LAUSR

Dear Editor, We truly thank Dr Plant and colleagues for taking an interest in our review, raising an important issue about the risk of resistance development and clinical failure when ceftolozane/tazobactam (TOL/TAZ) is used against multidrug-resistant (MDR) Pseudomonas aeruginosa (PA) [1,2]. TOL/TAZ belongs to the new wave of beta-lactam /beta-lactamase inhibitor combinations and bases its efficacy against Gram-negative bacteria on ceftolozane’s higher stability versus AmpC β-lactamase than the predecessor beta-lactam companions of tazobactam [3]. The combination with the beta-lactamase inhibitor allows TOL to target many Enterobacteriaceae producing extendedspectrum beta-lactamases [4]. Nevertheless, the most intriguing feature of TOL is its potent in vitro activity against PA, not impaired by the most important resistance mechanisms toward beta-lactams such as AmpC-type beta-lactamases, decrement of outer membrane permeability through loss of porins and up-regulation of efflux pumps [5]. There is a huge amount of data across the world confirming the potent activity of TOL/TAL against clinical isolates of PA, including MDR and even extensively-drug resistant (XDR) strains. For example, a large Italian multicenter study, conducted from September 2013 to November 2014, showed that TOL/TAZ was the most active antibiotic against PA [6]. The authors collected 935 PA strains (related to pneumonia or bloodstream infections), of which 37.2% expressed an MDR phenotype: overall, TOL/TAZ turned out to be activity against 90.9% of PA isolates, followed by amikacin (88.0% susceptibility) [6]. In a larger series from the United States, 3,851 clinical isolates of PA (15.8% classified as MDR, 9.4% as XDR) were collected from 2012 to 2015 [7]. TOL/TAZ was the most active against 97.0% of cases among the antibiotics tested, namely, meropenem, amikacin, piperacillin/tazobactam, colistin, cefepime, and ceftazidime [7]. Of note, TOL/TAZ showed highest activity among beta-lactams against MDR (84.0%) and XDR (76.9%) strains [7]. This pattern (superiority of TOL/TAZ over other antipseudomonal beta-lactams) has been also observed in studies from other parts of the world. For instance, a recent report from Australia and New Zealand on 449 clinical isolates (mainly related to bloodstream infections and pneumonia from 2013 and 2105) demonstrated that TOL/TAZ retained good activity against PA strains resistant to ceftazidime, piperacillin/tazobactam, meropenem [8]. Similar results emerged from another report related to four Latin American countries (Argentina, Brazil, Mexico, Chile) over a 3-year period (2013–2015) in which 537 PA isolates were collected: TOL/ TAZ inhibited 86.8% of the strains, being the most active betalactam agent [9]. On this basis, it does not come as a surprise the scientific attention given to TOL/TAZ as an important drug able to fruitfully enrich the therapeutic armamentarium against PA, especially MDR and XDR strains. A relevant issue is to better define its place in therapy: currently, TOL/TAZ has been approved only for complicated urinary tract infections, including pyelonephritis, and for complicated intra-abdominal infections [3]. Differently, physicians need to resort to off-label prescribing, as was the case described by Dr Plant and colleagues [1]. They authors describe the in vivo development of TOL/TAZ resistance in a patient suffering from nosocomial pneumonia caused by an MDR-PA strain (carbapenem-resistant), treated with TOL/TAZ at the following dosage: 1.5 g three times a day [1]. They make a plea not to underestimate the risk of resistance occurrence and clinical failure when using TOL/TAZ against PA. Of course, their appeal is sensible and it overlaps with similar reflections made by other authoritative authors, who have advised caution in the use of novel antibiotics such as TOL/TAZ, since a widespread utilization would likely result in an increase of resistance, as it occurs in most other antimicrobials, thereby leading to the loss of efficacy of a potent weapon [10]. So, the crucial question is the accurate selection of patients who deserve treatment with TOL/TAZ, both empiric and targeted, in order to achieve the best outcome for the patient. In the case described by Dr Plant and colleagues the choice of TOL/TAZ appears appropriate in the light of the resistance profile showed by the PA strain [1]. As matter of fact, being that PA is a remarkable cause of nosocomial pneumonia, TOL/ TAZ, although through off-label prescribing, has been already used for respiratory tract infections [2] prompting a randomized clinical trial (ClinicalTrials.gov identifier: NCT02070757).