Strategies to overcome extended-spectrum β-lactamases (ESBLs) and AmpC β-lactamases in shigellae

Oral cephalosporins and mecillinam are used to treat Shigella infections, but are compromised by extended-spectrum beta-lactamases (ESBLs) and plasmid AmpC beta-lactamases. Potential solutions include combining an oral or intravenous cephalosporin with a beta-lactamase inhibitor (BLI) or using an oral penem. These strategies were examined using Escherichia coli transconjugants and clinical isolates with ESBLs or AmpC, as a proxy for shigellae. The Clinical and Laboratory Standards Institute agar dilution method was used with inocula of 10(4) and 10(6) colony-forming units/spot. ESBLs conferred resistance to the cephalosporins and mecillinam, at least at high inoculum, although: (i) ceftibuten was significantly compromised only bySHVand CTX-M-15 ESBLs, but not by TEM or CTX-M-9 and -14; (ii) cefdinir was little affected by TEM-type ESBLs, and mecillinam was little affected by CTX-M-9 group enzymes. The BLI clavulanic acid reduced the minimum inhibitory concentrations (MICs) of cephalosporins and mecillinam to <= 2 mg/L for ESBL-producers, even at high inocula; sulbactam in particular and tazobactam were less effective, especially against SHV types. Strains with AmpC were resistant to all cephalosporins + inhibitors, but mecillinam remained active (MIC = 1 mg/L) against a strain with AmpC alone, whereas strains with TEM-1 + AmpC were susceptible to mecillinam + clavulanic acid at <= 2 mg/L. Faropenem was active against all ESBL-and AmpC-producers at 4 mg/L, with little inoculum effect or inhibitor potentiation. In conclusion, cephalosporin + clavulanic acid combinations overcame ESBLs, with ceftibuten + clavulanic acid being particularly promising. Mecillinam + clavulanic acid and faropenem overcame both ESBLs and AmpC enzymes. Clinical utility will depend also on a drug's ability to reach intracellular shigellae in the intestinal epithelium and this deserves exploration for clavulanic acid and faropenem. (C) 2010 Elsevier B. V. and the International Society of Chemotherapy. All rights reserved.