Plasmodium falciparum  crossresistance between trimethoprim and pyrimethamine

Iyer, Jayasree K.; Milhous, Wilbur K.; Cortese, Joseph F.; Kublin, James G.; Plowe, Christopher V.

doi:10.1016/s0140-6736(01)06201-8

Cited by 122 publications

(96 citation statements)

References 5 publications

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“…Cross-resistance between trimethoprim and pyrimethamine 31 and between sulfamethoxazole and sulfadoxine 32 has been documented in vitro with mutations in the dhfr and dhps genes, respectively. However, the in vivo effect of cotrimoxazole use on the acquisition of antifolate-resistant malaria parasites has not yet been established.…”

Section: Discussionmentioning

confidence: 99%

Plasmodium falciparum Dihydrofolate Reductase and Dihyropteroate Synthase Mutations and the Use of Trimethoprim-Sulfamethoxazole Prophylaxis among Persons Infected with Human Immunodeficiency Virus

Malamba

Sandison²,

Lule³

et al. 2010

The American Journal of Tropical Medicine and Hygiene

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Abstract. A prospective cohort design was used to measure the association between daily cotrimoxazole-prophylaxis and infection with Plasmodium falciparum containing mutations associated with antifolate resistance among persons infected with human immunodeficiency virus (HIV) in Tororo and Busia District, in eastern Uganda. Of 149 cases of P. falciparum parasitemia diagnosed, 147 (99%) (smears from participants taking prophylaxis = 91 and smears from those not taking cotrimoxazole prophylaxis = 56) were successfully assessed for mutations in the dihydrofolate reductase ( dhfr ) and dihydropteroate synthase ( dhps ) mutations associated with antifolate resistance. Prevalences of the dhfr pure triple mutant (74% and 70%; P = 0.71), the dhps pure double mutant (95% and 88%; P = 0.21), and the dhfr/dhps pure quintuple mutant (73% and 64%; P = 0.36), were not significantly different between those taking and those not taking cotrimoxazole-prophylaxis, respectively. The overall prevalence of the pure quintuple mutant in this study was 69%, which is among the highest in Africa. Although resistance rates of P. falciparum to antifolate drugs are high, cotrimoxazole-prophylaxis in HIV-infected persons was not associated with a higher prevalence of mutations associated with antifolate resistance.

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Section: Discussionmentioning

confidence: 99%

Plasmodium falciparum Dihydrofolate Reductase and Dihyropteroate Synthase Mutations and the Use of Trimethoprim-Sulfamethoxazole Prophylaxis among Persons Infected with Human Immunodeficiency Virus

Malamba

Sandison²,

Lule³

et al. 2010

The American Journal of Tropical Medicine and Hygiene

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“…Cotrimoxazole (CTX [trimethoprim-sulfamethoxazole]) is a drug used to treat acute respiratory infections, and cross-resistance between trimethoprim, a component of CTX, and pyrimethamine has been demonstrated in vitro (10,11). Similarly, cross-resistance between sulfamethoxazole and sulfadoxine has also been demonstrated (10).…”

Section: Discussionmentioning

confidence: 99%

Common Origin and Fixation of Plasmodium falciparum dhfr and dhps Mutations Associated with Sulfadoxine-Pyrimethamine Resistance in a Low-Transmission Area in South America

McCollum

Mueller

Villegas³

et al. 2007

Antimicrob Agents Chemother

118

155

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Recent studies indicated that sensitive parasites could increase in frequency in a population when drugs are removed, suggesting that the life span of affordable antimalarial drugs could be expanded. We studied 97 samples from Bolivar State, Venezuela, an area where sulfadoxine-pyrimethamine (SP) has not been used for 8 years due to its ineffectiveness. We characterized point mutations in two genes that have been implicated in resistance to SP, dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps). We also assayed neutral microsatellite markers around the dhfr (chromosome 4) and dhps (chromosome 8) genes and on chromosomes 2 and 3 to track the origin and spread of resistant alleles. We found that drug-resistant SP mutants are fixed in the population. Two genotypes were present in the samples, dhfr(50R/51I/108N) dhps(437G/540E/581G) (90.7%) and dhfr(51I/108N) dhps(437G/581G) (9.3%). We show a single microsatellite haplotype for all of the dhfr and dhps alleles, and the alleles at the microsatellite loci are different from those present in Africa. Thus, in these samples from Venezuela, there is a single origin for both dhfr and dhps SP-resistant alleles, and these alleles originated independently of those characterized from Africa. Furthermore, this is the first report of a "hitchhiking effect" on the genetic variation around dhps due to selection by SP using an extensive set of microsatellite markers. Our results indicate that, in areas where there is limited gene flow, the fixation of drug-resistant parasites in the population is stable, even after drug selection is relaxed.The emergence of drug-resistant Plasmodium falciparum is a serious public health problem in many countries where malaria is endemic (7, 28). Sulfadoxine-pyrimethamine (SP) is an antifolate drug commonly used to treat P. falciparum infections because of its ease of administration, affordability, and efficacy. Unfortunately, resistance to SP has been documented in many parts of the world, compromising the use of this drug for treating uncomplicated P. falciparum malaria.SP acts as an inhibitor of the P. falciparum folic acid pathway, and point mutations in the genes encoding dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) have been implicated in SP resistance (9). The dhfr(S108N) point mutation and additional mutations at codons 50, 51, 59, and 164 act synergistically to increase resistance to pyrimethamine (4, 21). Similarly, mutations at dhps codons 436, 437, 540, 581, and 613 act synergistically to increase the level of resistance to sulfadoxine (7).Recent studies following the frequency of chloroquine-resistant parasites over time showed that sensitive parasites could increase in frequency soon after the drug pressure on the parasite population was decreased (13). These results suggest that, with appro-

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“…In Uganda, sensitivity rates of P falciparum to sulphadoxine-pyrimethamine range between 80% and 99%, 25 although failure rates were higher when recrudescence during 42 days of follow-up was evaluated. 29 Assessment of whether sulphadoxinepyrimethamine remains an effective treatment for individuals receiving co-trimoxazole prophylaxis 30 and whether its use increases sulphadoxine-pyrimethamine resistance in the broader community will be important. 31 Compliance with co-trimoxazole treatment was excellent and, as in other studies in Africa, 3,4,6 the treatment was very well tolerated.…”

Section: Discussionmentioning

confidence: 99%

Effect of co-trimoxazole prophylaxis on morbidity, mortality, CD4-cell count, and viral load in HIV infection in rural Uganda

et al. 2004

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SummaryBackground Prophylaxis with co-trimoxazole (trimethoprim-sulphamethoxazole) is recommended for people with HIV infection or AIDS but is rarely used in Africa. We assessed the effect of such prophylaxis on morbidity, mortality, CD4-cell count, and viral load among people with HIV infection living in rural Uganda, an area with high rates of bacterial resistance to co-trimoxazole.Methods Between April, 2001, and March, 2003, we enrolled, and followed up with weekly home visits, 509 individuals with HIV-1 infection and their 1522 HIV-negative household members. After 5 months of follow-up, HIV-positive participants were offered daily co-trimoxazole prophylaxis (800 mg trimethoprim, 160 mg sulphamethoxazole) and followed up for a further 1·5 years. We assessed rates of malaria, diarrhoea, hospital admission, and death. Findings Co-trimoxazole was well tolerated with rare (<2% per person-year) adverse reactions. Even though rates of resistance in diarrhoeal pathogens were high (76%), co-trimoxazole prophylaxis was associated with a 46% reduction in mortality (hazard ratio 0·54 [95% CI 0·35-0·84], p=0·006) and lower rates of malaria (multivariate incidence rate ratio 0·28 [0·19-0·40], p<0·0001), diarrhoea (0·65 [0·53-0·81], p<0·0001), and hospital admission (0·69 [0·48-0·98], p=0·04). The annual rate of decline in CD4-cell count was less during prophylaxis than before (77 vs 203 cells per µL, p<0·0001), and the annual rate of increase in viral load was lower (0·08 vs 0·90 log 10 copies per mL, p=0·01).Interpretation Daily co-trimoxazole prophylaxis was associated with reduced morbidity and mortality and had beneficial effects on CD4-cell count and viral load. Co-trimoxazole prophylaxis is a readily available, effective intervention for people with HIV infection in Africa.

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Plasmodium falciparum crossresistance between trimethoprim and pyrimethamine

Cited by 122 publications

References 5 publications

Plasmodium falciparum Dihydrofolate Reductase and Dihyropteroate Synthase Mutations and the Use of Trimethoprim-Sulfamethoxazole Prophylaxis among Persons Infected with Human Immunodeficiency Virus

Plasmodium falciparum Dihydrofolate Reductase and Dihyropteroate Synthase Mutations and the Use of Trimethoprim-Sulfamethoxazole Prophylaxis among Persons Infected with Human Immunodeficiency Virus

Common Origin and Fixation of Plasmodium falciparum dhfr and dhps Mutations Associated with Sulfadoxine-Pyrimethamine Resistance in a Low-Transmission Area in South America

Effect of co-trimoxazole prophylaxis on morbidity, mortality, CD4-cell count, and viral load in HIV infection in rural Uganda

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