Risk-Stratified Effectiveness of Cephamycins Versus Carbapenems for ESBL-Producing Enterobacterales Infections: A Systematic Review and Meta-Analysis.

Background/Objectives: Carbapenems remain the standard treatment for infections caused by extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E), but their widespread use contributes to the emergence of carbapenem resistance. Cephamycins have been proposed as carbapenem-sparing alternatives because of their relative stability against ESBL-mediated hydrolysis; however, their clinical effectiveness remains uncertain. We aimed to compare the effectiveness of cephamycins versus carbapenems as definitive treatment for ESBL-E infections. Methods: We searched Scopus, PubMed, and Embase for studies comparing cephamycins with carbapenems for the treatment of ESBL-producing Enterobacterales infections, with the search conducted through January 2026. Observational studies and randomized trials comparing cephamycins (cefmetazole, flomoxef, cefoxitin) with carbapenems in adult patients with microbiologically confirmed ESBL-E infections were included. The primary outcome was all-cause mortality; secondary outcomes were clinical and microbiological cure. Risk of bias was assessed using ROBINS-I, and data were pooled using random-effects models. Results: Ten retrospective cohort studies (n = 653 for mortality) were included. Cephamycins were associated with a non-significant trend toward lower mortality compared with carbapenems (OR 0.48, 95% CI 0.22-1.03). Subgroup analyses suggested a potential benefit in Escherichia coli and urinary-source infections, whereas no advantage was observed in Klebsiella pneumoniae or non-urinary bloodstream infections. No significant differences were found for clinical or microbiological cure. The certainty of evidence was rated as very low. Conclusions: Cephamycins may represent a carbapenem-sparing option in carefully selected patients with low-risk ESBL-E infections, particularly urinary-source infections caused by E. coli. However, the current evidence is limited to retrospective observational studies with very low certainty and should be considered hypothesis-generating rather than practice-changing. Adequately powered randomized controlled trials are needed to confirm these findings.