Drug mode of action and resource constraints modulate antimicrobial resistance evolution

Abstract One of the key characteristics of an antibiotic drug is its mode of action: bacteriostatic or bactericidal. The effect of drug mode of action on the evolution of resistance has been surprisingly underinvestigated to date. We present a theoretical model comparing the efficacy of bacteriostatic and bactericidal drugs, and drugs of intermediate type, at preventing the evolutionary rescue of an initially susceptible bacterial population in a patient. Our results suggest that in resource-abundant environments bacteriostatic drugs are best, as they constrain cell divisions and thus cause fewer resistance mutations to occur. When multiple drugs are employed, using one bacteriostatic and one bactericidal drug is usually optimal, because the cell division rate cannot fall below zero, so there are diminishing returns to bacteriostatic activity from two drugs. We also provide a web-based simulation engine for other researchers to intuitively explore related dynamics without requiring programming expertise.