The risk of drug resistance during long-acting antimicrobial therapy

Abstract The emergence of drug resistance during antimicrobial therapy is a major global health problem, especially for chronic infections like HIV, hepatitis B and C, and TB. Sub-optimal adherence to long-term treatment is an important contributor to resistance risk. New long-acting drugs are being developed for weekly, monthly, or less frequent dosing to improve adherence, but may lead to long-term exposure to intermediate drug levels. In this study we analyze the effect of dosing frequency on the risk of resistance evolving in the presence of time-varying drug levels. We find that long-acting therapies can increase, decrease, or have little effect on resistance, depending on the source (pre-existing or de novo) and degree (full or partial) of resistance, and whether the drug is absorbed – as well as cleared – more slowly. For long-acting therapies with slow drug clearance but rapid absorption, and for partially-resistant strains, longer dosing intervals tend to reduce resistance risks even if they don’t improve adherence, and adherence improvements amplify these effects. In other scenarios, long-acting therapies are more susceptible to resistance and must substantially improve adherence to overcome this deficit. If subpopulations of microbes persist and can reactivate during suboptimal treatment, longer-acting therapies may substantially increase the risk of resistance. Our results show that drug kinetics affect selection for resistance in a complicated manner, and that pathogen-specific models are needed to evaluate the benefit of new long-acting therapies.