Plasmodium falciparum Malaria and Atovaquone- Proguanil Treatment Failure Rémy Durand,*†‡ Virginie Prendki,* Johann Cailhol,* Véronique Hubert,‡ Pascal Ralaimazava,* Laurent Massias,‡ Olivier Bouchaud,* and Jacques Le Bras*‡§ We noticed overrepresentation of atovaquone-progua- nil therapeutic failures among Plasmodium falciparum–in- fected travelers weighing >100 kg. We report here 1 of these cases, which was not due to resistant parasites or impaired drug bioavailability. The follow-up of such patients should be strengthened. F ewer than 25 cases of falciparum malaria that failed to respond to atovaquone-proguanil (A-P) have been noted in published articles since the 1996 registration of Malarone (GlaxoSmithKline, Marly-le-Roi, France) (1,2). Well-documented cases that were not attributed to subop- timal dosage or impaired bioavailability essentially due to vomiting, diarrhea, or both showed atovaquone-resistant parasites in the recrudescent isolate, with Y268S or Y268N cytochrome b mutations (2–10). We report the case of treatment failure that was not due to resistant parasites or impaired drug bioavailability. The Case During February 2007, a 39-year-old man who was born in Africa but lived in France since 1996 traveled to Kinshasa, Democratic Republic of Congo, for a 1-month vacation in which he visited friends and relatives. He was 6 feet tall with strong musculature and weighed 115 kg (body mass index = 34.3). He did not use chemoprophylaxis and did not take antimalarial self-treatment before seeking medical advice. Two days after returning to France, a fever and other signs of uncomplicated malaria attack developed (chills, arthralgia, asthenia) without vomiting. Three days after onset of symptoms, the patient sought care at the Avi- cenne Hospital, Bobigny, France. Blood smears performed at admission showed 1.6% Plasmodium falciparum parasit- emia. The patient was hospitalized and immediately treat- ed with the standard dosage of A-P (Malarone, 4 tablets each day for 3 days given with the main meal; each tablet contains 250 mg of atovaquone and 100 mg of proguanil hydrochloride). The patient experienced no vomiting or diarrhea. His fever abated by day 3 of treatment, and ma- laria smears at that time showed 0.07% of morphologically altered parasites (these figures are not uncommon because A-P is known to act relatively slowly). The patient was dis- charged on day 3. The patient did not return until his sched- uled appointments for control of parasitemia on days 7 and 28. The patient was apyretic, and parasitemia was negative by day 7 on thin and thick blood smears. On day 28, the patient was apyretic, but thin and thick smears showed P. falciparum trophozoites (0.001% parasitemia on thin smear and 16 trophozoites per 1,000 leukocytes on thick smear). The patient was then successfully retreated with 650 mg quinine base orally 3× daily for 7 days. Day 0 in vitro phenotype showed parasite suscepti- bility to atovaquone, with a 50% inhibitory concentration (IC 50 ) value of 10 nmol/L (in vitro resistance threshold >40 nmol/L [11]). Day 28 in vitro susceptibility was not assayed because of insufficient parasite density. DNA sequencing showed that both day 0 and day 28 isolates had wild-type sequence of cytochrome b. Genotyping of the pfdhfr gene showed that the 3 major pfdhfr mutations (at position 51, 59, and 108) associated with cycloguanil resistance were found in isolates from day 0 and day 28. The number and the pro- portions of genotypes within isolates were determined by a fragment analysis method based on the polymorphism of the gene encoding merozoite surface protein-2 (12). Day 0 and day 28 isolates contained the same majority genotype, with the 727-bp msp-2 allele representing >80% of iso- lates. This parasite population analysis did not show the se- lection of a minority-resistant genotype by A-P treatment. These results did not show either the emergence of mutant codon 268 cytochrome b within the 727-bp msp-2 domi- nant genotype. High-performance liquid chromatography on day 3 of treatment (performed 20 h after the last drug intake) showed an atovaquone plasma concentration of 3.1 μg/mL. High interpatient variability has been reported, but this value showed initial adequate drug concentration and excluded impaired bioavailability (13). Thus, this patient, who had correctly taken A-P tab- lets with food and did not vomit, showed correct plasma drug concentration on day 3 but did not show clearance of A-P–susceptible parasites on day 28, although he was as- ymptomatic. Reinfection was excluded because the patient was treated after returning to France (which is a non–ma- laria-endemic area). All these data suggest that the standard drug regimen led to suboptimal dosage in this patient. Ap- parently correct initial atovaquone concentration on day 3 did not predict the outcome of treatment because A-P acts slowly, and most reported A-P therapeutic failures were late failures. Drug interactions that could have lowered A-P 320 Emerging Infectious Diseases  www.cdc.gov/eid  Vol. 14, No. 2, February 2008 DISPATCHES *Hôpital Avicenne, Bobigny, France; †Université Léonard de Vinci, Bobigny, France; ‡Hôpital Bichat Claude Bernard, Paris, France; and §Université René Descartes, Paris, France