The new antibiotic combination ceftazidime-avibactam may be a useful alternative to meropenem for treating hospital-acquired pneumonia caused by Gram-negative pathogens, a recent study suggests.

Antoni Torres, MD, University of Barcelona, Spain, and colleagues published the results of their phase 3 trial online December 15, 2017, in The Lancet Infectious Diseases.

“Our results add to the evidence base showing the efficacy and safety of ceftazidime-avibactam in treating infections caused by Gram-negative pathogens, including those considered non-susceptible to ceftazidime, and support a role for ceftazidime-avibactam as a potential alternative to carbapenems in patients with nosocomial pneumonia (including ventilator-associated pneumonia) caused by Gram-negative pathogens,” the authors write.

Hospital-acquired pneumonia, or nosocomial pneumonia, is a common hospital-acquired infection and is often caused by Gram-negative bacteria.

Although the carbapenem antibiotic meropenem is a standard treatment for patients with hospital-acquired pneumonia, the emergence of carbapenem-resistant organisms has become an important public health concern.

With this in mind, Dr. Torres and colleagues conducted the phase 3 REPROVE trial, which was the first clinical trial of ceftazidime-avibactam for treatment of adults with hospital-acquired pneumonia.

This novel drug combines the anti-pseudomonal cephalosporin ceftazidime, with the beta-lactamase inhibitor avibactam.

“This microbiological profile covers most carbapenem-non-susceptible Enterobacteriaceae and multidrug-resistant P. aeruginosa (excluding metallo-β-lactamase producers), and thus, ceftazidime-avibactam is a potential alternative to carbapenems for the treatment of serious Gram-negative infections, including those caused by some carbapenemase-producing bacteria,” the authors write.

REPROVE was a prospective, randomized, double-blind non-inferiority trial that included adults with hospital-acquired pneumonia from 136 hospitals in 23 countries.

The researchers randomized 808 patients to receive either 2,000 mg ceftazidime and 500 mg avibactam or 1,000 mg meropenem for 7 to 14 days. They included 726 patients in the clinically modified intention-to-treat population and 527 in the clinically evaluable population.

They found that ceftazidime-avibactam was non-inferior to meropenem for treating hospital-acquired pneumonia.

In the clinically modified intention-to-treat population, 245 (68.8%) of 356 patients who received ceftazidime-avibactam were clinically cured, compared with 270 (73.0%) of 370 who received meropenem (difference —4·2% [95% confidence interval (CI) –10.8 to 2.5]). In the clinically evaluable population, 199 (77.4%) of 257 patients who received ceftazidime-avibactam were clinically cured, compared with 211 (78.1%) of 270 who received meropenem (difference –0.7% [95% CI –7.9 to 6.4]).

Efficacy of ceftazidime-avibactam was also similar against infections caused by ceftazidime-susceptible and ceftazidime-resistant pathogens, the authors note.

In terms of safety, however, patients who received ceftazidime-avibactam had higher rates of serious adverse events (19% vs 13%), and more adverse events leading to treatment discontinuation (4% vs 2·7%) than patients who received meropenem had.

In addition, 4 patients in the ceftazidime-avibactam group experienced serious adverse events that were thought to be possibly related to the study drug, compared with none in the meropenem group.

Nevertheless, Dr. Torres and colleagues emphasize that no new safety concerns were identified, and the overall pattern of adverse and serious adverse events in the ceftazidime-avibactam group was related to patients’ underlying disease and comorbidities.

“[O]ur data support a role for ceftazidime-avibactam as a carbapenem-sparing strategy for nosocomial pneumonia,” the authors conclude.

However, in an accompanying commentary, Andre C. Kalil, MD, MPH, University of Nebraska Medical Center, Omaha, and Michael Klompas, MD, Harvard Medical School, Boston, Massachusetts, advise caution before recommending this novel treatment combination for routine use as a first-line agent for hospital-acquired pneumonia.

Although Dr. Kalil and Dr. Klompas concur that the study’s findings suggest that ceftazidime-avibactam is a potentially alternative option for treating nosocomial pneumonia, they share concerns about the safety profile of this novel combination drug.

The safety data raise “the possibility that this treatment might confer a greater risk of harm than meropenem—a concern that merits further assessment,” they stress.

Dr. Parry graduated from the University of Liverpool, England in 1997 and is a board-certified veterinary pathologist. After 13 years working in academia, she founded Midwest Veterinary Pathology, LLC where she now works as a private consultant. She is passionate about veterinary education and serves on the Indiana Veterinary Medical Association’s Continuing Education Committee. She regularly writes continuing education articles for veterinary organizations and journals and has also served on the American College of Veterinary Pathologists’ Examination Committee and Education Committee.