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

Critical Care

Álvaro Réa-Neto¹  Martin Nováček²  Nobuaki Shime³  Ignacio Martin-Loeches⁴  Marin H. Kollef⁵  Jean-François Timsit⁶  Christopher J. Bruno⁷  Elizabeth G. Rhee⁷  Joan R. Butterton⁷  Jennifer A. Huntington⁷  Erin H. Jensen⁷  Brian Yu⁷  Dominik J. Wolf⁷  Richard G. Wunderink⁸  Ülo Kivistik⁹ 

[1] Departamento de Clínica Médica, Universidade Federal do Paraná, Curitiba, Brazil;Department of Anaesthesia and Intensive Care, General Hospital of Kolin, Kolin, Czech Republic;Department of Emergency and Critical Care Medicine, Hiroshima University, Hiroshima, Japan;Department of Intensive Care Medicine, Multidisciplinary Intensive Care Research Organization (MICRO), St James’ Hospital, Dublin, Ireland;Hospital Clinic, Universitat de Barcelona, IDIBAPS, CIBERES, Barcelona, Spain;Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, MO, USA;Intensive Care Medicine Department, Université Paris Diderot, Paris, France;MRL, Merck & Co., Inc., Kenilworth, NJ, USA;Pulmonary and Critical Care Division, Northwestern University Feinberg School of Medicine, Chicago, IL, USA;Pulmonology Centre, North Estonia Medical Centre, Tallinn, Estonia;

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

DOI  :  10.1186/s13054-021-03694-3

来源: Springer

【 摘 要 】

BackgroundCeftolozane/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.MethodsASPECT-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.ResultsOverall, 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.ConclusionsThere 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 registrationclinicaltrials.gov, NCT02070757. Registered 25 February, 2014, clinicaltrials.gov/ct2/show/NCT02070757.

【 授权许可】

CC BY