Ceftolozane/Tazobactam Noninferior to Meropenem for Nosocomial Pneumonia

According to data presented at the 29th European Congress of Clinical Microbiology & Infectious Diseases, held in Amsterdam April 13-16, 2019, a combination dose of ceftolozane/tazobactam is noninferior to meropenem for treating nosocomial pneumonia.

ASPECT-NP was a randomized, controlled, double-blind, multicenter, noninferiority trial (Clinicaltrials.gov identifier: NCT02070757) comparing ceftolozane/tazobactam with meropenem for ventilated nosocomial pneumonia. Intubated and mechanically ventilated adults diagnosed with ventilator-associated pneumonia ≥48 hours after intubation or ventilated hospital-acquired pneumonia whereby signs or symptom onset was ≤24 prior to or ≤48 hours after intubation in patients hospitalized ≥48 hours or discharged within the prior 7 days were included in the trial.

The intent-to-treat population consisted of 726 patients who were randomly assigned to receive either a 3-g combination of 2 g ceftolozane and 1 g tazobactam (n=362) or 1 g meropenem (n=364); both groups were administered their respective treatments as 1-hour infusions every 8 hours for 8 to 14 days. The baseline characteristics of both treatment arms were comparable and 71.5% or patients had ventilator-associated pneumonia.

In this trial, 28-day mortality was 24% in the combination ceftolozane/tazobactam group and met the prespecified noninferiority criterion while 28-day mortality in the meropenem group was 25.3%, leading to a weighted proportion difference of 1.1% (stratified 95% CI, -5.13% to 7.39%). Within key intent-to-treat subgroups, mortality was comparable, including patients with augmented renal clearance (ceftolozane/tazobactam 14.9%; meropenem 10.9%) and those who failed prior therapy for nosocomial pneumonia (ceftolozane/tazobactam 22.6%; meropenem 45.0%). When considering the secondary end point of clinical response at test-of-cure 7 to 14 days posttherapy, the combination treatment was also noninferior. The test of cure rates in the intent-to-treat population was comparable to those in the clinically evaluable population.

Combination and meropenem treatments also showed comparable numbers of reported adverse events, 85.9% and 83.3%, respectively. Most of the adverse event drug discontinuations were a result of fatal adverse events and not because of decisions made by researchers, which occurred in 24 of 37 cases in the combination group and 28 of 31 cases in the meropenem group where patients discontinued study drug because of adverse events.

The study investigators concluded that ceftolozane/tazobactam in combination is noninferior to meropenem for the treatment of nosocomial pneumonia and that both treatments had comparable adverse event rates. Further, “in the high-risk, critically ill patient population enrolled in this study; treatment-related adverse events leading to study drug discontinuation were rare.” Researchers believe these results, “support use of the ceftolozane/tazobactam 3 g [every] 8 h dose regimen as an efficacious and well-tolerated treatment option for nosocomial pneumonia caused by P aeruginosa, Enterobacteriaceae, and other gram-negative lower respiratory tract pathogens.”

Reference

Kollef M, Nováček M, Kivistik Ü, et al. ASPECT-NP: a randomized, double-blind, phase III trial comparing efficacy and safety of ceftolozane/tazobactam versus meropenem in patients with ventilated nosocomial pneumonia (VNP). Presented at: 29th European Congress of Clinical Microbiology & Infectious Diseases, April 13- 16, 2019, Amsterdam, The Netherlands. Poster 1917.