Activity of Ceftazidime-Avibactam against Extended-Spectrum- and AmpC β-Lactamase-Producing Enterobacteriaceae Collected in the INFORM Global Surveillance Study from 2012 to 2014

Abstract

The in vitro activity of ceftazidime-avibactam was evaluated against 34,062 isolates of Enterobacteriaceae from patients with intra-abdominal, urinary tract, skin and soft-tissue, lower respiratory tract, and blood infections collected in the INFORM (International Network For Optimal Resistance Monitoring) global surveillance study (176 medical center laboratories in 39 countries) in 2012 to 2014. Overall, 99.5% of Enterobacteriaceae isolates were susceptible to ceftazidime-avibactam using FDA approved breakpoints (susceptible MIC of <8 g/ml; resistant MIC of >16 g/ml). For individual species of the Enterobacteriaceae, the ceftazidime-avibactam MIC inhibiting >90% of isolates (MIC 90 ) ranged from 0.06 g/ml for Proteus species to 1 g/ml for Enterobacter spp. and Klebsiella pneumoniae. Carbapenem-susceptible isolates of Escherichia coli, K. pneumoniae, Klebsiella oxytoca, and Proteus mirabilis with a confirmed extended-spectrum ␤-lactamase (ESBL) phenotype, or a ceftazidime MIC of >16 g/ml if the ESBL phenotype was not confirmed by clavulanic acid inhibition, were characterized further to identify the presence of specific ESBL-and plasmid-mediated AmpC ␤-lactamase genes using a microarray-based assay and additional PCR assays. Ceftazidime-avibactam demonstrated potent activity against molecularly confirmed ESBL-producing (n ‫؍‬ 5,354; MIC 90 , 0.5 g/ml; 99.9% susceptible), plasmid-mediated AmpC-producing (n ‫؍‬ 246; MIC 90 , 0.5 g/ml; 100% susceptible), and ESBL-and AmpC-producing (n ‫؍‬ 152; MIC 90 , 1 g/ml; 100% susceptible) isolates of E. coli, K. pneumoniae, K. oxytoca, and P. mirabilis. We conclude that ceftazidime-avibactam demonstrates potent in vitro activity against globally collected clinical isolates of Enterobacteriaceae, including isolates producing ESBLs and AmpC ␤-lactamases.

Ceftolozane/tazobactam and ceftazidime/avibactam for the treatment of complicated intra-abdominal infections

“…Among an international collection of 177 gram-negative bacilli producing a variety of carbapenamases, ceftazidime/avibactam was active (93% susceptible) against all but metallo-β-lactamase producers, with the most active comparators being colistin (88%), tigecycline (79%), and fosfomycin (78%) 47. Similar results were observed against 609 non-class-B carbapenamase-producing Enterobacteriaceae; susceptibility rates were higher using ceftazidime/avibactam (98.7% susceptible) versus any other tested agent, including tigecycline (91.5%) and colistin (81.0%) 9,10. Ceftazidime/avibactam was also active against Enterobacteriaceae with carbapenem nonsusceptibility not mediated by carbapenemase production 48,49.…”

“…Ceftazidime/avibactam was not active in vitro against metallo-β-lactamases, with 96.6% resistant based on MIC interpretation breakpoints 9,10. Avibactam also failed to inhibit certain KPC-2 β-lactamase variants with amino acid substitutions at its binding site; however thus far these mutants have remained susceptible to ceftazidime and are therefore of limited clinical significance 51…”

“…While antibiotics within the carbapenem class have a broad spectrum of antimicrobial activity and have traditionally been considered the agents of first choice for confirmed or suspected infection with ESBL producers, reports of carbapenem nonsusceptibility have also been increasing, representing 2.8% (961/34,062) of all Enterobacteriaceae based on INFORM data 9,10. Treatment of P. aeruginosa is fraught with similar challenges, with 15.7% (310/1,971) of P. aeruginosa isolates collected 2011–2012 from 32 US medical centers characterized as MDR.…”

Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial

“…[13][14][15] This paper reports the primary data from the international, randomised phase 3 REPROVE trial (NCT01808092) evaluating the efficacy and safety of ceftazidime-avibactam versus meropenem in the treatment of NP, including ventilator-associated pneumonia (VAP).…”

What is the role of the new β-lactam/β-lactamase inhibitors ceftolozane/tazobactam and ceftazidime/avibactam?

“…Unfortunately, TOL/TAZ is not effective against pathogens producing metallo-β-lactamases (MBLs) or Klebsiella pneumoniae carbapenemases (KPCs) [16]. On the contrary, besides its excellent activity against ESBL-producing strains (susceptibility rates over 90% in a series of more than 5000 isolates tested) [17], CAZ/AVI inhibits KPC-producing organisms, thereby broadening the spectrum of ceftazidime to many CRE and Pseudomonas strains [18]. Notwithstanding this difference, the activity spectra of the two new BLBLI combinations overlap [5].…”