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Volume 17, Number 5—May 2011

Letter

Quinine-Resistant Malaria in Traveler Returning from French Guiana, 2010

Suggested citation for this article

To the Editor: Resistance of Plasmodium falciparum to antimalarial drugs is one of the most worrying problems in tropical medicine. For P. falciparum malaria acquired in French Guiana, the combination of quinine and doxycycline is one of the first-line recommended treatments (1). Since 1996, only 2 treatment failures with quinine have been reported from that country (2). An elevated 50% inhibitory concentration (IC50), classified as in vitro quinine resistance, was reported for 17% of 32 P. falciparum isolates obtained during 1983–1987 in French Guiana (3). Throughout 1994–2005, isolates were susceptible to quinine, with a mean IC50 <200 nmol/L (4).

We report quinine treatment failure in a 35-year-old man who was infected during a 3-month stay in Saül, a rural area of French Guiana. The patient did not use antivectorial or antimalarial prophylaxis. The patient sought treatment with fever 4 days after returning to France on June 22, 2010 (day 0), and a diagnosis of P. falciparum malaria was made on the basis of results of a rapid diagnostic test performed by a private medical laboratory. The man, who weighed 58 kg, was treated as an outpatient with 500 mg of quinine to be taken orally 3×/d for 7 days; he did not receive doxycycline. He was admitted to the Laveran Military Teaching Hospital in Marseille on July 15 (day 24 and first day of recrudescence) for uncomplicated malaria with a P. falciparum parasitemia level of 4%. He was given artemether, 80 mg/d, by intramuscular injection for 3 days. Blood samples taken on day 27 (third day of recrudescence) and day 52 (4 weeks of recrudescence) were negative for P. falciparum.

In vitro testing of drug susceptibility was performed by the standard 42-hour 3H-hypoxanthine uptake inhibition method (5). We assessed susceptibility to 11 antimalarial drugs on the fresh isolate and after culture adaptation (Table). The laboratory-adapted strain 3D7, tested 3× on the same batch of plates, was used as reference. The strain isolated from the blood sample on day 24 (first day of the recrudescence) showed reduced susceptibility to quinine (1,019 nmol/L), chloroquine (427 nmol/L), and monodesethylamodiaquine (157 nmol/L). The isolate was susceptible to all other antimalarial drugs tested. We assessed gene polymorphisms of pfcrt (P. falciparum chloroquine resistance transporter), pfmdr1 (P. falciparum multidrug resistance 1 protein), and pfnhe-1 (P. falciparum Na+/H+ exporter 1); the copy number of pfmdr1 involved in quinoline resistance; and gene polymorphisms of dhfr (dihydrofolate reductase, involved in proguanil or pyrimethamine resistance), dhps (dihydropteroate synthetase, involved in sulfadoxine resistance), and cytB (cytochrome B, involved in atovaquone resistance) (6).

The pfnhe ms4760 microsatellite showed a profile 3, with 1 repeat of DNNND and 2 repeats of DDDNHNDNHNN. Studies of the pfnhe-1 polymorphism of worldwide culture-adapted isolates showed that increased numbers of DNNND were associated with decreased quinine susceptibility (7). Association of 2 repeats of DNNND and a high quinine IC50 value was found in a case of clinical failure of quinine in a traveler returning from Senegal (8).

Reinfection was excluded because the patient had stayed in mainland France since his return. The patient reported that he took the quinine as instructed. We report here a clinical and parasitologic failure of quinine treatment associated with high IC50 but not linked with the ms4760 pfnhe-1 profile involved with quinine in vitro reduced susceptibility. A hypothesis that may explain our data is that unlike previous studies (7), in which the less susceptible strains originated from Asia, this isolate came from South America. The profile associated with quinine resistance for chloroquine resistance and pfcrt genotypes could be different in the 3 malaria-endemic continents. There are no data on ms4760 pfnhe-1 of P. falciparum isolates from South America. In another recent study (9), a multivariate analysis performed on 83 clinical isolates from Madagascar and 13 African countries did not confirm this association between quinine susceptibility and pfnhe-1 microsatellite polymorphisms.

The pfcrt gene had a point mutation on codon 76 (76T) and pfmdr1 on codons 184F, 1034C, 1042D, and 1246Y. These data are in agreement with those from previous studies that showed the mutation 76T in the pfcrt gene led to decreased susceptibility to chloroquine, amodiaquine, and quinine. The isolate had only 1 copy of pfmdr1. The data on mutations and copy number of pfmdr1 are consistent with data in Brazil (10). Nevertheless, the lack of gene amplification and specific point mutations in pfmdr1 were not associated with decreased in vitro susceptibility of quinine. dhfr and dhps genes had a 5-mutation haplotype, 51I C59 108N I164-S436 437G 540E 581G A613, which suggested in vitro resistance to proguanil, pyrimethamine, and sulfadoxine. This case confirms the need to always add doxycycline to quinine for treatment of P. falciparum malaria acquired in French Guiana as well as other parts of South America.

Lionel Bertaux, Philippe Kraemer, Nicolas Taudon, Aurélie Trignol, Maryse Martelloni, Redouan Saidi, Daniel Parzy, Bruno PradinesComments to Author , and Fabrice Simon
Author affiliations: Author affiliations: Institut de Recherche Biomédicale des Armées, Marseille, France (L. Bertaux, N. Taudon, M. Martelloni, D. Parzy, B. Pradines); Laveran Military Teaching Hospital, Marseille (P. Kraemer, A. Trignol, R. Saidi, F. Simon)

Acknowledgment

We thank Rémy Amalvict, Eric Baret, Nicolas Benoit, Julien Cren, and Dominique Travers for technical support.

References

  1. Société de Pathologie Infectieuse de Langue Française, Collège des Universitaires de Maladies Infectieuses et Tropicales, Société de Médeine des Armées, Société Française de Parasitologie, Société Française de Pédiatrie, Société de Médeine des Voyages, . Management and prevention of imported Plasmodium falciparum malaria: recommendations for clinical practice 2007 (revision 2007 of the 1999 consensus conference) [in French]. Med Mal Infect. 2008;38:68117.PubMed
  2. Demar M, Carme B. Plasmodium falciparum in vivo resistance to quinine: description of two RIII responses in French Guiana. Am J Trop Med Hyg. 2004;70:1257.PubMed
  3. Dedet JP, Germanetto P, Cordoliani G, Bonnevie O, Le Bras J. In vitro activity of various antimalarials (chloroquine, amodiaquine, quinine and mefloquine) against 32 isolates of Plasmodium falciparum in French Guiana [in French]. Bull Soc Trop Pathol Exot Filiales. 1988;81:8893.PubMed
  4. Legrand E, Volney B, Meynard JB, Mercereau-Puijalon O, Esterre P. In vitro monitoring of Plasmodium falciparum drug resistance in French Guiana: a synopsis of continuous assessment from 1994 to 2005. Antimicrob Agents Chemother. 2008;52:28898. DOIPubMed
  5. Parola P, Pradines B, Simon F, Carlotti MP, Minodier P, Ranjeva MP, Antimalarial drug susceptibility and point mutations associated with Plasmodium falciparum drug resistance of 248 isolates imported from Comoros to Marseilles, France in 2004–2006. Am J Trop Med Hyg. 2007;77:4317.PubMed
  6. Pradines B, Dormoi J, Briolant S, Bogreau H, Rogier C. La résistance aux antipaludiques. Revue Francophone des Laboratoires. 2010;422:5162. DOI
  7. Henry M, Briolant S, Zettor A, Pelleau S, Baragatti M, Baret E, Plasmodium falciparum Na+/H+ exchanger 1 transporter is involved in reduced susceptibility to quinine. Antimicrob Agents Chemother. 2009;53:192630. DOIPubMed
  8. Pradines B, Pistone T, Ezzedine K, Briolant S, Bertaux L, Receveur MC, Quinine-resistant malaria in traveler returning from Senegal, 2007. Emerg Infect Dis. 2010;16:5468. DOIPubMed
  9. Andriantsoanirina V, Menard D, Rabearimanana S, Hubert V, Bouchier C, Tichit M, Association of microsatellite variations of Plasmodium falciparum Na+/H+ exchanger (pfnhe-1) gene with reduced in vitro susceptibility to quinine: lack of confirmation in clinical isolates from Africa. Am J Trop Med Hyg. 2010;82:7827. DOIPubMed
  10. Zalis MG, Pang L, Silveira MS, Milhous WK, Wirth D. Characterisation of Plasmodium falciparum isolated from the Amazon region of Brazil: evidence for quinine resistance. Am J Trop Med Hyg. 1998;58:6307.PubMed

Table

Suggested citation for this article: Bertaux L, Kraemer P, Taudon N, Trignol A, Martelloni M, Saidi R, et al. Quinine-resistant malaria in traveler returning from French Guiana, 2010 [letter]. Emerg Infect Dis [serial on the Internet]. 2011 May [date cited]. http://dx.doi.org/10.3201/eid1705.101424

DOI: 10.3201/eid1705.101424

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Table of Contents – Volume 17, Number 5—May 2011

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Bruno Pradines, Institut de Recherche Biomédicale des Armées, Allée du Médecin-Colonel Jamot, Parc du Pharo, BP 60109, 13262 Marseille CEDEX 07, France





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