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 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 10⁴ and 10⁶ 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.