Original article
Effectiveness of ceftazidime-avibactam for the treatment of infections due to Pseudomonas aeruginosa

https://doi.org/10.1016/j.ijantimicag.2021.106517Get rights and content

HIGHLIGHTS

  • Ceftazidime-avibactam (CAZ-AVI) is an effective and safe therapy for multidrug or extremely resistant (MDR/XDR) Pseudomonas aeruginosa infections

  • It is especially useful for strains with class A carbapenemase production

  • Early therapy with CAZ-AVI is associated with better outcomes

  • CAZ-AVI as part of combination therapy provides no clear benefits over monotherapy

Abstract

Background

Clinical experience with ceftazidime-avibactam (CAZ-AVI) for treatment of infections due to multidrug or extremely resistant (MDR/XDR) Pseudomonas aeruginosa (P. aeruginosa) is limited.

Methods

A retrospective cohort study was conducted on patients with MDR/XDR P. aeruginosa infections treated with CAZ-AVI. The primary outcome was clinical cure by day 14, evaluated by logistic regression adjusted for the propensity score to receive CAZ-AVI as combination therapy. Secondary outcomes were 30-day all-cause mortality, 90-day recurrence, emerging CAZ-AVI resistance, and safety of therapy.

Results

Sixty-one first episodes of MDR/XDR P. aeruginosa infection were included. The most common source was lower respiratory tract infection (34.4%), 14.8% episodes developed bloodstream infection and 50.8% had sepsis at presentation. Ceftazidime-avibactam therapy was initiated at a median of 7.0 (interquartile range [IQR]: 3.5-12.0) days from symptom onset; it was used as combined therapy in 29 (47.5%) episodes. Clinical cure rate by day 14 was 54.1% and predictors of response were days to source control (adjusted odds ratio [aOR]: 0.84; 95% confidence interval [CI]: 0.72-0.98; P = 0.024), days until the initiation of CAZ-AVI therapy (aOR: 0.65; 95% CI: 0.49-0.86; P = 0.003), age (aOR: 1.07; 95% CI: 0.99-1.15; P = 0.066) and CAZ-AVI combination therapy (aOR: 0.02; 95% CI: 0.01-0.38; P = 0.009). Rates of 30-day all-cause mortality and 90-day recurrence were 13.1% and 12.5%, respectively. Emergence of drug resistance to CAZ-AVI was not detected. Treatment-related adverse events occurred in three episodes (4.9%).

Conclusions

CAZ-AVI constitutes a valid alternative for the treatment of infections due to MDR/XDR P. 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

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