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 ChromosomemecTypes

Abstract

ABSTRACTCeftaroline is a new cephalosporin with broad-spectrum activity against Gram-positive and -negative organisms. The prodrug of ceftaroline, ceftaroline fosamil, combined with the β-lactamase inhibitor avibactam (formerly NXL104), was tested againstEnterobacteriaceaestrains producing Ambler class A, B, C, and D enzymes, including strains producing multiple enzymes, as well asPseudomonas aeruginosa,Acinetobacterspp., and methicillin-susceptible and methicillin-resistantStaphylococcus 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 againstEnterobacteriaceaeproducing various β-lactamase types (MIC90, 0.25 to 2 μg/ml, except for metalloenzymes), including 99 strains carrying multiple enzymes (2 to 4 β-lactamases; MIC90, 2 μg/ml). All isolates were inhibited by ceftaroline-avibactam at ≤4 μg/ml. Ceftaroline-avibactam (MIC90, 0.5 to 1 μg/ml) was more active than meropenem (MIC90, >8 μg/ml) and other comparators when tested against KPC-producing strains.S. aureusstrains, including MRSA with four staphylococcal cassette chromosomemec(SCCmec) types, were dominantly (99.1%) inhibited by ceftaroline-avibactam at ≤2 μg/ml, and the ceftaroline MIC was not adversely affected by the addition of the β-lactamase inhibitor (MIC50/90, 1 and 2 μg/ml for ceftaroline with and without avibactam). Ceftaroline-avibactam demonstrated limited activity againstAcinetobacterspp. andP. aeruginosa(MIC50s, 32 and 16 μg/ml, respectively). These results document that ceftaroline-avibactam has potent activity againstEnterobacteriaceaethat 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 β-lactamase types, and its development as a therapeutic option for the treatment of infections caused by multidrug-resistantEnterobacteriaceaeas well as MRSA is warranted.