Download 12th Lecture 1435

PHL 424
Antimicrobials
12th Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Sulphonamides, Resistance & Pharmacokinetics
 Resistance,
 Sulfonamide resistance may occur as a result of mutations that cause:
1. overproduction of the natural substrate, PABA
2. production of an altered dihydropteroate synthetase that has low affinity for
sulfonamides
3. decreased permeability to the sulfonamide or active efflux of the drug
 Pharmacokinetics
 Most sulfonamides are readily absorbed in the GIT and reach maximum
concentrations in the plasma in 4-6 hours
Approximately 70% to 100% of an oral dose is absorbed
 Sulfonamides are distributed throughout all tissues of the body
They pass into inflammatory exudates and cross both placental and BBB
 A portion of absorbed drug is acetylated or glucuronidated in the liver. Sulfonamides
and inactivated metabolites are then excreted into the urine
In significant renal failure, the dosage of sulfonamide must be reduced
Sulphonamides, Actions & Uses
 Actions:
 Sulphonamides are broad spectrum bacteriostatic agents effective against Grampositive & Gram-negative bacteria
 They are bacteriostatic not bactericidal (i.e. they suppress division of the cells but
do not kill them), and are therefore only really effective in the presence of
adequate host defences
Activity is reduced in the presence of high levels of PABA, e.g., in pus
 Clinical Uses:
 For urinary tract, respiratory infections and ulcerative colitis
 Combined with pyrimethamine (which interferes with folic acid synthesis by inhibiting
the enzyme dihydrofolate reductase) for drug-resistant malaria and for toxoplasmosis
 Combined with trimethoprim (co-trimoxazole) for Pneumocystis carinii, which causes
pneumonia in patients with AIDS
 For skin wounds and infected burns (silver sulfadiazine given topically)
In burn units, sulfadiazine has been effective in reducing burn-associated sepsis,
because it prevents colonization of bacteria
 Sulfonamides are as efficacious as oral penicillin in preventing streptococcal
infections and recurrences of rheumatic fever among susceptible subjects
 For some sexually transmitted infections (e.g. trachoma, chlamydia)
Sulphonamides, Side Effects
 Side effects:
1. Hypersensitivity reactions (e.g., rashes and drug fever) in a small number of
patients
Other rare allergic reactions include photosensitivity, agranulocytosis and
thrombocytopenia
Stevens-Johnson syndrome is also associated with sulfonamide use
 It is characterized by fever, malaise, erythema and ulceration of the mucous
membranes of the mouth and genitalia
2. High concentration of sulfonamides with sufficiently low aqueous solubility may
cause the free drug or its metabolites to form crystals and cause bleeding or
complete obstruction of the kidneys. This may be controlled by:
I.
Administration of combinations of sulfa drugs (for lowering the dosage of
individual agents)
II. Increasing fluid intake
III. Alkalinization of the urine (e.g., by administration of sodium bicarbonate) to increase
sulfonamide excretion). This should reduce the chance of and can treat crystalluria
3. Sulfonamides can cause hemolytic or aplastic anemia
4. Sulfonamides may provoke hemolytic reactions in patients whose red cells are
deficient in glucose-6-phosphate dehydrogenase (idiosyncratic reaction)
Sulphonamides, Drug-drug interactions
 Drug-drug interactions:
1. Sulfonamides compete for sites on plasma proteins that are responsible for the
binding of bilirubin. As a result, less bilirubin is bound, and in the newborn, the
unbound bilirubin can be deposited in the basal ganglia, causing kernicterus (a
toxic encephalopathy)
For this reason, sulfonamides should not be administered to newborns or to women
during the last 2 months of pregnancy or lactating females
2. They can potentiate the effects of other drugs including oral anticoagulants &
the sulfonylurea hypoglycemic agents by mechanisms that appear to involve
primarily inhibition of metabolism and, possibly, displacement from albumin
Trimethoprim,
Overview, Basis for selective toxicity & Resistance
 The introduction of trimethoprim in combination with sulfamethoxazole cotrimoxazole
constitutes an important advance in the development of clinically effective antimicrobial
agents. Trimethoprim also is available as a single-entity preparation
 It also represents the practical application of a theoretical consideration; i.e., if two drugs
act on sequential steps in the pathway of an obligate enzymatic reaction in bacteria, the
result of their combination will be synergistic
 Basis for selective toxicity:
 Trimethoprim is a highly selective inhibitor of DHFR of lower organisms: About 100,000
times more drug is required to inhibit human reductase than the bacterial enzyme
 This relative selectivity is vital because this enzymatic function is essential to all species
 Similar to sulfonamides, trimethoprim alone is bacteriostatic. Its combination with
sulfonamides is often bactericidal (synergism)
 Resistance:
 Resistance in G-ve bacteria is due to the presence of an altered DHFR that has a lower
affinity for trimethoprim
 Overproduction of DHFR may also lead to resistance
 Genetic mutation so that bacteria do not need to make folic acid; they utilize already
formed folic acid
 Reduced drug permeability
 The combination with sulfamethoxazole will delay the emergence of resistance
Trimethoprim, Pharmacokinetics
 Pharmacokinetics
 Trimethoprim is usually given orally, alone or in combination with sulfamethoxazole,
the latter chosen because it has a similar t1/2. Trimethoprim-sulfamethoxazole can
also be given intravenously
 It is absorbed efficiently from the gut and distributed widely in body fluids and tissues,
including CSF
 Because trimethoprim is more lipid-soluble than sulfamethoxazole, it has a larger
volume of distribution than the latter drug
 Therefore, when 1 part of trimethoprim is given with 5 parts of sulfamethoxazole (the
ratio in the formulation), the peak plasma concentrations are in the ratio of 1:20,
which is optimal for the combined effects of these drugs in vitro
 Both sulfonamide and trimethoprim (or their respective metabolites) are excreted in
urine within 24 h. The dose should be reduced for patients with renal insufficiency
 Trimethoprim concentrates in prostatic fluid and in vaginal secretions. Thus, it has
more antibacterial activity in prostatic and vaginal fluids than many other antimicrobial
drugs
Trimethoprim, Antibacterial Activity & Uses
 Antibacterial Activity :
 The antibacterial spectrum of trimethoprim is similar to that of sulfamethoxazole,
although the former drug usually is 20 to 100 times more potent than the latter
 It is active against most G+ve and G-ve organisms. There is little activity against
anaerobic bacteria
 Uses
 Trimethoprim may be used alone in the treatment of acute urinary tract infections
 There is synergy between trimethoprim and sulfamethoxazole ; the combined effect is
greater that the expected sum of their activities. This combination is used for the
treatment of:
Chronic urinary tract infections
GI infections caused by ampicillin-resistant Shigella and for antibiotic-resistant
Salmonella
Traveler’s diarrhea due to susceptible E. coli
Prostatitis and vaginitis caused by sensitive organisms. This is because
trimethoprim accumulates in the prostatic fluid and vaginal secretions
Pneumocystis jiroveci pneumonia which occurs in HIV patients
Respiratory tract infections
Trimethoprim, Uses, contd.
Trimethoprim, Side Effects
 Side effects:
1. Trimethoprim can produce the effects of folic acid deficiency. These effects
include megaloblastic anemia, leukopenia and granulocytopenia, especially in
pregnant patients and those having very poor diets
These blood disorders can be reversed by the simultaneous administration of folinic
acid, which does not enter bacteria
There is no evidence that trimethoprim-sulfamethoxazole, when given in the
recommended doses, induces folate deficiency in normal persons
2. The combination trimethoprim-sulfamethoxazole may cause all of the untoward
reactions associated with sulfonamides, but may be to a lesser degree
3. Nausea and vomiting are the major GI reactions; diarrhea is rare. Glossitis and
stomatitis are relatively common