Chemotherapy, Within-Host Ecology and the Fitness of Drug-Resistant Malaria Parasites

Huijben, Silvie; Nelson, William A.; Wargo, Andrew R.; Sim, Derek G.; Drew, Damien R.; Read, Andrew F.

doi:10.1111/j.1558-5646.2010.01068.x

Cited by 60 publications

(137 citation statements)

References 88 publications

(124 reference statements)

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“…This will result in competitive release and enhanced transmission of any highly resistant strains that are present. In rodent models, this is precisely what happens (36,42,43) (Fig. 3).…”

Section: Aims Of Patient Treatmentmentioning

confidence: 96%

“…However, in a rodent malaria model, P. chabaudi in laboratory mice, we and others have experimentally demonstrated that densities of individual clones within an infection are severely suppressed when coinfecting clones are present (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44). This competitive suppression substantially reduces the density of transmission stages (42,43), and hence transmission of individual clones to mosquitoes (33,35,36). To date, there is no evidence of direct interference competition analogous to bacteriocin-mediated competition in bacteria (45).…”

Section: Aims Of Patient Treatmentmentioning

confidence: 99%

“…2, which details the transmission stage densities of resistant parasites in the untreated mice in the same experiment). Plotted points are the mean (±SEM) densities in peripheral blood from five to ten mice per group, estimated by quantitative PCR using protocols described elsewhere (43).…”

Section: (B and D) Resistant Parasites (Red Lines) (A And B) Densitimentioning

confidence: 99%

“…Could there be room to harness the in-host ecology to reduce the fitness advantages of resistance, in effect retaining some drug-sensitive pathogens to suppress resistance (42,43,71)? Critically, patient health does not necessarily require immediate parasite elimination by drugs.…”

Section: How To Treat Patients?mentioning

confidence: 99%

See 3 more Smart Citations

The evolution of drug resistance and the curious orthodoxy of aggressive chemotherapy

Read

Day

Huijben

2011

Proc. Natl. Acad. Sci. U.S.A.

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243

281

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The evolution of drug-resistant pathogens is a major challenge for 21st century medicine. Drug use practices vigorously advocated as resistance management tools by professional bodies, public health agencies, and medical schools represent some of humankind's largest attempts to manage evolution. It is our contention that these practices have poor theoretical and empirical justification for a broad spectrum of diseases. For instance, rapid elimination of pathogens can reduce the probability that de novo resistance mutations occur. This idea often motivates the medical orthodoxy that patients should complete drug courses even when they no longer feel sick. Yet “radical pathogen cure” maximizes the evolutionary advantage of any resistant pathogens that are present. It could promote the very evolution it is intended to retard. The guiding principle should be to impose no more selection than is absolutely necessary. We illustrate these arguments in the context of malaria; they likely apply to a wide range of infections as well as cancer and public health insecticides. Intuition is unreliable even in simple evolutionary contexts; in a social milieu where in-host competition can radically alter the fitness costs and benefits of resistance, expert opinion will be insufficient. An evidence-based approach to resistance management is required.

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“…This will result in competitive release and enhanced transmission of any highly resistant strains that are present. In rodent models, this is precisely what happens (36,42,43) (Fig. 3).…”

Section: Aims Of Patient Treatmentmentioning

confidence: 96%

Section: Aims Of Patient Treatmentmentioning

confidence: 99%

Section: (B and D) Resistant Parasites (Red Lines) (A And B) Densitimentioning

confidence: 99%

Section: How To Treat Patients?mentioning

confidence: 99%

See 2 more Smart Citations

The evolution of drug resistance and the curious orthodoxy of aggressive chemotherapy

Read

Day

Huijben

2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

243

281

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“…Each treatment group consisted of five mice, except for the group with an inoculum of 10 1 resistant parasites, which consisted of 10 mice to allow for the possibility that some mice failed to become infected because of stochastic loss due to the low inoculum size, which in the end did not occur. Drug treatment started on day 6 postinfection (PI), which is when pronounced anemia and weight loss begin to show, 16,17 and consisted of 8 mg/kg pyrimethamine dissolved in dimethyl sulfoxide (DMSO), administrated by intraperitoneal (i.p.) injection of 50 μL on 4 successive days.…”

Section: Methodsmentioning

confidence: 99%

Relevance of Undetectably Rare Resistant Malaria Parasites in Treatment Failure: Experimental Evidence from Plasmodium chabaudi

Huijben

Chan

Read

2015

The American Journal of Tropical Medicine and Hygiene

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Abstract. Resistant malaria parasites are frequently found in mixed infections with drug-sensitive parasites. Particularly early in the evolutionary process, the frequency of these resistant mutants can be extremely low and below the level of molecular detection. We tested whether the rarity of resistance in infections impacted the health outcomes of treatment failure and the potential for onward transmission of resistance. Mixed infections of different ratios of resistant and susceptible Plasmodium chabaudi parasites were inoculated in laboratory mice and dynamics tracked during the course of infection using highly sensitive genotype-specific quantitative polymerase chain reaction (qPCR). Frequencies of resistant parasites ranged from 10% to 0.003% at the onset of treatment. We found that the rarer the resistant parasites were, the lower the likelihood of their onward transmission, but the worse the treatment failure was in terms of parasite numbers and disease severity. Strikingly, drug resistant parasites had the biggest impact on health outcomes when they were too rare to be detected by any molecular methods currently available for field samples. Indeed, in the field, these treatment failures would not even have been attributed to resistance.

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Modelling the impact of antimalarial quality on the transmission of sulfadoxine-pyrimethamine resistance in Plasmodium falciparum

Brock¹,

Ross²,

Greenhalgh³

et al. 2017

Infectious Disease Modelling

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BackgroundThe use of poor quality antimalarial medicines, including the use of non-recommended medicines for treatment such as sulfadoxine-pyrimethamine (SP) monotherapy, undermines malaria control and elimination efforts. Furthermore, the use of subtherapeutic doses of the active ingredient(s) can theoretically promote the emergence and transmission of drug resistant parasites.MethodsWe developed a deterministic compartmental model to quantify the impact of antimalarial medicine quality on the transmission of SP resistance, and validated it using sensitivity analysis and a comparison with data from Kenya collected in 2006. We modelled human and mosquito population dynamics, incorporating two Plasmodium falciparum subtypes (SP-sensitive and SP-resistant) and both poor quality and good quality (artemether-lumefantrine) antimalarial use.FindingsThe model predicted that an increase in human malaria cases, and among these, an increase in the proportion of SP-resistant infections, resulted from an increase in poor quality SP antimalarial use, whether it was full- or half-dose SP monotherapy.InterpretationOur findings suggest that an increase in poor quality antimalarial use predicts an increase in the transmission of resistance. This highlights the need for stricter control and regulation on the availability and use of poor quality antimalarial medicines, in order to offer safe and effective treatments, and work towards the eradication of malaria.

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Chemotherapy, Within-Host Ecology and the Fitness of Drug-Resistant Malaria Parasites

Cited by 60 publications

References 88 publications

The evolution of drug resistance and the curious orthodoxy of aggressive chemotherapy

The evolution of drug resistance and the curious orthodoxy of aggressive chemotherapy

Relevance of Undetectably Rare Resistant Malaria Parasites in Treatment Failure: Experimental Evidence from Plasmodium chabaudi

Modelling the impact of antimalarial quality on the transmission of sulfadoxine-pyrimethamine resistance in Plasmodium falciparum

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