Original articleEffectiveness of ceftazidime-avibactam for the treatment of infections due to Pseudomonas aeruginosa
Introduction
Infections due to multidrug-resistant (MDR) and extensively drug-resistant (XDR) Pseudomonas aeruginosa (P. aeruginosa) constitute an emerging health problem, with high related mortality rates observed (30–50%) [1]. Most European countries report rates > 10% for combined resistance to ≥ 3 antimicrobial groups under surveillance (i.e. piperacillin/tazobactam, ceftazidime, carbapenems, fluoroquinolones and aminoglycosides) [2]. Patients suffering infections due to MDR/XDR P. aeruginosa are at an increased risk of receiving inadequate initial antimicrobial therapy and have poorer outcomes compared with those with susceptible strains [3,4]. Furthermore, targeted therapies for MDR/XDR isolates usually include agents as polymyxins, which are considered to be less effective and with a poorer safety profile [5].
Ceftazidime is a third-generation cephalosporin active against Enterobacterales and Pseudomonas spp. Avibactam is a new synthetic β-lactamase inhibitor with potent activity against class A (including extended-spectrum β-lactamases [ESBLs] and KPC-type carbapenemases), class C and some class D (including OXA-48-type) enzymes, although it lacks activity against metallo-β-lactamases (MBLs) [6,7]. Ceftazidime-avibactam (CAZ-AVI) may show activity against isolates producing class A carbapenemases that generally inactivate other broad-spectrum antipseudomonal agents such as ceftolozane-tazobactam (CEF-TAZ) [8]. This family of carbapenemases has been observed in P. aeruginosa isolates worldwide, but is most commonly found in Latin American and European countries, with some studies reporting prevalence rates up to 11% among imipenem-resistant strains [9]. In this way, depending on the underlying resistance mechanisms, CAZ-AVI could be the best option for some MDR/XDR P. aeruginosa strains, such as those harbouring class A carbapenemases (GES enzymes) or combinations of certain ESBLs with loss of the OprD porin [5].
Several in vitro studies have shown that CAZ-AVI displays good activity against a high proportion of MDR/XDR P. aeruginosa strains [10], [11], [12], [13], [14], [15], [16]. Unfortunately, data on the clinical efficacy in this specific setting are scarce because the pivotal clinical trials have included a low number of these infections [17], [18], [19], [20]. Conducting clinical trials to evaluate the optimal therapeutic approach to MDR/XDR Gram-negative bacilli is hampered by the relatively low incidence of these events, heterogeneity of resistance mechanisms involved (particularly in the case of P. aeruginosa) and targeted patient populations (in terms of predisposing factors, immune status, clinical severity or pharmacodynamic parameters), impact of empirical therapies administered prior to study entry, and difficulty in defining and operationalising study outcomes (i.e. clinical response or attributable mortality in critically ill patients exposed to concurrent or subsequent infections due to other pathogens). In fact, most of the reported studies on the effectiveness and safety of CAZ-AVI in clinical practice are focused on the treatment of carbapenemase-producing Enterobacterales [21], [22], [23], with few studies including patients with MDR/XDR P. aeruginosa [24], [25], [26].
Therefore, this study aimed to analyse the effectiveness and safety of CAZ-AVI for the treatment of this type of life-threatening infection.
Section snippets
Study design and setting
A retrospective cohort study was undertaken including adult patients (aged ≥ 18 years) with MDR/XDR P. aeruginosa infections treated with CAZ-AVI for at least 24 hours. The institutional central Pharmacy database was searched to identify patients who received CAZ-AVI between January 2016 and December 2019 at the University Hospital ‘12 de Octubre’, Madrid, Spain. All patients treated with CAZ-AVI were reviewed, and only first episodes of infection were included if MDR/XDR P. aeruginosa was
Study population
From January 2016 to December 2019, 61 first episodes of MDR/XDR P. aeruginosa infection treated with CAZ-AVI for at least 24 hours were included (patient flow chart depicted in Figure 1). Clinical and demographic characteristics are shown in Table 1. The mean age was 65.1 ± 15.9 years and 42 (68.9%) patients were male. The median Charlson comorbidity index was high (7 [IQR: 5–9] points). Virtually all of the episodes (60 [98.4%]) were hospital-acquired or healthcare-associated. Six (9.8%)
Discussion
It is believed that the present study is the largest cohort, reported to date, focusing on patients with MDR/XDR P. aeruginosa infection treated with CAZ-AVI. Clinical experience with CAZ-AVI has been focused on carbapenem-resistant Klebsiella pneumoniae (mainly KPC-producing strains), with other pathogens representing < 20% of cases included in previous studies [[21], [22], [23], [24],37]. The clinical cure rate by day 14 in the current serie was 54.1%, despite the 6-day median delay in the
References (49)
- et al.
Ceftazidime/avibactam tested against Gram-negative bacteria from intensive care unit (ICU) and non-ICU patients, including those with ventilator-associated pneumonia
Int J Antimicrob Agents
(2015) - et al.
Ceftolozane-tazobactam and ceftazidime-avibactam activity against beta-lactam-resistant Pseudomonas aeruginosa and extended-spectrum beta-lactamase-producing Enterobacterales clinical isolates from U.S. medical centres
J Glob Antimicrob Resist
(2020) - et al.
Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial
Lancet Infect Dis
(2018) - et al.
Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study
Lancet Infect Dis
(2016) - et al.
Clinical experience with ceftazidime/avibactam for treatment of antibiotic-resistant organisms other than Klebsiella pneumoniae
Int J Antimicrob Agents
(2018) - et al.
Evaluation of ceftazidime/avibactam for serious infections due to multidrug-resistant and extensively drug-resistant Pseudomonas aeruginosa
J Glob Antimicrob Resist
(2018) - et al.
Asymptomatic rectal carriage of blaKPC producing carbapenem-resistant Enterobacteriaceae: who is prone to become clinically infected?
Clin Microbiol Infect
(2013) - et al.
A new method of classifying prognostic comorbidity in longitudinal studies: development and validation
J Chronic Dis
(1987) - et al.
CDC definitions for nosocomial infections, 1988
Am J Infect Control
(1988) - et al.
CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting
Am J Infect Control
(2008)