Short Communication
Activity of ceftolozane/tazobactam against Pseudomonas aeruginosa and Enterobacterales isolates recovered from intensive care unit patients in Spain: The SUPERIOR multicentre study

https://doi.org/10.1016/j.ijantimicag.2019.02.004Get rights and content

Highlights

  • Activity of ceftolozane/tazobactam (C/T) against Enterobacterales and Pseudomonas aeruginosa collected from Spanish ICUs.

  • P. aeruginosa susceptibility to C/T was 95.7% in complicated UTIs and 85.3% in complicated IAIs.

  • The corresponding figures in Enterobacterales were 79.5% and 89.3%, respectively.

  • In vitro activity of C/T suggests that it can be considered as a therapeutic option in ICU patients.

ABSTRACT

Patients in intensive care units (ICUs) present a high risk of developing an infection caused by multidrug-resistant bacteria. Consequently, new antimicrobials and combinations are required. In this study, the activity of ceftolozane/tazobactam (C/T) was evaluated against Enterobacterales (n = 400) and Pseudomonas aeruginosa (n = 80) clinical isolates collected from patients in Spanish ICUs with complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI). Overall susceptibility to C/T in P. aeruginosa isolates by infection type was 95.7% in cUTI (MIC50/90, 1/4 mg/L) and 85.3% in cIAI (MIC50/90, 1/64 mg/L). Activity against P. aeruginosa was maintained regardless of its resistance pattern, confirming that C/T is one of the best antipseudomonal agents along with colistin and amikacin. Susceptibility to C/T in Enterobacterales by infection type was 79.5/81.9% and 89.3/92.3% (EUCAST/CLSI) in cIAI and cUTI isolates, respectively. Activity was excellent against wild-type organisms, with 100% susceptible and inhibited at MIC ≤1 mg/L. Nevertheless, C/T susceptibility decreased against extended-spectrum β-lactamase (ESBL)-producing isolates: Escherichia coli (80.4/84.8% susceptible by EUCAST/CLSI) and Klebsiella pneumoniae (59.1/77.3% susceptible by EUCAST/CLSI). No activity of C/T was observed in carbapenemase-producing isolates. The in vitro activity of C/T observed in this surveillance study suggests that this agent can be considered as a therapeutic option for cUTI and cIAI due to Enterobacterales and P. aeruginosa in ICU patients, particularly when carbapenemase-producing isolates are not involved.

Introduction

Multidrug-resistant (MDR) bacteria represent not only a worldwide problem in terms of increased patient morbidity and mortality but also a huge extra cost to healthcare systems [1]. Deaths attributed to antimicrobial resistance are expected to surpass those caused by cancer by 2050, with a total estimate of more than 10 million deaths [2]. Percentages of resistant bacteria in intensive care units (ICUs) vary between countries and hospitals, but surveillance reports from the European Centre for Disease Prevention and Control (ECDC) give an idea of the dimension of the problem in ICUs: oxacillin resistance in 23.1% of Staphylococcus aureus; ceftazidime resistance in 23.7% of Pseudomonas aeruginosa; and carbapenem resistance in 11.3% and 23.7% of Klebsiella spp. and P. aeruginosa, respectively. These figures may be higher in Spain [3].

Patients in ICUs are at increased risk of developing an infection caused by antimicrobial-resistant bacteria owing to prolonged hospital stay, use of invasive devices and antibiotic exposure [4]. This supports the use of new drugs or combinations [5]. Ceftolozane/tazobactam (C/T), a new β-lactam/β-lactamase inhibitor combination, combines a cephalosporin (ceftolozane), which is less affected by AmpC β-lactamases, porin loss or efflux systems in P. aeruginosa, and a β-lactamase inhibitor (tazobactam) that improves the activity against extended-spectrum β-lactamase (ESBL)-producing Enterobacterales. This combination has been approved for complicated urinary tract infections (cUTI), including pyelonephritis, and complicated intra-abdominal infections (cIAI), the latter in combination with metronidazole [6], [7].

The aim of the SUPERIOR study was to assess the in vitro activity of C/T and comparator antimicrobials against P. aeruginosa and Enterobacterales clinical isolates prospectively collected from ICU patients with cUTI and cIAI in Spain.

Section snippets

Study design and hospital participants

A prospective multicentre study was designed to assess the in vitro activity of C/T and comparator antimicrobials against clinical isolates of Enterobacterales and P. aeruginosa prospectively recovered in Spanish ICUs between April 2016 and April 2017. Eight hospitals participated in the study, namely Universitario Ramón y Cajal (co-ordinator laboratory) (Madrid), General Universitario Gregorio Marañón (Madrid), Hospital Clínic (Barcelona), Universitario Virgen Macarena (Seville), Universitario

Bacterial isolates

A total of 400 Enterobacterales isolates and 80 P. aeruginosa were collected from different ICUs in Spain. Regarding the infection type, 280 isolates (58.3%) were recovered from cUTI (83.6% Enterobacterales and 16.4% P. aeruginosa) and 200 (41.7%) were recovered from cIAI (83.0% Enterobacterales and 17.0% P. aeruginosa). The distribution by source in cIAI isolates was peritoneal fluid (47%), abdominal abscess (16.5%), bile (14%), wound (10.5%), abdominal drainage (10%) and liver abscess (2%).

Pseudomonas aeruginosa isolates

Discussion

The recent list of antibiotic-resistant bacteria published by the World Health Organization (WHO) alerts about the necessity of development of new antibiotics against these pathogens [11]. In this list, P. aeruginosa and Enterobacterales represent the highest level of risk. Overall data from the 2016 European Antimicrobial Resistance Surveillance Network (EARS-Net) report show worrisome mean levels of resistance for common treatment options against P. aeruginosa: TZP, 16.3%; fluoroquinolones,

Funding

This study was funded by MSD Spain and was supported by Plan Nacional de I+D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases [RD16/0016/0001, RD16/0016/0004, RD16/0016/0006, RD16/0016/0007, RD16/0016/0010 and REIPI RD16/0016/0011], co-financed by the European Development Regional Fund ‘A way to achieve Europe’ (ERDF),

Competing interests

RC and GB have participated in educational programmes organised by MSD and Pfizer. All other authors declare no competing interests.

Ethical approval

This study was approved by the Ethical Committee of Hospital Universitario Ramón y Cajal (Madrid, Spain) [Ref. 087-16] and the Spanish Medicines Agency [Ref. MSD-CEF-2016-01].

Acknowledgments

The SUPERIOR Study Group includes the following members: Antonio Oliver and Xavier Mulet (Hospital Universitario Son Espases, Palma de Mallorca, Spain); Emilia Cercenado (Hospital General Universitario Gregorio Marañón, Madrid, Spain); Germán Bou (Complejo Universitario de la Coruña, A Coruña, Spain); Álvaro Pascual and Mercedes Delgado (Hospital Universitario Virgen Macarena, Seville, Spain); Concepción Gimeno and Nuria Tormo (Consorcio Hospital General Universitario de Valencia, Valencia,

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