Discrepancies in Control Group Mortality Rates Within Studies Assessing Topical Antibiotic Strategies to Prevent Ventilator-Associated Pneumonia: An Umbrella Review

Supplemental Digital Content is available in the text. Objectives: To test the postulate that concurrent control patients within ICUs studying topical oropharyngeal antibiotics to prevent ventilator-associated pneumonia and mortality would experience spillover effects from the intervention. Data Sources: Studies cited in 15 systematic reviews of various topical antibiotic and other infection prevention interventions among ICU patients. Study Selection: Studies of topical antibiotics, stratified into concurrent control versus nonconcurrent control designs. Studies of nondecontamination-based infection prevention interventions provide additional points of reference. Studies with no infection prevention intervention provide the mortality benchmark. Data from additional studies and data reported as intention to treat were used within sensitivity tests. Data Extraction: Mortality incidence proportion data, mortality census, study characteristics, group mean age, ICU type, and study publication year. Data Synthesis: Two-hundred six studies were included. The summary effect sizes for ventilator-associated pneumonia and mortality prevention derived in the 15 systematic reviews were replicated. The mean ICU mortality incidence for concurrent control groups of topical antibiotic studies (28.5%; 95% CI, 25.0–32.3; n = 41) is higher versus the benchmark (23.7%; 19.2–28.5%; n = 34), versus nonconcurrent control groups (23.5%; 19.3–28.3; n = 14), and versus intervention groups (24.4%; 22.1–26.9; n = 62) of topical antibiotic studies. In meta-regression models adjusted for group-level characteristics such as group mean age and publication year, concurrent control group membership within a topical antibiotic study remains associated with higher mortality (p = 0.027), whereas other group memberships, including membership within an antiseptic study, are each neutral (p = not significant). Conclusions: Within topical antibiotic studies, the concurrent control group mortality incidence proportions are inexplicably high, whereas the intervention group mortality proportions are paradoxically similar to a literature-derived benchmark. The unexplained ventilator-associated pneumonia and mortality excess in the concurrent control groups implicates spillover effects within studies of topical antibiotics. The apparent ventilator-associated pneumonia and mortality prevention effects require cautious interpretation.