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Am. J. Trop. Med. Hyg., 73(1), 2005, pp. 174-177
Copyright © 2005 by The American Society of Tropical Medicine and Hygiene

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RESPONSE OF PLASMODIUM FALCIPARUM TO COTRIMOXAZOLE THERAPY: RELATIONSHIP WITH PLASMA DRUG CONCENTRATIONS AND DIHYDROFOLATE REDUCTASE AND DIHYDROPTEROATE SYNTHASE GENOTYPES

INSAF F. KHALIL*, ANITA M. RØNN, MICHAEL ALIFRANGIS, HYTHAM A. GABAR, THOMAS JELINEK, GWIRIA M. H. SATTI, AND IB C. BYGBJERG
Centre for Medical Parasitology, Institute of Medical Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark; Department of International Health, Institute of Public Health, University of Copenhagen, Copenhagen, Denmark; Department of Biochemistry, Faculty of Medicine, University of Khartoum, Khartoum, Sudan; Department of Infectious Diseases and Tropical Medicine, University of Munich, Munich, Germany; Department of Biochemistry, King Faisal University; Dammam, Saudi Arabia

We assessed the efficacy of trimethoprim/sulfamethoxazole (TRM/SMX) in vivo in relation to the frequency of dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) alleles in 45 Sudanese malaria patients. Plasma levels of TRM, SMX, and acetylsulfamethoxazole (AcSMX) were measured before treatment and at days 3, 7, and 14 or upon recrudescence to ascertain drug absorption. Forty patients (89%) had an adequate clinical response, one patient (2%) had an early treatment failure response, while four patients (8%) showed late treatment failure responses. Genotyping of merozoite surface protein 1, MSP-1, MSP-2, and glutamate-rich protein before treatment and upon recrudescence showed that all recurring parasites were recrudescences. The plasma levels of TRM, AcSMX, and SMX indicated adequate drug absorption in all patients. This suggests parasite resistance as a cause of treatment failure. The presence of dhfr Ile 51 and Asn 108 alone or coupled with dhps Ala-436 among parasites that were cleared after treatment indicates that these alleles alone are insufficient to cause in vivo resistance. However, the presence of the triple mutant dhfr (Ile-51/Arg-59/Asn-108) with the dhps Gly-437 genotype in all recurring infections, suggests the importance of codon 59 and 437 alleles in susceptibility to TRM/SMX. However, the number is too little to make firm conclusions.

Received July 14, 2004. Accepted for publication February 2, 2005.

Acknowledgments: We thank Jimmy Weng for excellent technical assistance and Dr. G. Snounou for providing MSP-1, MSP-2, and GLURP primers.

Financial support: This work was supported by the Danish International Development Agency (DANIDA).

* Address correspondence to Dr. Insaf F. Khalil, Centre for Medical Parasitology, Institute of Medical Microbiology and Immunology, University of Copenhagen, Panum Institute, Building 24.2, Blegdamsvej, 3, 2200 Copenhagen N, Denmark. E-mail: insafk{at}immi.ku.dk

Authors’ addresses: Insaf F. Khalil and Michael Alifrangis, Centre for Medical Parasitology, Institute of Medical Microbiology and Immunology, University of Copenhagen, Panum Institute, Building 24.2, Blegdamsvej 3, 2200 Copenhagen N, Denmark and Department of Infectious Diseases, Copenhagen University Hospital, Blegdamsvej 3, 2200 Copenhagen N, Denmark, Telephone: 45-35-327-680, Fax: 45-35-327-851, E-mails: InsafK{at}immi.ku.dk and malif{at}cmp.dk. Anita M. Rønn and Ib C. Bygbjerg, Department of International Health, Institute of Public Health, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark, E-mail: ARN{at}euro.alarm.dk. Hytham A. Gabar, Department of Biochemistry, Faculty of Medicine, University of Khartoum, PO Box 102, Khartoum, Sudan, E-mail: Hythan{at}hotmail.com. Thomas Jelinek, Department of Infectious Diseases and Tropical Medicine, University of Munich, Munich, Germany, E-mail: jelinek{at}bbges.de. Gwiria M. H. Satti, Department of Biochemistry, King Faisal University, PO Box 2114, Dammam, Saudi Arabia, E-mail: Gwiria{at}yahoo.com.




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