Sulfonamides are structural analogs of p-aminobenzoic acid (PABA) and compete with PABA to block its conversion to dihydrofolic acid. Organisms that utilize PABA in the synthesis of folates and pyrimidines are inhibited. Animal cells and some resistant microorganisms (eg, enterococci) use exogenous folate and thus are not affected by sulfonamides.
Trimethoprim and pyrimethamine are compounds that inhibit the conversion of dihydrofolic acid to tetrahydrofolic acid by blocking the enzyme dihydrofolate reductase. These two agents are generally used in combination with other medications (usually sulfonamides) to prevent or treat a number of bacterial and parasitic infections. At high doses, all can inhibit mammalian dihydrofolate reductase, but clinically this is a problem only with pyrimethamine. Folinic acid (leucovorin) is given concurrently with pyrimethamine to prevent bone marrow suppression.
Sulfonamides alone are rarely used in the treatment of bacterial infection. When used in combination with other medications, sulfonamides are useful in the treatment of toxoplasmosis and pneumocystosis.
The combination of trimethoprim (one part) plus sulfamethoxazole (five parts) is bactericidal for E coli, Klebsiella, Enterobacter, Salmonella, and Shigella, though substantial resistance has emerged with all these organisms. It is also active against many strains of M catarrhalis, H influenzae, H ducreyi, L monocytogenes, Serratia, Providencia, S maltophilia, B cepacia (formerly Pseudomonas cepacia), and Burkholderia pseudomallei, but not against P aeruginosa. It is inactive against anaerobes and enterococci but inhibits most Nocardia and S aureus (including methicillin-resistant S aureus) but only 50% of S epidermidis isolates.
PHARMACOKINETICS & ADMINISTRATION
Trimethoprim-sulfamethoxazole is well absorbed from the gastrointestinal tract and widely distributed in tissues and fluids, including cerebrospinal fluid, achieving similar serum levels with either intravenous or oral administration. Dosage adjustment is required for kidney disease (creatinine clearance 50 mL/min or less).
A. Urinary Tract Infections
Coliform bacteria, the most common cause of urinary tract infections, are moderately inhibited by sulfonamides. However, resistance of E coli to sulfonamides is common and IDSA cautions against using them in communities with high (defined as greater than 20%) rates of resistance. Since trimethoprim is concentrated in the prostate, trimethoprim-sulfamethoxazole, one double-strength tablet twice daily for 14–21 days, is effective in acute prostatitis due to susceptible pathogens. In chronic prostatitis, treatment for 6–12 weeks is indicated.
Trimethoprim-sulfamethoxazole is effective for prophylaxis and treatment of pneumonia due to Pneumocystis jirovecii and treatment of Cyclospora infection and Cystoisospora belli infection. For therapy of Pneumocystis pneumonia, 15 mg/kg/day of trimethoprim (with the associated 75 mg/kg/day of sulfamethoxazole) in three or four divided doses is administered intravenously or orally—depending on the severity of disease—for 3 weeks. The dose for prophylaxis is 160 mg of trimethoprim plus 800 mg of sulfamethoxazole daily or three times per week. (When ...