Response to: ‘Letter to the Editor: “Management of multidrug-resistant Pseudomonas aeruginosa in the Intensive Care Unit: state of the art”’

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 extended-spectrum 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 anti-pseudomonal 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 beta-lactam 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). This trial was aimed at assessing efficacy and safety of TOL/TAZ, compared with meropenem, in patients with ventilator-associated pneumonia or with nosocomial pneumonia in need of mechanical ventilation [11]. Researchers are still recruiting patients; of note, the planned dose of TOL/TAZ is equal to 3 g every 8 h (versus meropenem 1 g every 8 h) for 8–14 days, the longer course is just when a diagnosis of PA pneumonia is made [11].

The reason for this double dosage relies on an elegant study where a Monte Carlo simulation was used to assess the kinetics of TOL/TAZ between plasma and the epithelial lining fluid (ELF) [12]. In turn, the basis of the work was the 50% plasma-to-ELF penetration ratio of TOL/TAZ. The model clearly demonstrated that, in case of normal renal function, a 3-g dose (each 8 h) of TOL/TAZ is necessary to achieve a >90% probability of target attainment (namely 98%) against PA (as well as Enterobacteriaceae) strains with a minimum inhibitory concentrations (MIC) up to 8 mg/L in ELF [12].

The patient described by the case report suffered from nosocomial pneumonia whose causative agent was initially a PA strain with a MIC of TOL/TAZ equal to 0.5 mg/L [1]. Authors claim that their choice of a standard TOL/TAZ dosage (1.5 g three times a day) was justified by data extrapolated by the pharmacokinetic model previous described [12], according to the low MIC value exhibited by the clinical isolate. Theoretically, their interpretation of the model is correct; nevertheless, there are two elements warranting additional reflection on this choice.

First, Dr Plant and colleagues do not report on the tool to assess the MIC values [1]. For instance, Etest, compared with broth microdilution, seems to overestimate susceptibility of PA towards TOL/TAZ [13]. Second, a doubled dosage has a major probability of target attainment when MIC values get closer to the threshold of 8 mg/L [12]. Therefore, this choice would be more appropriate when facing nosocomial pneumonia, both to better manage possible inaccurate assessment of susceptibility and to guarantee a superior efficacy in case of in vivo gradual MIC shift under pharmacological pressure.

Of course, data from the above-mentioned clinical trial, entailing the use of 3 g of TOL/TAZ every 8 h for nosocomial pneumonia [11], are eagerly awaited. Likewise, and hopefully, further light on the topic will be also shed by another study that has been just completed, but results are not available yet (ClinicalTrials.gov identifier: NCT02387372) [14]. In particular, this phase 1 trial is aimed at evaluating the pharmacokinetics as well as the lung penetration of TOL/TAZ in critically ill patients with pneumonia, receiving up to 4–6 doses of 3-g TOL/TAZ every 8 h [14].

In conclusion, the peculiar features of the plasma-ELF penetration ratio of beta-lactams antibiotics require great attention, in order to select the optimal dosage for patients with difficult-to-treat infections, as for MDR-PA. TOL/TAZ is a useful addiction to the current antibiotic arsenal but, as all antibiotics developed so far, is not the definitive weapon against MDR or XDR bacteria. At any rate, literature data allows to state that TOL/TAZ is, among beta-lactams, the most active anti-pseudomonal agent. Unfortunately, when it comes to MDR- or XDR-PA there is still no consensus about paramount issues such as monotherapy versus combination therapy, and when choosing the second option, which would be the best association [2]. Nevertheless, there is an increasing number of successful off-label uses of TOL/TAZ against MDR- or XDR-PA strains [15]. Needless to say, further data from large studies are needed to assess its precise place in therapy and its correct dosage beyond the approved indications.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

The manuscript was not funded.