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Endocarditis due to extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae is a rare but challenging condition. Its treatment relies on carbapenems alone or in combination, and no alternative has been described to date. The cephamycin cefoxitin has been used for treatment of mild ESBL-producing Enterobacteriaceae infections.We report two patients with nosocomial endocarditis due to ESBL-producing Escherichia coli and Klebsiella pneumoniae who underwent clinical failure or adverse event, respectively, during treatment with imipenem-cilastatin. The first patient was subsequently treated with cefoxitin combined with ciprofloxacin with a favorable outcome. In the second patient, the endocarditis relapsed following a 6-week treatment with cefoxitin and fosfomycin. In time-kill assays, the cefoxitin/ciprofloxacin and cefoxitin/fosfomycin combinations showed synergistic effect.These cases illustrate that cefoxitin is an interesting alternative to carbapenems, even in severe infections such as endocarditis. Pharmacokinetic optimization and combination with another synergistic antibiotic should be considered whenever possible.