Battling Against Resistant Pseudomonas Infections in the ICU - Episode 8

Exploring Cephalosporin/&#946;-Lactamase Inhibitor Combinations for Treatment of <i>Pseudomonas</i>

Peter Salgo, MD; Yoav Golan, MD; Andrew Shorr, MD; and Marin Hristos Kollef, MD, provide their perspective on the cephalosporin/β-lactamase inhibitor combinations Zerbaxa, Avycaz, and Vabomere, with considerations for mechanisms of action and effectiveness.

Peter L. Salgo, MD: We have some new antibiotics. These are cephalosporin/β-lactamase inhibitors. We have 3 new ones. We have Zerbaxa, Avycaz, and Vabomere. Where do we go with these things? Can you run them down?

Yoav Golan, MD: All those antibiotics are a combination of some kind of a β-lactam and a β-lactamase inhibitor. The β-lactamase inhibitor will be a bodyguard. So, you give an antibiotic, and the bodyguard, knowing that the bacteria are going to try to break through, is going to take care of that. There are 2 different approaches. One approach is to take an antibiotic that has been very useful for many, many years—like a carbapenem or ceftazidime that we’ve been using—where a resistance to it has developed over the past several years, and attach to it a bodyguard that will prevent the enzyme and reinstitute the susceptibility to this antibiotic.

Avycaz is such an antibiotic, and studies with Avycaz have shown that by adding avibactam to ceftazidime, you will regain susceptibility against ceftazidime-resistant bacteria that would kill animals and humans as well. It would be susceptible to Avycaz.

Zerbaxa has a different approach, in which the cephalosporin β-lactam component is actually a new component. It’s a new cephalosporin that is particularly good at the ability to truly get through the outer membrane of Pseudomonas and resist some of the activity of some of the efflux and so forth. It’s given with an older β-lactamase inhibitor, tazobactam, to allow the antibiotic to resist those β-lactamases.

Vabomere, which is the newest addition, is a combination of meropenem and vaborbactam, vaborbactam being a very, very active β-lactamase inhibitor against those empiric bacteria that produce those ESBL type-A β-lactamases. It’s not that powerful against some of what Pseudomonas is producing. So, in many circumstances, Vabomere is actually not going to increase your ability to treat much more than just using ertapenem.

Andrew Shorr, MD: I think it’s important to realize, though, that besides talking about the in vitro activity of all these different agents, they all have very different clinical data sets that are currently available to us. For example, Avycaz, which has been around the longest, has just completed or just presented its nosocomial pneumonia data set. Marin was one of the lead authors on that, and I think there are issues with that data set because the mortality rate in that population was remarkably low. I think there are a lot of questions about the validity of whether it was actually studying pneumonia.

Peter L. Salgo, MD: He could just be remarkably good, you know.

Andrew Shorr, MD: Oh, he is remarkably good. I don’t deny that. But just not as good as you. Then you have CT, which has some interesting clinical data but no pneumonia data.

Peter L. Salgo, MD: CT is Zerbaxa, correct?

Andrew Shorr, MD: Correct. Zerbaxa is currently undergoing its pneumonia trials. I think it’s important to realize that the dose they’re studying for pneumonia is actually twice the dose that’s currently approved. So, you never want people arguing from one disease state to another without understanding the differences and the pharmacokinetics. And then, when you look at Vabomere, there’s no pneumonia clinical trial but a critically ill population, a highly drug-resistant population, in a study called TANGO-2 on top of their urinary study, also with a unique population. Although the boronic β-lactamase inhibitor doesn’t add anything to its antipseudomonal coverage, the dosing of the meropenem to optimize the pharmacokinetics, which you could do today if you wanted to, doesn’t require that you buy Vabomere. The dose of meropenem is huge and given over a 3-hour infusion 3 times a day to really pick off those higher MDR pseudomonal isolates. Again, it’s optimizing the principle that you could do it today without having to buy their molecule.

Realize all these drugs are very nuanced in their clinical trial data, and all of them have been designed to address different problems. In the pipeline beyond that, we have a molecule, plazomicin, an enhanced glycoside to hit carbapenem-resistant Enterobacteriaceae. You would think, “Oh, it’s an aminoglycoside, it’s going to do something for Pseudomonas.” It doesn’t do anything extra for Pseudomonas. Right? We have a drug called imipenem/relebactam that’s in clinical trials, which is another β-lactamase inhibitor. You think, “Well, it’s all added to imipenem; it’s not going to do anything for Pseudomonas; it’s really a CRE drug.” It turns out it may actually do something for Pseudomonas.

The story is unfinished for all these agents right now. There could soon be new data on all these issues. So, anybody who tells you they’re an expert on these novel agents is trying to sell you beachfront property in New Orleans. You’ve got to be very cautious about what you do with these data because they’re really constantly emerging.

Peter L. Salgo, MD: Somebody mentioned that one of these drugs is particularly good at getting through this gelatinous capsule. Which of those drugs was it?

Yoav Golan, MD: It’s ceftolozane, which was designed as an MDR pseudomonal cephalosporin, and it actually is the newest cephalosporin.

Peter L. Salgo, MD: So, that’s the Zerbaxa?

Yoav Golan, MD: That’s part of Zerbaxa. With those new agents, I think the likelihood that we’ll have to use colistin and drugs like that—desperation drugs, desperation antibiotics—is decreasing tremendously. Our ability to treat those very resistant Pseudomonas infections has increased with the antibiotics that we would consider to be effective drugs.

Peter L. Salgo, MD: Anytime anybody’s telling me that they want to give a polymyxin, I’m thinking they’re desperate.

Yoav Golan, MD: Yes.

Peter L. Salgo, MD: Because that’s a nasty, nasty drug.

Marin Hristos Kollef, MD: That’s not a drug you want to give to someone you love.

Peter L. Salgo, MD: No.

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