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Am. J. Trop. Med. Hyg., 70(6), 2004, pp. 635–637 Copyright 2004 by The American Society of Tropical Medicine and Hygiene SHORT REPORT: HIGH PREVALENCE OF MULTIDRUG-RESISTANT PLASMODIUM FALCIPARUM MALARIA IN THE FRENCH TERRITORY OF MAYOTTE FRANC¸OIS PETTINELLI, MARIE-EDITH PETTINELLI, PHILIPPE ELDIN DE PE´COULAS, JULIE MILLET, DELPHINE MICHEL, PHILIPPE BRASSEUR, AND PIERRE DRUILHE Centre Hospitalier de Mayotte, Mamoudzou, Mayotte; Faculté de Médecine, Rouen, France; Unité de Parasitologie Bio-Médicale, Abstract. A drug-resistance survey was conducted in the French territory of Mayotte in the Comorian Islands in the Indian Ocean where malaria is endemic. A high prevalence of resistant Plasmodium falciparum parasites was observed, not only to chloroquine (88%) and pyrimethamine (99%), but more surprisingly to quinine (17%), mefloquine (9%), and amodiaquine (24%). This leaves few treatment alternatives other than artemisine-mefloquine combinations. How- ever, despite notification to French Health authorities three years ago, inadequate treatment (chloroquine plus sulfa- doxine-pyrimethamine) is still used in this locality. Thus, people still die of malaria in this remote territory of France.
The island of Mayotte in the Comorian Islands in the In- double-site enzyme-linked LDH immunodetection (DELI) dian Ocean is in an unusual situation because from an epide- test.2 The correspondence between results obtained with miologic and sociologic point of view, it is an African-like the DELI assay and the classic isotopic microtest has been setting, yet it benefits from the French health system with previously established using laboratory-adapted strains2 and diagnosis and treatment facilities that are of much higher field isolates in Senegal,3 Burkina Faso,4 and Asia (Brasseur standards than those in Africa. However, the population of P, Druilhe P, unpublished data). Two strains of P. falciparum Mayotte is of east African origin and lives in modest housing, (3D7 and Palo Alto) were used as internal controls.
including huts along rare roads in a forested landscape. In The in vitro drug sensitivities of 132 isolates that were suc- contrast, since 1975 when Mayotte decided to remain a cessfully cultured are shown in Figure 1. We observed an French territory, a sophisticated health system has been extremely high prevalence (88%) and an extremely high de- implemented. This includes a modern, well-equipped central gree of resistance to chloroquine, which is consistent with the hospital, and numerous dispensaries run by doctors who de- clinical failures reported by rural dispensaries and the in- liver free medical care. This, along with other factors, has con- crease in the number of cases referred to the hospital. The tributed to massive immigration from other Comorian islands.
results also showed a substantial number (17%) of isolates Malaria has always been prevalent in this region and has resistant to quinine with high IC50 values (> 500 nM), which not been decreased by vector control. Until 2001, treatment may explain the fatality rate recently observed in the hospital relied on classic schemes, i.e., chloroquine for acute uncom- despite rapid infusions of quinine and adequate intensive plicated cases and parenteral quinine together with adequate care. Most likely as a consequence of quinine resistance, 9% nursing for complicated cases. The increasing number of ma- of the isolates were found resistant to mefloquine, despite laria fatalities, particularly among cases properly handled in the rare use of this drug. This finding is consistent with pre- the central hospital, led us to initiate a drug sensitivity survey vious observations of cross-resistance between quinine and to determine why many could still die of malaria in France in 2001, even though this is a remote territory of France. The Despite the absence of use of sulfadoxine-pyrimethamine, results showed an unexpectedly high prevalence of resistance all but one of the strains tested were resistant to pyrimeth- to many available antimalarial drugs.
amine (IC50 > 2,000 nM). This is most likely due to numerous The study was conducted from May 2000 to February 2001 treatments with other antifolates for microbial infections among the patients from the different health centers of the (e.g., cotrimoxazole). In contrast with many chloroquine- island and those admitted to Mamoudzou Hospital. It was resistant areas where amodiaquine is a suitable alternative to reviewed and approved by the health regional authority, and chloroquine as a first-line treatment,6 the prevalence of resis- samples were obtained from patients after informed consent tance to this drug is 24%. Therefore, amodiaquine cannot be was provided. All patients had a Plasmodium falciparum recommended as an alternative to chloroquine for treatment −positive histidine-rich protein 2 (Cape Biotech Malaria of a disease that can be fatal within 24−48 hours.
Rapid Test; Abbott Diagnostic, Rungis, France) or parasite Finally, as in many other areas where artemisinin deriva- lactate dehydrogenase (LDH) test (Optimal; Diamed, Paris, tives have not yet been used, a number of isolates showed France) result, which was verified by microscopic examina- IC50 values greater than the threshold of 10 nM and 20% tion of thin and thick blood smears. A venous blood sample showed values of 5−10 nM. Although resistance to artemisi- was taken either at the hospital or in dispensaries and kept nin derivatives remains debatable, it is known that even at 4°C for a maximum of four hours before performing an seven-day treatments have failure rates of 5−7%. This is con- in vitro culture. Drug sensitivity assays were determined for sistent with in vitro findings. No significant difference in sus- chloroquine sulfate, quinine hydrochloride, amodiaquine hy- ceptibility was found between patients from rural areas, who drochloride, mefloquine hydrochloride, pyrimethamine, and constituted the majority (82%) of the study population, and artemisinin. The conditions for in vitro culture of isolates in those from urban areas. In addition, resistance to pyrimeth- 96-well plates are the same as those previously described.1 amine was investigated in 40 additional parasite isolates with Antimalarial drugs solutions were prepared for each assay.
a nested polymerase chain reaction and restriction fragment Drug sensitivity was determined using the colorimetric length polymorphism as reported by Eldin de Pecoulas and FIGURE 1. Distribution of the 50% inhibitory concentrations (IC50s) of the antimalarial drugs studied with 132 isolates of Plasmodium falciparum from Myotte in the Comorian Islands. Results for pyrimethamine are not shown because all isolates were resistant and only one showed borderline resistance. CQ ס chloroquine; QN ס quinine; AQ ס amodiaquine; MF ס mefloquine; AT ס artemisinin. The shaded areas correspond to the threshold values between susceptibility and resistance. The values at the bottom of the figure are the geometric (Geo) mean ICSO concentration for each drug and the 95% confidence interval (CI).
DRUG-RESISTANT P. FALCIPARUM MALARIA IN MAYOTTE others.7 This showed a point mutation in codon 108 (Ser but would moreover constitute an outstanding opportunity to (AGC) to Asn (AAC)) in the dihydrofolate reductase gene in investigate its ability to control transmission and potentially 62% of the isolates (other mutations were not investigated).
eradicate malaria in a small, well-delineated territory, i.e., Our results are puzzling and in marked contrast with those without borders with other endemic countries.
obtained in neighboring areas such as Madagascar, where re-sults over the past 10 years have showed a moderate but Received September 4, 2003. Accepted for publication December 18, stable prevalence of resistance to chloroquine, together with a low prevalence of resistance to other drugs.8 Less numerous Authors’ addresses: Franc¸ois Pettinelli, Marie-Edith Pettinelli, Julie data are available from the neighboring islands of Anjouan Millet, and Delphine Michel, Centre Hospitalier de Mayotte, 97600 and other Comorian islands. The last survey conducted in Mamoudzou, Mayotte. Philippe Eldin de Pe´coulas and Philippe Bras- seur, Faculte´ de Me´decine, 22, Boulevard Gambetta, 76183 Rouen, 1992 showed a chloroquine resistance level of 22.2% in seven- France. Pierre Druilhe, Unite´ de Parasitologie Bio-Me´dicale, Institut day in vivo assays.9 This situation suggests that the improved availability in Mayotte, compared with Africa, of antimalari- Reprint requests: Pierre Druilhe, Unité de Parasitologie Bio- als and other drugs through a free and well-organized health Médicale, Institut Pasteur, 25 Rue du Dr Roux, 75015 Paris, France, system, has contributed to the emergence of multidrug- Telephone: 33-1-45-68-85-78, Fax: 33-1-45-68-86-40, E-mail: druilhe@ resistant P. falciparum malaria.
Given this state of affairs, it is somewhat puzzling that it took so many years of treatment failures to initiate a prelimi- nary evaluation of the actual status of susceptibility. Our re- 1. Brasseur P, Druilhe P, Kouamouo J, Brandicourt O, Danis M, sults should have at least triggered further in vitro and in vivo Moyou SR, 1986. High level of sensitivity to chloroquine of 72 Plasmodium falciparum isolates from southern Cameroon in investigations, which are known to be complementary. It is January 1985. Am J Trop Med Hyg 35: 711–716.
shocking that given the degree of health care in Mayotte new 2. Druilhe P, Moreno A, Blanc C, Brasseur PH, Jacquier P, 2001.
and more adequate regimens have not yet been implemented.
A colorimetric in vitro drug sensitivity assay for Plasmodium Indeed, the current recommendation for treatment is a com- falciparum based on a highly sensitive double-site lactate de- bination of chloroquine with sulfadoxine-pyrimethamine, hydrogenase antigen-capture enzyme-linked immunosorbent assay. Am J Trop Med Hyg 64: 233–241.
which in view of our observations, would constitute the worst 3. Moreno A, Brasseur P, Cuzin-Ouattara N, Blanc C, Druilhe P, possible option. In addition, this combination therapy has not 2001. Evaluation under field conditions of the colourimetric been the object of rigorous in vivo investigations to determine DELI-microtest for the assessment of Plasmodium falciparum its efficacy. It has unfortunately remained mandatory despite drug resistance. Trans R Soc Trop Med Hyg 95: 100–103.
4. Moreno A, Cuzin-Ouattara N, Nebie I, Sanon S, Brasseur P, reports of treatment failures and communication of the Druilhe P, 2001. Use of the DELI-microtest to determine the present data in January 2001 to the health authorities in May- drug sensitivity of Plasmodium falciparum in Burkina Faso.
otte, as well as to the Direction Generale de la Sante in Paris, Ann Trop Med Parasitol 95: 309–312.
and repeated recommendations to use artemisinin-based 5. Brasseur P, Kouamouo J, Moyou RS, Druilhe P, 1990. Emer- gence of mefloquine-resistant malaria in Africa without drug pressure (letter). Lancet 336: 59.
In view of the data in this report, therapeutic options are 6. Brasseur P, Guiguemde R, Diallo S, Guiyedi V, Kombila A, scarce and few alternatives are currently available, other than Ringwald P, Olliaro P, 1999. Amodiaquine remains effective drug combinations such as quinine-tetracycline or artesunate- for treating uncomplicated malaria in West and Central Africa.
mefloquine. However, the former combination has shown Trans R Soc Trop Med Hyg 93: 645–650.
7. Eldin de Pecoulas P, Basco LK, Abdallah B, Dje MK, Le BJ, insufficient compliance during ambulatory treatment in dis- Mazabraud A, 1995. Plasmodium falciparum: detection of an- pensaries. In our opinion, this suggests that the three-day tifolate resistance by mutation-specific restriction enzyme di- artesunate-mefloquine combination promoted by investiga- gestion. Exp Parasitol 80: 483–487.
8. Randrianarivelojosia M, Raharimalala LA, Randrianasolo L, One could argue that eradication through vector control Ratsimbasoa A, Rason MA, Ariey F, Jambou R, 2001. Mada- gascar isolates of Plasmodium falciparum showing low sensi- might be achievable in Mayotte, as on other small islands such tivity to artemether in vitro. Ann Trop Med Parasitol 95: 237– as la Réunion, Martinique, and Guadeloupe. However, sev- eral years of vector control in Mayotte has failed to prevent 9. Feillet N, Agnamey P, Brasseur P, Druilhe P, 1993. In vivo re- the present increase in endemicity and many breeding sites sistance of Plasmodium falciparum to chloroquine in Anjouan (Comoros). Bull Soc Pathol Exot 86: 48–51.
are hardly accessible in the relatively large, wild, forested 10. Looareesuwan S, Viravan C, Vanijanonta S, Wilairatana P, areas of Mayotte. In this regard, it is worth mentioning that Pitisuttithum P, Andrial M, 1996. Comparative clinical trial of the increased use of artemisinin derivatives in Southeast Asia artesunate followed by mefloquine in the treatment of acute indicates that they also exert a gametocytocidal effect,11 in uncomplicated falciparum malaria: two- and three-day regi- contrast to sulfadoxine-pyrimethamine, which tend to in- mens. Am J Trop Med Hyg 54: 210–213.
11. Price RN, Nosten F, Luxemburger C, ter Kuile FO, Paiphun L, crease transmission. Therefore, in the case of Mayotte, arte- Chongsuphajaisiddhi T, White NJ, 1996. Effects of artemisinin misinin may not only be the most efficient therapeutic option, derivatives on malaria transmissibility. Lancet 347: 1654–1658.

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