In vitro activity of ceftolozane/tazobactam against clinical isolates of Pseudomonas aeruginosa and Enterobacteriaceae recovered in Spanish medical centres: Results of the CENIT study

https://doi.org/10.1016/j.ijantimicag.2015.07.004Get rights and content

Highlights

  • Ceftolozane/tazobactam and ceftolozane were the most potent agents against Pseudomonas aeruginosa, including multidrug-resistant strains.

  • Ceftolozane/tazobactam shows good activity against most Enterobacteriaceae isolates, including most ESBL- and AmpC-producers.

  • Ceftolozane/tazobactam is inactive against carbapenemase-producing isolates.

Abstract

Ceftolozane/tazobactam is a novel antimicrobial agent with activity against Pseudomonas aeruginosa, including drug-resistant strains, and other Gram-negative pathogens, including most extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae. The CENIT study evaluated the in vitro activity of ceftolozane/tazobactam and comparators against clinical isolates of P. aeruginosa (n = 500) and Enterobacteriaceae (n = 500) collected from patients with complicated intra-abdominal, complicated urinary tract, lower respiratory tract or bloodstream infections in 10 medical centres in Spain (January–September 2013). Antimicrobial susceptibility was determined by the ISO broth microdilution method using commercial dry-form panels and results were interpreted per EUCAST and CLSI guidelines and for ceftolozane/tazobactam with FDA criteria. Ceftolozane/tazobactam and ceftolozane alone were the most potent (MIC50/90, 0.5/4 mg/L) agents tested against all P. aeruginosa isolates. This advantage was maintained regardless of resistance phenotype, even against isolates resistant to multiple antibiotics. Ceftolozane/tazobactam demonstrated excellent overall activity (MIC50/90, 0.25/0.5 mg/L) against all 250 Escherichia coli isolates, including isolates displaying a wild-type (MIC90, 0.25/0.25 mg/L) or ESBL (MIC50/90, 0.5/1 mg/L) phenotype, and good activity against isolates displaying an AmpC-like phenotype (MIC range 0.25–4 mg/L). Ceftolozane/tazobactam demonstrated good overall activity (MIC50/90, 0.25/4 mg/L) against all 104 Klebsiella spp. isolates, although activity was lower against those with an ESBL phenotype (MIC50/90, 4/16 mg/L), and was inactive against the carbapenemase-producing isolates (MIC  64 mg/L). Ceftolozane/tazobactam demonstrated excellent in vitro activity against most of the P. aeruginosa and Enterobacteriaceae clinical isolates obtained from medical centres in Spain, supporting the potential value of ceftolozane/tazobactam in treating infections due to these pathogens.

Introduction

Gram-negative bacteria are responsible for the majority of healthcare-associated infections, including urinary tract infections [1], intra-abdominal infections [2] and pneumonia [3], and are an important cause of nosocomial bloodstream infections (BSIs) [4]. Infections caused by Gram-negative bacteria have features that are of particular concern; in particular, Gram-negative bacteria are highly adaptive and often possess multiple mechanisms of antibiotic resistance, especially in the presence of antibiotic selection pressure [5]. In addition, there is increasing drug resistance in the absence of effective therapies, which makes selection of empirical therapy difficult [3], [5]. Inappropriate initial antibiotic therapy is associated with increased mortality [6], [7], hospital length of stay and hospital costs [8]. The majority of inappropriate initial antibiotic therapy is attributed to drug resistance [7], highlighting the need for new effective therapies.

Ceftolozane/tazobactam is an antibacterial consisting of ceftolozane, a novel antipseudomonal cephalosporin, and tazobactam, a well established β-lactamase inhibitor. In the phase 3 clinical trial ASPECT-cUTI, ceftolozane/tazobactam met its primary endpoint of non-inferior efficacy and was superior to high-dose extended-duration levofloxacin in the primary and key secondary endpoints in patients with complicated urinary tract infections (cUTIs), including pyelonephritis [9]. In the phase 3 trial ASPECT-cIAI, ceftolozane/tazobactam plus metronidazole met its primary endpoint of non-inferior efficacy to meropenem for clinical cure in patients with complicated intra-abdominal infections (cIAIs) [10]. The phase 3 trial to assess the efficacy and safety of ceftolozane/tazobactam versus meropenem in the treatment of ventilated nosocomial pneumonia is ongoing [11]. Ceftolozane has demonstrated potent in vitro activity against Pseudomonas aeruginosa, including multidrug-resistant isolates, as well as good activity against Enterobacteriaceae organisms but, similar to other cephalosporins [12], its activity can be reduced by the production of extended-spectrum β-lactamases (ESBLs), carbapenemases and, to some degree, hyperproduction of AmpC β-lactamases. The addition of tazobactam broadens the activity of ceftolozane to include most ESBL-producing Enterobacteriaceae [11], [13], [14].

Surveillance of antimicrobial resistance is a fundamental part of an effective response to the threat of resistance and provides an essential source of information on the magnitude and trends of resistance at the local, national, regional and global levels as well as geographical variations [15]. The purpose of the CENIT study (Ceftolozane/Tazobactam Activity Against Relevant Gram-negative Isolates) was to evaluate the in vitro activity of ceftolozane/tazobactam and several comparator agents against contemporary relevant clinical isolates of P. aeruginosa and Enterobacteriaceae prospectively collected in Spain from patients with cIAIs, cUTIs, lower respiratory tract infections (LRTIs) and BSIs. Isolates were further classified according to resistance phenotypes.

Section snippets

Sampling sites and organisms

Clinical isolates of P. aeruginosa and Enterobacteriaceae were prospectively and consecutively collected from January to September 2013 from inpatients and outpatients with cIAIs, cUTIs, LRTIs and BSIs at 10 Spanish tertiary care medical centres. Each medical centre submitted 100 clinical isolates (50 P. aeruginosa and 50 Enterobacteriaceae). Only one isolate per patient was included. Isolate identification was performed by the submitting site and was confirmed at the central laboratory

Distribution of isolates

A total of 1000 clinical isolates of P. aeruginosa (n = 500; Table 1) and Enterobacteriaceae (n = 500; Table 2) were collected from inpatients (81.1%) and outpatients (18.9%) with cIAIs, cUTIs, LRTIs and BSIs. There were 259 isolates obtained from cIAI specimens (25.9%), 263 from cUTIs (26.3%), 258 from LRTIs (25.8%) and 220 from BSIs (22.0%). Pseudomonas aeruginosa isolates were more commonly collected in LRTIs than Enterobacteriaceae (65.1% vs. 34.9%, respectively), whereas in cIAIs

Discussion

The results from this study are important in view of the growing public health threat posed by antimicrobial resistance [15]. In Europe, antimicrobial resistance rates are increasing and Spain has one of the highest rates of antimicrobial resistance as well as of antibiotic consumption [26], [27].

In Spain in 2012, resistance in E. coli isolates was found at rates of 65.4%, 33.9%, 15.6%, 13.5% and 0.1% for aminopenicillins, fluoroquinolones, aminoglycosides, third-generation cephalosporins and

Conclusion

In conclusion, currently no antimicrobial agent or combination allows complete coverage of multidrug-resistant Enterobacteriaceae and P. aeruginosa isolates. Ceftolozane/tazobactam demonstrated excellent in vitro activity against P. aeruginosa and most of the Enterobacteriaceae clinical isolates obtained from medical centres in Spain. Taken together, the data presented in this study confirm the activity of ceftolozane/tazobactam against organisms recovered from cIAIs, cUTIs, LRTIs and BSIs,

Acknowledgments

The authors thank the investigators of the CENIT study group: Dr Emilia Cercenado and Dr Emilio Bouza Santiago [Hospital General Universitario Gregorio Marañón and CIBER de Enfermedades Respiratorias (CIBERES) CB06/06/0058, Madrid, Spain], Dr Francesc Marco Reverte and Dr Vila (Hospital Clínic i Provincial de Barcelona, Barcelona, Spain), Dr Pilar Egea and Dr Álvaro Pascual Hernández (Hospital Universitario Virgen Macarena, Seville, Spain), Dr Jorge Calvo and Dr Luis Martínez-Martínez (Hospital

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