Ceftazidime-Avibactam Efficacious in 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.
- 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
- 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