MedicalResearch.com Interview with:
Amanda Paschke, MD, MSCE
Senior principal scientist
Infectious disease clinical research
Merck Research Laboratories
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: This study sought to evaluate a new beta-lactam/beta-lactamase inhibitor antibacterial combination, imipenem/relebactam (IMI/REL), compared with colistin plus imipenem for the treatment of infections caused by resistant Gram-negative bacteria.
Patients enrolled in the trial had hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP), complicated intra-abdominal infections (cIAI), or complicated urinary tract infections (cUTI) caused by pathogens that were non susceptible to imipenem, a carbapenem antibacterial.
In this study, the primary outcome was a favorable overall response to treatment, which was comparable between the IMI/REL vs colistin + IMI arms. Colistin (often combined with a carbapenem) is currently among the standard of care treatment regimens for MDR infections. A key secondary endpoint of the study was safety. IMI/REL was well tolerated; among all treated patients, drug-related adverse events (AEs) occurred in 16.1% of IMI/REL and 31.3% of colistin + IMI patients with treatment-emergent nephrotoxicity observed in 10% (3/29 patients) and 56% (9/16 patients), respectively (p=0.002). Results of the trial support the use of imipenem-relebactam (IMI/REL) as an efficacious and well-tolerated treatment option for carbapenem-resistant infections.
MedicalResearch.com: What should readers take away from your report?
Response: These findings suggest that IMI/REL could provide a new treatment option for serious, hard-to-treat gram-negative bacterial infections, with a lower likelihood of renal toxicity than a commonly used standard of care treatment regimen.
Conducting clinical trials in very ill patients with multi-drug resistant infections is challenging; a study needs to balance identification of eligible patients with the need to start appropriate antibacterial treatment immediately for optimal clinical outcomes. RESTORE-IMI 1 was a multicenter, randomized, double-blind trial using a single defined comparator. The trial design is unusual in its blinded design and use of a defined comparator, rather than comparing to “best-available therapy”. This allowed for a scientifically robust comparison to an appropriate treatment regimen. The comparable efficacy that we then observed between the treatment arms was expected because we optimized colistin dosing, based on current medical literature and PK/PD modeling, which allowed us to offer an effective treatment option to the critically ill patients enrolled in the trial.
Another important feature of the study is that patients were identified for enrollment based on a testing panel to confirm that pathogens were imipenem non-susceptible as well as colistin- and IMI/REL-susceptible. This testing, incorporated into first-line antibiotic susceptibility testing conducted as part of routine clinical care at the study site, enabled patients with resistant pathogens to be enrolled and given appropriate treatment without further delays, which can lead to poor outcomes in these patients. The testing panel used broth microdilution, currently the gold standard for susceptibility testing.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: The completed Phase 3 trial in resistant infections will be the basis of the initial US filing. IMI/REL was previously granted QIDP/Fast Track status by the FDA given its potential in an area of unmet medical need. Merck is conducting a second pivotal Phase 3 clinical study, RESTORE-IMI 2, comparing treatment with imipenem/cilastatin/relebactam, as a fixed-dose combination, versus piperacillin/tazobactam in patients with hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia.
We look forward to contributing to the knowledge of antibacterial therapy in this very challenging disease state. In addition, future research should continue to track the epidemiology of antimicrobial resistance, as knowledge of local ecology enables clinicians to select the most appropriate treatments for their patients. Since 2002, Merck has conducted the Study for Monitoring Antimicrobial Resistance Trends (SMART), a global surveillance study of antimicrobial resistance in gram-negative bacteria.
MedicalResearch.com: Is there anything else you would like to add?
Response: According to the CDC, more than 23,000 people in the United States die each year from infections caused by resistant organisms, which are difficult to treat due to limited available treatment options and to toxicity associated with some treatments. Patients who have acquired a serious infection caused by multi-drug resistant (MDR) Gram-negative bacteria generally are at greater risk for adverse outcomes, have increased hospital length of stays, and have increased healthcare costs. Effective, safe treatments are needed for patients with these infections.
RESTORE-IMI 1: A multicenter, randomized, double-blind, comparator-controlled trial comparing the efficacy and safety of imipenem/relebactam versus colistin plus imipenem in patients with imipenem-non-susceptible bacterial infections
Presented at the 28th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) in Madrid, April 21-24.
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