Improving Empiric Antibiotic Selection for Patients Hospitalized with Skin and Soft Tissue Infection: The INSPIRE 3 Skin and Soft Tissue Randomized Clinical Trial

Importance: Empiric extended-spectrum antibiotics are routinely prescribed for patients hospitalized with skin and soft tissue infections (SSTIs) despite low likelihoods of infection with multidrug-resistant organisms (MDROs). Objective: To evaluate whether computerized provider order entry (CPOE) prompts presenting patient-specific and pathogen-specific MDRO infection risk estimates could reduce empiric extended-spectrum antibiotics for noncritically ill patients admitted with SSTI. Design, Setting, and Participants: This cluster randomized clinical trial included 92 hospitals and assessed the effect of an antibiotic stewardship bundle that included CPOE prompts vs routine stewardship on antibiotic selection during the first 3 hospital days (empiric period) in noncritically ill adults hospitalized with SSTI. The trial population included adults 18 years and older treated with empiric antibiotics for SSTI in non-intensive care unit (ICU) settings. Data were collected from January 2019 to December 2023. Interventions: CPOE prompts recommending standard-spectrum antibiotics in patients prescribed extended-spectrum antibiotics during the empiric period when absolute risk of MDRO SSTI was estimated to be less than 10%, coupled with feedback and education. Main Outcomes and Measures: The primary outcome was empiric extended-spectrum antibiotic days of therapy (summed number of different extended-spectrum antibiotics targeting Pseudomonas and/or MDR gram-negative bacteria received per patient each calendar day). The secondary outcome was antipseudomonal days of therapy. Safety outcomes included days to ICU transfer and hospital length of stay. Outcomes compared differences between baseline and intervention periods across strategies. Results: Among 118562 patients admitted with SSTI at 92 hospitals, 67033 (56.7%) were male and the mean (SD) age was 58.0 (17.5) years. A total of 57837 patients were included in the baseline period and 60725 in the intervention period. Receipt of any empiric extended-spectrum antibiotic during the baseline and intervention periods was 57.0% (16855 of 29595) and 56.0% (17534 of 31337), respectively, for the routine stewardship group compared with 55.4% (15650 of 28242) and 43.0% (12647 of 29388), respectively, for the CPOE group. Empiric extended-spectrum days of therapy per 1000 empiric days targeting Pseudomonas and/or MDR gram-negative pathogens was 511.5 during the baseline period and 488.7 during the intervention period in the routine stewardship group and was 496.2 and 359.1, respectively, in the CPOE bundle group (rate ratio, 0.72; 95% CI, 0.67-0.79; P <.001). There was no evidence of inferiority in the CPOE bundle group for mean (SD) hospital length of stay (routine stewardship, 6.5 [3.8] days; CPOE bundle, 6.4 [3.8] days) and days to ICU transfer (routine stewardship, 6.3 [3.2] days; CPOE bundle, 6.3 [3.1] days). Conclusions and Relevance: In this randomized clinical trial, CPOE prompts recommending standard-spectrum empiric antibiotics for low-risk patients hospitalized with SSTI coupled with education and feedback significantly reduced use of extended-spectrum antibiotics without increasing admissions to ICUs or hospital length of stay. Trial Registration: ClinicalTrials.gov Identifier: NCT05423756.