Atovaquone

Observational studies

In a 3-week study with test doses of 100–3000 mg/day, atovaquone was well tolerated. Three patients reported increased appetite; two of these had transient sinus arrhythmia. One of the 24 patients had a transient maculopapular rash that resolved without withdrawal. There were no abnormalities in hematological parameters or renal function. Two patients had slightly raised serum bilirubin concentrations and one each had raised transaminase activities. Two other patients had mildly increased transaminase activities, but both were known to have chronic hepatitis B [ ].

Comparative studies

Atovaquone 250 mg tds has been compared with co-trimoxazole 320/1600 mg/day for 21 days in the treatment of Pneumocystis jirovecii pneumonia in 408 patients. Therapeutic efficacy was similar, but atovaquone was much better tolerated, with a far lower incidence of rash, liver dysfunction, fever, nausea, and pruritus, and no neutropenia, chills, headache, renal impairment, or thrombocytopenia [ ]. However, pre-existing diarrhea was associated with an increased mortality in the atovaquone group.

Of 39 patients who had bone marrow transplants and who were randomized to receive either co-trimoxazole or atovaquone as prophylaxis in an open-label trial, eight taking co-trimoxazole withdrew because of presumed drug reactions, although in five of these the reported neutropenia and thrombocytopenia could have been a consequence of transplantation itself or of other drugs [ ]. None of 16 patients treated with atovaquone withdrew. This rate of reported adverse effects with co-trimoxazole is higher than usually reported in clinical practice with prophylactic dosages.

A study conducted by the AIDS Clinical Trials Group (ACTG) has shown that among patients who cannot tolerate treatment with co-trimoxazole, atovaquone and dapsone are similarly effective in preventing Pneumocystis jirovecii pneumonia. Among patients who did not originally take dapsone, atovaquone was better tolerated and it might be the preferred choice for prophylaxis of Pneumocystis jirovecii pneumonia in this setting [ ]. Inexplicably the rate of Pneumocystis jirovecii pneumonia showed a greater fall in patients who discontinued the study drugs compared with those who continued to take them.

When atovaquone was compared with intravenous pentamidine in the treatment of mild and moderate Pneumocystis jirovecii pneumonia in an open trial, the success rates were similar. However, withdrawal of the original treatment was much more frequent with pentamidine (36%) than atovaquone (4%) [ ]. However, the authors’ conclusion that the two approaches have a similar success rate has been challenged, and their series was small [ , ]. Treatment-limited adverse effects occurred in only 7% of patients given atovaquone, compared with 41% given pentamidine. They included cases of rash and an increase in creatinine concentrations; atovaquone (unlike pentamidine) produced no vomiting, nausea, hypotension, leukopenia, acute renal insufficiency, or electrocardiographic abnormalities, but it did cause one case of dementia [ ].

Combination studies