Aggressive Chemotherapy and the Selection of Drug Resistant Pathogens

Abstract

Drug resistant pathogens are one of the key public health challenges of the 21st century. There is a widespread belief that resistance is best managed by using drugs to rapidly eliminate target pathogens from patients so as to minimize the probability that pathogens acquire resistance de novo. Yet strong drug pressure imposes intense selection in favor of resistance through alleviation of competition with wild-type populations. Aggressive chemotherapy thus generates opposing evolutionary forces which together determine the rate of drug resistance emergence. Identifying treatment regimens which best retard resistance evolution while maximizing health gains and minimizing disease transmission requires empirical analysis of resistance evolution in vivo in conjunction with measures of clinical outcomes and infectiousness. Using rodent malaria in laboratory mice, we found that less aggressive chemotherapeutic regimens substantially reduced the probability of onward transmission of resistance (by >150-fold), without compromising health outcomes. Our experiments suggest that there may be cases where resistance evolution can be managed more effectively with treatment regimens other than those which reduce pathogen burdens as fast as possible.

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

“…As found previously, 4,17,19 drug treatment rapidly reduced the susceptible parasite population, allowing the expansion of the resistant parasite population, even of the rare resistant parasites (Figure 1). This relapse of resistant parasites was considerable in all treatment groups, but counterintuitively, the lower the relative abundance of resistance at time of treatment, the greater the posttreatment relapse (F 1,20 = 9.5, P = 0.006) (Figure 2A, 3A).…”

“…19 To measure gametocyte density, qPCR was performed on cDNA, using the same clone-specific assays. 19,20 Asexual parasite density was estimated by subtracting the gametocyte density from the total parasite density.…”

“…19 To measure gametocyte density, qPCR was performed on cDNA, using the same clone-specific assays. 19,20 Asexual parasite density was estimated by subtracting the gametocyte density from the total parasite density. 20 The PCR reaction volume of 25 μL for all assays consisted of 7 μL DNA or cDNA, 900 nM forward and reverse clone-specific primers, 250 nM TaqMan MGB probe (Applied Biosystems) and 1x PerfeCTa ™ qPCR FastMix ™ (Quanta Biosciences, Gaithersburg, MD).…”

Six wedges to curing disease

“…resistant) populations [2]. Day and colleagues [28] differentiated competitive release from competitive suppression, the latter occurring when one competitor suppresses another through a shared density dependent response, such as an immune reaction or environmental degradation [29]. With a few exceptions, competitive release is not well understood in the context of disease ecosystems.…”

“…They identified the "selective window": doses that eliminate sensitive strains and favor relatively resistant ones. Work on Plasmodium has shown sensitivity to treatment dose [29], and Wargo and colleagues [30] demonstrated an effect of treatment duration on the emergence of resistance. A corollary to dosing (intensity, schedule and duration) is whether the therapy should actually kill DCAs (cytotoxic) or rather render them unable to proliferate (cytostatic).…”