Leveraging laboratory and clinical studies to design effective antibiotic combination therapy

• The need for effective antibiotic combination therapy will continue to increase. • Clinical trials have shown mixed results for the superiority of combination therapy. • Bacterial susceptibility profiles and growth conditions affect combination efficacy. • New technologies facilitate testing greater numbers of combinations. • Careful lab study design and metrics reporting should help inform clinical trials. Interest in antibiotic combination therapy is increasing due to antimicrobial resistance and a slowing antibiotic pipeline. However, aside from specific indications, combination therapy in the clinic is often not administered systematically; instead, it is used at the physician’s discretion as a bet-hedging mechanism to increase the chances of appropriately targeting a pathogen(s) with an unknown antibiotic resistance profile. Some recent clinical trials have been unable to demonstrate superior efficacy of combination therapy over monotherapy. Other trials have shown a benefit of combination therapy in defined circumstances consistent with recent studies indicating that factors including species, strain, resistance profile, and microenvironment affect drug combination efficacy and drug interactions. In this review, we discuss how a careful study design that takes these factors into account, along with the different drug interaction and potency metrics for assessing combination performance, may provide the necessary insight to understand the best clinical use-cases for combination therapy.