Comparison of Atovaquone (566C80) with Trimethoprim-Sulfamethoxazole to Treat Pneumocystis carinii Pneumonia in Patients with AIDS

Walter Hughes, Gifford Leoung, Francoise Kramer, Samuel A. Bozzette, Sharon Safrin, Peter Frame, Nathan Clumeck, Henry Masur, Danny Lancaster, Charles Chan, James Lavelle, Joel Rosenstock, Judith Falloon, Judith Feinberg, Stephen Lafon, Michael Rogers, Fred Sattler

Research output: Contribution to journalArticle

Abstract

Background: Both trimethoprim-sulfamethoxazole and pentamidine are effective as treatments for Pneumocystis carinii pneumonia, but adverse effects frequently limit their use. Atovaquone (566C80) is a new hydroxynaphthoquinone with activity against P. carinii. Methods: We conducted a double-blind, multicenter study in patients with the acquired immunodeficiency syndrome and mild or moderately severe P. carinii pneumonia. They were randomly assigned to 21 days of orally administered treatment three times daily with either atovaquone (750 mg) or trimethoprim (320 mg) plus sulfamethoxazole (1600 mg). Results: Of the 322 patients with histologically confirmed P. carinii pneumonia, 160 received atovaquone and 162 received trimethoprim-sulfamethoxazole. Of those who could be evaluated for therapeutic efficacy, 28 of 138 patients given atovaquone (20 percent) and 10 of 146 patients given trimethoprim-sulfamethoxazole (7 percent) did not respond (P = 0.002). Treatment-limiting adverse effects required a change of therapy in 11 patients in the atovaquone group (7 percent) and 33 patients in the trimethoprim-sulfamethoxazole group (20 percent) (P = 0.001). Therapy involving only the initial drug was successful and free of adverse effects in 62 percent of those assigned to atovaquone and 64 percent of those assigned to trimethoprim-sulfamethoxazole. Within four weeks of the completion of treatment, there were 11 deaths in the atovaquone group (4 due to P. carinii pneumonia) and 1 death in the trimethoprim-sulfamethoxazole group (P = 0.003). Diarrhea at entry was associated with lower plasma drug concentrations (P = 0.009), therapeutic failure (P<0.001), and death (P<0.001) in the atovaquone group but not in the trimethoprim-sulfamethoxazole group. Conclusions: For the treatment of P. carinii pneumonia, atovaquone is less effective than trimethoprim-sulfamethoxazole, but it has fewer treatment-limiting adverse effects., More than half of patients with the acquired immunodeficiency syndrome (AIDS) have adverse effects when they are treated with either pentamidine or trimethoprim-sulfamethoxazole1. In laboratory animals a 1,4-hydroxynaphthoquinone designated as 566C80, or atovaquone, is at least as effective as trimethoprim-sulfamethoxazole in the prevention and treatment of murine Pneumocystis carinii pneumonia,2 although the mechanism of action has not been determined. In Plasmodium falciparum, hydroxynaphthoquinones interfere with the electron-transport chain, indirectly inhibit the activity of dihydroorotate dehydrogenase, and stop the de novo synthesis of pyrimidines35. Because initial clinical studies6,7 showed atovaquone to be effective and well-tolerated by patients…

Original languageEnglish (US)
Pages (from-to)1521-1527
Number of pages7
JournalNew England Journal of Medicine
Volume328
Issue number21
DOIs
StatePublished - May 27 1993

ASJC Scopus subject areas

  • Medicine(all)

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