Editor’s Note:

Staphylococcus aureus bacteremia is a major cause of bloodstream infections, and hospital-acquired bacterial pneumonia is often caused by multidrug-resistant bacteria. And developing new antibiotics requires patient-centered clinical outcomes. How to conduct a patient-centered benefit-risk assessment in the design, analysis, and interpretation of clinical trials, so that more bacterial clinical studies can achieve the expected efficacy? At the recently Infectious Disease Week (IDWeek 2023), “Infectious Disease Frontline” invited Dr. Thomas L. Holland from Duke University Medical Center to introduce the practical application and potential challenges of DOOR research on ordinal outcome, and shared its importance to future clinical trials and treatment plans.

Dr. Thomas L. Holland is an Associate Professor of Infectious Diseases at Duke University and a faculty member of the Duke Clinical Research Institute. His research interests include antibacterial trials, particularly for S. aureus bacteremia and antibiotic-resistant pathogens, as well as the design and implementation of novel clinical trial endpoints including ordinal outcomes and quality of life measures. He is active in COVID clinical care and research as well as reseach in novel diagnostics.

Infectious Disease Frontline : Good afternoon, Dr. Holland. In the context of your studies involving the Desirability of Outcome Ranking (DOOR) endpoints for Hospital-Acquired Bacterial Pneumonia and Complicated Intra-Abdominal Infections, how do you envision DOOR methodology altering the landscape of clinical trials in bacterial diseases? Can you provide insights on its practical application and the potential challenges?

• Dr. Holland：Yeah, thanks for that question. The DOOR is an ordinal outcome, right? And so ordinal outcomes have become a lot more familiar. I think in the era of COVID trials where ordinal outcomes were standard. You know patients were ranked according to the most desirable outcome. And that’s what DOOR does for bacterial trials or any trials as well. I think that the challenge of DOOR, the appeal of DOOR is that it really integrates all of your relevant outcomes into one endpoint, so you can integrate efficacy outcomes, and safety outcomes, adverse event outcomes, all into one thing that really makes sense. What’s the most desirable way to end up after a treatment? down to the least desirable which is usually death. So there’s a lot of appeal and using a sort of an intuitive ordinal outcome for these trials.

I think the challenge probably is two. One is agreeing on what that ranking should look like, so really getting consensus from both scientists in trial list, but also patients and other stakeholders as to what makes sense to include in that ordinal endpoint. That’s one challenge. Probably the second challenge is Regulators to accept or embrace a novel endpoint as a whole process, but we hope that the work on intradermal infections will help move that forward.

Infectious Disease Frontline : Considering the conference’s focus, how does your proposal of a clinical trial evaluating next-generation sequencing for individualizing therapy in Staphylococcus aureus bacteraemia align with the evolving trends in clinical trials for bacterial diseases? How might this influence treatment protocols and practices?

• Dr. Holland：Thanks for that question as well. Yeah, we took the chance to think about a publication in CMI as to what would be a trial that might move the needle in staph infections. I was just talking in the recent session about mortality in patient is still terrible. It’s still 20%, 25% at 90 days. And we need ways to change that and move that. One round is to have better drugs or better combinations of drugs, but another that we think has some merit as an idea is could you use personalized duration of bacteraemia or DNA in the blood as a way to tailor therapy. So the idea there is because you get a test like a qPCR or a next generation sequencing test. That’s really sensitive and then once a patient is on treatment for staph bacteraemia, once they’re no longer a detectable DNA, that’s when you stop therapy. That might be a way to shorten therapy for people that don’t need it to go on any longer or to extend therapy for people who aren’t clearing like you think they should be or to go looking for other sources. So it’d be a way to personalize duration and approach to therapy that hopefully if we can actually manage to test that and our patients can move the needle on the staph orious mortality.

Infectious Disease Frontline： Okay. And with the ERADICATE Study findings indicating Ceftobiprole’s noninferiority in treating complicated Staphylococcus aureus bacteraemia, how might this outcome influence future clinical trials and treatment approaches in similar bacterial infections? What are the anticipated implications for clinical practice?

• Dr. Holland：Yeah. So the ERADICATE trial looked at Cepthibrioprol which is a new antibiotic. It’s approved in some countries in Europe not currently approved in the US. So it was tested in staph orious bacteraemia, and it was compared to Daptomycin. It was not inferiority trial and Cepthibrioprol was not inferior. So the next steps for that antibiotic, it’ll go to the FDA for a decision. The FDA has already accepted the new drug application, hasn’t ruled on it as accepted the application. And we’ll see if it becomes an approved treatment option for staph bacteraemia. I think ultimately we’ll see where it ends up getting used. I think it will potentially be an upfront therapy especially for MRSA having a beta-lactam, that’s active against methicillin resistant staph orious would be an exciting thing to have high-quality data, and might get either used as a first-line therapy for MRSA bacteraemia or in salvage therapy treatments.

Infectious Disease Frontline：Thank you. The last question. Given your extensive work in both bacterial and viral infections, specifically your recent study on dexamethasone for COVID-19 patients, how can learnings from antiviral treatments inform advancements and innovations in bacterial disease treatments and clinical trials?

• Dr. Holland：Yeah, we’ve learned a lot of things from COVID. I’ve had the chance to participate in COVID trials in the last few years as well. I think probably two big picture lessons that would translate to bacterial diseases are one, your endpoint that you choose is absolutely critical. Early in COVID, we didn’t know if the best endpoint was a mortality endpoint or a recovery or time to recovery endpoint. And I think really careful attention to the right endpoint that helps you understand how a treatment strategy works. That’s a universal challenge in trials. And we’ve got to be sharper in our thinking about endpoints for trials. And the second is that it, I think the other thing we’ve learned from COVID is it is possible to get trial networks and networks of sites up and running quickly to answer questions. And there’s been a real explosion of adaptive and platform trials that can rapidly test different treatments. We need that in bacterial diseases as well.