Treating <i>Pseudomonas</i> Infections With Zerbaxa or Avycaz

Peter L. Salgo, MD; Jason Pogue, PharmD, BCPS-AQID; Marin Hristos Kollef, MD; Yoav Golan, MD; and Andrew Shorr, MD, provide their perspective on the appropriate settings in which to use Zerbaxa (ceftolozane) or Avycaz (ceftazidime/avibactam) for Pseudomonas infections and reflect on which dosing methods are the safest.

Peter L. Salgo, MD: Let’s bring this all the way back to when we were talking about some of the newer agents against the resistant Pseudomonas drugs. Is there a clinical rationale for starting therapy with a cephalosporin β-lactamase inhibitor combination right away?

Jason Pogue, PharmD, BCPS-AQID: Absolutely

Peter L. Salgo, MD: OK, what would that be?

Jason Pogue, PharmD, BCPS-AQID: Clearly, you give the patient what antibiotic is most likely to work in that patient. If you have a patient who is critically ill or unstable, or even a patient who’s borderline and you know they have a history of an organism that’s resistant to everything else, it’s foolish to not give them an antibiotic that’s going to be active against that pathogen. I think that’s the very nature of what an antimicrobial surgeon should do, identifying those patients and getting them on therapy first.

Peter L. Salgo, MD: Kill them fast, kill them a lot, and get the hell out of Dodge.

Jason Pogue, PharmD, BCPS-AQID: Kind of. Again, it’s the right patient. You’ve heard it over and over again from all of us. Marin talked about that alert system that comes up. If he gets an alert that says, “A guy just to the unit had an XDR [extensively drug-resistant] Pseudomonas infection the last time he was here,” you should absolutely put that patient under the empiric Zerbaxa [ceftolozane], absolutely.

Peter L. Salgo, MD: Let’s talk about this. Let’s get down to the nuts and bolts just briefly, before we go on. We’ll talk about Zerbaxa first. When do you choose Zerbaxa, how do you dose it, and does it change based on what you’re using the Zerbaxa for?

Jason Pogue, PharmD, BCPS-AQID: I’ll answer. We talked a little bit about when you would choose it, in particular when you’re that concerned for drug-resistant Pseudomonas. I think this is an absolutely antipseudomonal drug.

Andy talked about this a little bit. The label dose is 1.5 g every 8 hours. I’ve actually personally never used that dose because that is the dose for complicated urinary tract infections and complicated intra-abdominal infections. When I have an XDR Pseudomonas that’s causing pneumonia, it’s causing an invasive infection in a critically ill patient. They’re studying the drug right now in a nosocomial pneumonia study at 3 g every hour, based partially on ELF [epithelial lining fluid] penetration with the drug. But we also know that in critically ill patients, pharmacokinetics fell out the window, right? You couldn’t see any type of kinetic exposure. The 3-g dose has been proved to be pretty safe. I will tell you that I’ve never not given this drug 3 g every 8 hours for a patient from this standpoint, unless they have renal insufficiency that requires a dose reduction. But it’s the 3-g base that I’m starting with.

Marin Hristos Kollef, MD: Yes, I was just going to echo that point about underlying renal dysfunction, since many of our patients do have it. It seems like they run into 2 categories: The majority of patients, at least in our medical ICU, tend to have some renal dysfunction; but then we also get our trauma unit in some of our transplant patients who have augmented renal function. It becomes even more important in those patients, as you said, to give them that higher dose or the appropriate dose of the drug.

Yoav Golan, MD: And to extend the activity by giving long infusions as well.

Peter L. Salgo, MD: Forgive my ignorance, but can you dose this drug by level?

Jason Pogue, PharmD, BCPS-AQID: I wish.

Peter L. Salgo, MD: You wish, huh?

Jason Pogue, PharmD, BCPS-AQID: It happened that the β-lactam therapeutic drug monitoring is in vogue. People are interested in it because we’re learning, particularly in ICU patients, that Andy and I could have 50-fold different concentrations in exposure with the same dose. And so we want to get there. We are not there at this point.

Peter L. Salgo, MD: Let’s move on to Avycaz [ceftazidime/avibactam]. How do you dose that? Are you using it for the same indications? What do you do?

Yoav Golan, MD: Avycaz is a potent drug against enteric bacteria, including those carbapenemase producers. As I mentioned earlier, in those hospitals that have ampC-hyperproducing Pseudomonas, it may actually be a much better drug for Pseudomonas compared with ceftazidime by itself, perhaps increasing susceptibility by about 10% or so. Avycaz is primarily being used for those 2 indications in those hospitals, where they have the specific Pseudomonas that are susceptible to it or carbapenemase-producing bacteria.

There was this patient I mentioned earlier who came with 2 sepsis episodes of multidrug-resistant [MDR] Pseudomonas who actually had an ESBL [extended-spectrum β-lactamases]—producing E coli [Escherichia coli] sepsis and was not treated earlier. Avycaz would have been an empiric regimen for her because it would have treated her Pseudomonas, and there are very, very few antibiotics that would have done that. Traditionally, we had to decide whether to go to Pseudomonas or the enterobacteria. It was an educated guess, and you either get it or not. Avycaz has been used for carbapenemase producers, sometimes ESBL producers if you don’t have alternatives.

Andrew Shorr, MD: I would echo that. At our institution, it has been our drug for our CRE [carbapenem-resistant Enterobacteriaceae]. Fortunately, we don’t have a big CRE problem, but that’s where we use it. We try not to use it for Pseudomonas because we have other agents for MDR Pseudomonas such as Zerbaxa CT [ceftolozane/tazobactam] that I could move to. Both of them are important tools for pathogens that aren’t usually prevalent right now in terms of an empiric option I’m contemplating. I’m doing it based on an individual level, but I’m trying not to overuse one or the other because I need both of them to sustain my armamentarium.

Jason Pogue, PharmD, BCPS-AQID: Yes, and I think that we’ve beat this dead horse a lot today, but knowing your local epidemiology is huge. You need to know what your XDR Pseudomonas look like to those 2 drugs. Although if you look globally, ceftolozane seems to be more potent and seems to be more active. That makes sense from a mechanistic standpoint. If you happened to have a predominance of certain mechanisms of resistance at your institution, the flip side can be true. And so I think it’s very important that institutions are aware of what their Pseudomonas look like to those 2 agents.