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Keith S. Kaye, MD, MPH: RESTORE-IMI 2 and Treating Critically Ill Patients With Respiratory Infections

Segment Description: In an interview at IDWeek 2019, Keith S. Kaye, MD, MPH, director of research in the Division of Infectious Disease at University of Michigan, discusses the current treatment landscape for pneumonia in the ICU setting, and previews the topline results of the phase 3 RESTORE-IMI 2 trial.

Interview transcript: (modified slightly for readability)

Contagion®: What are some of the issues critically ill patients with respiratory infections face?

Dr. Kaye: Critically ill patients with respiratory infections represent some of the sickest patients that we care for in the hospital. When you look at outcomes of patients who have bacteremia, by and far the worst outcomes are always those patients who have a primary source of pneumonia. In order to get in the ICU these days, you have to be pretty sick, often with multiple co-morbid conditions. So you have that chronic illness and you also typically have a high acute severity of illness as well. And when you deal with a respiratory infection, it often involves mechanical ventilation, or borderline high oxygen percentage delivery. You're sort of dealing with patients who have a double whammy of underlying medical issues and acute severity of illness. From these patients, you usually don't have much wiggle room or comfort zone to get your empiric therapy wrong for pneumonia. So your first choice is your most important choice. And in these patients every hour or sort of delay of effective therapy can increase the risk for sepsis and for death...So very challenging group. Obviously the other major challenges are these severely ill patients often have repeated antibiotic exposures...devices and extensive health care exposure, so antibiotic resistance plays an important role. Many of our standard guideline options of antibiotics may not be as active or have a less likelihood of being active against the infecting pathogens the sicker the patient is and the more healthcare exposed they are.

Contagion®: What is the current treatment landscape for these patients? 

Dr. Kaye: The current treatment landscape for pneumonia in the ICU setting typically would be a combination of vancomycin and, in many cases, Zosyn or cefepime, 2 sort of anti-Pseudomonal beta-lactams. In some cases, in patients who might be heavily antimicrobial-exposed before, empiric therapy might be with a carbapenem, like an meropenem or an imipenem, again in combination with vancomycin or in some cases linezolid. And depending on how severely ill the patient is and whether they've had prior highly resistant pathogens or they're at risk for those pathogens, guidelines recommend—and many practitioners would also give—a second non-beta-lactam agent that might increase the likelihood of getting an inactive antibiotic on-board empirically before you know the infecting pathogen. Typically, the most effective combination agent is an aminoglycoside, something like a tobramycin, gentamicin, or an amikacin, although in some cases a fluoroquinolone like ciprofloxacin or levofloxacin might be an option as well.

Contagion®: What are some of the issues with the current treatment options for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) that require us to develop new agents?

Dr. Kaye: One of the reasons why we're having this conversation right now and why we're having infectious disease meetings and IDWeek is because our current treatment options for severe infections like pneumonia are effective for many patients, but there's a growing population of patients for which antibiotic resistance has rendered these antibiotics either less effective or, in some cases, completely ineffective. I think some of the the biggest threats in the ID world for the hospitalized patients are related to carbepenem resistance. When I say carbepenem, I'm not talking about any of our new combination agents, inhibitor combinations, but if you go back to meropenem and imipenem, we're seeing more and more resistance amongst Pseudomonas and Enterobacteriaceae and Acinetobacter. Carbepenem resistance often—not always, but often— goes hand-in-hand with other beta-lactam agent resistance profiles. And often resistance to other classes of antimicrobials like the fluoroquinolones, for example. So when we are dealing with carbapenem-resistant gram negatives in pneumonia and other invasive infections, we're also dealing with multidrug or, in some cases, extremely drug resistant and, in a few cases, pan-drug-resistant pathogens. This has really led IDSA to focus on the 10 by '20 campaign to get to 10 new agents by 2020, and now moving beyond that, calling for new antimicrobials that have novel mechanisms of action that can address some of these most resistant virulent pathogens like Pseudomonas and CRE.

Contagion®: Can you summarize, in general, the results of the RESTORE-IMI 2 Phase 3 clinical trial evaluating imipenem/cilastatin/relebactam for HAPB/VABP?

Dr. Kaye: The RESTORE-IMI 2, the imipenem/relebactam pneumonia trial, compared imipenem/relebactam to piperacillin/tazobactam, or Zosyn as many of us know it, for the treatment of hospital-acquired/ventilator-associated bacterial pneumonia in ICU settings. The bottom line was in this very sick population of patients with severe pneumonia and who were quite ill from both chronic underlying illnesses as well as acute severity of illness indices, imipenem/relebactam performed very well. It was non-inferior to piperacillin/tazobactam and also, importantly, it had a very good safety profile. It was well-tolerated and was effective. I think the major take-home message and, again, we have topline results only publicly available, but the main message is this is a very welcome, interesting new option for the treatment of pneumonia, at least potentially. It doesn't have the indication yet, but it's exciting because it performed very well compared to a standard agent that we use for the treatment of pneumonia.

Some of the issues that go beyond just the clinical trial is imipenem/relebactam has unique niche activity against some of the resistant gram negatives. And the reason why it's niche is the relebactam is a novel, relatively broad spectrum beta-lactamase inhibitor that inhibits KPCs, the Klebsiella pneumoniae carbapenemases. And, interestingly, it also improves imipenem's activity against Pseudomonas. Because it's a pretty powerful beta-lactamase inhibitor, relebactam can inhibit AmpC cephalosporinase, which is frequently or in some cases produced in significant levels by Pseudomonas and also can inhibit other ESBLs that might be produced by Pseudomonas. So I think that unique niche of notable increased activities and restoring imipenem's activity not only against Enterobacteriaceae or not only against imipenem is truly unique. I think when you're grabbing or selecting or thinking about an effective empiric agent for your patient who has risk factors for highly resistant Pseudomonas and potentially CRE, I think imipenem/relebactam is really a unique option, and it's very welcome.
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