Chloroquine Resistance in Plasmodium Falciparum

Young, Martin D.; Moore, Donald V.

doi:10.4269/ajtmh.1961.10.317

Cited by 117 publications

(28 citation statements)

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“…Chloroquine (CQ)-resistant strains of P. falciparum first appeared in the late 1950s, almost simultaneously in Southeast Asia and South America (51,58,64), and subsequently spread through most regions where P. falciparum is endemic. Sulfadoxinepyrimethamine (SP) was next used as the drug of choice against CQ-resistant malaria; however, resistance quickly emerged on the Thai-Cambodian border around 1980 and is now found throughout most of Southeast Asia, the Amazonian basin of South America, and Africa (1,2,7,17,40,53).…”

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Evidence of Selective Sweeps in Genes Conferring Resistance to Chloroquine and Pyrimethamine in Plasmodium falciparum Isolates in India

Mixson‐Hayden

Jain

McCollum

et al. 2010

Antimicrob Agents Chemother

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Treatment of Plasmodium falciparum is complicated by the emergence and spread of parasite resistance to many of the first-line drugs used to treat malaria. Antimalarial drug resistance has been associated with specific point mutations in several genes, suggesting that these single nucleotide polymorphisms can be useful in tracking the emergence of drug resistance. In India, P. falciparum infection can manifest itself as asymptomatic, mild, or severe malaria, with or without cerebral involvement. We tested whether chloroquine-and antifolate drug-resistant genotypes would be more commonly associated with cases of cerebral malaria than with cases of mild malaria in the province of Jabalpur, India, by genotyping the dhps, dhfr, pfmdr-1, and pfcrt genes using pyrosequencing, direct sequencing, and real-time PCR. Further, we used microsatellites surrounding the genes to determine the origins and spread of the drug-resistant genotypes in this area. Resistance to chloroquine was essentially fixed, with 95% of the isolates harboring the pfcrt K76T mutation. Resistant genotypes of dhfr, dhps, and pfmdr-1 were found in 94%, 17%, and 77% of the isolates, respectively. Drugresistant genotypes were equally likely to be associated with cerebral malaria as with mild malaria. We found evidence of a selective sweep in pfcrt and, to a lesser degree, in dhfr, indicating high levels of resistance to chloroquine and evolving resistance to pyrimethamine. Microsatellites surrounding pfcrt indicate that the resistant genotypes (SVMNT) were most similar to those found in Papua New Guinea.

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Evidence of Selective Sweeps in Genes Conferring Resistance to Chloroquine and Pyrimethamine in Plasmodium falciparum Isolates in India

Mixson‐Hayden

Jain

McCollum

et al. 2010

Antimicrob Agents Chemother

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“…Shortly thereafter, Young and Moore (49) provided unequivocal documentation of the resistance of this strain to the above drug via studies on blood-induced infections in a group of patients with neurosyphilis. Young (45) went on to demonstrate (i) that established infections with this parasite, of Colombian origin, were also refractory to treatment with recommended therapeutic doses of amodiaquin and hydrbxychloroquine (two other 4-aminoquinolines) and (ii) that neither chloroquine nor amodiaquin, delivered in conventional suppressive regimens, would prevent evolution of clinical disease in patients bitten by mosquitoes infected with this plasmodium.…”

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Activities of Various 4-Aminoquinolines Against Infections with Chloroquine-Resistant Strains of Plasmodium falciparum

Schmidt

Vaughan

Mueller

et al. 1977

Antimicrob Agents Chemother

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The studies reported here stemmed from a personal report by Geiman on the capacity of the 4-aminoquinoline amodiaquin to inhibit in vitro maturation of ring stages of the chloroquine-resistant Monterey strain ofPlasmodium falciparum. This observation, confirmed in owl monkeys infected with this strain, led to a comparison of the activities of chloroquine, amodiaquin, amopyroquin, and dichlorquinazine (12,278 RP) against infections with various chloroquine-susceptible and chloroquine-resistant strains. The results showed that: (i) these 4-aminoquinolines were essentially equally active against infections with chloroquine-susceptible strains and (ii) the activities of amodiaquin, amopyroquin, and dichlorquinazine were reduced significantly in the face of chloroquine resistance, but (iii) well-tolerated doses of these compounds would cure infections with strains that fully resisted treatment with maximally tolerated doses of chloroquine. Two other 4-aminoquinolines, SN-8137 and SN-9584, which also exhibited activity against chloroquine-resistant parasites in vitro, displayed curative activity in monkeys infected with a chloroquine-resistant strain. These observations show that there is cross-resistance among the 4-aminoquinolines, confirming earlier findings, but indicate that the dimensions of this phenomenon are sufficiently limited so that some derivatives are therapeutically effective against infections refractory to maximally tolerated doses of chloroquine.

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“…The high pressure overimposed on this drug response was one of the most important factors in the appearance of in- creased resistance of P. falciparum,, as noted by Young and Moore. 7 In mining areas of the municipality, self-medication with diverse antimalarial drugs is frequent; such drugs include medicinal plants, chloroquine, and other patented drugs. As is known, self-medication and subcurative doses favor the selection of resistant parasite populations, which are frequent in areas of high malarial transmission.…”

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confidence: 99%

Chemotherapy of malaria and resistance to antimalarial drugs in Guayana area, Venezuela.

Caraballo¹,

Rodrı́guez-Acosta²

1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. Resistance to antimalarial chemotherapy is one of the greatest difficulties for the control of malaria transmission. Seventy patients with Plasmodium falciparum malaria were included in a study of resistance to chloroquine and sulfadoxine-pyrimethamine therapy. Resistance levels RI, RII, and RIII were established. Eighteen infections (51%) cleared after chloroquine treatment and did not recur within 28 days of follow-up; these were classified as sensitive. Ten infections (29%) were resistant at the RI level. Resistance at level RII was observed in 5 (14%) cases, and RIII resistance was demonstrated in 2 infections (6%). With sulfadoxine-pyrimethamine, 28 (80%) infections were classified as sensitive. Six infections (17%) showed resistance at level RII, and 1 (3%) infection was resistant at the RI level. Resistance at level RIII was not observed. In a microtest for chloroquine and sulfadoxinepyrimethamine sensitivity in vitro, schizont development was accomplished successfully in 70 blood samples. In vitro resistance to chloroquine was demonstrated in 15 of 70 (21%) of all isolates. Eight of 70 (11%) of all isolates showed resistance to sulfadoxine-pyrimethamine. Diversity of response of P. falciparum to the studied antimalarial drugs in the Guayana area of Venezuela is considered a problem restricting the control of malaria in this geographical area. A constant evaluation program monitoring P. falciparum drug sensitivity is necessary for preserving the efficacy of the established treatment.After a successful eradication program implemented over several decades, malaria is now endemic in Venezuela in patchy forest areas where activities associated with gold mining are limiting control efforts. From 1992 to 1995, Plasmodium falciparum infections and outbreaks were registered only in remote areas in southern Venezuela, in 11 municipalities that are located in Bolívar State and Amazonas and Delta Amacuro territories. Bolívar State has contributed more than 60% of all malaria cases in Venezuela; of these, 20% correspond to P. falciparum infections. On average, the infection rates of the parasite reach 2 cases per 1,000 inhabitants among a population composed mainly of gold and diamond miners and indigenous groups.Resistance to antimalarial chemotherapy is one of the obstacles for the control of malaria transmission in various regions of the world. The adequate use of antimalarial drugs is essential for reducing the high morbidity and mortality associated with P. falciparum malaria in nonimmune hosts. Therefore, knowledge of the geographical distribution of P. falciparum strains that are resistant and the identification of the severity of this resistance are important in the choice of an effective therapeutic regimen.Chloroquine resistance was first reported in Venezuela, 1 and soon after was confirmed in several countries. Since 1975, very few studies on resistant P. falciparum strains have been carried out in Venezuela; some of them have shown different resistance levels in vivo for chloroquine 2 (Navarret...

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Chloroquine Resistance in Plasmodium Falciparum

Cited by 117 publications

References 0 publications

Evidence of Selective Sweeps in Genes Conferring Resistance to Chloroquine and Pyrimethamine in Plasmodium falciparum Isolates in India

Evidence of Selective Sweeps in Genes Conferring Resistance to Chloroquine and Pyrimethamine in Plasmodium falciparum Isolates in India

Activities of Various 4-Aminoquinolines Against Infections with Chloroquine-Resistant Strains of Plasmodium falciparum

Chemotherapy of malaria and resistance to antimalarial drugs in Guayana area, Venezuela.

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