Orthodox and unorthodox clavulanate combinations against extended-spectrum β-lactamase producers

ABSTRACTClavulanate is a highly effective inhibitor of extended-spectrum β-lactamases (ESBLs) in detection tests, but the commercial amoxycillin–clavulanate and ticarcillin–clavulanate combinations have borderline activity, at best, against most ESBL producers. Oxyimino-cephalosporin–clavulanate combinations are active in vitro against most ESBL-producing Escherichia coli and Klebsiella spp. isolates at ≤1–2 mg/L but are compromised against Enterobacter spp., whether ESBL-producing or not, where clavulanate-induced AmpC enzymes attack the cephalosporin. These problems can be overcome by combining clavulanate with cefepime or cefpirome, which are more stable to AmpC. The resulting combinations are active in vitro at ≤1 mg/L against virtually all ESBL-producing Enterobacteriaceae, including Enterobacter spp. AmpC-inducible organisms, such as Enterobacter, are less of a concern in the community, where ESBL-producing E. coli strains present growing problems, and where new oral treatments would be useful. Cefpodoxime–clavulanate is not ideal, in terms of pharmacological matching, but might be fit for purpose, certainly in comparison with fosfomycin and nitrofurantoin, which are used at present but which are suitable only for lower urinary tract infections. Clinical development of clavulanate with cefepime, cefpirome or cefpodoxime does not seem likely in the West, considering ownership and patent issues. Cefpisome-tazobactum is, however, being launched in India, where the licensing regime is more liberal. Combinations of clavulanate with modern anti-methicillin-resistant Staphylococcus aureus cephalosporins also deserve investigation, as these compounds remain labile to ESBLs.