Activity of Ceftaroline-Avibactam Tested against Gram-Negative Organism Populations, including Strains Expressing One or More β-Lactamases and Methicillin-Resistant Staphylococcus aureus Carrying Various Staphylococcal Cassette Chromosome mec Types

Ceftaroline is a new cephalosporin with broad-spectrum activity against Gram-positive and -negative organisms. The prodrug of ceftaroline, ceftaroline fosamil, combined with the beta-lactamase inhibitor avibactam (formerly NXL104), was tested against Enterobacteriaceae strains producing Ambler class A, B, C, and D enzymes, including strains producing multiple enzymes, as well as Pseudomonas aeruginosa, Acinetobacter spp., and methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MRSA) strains. Isolates were collected from 1999 to 2008 from global surveillance programs, and susceptibility testing was performed by reference broth microdilution methods. Ceftaroline-avibactam exhibited potent activity against Enterobacteriaceae producing various beta-lactamase types (MIC90, 0.25 to 2 mu g/ml, except for metalloenzymes), including 99 strains carrying multiple enzymes (2 to 4 beta-lactamases; MIC90, 2 mu g/ml). All isolates were inhibited by ceftaroline-avibactam at <= 4 mu g/ml. Ceftaroline-avibactam (MIC90, 0.5 to 1 mu g/ml) was more active than meropenem (MIC90, >8 mu g/ml) and other comparators when tested against KPC-producing strains. S. aureus strains, including MRSA with four staphylococcal cassette chromosome mec (SCCmec) types, were dominantly (99.1%) inhibited by ceftaroline-avibactam at <= 2 mu g/ml, and the ceftaroline MIC was not adversely affected by the addition of the beta-lactamase inhibitor (MIC50/90, 1 and 2 mu g/ml for ceftaroline with and without avibactam). Ceftaroline-avibactam demonstrated limited activity against Acinetobacter spp. and P. aeruginosa (MIC(50)s, 32 and 16 mu g/ml, respectively). These results document that ceftaroline-avibactam has potent activity against Enterobacteriaceae that produce KPC, various ESBL types (CTX-M types), and AmpC (chromosomally derepressed or plasmid-mediated enzymes), as well as against those producing more than one of these beta-lactamase types, and its development as a therapeutic option for the treatment of infections caused by multidrug-resistant Enterobacteriaceae as well as MRSA is warranted.