In adult patients with ventilated hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (vHABP/VABP) who failed prior therapy, all-cause mortality (ACM) may be lower in those treated with ceftolozane/tazobactam vs meropenem, despite the lack of significant differences in clinical cure rates, according to clinical trial findings published in Critical Care.
The combination antibacterial agent ceftolozane/tazobactam, which comprises an antipseudomonal cephalosporin and a β-lactamase inhibitor, has been approved for the treatment of HABP/VABP in adults based on results of the phase 3 ASPECT-NP trial (ClinicalTrials.gov identifier: NCT02070757), which demonstrated that ceftolozane/tazobactam was noninferior to meropenem for treatment of HABP/VABP in ventilated participants, based on 28-day all-cause mortality (ACM) and clinical response.
In ASPECT-NP, participants were treated with ceftolozane/tazobactam 3 g (ceftolozane 2 g/tazobactam 1 g) every 8 hours or meropenem 1 g every 8 hours. Those individuals who had failed prior antibacterial therapy for their current episode of HABP/VABP at study entry had lower 28-day ACM rates with ceftolozane/tazobactam compared with meropenem. The investigators of the current post hoc analysis sought to examine this result.
In the ASPECT-NP study, 12.8% (93 of 726) of participants (ceftolozane/tazobactam: n=53; meropenem: n=40) were failing prior antibacterial therapy at study entry. The current subgroup analysis examined the 28-day ACM rates, which were higher in patients treated with meropenem vs ceftolozane/tazobactam (45.0% [18 of 40] vs 22.6% [12 of 53], respectively; percentage difference, 22.4%; 95% CI, 3.1-40.1). Multivariable regression analysis found that concomitant vasopressor use and treatment with meropenem were significant factors associated with risk for 28-day ACM. Moreover, following adjustment for vasopressor use, the risk of dying after treatment with ceftolozane/tazobactam was approximately one-fourth the risk of dying after treatment with meropenem.
Rates of clinical response at test of cure were 49.1% (26 of 53) in patients receiving ceftolozane/tazobactam vs 37.5% (15 of 40) in those receiving meropenem (percentage difference, 11.6%; 95% CI, -8.6 to 30.2).
Limitations of the current analyses include their retrospective design, the small sample size of individuals who were failing prior antibacterial therapy, a lack of information with regard to the appropriateness of the initial antibiotic therapy, and the low frequency of certain baseline factors, including bacteremia. Additionally, in the subgroup of ASPECT-NP participants who had failed prior antibacterial therapy, it is possible that mortality rates were affected by nonpneumonia-related deaths. Likewise, it is possible that in the post hoc analyses, unidentified baseline characteristics were imbalanced between treatment groups, thus leading to observed differences in outcomes.
Study authors stressed the importance of their finding that after adjusting for vasopressor use, the risk of dying was roughly 25% less after treatment with ceftolozane/tazobactam vs meropenem. Study authors concluded that “Based on the findings from this retrospective analysis, ceftolozane/tazobactam may provide a survival advantage over meropenem within this population of patients with treatment-refractory vHABP/VABP, despite the lack of significant differences in clinical cure rate between the treatment arms.”
Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Kollef MH, Timsit JF, Martin-Loeches I, et al. Outcomes in participants with failure of initial antibacterial therapy for hospital-acquired/ventilator-associated bacterial pneumonia prior to enrollment in the randomized, controlled phase 3 ASPECT-NP trial of ceftolozane/tazobactam versus meropenem. Crit Care. 2022;26(1):373. doi:10.1186/s13054-022-04192-w