Treatment outcome measures for randomized controlled trials of antibiotic treatment for acute bacterial skin and skin structure infections in the emergency department setting

Michael Quirke, Abel Wakai

Acute bacterial skin and skin structure infections (ABSSSIs), which include cellulitis, abscesses, and wound infections, are among the most commonly encountered conditions in emergency departments (EDs) internationally. Primarily, as a result of the recent epidemic of community-associated methicillin resistant Staphylococcus aureus (CA-MRSA) in North America, ED attendances and hospital admissions secondary to ABSSSIs have increased significantly. First-line antibiotic drug therapies for ABSSSIs have therefore changed to take account of CA-MRSA and the threat of evolving antibiotic resistance. Prior to 2010, randomized controlled trials (RCTs) of antibiotic therapy for ABSSSI used broad trial inclusion criteria and utilized investigator-determined clinical resolution, 7 to 14 days after the end of therapy, as the primary outcome measure. In order to produce more objective, reproducible, and quantifiable primary outcome measures, the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research and a multidisciplinary consortium convened by the Foundation for the National Institutes of Health (FNIH) issued significantly changed trial guidance criteria. The currently recommended primary outcome measure is an assessment of greater than 20% reduction in the area of erythema, edema, or induration from baseline, measured at 48 to 72 h after randomization and initiation of drug treatment. In contrast, the European Medicines Agency (EMA) still recommends measurement of clinical resolution at a later time period. We discuss the evolution of changes to trial guidance criteria issued by the FDA since 1998 and the potential difficulties of implementing the recommended primary outcome measured at an earlier time point in RCTs of outpatient antibiotic treatment performed in the ED setting.