Chequerboard titration of cephalosporin CXA-101 (FR264205) and tazobactam versus β-lactamase-producing Enterobacteriaceae

The developmental oxyimino-cephalosporin CXA-101 (FR264205) is notable for having greater antipseudomonal activity than ceftazidime. It is active against Enterobacteriaceae too, but is compromised by extended-spectrum, AmpC and carbapenem-hydrolysing beta-lactamases. We investigated the tazobactam concentrations needed to potentiate this cephalosporin against strains with these mechanisms. MIC chequerboards were prepared between CXA-101 and tazobactam (1-32 mg/L) using CLSI agar dilution methodology and a challenge panel of 'difficult' Enterobacteriaceae isolates. Only 20% of 59 extended-spectrum beta-lactamase (ESBL) producers were susceptible to unprotected CXA-101 at 8 mg/L (5% at 2 mg/L), but 76% were susceptible to CXA-101 + tazobactam at 8 + 4 mg/L and 93% at 8 + 8 mg/L. Among 20 AmpC-derepressed organisms, three of four Serratia spp. were susceptible to CXA-101 at 1-2 mg/L, but other species with the mechanism were more resistant; nevertheless, 70% were susceptible to CXA-101 + tazobactam at 8 + 4 mg/L and 95% at 8 + 8 mg/L. The six least-susceptible AmpC-derepressed isolates were all Enterobacter spp. The MICs of CXA-101 for Klebsiella oxytoca isolates hyperproducing K1 enzyme were 4 mg/L and were not significantly reduced by tazobactam: those for Klebsiella pneumoniae with KPC enzymes were >= 128 mg/L and, in four out of five cases, were not significantly reduced by tazobactam. Tazobactam achieved concentration-dependent potentiation of CXA-101 versus ESBL producers and AmpC hyperproducers. If a breakpoint of 8 + 8 mg/L can be justified pharmacokinetically, CXA-101 + tazobactam should be active versus > 90% of ESBL producers, AmpC hyperproducers and K1 hyperproducers. Most isolates with KPC or other carbapenemases will remain resistant.