Keith Kaye, MD, MPH, on the Approval of Imipenem/Cilastatin + Relebactam

Yesterday the US Food and Drug Administration announced the approval of Merck’s imipenem/cilastatin plus relebactam (Recarbrio) for the treatment of complicated urinary tract infections and complicated intra-abdominal infections in adult patients with limited or no available treatment options.

Following the approval, Contagion® spoke to Keith Kaye, MD, MPH, professor of Internal Medicine and director of research in the Division of Infectious Diseases at the University of Michigan Medical School.

Kaye is also a principal investigator in Merck’s clinical program on imipenem/cilastatin plus relebactam and a member of Contagion®’s Editorial Advisory Board.

Here is part 1 of the interview:

Contagion®: Can you describe the makeup of imipenem/cilastatin plus relebactam?

Kaye: This novel agent combines an old, broad-spectrum, trusted agent, which is imipenem/cilastatin, with a novel beta-lactamase inhibitor, relebactam, which is very effective and active against carbapenemases and also different types of

Keith Kaye, MD, MPH

extended-spectrum beta-lactamases (ESBLs) and cephalosporinases like AmpC. So essentially, it takes an old, trusted, very effective carbapenem beta-lactam and combines it with a novel beta-lactamase inhibitor, which has can restore the activity of imipenem in the presence of emerging and disseminating resistance mechanisms.

Contagion®: The approval press release states that the decision was based on “limited clinical safety and efficacy data.” Can you summarize the data that the decision was based upon?

Kaye: Important studies were related to complicated urinary tract infections and complicated intra-abdominal infections. We know that phase 3 trials are very important and valuable, but we also know that certain patient populations—whether they be immunocompromised patients or patients with a resistant pathogen—sometimes cannot be included in those types of trials. I think from standard FDA-level approvals, imipenem/cilastatin plus relebactam performed very well and had very positive safety and clinical efficacy findings in comparison with comparators.

Obviously, whenever you have new agents you need a lot of post-marketing data once [they’re] being used widely in the clinics, not only in patients who qualify for clinical trials but also in general populations in the hospitals and beyond. I think that the fact that the FDA approved the agent with these 2 indications speaks very strongly for positive features of clinical efficacy and safety.

I will also say that the RESTORE-IMI study focused more on imipenem-resistant invasive-infections—so not only the types of infections that were studied in the clinical trial, but more of a real-world look of patients with pneumonia, blood-stream infections, and various types of resistant gram-negative infections. And in this study, which has not been published yet but likely will be in the near future, imipenem/cilastatin plus relebactam performed extremely well compared with imipenem plus colistin.

So additional data are on the way that will be valuable to clinicians and give them more of a ‘real-world view’ of the use of this drug in patients with infections caused by resistant pathogens. This is very exciting.

Contagion®: Apart from determining non-inferiority to colistin + imipenem in the RESTORE-IMI 1 trial, were there any significant advantages observed in patients treated with imipenem/cilastatin plus relebactam?

Kaye: The bottom line is, from an efficacy perspective, in terms of clinical outcomes, there is significant advantage in using imipenem/cilastatin plus relebactam over imipenem plus colistin. Also, importantly, from a safety perspective (eg looking at nephrotoxicity), there are notable safety advantages with imipenem/cilastatin plus relebactam. This points to the fact that, while colistin is an important antimicrobial that we have historically leaned on for the treatment of resistant pathogens such as carbapenem resistant-Enterobacteriaceae (CRE), newer agents such as imipenem/cilastatin plus relebactam offer a safety advantage with regards to nephrotoxicity and also offer a pharmacokinetic/pharmacodynamic (PK/PD) advantage in terms of safely attainable, effective levels in the serum and sites of active infections. Imipenem-relebactam performed very impressively from efficacy and safety perspectives, including in studies of resistant infections in the RESTORE-IMI 1 trial.

It’s an exciting time to be in infectious diseases. It’s very exciting that we have these new effective and safe agents that can treat MDR and XDR gram-negatives, such as imipenem/cilastatin plus relebactam. I am very excited to see this drug come to the clinic.