How should we study the indirect effects of antimicrobial treatment strategies? A causal perspective

Effective antimicrobial stewardship requires unbiased assessment of the benefits and harms of different treatment strategies, considering both immediate patient outcomes and patterns of antimicrobial resistance. In principle, these benefits and harms can be expressed as causal contrasts between treatment strategies and therefore should be ideally suited for study under the potential outcomes framework. However, causal inference in this setting is complicated by interference between individuals (or units) due to the indirect effects of antibiotic treatment, including the spread of resistant bacteria to others. These indirect effects complicate the assessment of trade-offs as benefits are mostly due to the direct effects among those treated, while harms are more diffuse and therefore harder to measure. While causal frameworks and study designs that accommodate interference have previously been proposed, they have been applied predominately to the study of vaccines, which differ from antimicrobial interventions in fundamental ways. In this article, we review these existing approaches and propose alternative adaptations tailored to the study of antimicrobial treatment strategies.