e1-13: Sulfonamides & Antifolate Medications

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 reduce the risk of 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) and about 50% of S epidermidis isolates.

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).

Present indications for sulfonamides are outlined below.

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 (ie, 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. In chronic prostatitis, treatment for 6–12 weeks is indicated.

B. Parasitic Infections

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 given daily, it is also effective prophylaxis against toxoplasmal encephalitis.) C belli infection in HIV/AIDS has been successfully treated with 160 mg of trimethoprim plus 800 mg of sulfamethoxazole orally four times daily for 10 days followed by twice-daily administration for 3 weeks. Cyclosporiasis is successfully treated with 160 mg of trimethoprim and 800 mg of sulfamethoxazole twice daily for 7–10 days. Sulfadiazine with pyrimethamine is also used to treat and prevent recurrence of toxoplasmosis.

C. Other Bacterial Infections

Considering the increased observation of CA-MRSA, trimethoprim-sulfamethoxazole is useful in the outpatient treatment of this organism. Epidemiologic evaluations demonstrate that antibacterials often have only a modest role in the treatment of skin and soft-tissue infection due to CA-MRSA. Nonetheless, trimethoprim-sulfamethoxazole is associated with a high cure rate among patients with a drained cutaneous abscess.

Sulfonamides are the medications of choice for Nocardia infections. Trimethoprim-sulfamethoxazole is widely distributed in tissues, penetrates into the cerebrospinal fluid, and has been used to treat meningitis caused by gram-negative rods, although third-generation cephalosporins have greater clinical experience and are preferred.

Trimethoprim-sulfamethoxazole is also effective for infections with Enterobacter, B pseudomallei (melioidosis), S maltophilia, or B cepacia; in combination with rifampin for eradication of nasopharyngeal carriage of staphylococci; for Pneumocystis prophylaxis in organ and stem cell transplant recipients and HIV/AIDS patients with CD4 counts less than 200 cells/mcL; and as an option for treatment of L monocytogenes meningitis.

D. Leprosy

Certain sulfones are widely used (see below).

A. Systemic Side Effects

Fever, skin rashes, urticaria; nausea, vomiting, or diarrhea; stomatitis, conjunctivitis, arthritis, aseptic meningitis, exfoliative dermatitis; bone marrow depression, thrombocytopenia, hemolytic anemia (in glucose-6-phosphate dehydrogenase [G6PD] deficiency) or aplastic anemia, granulocytopenia, leukemoid reactions; hepatitis, polyarteritis nodosa, vasculitis, Stevens-Johnson syndrome; reversible hyperkalemia; and many others have been reported. Because of the risk of Stevens-Johnson syndrome, patients with a previous rash with receipt of trimethoprim-sulfamethoxazole should not be rechallenged.

Patients intolerant to trimethoprim-sulfamethoxazole can often be desensitized. While a number of desensitization protocols exist, one effective method is giving 0.004 mg trimethoprim/0.02 mg sulfamethoxazole as oral suspension and increasing the dose tenfold each hour to achieve a final dose of 160 mg trimethoprim/500 mg sulfamethoxazole.

B. Urinary Tract Disturbances

Older sulfonamides were relatively insoluble and would precipitate in urine. The most commonly used sulfonamides presently (sulfamethoxazole) are quite soluble, and the old admonition to force fluids is no longer warranted. Sulfonamides have been implicated in interstitial nephritis. Patients with toxoplasmosis receiving high-dose sulfadiazine therapy are predisposed to crystalluria.