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

DEC 13, 2019 | MICHAELA FLEMING
In July, 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 (cUTIs) and complicated intra-abdominal infections (cIAIs) in adult patients with limited or no
Keith Kaye, MD, MPH

Keith Kaye, MD, MPH

available treatment options.

Following the approval, Contagion® spoke with Keith Kaye, MD, MPH, professor of internal medicine and director of research in the Division of Infectious Diseases at Michigan Medicine at the University of Michigan in Ann Arbor.

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.

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

Keith Kaye, MD, MPH: This novel agent combines an old, broad-spectrum, trusted agent, which is imipenem/cilistatin, with a novel β-lactamase inhibitor, relebactam, which is very effective and active against carbapenemases and also different types of extended spectrum β-lactamases [ESBLs] and cephalosporinases like AmpC. So, essentially, it takes an old, trusted, very effective carbapenem β-lactam and combines it with a novel β-lactamase inhibitor, which can restore the activity of imipenem in the presence of emerging and disseminating resistance mechanisms.

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

Keith Kaye, MD, MPH: The bottom line is, from an efficacy perspective, in terms of clinical outcomes, there is significant advantage in using imipenem/cilistatin plus relebactam over imipenem plus colistin. Also, importantly, from a safety perspective [eg, looking at nephrotoxicity], there are notable safety advantages with imipenem/cilistatin plus relebactam. This points to the fact that, although 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/cilistatin plus relebactam offer a safety advantage with regard to nephrotoxicity and a pharmacokinetic/pharmacodynamic 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.

Contagion®: Can you discuss the importance of using culture and susceptibility information when considering use of this drug?
Keith Kaye, MD, MPH: Obviously, it’s true that with any antibiotic you use, you want to know if it has in vitro activity and will work against the pathogen that you’re treating. On the flip side, when you have a valuable new broad-spectrum agent, you want to avoid using it when narrower-spectrum agents would work. For example, you would not want to use imipenem-relebactam in scenarios where imipenem alone would do the trick.

The other thing I would say is that imipenem/cilistatin plus relebactam will be very active against ESBLs and KPC [Klebsiella pneumoniae carbapenemase] producers. But for organisms that produce metallo-β-lactamases, such as the New Delhi metallo-β-lactamase [NDM], imipeneme-relebactam will likely not have notable activity in these scenarios. If you have rapid diagnostics available, and if a CRE pathogen is positive for KPC production and NDM negative, imipenem relebactam is a good option. Of course, it is always important evaluate phenotypic susceptibility results when they are available.

And remember: Do not treat colonization, even for CRE! There is no benefit toward treating colonizers.

Contagion®: What does imipenem/cilistatin plus relebactam bring to the armamentarium for clinicians treating cUTIs and cIAIs with limited treatment options?

Keith Kaye, MD, MPH: As recently as 4 years, ago we had 1 tool to treat CRE and highly resistant Pseudomonas, and that was the polymyxin class. We now have a tool kit of therapeutic options that are safe and effective. Imipenem/cilistatin plus relebactam offers a unique option that is part of a newer class of advance β-lactam/β-lactamase inhibitor combinations. It couples an old school carbapenem, imipenem, which we know and love, with a relatively broad-spectrum β-lactamase inhibitor. It is an inhibitor that can not only inhibit carbapenemases like KPCs but also cephalosporinases like AmpC. In doing so, it not only provides enhanced activity against ESBLs and many strains of CRE but also restores susceptibility in some Pseudomonas.  

Imipenem/cilistatin plus relebactam offers enhanced CRE and ESBL coverage and also provides, in many scenarios, enhanced Pseudomonas coverage.

I think also, due to it being coupled with cilistatin, there are potential nephroprotective effects. If imipenem/cilistatin plus relebactam is used in combination with nephrotoxic agents, such as the polymyxins, it might offer some nephroprotective advantages over combinations that do not include cilastatin. This is hypothetical but deserves consideration.