Pyrimethamine and sulfadiazine are used in the treatment of toxoplasmosis. The dosage of sulfadiazine is 1–1.5 g four times daily, with pyrimethamine given as a 200-mg loading dose followed by a once-daily dose of 50–75 mg. Leucovorin, also known as folinic acid, 10 mg orally each day, should be administered to minimize bone marrow suppression seen with pyrimethamine. Some clinicians recommend using trimethoprim-sulfamethoxazole as an alternate option if pyrimethamine is not available.
In falciparum malaria, the combination of pyrimethamine with sulfadoxine (Fansidar) has been used (see Chapter 52); however, it is no longer commercially available in the USA.
Trimethoprim produces the predictable adverse effects of an antifolate drug, especially megaloblastic anemia, leukopenia, and granulocytopenia. The combination trimethoprim-sulfamethoxazole may cause all of the untoward reactions associated with sulfonamides. Nausea and vomiting, drug fever, vasculitis, renal damage, and central nervous system disturbances occasionally occur. Patients with AIDS and pneumocystis pneumonia have a particularly high frequency of untoward reactions to trimethoprim-sulfamethoxazole, especially fever, rashes, leukopenia, diarrhea, elevations of hepatic aminotransferases, hyperkalemia, and hyponatremia. Trimethoprim inhibits secretion of creatinine at the distal renal tubule, resulting in mild elevation of serum creatinine without impairment of glomerular filtration rate. This nontoxic effect is important to distinguish from true nephrotoxicity that may be caused by sulfonamides.
The clinically relevant quinolones are synthetic fluorinated analogs of nalidixic acid (Figure 46–3). They are active against a variety of Gram-positive and Gram-negative bacteria.
Mechanism of Action
Quinolones block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication. Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division.
Earlier quinolones such as nalidixic acid did not achieve systemic antibacterial levels and were useful only in the treatment of lower urinary tract infections. Fluorinated derivatives (ciprofloxacin, levofloxacin, and others; Figure 46–3 and Table 46–1) have greatly improved antibacterial activity compared with nalidixic acid and achieve bactericidal levels in blood and tissues.
Fluoroquinolones were originally developed because of their excellent activity against Gram-negative aerobic bacteria; the earliest agents had limited activity against Gram-positive organisms. Subsequent members of the group have improved activity against Gram-positive cocci. The relative activity against Gram-negative
FIGURE 46–3 Structures of nalidixic acid and some fluoroquinolones.