Elsevier

Journal of Infection

Volume 69, Issue 3, September 2014, Pages 266-277
Journal of Infection

Ceftolozane/tazobactam activity tested against aerobic Gram-negative organisms isolated from intra-abdominal and urinary tract infections in European and United States hospitals (2012)

https://doi.org/10.1016/j.jinf.2014.04.004Get rights and content

Summary

Ceftolozane/tazobactam is under clinical development for treatment of complicated intra-abdominal infections (IAI), complicated urinary tract infections (UTI) and ventilator-associated pneumonia. We evaluated the in vitro activity of ceftolozane/tazobactam and comparator agents tested against Gram-negative aerobic bacteria causing IAI and healthcare-associated UTI (HCA-UTI). The organisms were consecutively collected from January to December 2012 from 59 medical centers located in the United States (USA) and 15 European countries by the Program to Assess Ceftolozane/Tazobactam Susceptibility (PACTS). The collection included 809 organisms from IAI and 2474 organisms from HCA-UTI, and susceptibility testing was performed by reference broth microdilution methods as described by the Clinical and Laboratory Standards Institute (CLSI) M07-A9 document. Overall, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa were the most frequently isolated pathogens from both infection types. Ceftolozane/tazobactam was very active against E. coli (MIC50/90, 0.25/0.5 mg/L; 98.5–99.9% inhibited at an MIC of ≤8 mg/L) and retained activity against many of the multidrug-resistant (MDR; MIC50/90, 0.5/2–>32 mg/L) and ESBL-phenotype strains (MIC50/90, 0.5/2–32 mg/L). Ceftolozane/tazobactam was active against most K. pneumoniae strains (MIC50/90, 0.25/16 mg/L, 88.9–89.6% inhibited at an MIC of ≤8 mg/L), but some ESBL-phenotype (MIC50/90, 4–8/>32 mg/L) and MDR (MIC50/90, 16/>32 mg/L) isolates exhibited elevated MIC values. Ceftolozane/tazobactam was the most active agent tested against P. aeruginosa (MIC50/90, 0.5/4 mg/L; 93.4–95.7% inhibited at ≤8 mg/L) and retained potency against many MDR (MIC50/90, 2–4/>32 mg/L), ceftazidime-nonsusceptible (MIC50/90, 2–4/>32 mg/L) and meropenem-nonsusceptible (MIC50/90, 2/>32 mg/L) strains. Ceftolozane/tazobactam was also active against Klebsiella oxytoca (MIC50/90, ≤0.12–0.25/0.5–1 mg/L), Enterobacter spp. (MIC50/90, 0.25–0.5/4–8 mg/L), Citrobacter spp. (MIC50/90, 0.25/2–32 mg/L), Proteus mirabilis (MIC50/90, 0.5/0.5 mg/L), indole-positive Proteae (MIC50/90, 0.25/0.5–1 mg/L), and Serratia spp. (MIC50/90, 0.5/1–2 mg/L). In summary, ceftolozane/tazobactam demonstrated potent in vitro activity when tested against contemporary aerobic Gram-negative pathogens causing IAI and HCA-UTI in USA and European medical centers.

Introduction

Ceftolozane is a novel cephalospirin that is currently under clinical development in combination with the β-lactamase inhibitor tazobactam for treatment of complicated intra-abdominal infections (IAI; http://clinicaltrials.gov, identifiers NCT01147640, NCT01445665 and NCT01445678), complicated urinary tract infections (UTI; NCT01345955, NCT01345929 and NCT00921024) and ventilator-associated pneumonia (VAP; NCT01853982). This compound has shown remarkable stability against various resistance mechanisms employed by Pseudomonas aeruginosa to other β-lactam compounds, and has demonstrated activity against ceftazidime-resistant, as well as meropenem-resistant strains.1, 2, 3

Ceftolozane has also demonstrated good activity against members of the Enterobacteriaceae, but similar to other established oxyimino-cephalosporins, its activity can be compromised by production of extended-spectrum β-lactamases (ESBLs), carbapenemases and, to some degree, hyperproduction of AmpC β-lactamases. Thus, the addition of tazobactam, a well-established β-lactamase inhibitor, broadens the spectrum of ceftolozane activity to include many ESBL-producing organisms as well as some anaerobes, such as Bacteroides spp.4, 5, 6

In this study, we evaluated the activity of ceftolozane/tazobactam and comparator agents tested against Gram-negative aerobic bacteria causing IAI and healthcare-associated UTI (HCA-UTI) in United States (USA) and European hospitals during 2012.

Section snippets

Bacterial isolates

The organism collection included only aerobic Gram-negative bacilli collected from hospitalized patients with a diagnosis of IAI or HCA-UTI. The organisms were consecutively collected from January to December 2012 from 28 medical centers located in the USA and 31 medical centers in 15 European countries by the Program to Assess Ceftolozane/Tazobactam Susceptibility (PACTS). A total of 809 organisms from IAI and 2474 organisms from UTI were included in this investigation. Species identification

Intra-abdominal infections

The aerobic Gram-negative bacilli most frequently isolated from IAI were E. coli (42.2%), K. pneumoniae (15.6%) and P. aeruginosa (14.2%). Ceftolozane/tazobactam was very active (MIC50/90, 0.25/0.5 mg/L) against 341 E. coli isolates and retained activity against many of the 16 (4.7%) MDR isolates (MIC50/90, 0.5/>32 mg/L; 75.0% of isolates inhibited at an MIC of ≤8 mg/L) and 38 (11.1%) ESBL-phenotype strains (MIC50/90, 0.5/32 mg/L; 86.8% of isolates inhibited at an MIC of ≤8 mg/L; Table 1).

Discussion

Most complicated IAI are polymicrobial, and enteric Gram-negative bacilli, Gram-positive cocci and anaerobic organisms are the predominant pathogens.11, 12 E. coli is the most common organism, but other Enterobacteriaceae, such as Klebsiella spp. and Enterobacter spp., and P. aeruginosa are also frequently isolated from patients with complicated IAI. Obligate anaerobic organisms are important components of most IAI, even though microbiology laboratories may not recover or report these

Acknowledgments

This study was funded by research grants from Cubist Pharmaceuticals (Lexington, MA, USA).

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