Ceftolozane/tazobactam for the treatment of serious Pseudomonas aeruginosa infections: a multicentre nationwide clinical experience

https://doi.org/10.1016/j.ijantimicag.2018.11.001Get rights and content

Highlights

  • We report real-life clinical experience with ceftolozane/tazobactam (C/T) since its approval in Italy.

  • C/T appears to be effective for many serious Pseudomonas aeruginosa infections, including VAP and HAP.

  • Septic patients receiving continuous renal replacement therapy had a higher risk of clinical failure.

ABSTRACT

This study describes the largest clinical experience using ceftolozane/tazobactam (C/T) for different Pseudomonas aeruginosa infections. A retrospective study was performed at 22 hospitals in Italy (June 2016–March 2018). All adult patients treated with ≥4 days of C/T were enrolled. Successful clinical outcome was defined as complete resolution of clinical signs/symptoms related to P. aeruginosa infection and lack of microbiological evidence of infection. C/T treatment was documented in 101 patients with diverse infections, including nosocomial pneumonia (31.7%), acute bacterial skin and skin-structure infection (20.8%), complicated UTI (13.9%), complicated IAI (12.9%), bone infection (8.9%) and primary bacteraemia (5.9%). Over one-half of P. aeruginosa strains were XDR (50.5%), with 78.2% of isolates resistant to at least one carbapenem. C/T was used as first-line therapy in 39 patients (38.6%). When used as second-line or later, the most common reasons for discontinuation of previous antibiotics were in vitro resistance of P. aeruginosa and clinical failure of previous therapy. Concomitant antibiotics were reported in 35.6% of patients. C/T doses were 1.5 g q8h in 70 patients (69.3%) and 3 g q8h in 31 patients (30.7%); median duration of C/T therapy was 14 days. Overall clinical success was 83.2%. Significant lower success rates were observed in patients with sepsis or receiving continuous renal replacement therapy (CRRT). Mild adverse events were reported in only three patients. C/T demonstrated a favourable safety and tolerability profile regardless of the infection type. Clinicians should be aware of the risk of clinical failure with C/T therapy in septic patients receiving CRRT.

Introduction

Pseudomonas aeruginosa is a leading cause of nosocomial infections, which are often severe [1], [2] and difficult to treat because of their increasing resistance to several antibiotics, including carbapenems [3], [4], [5], [6]. There are limited therapeutic options for such infections, and old antibiotics such as colistin, aminoglycosides or fosfomycin are frequently prescribed [7]. Clinical failure [8], the emergence of in vivo resistance [9], superinfection and nephrotoxicity [10], [11] represent the main limitations of currently available drugs, leading to the search of new treatment options.

Ceftolozane/tazobactam (C/T) is a novel β-lactam/β-lactamase inhibitor combination with potent activity against Gram-negative bacteria, particularly against P. aeruginosa for which it is the most active available β-lactam antibiotic [5]. Although C/T has only been approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) [12], [13], it has become a suitable and attractive option for the treatment of different infections caused by multidrug-resistant (MDR) or extensively drug-resistant (XDR) P. aeruginosa [14]. In recent years clinical experience with C/T is accumulating and expanding, but only a limited number of cases series have been published [15], [16], [17], [18], [19], [20], [21].

A multicentre nationwide study was performed to report the Italian experience with C/T in the treatment of severe P. aeruginosa infections and to evaluate risk factors associated with clinical failure.

Section snippets

Study setting and design

A multicentre, retrospective, real-world study of hospitalised patients in 22 public hospitals in Italy who were treated for P. aeruginosa infections between June 2016 and March 2018 (21-month period) was performed. Hospitals were located in 12 Italian regions, namely Friuli Venezia Giulia, Veneto, Lombardia, Emilia Romagna, Liguria, Toscana, Lazio, Abruzzo, Campania, Puglia, Calabria and Sicilia. The Internal Review Board of Medical Area (D.A.M.E) of the co-ordinating centre (Azienda

Results

A total of 101 patients treated with ≥4 days of C/T were evaluated. The clinical characteristics of the patients are shown in Table 1. The median patient age was 67 years (interquartile range 49–74 years) and 66 (65.3%) were male. Almost one-third of the patients (30.7%) showed a chronic renal disease prior to P. aeruginosa infection and, with the exception of seven cases, all patients had at least one serious underlying disease with a mean Charlson comorbidity index of 4.4. At the time of

Discussion

Here we present the largest clinical experience with C/T therapy for the treatment of serious P .aeruginosa infection published so far. We showed that C/T is an effective and safe drug for treating different types of P. aeruginosa infection, including those with off-label indications. Of importance, clinical success was observed in nearly 85% of the patients, notwithstanding the fact that almost 70% of the isolates were MDR or XDR. Importantly, this analysis also indicated that CRRT and sepsis

Acknowledgments

The authors acknowledge as co-authors all of the following CEFTABUSE-IT Study Group members: Matteo Bassetti, Antonio Vena, Nadia Castaldo, Davide Pecori, Elda Righi, Alessia Carnellutti, Filippo Givone, Elena Graziano, Maria Merelli, Barbara Cadeo and Maddalena Peghin (Infectious Diseases Division, Santa Maria della Misericordia University Hospital, Udine, Italy); Annamaria Cattelan, Ludovica Cipriani and Davide Coletto (Unit of Infectious Diseases, Department of Internal Medicine, Azienda

Funding

None.

Competing interests

MB serves on scientific advisory boards for Angelini, AstraZeneca, Bayer, Cubist, Pfizer, Menarini, MSD, Nabriva, Paratek, Roche, Shionogi, Tetraphase, The Medicine Company and Astellas Pharma Inc., and has received funding for travel or speaker honoraria from Algorithm, Angelini, Astellas Pharma Inc., AstraZeneca, Cubist, Pfizer, MSD, Gilead Sciences, Menarini, Novartis, Ranbaxy and Teva; CT has received funds for speaking at symposia organised on behalf of Pfizer, Gilead, Novartis, Merck,

Ethical approval

The Internal Review board of Medical Area (D.A.M.E) of Azienda Ospedaliera Universitaria Integrata di Udine (Udine, Italy) approved this study [18/I.R.B_Bassetti_18], which waived the requirement of informed consent owing to the retrospective design of the study.

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