Strategies to Address Beta-Lactam Dosing Issues

Kenneth P. Klinker, PharmD, clinical associate professor from the University of Florida, and Jason M. Pogue, PharmD, clinical associate professor of medicine from the Wayne State University School of Medicine share some strategies to address beta-lactam dosing issues that they employ at their institutions.

Interview transcript (modified slightly for readability):

Kenneth Klinker, PharmD: There’s a fair amount of variability in drug exposure from patient to patient and we want to move towards dosing medication in a way that is specific for each patient. The minimally effective doses that have been identified in package labels are good for a certain population of patients but not for everyone, and we need to be more thoughtful.

A strategy that’s been employed at the University of Florida has been to develop assays to detect common beta-lactams: cefepime, piperacillin, meropenem, and ceftriaxone. We have 10 total beta-lactams that we will do assays on different samples in order to identify how much drug is in any one particular patient. As patients who have an active infection come in, we are able to grab samples, assay them, and make dosage adjustments based off that assessment, early on in the process.

In contrast, most other facilities are just changing the infusion strategy in order to achieve that goal of maximizing drug exposure. We’ve taken it one step further in saying, we want to know exactly how much drug is flowing through the vein at that point in time. We get 2 concentrations, we make an assessment, and then our goal is that we get enough drug on board to achieve cure, and hopefully get enough drug on board to minimize resistance selection, as well as, make sure that we don’t overshoot our target and increase the risk for toxicity. Our outcomes have really been centered on whether we are able to achieve our desired goals.

What we’ve seen is that [our results have been] consistent with what’s published in the literature. There’s a fair amount of variability in that most of our dosing strategies that we’ve integrated into practice, such as those using intermittent infusion strategies, oftentimes don’t achieve our desired targets and our desired target is a time above the MIC for a clinical cure of 100%. This is a more aggressive target in order to suppress resistance we actually looked at a CM/MIC ratio of 4 to really push the envelope to make sure that we not only kill the organism, but that we also don’t allow it to select out for more resistant pathogens.

We don’t have a ton of outcome data, but some that we do have is in the cystic fibrosis population which is a little bit different and a little more complex in regard to their infections. However, are seeing much longer windows of time that they are out of the hospital for exacerbations. We believe part of that (and the only thing we’ve changed) is that we’ve maximized drug exposure to try to decrease the bacterial count enough to where they have a longer time that they’re at home and don’t need to return again.

That is some of our earlier data focusing on pharmacokinetics, and really that is the real issue. The other variable is what are we starting to see is from an outcome perspective, and more is to come on that.

Jason Pogue, PharmD: I think it’s important to remember that with the beta-lactams, they are optimized by time above the MIC. This means that you need a sufficient amount of concentration for a given amount of the dosing interval from that standpoint. One thing that’s really nice about the beta-lactams is that they are generally well-tolerated agents and that gives you some opportunities to do some things.

The first thing you should be doing in these patients is giving them the maximum tolerable dose. You should be at the upper end of those package insert doses and I think that should be standard of care for patients when they are getting beta-lactams. They are safe because of all that variability that we just talked about, and you can get past that the best you can by giving them the most drug that you can.

In addition to that, because they are time-dependent antibiotics, you can do things with the infusion in order to keep concentrations above that MIC for longer periods of times. Ideally, you would give them as a continuous infusion, and you would always be above the MIC, but that can create some logistical hurdles, and so one thing we try to do at my institution as a standard practice to optimize those exposures is split the difference. We give the beta-lactams as extended infusions. About 3 hours is our standard and again, that allows us to be able to keep the concentration above that MIC for longer.

Hopefully this will optimize patient outcomes, including clinical care, and hopefully, it will decrease resistance development.

I think it’s worth mentioning that there are folks who are hesitant to go to extended infusions because what’s happening is that for 4 times a day, you are tying up a line for 3 hours. That’s 12 hours—half the day—and there are concerns that line needs to be there for other reason. The patient might have to give other medications; the patient might not want to be tied up to a pole the whole day from that standpoint, etc. What I’ll tell you, however, is that with everything we’ve talked about so far, the risk of not doing that is simply too high. The benefits of extended infusions outweigh any of those issues and I found in my experience, as long as you detail and talk to those end-users, and you explain to them what you’re trying to accomplish and why you can be very successful in getting that done.