From the Journals

REPROVE: Ceftazidime-avibactam noninferior to meropenem for nosocomial pneumonia



Ceftazidime-avibactam was noninferior to meropenem for nosocomial pneumonia including ventilator-associated pneumonia from gram-negative organisms, results from the REPROVE trial demonstrated.

Nosocomial or hospital-acquired pneumonia is a common hospital-acquired infection associated with increased cost and mortality. Further, nosocomial pneumonia is associated with gram-negative pathogens such as Pseudomonas aeruginosa and Enterobacteriaceae that may carry extended-spectrum beta-lactamases and carbapenemase, thereby limiting the treatment options. However, ceftazidime-avibactam has both antipseudomonal and extended beta-lactamase coverage for multidrug-resistant gram-negative infections, and may provide an alternative to meropenem.

Chest x-ray showing pneumonia copyright stockdevil/Thinkstock

Antoni Torres, MD, of the University of Barcelona and his colleagues sought to compare the safety and efficacy of ceftazidime-avibactam to meropenem in patients with nosocomial and ventilator-associated pneumonia. The REPROVE study was a phase 3, double-blind, noninferiority trial performed at 136 centers in 23 countries. Patients were randomly assigned 1:1 to receive either ceftazidime-avibactam (500-2,000 mg every 8 hours) or meropenem (1,000 mg every 8 hours) with adjustment as needed for renal function.

Participants included in the study were 18-90 years of age with nosocomial pneumonia as evidenced by pneumonia 48 hours or more after admission or within 7 days after discharge from an inpatient facility. Patients with ventilator-associated pneumonia had lung infection within 48 hours of intubation and mechanical ventilation. Sputum culture and gram stains were obtained within 48 hours before randomization, and patients were excluded for evidence of gram-positive–only pathogens or those not expected to respond to meropenem or ceftazidime-avibactam.

The study involved a safety population (808 patients), a clinically modified intention-to-treat population (726), and a clinically evaluable population (527). The intention-to-treat population demonstrated a predominance of Klebsiella pneumoniae (37%), and Pseudomonas aeruginosa (30%); 28% of the intention-to-treat population were identified as not susceptible to ceftazidime.

Overall, the clinically modified intention-to-treat group demonstrated a clinical cure rate of 68.8% (245/356) in the ceftazidime-avibactam and 73.0% (270/370) for the meropenem group (difference, –4.2%; 95% confidence interval, –10.8 to 2.5). The evaluable population demonstrated a clinical cure rate of 77.4% (199/257) in the ceftazidime-avibactam group and 78.1% (211/270) in the meropenem group (–0.7%; 95% CI, –7.9 to 6.4).

The all-cause mortality rate was similar between groups at the test-of-cure date and at day 28. The clinically modified intention-to-treat population demonstrated a mortality of 8.1% vs. 6.8% at the test-of-cure date and 8.4% vs. 7.3% at day 28 for ceftazidime-avibactam and meropenem, respectively.

Adverse events were noted in 75% vs. 74% of patients in the ceftazidime-avibactam groups and meropenem groups, respectively. Most adverse events were rated as mild to moderate and deemed likely unrelated to the treatment.

However, serious adverse events occurred in 19% (n = 75) in the ceftazidime-avibactam group and 13% (n = 54) in the meropenem group. Four serious adverse events were thought to be possibly related to the study drug ceftazidime-avibactam and included diarrhea, acute coronary syndrome, subacute hepatic failure, and abnormal liver function test results. The authors noted the adverse events in the trial were consistent and detected no new safety concerns for ceftazidime-avibactam.

Limitations of the study included an inability to establish the optimal duration of treatment for nosocomial pneumonia treated with meropenem or ceftazidime-avibactam.

“Our results show noninferiority for the treatment of nosocomial pneumonia caused by ceftazidime-nonsusceptible or ceftazidime-susceptible gram-negative aerobic pathogens,” the authors concluded.

The study was initially funded by AstraZeneca until the rights to ceftazidime-avibactam were acquired by Pfizer. Multiple authors reported financial relationships with AstraZeneca including grant funding, employment, and shareholding.

SOURCE: Torres A et al. Lancet Infect Dis. 2017. doi: 10.1016/S1473-3099(17)30747-8.

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