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

Abstract

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.

Fig. 1.

Hypothetical path to drug resistance. Solid curves show drug concentration in a treated patient for two drugs with different half-lives; concentrations wane when treatment ceases. In this schematic, wild type parasites can survive very low concentrations, with mutations A, B, and C conferring the ability to survive (“tolerate”) successively higher drug concentrations. High-level resistance (full clinical resistance) is where treatment has a negligible direct impact on pathogens with all three mutations. The windows of selection for mutation A are shown. In those windows, parasites with mutation A have a selective advantage over wild type parasites. Note that the duration of the window depends critically on the drug half-life, which for antimalarial drugs can vary from hours (e.g., artemisinin), to weeks (e.g., SP), to months (e.g., mefloquine).

Fig. 2.

Costs of resistance are greatly affected by competition. Transmission stage densities of the resistant P. chabaudi clone in laboratory mice in the absence of drug treatment are shown. Infections were initiated with with 10⁶ (Left) or 10¹ (Right) resistant parasites and either no sensitive parasites (no competition, black lines) or 10⁶ sensitive parasites (competition, red dashed lines). Performance of the resistant clone alone includes any physiological costs to resistance. When the resistant clone shares a host with a sensitive clone, performance is greatly reduced, and is effectively zero when rare in the inoculum (Right). Thus, the costs of resistance depend critically on whether competitors are present and the frequency of resistant parasites in an infection. PI, post-infection. 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).

Fig. 3.

Competitive release of drug resistance. Infections of P. chabaudi were initiated in laboratory mice with 10⁶ sensitive parasites (black lines) and either 10⁶ (A and C) or 10¹ (B and D) resistant parasites (red lines). (A and B) Densities of asexual parasites (within-host replicative stages). (C and D) Densities of gametocytes (transmission stages). Gray bars indicate period of drug treatment (four daily doses of 8 mg/kg of pyrimethamine). R, resistant; S, sensitive; PI, post-infection. Drug treatment rapidly suppresses sensitive parasites, allowing resistant parasites to dominate posttreatment populations; the expansion following competitive release is especially marked when the resistant clone is rare. In untreated mice, resistant parasite densities are markedly lower than sensitive parasite densities throughout the infections, particularly when they were rare initially (compare with Fig. 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).