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

Abstract

Background Ceftolozane/tazobactam, a combination antibacterial agent comprising an anti-pseudomonal cephalosporin and β-lactamase inhibitor, is approved for the treatment of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) in adults. Participants in the ASPECT-NP trial received ceftolozane/tazobactam (3 g [2 g ceftolozane/1 g tazobactam] every 8 h) or meropenem (1 g every 8 h). Participants failing prior antibacterial therapy for the current HABP/VABP episode at study entry had lower 28-day all-cause mortality (ACM) rates with ceftolozane/tazobactam versus meropenem treatment. Here, we report a post hoc analysis examining this result. Methods The phase 3, randomized, controlled, double-blind, multicenter, noninferiority trial compared ceftolozane/tazobactam versus meropenem for treatment of adults with ventilated HABP/VABP; eligibility included those failing prior antibacterial therapy for the current HABP/VABP episode at study entry. The primary and key secondary endpoints were 28-day ACM and clinical response at test of cure (TOC), respectively. Participants who were failing prior therapy were a prospectively defined subgroup; however, subgroup analyses were not designed for noninferiority testing. The 95% CIs for treatment differences were calculated as unstratified Newcombe CIs. Post hoc analyses were performed using multivariable logistic regression analysis to determine the impact of baseline characteristics and treatment on clinical outcomes in the subgroup who were failing prior antibacterial therapy. Results In the ASPECT-NP trial, 12.8% of participants (93/726; ceftolozane/tazobactam, n = 53; meropenem, n = 40) were failing prior antibacterial therapy at study entry. In this subgroup, 28-day ACM was higher in participants who received meropenem versus ceftolozane/tazobactam (18/40 [45.0%] vs 12/53 [22.6%]; percentage difference [95% CI]: 22.4% [3.1 to 40.1]). Rates of clinical response at TOC were 26/53 [49.1%] for ceftolozane/tazobactam versus 15/40 [37.5%] for meropenem (percentage difference [95% CI]: 11.6% [− 8.6 to 30.2]). Multivariable regression analysis determined concomitant vasopressor use and treatment with meropenem were significant factors associated with risk of 28-day ACM. Adjusting for vasopressor use, the risk of dying after treatment with ceftolozane/tazobactam was approximately one-fourth the risk of dying after treatment with meropenem. Conclusions This post hoc analysis further supports the previously demonstrated lower ACM rate for ceftolozane/tazobactam versus meropenem among participants who were failing prior therapy, despite the lack of significant differences in clinical cure rates. ClinicalTrials.gov registrationNCT02070757. Registered February 25, 2014, clinicaltrials.gov/ct2/show/NCT02070757.

Resistance in Pseudomonas aeruginosa: A Narrative Review of Antibiogram Interpretation and Emerging Treatments

“…In the subgroup of vHAP, the ASPECT-NP trial also demonstrated lower mortality in the arm of patients treated with TOL-TZB compared with the arm of patients treated with MEM [172]. This result was further evaluated with multivariable analysis by Kollef et al, confirming the protective effect of TOL-TZB in this special subgroup population [173], although additional studies are needed for confirmation of these findings.…”

Global evaluation of the antibacterial activity of Ceftolozane/Tazobactam against ESBLs-producing Escherichia coli and Klebsiella pneumoniae: a systematic review and meta-analysis

“…2,30–32,46–48 Based on several randomized clinical trials conducted in recent years, Ceftolozane/Tazobactam has been found to be comparable to meropenem as an effective and safe treatment option for complicated and life-threatening infections caused by ESBL-producing Enterobacterales. 49–55 Ceftolozane/Tazobactam may confer a survival advantage over meropenem in invasive ESBLs-related infections, leading to lower mortality. 52,54 However, this effect needs confirmation through adequately powered prospective studies.…”

“…49–55 Ceftolozane/Tazobactam may confer a survival advantage over meropenem in invasive ESBLs-related infections, leading to lower mortality. 52,54 However, this effect needs confirmation through adequately powered prospective studies.…”

Perspectives on the use of ceftolozane/tazobactam: a review of clinical trial data and real-world evidence

“…Participants whose prior antibacterial therapy had failed for the current episode of pneumonia at study entry had lower 28-day all-cause mortality rates with ceftolozane/tazobactam versus meropenem treatment in the ASPECT-NP trial (22.6% [n = 12/53] vs 45.0% [n = 18/40], respectively) [ 61 ]. To examine this outcome in more detail, a post hoc analysis examining this important pre-defined patient population was conducted [ 61 ].…”

“…Participants whose prior antibacterial therapy had failed for the current episode of pneumonia at study entry had lower 28-day all-cause mortality rates with ceftolozane/tazobactam versus meropenem treatment in the ASPECT-NP trial (22.6% [n = 12/53] vs 45.0% [n = 18/40], respectively) [ 61 ]. To examine this outcome in more detail, a post hoc analysis examining this important pre-defined patient population was conducted [ 61 ]. Multivariable regression analysis determined that, after controlling for other factors, the risk of dying after treatment with ceftolozane/tazobactam was approximately one-quarter of that following treatment with meropenem (28-day all-cause mortality; odds ratio [OR] 0.23; 95% CI, 0.08–0.68), further supporting the use of ceftolozane/tazobactam in this patient population [ 61 ].…”