To the Editor: In their article on the efficacy of chloroquineagainst Plasmodium falciparum in Blantyre, Malawi, Laufer andcolleagues (Nov. 9 issue)1 report adequate clinical and parasitologicresponses to chloroquine and the microevolutionary replacementof the T76 marker for the P. falciparum chloroquine-resistancetransporter gene (PfCRT)2 by the sensitive wild-type markerfor choroquine susceptibility (K76) — the prevalence ofwhich increased in local parasite populations after use of thedrug had been suspended for several years3 — as a resultof restored fitness of the wild-type strains. If the authors'recommendation to largely withdraw chloroquine from use as atreatment for malaria and reserve it for future chemotherapyand prophylaxis (including its use in intermittent preventivetreatment strategies) were to become a public health initiative,potential cross-resistance would have to be considered. Amodiaquineis a partner drug for artemisinin-based combination therapiesin many African countries. There is strong evidence that themechanisms of resistance to chloroquine and amodiaquine aresimilar, since in vivo amodiaquine resistance is also associatedwith the critical T76 PfCRT mutation.4,5 Persistent drug pressureexerted by amodiaquine might be a biologic barrier against thesuccessful return of chloroquine-sensitive phenotypes.
Robin Kobbe, M.D. Christian G. Meyer, M.D. Jürgen May, M.D. Bernhard Nocht Institute for Tropical Medicine D-20359 Hamburg, Germany
References
Laufer MK, Thesing PC, Eddington ND, et al. Return of chloroquine antimalarial efficacy in Malawi. N Engl J Med 2006;355:1959-1966. [Free Full Text]
Sidhu AB, Verdier-Pinard D, Fidock DA. Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 2002;298:210-213. [Free Full Text]
Kublin JG, Cortese JF, Njunju EM, et al. Reemergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi. J Infect Dis 2003;187:1870-1875. [CrossRef][Web of Science][Medline]
Happi CT, Gbotosho GO, Folarin OA, et al. Association between mutations in Plasmodium falciparum chloroquine resistance transporter and P. falciparum multidrug resistance 1 genes and in vivo amodiaquine resistance in P. falciparum malaria-infected children in Nigeria. Am J Trop Med Hyg 2006;75:155-161. [Free Full Text]
Holmgren G, Gil JP, Ferreira PM, Veiga MI, Obonyo CO, Bjorkman A. Amodiaquine resistant Plasmodium falciparum malaria in vivo is associated with selection of pfcrt 76T and pfmdr1 86Y. Infect Genet Evol 2006;6:309-314. [CrossRef][Web of Science][Medline]
To the Editor: Laufer et al. report that chloroquine is onceagain effective in Malawi and suggest that a chloroquine-containingdrug combination might be a treatment option. However, a combinationincluding the standard dose of 25 mg of chloroquine per kilogramof body weight might rapidly select for the chloroquine-resistantgenotype PfCRT T76, leaving a partner drug unprotected. In Guinea-Bissau,the officially recommended dose of 25 mg of chloroquine perkilogram has 80% efficacy at day 28. Doubling the dose to 50mg per kilogram increases the efficacy to 92%.1 Chloroquineis routinely prescribed at an average dose of 76 mg per kilogramin health centers in Bissau.2 We found PfCRT T76 in only 23of 109 blood samples obtained from children who were recruitedduring the first year of a recently completed study. The lowprevalence of PfCRT T76, the improved efficacy of chloroquineat a dose of 50 mg per kilogram, and the decreased fitness ofresistant parasites suggest that treatment with higher dosesof chloroquine may limit the spread of chloroquine-resistantparasites.
Johan Ursing, M.D. Karolinska Hospital 171 76 Stockholm, Sweden johan.ursing{at}ki.se
Kofoed PE, Ursing J, Poulsen A, et al. Different doses of amodiaquine and chloroquine for treatment of uncomplicated malaria in children in Guinea-Bissau: implications for future treatment recommendations. Trans R Soc Trop Med Hyg 2007;101:231-238. [CrossRef][Medline]
Kofoed PE, Lopez F, Johansson P, et al. Treatment of children with Plasmodium falciparum malaria with chloroquine in Guinea-Bissau. Am J Trop Med Hyg 2002;67:28-31. [Abstract]
To the Editor: Laufer et al. build on previous observationalstudies of malaria treatment in Malawi. One question that isstill outstanding is the implication that this study was conductedat Ndirande Health Center, on the outskirts of Blantyre. Thequestion is whether the findings of Laufer et al. are representativeof the general malaria-related drug–parasite interactionin Malawi. In addition, the possible importation of chloroquineresistance from neighboring countries where significant chloroquineresistance can still be found, such as Mozambique, Zambia, andTanzania, remains a concern.
Adamson S. Muula, M.D. University of North Carolina at Chapel Hill Chapel Hill, NC 27514 muula{at}email.unc.edu
The authors reply: Kobbe and colleagues raise the possibilityof continued selection of chloroquine-resistant malaria by amodiaquine,which is being used in combination with artesunate in some Africancountries. Indeed, it will be of interest to track and comparethe prevalence of the molecular marker for chloroquine resistancein areas where chloroquine is being withdrawn and replaced bycombinations that include amodiaquine and in areas where itis being replaced by drugs that are unrelated to chloroquine.Such molecular ecologic studies may inform strategies for rotatingdrugs in specific sequences to prevent the emergence and reemergenceof resistant phenotypes.
Ursing and colleagues suggest that doubling the dose of chloroquinemay deter the emergence of resistant phenotypes if chloroquineis used in combination therapies. Their hypothesis that increasingthe dose of medication may improve activity against drug-resistantparasites is sound. However, the effect of the higher dose onthe emergence and spread of resistance requires extensive investigation.In the small studies they cite, the higher dose of chloroquineappeared to be safe, but doubling or tripling the standard doseof a medication requires a much more thorough safety assessment.Chloroquine has a narrow therapeutic index, and reported ingestionsof two to five times the therapeutic dose of chloroquine havebeen associated with fatal poisonings.1 In areas where malariais endemic, children may receive repeated doses of antimalarialmedication, increasing the risk of toxicity.
Muula wonders whether our findings from the single-center studyin Blantyre can be generalized to other parts of Malawi. Similarreductions in chloroquine resistance have been found in Salima,a town located on Lake Malawi, approximately 200 miles fromBlantyre.2 We are currently analyzing specimens obtained fromother regions of Malawi to determine the geographic extent ofthis phenomenon. As we noted in our discussion, chloroquineresistance remains prevalent in the region, and the reintroductionof chloroquine for intermittent preventive therapy or as a componentof combination therapy should be considered only after chloroquine-resistantmalaria has been eliminated from widespread areas — possiblyfrom the entire African continent. Population genetics studieson a regional level are needed to gain a better understandingof the ebb and flow of drug-resistant malaria in Africa.
Miriam K. Laufer, M.D. Christopher V. Plowe, M.D., M.P.H. University of Maryland School of Medicine Baltimore, MD 21201 cplowe{at}medicine.umaryland.edu
Terrie E. Taylor, D.O. Michigan State University College ofOsteopathic Medicine East Lansing, MI 48828
References
Cann HM, Verhulst HL. Fatal acute chloroquine poisoning in children. Pediatrics 1961;27:95-102. [Free Full Text]
Mita T, Kaneko A, Lum JK, et al. Recovery of chloroquine sensitivity and low prevalence of the Plasmodium falciparum chloroquine resistance transporter gene mutation K76T following the discontinuance of chloroquine use in Malawi. Am J Trop Med Hyg 2003;68:413-415. [Free Full Text]
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