Antimicrobial Activity of Ceftazidime-Avibactam against Gram-Negative Organisms Collected from U.S. Medical Centers in 2012

Abstract

The activities of the novel ␤-lactam-␤-lactamase inhibitor combination ceftazidime-avibactam and comparator agents were evaluated against a contemporary collection of clinically significant Gram-negative bacilli. Avibactam is a novel non-␤-lactam ␤-lactamase inhibitor that inhibits Ambler class A, C, and some D enzymes. A total of 10,928 Gram-negative bacilli-8,640 Enterobacteriaceae, 1,967 Pseudomonas aeruginosa, and 321 Acinetobacter sp. isolates-were collected from 73 U.S. hospitals and tested for susceptibility by reference broth microdilution methods in a central monitoring laboratory (JMI Laboratories, North Liberty, IA, USA). Ceftazidime was combined with avibactam at a fixed concentration of 4 g/ml. Overall, 99.8% of Enterobacteriaceae strains were inhibited at a ceftazidime-avibactam MIC of <4 g/ml. Ceftazidime-avibactam was active against extendedspectrum ␤-lactamase (ESBL)-phenotype Escherichia coli and Klebsiella pneumoniae, meropenem-nonsusceptible (MIC > 2 g/ml) K. pneumoniae, and ceftazidime-nonsusceptible Enterobacter cloacae. Among ESBL-phenotype K. pneumoniae strains, 61.1% were meropenem susceptible and 99.3% were inhibited at a ceftazidime-avibactam MIC of <4 g/ml. Among P. aeruginosa strains, 96.9% were inhibited at a ceftazidime-avibactam MIC of <8 g/ml, and susceptibility rates for meropenem, ceftazidime, and piperacillin-tazobactam were 82.0, 83.2, and 78.3%, respectively. Ceftazidime-avibactam was the most active compound tested against meropenem-nonsusceptible P. aeruginosa (MIC 50 /MIC 90 , 4/16 g/ml; 87.3% inhibited at <8 g/ml). Acinetobacter spp. (ceftazidime-avibactam MIC 50 /MIC 90 , 16/>32 g/ml) showed high rates of resistance to most tested agents. In summary, ceftazidime-avibactam demonstrated potent activity against a large collection of contemporary Gram-negative bacilli isolated from patients in U.S. hospitals in 2012, including organisms that are resistant to most currently available agents, such as K. pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae and meropenem-nonsusceptible P. aeruginosa.

Effects of Klebsiella pneumoniae Carbapenemase Subtypes, Extended-Spectrum β-Lactamases, and Porin Mutations on the In Vitro Activity of Ceftazidime-Avibactam against Carbapenem-Resistant K. pneumoniae

“…At the same time, it is notable that 24% (17/72) of the strains exhibited MICs within two 2-fold dilutions of the CLSI breakpoint and would be classified as ceftazidime nonsusceptible by EUCAST criteria (susceptible MIC, Յ1 g/ml) (11). Previous studies have demonstrated higher ceftazidime-avibactam MICs against CRE-and ESBL-expressing strains than against susceptible strains (1,12). Taken together, those data and ours provide important cautionary notes as clinicians begin to integrate the use of ceftazidime-avibactam into clinical practice.…”

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

“…Moreover, several new cephalosporin-␤-lactamase-inhibitor combinational products in clinical trials (e.g., ceftazidime-avibactam, ceftaroline-avibactam, and ceftolozane-tazobactam) (944) are still likely to be the substrates of RND pumps, as are other ␤-lactams and ␤-lactamase inhibitors (13,390,439,545), because avibactam cannot reverse efflux-mediated ceftazidime resistance (956), and both ceftaroline and ceftolozane (a new antipseudomonal cephalosporin) are still affected by efflux pump-and/or porin-related resistance mechanisms (although ceftolozane, containing multiple charged groups, appears less impacted by Mex pumps than many other ␤-lactams and did not select in vitro for pump overproducers in P. aeruginosa, unlike other agents) (417,(957)(958)(959). These observations could also illustrate their reduced or lack of synergistic activity against multidrug-resistant A. baumannii and P. aeruginosa (960)(961)(962). Additionally, a target-based inhibitor of LpxC (a metalloamidase involved in LPS biosynthesis), CHIR-090, is also a substrate for MexAB-OprM, MexCDOprJ, and MexEF-OprN (963).…”

The Use of Noncarbapenem β-Lactams for the Treatment of Extended-Spectrum β-Lactamase Infections

“…The MIC 50 /MIC 90 of this agent for ESBL-producing E. coli and K. pneumoniae are 0.12/0.25 µg/mL and 0.5/1 µg/mL, respectively [60]. Similar to ceftolozane-tazobactam, phase 2 [61] and phase 3 studies [62] compared ceftazidime-avibactam (plus metronidazole) vs meropenem for intra-abdominal infections, but did not specifically compare outcomes of ESBL-confirmed pathogens.…”