Outsmarting Resistant Infections - Episode 5

Factors in Choosing Therapy for Gram-Negative NIs

Peter L. Salgo, MD: Now that we sort of set the landscape here, I don’t think anybody is really that ignorant of what’s going on in terms of where patients go, what they get, and how they get treated. You get a patient. What are the important patient and disease factors that you consider when you’re deciding on a treatment?

Sandy J. Estrada Lopez, PharmD, BCPS (AQID): This is key. We mentioned earlier that you get a student or resident, and they think, “OK, infection. I want to give an antibiotic.” And so, they come to an ID rotation perhaps wanting to be told, “OK, this infection, this antibiotic, get the little checklist, and get it right.” But unfortunately, as I’ve heard my colleagues and I say recently, the answer to every question in ID depends, and it’s very much because of all of this.

Peter L. Salgo, MD: Is that true? Oh, it depends.

Sandy J. Estrada Lopez, PharmD, BCPS (AQID): It is true because every patient is different. And so those patient factors, as Andy already mentioned, immunocompromised, these types of things are important to other risk factors that the patient may have. Have they been in the hospital recently? Did they just come from an LTACH (long-term acute care hospital), or are they a previously healthy person? Do we suspect a bug? Do we have a high suspicion, based on what we know about the patient, of a bug, or even better yet, do we actually have a culture and susceptibility?

Peter L. Salgo, MD: OK, well, that implies something. Let me stop you right there because I know he mentioned in passing it means somebody sent a culture, right?

Sandy J. Estrada Lopez, PharmD, BCPS (AQID): Exactly.

Peter L. Salgo, MD: So, one of the things you’re going to do is get a culture. That would be useful, right?

Sandy J. Estrada Lopez, PharmD, BCPS (AQID): Right, that would be useful.

Peter L. Salgo, MD: You’re going to consider the pathogen.

Sandy J. Estrada Lopez, PharmD (AQID): Yes.

Peter L. Salgo, MD: You’re going to consider, as you pointed out, the institutional history. What do we see in this hospital. Is that what you’re talking about?

Sandy J. Estrada Lopez, PharmD, BCPS (AQID): Right. If I’ve never seen a CRE (carbapenem-resistant enterobacteriaceae) before then, yes, I’m aware of it, but I’m not probably going to say, “Oh, I really think we should empirically cover for it until I do start seeing it.”

Peter L. Salgo, MD: What about source control in the sense of where is this bug coming from. Does that make a difference?

Sandy J. Estrada Lopez, PharmD, BCPS (AQID): Absolutely. If my source is urine, then it’s very different empiric coverage than if it is pneumonia or something else.

Peter L. Salgo, MD: And does it matter how sick the patient is? In other words, if you suspect this is from here with this bug, and you’re going to give this drug because you’re convinced that probably is a good idea, does it matter whether the patient is a little bit sick or making lactate like there’s no tomorrow and there may be no tomorrow?

Debra Goff, PharmD, FCCP: You know, that’s the “It depends.”

Peter L. Salgo, MD: Oh, thank you so much. You were right, you know that?

Debra Goff, PharmD, FCCP: But I think when you see a 23-year-old bone marrow transplant patient, your threshold to pull out the big guns—one of the newer agents—you know you’ve got 1 shot to get it right. And if you don’t have rapid diagnostic tests in your hospital to tell you immediately what the organism is, you can’t blow that 1 shot. So, my trigger to allow a newer agent to be used in that patient absolutely is a little different from the 90-year-old nursing home patient who the family is already contemplating whether this is a DNR do not resuscitate and we are calling it a day. They are different patients, even though they might have an equal risk for multidrug-resistant gram-negative infection. How we would approach might actually be different.

Peter L. Salgo, MD: And I think the severity-of-illness piece comes into that same story, as well, right? So if they’re going right to Andy in the ICU and they’re hemodynamically unstable, they’re getting dumped with fluids, the patient is at the same risk for drug resistance. But my threshold for needing to cover is much larger than a patient who’s coming from the nursing home with “mental status” changes because they’re dehydrated. And, sure, 40% of the time, that urine, if they culture it, it’s going to have an ESBL (extended spectrum β-lactamase) in it, but that doesn’t mean a) the patient has an infection and b) that I have to be crazy up front from that standpoint.

Andrew Shorr, MD: Two other issues, I think, that are important to consider are focusing on what is the clinical evidence supporting the molecule. There are some drugs where we actually have head-to-head trials and we can argue about, say, the linezolid versus vancomycin literature in nosocomial pneumonia. But there are some cases where we have in vitro active options and we look at the clinical data to guide us. For some of the newer agents, some of them have clinical data in certain disease states or certain syndromes and don’t in others. Now, the absence of proof isn’t proof of an absence, but I think we all prefer to go where there are actual clinical trial data than when there are not, or at least some guidance on how to dose some of these drugs. Because the history of drug development is littered with pneumonia failures where it looked great in the urine or looked great in skin, and they studied it in pneumonia and, lo and behold, it didn’t work because it was inactivated by surfactant—which, last I checked, happens to be in the lung—or, for example, it’s underdosed because of lung penetration.

All those things matter, and at the same time, I think another thing that’s important to consider is the patient’s renal function. And those are issues that I consider in terms of not only the dosing of the drug but how nephrotoxic might the drug be, what are the issues with nephrotoxicity. I think that relates a lot to the recent literature on the interaction between piperacillin/tazobactam and vancomycin because I think vancomycin is given like water, and piperacillin/tazobactam is abused considerably. And everybody thinks, “Well, there’s no harm,” and then we look, and it’s like, “Ew.” The interaction might be something here that we never consider. This might be dangerous because of what this kind of penicillin is doing with this kind of glycopeptide. And so, I think all those things need to go into consideration.

Jason Pogue, PharmD, BCPS-AQID: But I would kind of counter a little bit that absolutely you want to see clinical trial data, but when you’re talking about using one of the new agents for an XDR (extremely drug resistant) or Pseudomonas or CRE, the chances of having good robust data in that population are poor. But your point is really well taken that, is there surfactant? So, if the right preclinical work is done, you can predict that you have a pretty good likelihood of having a good outcome in that situation. I would disagree to a degree that I need robust clinical data in this exact disease state.

Andrew Shorr, MD: Right, especially when you’re all trying to use colistin. The concept of robust data is nonexistent. And so, again, it’s a trade-off question. It’s a risk versus benefit, and this is why it’s 2 to 3 years of training to figure out how to do this, because it’s a complicated calculus. And that’s why all these things need to be considered.