Timing of antimicrobial use influences the evolution of antimicrobial resistance during disease epidemics

Background: Although the emergence and spread of antibiotic resistance have been well studied for endemic infections, comparably little is understood for epidemic infections such as influenza. The availability of antimicrobial treatments for epidemic diseases raises the urgent question of how to deploy treatments to achieve maximum benefit despite resistance evolution. Recent simulation studies have shown that the number of cases prevented by antimicrobials can be maximized by delaying the use of treatments during an epidemic. Those studies focus on indirect effects of antimicrobial use: preventing disease among untreated individuals. Here, we identify and examine direct effects of antimicrobial use: the number of successfully treated cases. Methodology: We develop mathematical models to study how the schedule of antiviral use influences the success or failure of subsequent use due to the spread of resistant strains. Results: Direct effects are maximized by postponing drug use, even with unlimited stockpiles of drugs. This occurs because the early use of antimicrobials disproportionately drives emergence and spread of antibiotic resistance, leading to subsequent treatment failure. However, for antimicrobials with low effect on transmission, the relative benefit of delaying antimicrobial deployment is greatly reduced and can only be reaped if the trajectory of the epidemic can be accurately estimated early. Conclusions and implications: Health planners face uncertainties during epidemics, including the possibility of early containment. Hence, despite the optimal deployment time near the epidemic peak, it will often be preferable to initiate widespread antimicrobial use as early as possible, particularly if the drug is ineffective in reducing transmission.