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Battling Against Resistant Pseudomonas Infections in the ICU - Episode 16

The Future Treatment of Pseudomonas Infections

Peter L. Salgo, MD; Andrew Shorr, MD; Yoav Golan, MD; Jason Pogue, PharmD, BCPS-AQID; and Marin Hristos Kollef, MD, share their closing thoughts on which agents and methods are most promising in the future treatment of Pseudomonas infections.

Peter L. Salgo, MD: Let’s take a look now into the future, which human beings are notoriously poor at doing. What do you see changing in the management of Pseudomonas infections going forward?

Andrew Shorr, MD: I think going forward, we will have rapid diagnostics that tell us the actual susceptibilities very quickly, certainly in the blood. I think their application to the respiratory tract is going to be a little bit more challenging because of the colonization versus infection issue. But I think for the blood, Marin started really contributing these data and they’re almost ready for prime time. I think we’re going to see roles reexamined for the use of monoclonal antibodies as adjunctive therapy in these things. Whether they’re ever going to be cost-effective is going to be a very, very challenging issue. There has been a lot of interest in vaccine development for Pseudomonas. It’s hard to identify who you need to vaccinate, and the vaccine effect doesn’t seem to be very pronounced. I think that’s fallen off the table in the current situation. I think you’re going to see a lot more emphasis on prevention, generally, as we get better and better at doing it.

Peter L. Salgo, MD: Source control too.

Andrew Shorr, MD: Absolutely.

Yoav Golan, MD: I also see more of the antibiotic initiation and maintenance falling in the hands of infectious disease doctors and stewardships.

Peter L. Salgo, MD: Of course, you do.

Yoav Golan, MD: Maybe not, but I think it’s a clear trend. We talk about how only oncologists give chemotherapy, even though chemotherapy can only affect, as Andy said, the person in front of you. But everyone is prescribing antibiotics and basically producing resistance that affects everyone. This is one of the changes that I see. Another change, which is remote, is that we’re going to see more targeted therapies for Pseudomonas, not just biologics but also small molecules that target Pseudomonas specifically. Maybe in the future we’ll see more of those virulence factor inhibitors, but I don’t see any of those. We had hope 10 or 20 years ago that by this time, we would see some of those coming, but maybe in another 10, 20, or 30 years.

Peter L. Salgo, MD: To me, Pseudomonas has been the most frustrating bug I can imagine. It’s a nasty bug. It kills people and it’s hard to treat. It’s a bad trilogy there, isn’t it? It’s a trifecta of death. I don’t like this bug. What is in the pipeline going forward, other than those magic bullets and the small monoclonal antibodies? What’s coming up?

Jason Pogue, PharmD, BCPS-AQID: There are a couple things. Andy had touched on them earlier, but the one is imipenem/relebactam. Relebactam takes care of the ampC part of the imipenem resistance. What you’ll see is it actually restores, to Andy’s point from earlier, a lot more of Pseudomonas’ susceptibility to imipenem than you would have thought going in.

Other than that, in the pseudomonal space there’s not a lot. There’s one agent, cefiderocol, which is a very interesting molecule. We don’t know a lot about it yet. There are not a lot of data out there about it yet, but it seems to retain activity. It has a very unique mechanism that actually uses iron transport to get into the gram-negative cell. Again, the in vitro data are incredibly encouraging. You name your carbapenem-resistant organism of choice, and it seems to have activity. I would say that for Pseudomonas, those are the big ones. The rest of the pipeline in the gram-negative space, which is nice now, largely targets CRE [carbapenem-resistant Enterobacteriaceae], and that’s one of the issues.

Peter L. Salgo, MD: But that’s it. Good luck with the Pseudomonas. We’re fighting this war, but it’s not easy, is it? All right. Before we leave, I think we’re going to give each of you an opportunity to have some closing remarks without being interrupted by anyone else, including me. Is there anything that you haven’t thought of or some pearl of wisdom you’d like to share with our audience? Why don’t we start with you, Dr. Golan?

Yoav Golan, MD: I would just say that it all starts with a patient and ends with a patient. I think that a part of cure has gone away from old-school medicine in which you were able to look at a patient and say how sick the patient is and to what extent the patient would benefit from therapy. I think that before you talk about broad spectrum, neuro spectrum, short therapy, or long therapy, ask the question: Is the patient really going to benefit from antibiotic therapy and from aggressive antibiotic therapy? That’s where all it starts.

Peter L. Salgo, MD: Dr. Kollef?

Marin Hristos Kollef, MD: What I would say is—and this a little bit of a rebuttal to what you all said earlier, about how infectious disease is becoming the conductor of all antibiotic use—in the intensive care unit specifically, decisions have to be made quickly. Oftentimes, it’s the intensivist or the surgeon or maybe the anesthesiologist who’s there in the trenches having to deal with that particular individual. Understanding these issues related to Pseudomonas and other resistant gram negatives really becomes a key factor. I would hate to see a situation where those clinicians are not expert enough to deal with those problems and at least initiate an initial therapy for that patient, because it’s going to make all the difference in the world.

Peter L. Salgo, MD: Dr. Pogue?

Jason Pogue, PharmD, BCPS-AQID: I’ll take the stewardship angle and I’ll highlight to the audience that the primary function of antimicrobial stewardship is to optimize patient outcome. It’s not to restrict antibiotics; it’s not to deescalate antibiotics. For patients who have infection, it’s to get them on the appropriate antibiotic, the right dose, the right duration, and so on. I actually very much agree with Dr. Kollef. I think that the most important way that we can do that is identifying patients who are sick, who are at high risk for drug-resistant organisms and getting them on optimal therapy faster.

Peter L. Salgo, MD: All right. Dr. Shorr?

Andrew Shorr, MD: I’d like to end with the plea I made earlier, which was that it takes a village in the sense that you have a multidisciplinary group here struggling with very difficult issues at the bedside. But it also is going to take this group to approach policymakers to get the system fixed. By the system being fixed, I mean incentives for people to actually develop molecules that we can have at the bedside that are reasonably priced. That actually requires having a whole different regulatory approach, intellectual property approach, and reimbursement approach at a congressional level and administration level to actually engineer us out of this problem. Otherwise, we’re going to keep hitting our heads against the same wall because we’re never going to have new tools in the toolkits. There will be minor advances here and there, but we won’t have the paradigm shift that we need.

I think the experience in Europe demonstrates that you can get all those people at the table. If you look at what’s going on in the United Kingdom, if you look at what’s going in the European Union, they’re interested in coming up with pathways to change reimbursement mechanisms so that people actually get paid for not giving things when they used to get paid for giving them. People have reasons to develop antibiotics and put capital at risk. People understand that these are unique tools that have important uses, and you never want to call that fire station and have them say, “I’m sorry, we’re not here today.” That’s a policy level issue.

Peter L. Salgo, MD: I want to thank all of you for being here for just a tremendous, tremendous discussion. Of course, one of our enemies, as opposed to pseudomonas, is the clock, and here we are. I want to thank you, too, for joining us, and I hope you found this Contagion® Peer Exchange discussion to be both useful and informative. I’m Dr. Peter Salgo, and I’ll see you next time.