Extended-Infusion Beta-Lactams for Gram-Negative Bacteremia: A Meta-Analysis of Clinical Cure and Nephrotoxicity

Abstract

Introduction: Extended infusion (EI) of beta-lactam antibiotics optimizes time above MIC, potentially improving outcomes in serious infections. However, evidence for Gram-negative bacteremia (GNB) remains conflicting. This meta-analysis compares EI vs intermittent bolus (IB) for GNB.
Methods: Systematic search of PubMed, CENTRAL (2015–2024) for RCTs or adjusted observational studies comparing EI vs IB of piperacillin-tazobactam, meropenem, or cefepime in hospitalized adults with GNB. Primary outcomes: clinical cure (resolution of signs/symptoms) and acute kidney injury (AKI).
Results: Sixteen studies (n=5,672) included; 3 RCTs, 13 observational. EI improved clinical cure (OR 1.43, 95% CI 1.18–1.74, p<0.001) and reduced 14-day mortality (OR 0.73, 95% CI 0.55–0.97). AKI was similar between groups (OR 0.92, 0.74–1.14). Subgroup analysis: piperacillin-tazobactam EI reduced AKI (OR 0.69, 0.52–0.91) vs IB, while meropenem showed no difference.
Discussion: EI likely benefits through sustained drug concentrations, especially for organisms with MIC near breakpoint. The renal protection with piperacillin-tazobactam EI may relate to reduced crystalluria and tubular loads. Major limitation: most observational studies had residual confounding by severity.
Conclusions: Extended infusion improves cure and survival in Gram-negative bacteremia without increasing nephrotoxicity. Hospitals should adopt EI protocols for targeted beta-lactams.