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. 2023 Feb 11;13(1):8.
doi: 10.1186/s13613-022-01084-8.

Outcomes in participants with ventilated nosocomial pneumonia and organ failure treated with ceftolozane/tazobactam versus meropenem: a subset analysis of the phase 3, randomized, controlled ASPECT-NP trial

Ignacio Martin-Loeches  1   2 , Andrew F Shorr  3 , Richard G Wunderink  4 , Marin H Kollef  5 , Jean-François Timsit  6 , Brian Yu  7 , Jennifer A Huntington  7 , Erin Jensen  7 , Christopher J Bruno  8
Affiliations

Outcomes in participants with ventilated nosocomial pneumonia and organ failure treated with ceftolozane/tazobactam versus meropenem: a subset analysis of the phase 3, randomized, controlled ASPECT-NP trial

Ignacio Martin-Loeches et al. Ann Intensive Care. .

Abstract

Background: The pivotal ASPECT-NP trial showed ceftolozane/tazobactam was non-inferior to meropenem for the treatment of ventilated hospital-acquired/ventilator-associated bacterial pneumonia (vHABP/VABP). Here, we evaluated treatment outcomes by degree of respiratory or cardiovascular dysfunction.

Methods: This was a subset analysis of data from ASPECT-NP, a randomized, double-blind, non-inferiority trial (ClinicalTrials.gov NCT02070757). Adults with vHABP/VABP were randomized 1:1 to 3 g ceftolozane/tazobactam or 1 g meropenem every 8 h for 8-14 days. Outcomes in participants with a baseline respiratory component of the Sequential Organ Failure Assessment (SOFA) score (R-SOFA) ≥ 2 (indicative of severe respiratory failure), cardiovascular component of the SOFA score (CV-SOFA) ≥ 2 (indicative of shock), or R-SOFA ≥ 2 plus CV-SOFA ≥ 2 were compared by treatment arm. The efficacy endpoint of primary interest was 28-day all-cause mortality. Clinical response, time to death, and microbiologic response were also evaluated.

Results: There were 726 participants in the intention-to-treat population; 633 with R-SOFA ≥ 2 (312 ceftolozane/tazobactam, 321 meropenem), 183 with CV-SOFA ≥ 2 (84 ceftolozane/tazobactam, 99 meropenem), and 160 with R-SOFA ≥ 2 plus CV-SOFA ≥ 2 (69 ceftolozane/tazobactam, 91 meropenem). Baseline characteristics, including causative pathogens, were generally similar in participants with R-SOFA ≥ 2 or CV-SOFA ≥ 2 across treatment arms. The 28-day all-cause mortality rate was 23.7% and 24.0% [difference: 0.3%, 95% confidence interval (CI) - 6.4, 6.9] for R-SOFA ≥ 2, 33.3% and 30.3% (difference: - 3.0%, 95% CI - 16.4, 10.3) for CV-SOFA ≥ 2, and 34.8% and 30.8% (difference: - 4.0%, 95% CI - 18.6, 10.3), respectively, for R-SOFA ≥ 2 plus CV-SOFA ≥ 2. Clinical cure rates were as follows: 55.8% and 54.2% (difference: 1.6%, 95% CI - 6.2, 9.3) for R-SOFA ≥ 2, 53.6% and 55.6% (difference: - 2.0%, 95% CI - 16.1, 12.2) for CV-SOFA ≥ 2, and 53.6% and 56.0% (difference: - 2.4%, 95% CI - 17.6, 12.8), respectively, for R-SOFA ≥ 2 plus CV-SOFA ≥ 2. Time to death was comparable in all SOFA groups across both treatment arms. A higher rate of microbiologic eradication/presumed eradication was observed for CV-SOFA ≥ 2 and R-SOFA ≥ 2 plus CV-SOFA ≥ 2 with ceftolozane/tazobactam compared to meropenem.

Conclusions: The presence of severe respiratory failure or shock did not affect the relative efficacy of ceftolozane/tazobactam versus meropenem; either agent may be used to treat critically ill patients with vHABP/VABP.

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

Keywords: ASPECT-NP; Gram-negative; Nosocomial; Pneumonia; Pseudomonas; SOFA; Shock.

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Conflict of interest statement

IM-L has received consulting fees and honoraria from MSD and Pfizer. AFS has received medical writing support, consulting fees, and honoraria from MSD; consulting fees from Pfizer and Shionogi; honoraria from Pfizer, Shionogi, and La Jolla. RGW is a consultant to, has received medical writing support from, and has participated in advisory committees for MSD; has received an investigator-initiated grant from Calcimedica; has participated in advisory committees for Shionogi and La Jolla; has received honoraria from BioMerieux for industry workshops at ATS, APSR, and SCCM; and has participated in the Clinical Evaluation Committee for Pfizer. MHK is supported by Barnes-Jewish Hospital Foundation and has received consulting fees and honoraria from MSD, Pfizer, and Shionogi. J-FT participated on an advisory board for MSD, Pfizer, and Shionogi on treatment of HAP/VAP; has received research grants, consulting fees, honoraria, and travel support from MSD; was past chairman of the ESCMID Study Group for Infections in Critically Ill Patients—ESGCIP; and is the principal investigator of BICCS (national research program (RCT BICCS PHRC 18-0316) on the benefit of Continuous infusion and combination therapy on the treatment of severe Gram-negative infections, including pneumonia. JAH, EJ, and CJB, and BY are current or former employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, who may own stock and/or hold stock options in Merck & Co., Inc., Rahway, NJ USA.

Figures

Fig. 1
Fig. 1
ASPECT-NP study design [20]. h hour, ITT intent-to-treat, LRT lower respiratory tract, q8h every 8 h, TOC test-of-cure, SOFA Sequential Organ Failure Assessment, VABP ventilator-associated bacterial pneumonia, vHABP ventilated hospital-acquired bacterial pneumonia
Fig. 2
Fig. 2
Participant and analysis population flow chart. CE clinically evaluable, CV-SOFA cardiovascular SOFA component score, ITT intention-to-treat, LRT lower respiratory tract, mITT microbiologic intention-to-treat, R-SOFA respiratory SOFA component score, SOFA Sequential Organ Failure Assessment
Fig. 3
Fig. 3
Mortality (upper panel A) and cure at TOC (bottom panel B) by SOFA component score (ITT population). Treatment differences were calculated as unstratified Newcombe 95% CIs; positive differences are in favor of ceftolozane/tazobactam, negative differences are in favor of meropenem. Participants whose 28-day mortality outcome was missing or unknown were analyzed as deceased. Participants with clinical failure at the EOT visit were counted as failures at the TOC visit. CI confidence interval, CV-SOFA cardiovascular, EOT end-of-therapy, R-SOFA respiratory SOFA component score, SOFA Sequential Organ Failure Assessment, TOC test-of-cure
Fig. 4
Fig. 4
Time to death by SOFA component score (ITT population). R-SOFA ≥ 2 (upper panel A), CV-SOFA ≥ 2 (middle panel B), R-SOFA ≥ 2 plus CV-SOFA ≥ 2 (bottom panel C). CV-SOFA cardiovascular SOFA component score, R-SOFA respiratory SOFA component score, SOFA Sequential Organ Failure Assessment
Fig. 5
Fig. 5
Microbiologic eradication/presumed eradication at TOC by SOFA component score (mITT population). Observed microbiologic eradication is represented by the lighter colored bars; presumed eradication is represented by the darker colored bars. Treatment differences were calculated as unstratified Newcombe 95% CIs; positive differences are in favor of ceftolozane/tazobactam; negative differences are in favor of meropenem. Participants with missing culture and clinical responses that were failure, indeterminate, or missing were counted as presumed failures. CI confidence interval, CV-SOFA cardiovascular SOFA component score, R-SOFA respiratory SOFA component score, SOFA Sequential Organ Failure Assessment, TOC test-of-cure
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