Activity of chequerboard combinations of ceftaroline and NXL104 versus beta-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 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.
Mushtaq
S
S
Antibiotic Resistance Monitoring and Reference Laboratory, Health Protection Agency Centre for Infections, 61 Colindale Avenue, London NW9 5EQ, UK.
Warner
M
M
Williams
G
G
Critchley
I
I
Livermore
D M
DM
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis*; D002511:Cephalosporins / Q000494:pharmacology*; D004357:Drug Synergism; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008826:Microbial Sensitivity Tests; D001618:beta-Lactamases / Q000096:biosynthesis*; D000097583:Ceftaroline
D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D001426:Bacterial Proteins; D002511:Cephalosporins; D004791:Enzyme Inhibitors; D001618:beta-Lactamases; D000097583:Ceftaroline; C543519:avibactam