Patients should be tested for G6PD deficiency before primaquine is prescribed. When a patient is deficient in G6PD, treatment strategies may include withholding therapy and treating subsequent relapses, if they occur, with chloroquine; treating patients with standard dosing, paying close attention to their hematologic status; or treating with weekly primaquine (45 mg base) for 8 weeks. G6PD-deficient individuals of Mediterranean and Asian ancestry are most likely to have severe deficiency, whereas those of African ancestry usually have a milder biochemical defect. This difference can be taken into consideration in choosing a treatment strategy. In any event, primaquine should be discontinued if there is evidence of hemolysis or anemia. Primaquine should be avoided in pregnancy because the fetus is relatively G6PD-deficient and thus at risk of hemolysis.
Atovaquone, a hydroxynaphthoquinone (Figure 52–2), is a component of Malarone, which is recommended for the treatment and prevention of malaria. Atovaquone has also been approved by the FDA for the treatment of mild to moderate P jiroveci pneumonia.
The drug is only administered orally. Its bioavailability is low and erratic, but absorption is increased by fatty food. The drug is heavily protein-bound, has a half-life of 2–3 days, and is mostly eliminated unchanged in the feces. Atovaquone acts against plasmodia by disrupting mitochondrial electron transport. It is active against tissue and erythrocytic schizonts, allowing chemoprophylaxis to be discontinued only 1 week after the end of exposure (compared with 4 weeks for mefloquine or doxycycline, which lack activity against tissue schizonts).
Initial use of atovaquone to treat malaria led to disappointing results, with frequent failures due to the selection of resistant parasites during therapy. In contrast, Malarone, a fixed combination of atovaquone (250 mg) and proguanil (100 mg), is highly effective for both the treatment and chemoprophylaxis of falciparum malaria, and it is now approved for both indications in the USA. For chemoprophylaxis, Malarone must be taken daily (Table 52–2). It has an advantage over mefloquine and doxycycline in requiring shorter periods of treatment before and after the period at risk for malaria transmission, but it is more expensive than the other agents. It should be taken with food.
Atovaquone is an alternative therapy for P jiroveci infection, although its efficacy is lower than that of trimethoprim-sulfamethoxazole. Standard dosing is 750 mg taken with food twice daily for 21 days. Atovaquone has also been effective in small numbers of immunocompromised patients with toxoplasmosis unresponsive to other agents.
Malarone is generally well tolerated. Adverse effects include abdominal pain, nausea, vomiting, diarrhea, headache, insomnia, and rash, and these are more common with the higher dosage required for treatment. Reversible elevations in liver enzymes have been reported. The safety of atovaquone in pregnancy is unknown, and its use is not advised in pregnant women. It is considered safe for use in children with body weight above 5 kg. Plasma concentrations of atovaquone are decreased about 50% by co-administration of tetracycline or rifampin.
Inhibitors of enzymes involved in folate metabolism are used, generally in combination regimens, in the treatment and prevention of malaria.