Activity of chequerboard combinations of ceftaroline and NXL104 versus β-lactamase-producing Enterobacteriaceae

Background: Ceftaroline is a novel oxyimino-cephalosporin, strongly active against methicillin-resistant staphylococci and pneumococci. It is active against Enterobacteriaceae too, but is labile to common β-lactamases, including AmpC and extended-spectrum types. To counteract these enzymes, ceftaroline is also being developed combined with NXL104, α β-lactamase inhibitor. Methods: Chequerboard MIC titrations were performed to determine the NXL104 concentrations needed to protect ceftaroline against β-lactamase-producing Enterobacteriaceae, most of them with ceftaroline MICs .16 mg/L. Results: All of 60 extended-spectrum β-lactamase (ESBL) producers were susceptible to ceftaroline+NXL104, 1+1 mg/L, as were 5/5 Klebsiella oxytoca with high-level K1 enzyme. Among 30 Enterobacteriaceae with highlevel chromosomal AmpC, 18 were susceptible at 1+1 mg/L, 28 at 1+4 mg/L and all at 4+4 mg/L; among 10 with plasmid AmpC enzymes, nine were susceptible at 1+1 mg/L and all at 1+4 mg/L. None of 10 isolates with combinations of AmpC or ESBL and impermeability was susceptible at 1+1 mg/L, but nine were susceptible at 1+4 mg/Land all at 4+4 mg/L. Among 12 with KPC carbapenemases, only twowere susceptible at 1+1 mg/L, compared with 10 at 1+4 mg/L and 11 at 4+4 mg/L; 8/8 with OXA-48 carbapenemase were susceptible at 1+1 mg/L whilst 0/5 with metallo-b-lactamases were inhibited by ceftaroline+NXL104, even at 8+4 mg/L. NXL104 potentiated the activity of ceftaroline against many ESBL- and AmpC-negative isolates for which ceftaroline MICswere 1-4 mg/L but not those for which MICs were≤0.5 mg/L, probably reflecting the slight lability of this cephalosporin to classical penicillinases, which were present in the former group but not the latter. Conclusions: At concentrations of ≤4 mg/L, NXL104 protected ceftaroline against all relevant β-lactamases except metalloenzymes.