Ceftolozane/tazobactam versus meropenem in patients with ventilated hospital-acquired bacterial pneumonia: subset analysis of the ASPECT-NP randomized, controlled phase 3 trial

Jean-François Timsit, Jennifer A Huntington, Richard G Wunderink, Nobuaki Shime, Marin H Kollef, Ülo Kivistik, Martin Nováček, Álvaro Réa-Neto, Ignacio Martin-Loeches, Brian Yu, Erin H Jensen, Joan R Butterton, Dominik J Wolf, Elizabeth G Rhee, Christopher J Bruno, Jean-François Timsit, Jennifer A Huntington, Richard G Wunderink, Nobuaki Shime, Marin H Kollef, Ülo Kivistik, Martin Nováček, Álvaro Réa-Neto, Ignacio Martin-Loeches, Brian Yu, Erin H Jensen, Joan R Butterton, Dominik J Wolf, Elizabeth G Rhee, Christopher J Bruno

Abstract

Background: Ceftolozane/tazobactam is approved for treatment of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) at double the dose approved for other infection sites. Among nosocomial pneumonia subtypes, ventilated HABP (vHABP) is associated with the lowest survival. In the ASPECT-NP randomized, controlled trial, participants with vHABP treated with ceftolozane/tazobactam had lower 28-day all-cause mortality (ACM) than those receiving meropenem. We conducted a series of post hoc analyses to explore the clinical significance of this finding.

Methods: ASPECT-NP was a multinational, phase 3, noninferiority trial comparing ceftolozane/tazobactam with meropenem for treating vHABP and VABP; study design, efficacy, and safety results have been reported previously. The primary endpoint was 28-day ACM. The key secondary endpoint was clinical response at test-of-cure. Participants with vHABP were a prospectively defined subgroup, but subgroup analyses were not powered for noninferiority testing. We compared baseline and treatment factors, efficacy, and safety between ceftolozane/tazobactam and meropenem in participants with vHABP. We also conducted a retrospective multivariable logistic regression analysis in this subgroup to determine the impact of treatment arm on mortality when adjusted for significant prognostic factors.

Results: Overall, 99 participants in the ceftolozane/tazobactam and 108 in the meropenem arm had vHABP. 28-day ACM was 24.2% and 37.0%, respectively, in the intention-to-treat population (95% confidence interval [CI] for difference: 0.2, 24.8) and 18.2% and 36.6%, respectively, in the microbiologic intention-to-treat population (95% CI 2.5, 32.5). Clinical cure rates in the intention-to-treat population were 50.5% and 44.4%, respectively (95% CI - 7.4, 19.3). Baseline clinical, baseline microbiologic, and treatment factors were comparable between treatment arms. Multivariable regression identified concomitant vasopressor use and baseline bacteremia as significantly impacting ACM in ASPECT-NP; adjusting for these two factors, the odds of dying by day 28 were 2.3-fold greater when participants received meropenem instead of ceftolozane/tazobactam.

Conclusions: There were no underlying differences between treatment arms expected to have biased the observed survival advantage with ceftolozane/tazobactam in the vHABP subgroup. After adjusting for clinically relevant factors found to impact ACM significantly in this trial, the mortality risk in participants with vHABP was over twice as high when treated with meropenem compared with ceftolozane/tazobactam.

Trial registration: clinicaltrials.gov, NCT02070757. Registered 25 February, 2014, clinicaltrials.gov/ct2/show/NCT02070757.

Keywords: All-cause mortality; Clinical response; ESBL; HABP/VABP; Mechanical ventilation; Multivariable analysis; Nosocomial pneumonia; Pseudomonas aeruginosa.

Conflict of interest statement

J-FT has received institutional research support from MSD. RGW has received institutional research support and consultancy fees from Merck & Co., Inc. NS has received lecture fees and consultancy fees from Pfizer, MSD, and Sumitomo Dainippon Pharma Co. MHK is a consultant for Merck & Co., Inc. and Shionogi and his efforts are supported by the Barnes-Jewish Hospital Foundation. ÜK has received institutional research support from MSD. MN has received institutional research support from MSD. ÁR-N has received institutional research support from MSD. IM-L has received institutional research support from MSD. JAH, BY, CJB, EHJ, JRB, DJW, and EGR are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and own stock and/or hold stock options in Merck & Co., Inc., Kenilworth, NJ, USA.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Patient and analysis population flow chart. CE, clinically evaluable. C/T, ceftolozane/tazobactam. ITT, intent-to-treat. ME, microbiologically evaluable. mITT, microbiologic intent-to-treat. N, number of participants in specific analysis population. VABP, ventilator-associated bacterial pneumonia. vHABP, ventilated hospital-acquired pneumonia
Fig. 2
Fig. 2
Time to death in participants with vHABP (ITT population). C/T, ceftolozane/tazobactam. ITT, intention to treat population (all randomized patients). vHABP, ventilated hospital-acquired bacterial pneumonia

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