title: Strategies to overcome extended-spectrum β-lactamases (ESBLs) and AmpC β-lactamases in shigellae.
abstract: Oral cephalosporins and mecillinam are used to treat Shigella infections, but are compromised by extended-spectrum β-lactamases (ESBLs) and plasmid AmpC β-lactamases. Potential solutions include combining an oral or intravenous cephalosporin with a β-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 by SHV and 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.
authors.affiliation: Antibiotic Resistance Monitoring & Reference Laboratory, Health Protection Agency Microbiology Services-Colindale, 61 Colindale Avenue, London NW9 5EQ, UK. david.livermore@hpa.org.uk
authors.forename: David M
authors.initials: DM
authors.lastname: Livermore
authors.forename: Shazad
authors.initials: S
authors.lastname: Mushtaq
authors.forename: Tue
authors.initials: T
authors.lastname: Nguyen
authors.forename: Marina
authors.initials: M
authors.lastname: Warner
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D012760:Shigella / Q000187:drug effects* / Q000201:enzymology*; D018440:beta-Lactam Resistance; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000096:biosynthesis*; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; D001618:beta-Lactamases