Ceftazidime-avibactam noninferior to meropenem in nosocomial pneumonia
The combination of ceftazidime and avibactam proved noninferior to meropenem in adults with nosocomial pneumonia, positioning it as a potential treatment option for this condition, results from the phase III REPROVE* trial show. Nonetheless, the combination was associated with a higher number of safety events compared with meropenem.
“Efficacy of ceftazidime-avibactam was similar against infections caused by ceftazidime-susceptible and ceftazidime-resistant pathogens [with a] safety profile … consistent with that previously noted with ceftazidime alone and with the known profile of ceftazidime-avibactam in patients with complicated intra-abdominal or urinary tract infections,” said the researchers.
“These results 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,” they said.
Researchers of this multinational (136 centres in 23 countries), double-blind, noninferiority trial randomized 879 adults with nosocomial pneumonia to 2-hour intravenous infusions of ceftazidime (2,000 mg) plus avibactam (500 mg; mean age 62.1 years, 75 percent male, 56 percent Asian) or 30-minute intravenous infusions of meropenem (1,000 mg; mean age 61.9 years, 74 percent male, 54 percent Asian) every 8 hours for 7–14 days.
The most common Gram-negative pathogens detected at respiratory site or in blood were Klebsiella pneumoniae and Pseudomonas aeruginosa (37 and 30 percent, respectively), with 28 percent being nonsusceptible to ceftazidime.
Ceftazidime-avibactam proved noninferior to meropenem in terms of clinical cure rate (CCR) at 21–25 days post-randomization, be it among the 726 patients included in the clinically modified intention-to-treat population (ITT; 68.8 percent vs 73.0 percent, difference -4.2 percent, 95 percent confidence interval [CI], -10.76 to 2.46; p=0.0066) or the 527 patients included in the clinically evaluable population (77.4 percent vs 78.1 percent, difference -0.7 percent, 95 percent CI, -7.86 to 6.39; p=0.0007). [Lancet Infect Dis 2017;doi:10.1016/S1473-3099(17)30747-8]
After accounting for the receipt of concomitant antibiotics (7 and 9 percent of patients on ceftazidime-avibactam and meropenem, respectively, in the ITT population), CCR was 62.1 and 64.1 percent, respectively.
There was no difference in CCR between patients with ventilator-associated and non-ventilator-associated pneumonia. All-cause mortality was also similar between patients on ceftazidime-avibactam (9 percent) and meropenem (7 percent).
The proportion of patients with adverse events (AEs) was also comparable between the ceftazidime-avibactam and meropenem groups (75 percent vs 74 percent), with 16 and 13 percent, respectively, considered treatment-related.
Serious AEs were reported in 19 and 13 percent of patients on ceftazidime-avibactam and meropenem, respectively. Four patients on ceftazidime-avibactam had serious AEs that were considered treatment-related, with two events leading to treatment discontinuation.
According to the researchers, the optimal treatment duration of either drug could not be determined from this study, while the duration of treatment as utilized in this study may not be reflective of clinical practice, they said.
“The severity of nosocomial pneumonia and the high likelihood that antibiotic-resistant pathogens are implicated make treatment of this infection a formidable clinical challenge and often result in unintended overuse of antibiotics,” said Professors Andre Kalil and Michael Klompas from the University of Nebraska Medical Center, Omaha, Nebraska, and Harvard Medical School, Boston, Massachusetts, US, respectively, in a commentary. [Lancet Infect Dis 2017;doi:10.1016/S1473-3099(17)30748-X]
“It stands to reason that [with the rising rates of antibiotic resistance], fewer and fewer antibiotics will be available to treat patients with nosocomial pneumonia.”
“[While the] findings suggest that ceftazidime-avibactam is a potentially valuable alternative for the treatment of nosocomial pneumonia, [its] safety profile … raises the possibility that this treatment might confer a greater risk of harm than meropenem—a concern that merits further assessment,” they said, advising exercising caution before recommending the routine use of ceftazidime-avibactam in the first-line setting.