:
- Avoid if E. coli
resistance ≥ 20%
or unknown
- Use in previous 3
months
Fosfomycin:
- Avoid if
pyelonephritis is
suspected
- Lower efficacy
- Availability (?)
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Gu tp a K e t a l . Cl i n In fe ct Di s. 2 0 11 ;5 2:e 1 0 3-2 0 .
Empiric Agents:
nitrofurantoin
TMP/SMX
fosfomycin
Fluoroquinolone:
- Resistance prevalence high is
some areas
Alternate Agents:
fluoroquinolone
β-lactam
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β-lactam:
- Lower efficacy than other agents
so close follow-up recommended
- Avoid ampicillin or amoxicillin
alone
Gu tp a K e t a l . Cl i n In fe ct Di s. 2 0 11 ;5 2:e 1 0 3-2 0 .
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Uncomplicated Cystitis
Treatment
Culture Driven Recommendations
TMP/SMX
160/800 mg BID x 3 days
nitrofurantoin
100 mg BID x 5 days
fosfomycin
3 g single dose
ciprofloxacin
250 mg BID x 3 days
levofloxacin
250 mg daily x 3 days
amoxicillin/clavulanat e
500/125mg BID x 5 – 7 days
cefuroxime
500 mg BID x 3-7 days
trimethoprim
100 mg BID x 3 – 5 days
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Complicated Cystitis
Treatment
• E coli resistance to TMP/SMX < 20%
• Preferred: TMP/SMX x 3 days
• Alternatives:
• nitrofurantoin x 5 days
• fluoroquinolone x 3 days (reserved for patients with multiple intolerances)
• E coli resistance to TMP/SMX ≥ 20%
• nitrofurantoin x 7 days
• fluoroquinolone x 5 – 7 days
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Pyelonephritis
Treatment
• Both complicated and uncomplicated infections
• Important to obtain urine culture with sensitivities
Empiric Treatment Recommendations
Preferred: fluoroquinolone x 7 days*
Alternatives: TMP/SMX or broad spectrum cephalosporin
x 14 days
Not suitable: nitrofurantoin and fosfomycin
* Consider initial dose of parental antibiotic if local E coli resistance to
fluoroquinolone is > 10%, patients who require treatment response to avoid
hospital admission, or patients with fluoroquinolone use in past 3 months
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Gu tp a K e t a l . Cl i n In fe ct Di s. 2 0 11 ;5 2:e 1 0 3-2 0 .
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Patient Case 1:
PT is a 23 year old female with a past medical history of allergic
rhinitis. Her only medication is an estrogen containing oral
contraceptive and only known drug allergy is a history of rash
when she takes “sulfa drugs.” She calls her primary care provider
(PCP) today describing recent onset of dysuria and urinary
urgency. She denies any fever, chills, or flank pain.
Which of the following is the best therapeutic choice for PT ?
1. Nitrofurantoin monohydrate 100 mg BID x 5 days
2. Ciprofloxacin 500 mg BID x 3 days
3. Fosfomycin 3 g packet as a single dose
4. TMP/SMX 1 DS tablet BID x 3 days
15
Patient Case 1:
PT’s PCP collects a urine sample for UA and culture and starts her
on nitrofurantoin as empiric therapy. Two days later, the culture
results are finalized (next slide).
Does PT need to be changed to culture driven therapy?
1. Yes
2. No
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ESCHERICHIA COLI
Antibiotic
Sensitivity
SuscT ype
Status
Ampicillin
Resistant
>= 32
Final
Cefazolin
Resistant
>= 64
Final
Ceftriaxone
Resistant
>= 64
Final
Ciprofloxacin
Resistant
>= 4
Final
Ertapenem
Susceptible
<=0.5
Final
Gentamicin
Resistant
>= 16
Final
Imipenem
Susceptible
<=1
Final
Nitrofurantoin
Susceptible
32
Final
Tobramycin
Intermediate
8
Final
T rimethoprim +
Sulfamethoxazole
Resistant
>=320
Final
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Patient Case 2:
PT is a 78 year old female with a past medical history of allergic
hypertension and hyperlipidemia. Her only medications are
lisinopril 10 mg and pravastatin 20 mg. She has NKDA. Her annual
labs were completed about 1 month ago. At the time, her SCr was
1.2 mg/dL (CrCl 48 mL/min). She calls her PCP today describing
recent onset of dysuria and urinary urgency. She denies any fever,
chills, or flank pain.
Which of the following is the best therapeutic choice for PT ?
1. Nitrofurantoin monohydrate 100 mg BID x 5 days
2. Ciprofloxacin 500 mg BID x 3 days
3. Fosfomycin 3 g packet as a single dose
4. TMP/SMX 1 DS tablet BID x 3 days
18
Patient Case 2:
PT’s PCP collects a urine sample for UA and culture and starts her
on TMP/SMX as empiric therapy. Two days later, the culture results
are finalized (next slide).
Does PT need to be changed to culture driven therapy?
1. Yes
2. No
19
ESCHERICHIA COLI
Antibiotic
Sensitivity
SuscT ype
Status
Ampicillin
Resistant
>= 32
Final
Cefazolin
Resistant
>= 64
Final
Ceftriaxone
Resistant
>= 64
Final
Ciprofloxacin
Resistant
>= 4
Final
Ertapenem
Susceptible
<=0.5
Final
Gentamicin
Resistant
>= 16
Final
Imipenem
Susceptible
<=1
Final
Nitrofurantoin
Susceptible
32
Final
Tobramycin
Intermediate
8
Final
T rimethoprim +
Sulfamethoxazole
Resistant
>=320
Final
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Nitrofurantoin &
Reduced Renal Function
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Introduction
Nitrofurantoin & Reduced Renal Function
• Current package labeling states that the use of
nitrofurantoin is contraindicated in patients with a CrCl
< 60 mL/min
• Historical perspective:
• 1988: Macrodantin product information had a CrCl < 40
mL/min
• 2003: Macrobid product information had a CrCl < 60 mL/min
• Why?
• Concentrations may be insufficient to treat infection
• Increased risk of side effects
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Urinary Excretion Data
Nitrofurantoin & Reduced Renal Function
CrCl (mL/min)
Patients & Dose
Outcomes
N = ~ 18
100 mg x 1
Max concentration
(mg/dL) 10-hr urine
collection
Schlegel
(1967)
N = ~ 11
100 mg repeated
Lippman
(1958)
Felts
(1971)
N=8
50 mg repeated
N=6
100 mg x 1
Sachs
(1968)
< 20
20 – 40
41 – 60
> 60
<5
<5 –
< 10
< 5 – 15
< 5 - 15
Amount (mg), 24-hr urine
collection
< 50
75 – 150
25 – 150
100 250
Mean (range) maxurine
concentration (mg/dL)
Mean (range) maxurine
concentration (mg/dL)
“Normal” renal function: 11 (4 – 23)
“Azotemia:” 2 (0- 5)
“Normal” renal function: 7.4 (0.6 – 10.6)
Renal insufficiency:
CrCl < 20 mL/min: 0.6
CrCl 20 – 59 mL/min: 1.6
Ta b l e a d a p te d fro m Op l i ng e r M e t al . An n Ph a rm ac o th e r. 20 1 3 ;47 :1 06 -1 1 .
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Sa c h s J e t a l . Ne w En gl J M e d. 1 9 68 ;2 7 8;1 0 32 -5 .
Sc h l e g a l J U e t a .l Ge n i tou ri n Surg . 1 96 7 ;5 9:3 2 -6.
L i p p m a n RW e t a l . J Uro l . 1 9 5 8;8 0 :77 -8 1 .
Fe l ts J H e t a l . Am J M ed . 1 97 1 ;51 :3 3 1-9 .
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Study Limitations
Nitrofurantoin & Reduced Renal Function
• The number of patients included within each CrCl
group is unclear
• Information on key parts of the methodology is scarce
• Endpoints not consist between studies and may not be
consistent with treatment dosing and/or clinical
practice
• No evaluation of clinical endpoints
24
Clinical Data
Nitrofurantoin & Reduced Renal Function
• Retrospective chart review of 356 patients treated with
nitrofurantoin for suspected UTI between 2004 – 2008
in long-term and acute care hospitals
• Impaired renal function was defined as CrCl < 50
mL/min
• Primary endpoint:
• Clinical cure: Absence of clinical symptoms and no additional
antimicrobials within 14 days of nitrofurantoin treatment
completion
• Microbiologic cure: Repeat negative cultures
25
Ba i n s A e t a l . Ca n Ph a rm J . 2 0 0 9;1 4 2:2 4 8 -2.
Clinical Data
Nitrofurantoin & Reduced Renal Function
• Primary endpoint:
• Cure rates were comparable in both groups - - 71% (95% CI 63
– 79) in the renally impaired groups vs 78% (95% CI 73 – 84).
• Limitations:
• Retrospective nature
• Suspected UTI (not microbiologically confirmed)
• Relatively moderate renal impairment (average CrCl 40
mL/min, range 15 – 50 mL/min)
• Under powered
• Selection bias as patients needed to be hospitalized at 14 days
26
Ba i n s A e t a l . Ca n Ph a rm J . 2 0 0 9;1 4 2:2 4 8 -2.
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Conclusions
Nitrofurantoin & Reduced Renal Function
• There is a need for additional research that incorporates
clinical outcomes to better assess the use of nitrofurantoin
in patients with reduced renal function
• Conflict exists between package labeling and the realities of
clinic practice including implementation of the IDSA
guidelines
• Use of nitrofurantoin in patients with in patients with
reduced renal function should be evaluated on a case by
case basis
27
Patient Case 2:
PT’s PCP had started her on TMP/SMX. However, after seeing the
results of her urine culture decides to changes her antibiotic
therapy.
Which of the following is now the best option for PT ?
1. Start nitrofurantoin monohydrate 100 mg BID x 5 days
2. Start ertapenem 1 g IM qday
3. Call the laboratory to see if they have susceptibilities to
fosfomycin.
4. All of the above
28
ESCHERICHIA COLI
Antibiotic
Sensitivity
SuscT ype
Status
Ampicillin
Resistant
>= 32
Final
Cefazolin
Resistant
>= 64
Final
Ceftriaxone
Resistant
>= 64
Final
Ciprofloxacin
Resistant
>= 4
Final
Ertapenem
Susceptible
<=0.5
Final
Gentamicin
Resistant
Imipenem
Nitrofurantoin
Tobramycin
T rimethoprim +
Sulfamethoxazole
Finalthe best
Which>=of16
the following is now
for PT ?
Susceptible option
<=1
Final
1.
Start nitrofurantoin monohydrate 100
Susceptible
32
Final
mg BID x 5 days
Intermediate 2.
8
Final
Start ertapenem 1 g IM
qday
3.
Call the laboratory toFinal
see if they have
Resistant
>=320
susceptibilities to fosfomycin.
4.
All of the above
29
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UTIs & ESBL Producing Organisms
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“…alarmed by the prospect that
effective antibiotics may not be
available to treat seriously ill
patients in the near future.”
— Joseph R Dalovisio, MD, IDSA President
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Introduction
ESBL Producing Organisms
What is an ESBL?
• Extended spectrum β-lactamase(ESBL)
• Beta lactamase capable of hydrolyzing…
• Pencillins
• Cephalosporins
• Monobactams (e.g., aztreonam)
• Plasmid mediated form of resistance - - > Multiple resistance
genes transferred between bacteria
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Antibiotic Resistance Pattern
ESBL Producing Organisms
Auer et al
(2010)
Ena et al
(2006)
Melzer et al
(2007)
Source
Antibiotic
Urine
Urine
Blood
Ampicillin
-
0%
0%
Ceftazidime
-
0%
0%
Carbapenem
100%
100%
100%
68.4%
Aminoglycoside
78%
79%
Ciprofloxacin
22%
43%
8.7%
TMP/SMX
27%
48%
15.2%
Nitrofurantoin
94%
92%
-
Trimethoprim/sulfamethoxazole (TMP/SMX)
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Clinical Data
ESBL Producing Organisms
Study Design
Subjects
Primary Endpoint & Conclusion
Burgess
(2003)
Retrospective
cohort study
ESBL
infections
(n = 18)
1˚ endpoint: Clinical cure
– Carbapenem: 100%
– Pip/tazo + FQ or AG: 56%
Endimiani
(2004)
Retrospective
cohort study
ESBL
1˚ endpoint: Clinical failure
K pneumoniae
– Imipenem: 20% (2 of 10)
bacteremia
– Ciprofloxacin: 71.4% (5 of 7)
(n = 17)
Paterson
(2004)
Prospective
cohort study
ESBL
1˚ endpoint: Mortality
K pneumoniae
– Carbapenem: 4.8%
bacteremia
– Non-carbapenem: 27.6%
(n = 71)
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Conclusions
ESBL Producing Organisms
• Most clinical literature on the treatment of ESBL bacteria
involves parental agents in the hospital setting.
• Current literature provides little guidance on managing
UTIs in the outpatient setting. Selecting therapy requires
assessment of infection severity, patient characteristics, and
patient convenience.
• Fluoroquinolones, nitrofurantoin, TMP/SMX, and possibly
fosfomycin are usually the only oral antibiotics to consider
when reviewing an ESBL susceptibility report.
35
Pullukcu H et al. In J AntimicrobAgents. 2007;29:62-5.
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Common Questions
36
UTI Recurrences
Common Questions
• Recurrences generally do not require prolonged
therapy and can be treated with standard empiric
therapy.
• Time to recurrence:
• Less than 6 months - - > Choose a different agent
• Greater than 6 months - - > May choose same agent
37
UTI Recurrences
Common Questions
• Recurrences generally do not require prolonged
therapy and can be treated with standard empiric
therapy.
• Time to recurrence:
• Less than 6 months - - > Choose a different agent
• Greater than 6 months - - > May choose same agent
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Prophylaxis
Common Questions
1. Self initiated therapy at the onset of symptoms
2. Postcoital therapy
3. Continuous low dose prophylaxis
‾
‾
‾
‾
Individuals with > 3 episodes per year
Nitrofurantoin 50 mg qday x 6 months
TMP/SMX ½ SS tablet qday x 6 months
Other agents may be acceptable based on patient characteristics
39
UTIs & Pregnancy
Common Questions
• Asymptomatic bacteriuria in pregnancy translates to an
increased risk - - > (1) pyelonephritis and (2) preterm
delivery and low birth weight
• Optimal agent and duration is unclear. Culture with
sensitivities often recommended prior to selection of agent
Good
β-lactams*
Okay
T MP/SMX and nitrofurantion
(except in women near term)
Avoid
tetracyclines, fluoroquinolones
*Due to resistance, may need to consider broad-spectrum oral
cephalosporins such as cefuroxime or cefpodoxime
40
Cefuroxime Susceptibility
Common Questions
• Most E. coli are susceptible to cefuroxime
• Reasonable empiric choice for symptomatic patients and/or
pregnant women with bacteriuria
• Culture results:
• cefazolin (susceptible) - - > cefuroxime (susceptible)
• ceftriaxone (susceptible) - - > cefuroxime (likely susceptible)
• ceftriaxone (resistant) - - > cefuroxime (resistant)
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Enterococcus Species
Common Questions
• Preferred - - > amoxicillin or nitrofurantoin
• Alternatives - - ->
• linezolid: not renally eliminated
• vancomycin: often the only option due to resistance, intolerances, and
renal impairment
• Not acceptable - - > cephalosporins
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Urinary Tract Infections:
From Simple to Complex
Adriane N Irwin, MS, PharmD, BCACP
Clinical Assistant Professor – Ambulatory Care
October 25, 2014
15