Evaluation of in vitro activity of ceftolozane-tazobactam compared to other antimicrobial agents against Pseudomonas aeruginosa isolates from cystic fibrosis patients Giovanni Gherardi a , Giulia Linardos b , Arianna Pompilio c, d , Ersilia Fiscarelli b , Giovanni Di Bonaventura c, d, ⁎ a Department of Medicine, Campus Biomedico University, Via Alvaro del Portillo 200, 00128 Rome, Italy b Cystic Fibrosis Microbiology, Children’s Hospital and Research Institute “Bambino Gesù”, Piazza S. Onofrio 4, 00165 Rome, Italy c Department of Medical, Oral and Biotechnological Sciences; “G. d'Annunzio” University of Chieti, Via Vestini 31, 66100 Chieti, Italy d Center of Excellence on Aging and Translational Medicine (CeSI-MeT), “G. d'Annunzio” University of Chieti, Via Luigi Polacchi 11, 66100 Chieti, Italy abstract article info Article history: Received 16 November 2018 Received in revised form 31 December 2018 Accepted 18 January 2019 Available online xxxx Keywords: Ceftolozane-tazobactam Pseudomonas aeruginosa Cystic fibrosis The in vitro activity of ceftolozane-tazobactam (C-T) was evaluated comparatively to other antibiotics against 188 Pseudomonas aeruginosa isolates collected from cystic fibrosis (CF) patients. Overall, the activity of C-T was compa- rable to colistin (susceptibility rate: 85.1% vs. 89.4%) but significantly higher than other antimicrobials. Particularly, C-T was active against 70% of meropenem nonsusceptible isolates and 64.1% of those nonsusceptible to beta- lactams. C-T was active against 70%, 58.1%, and 100% of multidrug-resistant, extensively drug-resistant (XDR), and pandrug-resistant isolates, respectively. No differences in C-T activity were found between isolates from children and adult patients, except for XDR ones significantly more susceptible in older patients. C-T and colistin exhibited comparable susceptibility rate (91.1% vs. 86.7%) also against 68 isolates collected during pulmonary exacerbations. Activity of C-T towards mucoid isolates was less than colistin (82.9% vs. 97.6%) but higher compared with other antibiotics. C-T represents a promising agent for treating CF lung infections. © 2019 Elsevier Inc. All rights reserved. 1. Introduction Carbapenems remain effective in treating serious multidrug-resistant (MDR) P. aeruginosa infections, although carbapenem-resistant P. aeruginosa has emerged worldwide as an important nosocomial pathogen, particularly in immunocompromised patients (Bodey et al., 1985; Poole, 2011). Infections caused by resistant P. aeruginosa are of concern in many hospitals since they are associated with a delayed start of appropriate antibiotic therapy and with significant mortality (Giamarellou, 2002). MDR P. aeruginosa infections are frequently resis- tant to carbapenems and other beta-lactams. P. aeruginosa resistance to beta-lactams is mediated through multiple mechanisms, including the acquisition of metallo-beta-lactamases, increased production of chromosomal AmpC, increased drug efflux, and changes in membrane permeability (Castanheira et al., 2014; Lister et al., 2009). P. aeruginosa is the most common pathogen in cystic fibrosis (CF), colonizing the respiratory tract of approximately 65% of adult CF patients (Flume et al., 2009). Frequent acute pulmonary exacerbations during P. aeruginosa infection are responsible for progressive pulmonary decline, which contributes to early CF patient mortality (Flume et al., 2009). In these patients, the repeated exposure to intravenous antibiotics selects many P. aeruginosa MDR isolates (Chen et al., 2007; Smith et al., 2016); furthermore, the formation of intrinsically antibiotic-resistant biofilms during chronic infection renders treatment of exacerbations more challenging, highlighting the need for new antibiotics (Llanes et al., 2013). Ceftolozane-tazobactam (C-T) is a novel fifth-generation cephalosporin- beta-lactamase inhibitor combination with broad-spectrum activity against Gram-negative bacteria, including MDR P. aeruginosa. C-T was approved by the U.S. Food and Drug Administration in 2014 and by the European Medicines Agency in 2015 for the treatment of complicated intra-abdominal infections, in combination with metronidazole, and complicated urinary tract infections (van Duin and Bonomo, 2016). Ceftolozane has stability against chromosomal AmpC-lactamases, overexpressed MexAB-OprM efflux pumps, and deleted OprD porins (Livermore et al., 2009); its activity against P. aeruginosa is due to its affinity for the penicillin-binding proteins (Zhanel et al., 2014). C-T demonstrates activity against many MDR P. aeruginosa, including carbapenemase-nonproducing carbapenem-resistant strains (Wright et al., 2017). The goal of this study was to evaluate the in vitro activity of C-T against a collection of not duplicated, consecutive, P. aeruginosa isolates colonizing the respiratory tract of CF patients admitted to an Italian CF Diagnostic Microbiology and Infectious Disease xxx (xxxx) xxx Abbreviations: C-T, ceftolozane-tazobactam; CF, cystic fibrosis; MDR, multidrug-resistant; XDR, extensively drug-resistant; PDR, pandrug-resistant. ⁎ Corresponding author. Tel.: +39-0871-541509; fax: +39-0871-541520. E-mail address: gdibonaventura@unich.it (G. Di Bonaventura). DMB-14766; No of Pages 7 https://doi.org/10.1016/j.diagmicrobio.2019.01.012 0732-8893/© 2019 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Diagnostic Microbiology and Infectious Disease journal homepage: www.elsevier.com/locate/diagmicrobio Please cite this article as: G. Gherardi, G. Linardos, A. Pompilio, et al., Evaluation of in vitro activity of ceftolozane-tazobactam compared to other antimicrobial agents against ..., Diagnostic Microbiology and Infectious Disease, https://doi.org/10.1016/j.diagmicrobio.2019.01.012