Ceftolozane/Tazobactam for Resistant Drugs Pseudomonas aeruginosa Respiratory Infections: A Systematic Literature Review of the Real-World Evidence

Background: Ceftolozane/tazobactam (C/T) is a β-lactam/β-lactamase inhibitor combination that mainly targets Gram-negative bacteria. The current international guidelines recommend including C/T treatment in the empirical therapy for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). Pseudomonas aeruginosa (PA) is one of the most challenging Gram-negative bacteria. We conducted a systematic review of all cases reported in the literature to summarize the existing evidence. Methods: The main electronic databases were screened to identify case reports of patients with drug-resistant PA respiratory infections treated with C/T. Results: A total of 22 publications were included for a total of 84 infective episodes. The clinical success rate was 72.6% across a wide range of comorbidities. The 45.8% of patients treated with C/T presented colonization by PA. C/T was well tolerated. Only six patients presented adverse events, but none had to stop treatment. The most common therapeutic regimens were 1.5 g every 8 h and 3 g every 8 h. Conclusion: C/T may be a valid therapeutic option to treat multidrug-resistant (MDR), extensively drug-resistant (XDR), pandrug-resistant (PDR), and carbapenem-resistant (CR) PA infections. However, further data are necessary to define the optimal treatment dosage and duration.

C/T was soon investigated as a possible therapeutic agent for nosocomial pneumonia due to its potent activity against Pseudomonas aeruginosa (PA) [6], responsible for a large proportion of hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) [7,8]. The current international guidelines recommend including C/T treatment in the empirical therapy for HAP and VAP [9,10].
In 2019, the FDA and EMA approved C/T as a therapeutic option for treating HAP and VAP [11,12]. The recommended dosage regimen of C/T was 3 g three times a day (t.i.d.) by intermittent infusion.
PA is one of the most challenging Gram-negative bacteria due to its intrinsic and acquired resistance mechanisms such as its ability to develop biofilms [13]. PA exhibits multidrug-resistant (MDR), extensively drug-resistant (XDR), and pandrug-resistant (PDR) phenotypes, reducing the number of antimicrobial agents available for clinical use [14]. In 2018, the World Health Organization (WHO) selected carbapenem-resistant (CR) PA as a critical-priority bacterium for future development strategies focused on new antibiotics [15].
In this scenario, C/T could play a central role. Ceftolozane is a cephalosporin with potent in vitro activity against PA that is not influenced by the β-lactam resistance mechanisms present in this species [16]. The combination with the tazobactam, a β-lactamase inhibitor, extends ceftolozane activity against many Enterobacteriaceae producing ES-BLs [17,18]. According to the Italian survey on PA, C/T was the most active anti-PA agent and, moreover, it was active against approximately half the isolates that are resistant to all other β-lactams or resistant to all other agents except colistin [14].
Objectives. We conducted a systematic review of all cases reported in the literature to summarize the existing evidence. To our knowledge, no previously published systematic reviews have evaluated real-world evidence studies of C/T in the treatment of PA resistant to multiple antimicrobial agents. Although a systematic review of case reports cannot support efficacy between drug-resistant PA respiratory infections and C/T therapy, it may identify unrecognized or rare associations and may generate hypotheses for subsequent studies.

Protocol and Registration
A systematic review was performed on the basis of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [19]. The protocol was not published, but is available on request. The review was not registered with the international prospective register of systematic reviews (PROSPERO) due to the long waiting times for the current situation.

Literature Search Strategy
The main electronic databases (Medline, EMBASE, PubMed, Google Scholar, and The Cochrane Library-CENTRAL) were screened to identify case reports of patients with drugresistant PA respiratory infections treated with C/T. Other relevant studies were identified from the reference lists. We used a combination of terms such as "ceftolozane-tazobactam", "Pseudomonas aeruginosa", "drug resistance", and "pneumonia". The titles and abstracts were screened by two researchers (L.G.G. and M.C.P.) to identify the keywords. The selected papers were read in full by the two independent reviewers, and a third reviewer (P.S.) was consulted in cases of disagreement.
The initial search was performed on 1 April 2021. All publications were included since inception up until the end of March 2021.
All the papers with available full text, reporting original data of patients with drugresistant PA respiratory infections treated with C/T, of any age, gender, and in any setting, were included. No language restrictions were applied.
− the study did not report clinical outcome; − the study had duplicate data with others (in these cases, only the largest study was retained); − the study presented pooled data that did not allow for extrapolation of useful information.

Data Extraction
Data were independently extracted by one of the three reviewers (L.G.G., M.C.P., P.S.) according to a predefined protocol. The data extraction was then checked by one of the other two reviewers, and the discrepancies were resolved by discussion between all of them.
Variables of interest included: − demographic characteristics (sex and age); − clinical characteristics (commodities); − type of infection and resistance profile; − therapeutic regimen (empirical and targeted) and dosage; − co-infections; − adverse events (AEs); − clinical and microbiological outcome.
According to an international expert proposal, MDR is defined as "non-susceptibility to at least one agent in three or more antimicrobial categories", XDR is defined as "nonsusceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e., bacterial isolates remain susceptible to only one or two categories)", and PDR is defined as "non-susceptibility to all agents in all antimicrobial categories (i.e., no agents tested as susceptible for that organism)" [20].

Results
A total of 22 full texts were eligible for inclusion, namely, 4 cohort studies and 18 case reports/case series investigating 84 infective episodes in total. As shown in Figure 1, the flow diagram reports the results from the literature search and the study selection process.

Study Characteristics
In Table 1, all the studies are presented in alphabetical order with a brief clinical description for each case.  [27]).

Discussion
PA is a challenging Gram-negative bacterium due to its intrinsic and acquired resistance mechanisms and its ability to develop biofilms [13]. To date, the optimal management of the PA infections, especially in cases of multidrug-resistant strains, it is not clarified. First, the superiority of combination therapy over monotherapy as definitive treatment is not established [43]. Current recommendations suggest double anti-PA empirical therapy, especially if resistant isolates are suspected [44,45]. Second, there is no agreement on the antibiotic treatment to choose. C/T is emerging as a good option among β-lactams alone or in combination (especially with colistin or amikacin) for acute invasive PA infections [14,45]. In vitro, C/T is the most active β-lactam against PA, even in the case of resistant strains. C/T is active against 75-89% of the isolates not sensitive to ceftazidime, piperacillin/tazobactam, and meropenem [46].
In our systematic review, the clinical success rate was 72.6% across a wide range of comorbidities. According to the literature, PA causes infections in patients with comorbidities, such as cystic fibrosis, chronic structural lung disease (e.g., bronchiectasis, COPD), impaired immune defenses (e.g., HIV infection, malignancy with neutropenia or recent chemotherapy, organ transplant recipients), diabetes mellitus, renal failure and hemodialysis, and chronic cardiovascular or neurological disease [47]. Notably, clinical success was even higher when considering MDR-PA cases only (83.6%). According to previous data, CR-PA represents a therapeutic problem with a failure rate of 40% in present studies. In this direction, the WHO supports the development of new antibiotics that are active against multidrug-resistant Gram-negative bacteria [15]. The 45.8% of patients treated with C/T presented colonization by PA.
The most common therapeutic regimens were 1.5 g every 8 h and 3 g every 8 h. The latter represents the recommended dosage regimen for treating HAP and VAP [11,12]. Ceftolozane has shown adequate penetration in lung tissue, close to 50%, with 2 g doses in an extended infusion of 3 h [48].
Importantly, C/T was well tolerated. Only six patients presented adverse events, but no one had to stop the treatment. The increased dose of C/T could be associated with an increase in the occurrence of adverse effects, such as elevation of liver enzymes, hypotension, or cutaneous reactions [48].
This study contributes to the accumulation of so-called "real world data", which, when properly interpreted, can provide suggestions and guidelines [49]. Indeed, due to the recognized gap between the global burden of resistance bacteria and new antibiotics under development, many proposals have been made to optimize the design of clinical trials, but not all recommendations are feasible or immediately applicable [50,51]. In this way, real-world evidence may come as useful.
To summarize, this is the first systematic review of the use of C/T in resistant pulmonary PA infections. Its strength is based on rigorous inclusion criteria, which allow it to collect data exclusively on MDR-PA, XDR-PA, PDR-PA, and CR-PA infections and determine the outcome.
Limitations. This study presents some limitations. First, it was based on observational studies, the majority of which were case series or case reports. Due to the greater potential for bias, they are often excluded from systematic reviews of treatments. In this report, case series and observational studies contribute substantially to the available evidence base, and their results supplement the limited evidence available from other studies. Second, a meta-analysis was not performed, owing to the design of most of the studies (case report, case series) and the lack of a comparator.

Conclusions
C/T may be a valid therapeutic option to treat MDR-PA, XDR-PA, PDR-PA, and CR-PA infections. However, further data are necessary to define its optimal treatment dosage and duration.