Short-course aminoglycosides as adjunctive treatment in adults with sepsis: A post-hoc analysis of a prematurely terminated cluster randomized trial

Background Cephalosporin monotherapy or cephalosporin-aminoglycoside combination therapy are both used for empirical sepsis treatment in The Netherlands, with no evidence favouring either. We hypothesized that ceftriaxone or cefuroxime monotherapy is non-inferior to cefuroxime combined with gentamicin or tobramycin for empirical treatment of community-acquired sepsis. Methods A cluster-randomized cross-over trial was conducted in nine Dutch hospitals, with a 1:1 randomization, comparing monotherapy to combination therapy in adults with severe community-acquired sepsis of unknown, suspected urinary tract or abdominal origin. The primary endpoint was 30-day all-cause mortality, with a non-inferiority margin of <5% adjusted absolute risk difference (aARD). Secondary endpoints included hospital re-admission and nephrotoxicity. The study stopped prematurely (before first cross-over) due to slow recruitment and 46% non-compliance to combination therapy. Patients treated with combination therapy (reference) and monotherapy were compared using logistic regression on multiple imputed data and propensity score overlap weighting for confounder adjustment. Results Between May 2022 and May 2023, 451 patients were included; 158 received combination and 293 monotherapy. Thirty-day mortality was 11.4% (18/158) with combination therapy and 17.1% (50/293) with monotherapy, yielding an adjusted odds ratio (aOR) of 0.81 (95% CI:0.37–1.75) and an aARD of -2.8% (95% CI:-14.0–7.1). Nephrotoxicity incidence occurred in 11.9% (17/143) with combination therapy and 14.8% (38/256) with monotherapy (aOR 1.08, 95% CI:0.46–2.55). Conclusions In an as-treated analysis, non-inferiority of monotherapy compared to combination therapy could not be demonstrated. The absolute risk difference for all-cause 30-day mortality was -2.8% and not statistically significant. Short-course aminoglycoside therapy was not associated with nephrotoxicity.