Ceftazidime-Avibactam Efficacious in Nosocomial Pneumonia

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Phase 3 REPROVE trial is the first clinical study of ceftazidime-avibactam in adults with nosocomial pneumonia.
Phase 3 REPROVE trial is the first clinical study of ceftazidime-avibactam in adults with nosocomial pneumonia.

According to the results of a recent phase 3 study published in The Lancet Infectious Diseases, the efficacy of ceftazidime-avibactam was comparable to that of meropenem for the treatment of nosocomial pneumonia, but ceftazidime-avibactam may have been associated with more serious treatment-related adverse events.

In this phase 3, randomized controlled trial (REPROVE; ClinicalTrials.gov identifier: NCT01808092), 879 adults with nosocomial pneumonia, defined as pneumonia with an onset at least 48 hours after hospital admission or within 7 days of discharge, were randomly assigned to receive 2000 mg ceftazidime and 500 mg avibactam or 1000 mg meropenem intravenously for 7 to 14 days. Patients with ventilator-associated pneumonia were included. Microbiologic testing was performed, and patients with confirmed Gram-positive bacteria were excluded. Patients with Gram-negative or unconfirmed bacteria were included in the analyses. Clinical cure at the test-of-cure visit was the primary end point of the study. Secondary end points included clinical response, all-cause mortality, and microbiologic responses.1

 

Among the 355 patients with identified baseline pathogens, the predominant Gram-negative bacteria were Klebsiella pneumoniae (37%) and Pseudomonas aeruginosa (30%). A total of 28% of identified pathogens were not susceptible to ceftazidime.1

The clinical cure rate for ceftazidime-avibactam met the predetermined criteria for non-inferiority. In an intention-to-treat analysis of patients who met minimum disease criteria, 68.8% of patients who received ceftazidime-avibactam (n=245/356) and 73.0% of patients who received meropenem (n=270/370) were clinically cured.1

Among patients who received an adequate course of treatment and had an assessable clinical outcome within the assessment window, clinical cure rates were 77.4% and 78.1% in the ceftazidime-avibactam and meropenem groups, respectively. All-cause mortality was not significantly different between the ceftazidime-avibactam and meropenem groups (8.1% vs 6.8%).1

The rates of adverse events were similar between groups, with 75% of patients in the ceftazidime-avibactam group experiencing any adverse event compared with 74% in the meropenem group. Most adverse events were mild or moderate in intensity. Potentially treatment-related serious adverse events occurred only in the ceftazidime-avibactam group and included diarrhea, acute coronary syndrome, subacute hepatic failure, and abnormal liver function test results.1

In an editorial published in The Lancet Infectious Diseases, Andre C Kalil, MD, MPH, of the University of Nebraska Medical Center and Michael Klompas, MD, MPH, of Harvard Medical School explained that the study results suggest that, “ceftazidime-avibactam is a potentially valuable alternative for the treatment of nosocomial pneumonia. Ceftazidime-avibactam's safety profile, however, raises the possibility that this treatment might confer a greater risk of harm than meropenem — a concern that merits further assessment.” They concluded that, “caution is thus warranted for now before recommending ceftazidime-avibactam for routine use as a first-line agent.”2

Disclosure: This study was funded by AstraZeneca. The study sponsor was involved in the study design including data collection, analysis, interpretation, and data checking.

Reference

  1. Torres A, Zhong N, Pachl J, et al. Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial [published online December 15, 2017]. Lancet Infect Dis. doi: 10.1016/S1473-3099(17)30747-8
  2. Kalil AC, Klompas M. Ceftazidime-avibactam versus meropenem for the treatment of nosocomial pneumonia [published online December 15, 2017]. Lancet Infect Dis. doi: 10.1016/S1473-3099(17)30748-X
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