In vitro activity of ceftolozane/tazobactam against clinical isolates of Pseudomonas aeruginosa and Enterobacteriaceae recovered in Spanish medical centres: Results of the CENIT study
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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2020, Infectious Disease Clinics of North AmericaCitation Excerpt :Limitations for the combination against indicated organisms include P aeruginosa or Enterobacterales that carry class A and class B carbapenemases (eg, KPC, VIM, NDM, and IMP) or class A, class C, and class D extended-spectrum β-lactamases (ESBLs) (eg, GES-6, PER-1, FOX-4, and OXA-539) that are not readily inhibited by tazobactam.30–34 E coli–producing class A ESBLs are more susceptible to ceftolozane-tazobactam than K pneumoniae-expressing or Enterobacter cloacae–expressing class A ESBLs.35–38 Chromosomal and acquired blaAmpCs likely contribute to the former phenotype, because the hyperproduction of AmpCs or class A ESBLs was shown to reduce efficacy of ceftolozane-tazobactam.33,36,39–41
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2019, International Journal of Antimicrobial AgentsCitation Excerpt :It depends both on the species level and the resistance mechanism. As we previously described [19], the activity of C/T is excellent against WT organisms (MIC50/90 ranges, 0.25–0.5 mg/L and 0.25–1 mg/L, respectively) and 100% inhibited at MIC ≤1 mg/L (Supplementary Table S1). However, the activity decreased against ESBL-producing K. pneumoniae, as noted in other studies [15].
New Antibiotics for Pneumonia
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