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J Antimicrob Chemother. 2010 Jul;65(7):1428-32. doi: 10.1093/jac/dkq161. Epub 2010 May 17.

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

Author information

1
Antibiotic Resistance Monitoring and Reference Laboratory, Health Protection Agency Centre for Infections, 61 Colindale Avenue, London NW9 5EQ, UK.

Abstract

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 beta-lactamases, including AmpC and extended-spectrum types. To counteract these enzymes, ceftaroline is also being developed combined with NXL104, a beta-lactamase inhibitor.

METHODS:

Chequerboard MIC titrations were performed to determine the NXL104 concentrations needed to protect ceftaroline against beta-lactamase-producing Enterobacteriaceae, most of them with ceftaroline MICs >16 mg/L.

RESULTS:

All of 60 extended-spectrum beta-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 high-level 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/L and all at 4 + 4 mg/L. Among 12 with KPC carbapenemases, only two were 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-beta-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 MICs were 1-4 mg/L but not those for which MICs were < or = 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 < or = 4 mg/L, NXL104 protected ceftaroline against all relevant beta-lactamases except metalloenzymes.

PMID:
20478991
DOI:
10.1093/jac/dkq161
[Indexed for MEDLINE]

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