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.

Evolutionary medicine: its scope, interest and potential

“…However, an important insight of theory into consequences for therapy has not yet been widely recognized much less accepted [96]. That insight is that the expansion of the more malignant clones is dampened by competition with less malignant clones, but if aggressive chemotherapy selectively eliminates the less malignant clones, it is removing competitors and allowing malignant clones to expand.…”

“…Current practise creates strong selection, and because most resistance genes are not de novo mutations but pre-existing and horizontally transferred, strong selection efficiently promotes the very resistance that it is trying to prevent. Instead of using maximal doses of antibiotics for long periods, evolutionary models suggest using doses no larger than is absolutely necessary to control infections [96].…”

Six wedges to curing disease

“…What will cure most patients may not be optimal for the general population in which resistant variants may emerge and spread 1 . This problem is in many ways similar to the objectives of classical pest control [2], where short-term 'success' is to attain economic targets for the treated area (e.g., an agricultural field), subject to meeting the global objective of slowing the spatial spread of resistance [3].…”

“…Rapid administration of the drug means forestalling further DCA growth and associated symptoms, but also reducing the probability of the appearance of resistant mutant strains. Despite decades of research on pest and disease control (much of it with an ecological basis) this approach and the many alternatives described below remain highly controversial (e.g., [1]). …”

In the light of evolution V: Cooperation and conflict

“…Read et al (36) treat the vital problem of how to minimize the evolution of pathogen resistance and thereby extend the useful lives of our arsenal of antibiotic drugs. This involves a complex set of interacting causes, some of which have a social element and others do not.…”