Avycaz noninferior to meropenem for nosocomial pneumonia

Avycaz is noninferior to meropenem for treating nosocomial pneumonia, according to findings from the randomized, phase 3 REPROVE trial.

“Gram-negative pathogens — particularly Pseudomonas aeruginosa and Enterobacteriaceae — predominate in nosocomial pneumonia. These pathogens often harbor several antimicrobial resistance mechanisms — particularly extended-spectrum beta-lactamases, and increasingly, carbapenemases,” Antoni Torres, MD, of Hospital Clinic Barcelona, University of Barcelona, and colleagues wrote. “Very few treatment options are available for infections caused by pathogens with extended-spectrum beta-lactamases, and especially for those with carbapenemases.”

Avycaz (ceftazidime/avibactam, Allergan) is a combination of a cephalosporin and a beta-lactamase inhibitor that was approved by the FDA in 2015 for the treatment of adults with complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis. According to the researchers, the microbiological profile of the treatment “covers most carbapenem-non-susceptible Enterobacteriaceae and multidrug-resistant P. aeruginosa (excluding metallo-beta-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.”

Torres and colleagues conducted a randomized, double-blind, phase 3 noninferiority study of adults with nosocomial pneumonia at 136 facilities in 23 different countries. They randomly assigned patients (n = 879) to receive an IV infusion of either 2,000 mg of ceftazidime and 500 mg of avibactam or 1,000 mg of meropenem every 8 hours for 7 to 14 days. The patients’ regimens were adjusted according to each individual’s renal function. The main outcome was clinical cure at the time of the test-of-cure visit, or 21 to 25 days after randomization.

The safety population included 808 patients, the modified intention-to-treat population included 726 patients and the clinically evaluable population included 527 patients.

The most common gram-negative pathogens at baseline among patients in the microbiologically modified intention-to-treat population (n = 355) were Klebsiella pneumoniae (37%) and Pseudomonas aeruginosa (30%), followed by ceftazidime-nonsusceptible pathogens (28%), Torres and colleagues reported.

According to the researchers, 68.8% of patients assigned to ceftazidime-avibactam in the clinically modified intention-to-treat population were clinically cured, compared with 73% of patients assigned to meropenem (difference, –4.2%; 95% CI, –10.8 to 2.5).

Within the clinically evaluable population, 77.4% of patients assigned to ceftazidime-avibactam were clinically cured, compared with 78.1% of those assigned to meropenem (difference, –0.7%; 95% CI, –7.9 to 6.4).

Torres and colleagues reported that in the safety population, the incidence of adverse events was similar in both groups, occurring in 75% of patients assigned to ceftazidime-avibactam and 74% of those assigned to meropenem. These were mostly moderate or mild, they said, and were not related to the study treatment. Another 19%  of patients in the ceftazidime-avibactam group experienced serious adverse events, compared with 13% of patients in the meropenem group. Four serious adverse events — all of which occurred in the ceftazidime-avibactam group — were related to treatment, Torres and colleagues reported.

In an accompanying editorial, Andre C. Kalil, MD, associate professor of infectious disease at the University of Nebraska Medical Center, and Michael Klompas, MD, associate professor of infectious disease at Harvard Medical School, wrote that “Torres and colleagues’ findings 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 wrote. “Caution is thus warranted for now before recommending ceftazidime-avibactam for routine use as a first-line agent.” – by Andy Polhamus

Disclosures: The authors report no relevant financial disclosures.