A. Classification and Pharmacokinetics
The antifolate drugs used in the treatment of infectious diseases are the sulfonamides, which inhibit microbial enzymes involved in folic acid synthesis, and trimethoprim, a selective inhibitor of dihydrofolate reductase.
The sulfonamides are weakly acidic compounds that have a common chemical nucleus resembling p-aminobenzoic acid (PABA). Members of this group differ mainly in their pharmacokinetic properties and clinical uses. Pharmacokinetic features include modest tissue penetration, hepatic metabolism, and excretion of both intact drug and acetylated metabolites in the urine. Solubility may be decreased in acidic urine, resulting in precipitation of the drug or its metabolites. Because of the solubility limitation, a combination of 3 separate sulfonamides (triple sulfa) has been used to reduce the likelihood that any one drug will precipitate. The sulfonamides may be classified as short-acting (eg, sulfisoxazole), intermediate-acting (eg, sulfamethoxazole), and long-acting (eg, sulfadoxine). Sulfonamides bind to plasma proteins at sites shared by bilirubin and by other drugs.
This drug is structurally similar to folic acid. It is a weak base and is trapped in acidic environments, reaching high concentrations in prostatic and vaginal fluids. A large percentage of trimethoprim is excreted unchanged in the urine. The half-life of this drug is similar to that of sulfamethoxazole (10–12 h).
High-Yield Terms to Learn
|Antimetabolite ||A drug that, through chemical similarity, is able to interfere with the role of an endogenous compound in cellular metabolism |
|Sequential blockade ||The combined action of 2 drugs that inhibit sequential steps in a pathway of bacterial metabolism |
|DNA gyrase ||Bacterial topoisomerase responsible for negative supercoiling of double-stranded DNA that balances the positive supercoiling of DNA replication, preventing damage to the DNA strand |
|Topoisomerase IV ||Bacterial topoisomerase initiating decatenation, the mechanism by which 2 daughter DNA molecules are separated at the conclusion of DNA replication |
The sulfonamides are bacteriostatic inhibitors of folic acid synthesis. As antimetabolites of PABA, they are competitive inhibitors of dihydropteroate synthase (Figure 46–1). They can also act as substrates for this enzyme, resulting in the synthesis of nonfunctional forms of folic acid. The selective toxicity of sulfonamides results from the inability of mammalian cells to synthesize folic acid; they must use preformed folic acid that is present in the diet.
Inhibitory effects of sulfonamides and trimethoprim on folic acid synthesis. Inhibition of 2 successive steps in the formation of tetrahydrofolic acid constitutes sequential blockade and results in antibacterial synergy.
Trimethoprim is a selective inhibitor of bacterial dihydrofolate reductase that prevents formation of the active tetrahydro form of folic acid (Figure 46–1). Bacterial dihydrofolate reductase is 4–5 orders of magnitude more sensitive to inhibition by trimethoprim than the mammalian enzyme.
3. Trimethoprim plus sulfamethoxazole
When the 2 drugs are used in combination, antimicrobial synergy results from the sequential blockade of folate synthesis (Figure 46–1). The drug combination is bactericidal against susceptible organisms.
Bacterial resistance to sulfonamides is common and may be plasmid-mediated. It can result from decreased intracellular accumulation of the drugs, increased production of PABA by bacteria, or a decrease in the sensitivity of dihydropteroate synthase to the sulfonamides. Clinical resistance to trimethoprim most commonly results from the production of dihydrofolate reductase that has a reduced affinity for the drug.
The sulfonamides are active against gram-positive and gram-negative organisms, Chlamydia, and Nocardia. Specific members of the sulfonamide group are used by the following routes for the conditions indicated:
a. Simple urinary tract infections
Oral (eg, triple sulfa, sulfisoxazole).
Topical (eg, sulfacetamide).
d. Ulcerative colitis, rheumatoid arthritis
Oral (eg, sulfa-salazine).
Oral sulfadiazine plus pyrimethamine (a dihydrofolate reductase inhibitor) plus folinic acid.
2. Trimethoprim-sulfamethoxazole (TMP-SMZ)
This drug combination is effective orally in the treatment of urinary tract infections and in respiratory, ear, and sinus infections caused by Haemophilus influenzae and Moraxella catarrhalis. In the immunocompromised patient, TMP-SMZ is used for infections due to Aeromonas hydrophila and is the drug of choice for prevention and treatment of pneumocystis pneumonia. An intravenous formulation is available for patients unable to take the drug by mouth and is used for treatment of severe pneumocystis pneumonia and for gram-negative sepsis. TMP-SMZ is also the drug of choice in nocardiosis, a possible backup drug for cholera, typhoid fever, and shigellosis, and has been used in the treatment of infections caused by methicillin-resistant staphylococci and Listeria monocytogenes.
E. Toxicity of Sulfonamides
Allergic reactions, including skin rashes and fever, occur commonly. Cross-allergenicity between the individual sulfonamides should be assumed and may also occur with chemically related drugs (eg, oral hypoglycemics, thiazides). Exfoliative dermatitis, polyarteritis nodosa, and Stevens-Johnson syndrome have occurred rarely.
Nausea, vomiting, and diarrhea occur commonly. Mild hepatic dysfunction can occur, but hepatitis is uncommon.
Although such effects are rare, sulfonamides can cause granulocytopenia, thrombocytopenia, and aplastic anemia. Acute hemolysis may occur in persons with glucose-6-phosphate dehydrogenase deficiency.
Sulfonamides may precipitate in the urine at acidic pH, causing crystalluria and hematuria.
Competition with warfarin and methotrexate for plasma protein binding transiently increases the plasma levels of these drugs. Sulfonamides can displace bilirubin from plasma proteins, with the risk of kernicterus in the neonate if used in the third trimester of pregnancy.
Trimethoprim can cause the predictable adverse effects of an antifolate drug, including megaloblastic anemia, leukopenia, and granulocytopenia. These effects are usually ameliorated by supplementary folinic acid. The combination of TMP-SMZ may cause any of the adverse effects associated with the sulfonamides. AIDS patients given TMP-SMZ have a high incidence of adverse effects, including fever, rashes, leukopenia, and diarrhea.