MedicalResearch.com Interview with:
Elizabeth Rhee, MD
Executive Director, Infectious Disease Clinical Research
Merck Research Laboratories
MedicalResearch.com: What is the background for this study? Would you briefly explain the condition of ventilated nosocomial pneumonias?
Dr. Rhee: Nosocomial pneumonia (NP) is a lung infection that occurs during a hospital stay. NP is often serious, and is associated with high mortality. It is one of the most common health-care associated infections in both the U.S. and Europe, accounting for over 20% of such cases. Gram-negative bacteria, mainly Pseudomonas aeruginosa (PSA) and Enterobacteriaceae, are frequent causes of nosocomial pneumonia. Limited options currently exist for the management of NP caused by Gram-negative pathogens. This is concerning because rates of resistance to Gram-negative bacteria are growing, and they are becoming increasingly difficult to treat.
Forms of nosocomial pneumonia include hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and ventilated HAP. High rates of death (ranging from 20% to more than 50%) are especially associated with ventilated HAP. Pseudomonas aeruginosa, a Gram-negative bacterium, is the most common cause of HAP/VAP in both the U.S. and Europe. Patients with NP are often critically ill, requiring ventilator support and time in intensive care, and it was important to look at this population as we explore new options for the treatment of NP.
Ceftolozane/tazobactam (C/T) is an antipseudomonal cephalosporin/beta-lactamase inhibitor combination with broad in vitro activity against Gram-negative pathogens, including multi-drug resistant (MDR) P. aeruginosa and many extended-spectrum beta-lactamase (ESBL) producers. It is FDA approved for complicated intra-abdominal and urinary tract infections in adults at 1.5g (1g ceftolozane/0.5g tazobactam) q8h. C/T is currently being studied at an investigational new dose of 3g (2g/1g) q8h, for the treatment of ventilated nosocomial pneumonia, in the ASPECT-NP Phase 3 trial.
MedicalResearch.com: What are the main findings?
Dr. Rhee: ASPECT-NP is a randomized, double-blind, multi-center Phase 3 clinical trial evaluating the efficacy and safety of C/T for the treatment of adult patients with ventilated nosocomial (hospital acquired) pneumonia. The results demonstrated non-inferiority of an investigational 3g dose of C/T to meropenem, the active comparator, in the primary and key secondary endpoints.
C/T was non-inferior to meropenem for the primary endpoint of 28-day all-cause mortality in the intent-to-treat (ITT) population (all randomized patients), 24.0% (87/362) and 25.3% (92/364) respectively, for a weighted proportion difference of 1.1% (stratified 95% CI: -5.13%, 7.39%; non-inferiority margin of 10%). In addition, ZERBAXA was non-inferior to meropenem in the key secondary endpoint, clinical cure at Test-of-Cure (7-14 days after the end of therapy) in the ITT population, 54.4% (197/362) and 53.3% (194/364) respectively, for a weighted proportion difference of 1.1% (stratified 95% CI: -6.17%, 8.29%; non-inferiority margin of 12.5%).
Additionally, an analysis of efficacy outcomes by causative pathogens showed that clinical and microbiologic response rates for C/T were comparable to meropenem for Gram-negative respiratory tract pathogens, including Pseudomonas aeruginosa and Enterobacteriaceae. In the microbiologically evaluable (ME) population in patients with a Gram-negative pathogen at baseline clinical cure rates were 75.2% (85/113) and 66.7% (78/117) and microbiologic response rates were 69.9% (79/113) and 62.4% (73/117) for C/T and meropenem respectively. Results were consistent in the microbiologic intention-to-treat (mITT) population with clinical cure rates of 73% (189/259) and 67.9% (163/240) for ZERBAXA and meropenem respectively.
Treatment-emergent adverse events (AE) were reported in 85.9% (310/362) of C/T versus 83.3% (299/364) of meropenem treated patients. The incidence of treatment-related AEs was 10.5% (38/362) in the C/T group and 7.5% (27/364) in the meropenem group. The most commonly reported AEs with C/T were abnormal liver function tests, Clostridium difficile colitis and diarrhea. Comparable rates of AEs were reported for C/T and meropenem in critically ill patients (those with high APACHE scores), and approximately 1% of patients had treatment-related AEs leading to discontinuation of therapy.
MedicalResearch.com: What should readers take away from your report?
Dr. Rhee: ASPECT-NP showed that the investigational C/T 3 g dose regimen can be efficacious and well-tolerated in critically ill patients with ventilated, Gram-negative nosocomial pneumonia. This was the first global Phase 3 trial ever conducted to successfully evaluate the safety and efficacy of an antibiotic among ventilated HAP and VAP patients, which are challenging populations to study. Because 100% of the patients in the trial were on mechanical ventilation, they represented a critically ill patient population that will likely benefit from C/T 3 g treatment. New treatment options for nosocomial pneumonia are needed due to rising antibacterial resistance rates among gram-negative bacteria, particularly Pseudomonas aeruginosa.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Dr. Rhee: ASPECT-NP is a major global trial that spanned 5 continents and has been ongoing for some time. The eligibility criteria that enabled enrolment of all ventilated patients and quantitative respiratory tract cultures has provided a large data set in critically ill patients. Now that our initial analyses around the primary endpoints and safety in the primary population are completed, we’ll be focusing our attention to additional analyses, particularly some of the interesting patient sub-populations and pathogens in the trial.
MedicalResearch.com: Is there anything else you would like to add? Any disclosures?
Dr. Rhee: Pseudomonas aeruginosa is one of a handful of bacterial strains that accounts for the majority of HAP/VAP infections – which can be serious and, in some cases, life-threatening. It is important to continue researching new treatments and optimal doses to give critically ill patients the best chance of survival.
Dr. Elizabeth Rhee is an employee of Merck Research Laboratories.
ASPECT-NP: a randomized, double-blind, phase III trial comparing efficacy and safety of ceftolozane/tazobactam versus meropenem in patients with ventilated nosocomial pneumonia (VNP)
This study was presented at the 2019 European Congress of Clinical Microbiology & Infectious Diseases (ECCMID 2019) April 13-16, 2019, Amsterdam, The Netherlands.
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