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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

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Summary

Background

Carbapenems are frequently the last line of defence in serious infections due to multidrug-resistant Gram-negative bacteria, but their use is threatened by the growing prevalence of carbapenemase-producing pathogens. Ceftazidime-avibactam is a potential new agent for use in such infections. We aimed to assess the efficacy, safety, and tolerability of ceftazidime-avibactam compared with best available therapy in patients with complicated urinary tract infection or complicated intra-abdominal infection due to ceftazidime-resistant Gram-negative pathogens.

Methods

REPRISE was a pathogen-directed, international, randomised, open-label, phase 3 trial that recruited patients from hospitals across 16 countries worldwide. Eligible patients were aged 18–90 years with complicated urinary tract infection or complicated intra-abdominal infection caused by ceftazidime-resistant Enterobacteriaceae or Pseudomonas aeruginosa. Patients were randomised (1:1) to 5–21 days of treatment with either ceftazidime-avibactam (a combination of 2000 mg ceftazidime plus 500 mg avibactam, administered via a 2-h intravenous infusion every 8 h) or best available therapy. The primary endpoint was clinical response at the test-of-cure visit, 7–10 days after last infusion of study therapy, analysed in all patients who had at least one ceftazidime-resistant Gram-negative pathogen, as confirmed by the central laboratory, and who received at least one dose of study drug. Safety endpoints were assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01644643.

Findings

Between Jan 7, 2013, and Aug 29, 2014, 333 patients were randomly assigned, 165 to ceftazidime-avibactam and 168 to best available therapy. Of these, 154 assigned to ceftazidime-avibactam (144 with complicated urinary tract infection and ten with complicated intra-abdominal infection) and 148 assigned to best available therapy (137 with complicated urinary tract infection and 11 with complicated intra-abdominal infection) were analysed for the primary outcome. 163 (97%) of 168 patients in the best available therapy group received a carbapenem, 161 (96%) as monotherapy. The overall proportions of patients with a clinical cure at the test-of-cure visit were similar with ceftazidime-avibactam (140 [91%; 95% CI 85·6–94·7] of 154 patients) and best available therapy (135 [91%; 85·9–95·0] of 148 patients). 51 (31%) of 164 patients in the ceftazidime-avibactam group and 66 (39%) of 168 in the best available therapy group had an adverse event, most of which were mild or moderate in intensity. Gastrointestinal disorders were the most frequently reported treatment-emergent adverse events with both ceftazidime-avibactam (21 [13%] of 164 patients) and best available therapy (30 [18%] of 168 patients). No new safety concerns were identified for ceftazidime-avibactam.

Interpretation

These results provide evidence of the efficacy of ceftazidime-avibactam as a potential alternative to carbapenems in patients with ceftazidime-resistant Enterobacteriaceae and P aeruginosa.

Funding

AstraZeneca.

Introduction

The prevalence of multidrug-resistant Gram-negative pathogens, including extended-spectrum β-lactamase (ESBL)-producing and carbapenemase-producing Enterobacteriaceae and Pseudomonas aeruginosa, is increasing worldwide.1, 2, 3 Contributing factors are the extensive use of antibiotics, both in human beings and animals, poor infection control, and the greatly increased global mobility of people, allowing the rapid spread of multidrug-resistant pathogens.1, 4, 5 As the prevalence of ESBL-producing pathogens has increased, so has the use of carbapenem antibiotics—frequently the last line of defence against multidrug-resistant Gram-negative bacteria, but now threatened by the growing prevalence of carbapenemase-producing pathogens.6 Therefore, alternative treatment options and carbapenem-sparing regimens for patients with serious infections caused by multidrug-resistant Gram-negative pathogens are urgently needed.

Research in context

Evidence before this study

We searched PubMed with the search terms “ceftazidime-avibactam” AND “randomised”, and the European Congress of Clinical Microbiology and Infectious Diseases 2015 abstracts with the search term “ceftazidime-avibactam”, for articles published on or before July 16, 2015. No other restrictions were applied to the search, but we excluded preclinical and surveillance studies and reviews from the results. PubMed searches using the above terms identified three reports of phase 1 trials assessing the safety, tolerability, and pharmacokinetics of ceftazidime-avibactam, and two phase 2 trials of ceftazidime-avibactam in patients with complicated urinary tract infection and complicated intra-abdominal infection caused by Gram-negative pathogens. The phase 2 trial in patients with complicated urinary tract infection demonstrated clinical response rates with ceftazidime-avibactam similar to those for imipenem-cilastatin. In patients with complicated intra-abdominal infection, ceftazidime-avibactam (in combination with metronidazole) achieved a response that was similar to that achieved with meropenem. Both studies included some patients with ceftazidime-resistant infections, but this was not an inclusion criterion in either trial. The ECCMID 2015 search identified the results of some phase 3 studies of ceftazidime-avibactam: the REPRISE study reported here, and a single report of two identical phase 3 studies in complicated intra-abdominal infection (RECLAIM 1 and 2), which included some patients with ceftazidime-resistant Gram-negative infections. Ceftazidime-avibactam plus metronidazole was shown to be non-inferior to meropenem. Other ongoing or recently completed (but not yet published) phase 3 trials of ceftazidime-avibactam, including patients with complicated urinary tract infection, complicated intra-abdominal infection, or nosocomial pneumonia, also included all-comers rather than specifically recruiting patients with ceftazidime-resistant infections.

Added value of this study

The REPRISE study was specifically designed to assess the efficacy of ceftazidime-avibactam and best available therapy in patients with ceftazidime-resistant Gram-negative complicated urinary tract infection or complicated intra-abdominal infection. The proportion of patients who were clinically cured were similar in both treatment groups, with a numerically higher proportion of patients achieving a favourable microbiological response in the ceftazidime-avibactam group. The observed safety and tolerability ceftazidime-avibactam was similar to the recognised profile of ceftazidime alone.

Implications of all the available evidence

These results support the further development of ceftazidime-avibactam as a potential alternative to carbapenems in patients with resistant Gram-negative infections.

Ceftazidime-avibactam could be an important new option for such cases, consisting of ceftazidime, a widely used expanded-spectrum anti-pseudomonal cephalosporin, and avibactam, a novel non-β-lactam β-lactamase inhibitor.7, 8 Avibactam has a broader spectrum of activity than available β-lactamase inhibitors, and has been shown in vitro to restore the activity of ceftazidime against most multidrug-resistant Enterobacteriaceae and P aeruginosa by inhibiting a wide variety of β-lactamases, including class A (such as ESBLs, Klebsiella pneumoniae carbapenemases), class C (AmpC), and some class D enzymes (eg, OXA 48).9

Two phase 3 studies of ceftazidime-avibactam in patients with complicated intra-abdominal infection (RECLAIM 1 and 2 [NCT01499290 and NCT01500239]) have recently been reported,10 and other phase 3 trials are ongoing, including patients with complicated urinary tract infections (RECAPTURE 1 and 2 [NCT01595438 and NCT01599806]), complicated intra-abdominal infection (RECLAIM 3 [NCT01726023]), and nosocomial pneumonia (REPROVE [NCT01808092]). However, on the basis of data from phase 2 trials,7, 8 the US Food and Drug Administration recently approved ceftazidime-avibactam for use in the treatment of adults with complicated intra-abdominal infection, in combination with metronidazole, and complicated urinary tract infection, including kidney infections (pyelonephritis), who have limited or no alternative treatment options.11

The phase 3 studies listed above enrolled patients with or without drug-resistant pathogens. Thus, although they can provide valuable information about safety, tolerability, and efficacy, they might not provide extensive information about efficacy against resistant pathogens. Given the need for new therapies to treat patients with drug-resistant infections, pathogen-directed studies have been recommended.12 The international, randomised, phase 3 study (REPRISE; NCT01644643) reported here is the first multidrug-resistant Gram-negative pathogen-directed study for ceftazidime-avibactam, focusing specifically on the efficacy, safety, and tolerability in patients with complicated urinary tract infection or complicated intra-abdominal infection due to ceftazidime-resistant Gram-negative pathogens.

Section snippets

Study design and participants

REPRISE was an international, randomised, open-label, phase 3 trial that recruited patients from hospitals worldwide. Male and female patients aged 18–90 years with complicated urinary tract infection or complicated intra-abdominal infection caused by ceftazidime-resistant Gram-negative pathogens were eligible for inclusion in the trial. Specified diagnoses for patients with complicated urinary tract infection were either confirmed acute pyelonephritis or complicated lower urinary tract

Results

Between Jan 7, 2013, and Aug 29, 2014, 333 patients were enrolled and randomised at 53 hospitals in 16 countries worldwide: 165 to ceftazidime-avibactam (153 with complicated urinary tract infection and 12 with complicated intra-abdominal infection), and 168 to best available therapy (153 with complicated urinary tract infection and 15 with complicated intra-abdominal infection; figure 1). Although we had planned to include 400 patients, recruitment was ended early because the funder considered

Discussion

The REPRISE study is the first pathogen-directed clinical trial for ceftazidime-avibactam examining its efficacy against ceftazidime-resistant Gram-negative pathogens. Therefore, this study provides valuable information for clinicians and represents an important addition to the ceftazidime-avibactam trial programme, providing supporting data for the pivotal phase 3 trials in complicated intra-abdominal infection and complicated urinary tract infection.

The study showed that ceftazidime-avibactam

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