Sulfonamides and Trimethoprim

GENERAL PRINCIPLES

Sulfadiazine, sulfamethoxazole, and trimethoprim slowly kill bacteria by inhibiting folic acid metabolism. This class of antibiotics is most commonly used for uncomplicated UTIs, sinusitis, and otitis media.

TREATMENT

• Trimethoprim (100 mg PO q12h) is occasionally used as monotherapy for treatment of UTIs. Trimethoprim is more often used in the combination preparations outlined below. Trimethoprim in combination with dapsone is an alternate therapy for mild P. jirovecii pneumonia.

• Trimethoprim-Sulfamethoxazole is a combination antibiotic (IV or PO) with a 1:5 ratio of trimethoprim to sulfamethoxazole. The IV preparation is dosed at 5 mg/kg IV q8h (based on the trimethoprim component) for serious infections. The oral preparations (160 mg trimethoprim/800 mg sulfamethoxazole per double-strength [DS] tablet) are extensively bioavailable, with similar drug concentrations obtained with IV and PO formulations. The combination has a broad spectrum of activity but does not cover P. aeruginosa, anaerobes, or Streptococcus pyogenes. It is the treatment of choice for P. jirovecii pneumonia, Stenotrophomonas maltophilia, Tropheryma whipplei, and Nocardia infections. It is commonly used for treating sinusitis, otitis media, bronchitis, prostatitis, and UTIs (one DS tab PO q12h). Trimethoprim-sulfamethoxazole is active against MRSA and is widely used for uncomplicated cases of skin/soft tissue infections caused by this organism (often two DS tabs PO q12h). It is used as P. jirovecii pneumonia prophylaxis in HIV-infected patients, solid organ transplant patients, bone marrow transplant patients, and in patients receiving fludarabine. IV therapy is routinely converted to the PO equivalent for patients who require prolonged therapy.

For serious infections, such as Nocardia brain abscesses, drug levels should be monitored. Sulfamethoxazole peaks (goal 100-150 μg∕mL) and troughs (goal 50-100 μg∕mL) should be monitored and doses adjusted accordingly. In patients with renal insufficiency, doses can be adjusted according to trimethoprim peaks (goal 5-10 μg∕mL). Prolonged therapy can cause bone marrow suppression, which can be managed with leucovorin (5-10 mg PO q24h) until cell counts normalize.

• Sulfadiazine (1.0-1.5 g PO q6h) in combination with pyrimethamine (200 mg PO followed by 50-75 mg PO q24h) and leucovorin (10-20 mg PO q24h) is the regimen of choice for toxoplasmosis. Sulfadiazine is also occasionally used to treat Nocardia infections.

SPECIAL CONSIDERATIONS

Adverse events: These drugs are associated with cholestatic jaundice, bone marrow suppression, hyperkalemia (with trimethoprim/sulfamethoxazole), hyponatremia, obstructive uropathy, interstitial nephritis, “false” elevations in serum creatinine, and severe hypersensitivity reactions (including Stevens- Johnson syndrome). Nausea is common with higher doses. All patients should be asked whether they are allergic to “sulfa drugs,” and specific commercial names should be mentioned (e.g., Bactrim or Septra). Hemolysis in the setting of glucose-6-phosphate dehydrogenase deficiency may also occur.