The results of a phase 3 trial show that the novel antibiotic combination ceftazidime-avibactam is non-inferior to meropenem in the treatment of hospital-acquired pneumonia caused by gram-negative pathogens and may offer an alternative treatment choice, an international team of researchers report in The Lancet Infectious Diseases.
An accompanying commentary, though, offered some cautions about the new treatment.
The phase 3 REPROVE trial is the first large-scale trial of ceftazidime-avibactam for the treatment of the hospital-acquired pneumonia. The drug, which combines the anti-pseudomonal cephalosporin ceftazidime with the beta-lactamase inhibitor avibactam, was developed to treat serious infections that have become resistant to current antibiotics. It was approved by the US Food and Drug Administration in 2015 for treating complicated intra-abdominal and urinary tract infections.
Hospital-acquired (or nosocomial) pneumonia is one of the most common healthcare-associated infections and is often caused by antibiotic-resistant gram-negative bacteria.
Meropenem, a carbapenem antibiotic, is a standard therapy for patients who have nosocomial pneumonia, but the emergence and spread of mechanisms that confer resistance to carbapenems has created the need for new treatment options.
More than two-thirds cured
For the prospective, randomized, double-blind non-inferiority trial, the researchers enrolled adults with hospital-acquired pneumonia from 136 hospitals in 23 countries and assigned them treatment with 2,000 milligrams (mg) ceftazidime and 500 mg avibactam or 1,000 mg meropenem for 7 to 14 days.
The primary end point was clinical cure at the test-of-cure visit (21 to 25 days after randomization) in two coprimary populations: Clinically modified intention-to-treat and clinically evaluable. Non-inferiority of ceftazidime-avibactam to meropenem was deemed to be shown if the lower limit of the two-sided 95% confidence interval (CI) for the treatment difference was greater than −12.5.
Altogether, 808 patients were randomly assigned for treatment from April 2013 to December 2015, with 726 in the clinically modified intention-to-treat population and 527 in the clinically evaluable (per-protocol) population. The predominant gram-negative baseline pathogens in the microbiologically modified intention-to-treat population were Klebsiella pneumoniae (37%) and Pseudomonas aeruginosa (30%); 100 patients (28%) had one or more ceftazidime non-susceptible pathogens.
Ceftazidime-avibactam was found to be non-inferior to meropenem in both coprimary analysis populations. In the clinically modified intention-to-treat group, 245 of 356 patients (68.8%) treated with ceftazidime-avibactam were clinically cured at the test-of-cure visit, compared with 270 of 370 (73.0%) in the meropenem group (difference −4.2). In the clinically evaluable population, 199 of 257 (77.4%) were in cured in the ceftazidime-avibactam group, compared with 211 of 270 (78.1%) in the meropenem group (difference −0.7).
Adverse events were similar in the two groups, occurring in 302 of 405 (75%) patients in the ceftazidime-avibactam group versus 299 of 403 (74%) in the meropenem group. Serious adverse events, however, occurred in 19% of patients in the ceftazidime-avibactam group versus 13% in the meropenem group, with four thought to be possibly related to treatment with ceftazidime-avibactam.
Outside experts express caution
While the authors conclude that their data support a role for ceftazidime-avibactam as a carbapenem-sparing strategy for hospital-acquired pneumonia, the authors of an accompanying commentary note that the clinical cure rate was numerically higher for meropenem, and that clinical cure estimates also numerically favored meropenem in clinically modified intention-to-treat sub-populations.
In addition, they argue that the safety profile of ceftazidime-avibactam raises the possibility that the drug may confer a greater risk of harm than meropenem. "Caution is thus warranted for now before recommending ceftazidime-avibactam for routine use as a first-line agent," they write.
The study was funded by drugmaker AstraZeneca, which sold the rights to ceftazidime-avibactam to Pfizer in 2016.
Dec 15 Lancet Infect Dis study
Dec 15 Lancet Infect Dis comment