Competitive release and facilitation of drug-resistant parasites after therapeutic chemotherapy in a rodent malaria model

Abstract

Malaria infections frequently consist of mixtures of drug-resistant and drug-sensitive parasites. If crowding occurs, where clonal population densities are suppressed by the presence of coinfecting clones, removal of susceptible clones by drug treatment could allow resistant clones to expand into the newly vacated niche space within a host. Theoretical models show that, if such competitive release occurs, it can be a potent contributor to the strength of selection, greatly accelerating the rate at which resistance spreads in a population. A variety of correlational field data suggest that competitive release could occur in human malaria populations, but direct evidence cannot be ethically obtained from human infections. Here we show competitive release after pyrimethamine curative chemotherapy of acute infections of the rodent malaria Plasmodium chabaudi in laboratory mice. The expansion of resistant parasite numbers after treatment resulted in enhanced transmission-stage densities. After the elimination or near-elimination of sensitive parasites, the number of resistant parasites increased beyond that achieved when a competitor had never been present. Thus, a substantial competitive release occurred, markedly elevating the fitness advantages of drug resistance above those arising from survival alone. This finding may explain the rapid spread of drug resistance and the subsequently brief useful lifespans of some antimalarial drugs. In a second experiment, where subcurative chemotherapy was administered, the resistant clone was only partly released from competitive suppression and experienced a restriction in the size of its expansion after treatment. This finding raises the prospect of harnessing in-host ecology to slow the spread of drug resistance.competition ͉ evolution of drug resistance ͉ Plasmodium chabaudi ͉ transmission ͉ in-host ecology

An alternative host model of a mixed fungal infection by azole susceptible and resistantAspergillusspp strains

“…45 Similarly, with malaria it has been proposed that when sensitive and resistant parasites co-infect the same host individuals, drug use would further increase the relative fitness of drugresistant clones by removing drug-sensitive competitors. 46 It may seem that there is a discrepancy between the decrease in fungal burden and the lack of response in survival of G. mellonella infected with A. lentulus in the single and the mixed infection. It has been described that A. lentulus VRC MICs range from 4 to 6 mg/L.…”

Is parasite clearance clinically important after malaria treatment in a high transmission area? A 3-month follow-up of home-based management with herbal medicine or ACT

“…those >5 years old in a high transmission area, may also help to reduce the spread of resistance to ACTs. Wargo et al 15 have shown that the development of resistant strains might in fact be slower when parasite clearance is not achieved: where subcurative chemotherapy was administered, the resistant clone was only partly released from competitive suppression and experienced a restriction in the size of its expansion after treatment.…”

A closer look at multiple-clone Plasmodium vivax infections: detection methods, prevalence and consequences

“…This can lead to increased gametocyte production in multiple-clone infections, which may have a major public health impact even in those areas where early diagnosis and treatment of malaria can be achieved (Sattabongkot et al 2004). In addition, when clone mixtures are comprised of drug-resistant and drug-sensitive P. chabaudi strains, the removal of susceptible clones by drug therapy promoted the expansion of resistant parasites to a level far beyond that achieved when a competitor had never been present (Wargo et al 2007). Therefore, these experimental results imply that within-host competition may accelerate the spread of drug resistance in malaria parasites.…”