Lipoglycopeptide Therapies for Gram-Positive Infections

Segment description: Peter L. Salgo, MD; Yoav Golan, MD; and Bruce M. Jones, PharmD, BCPS, review the advantages and disadvantages of newer long-acting lipoglycopeptide antibiotics, such as dalbavancin and oritavancin, compared with the standard treatment of vancomycin.

Peter L. Salgo, MD: Now, you did mention that we had some new agents coming up, and I promised we’d get to them. There are at least 2; let’s take a look at these. There’s dalbavancin and oritavancin, right? What’s so special about these drugs that we’re talking about them today in this setting?

Yoav Golan, MD: What makes them special is that they both have activity against the relevant pathogens that are the most common causes of skin infections, which are gram-positives: Streptococcus and Staphylococcus, including MRSA (methicillin-resistant Staphylococcus aureus). Their spectrum of activity is very relevant to skin infections, and both are indicated for acute bacterial skin and skin structure infections.

Peter L. Salgo, MD: These are lipoglycopeptides, right?

Yoav Golan, MD: That’s right. They are like, in a sense, a new-generation vancomycin with some additional properties. Of course, what makes them unique is their very long half-life, which allows the entire course to be given in 1 infusion.

Peter L. Salgo, MD: The entire course in 1 infusion. What does that mean?

Yoav Golan, MD: Well, it means that once you are done infusing the antibiotic, you take away the need for IV antibiotic, as an indication for anything. We just had a long discussion about the fact that many patients get admitted from the emergency department for the sole reason of requiring IV antibiotics. Once you give them the last drop of one of those 2, oritavancin or dalbavancin, by that, you have taken away the IV antibiotics. You took away the 1 indication for admitting them, and now there’s no reason to admit them. That’s only 1 example for that; another example is, if you compare them with a long course of a multiple-times-a-day antibiotic like vancomycin, for example, their effectiveness is equivalent.

Peter L. Salgo, MD: Let me be sure I’m hearing this correctly; maybe I’m not. Their half-life is such that if you give them 1 dose, they don’t have to come back ever again for more antibiotics, or 1 dose is good for the day? What are you saying?

Yoav Golan, MD: It’s 1 dose, and then they don’t have to come back. You gave them all the antibiotics that they needed, and they don’t have to get any additional antibiotic therapy.

Peter L. Salgo, MD: You’re kidding, right? This is good.

Yoav Golan, MD: Well, try to imagine we have a 1-dose antibiotic for any type of infection.

Peter L. Salgo, MD: I’m just flabbergasted; this is wonderful. Now we have these 2 agents. First of all, activity against gram-positive and gram-negative. What are the advantages and disadvantages here in terms of resistant species? What does all of this look like?

Bruce M. Jones, PharmD, BCPS: Activity specifically against gram-positives—a very similar profile to that of vancomycin—you’re not going to have the gram-negative coverage. Outside that, as he mentioned, being able to give a full course of therapy at one time. Very similar profile between oritavancin and dalbavancin, but there are some unique properties that distinguish them. If you look at a cost standpoint, there’s a little bit of a difference, but specifically, infusion time as an example. Dalbavancin, 30-minute infusion versus a 3-hour infusion for oritavancin. Some of the other things that get lost in there, too, are also minimum volume. Dalbavancin can go in as little as 300 mL, where you have to put oritavancin in a liter. If you look at mechanism of action, dalbavancin has one mechanism of action, very similar to vancomycin. Oritavancin has 2, maybe 3; so multiple mechanisms of action. If you look at profile, we touched on a little bit about gram-positive coverage. I will say, too, especially with enterococci species that are vancomycin-resistant, I would have a lot more confidence in oritavancin. Overall, besides that, they have pretty similar properties.

Peter L. Salgo, MD: What about allergic responses, side effects of these drugs, downsides of either? Compare the 2.

Bruce M. Jones, PharmD, BCPS: Especially with these drugs, the biggest thing I would worry about if I’m giving one of these is that it is going to stay therapeutic for 2 weeks and going to stay in the body maybe even as long as a month. What happens if they have an allergic reaction or a side effect? When you have specifically some of those, like dalbavancin as an example, they have over 2500 patients in their phase II and phase III studies that they’ve looked at. They specifically looked at safety and tolerability, and what they found was that from a side effect standpoint, they were very similar to competitors—linezolid and vancomycin. Also, they looked at how long those adverse events last. They actually lasted shorter amounts of time, so good safety and tolerability.

Peter L. Salgo, MD: Even though the main drug antibacterial effect lasted longer, the side effects were not a bigger issue.

Bruce M. Jones, PharmD, BCPS: Absolutely.

Peter L. Salgo, MD: That’s reassuring anyway.

Yoav Golan, MD: There were a few additional advantages over vancomycin. We mentioned earlier that we push the trough levels of vancomycin high, and we now see more and more kidney toxicity.

Peter L. Salgo, MD: You’re scaring me with that.

Yoav Golan, MD: Well, that’s the reality of life. I think that the kidney toxicity is lower with dalbavancin. We don’t have to monitor levels, by the way, so it takes away this entire system of having to monitor levels and what do you do with the levels. The other thing is that you can infuse it relatively quickly, as you heard; 30 minutes. With vancomycin, we tend to start with an hour, and if someone has any type of itchiness or other side effect, we usually increase it to 2 hours. Despite that, infusion-related side effects that have been an issue with this class of antibiotics have actually been seen in far less than 2% of patients in the clinical trials, and there were quite a few people in the clinical trials. Both of those antibiotics are convenience antibiotics, and when you look at convenience, you also have to look at the convenience of the infusion itself. Part of the fact is that you can give an entire course in a half hour; another fact is that you don’t need a PICC (peripherally inserted central catheter) line or a mid-line, which is a procedure by itself. As you know, in many hospitals, you need to have special procedures to do that, and the cost is very, very high; it’s many hundreds of dollars. You don’t have to go with that stuck in your arm and having the risk of bacteremia and other infections related to the line. There are multiple advantages, and I’m not even mentioning all the advantages that have to do with the fact that if you get this, you don’t have to be admitted and all those risks of being admitted.

Bruce M. Jones, PharmD, BCPS: That’s a very big point, too, that gets lost: the central line, the PICC line. You mentioned cost, over $1000 to get a PICC line in, especially if you start including adverse effects from having it, if you take an average. Being able to not have a central line in these patients. I can’t say for other institutions, but for us, we have a very low threshold in patients who are admitted, putting a PICC line in.

Yoav Golan, MD: There is 1 more difference; both antibiotics are terrific antibiotics that, for the very first time, expand our ability to treat patients and actually make us change a paradigm. We were talking about the paradigm change from admitting everyone for IV to maybe not admitting many of them and treating them in outpatient settings, with at least as effective a strategy, if not even better, in terms of safety and not having to be admitted to the hospital. Another difference between the 2 is the stability. Dalbavancin is stable for a longer period of time, and sometimes it doesn’t really mean much, but once you dispense the antibiotic in the emergency department, you really have to complete the infusion of oritavancin within 6 hours. Three of those 6 hours are the infusion time. Sometimes what happens in the ED, maybe more so than in the ward, is that the patient was just sent to the CAT scan or to have an X-ray, and by the time the patient comes back, it may be too late. When you talk about convenience, you have to look at all those factors that determine convenience, like the infusion time and stability and interference with blood tests for coagulation and so on.

Bruce M. Jones, PharmD, BCPS: I’ll be the pharmacist in the room. That’s the great thing with dalbavancin: no drug interaction. We know oritavancin does have interactions with some of our routinely used anticoagulation tests, but besides that, from a drug interaction standpoint, these are great options.

Peter L. Salgo, MD: The INR (international normalized ratio) is the INR, the APTT (activated partial thromboplastin time) is the APTT?

Bruce M. Jones, PharmD, BCPS: Yes.

Peter L. Salgo, MD: Let me ask some standard questions about any antibiotic. Platelets; any activity against platelets? Do you see platelet counts drop?

Yoav Golan, MD: It’s not a major problem for any of those 2.

Peter L. Salgo, MD: Do you see red man syndrome?

Yoav Golan, MD: Well, red man syndrome, you can see with any glycopeptide, but it’s far less common with those long-acting ones, compared with vancomycin, and it’s far, far less common with dalbavancin. That’s the main reason why you can give it in a relatively quick infusion.

Peter L. Salgo, MD: I get it. So that, in fact, is one of the reasons that you can speed it up.

Yoav Golan, MD: It’s one of the reasons that you can speed it up.

Peter L. Salgo, MD: I’ve seen red man syndrome. I don’t want to see it again. Are these drugs bactericidal, or are they static?

Yoav Golan, MD: They belong to a class of antibiotics that’s considered to be bactericidal. As you know, all antibiotics inhibit the growth of bacteria; that’s why they’re antibiotics. Some antibiotics kill bacteria quickly, and those are bactericidal antibiotics. If you compare the MIC, or the minimal inhibitory concentration, of Staphylococcus aureus with vancomycin versus that of any of those 2—milligram per milligram—the concentration of antibiotic that you need for those 2 is much, much lower than that of vancomycin. These are far more potent antibiotics, and that’s why you can give far less of those 2, compared with vancomycin, to achieve the same result.

Bruce M. Jones, PharmD, BCPS: Both of these are bactericidal agents, but if you compare them to vancomycin specifically, I would probably consider vancomycin more of a slowly bactericidal agent. I think that’s one of the big differences.

Peter L. Salgo, MD: When the residents ask, “Does it matter if something is bactericidal or static?” …I’m not actually sure it does, except in those patients who are immunocompromised and whose white cells don’t work very well; maybe a bactericidal agent is better.

Yoav Golan, MD: We don’t know. Bactericidal is better than inhibitory because bactericidal is inhibitory as well. You have 2 antibiotics that inhibit the growth of bacteria, but one also kills bacteria quicker; so, it’s definitely not a bad attribute. To what extent is it a good or necessary attribute, we don’t really know. I would argue that in skin infections in most patients, it’s probably not necessary.