PHL 424 Antimicrobials

12th Lecture

By

Abdelkader Ashour, Ph.D. Phone: 4677212 Email: aeashour@ksu.edu.sa

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

Sulphonamides, Resistance & Pharmacokinetics

Pharmacokinetics Most sulfonamides are readily absorbed in the GIT and reach maximum

concentrations in the plasma in 4-6 hoursApproximately 70% to 100% of an oral dose is absorbed

Sulfonamides are distributed throughout all tissues of the bodyThey 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

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)

Actions: Sulphonamides are broad spectrum bacteriostatic agents effective against Gram-

positive & 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

Sulphonamides, Side Effects

Side effects:1. Hypersensitivity reactions (e.g., rashes and drug fever) in a small number of

patientsOther 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 intakeIII. 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 infectionsGI infections caused by ampicillin-resistant Shigella and for antibiotic-resistant SalmonellaTraveler’s diarrhea due to susceptible E. coliProstatitis and vaginitis caused by sensitive organisms. This is because trimethoprim accumulates in the prostatic fluid and vaginal secretionsPneumocystis jiroveci pneumonia which occurs in HIV patientsRespiratory 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 bacteriaThere 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