Gram-Negative NIs: Cephalosporin/β-Lactamase Inhibitors

Peter L. Salgo, MD: There are 3 newer cephalosporin/β-lactamase—inhibiting drugs. There’s Vabomere (meropenem and vaborbactam), Avycaz (ceftazidime and avibactam), and Zerbaxa (ceftolozane and tazobactam). So, why don’t you start us off. Let’s run through these things and just tease them out. When do you use them? What are they good for in gram-negative infections? How do you use them? You’re up. They all volunteered you.

Debra Goff, PharmD, FCCP: Did they? Thank you. So, CRE, CRE, Pseudomonas, that’s my answer in that order.

Peter L. Salgo, MD: Oh, thank you so much.

Debra Goff, PharmD, FCCP: So, they’re very targeted agents. They’re not the catchall. Give me the gorillacillin that covers everything.

Peter L. Salgo, MD: Wait, gorillacillin?

Debra Goff, PharmD, FCCP: Yes.

Peter L. Salgo, MD: That’s new. I like that phrase. I like that. That approaches his brain-dead approach to antibiotics, gorillacillin?

Debra Goff, PharmD, FCCP: Yes. So, you have to know where they’re best utilized. Even though they have a diverse spectrum of activity, I really see them in that order. CRE is the targeting of meropenem—vaborbactam.

Peter L. Salgo, MD: That would be Vabomere.

Debra Goff, PharmD, FCCP: Yes. And that’s where it’s best used. Ceftazidime/avibactam, CRE. Those are the agents.

Peter L. Salgo, MD: Avycaz, CRE.

Debra Goff, PharmD, FCCP: Right. And then ceftolozane/tazobactam we would target for Pseudomonas, and that’s a very simplistic bug—drug matching, which is sort of how I put that.

Peter L. Salgo, MD: Why is she laughing?

Sandy J. Estrada Lopez, PharmD, BCPS (AQID): Because I know the comments coming from the other side.

Jason Pogue, PharmD, BCPS-AQID: No, no, no. So, that was a good overview, and I agree with that overview. I think there are a couple of key pieces to know, and one is that, again, this is not a class. These are 3 new drugs, and I pick 1 of them, and I’m going to use that for my gross-resistant organisms. They each have their particular niches. And I agree. I just know that your own institution might favor one of these versus one of the other ones. And so, understanding how these perform and your local microbiology becomes crucial to making that decision.

Andrew Shorr, MD: And they also all have other attributes. Although your paradigm, I think, is straightforward and to the point. With meropenem/vaborbactam, giving the dose of meropenem, you’re giving in the extended infusion to optimize pharmacokinetics. It picks up a lot of ugly-looking Pseudomonas cases that you wouldn’t pick up necessarily. It has nothing to do with the β-lactamase inhibitor. It’s all because of the dosing of the carbapenem, but it’s optimizing these 2 concepts. Ceftolozane/tazobactam has some ESBL activity. That’s why it’s paired with the β-lactamase inhibitor. It’s not the world’s super-reliable ESBL activity, but it kills some of them. And, again, Avycaz, on the other hand, still will pick up some extra Pseudomonas cases you might have missed, particularly ceftazidime-resistant Pseudomonas, where the susceptibility is now restored. So, there are other pieces to this complex puzzle, but I think all those attributes are really secondary. And Deb’s point is correct about where we really need to be targeting them because we don’t want them abused just because they can do something else.

Peter L. Salgo, MD: What about safety issues? Are they all safe? Safe is a relative term. Like, wait a minute, I get to say it—it depends. Can I be an ID specialist now?

Sandy J. Estrada Lopez, PharmD, BCPS (AQID): You’re getting there.

Peter L. Salgo, MD: I’m getting there. But what about the safety issues of these drugs? What do we know about them?

Jason Pogue, PharmD, BPCS-AQID: I’ll chime in again. We’re limited at this point by clinical trial data. We’re limited by sometimes small numbers from that standpoint, but they’re β-lactams. Ceftazidime is the same ceftazidime that you give by itself and you’re adding avibactam, and there’s no real safety signals that have come up from that standpoint. Meropenem is meropenem, and ceftolozane, to date, has been, at least I can speak to my own experience, very well tolerated in patients. And I say that so when people ask whether they have side effects, they behave like cephalosporins, they behave like carbapenems, from that standpoint.

Sandy J. Estrada Lopez, PharmD, BCPS (AQID): There’s a confidence that we don’t have with colistin, polymyxin B, even aminoglycosides from that standpoint. So, when you think about the alternatives, then you feel even better about the safety.

Jason Pogue, PharmD, BCPS-AQID: And you can even see that in some of, to Sandy’s point, the small retrospective case series that have come out with ceftazidime/avibactam. For example, you see not only improved outcomes, but you also see significantly decreased toxicity when you compare it with the polymyxins, which are poison.

Andrew Shorr, MD: But in that same vain, I think for all these agents, there is the risk for emergence of resistance on therapy or the risk for creating emergence, particularly as we’ve seen with Avycaz and the Pittsburgh experience. If you use that drug over and over again in the same patient, you will create, in the patient, a clone that is causing infection that is Avycaz resistant. These are not tools that engineer us out of the entire problem. They still need to be used smartly, and I think Brad Spellberg’s editorial, that one with the Pittsburgh papers kind of describing their experience, was quoting from Jaws: “We need a bigger boat.” So, I don’t think you could use these willy-nilly and they’re going to solve the problems. The principles of stewardship, that I know we’ll talk about in a minute and that my colleagues all live every day and really enforce, become even that much more important and that much more crucial if you’re going to bring one of these drugs into your hospital.

Jason Pogue, PharmD, BCPS-AQID: So, to that point, I just want to elaborate or add a couple of things on to there.

Andrew Shorr, MD: At least you’re not disagreeing.

Jason Pogue, PharmD, BCPS-AQID: I’m slightly disagreeing.

Peter L. Salgo, MD: He’s getting there.

Jason Pogue, PharmD, BCPS-AQID: So, again, obviously resistance, and I think you’ve seen it a lot with ceftazidime/avibactam in the published stuff, and a lot of that comes from the fact that it has borderline activity to begin with. Some of those MICs to begin with are 4 or 8, and if I had ceftazidime at a 4 or an 8, I’d expect certain things to occur in that scenario. And I think that when people are actually comparing it—as Deb said, CRE, CRE, Pseudomonas—I think one of the most notable differences between the 2 new agents is potency. Again, meropenem is often active against KPC on its own, and so now you’re adding a β-lactamase inhibitor to that instead of ceftazidime. And I think that that thought process should go into your choice between the 2 because they’ve actually done some data that suggest that because they pharmacodynamically optimize meropenem and because they give 6 g of a β-lactamase inhibitor, it seems to have less of a propensity to have that situation occur.