Beyond dose: Pulsed antibiotic treatment schedules can maintain individual benefit while reducing resistance

The emergence of treatment-resistant microbes is a key challenge for disease treatment and a leading threat to human health and wellbeing. New drugs are always in development, but microbes regularly and rapidly acquire resistance. We must consider if altering how we administer drugs at the individual level could slow development of resistance. Here we use mathematical models to show that exposing microbes to drug pulses could greatly reduce resistance without increasing individual pathogen load. Our results stem from two key factors: the presence of antibiotics creates a selection pressure for antibiotic resistant microbes, and large populations of bacteria are more likely to harbor drug resistance than small populations. Drug pulsing targets these factors simultaneously. Short duration pulses minimize the time during which there is selection for resistance, and high drug concentrations minimize pathogen abundance. Our work provides a theoretical basis for the design of in vitro and in vivo experiments to test how drug pulsing might reduce the impact of drug resistant infections.