Authors: Keith Kaye (University of Michigan, MI, USA)
At ID Week this year (2–6 October, DC, USA) new results were presented on Merck’s (NJ, USA) investigational beta-lactamase inhibitor, relebactam, in combination with imipenem for the treatment of pneumonia. In this interview we speak to Keith Kaye, from the University of Michigan (MI, USA) about the RESTORE-IMI 2 study, its results and why ICU patients represent an unmet need.
First, could you just introduce yourself and tell me a bit about your background?
My name is Keith Kaye, I am an adult infectious diseases physician at the University of Michigan in Ann Arbor (MI, USA). My career has been focused on the prevention and management of healthcare-associated infections with a focus on antibiotic-resistant pathogens. I worked in infection prevention, antibiotic stewardship and quality for about 16 years and while I am still active in those areas, I am focusing more exclusively on research now. A lot of my current research focuses on the treatment of resistant Gram-negative pathogens, the prevention of healthcare-associated infections and antimicrobial stewardship.
Could you introduce the RESTORE-IMI 2 study and tell us a bit about the rationale behind it?
The RESTORE-IMI 2 was a Phase III study looking at pneumonia – in many cases, ventilator-associated pneumonia – in the intensive care unit (ICU) and the trial comapred the novel agent imipenem–relebactam with a more standard anti-psuedomonal agent Zosyn (piperacillin–tazobactam). These two treatments were compared head-to-head for the treatment of pneumonia. It was discovered that imipenem–relebactam was not inferior to Zosyn and performed very well and had a very good safety profile. Imipenem–relebactam was safe and effective.
The rationale for the study was to obtain a pneumonia indication from the US FDA for imipenem–relebactam. Imipenem is an old friend of the ID clinician and what makes this a new agent is the role of the relebactam component, which is a relatively broad-spectrum beta-lactamase inhibitor with notable inhibitory activity against the Klebsiella pneumoniae carbapenemase (KPC) producers as well as against the extended-spectrum beta-lactamases (ESBLs) and AmpC.
The importance of studying this combination in pneumonia is that drugs like imipenem–relebactam are more likely to be used in patients at high risk for resistant pathogens. These patients also tend to have more underlying chronic illnesses and, in some cases, such as in the ICU, they are more acutely ill. I think the population in this RESTORE-IMI 2 study, with regards to acute and chronic severities of illness, is representative of many of the types of patients who will receive imipenem–relebactam in real-world clinical practice.
Why is imipenem–relebactam an important agent to consider for invasive infections like pneumonia? Well, it has a unique coverage profile by combining the carbapenem with a novel, strong, broad-spectrum beta-lactamase inhibitor, which increases activity against carbapenem-resistant Enterobacteriaceae (CRE), particularly those strains where KPC production is present. In addition, it retains activity against some strains of carbapenem-resistant Pseudomonas, particularly when carbapenem-resistance is being driven in part by AmpC hyperproduction and/or ESBL production. Thus, imipenem–relebactam provides enhanced coverage against two important types of ESKAPE pathogens (Enterobacteriacea and Pseudomonas) that often impact and affect similar patient populations.
What impacts do you think these findings could have on patients in clinic?
I think this study suggests that imipenem–relebactam is a very reasonable choice and a relatively safe and effective choice for patients in the ICU with pneumonia. I think individuals who have a resistant Pseudomonas or CRE pneumonia would be very appropriate patients for definitive or salvage therapy with imipenem–relebactam. But I also think that in individuals who have a lot of the risk factors for, or a prior history of colonization of infection with, a resistant strain of Pseudomonas or CRE, empiric therapy with imipenem–relebactam should be considered. I think imipenem–relebactam represents not only important niche activity for definitive therapy, but I also think it could be used effectively empirically for certain patient populations as well.
Thinking about developing and trialing drugs and drug combinations, could you just talk about clinical trial design? How important is it?
Studying antibiotics is challenging; for acute infections, you have a very narrow enrollment window. We know that time to effective therapy is critically important in the outcomes of serious infections. However, if patients have received effective antimicrobial therapy prior to being screened for study enrollment they might no longer be eligible. Study design is very important because you need to think about the real world and how to successfully enroll subjects who are generalizable to the real-world ICU setting.
The design in this study is a fairly straightforward Phase III randomized controlled trial, where patients either received piperacillin–tazobactam or imipenem–relebactam in a blinded fashion. The participants were then followed for clinical outcomes, including not only clinical cure, but also microbiologic cure and adverse effects, both acute and longer-term.
This is a fairly standard type of study that is conducted to present to the US FDA or to EU’s Public Health division to be considered for approval for a pneumonia indication. For RESTORE-IMI 2 it is important to realize that safety outcomes were very important. Safety isn’t just about immediate, allergic events, but it is also about things like rates of C. difficile, and antimicrobial resistant superinfection. We have started thinking about collateral damage and factors like the microbiome when evaluating antibiotics. So, I think that outcome metrics have really matured over the past several years, from both clinical efficacy and from safety perspectives.
Could you give us a broader perspective on ICU patients, why are they a particular unmet need in terms of treatment?
ICU patients represent the sickest patients that we care for in the hospital, meaning that effective, timely, empiric therapy is even more important to those individuals than in patients who reside outside of the ICU. In addition, ICU patients are also more likely to have infections due to resistant pathogens. Using your standard hospital algorithm-based treatment approaches, you might be less likely to get effective empiric therapy rapidly on board in an ICU patient as compared with non-ICU patients.
So, when empirically treating critically ill patients, we need to be very thoughtful and consider options like combination therapy, which helps provide broader coverage for resistant Gram-negative pathogens. We need to more seriously think about more frequent, empiric use of some of the newer agents like imipenem–relebactam, which safely provide broad-spectrum coverage that addresses many of the treatment gaps that challenge clinicians today.
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