The evolution of drug-resistant pathogens significantly affects human well-being and health budgets. Consequently, existing and new antimicrobials should be viewed as precious resources in need of careful stewardship (Owens, 2008; Spellberg et al., 2008). An important aspiration is to maximize the therapeutically useful life span of a compound, the time a given antimicrobial yields clinical benefits before drug efficacy is undermined by resistance evolution. Attempting to do so is essentially an exercise in evolutionary management.
Various practices are widely thought to be effective resistance management strategies (American Academy of Microbiology, 2009; World Health Organization, 2010a; zur Wiesch et al., 2011). For instance, there is near-universal agreement that combination drug therapy, the coad-ministration of drugs with unrelated modes of action, prolongs the useful life of the component compounds for diseases as diverse as leprosy, HIV, malaria, and tuberculosis (TB). Another practice is the restriction of treatment to those patients who need it on clinical grounds, so as to reduce unnecessary selection for resistance. This philosophy underpins restrictions on the use of antibiotics in hospitals and in the community at large, and it has led to calls for reductions in drug use in animal feed.
A third practice thought to be an effective resistance management strategy is the use of drugs to clear all target pathogens from a patient as fast as possible. We hereafter refer to this practice as “radical pathogen cure.” For a wide variety of infectious diseases, recommended drug doses, interdose intervals, and treatment durations (which together constitute “patient treatment regimens”) are designed to achieve complete pathogen elimination as fast as possible. This is often the basis for physicians exhorting their patients to finish a drug course long after they feel better (long-course chemotherapy). Our claim is that aggressive chemotherapy cannot be assumed to be an effective resistance management strategy a priori. This is because radical pathogen cure necessarily confers the strongest possible evolutionary advantage on the very pathogens that cause drugs to fail.
At one level, our argument is simple. Elementary population genetics shows that, all else being equal, the stronger the strength of selection, the more rapid is the spread of a favored allele (Maynard Smith, 1989a). For drug use, the strength of selection is determined by how many people are being treated and, among the treated people, the treatment regimen. The more aggressive the regimen, the greater is the selection pressure in favor of resistance. Because overwhelming chemical force necessarily confers the strongest possible selective advantage on any pathogen capable of resisting it, radical pathogen cure can very effectively drive resistant pathogens through a population. As we will argue, this