Antimicrobial Susceptibility Study
Antimicrobial activity of ceftolozane-tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa collected from patients with bloodstream infections isolated in United States hospitals (2013–2015) as part of the Program to Assess Ceftolozane-Tazobactam Susceptibility (PACTS) surveillance program

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Highlights

  • A total of 2647 Enterobacteriaceae and 355 Pseudomonas aeruginosa from hospitalized patients with bloodstream infections in US hospitals from 2013 to 2015 were evaluated.

  • Ceftolozane-tazobactam (95.5% susceptible), amikacin (99.2% susceptible), and meropenem (98.4% susceptible) were the most active against Enterobacteriaceae.

  • Ceftolozane-tazobactam was the most potent (MIC50//90, 0.5/1 mg/L) β-lactam agent tested against P. aeruginosa isolates, with 97.5% susceptible.

Abstract

This study evaluated the in vitro activity of ceftolozane-tazobactam and comparators against 2647 Enterobacteriaceae and 355 Pseudomonas aeruginosa nonduplicate isolates collected from hospitalized patients with bloodstream infections in US hospitals from 2013 to 2015.Ceftolozane-tazobactam (95.5% susceptible), amikacin (99.2% susceptible), and meropenem (98.4% susceptible) were the most active against Enterobacteriaceae. For Enterobacteriaceae, 1.4% (n = 37) were carbapenem-resistant (CRE), and 10.2% (n = 271) exhibited an extended-spectrum β-lactamase (ESBL) non-CRE phenotype. The most common ESBL enzyme detected was blaCTX-M-15-like (n = 159). Whereas ceftolozane-tazobactam showed good activity against ESBL non-CRE phenotype Enterobacteriaceae (87.1% susceptible), it lacked useful activity against CRE strains. Ceftolozane-tazobactam was the most potent (MIC50/90, 0.5/1 mg/L) β-lactam agent tested against P. aeruginosa isolates, with 97.5% susceptible. Only colistin was more active (98.9% susceptible). Ceftolozane-tazobactam was the most active β-lactam agent tested against P. aeruginosa and demonstrated higher in vitro activity than available cephalosporins and piperacillin-tazobactam when tested against Enterobacteriaceae.

Introduction

Bloodstream infections are a serious healthcare-associated infection in the United States (Bassetti et al., 2016, Magill et al., 2014). Appropriate initial antimicrobial therapy has been strongly associated with reduced mortality in patients and is particularly critical for bloodstream infections (Seymour et al., 2017, Zilberberg et al., 2014). In some US regions, multidrug-resistant gram-negative pathogens, such as Pseudomonas aeruginosa and carbapenem-resistant (CRE) and extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae, are increasingly common (Castanheira et al., 2016, Cerceo et al., 2016). Due to the relative lack of new agents to treat these infections, empiric therapy is often ineffective and requires antibacterial agent combinations to achieve optimal coverage (Tangden and Giske, 2015).

These findings underscore the continued importance of antibiotic resistance surveillance and the need to assess the potential impact of newly introduced and novel antibacterial agents that target specific resistance phenotypes. Systematic and comprehensive antibiotic resistance surveillance is essential to document the extent of the resistance problem and to inform local, regional, national, and global efforts to combat the resistance challenge.

Ceftolozane-tazobactam is a combination of a novel cephalosporin and a well-described beta-lactamase inhibitor with activity against P. aeruginosa, including antibiotic-resistant strains, and other common gram-negative bacilli (GNB), including most ESBL-producing Enterobacteriaceae strains (Sader et al., 2011). Ceftolozane-tazobactam has limited activity against Acinetobacter spp.; Stenotrophomonas maltophilia; gram-positive cocci; organisms producing carbapenemases or metallo-β-lactamases; or a minority of AmpC β-lactamases found in Enterobacteriaceae. Ceftolozane-tazobactam was recently approved to treat complicated intra-abdominal infections (with metronidazole) and complicated urinary tract infections (ZERBAXA, 2016). A Phase 3 clinical trial of ceftolozane-tazobactam to treat nosocomial pneumonia is ongoing.

In this study, we assessed the activity of ceftolozane-tazobactam against 3176 gram-negative bloodstream infection isolates from the Program to Assess Ceftolozane-Tazobactam Susceptibility (PACTS) collected in the US from 2013 to 2015. In addition to susceptibility testing for ceftolozane-tazobactam and 9 comparator agents, the ESBL genes were characterized using the Check-Points assay in Klebsiella pneumoniae and Escherichia coli isolates that were ESBL phenotype screen-positive.

Section snippets

Bacterial isolates

A total of 3176 nonduplicate gram-negative isolates (including 2647 Enterobacteriaceae, 355 P. aeruginosa, and 174 other gram-negative species) were collected prospectively from 32 US medical centers in all 9 US Census Bureau divisions from 2013 to 2015. Participating centers submitted clinical bacterial isolates (1 isolate per patient per infection episode) that were collected consecutively by infection type according to a common protocol. The common SENTRY Antibacterial Surveillance Program

Susceptibilities

The 3 most commonly isolated gram-negative species from the bloodstream were E. coli (n = 1306; 41.1%), K. pneumoniae (n = 574; 18.1%), and P. aeruginosa (n = 355; 11.2%). Susceptibility of 2647 Enterobacteriaceae to ceftolozane-tazobactam was 95.5%, while susceptibility to piperacillin-tazobactam was 93.2% (Table 1). Amikacin, meropenem, and tigecycline were the most active with 99.2%, 98.4%, and 98.7% susceptible, respectively. A total of 271 Enterobacteriaceae (10.2%) had the ESBL non-CRE

Discussion

Increasing antibiotic resistance among GNB has been documented by population-based surveys in medical centers around the US (Sievert et al., 2013, Weiner et al., 2016). Weiner et al. showed increases in central line-associated bloodstream infections caused by gram-negative pathogens, including resistant E. coli and P. aeruginosa, which were among the most frequently isolated (Weiner et al., 2016). Prompt initiation of effective antimicrobial therapy is complicated by the prevalence and types of

Acknowledgments

The authors would like to thank the US hospitals participating in the Program to Assess Ceftolozane-Tazobactam Susceptibility (PACTS).

Author disclosure statement

This study was performed by JMI Laboratories and supported by Merck & Co., which included funding for services related to preparing this manuscript.

JMI Laboratories was contracted to perform services in 2017 for Achaogen, Allecra Therapeutics, Allergan, Amplyx Pharmaceuticals, Antabio, API, Astellas Pharma, AstraZeneca, Athelas, Basilea Pharmaceutica, Bayer AG, BD, Becton, Dickinson and Co., Boston, CEM-102 Pharma, Cempra, Cidara Therapeutics, Inc., CorMedix, CSA Biotech, Cutanea Life Sciences,

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