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Volume 16, Number 3—March 2010
Dispatch

Quinine-Resistant Malaria in Traveler Returning from Senegal, 2007

Author affiliations: Institut de Médecine Tropicale du Service de Santé des Armées, Marseille, France (B. Pradines, S. Briolant, L. Bertaux, D. Parzy, C. Rogier); Centre Hospitalier Universitaire St.-André, Bordeaux, France (T. Pistone, K. Ezzedine, M.-C. Receveur, D. Malvy); Université Victor Segalen Bordeaux 2, Bordeaux (K. Ezzedine, P. Millet, D.Malvy)

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Abstract

We describe clinical and parasitologic features of in vivo and in vitro Plasmodium falciparum resistance to quinine in a nonimmune traveler who returned to France from Senegal in 2007 with severe imported malaria. Clinical quinine failure was associated with a 50% inhibitory concentration of 829 nmol/L. Increased vigilance is required during treatment follow-up.

Resistance of Plasmodium falciparum to antimalarial drugs is one the most worrisome problems in tropical medicine. Quinine remains the first-line antimalarial option for treatment of patients with complicated malaria in Europe and Africa. However, emergence of quinine resistance has been sparsely documented (1). Maximizing the efficacy and longevity of quinine as a drug to control malaria will critically depend on pursuing intensive research into identifying in vitro markers and implementing active in vitro and in vivo surveillance programs such as those supported by the World Antimalarial Resistance Network. Such molecular markers are needed to monitor temporal trends in parasite susceptibility (2). We report quinine-resistant P. falciparum malaria in a patient who returned to France from Senegal.

The Patient

A 17-year-old white man from France spent ≈2 months (April and most of May) in 2007 in Dielmo, Senegal, where malaria is highly endemic and shows intense perennial transmission (3). He did not use antimalarial prophylaxis or protection against mosquitoes. After returning to France, he was admitted to the Bordeaux University Hospital Center on May 27, 2007 (day 0). The patient had P. falciparum parasitemia level of 7% and a 2-day history of fever, myalgia, vomiting, and rapid deterioration of consciousness into an arousable coma. A diagnosis of severe malaria with cerebral involvement was confirmed.

Intravenous quinine formiate (loading dose 17 mg/kg) was administered, followed by a maintenance dose (8.3 mg/kg 3×/day for 7 days). The patient was afebrile on day 3, and his thin and thick blood films became negative for P. falciparum on day 6. He was discharged from the hospital on day 7. However, on day 26, he relapsed and had fever and vomiting. He was hospitalized again on day 27 with a core temperature of 40°7C, deterioration of consciousness, and a P. falciparum parasitemia level of 4%. He received the same regimen of quinine formiate plus intravenous clindamycin (10 mg 3×/day) for 7 days. His serum quinine level (free and bound drug assayed by high performance liquid chromatography) taken immediately before the fourth drug dose was low (7 mg/L). The patient was then given quinine (10 mg/kg 3×/day from day 30 through day 34). Serum quinine levels then increased and fever cleared within 72 hours. However, a blood smear was positive on day 34.

Because of the treatment failure with quinine and clindamycin, the patient was treated with oral co-artemether (20 mg artemether and 120 mg lumefantrine, given as 4 tablets, followed by 4 tablets after 8 hours, and 4 tablets 2×/day for 2 days; total = 24 tablets). Parasitic clearance was observed within 48 hours. Blood smears and results of a PCR for P. falciparum were negative from day 36 through day 62. No further recrudescence occurred over the next 12 months.

The isotopic microdrug susceptibility tests used have been described (4). The chloroquine-susceptible 3D7 P. falciparum clone (Africa) and the chloroquine-resistant W2 clone (Indochina), after 2 rounds of sorbitol synchronization, were used as controls. The 50% inhibitory concentration (IC50) values for 12 antimalarial drugs for the study isolate and these 2 controls are shown in the Table. The strain isolated on day 27 showed reduced susceptibility to quinine (IC50 829 nmol/L, threshold 800 nmol/L) and chloroquine (472 nmol/L, threshold 100 nmol/L). The IC50 for clindamycin was 39 μmol/L (the in vitro resistance cutoff value was not determined). The isolate was susceptible to all other antimalarial drugs tested. Phenotypes and genotypes were assessed only for parasites obtained on day 27.

We concurrently screened blood samples for resistance-associated point mutations. A sequence containing the ms4760 microsatellite was amplified as described (5). The observed ms4760–18 profile was composed of 2 DNNND repeats and 2 DDDNHNDNHNN repeats. Genotyping of the P. falciparum chloroquine resistance transporter (Pfcrt) gene, which encodes a transport protein involved in chloroquine resistance (K76T), and the dihydroopteroate synthase gene, which encodes the sulfadoxine target (A437G), identified the resistant allele in our isolate (6). There was no mutation in codon 268, which encodes the atovaquone target (4). The isolate had only 1 copy of the P. falciparum multidrug resistance (Pfmdr1) gene and a mutation in codon 184, which suggested in vitro susceptibility to mefloquine (7). Amplification of DNA from parasites obtained on day 0 and preserved on fixed and stained thin blood films by a modification of the procedure of Edoh et al. (8) was not successful.

Conclusions

Quinine remains a reliable treatment for patients with complicated or severe P. falciparum malaria outside southern Asia. Clinical failure with quinine used alone or in combination with clindamycin is common in Africa. In our case-patient, a correlation between the results of the in vivo and in vitro assessments was demonstrated at day 27. Because of the lack of reliable data on the correlation between quinine IC50 and clinical failure, arbitrary IC50 cutoff values were chosen for in vitro quinine resistance (300 nmol/L, 500 nmol/L, or 800 nmol/L) (9).

Quinine resistance appears to share common characteristics with chloroquine resistance. It is associated with mutations in the pfmdr1 (10) and pfcrt (11) genes. Nevertheless, the mechanism of quinine resistance is still unknown. In addition to the pfmdr1 and pfcrt genes, other genetic polymorphisms such as microsatellite length variations in the P. falciparum sodium/hydrogen exchanger (pfnhe-1) gene (5) and mutations in the P. falciparum multidrug resistance protein gene may contribute to quinine resistance (12).

We report an association of clinical failure of quinine treatment with an IC50 of 829 nmol/L, a mutation in codon 76 of the pfcrt gene, and an ms4760–18 profile for pfnhe-1 composed of 2 DNNND repeats. Isolates of P. falciparum with >2 DNNND repeats may be associated with reduced susceptibility to quinine. Henry et al. (5) reported that 2 DNNND repeats were associated with quinine IC50 values ranging from 300 nmol/L to 700 nmol/L, and that 3 repeats were associated with an IC50 >600 nmol/L. However, the 3 strains with IC50s >800 nmol/L had >2 DNNND repeats (6). Our results are consistent with these data.

P. falciparum resistance levels may differ depending on malaria transmission and drug pressure. Data from Senegal are fragmentary and were obtained by in vitro susceptibility studies conducted with isolates reported to have decreased in vitro susceptibility to quinine (6). Our patient had traveled to Dielmo, Senegal, where in vitro surveillance of antimalarial drug susceptibility has been conducted since 1996. During 1996–2005, the overall prevalence of isolates with IC50 >800 nmol/L for quinine was <6%: 1% in 1996, 4% in 1997, 0% in 1998, 6% in 1999, and 0% in 2005 (13). Quinine was used for 96.4% of the treatments administered in Dielmo during 1990–1995 (14). This drug has since been replaced by chloroquine, sulfadoxine-pyrimethamine, and artemisinin-based combination therapies.

We report a patient with clinical failure associated quinine resistance in a traveler to Senegal. Our results are consistent with those of a recent review of the Uganda Malaria Surveillance Project that reported a higher risk for selecting quinine-resistant parasites associated with a 7-day quinine treatment course (15). Thus, resistance to quinine should be monitored in West Africa. Although such clinical failure of therapy is rare, increased vigilance is required during treatment follow-up, and surveillance of the parasite population should also be increased.

Dr Pradines is a senior researcher at the Research Unit in Parasitological Biology and Epidemiology of the Institute for Tropical Medicine of the French Army, Le Pharo, Marseille, France. His primary research interests are the epidemiology and population genetics of malaria.

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References

  1. Bjorkman  A, Phillips-Howard  PA. The epidemiology of drug-resistant malaria. Trans R Soc Trop Med Hyg. 1990;84:17780. DOIPubMedGoogle Scholar
  2. Plowe  CV, Rooper  C, Barnwell  JW, Happi  CT, Joshi  HH, Mbacham  W, World Antimalarial Resistance Network (WARN) III: molecular markers for drug resistant malaria. Malar J. 2007;6:121. DOIPubMedGoogle Scholar
  3. Trape  JF, Rogier  C, Konate  L, Diagne  N, Bouganali  H, Canque  B, The Dielmo project: a longitudinal study of natural malaria infection and the mechanism of protective immunity in a community living in a holoendemic area of Senegal. Am J Trop Med Hyg. 1994;51:12337.PubMedGoogle Scholar
  4. Parola  P, Pradines  B, Simon  F, Carlotti  MP, Minodier  P, Ranjeva  MP, Antimalarial drug susceptibility and point mutations associated with drug resistance in 248 Plasmodium falciparum isolates imported from Comoros to Marseille, France in 2004–2006. Am J Trop Med Hyg. 2007;77:4317.PubMedGoogle Scholar
  5. 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. DOIPubMedGoogle Scholar
  6. Henry  M, Diallo  L, Bordes  J, Ka  S, Pradines  B, Diatta  B, Urban malaria in Dakar: chemosusceptibility and genetic diversity of Plasmodium falciparum isolates. Am J Trop Med Hyg. 2006;75:14651.PubMedGoogle Scholar
  7. Price  RN, Uhleman  UC, Brockman  A, McReady  R, Asley  E, Phaipun  L. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet. 2004;364:43847. DOIPubMedGoogle Scholar
  8. Edoh  D, Steiger  S, Genton  B, Beck  HP. PCR amplification of DNA from malaria parasites on fixed and stained thick and thin blood films. Trans R Soc Trop Med Hyg. 1997;91:3613. DOIPubMedGoogle Scholar
  9. Brasseur  P, Kouamouo  J, Moyou-Somo  R, Druilhe  P. Multi-drug resistant falciparum malaria in Cameroon in 1987–1988. I. Stable figures of prevalence of chloroquine- and quinine-resistant isolates in the original foci. Am J Trop Med Hyg. 1992;46:17.PubMedGoogle Scholar
  10. Reed  MB, Saliba  KJ, Caruana  SR, Kirk  K, Cowman  AF. Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature. 2000;403:9069. DOIPubMedGoogle Scholar
  11. Cooper  RA, Lane  KD, Deng  B, Mu  J, Patel  JJ, Wellems  TE, Mutations in transmembrane domains 1, 4 and 9 of the Plasmodium falciparum chloroquine resistance transporter alter susceptibility to chloroquine, quinine and quinidine. Mol Microbiol. 2007;63:27082. DOIPubMedGoogle Scholar
  12. Mu  J, Ferdig  MT, Feng  X, Joy  DA, Duan  J, Furuya  T, Multiple transporters associated with malaria parasite responses to chloroquine and quinine. Mol Microbiol. 2003;49:97789. DOIPubMedGoogle Scholar
  13. Pradines  B, Tall  A, Rogier  C, Spiegel  A, Mosnier  J, Marrrama  L, In vitro activities of ferrochloroquine against 55 Senegalese isolates of Plasmodium falciparum in comparison with those of standard antimalarial drugs. Trop Med Int Health. 2002;7:26570. DOIPubMedGoogle Scholar
  14. Noranate  N, Durand  R, Tall  A, Marrama  L, Spiegel  A, Sokhna  C, Rapid dissemination of Plasmodium falciparum drug resistance despite strictly controlled antimalarial use. PLoS One. 2007;2:e139. DOIPubMedGoogle Scholar
  15. Yeka  A, Achan  J, D’Alessandro  U, Talisuna  AO. Quinine monotherapy for treating uncomplicated malaria in the era of artemisinin-based combination therapy: an appropriate public health policy? Lancet Infect Dis. 2009;9:44852. DOIPubMedGoogle Scholar

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DOI: 10.3201/eid1603.091669

Table of Contents – Volume 16, Number 3—March 2010

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Please use the form below to submit correspondence to the authors or contact them at the following address:

Khaled Ezzedine, Centre René Labusquière, Tropical Disease Branch, PPF Parasitologie, Université Victor Segalen Bordeaux 2, 146 Rue Léo Saignat, 33076 Bordeaux CEDEX, France

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Page created: December 14, 2010
Page updated: December 14, 2010
Page reviewed: December 14, 2010
The conclusions, findings, and opinions expressed by authors contributing to this journal do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors' affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above.
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