Hyperparasitaemia and low dosing are an important source of anti-malarial drug resistanceReport as inadecuate




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Malaria Journal

, 8:253

First Online: 11 November 2009Received: 09 August 2009Accepted: 11 November 2009

Abstract

BackgroundPreventing the emergence of anti-malarial drug resistance is critical for the success of current malaria elimination efforts. Prevention strategies have focused predominantly on qualitative factors, such as choice of drugs, use of combinations and deployment of multiple first-line treatments. The importance of anti-malarial treatment dosing has been underappreciated. Treatment recommendations are often for the lowest doses that produce -satisfactory- results.

MethodsThe probability of de-novo resistant malaria parasites surviving and transmitting depends on the relationship between their degree of resistance and the blood concentration profiles of the anti-malarial drug to which they are exposed. The conditions required for the in-vivo selection of de-novo emergent resistant malaria parasites were examined and relative probabilities assessed.

ResultsRecrudescence is essential for the transmission of de-novo resistance. For rapidly eliminated anti-malarials high-grade resistance can arise from a single drug exposure, but low-grade resistance can arise only from repeated inadequate treatments. Resistance to artemisinins is, therefore, unlikely to emerge with single drug exposures. Hyperparasitaemic patients are an important source of de-novo anti-malarial drug resistance. Their parasite populations are larger, their control of the infection insufficient, and their rates of recrudescence following anti-malarial treatment are high. As use of substandard drugs, poor adherence, unusual pharmacokinetics, and inadequate immune responses are host characteristics, likely to pertain to each recurrence of infection, a small subgroup of patients provides the particular circumstances conducive to de-novo resistance selection and transmission.

ConclusionCurrent dosing recommendations provide a resistance selection opportunity in those patients with low drug levels and high parasite burdens often children or pregnant women. Patients with hyperparasitaemia who receive outpatient treatments provide the greatest risk of selecting de-novo resistant parasites. This emphasizes the importance of ensuring that only quality-assured anti-malarial combinations are used, that treatment doses are optimized on the basis of pharmacodynamic and pharmacokinetic assessments in the target populations, and that patients with heavy parasite burdens are identified and receive sufficient treatment to prevent recrudescence.

AbbreviationsPMFparasite multiplication factor

PRRparasite reduction ratio

ICinhibitory concentration

Eparasite blood stage multiplication efficiency

mdr1genes encoding the parasite multidrug resistance transporter

dhfrgenes encoding the parasite dihydrofolate reductase

dhpsgenes encoding the parasite dihydropteroate synthase

MPCminimum parasiticidal concentration

MICminimum inhibitory concentration

ACTartemisinin combination treatment.

Electronic supplementary materialThe online version of this article doi:10.1186-1475-2875-8-253 contains supplementary material, which is available to authorized users.

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Author: Nicholas J White - Wirichada Pongtavornpinyo - Richard J Maude - Sompob Saralamba - Ricardo Aguas - Kasia Stepniewska - Su

Source: https://link.springer.com/







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