FDA Okays Merck ‘s Combination Antibiotic for Hospital-Acquired Bacterial Pneumonia
By Ruchi Jhonsa, Ph.D.
Hospital-acquired or ventilator acquired bacterial pneumonia (HABP/VABP) is a commonly encountered infection when a patient is admitted into the hospital. Despite advances in the prevention and treatment of HABP/VABP, it is one of the leading causes of death among patients. Antibiotic administration is the most common treatment. However, they stop working overtime as bacteria develop drug resistance through various mechanisms. It can either flush out the antibiotic through efflux pumps, or kill it by beta-lactamase enzymes, or modify the properties of antibiotics altogether.
At the 30th European Congress of Clinical Microbiology and Infectious Diseases, Merck presented the results of its combination antibiotic, Recarbrio that can kill the bacteria causing HABP/VABP and simultaneously prevent it from developing antibiotic resistance. On June 5, the FDA approved the supplemental new drug application for Recarbrio for the treatment of HAP caused by a list of gram-negative microorganisms, including E. coli and Pseudomonas.
The regulatory approval is based on the RESTORE-IMI 2 data that showed successful attainment of primary and key secondary endpoints and demonstrated the drug’s non-inferiority to currently used Piperacillin/Tazobactam treatment. However, the company highly recommends that the drug be administered only when the presence of gram-negative bacteria is confirmed to prevent the development of antimicrobial resistance.
“Hospital-acquired infections continue to be a significant cause of illness and death despite advances in our understanding of the contributing factors and prevention of these diseases,” said Dr. Keith Kaye, professor of medicine and director of research for the division of infectious diseases, University of Michigan Health System, and a principal investigator in the clinical program. “Because these infections are often caused by difficult to treat Gram-negative organisms, new therapeutic options such as RECRABRIO are urgently needed for patients.”
Triple Drug Combo
The drug is a combination of three compounds: imipenem, a carbapenem antibacterial, cilastatin, a renal dehydropeptidase inhibitor, and relebactam, a beta-lactamase inhibitor. Relebactam protects imipenem from degradation by serine beta-lactamases produced by bacteria such as SHV (Sulfhydryl Variable), TEM (Temoneira), CTX-M (Cefotaximase-Munich), P99 (Enterobacter cloacae), PDC (Pseudomonas-derived cephalosporinase), and KPC (Klebsiella–pneumoniae carbapenemase) whereas cilastatin inhibits dehyrdopeptidase in the kidneys, which is responsible for degrading the antibiotic.
RESTORE-IMI 2 Trial
RESTORE is a Phase 3, a multinational trial that evaluated the efficacy and safety of recarbrio (500mg imipenem, 500mg cilastatin, and 250mg relebactam) compared with PIP/TAZ (piperacillin 4000mg and tazobactam 500mg) in patients with hospital-acquired or ventilator acquired bacterial pneumonia. A total of 535 patients were enrolled in the study at 113 sites and were randomly assigned to either recarbrio or PIP/TAZ combo intravenously every 6 hours for 7 to 14 days. The primary endpoint was the incidence of mortality due to any reason (all-cause mortality) through day 28 in the modified intent-to-treat (MITT) population, and the secondary endpoint was clinical response at early follow-up (7 to 14 days after completion of the treatment) in the MITT population.
For patients treated with the combo drug, 28-day all-cause mortality was 15.9%, whereas it was 21.3% in the arm treated with PIP/TAZ. Moreover, the clinical response at early follow-up was 61% for the drug versus 55.8% for the PIP/TAZ arm. In terms of safety, recarbrio was found much safer than the PIP/TAZ treatment. Serious adverse reactions occurred in 27% of patients receiving the Merck’s combo, whereas 32% showed these events with PIP/TAZ treatment.
“At a time of great public health concern about the need for new treatments to meet the evolving challenges posed by Gram-negative bacteria, we are proud to continue bringing new therapeutic options to health care practitioners in an effort to help them overcome the challenges in patient care,” said Dr. Nicholas Kartsonis, Senior Vice President, clinical research, infectious diseases and vaccines, Merck Research Laboratories. “ Today’s approval is further affirmation of Merck’s steadfast commitment to meeting the needs of the health care community.”
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