SCCM Resource Library-How Slow Can You Go? Alternate Dosing Strategies for Beta-Lactam Antibiotics

Video Transcription

be here today and wrapping up our session on optimizing antibiotic dosing in our critically  ill patients. So I'll be discussing how slow can you go alternate dosing strategies for beta-lactam  antibiotics. My name is Melissa Thompson-Baston. I'm a clinical pharmacist and researcher at the  University of Kentucky, assistant professor of pharmacy at the University of Kentucky College  of Pharmacy. I have a couple of disclosures to provide. I have consulting advising agreements  with Baxter Healthcare and Ledient Biosciences and funding in this area of research with the American Society of Health System Pharmacists and the University Hospital Foundation.  Our main three objectives today are to review the clinical data and controversies surrounding beta-lactam dosing in sepsis patients, to examine the relationship between beta-lactam  pharmacokinetic and pharmacodynamic target attainment with clinical outcomes in these patients, and then to provide rationale for alternative beta-lactam dosing strategies  in critically ill patients in order to improve outcomes. So to briefly touch on the background  that we're talking about today of sepsis, it's a devastating diagnosis affecting almost a million United States patients a year, and it's extremely expensive and costly to the  healthcare system. And it's responsible for a million cases globally worldwide, causing 11  million deaths annually. It has a mortality rate of 20 to 30 percent, which increases with increase  in organ dysfunction. And we know that early administration and appropriate dosing of  antibiotics can reduce mortality. And unfortunately, the care of sepsis patients over the last 10 to  15 years has been a little bit static. Without any new direct drugs to help benefit patients  with sepsis, we're going back to some of our old tools in the box and looking at the way we're  dosing antibiotics, specifically our beta-lactam antibiotics. And so today, we're re-evaluating  how we're giving these antibiotics in order to help improve the mortality outcomes for these  patients. And the real crux of the problem today is that the backbone for sepsis treatment,  being the beta-lactam class of antibiotics, was studied and approved and is labeled for use in  patients without critical illness. And so the FDA-labeled dosing was not studied in a critically  ill patient that we're seeing at the bedside. And the extrapolation of the package insert,  and the dosing information, and the expected pharmacokinetic parameters that we would achieve  with these doses that have been approved and labeled, do not extrapolate well into our ICU  patients. And so understanding that these drugs were studied in a controlled setting with healthy  young men, usually, and few of them because they're pharmacokinetic studies. So how this drug performs in an ICU patient is much different than what we would have expected  as it performed in the labeling studies. So critical illness drastically increases beta-lactam volume of distribution, among other pharmacokinetic parameters. Volume of  distribution increases are due to multiple mechanisms. We're seeing a net increase in interstitial fluid accumulation. This can be due to endothelial injury, resulting in increased  capillary permeability. And this is exacerbated by one of the mainstay treatments for sepsis-induced  hypotension, which is intravascular volume expansion with our crystalloid or colloid products. This can be especially notable and detrimental for hydrophilic drugs,  like our beta-lactam antibiotics. And one of the good studies to look at down here below is looking at patients who were treated for their sepsis in the early stages of sepsis,  and they had hyperdynamic sepsis. So this was an 80-patient study. 27% of these patients had  acute kidney injury. 71% were on the ventilator. They had a high APACHE-2 score. And their 24-hour  fluid balance was about 2.5 liters positive. So a very sick ICU patient that we would see at the  bedside, in our medical ICU at least. And what they did was they measured the volume of distribution  of piptezoarzoosin, meropenem, and cefepime in these patients, and they compared it to the labeled  volume of distribution found in the package insert. What they found was that the critically  ill patients' mean volume of distribution was almost double that what we would expect from  the healthy volunteers in labeling and package insert. And so thus, if the volume of distribution  is almost double, you would essentially need to double your dose to overcome this pharmacokinetic  alteration seen in these critically ill patients. Another study highlighting the volume of  distribution changes in critically ill patients who are administered beta-lactam antibiotics.  This figure comes from a meta-analysis and systematic review of 57 studies looking at  beta-lactam dosing in ICU patients. And just to orient you to the graph, we have liters of volume  of distribution on the x-axis, and the y-axis is the drug that was measured. The open circles reflect  the median volume of distribution labeled in the package insert, so what we would expect from our  healthy volunteers. The filled-in box with the line through it is the mean median and intracortial  range of what was measured in these critically ill patients in the systematic review. And so you can  see, for example, meropenem at the very top, the volume of distribution being somewhere between 10  and 20 liters. And what was measured in these patients was closer to 30 liters with a very  wide range. It doesn't even cross into the value of what we would expect in a normal healthy  volunteer. And so this is similar for piperacillin and cefepime. Those are the big three that we use  in the United States, but again, all of these antibiotics showed alterations. And what really  highlighting the fact that these patients have a wide range of measurements in their volume of  distribution, and sometimes it doesn't even come close to looking what it would expect from healthy  volunteers. Another relevant pharmacokinetic alteration found in critically ill patients that  impacts beta-lactam distribution and clearance is augmented renal clearance. Augmented renal  clearance is defined as an elevation in creatinine clearance above 130 mLs per minute, and it has a  16 to 100 percent incidence in ICU patients, depending on what population we're looking at. It has a set of risk factors that have been pretty well established across different  populations. So a younger age, a low baseline serum creatinine and sepsis is what we're really  focusing on today. But also if your patient has any of these concomitant injuries,  specifically burn or brain injured patients, are really susceptible to augmented renal clearance.  Also in neutropenic fever patients and patients with cystic fibrosis. So augmented renal  clearance is really ultimately an increase in glomerular filtration that is a result of direct impact of the critical illness, releasing inflammatory mediators, and combined with  the drugs and the therapies that we're using to help counteract sepsis-induced hypotension  and treat the sepsis in general. And so you have pro-inflammatory mediators, vasoactive drugs,  and fluids also expanding the intravascular space. It can increase cardiac output. It results in  increased renal blood flow. And this can be directly measured with our creatinine-based  equations like Cockcroft and Galt and Salazar equation. And it's also most accurately measured  with a 24-hour urine creatinine collection. But regardless of how it's diagnosed and measured,  the presence of augmented renal clearance is going to enhance elimination of our drugs like  our beta-lactam antibiotics. So throughout the rest of the talk today, we're going to be discussing  beta-lactam target attainment as it relates to therapeutic drug monitoring and concentrations  that we can measure. And so it's important to understand that beta-lactams are time-dependent  killers. And to orient you to this concentration time curve that we have here, so we have  antibiotic serum concentration on the y-axis and then time after the antibiotic administration on  the x-axis. And as you can see, with the rapid infusion of a drug, you achieve a Cmax. And then  you have slow elimination over a set time frame. And this really is dependent on the half-life of  the drug. And so for example, if the dotted line at the bottom here is labeled MIC, this is the  minimum inhibitory concentration of your bacteria. And so you're going to want your antibiotic  concentration to be at least at the MIC level. And for beta-lactam antibiotics specifically,  this sweet spot, if you will, is a threshold concentration above the MIC for a certain amount  of time above the MIC. And so we're not really that interested in the peak concentration of the Cmax concentration. As suggested here, aminoglycosides and fluoroquinolones are best  to find their bacterial acetyl activity by the Cmax to MIC ratio. And then again, like vancomycin,  we're all used to AUC monitoring of vancomycin. But really, beta-lactams are time-dependent killers,  but they also are dependent on this concentration that we're achieving as well as the time above the  MIC. And so it's been established that the beta-lactam killing improves with the time and the concentration above the MIC. And we can see bacteriostatic effects of our beta-lactams  at 35% time above the MIC for cefepime, 30% for piperacillin, 20% for maripenem. This improves  the bacteriocidal effects when you improve that time above the MIC to above 60 to 70% for cefepime,  50% for piperacillin, and 40% for maripenem. But it's been suggested in the literature and something we're going to argue today is that perhaps a more aggressive pharmacokinetic  target of 100% time fourfold above the MIC. And so this would be the most aggressive pharmacokinetic dynamic target we could achieve with beta-lactam dosing. And it's been suggested  that this can improve bacterial killing, reduce resistant isolates, increase microbiologic care,  and improve outcomes in critically ill patients. We're going to go into some of the literature  that supports these claims here in a minute. So one of the most important and groundbreaking studies that has evaluated beta-lactam concentrations in ICU patients is the DALI study.  And so it's defining antibiotic levels in intensive care patients. Are current beta-lactam  doses sufficient for critically ill patients? So this was a prospective multinational point  prevalence study. Patients who consented into the study had two beta-lactam levels drawn during  the study period. One was a med dose and one was a trough. And what the investigators wanted to  look at was the probability of having a good outcome for these patients, which was defined  as finishing your course of antibiotics without need to escalate and without need to change therapy  at the end of course. They also looked at achieving the pharmacokinetic pharmacodynamic goal. And this is really where we see the separation of this more aggressive goal 100%  above the MIC. And so what they found here in results of the multivariable regression  for patients who did not require dialysis was that controlling for other variables in the model,  achievement of the 50% time above the MIC threshold was associated with the 2% positive  odds positive outcome. And achievement of the more aggressive goal of 100% time above the MIC  was associated with the probability of positive outcome 2%.  And overall, 35% of patients achieved these pharmacokinetic and pharmacodynamic goals.  What we don't have in this study is any dose adjustments based off of these concentrations.  And so this was really just an observational study looking at these antibiotic concentrations  in these patients. But it is one of the first studies that really lays the framework for us to  understand that this is a reasonable pharmacokinetic target for beta-lactam antibiotics. And it can be associated with improved outcomes in critically ill patients.  And so this is another study that evaluated the relationship between beta-lactam antibiotic concentrations and different outcomes in ICU patients. This was  a prospective observational trial of 79 patients receiving continuous infusion antibiotics,  beta-lactam antibiotics. 50% of these patients were on vasopressors, 20% had ARDS, which was  a critically ill patient population that they were able to obtain this data from. And so this was,  this data was a result of their logistic regression modeling, looking at risk factors for sub-exposure and the impact of sub-exposure on therapy failure. And so highlighted in the  middle, patients who failed to achieve this higher time above the MIC threshold of four-fold above  the MIC actually had a six-fold increase in the odds of therapeutic failure. And then looking at  variables that were associated with being in the group of sub-exposed to these antibiotics. And what they found was that patients with elevated creatinine clearance of above 170  mils per minute, so well into this augmented renal clearance range, were actually much more likely to experience sub-exposure. So 10-fold more likely to experience sub-exposure.  And then additionally, of all the patients in the study, 20% of these patients failed to  meet this target. And within that population, it was associated with development of resistant  organisms. And so it's one of the first studies that really starts to put together multiple  outcomes that are associated with sub-exposing these patients to the ideal beta-lactam dose.  So development of resistant organisms was independent of the beta-lactam administered,  independent of combination therapy. So many of these patients received dual gram-negative rod coverage with either aminoglycoside or fluoroquinolone, and it was also independent  of infecting organism. And so we have some efficacy and some potential safety  data emerging from this study to really help us guide what is the ideal  beta-lactam pharmacodynamic target. And so in this same study, the authors sought to really evaluate the impact of creatinine clearance on this sub-exposure or this underdosing.  And so this figure A is the ROC curve for creatinine clearance and  underdosing. And so you can see that patients with an elevated creatinine clearance above 170 mLs per minute, very highly predicted underdosing in these patients, an AUC of 0.83.  So it really highlights some of the emerging data that we're talking about,  looking at the impact of augmented renal clearance on antibiotic levels in these ICU patients.  So taken together, the consequences of these pharmacokinetic changes in these critically ill patients and the impact on beta-lactam concentrations are really, they're dual-fold  that are especially important for our beta-lactam class of antibiotics. So a potential increase in  glomerular filtration or augmented renal clearance coupled with an increase in volume of distribution  is going to increase the total body clearance of these drugs. And so it's resulting in variable  drug concentrations, and it's increasing the risk of underdosing in these critically ill patients.  So I think we've thoroughly outlined the problem that we're really discussing today, which is sepsis is a highly morbid and deadly disease state. And the antibiotics that we're  using in these patients off of FDA labeling are probably inadequate in many cases. So I'm going to suggest moving forward in the rest of the talk, a multi-pronged approach to  really optimize antibiotic exposure to achieve this pharmacokinetic pharmacodynamic goal, and hopefully improve outcomes for these patients. So specifically, we're going to  look at the impact of aggressive dosing on this condition, the impact of prolonged or continuous  infusion administration strategies, and then go into some of the data regarding therapeutic drug  monitoring of beta-lactam antibiotics. So we're really beginning to learn that the one size fits  all approach does not work for beta-lactam antibiotics in patients with sepsis and now in hospitalized patients. And so the ASPECT trials were evaluating the efficacy of ceftolazone  tazobactam in a phase three non-inferiority study. So this was looking at complicated  intra-abdominal infections and complicated UTIs. What they found in a subgroup analysis of patients  with a GFR of less than 50 mils per minute were that the renal dose adjustments recommended for  these patients in this category of acute kidney injury was actually associated with poor microbiologic  response. And there's an emerging school of thought among ID and critical care experts that  this potential for renally dose adjusting your beta-lactam antibiotics within the first couple of days of their hospital stay and ICU stay specifically could be potentially really  detrimental. And so another paper that really highlights some of the controversy surrounding this  was a large database study done by Crass et al. And they looked at these patients who came in with  AKI and they wanted to see, you know, what does this AKI do over the course of time for these  patients in this hospital, their hospital stay. So there's hospitalized patients including ICU and  non-ICU patients. And so the rates of AKI in admission to the hospital is around 17.5 percent.  But interestingly, almost 60 percent of these cases resolved within 48 hours.  And so applying what we know about the altered volume of distribution for beta-lactam antibiotics  and then, you know, if we're using a measured creatinine clearance within the first, you know,  the first measurements of admission, if these AKI patients are going to potentially improve  their clearance over the next 48 hours, not only are we providing these patients with a lower dose,  assuming that this AKI is at steady state, which it is not, but we're also probably not achieving  the concentration large enough to overcome this altered and increased volume of distribution that  we're seeing or that we know to be seen in these patients. A lot of this is very difficult to do because we don't often have the ability to directly measure these concentrations.  But taking all of this together, the package insert dosing adjustments in acute kidney injury  patients for beta-lactams really may be inadequate in certain patient populations. And so it's really  difficult to predict whose AKI is going to resolve within 48 hours. But it's been suggested among  expert circles that potentially not dose adjusting your beta-lactam within the first one to two days of therapy could provide somewhat of a loading dose for these patients  to not only overcome that large volume of distribution that we're expecting to see, but also it gives the clinicians a couple of days to see, well, what is this AKI actually doing?  Because if the patient just needs a little bit of volume resuscitation and their pre-renal AKI  reverses quickly, you're going to want to have that patient on a larger dose or a dose at least  adequate to treat the potential infection that's underlying this condition altogether.  And so this is another study that really highlights that in certain patient populations,  we need to use much larger doses of our beta-lactams. And so this was a 59 patient study in a surgical trauma ICU. 61% of these patients had augmented renal clearance,  again defined as a glomerular filtration greater than 130 mils per minute. And what they found was  that a GFR of greater than 170 predicted underdosing perfectly in these patients. This  was associated with therapeutic failure in 4% of the non-ARC patients versus 19% of the patients  in the ARC group. And in order to overcome this accelerated clearance seen in the patients with  ARC, they did some modeling to find out exactly what dose of piperacillin would be needed for  different measurements of creatinine clearance. And so in table two here, if I followed down to  the highlighted row, so for an MIC of 16, we have the probability of target attainment at different  piperacillin doses. So at a dose of 12 grams, you have 55% chance of target attainment if your  creatinine clearance is above 200. And so what you would need essentially is if your creatinine  clearance is above 200, which many of these patients are who are young in the surgical trauma ICU, for example, who are highly susceptible to augmented renal clearance,  you're going to need doses of 20 grams a day or higher that would be needed for high MICs, such as the MIC for Pseudomonas to Proprosilin, would be 16,  you'll need a higher than labeled FDA labeled dose to achieve the concentration needed for optimal bacteriocidal effects.  So we've presented an argument for potentially using more aggressive dosing in these patients  and considering not dose adjusting for patients with acute kidney injury upon admission to their  ICU. Now we're going to move into some of the administration strategies, including continuous  and prolonged infusion of beta-lactam antibiotics. And so administering these antibiotics by  continuous or prolonged infusion will drastically increase the time above the MIC. And taking us  back to our concentration time curve here, you can see that with rapid infusion of the antibiotic,  you have achieving of a high C-max or C-peak, and then rapid elimination thereafter.  So just imagine if you had more studies, administration of the antibiotic, and then you find the concentration, and then you just deliver this drug at a set rate. And so instead  of delivering, you know, 12 grams of Proprosilin all at once, you deliver it over a 24-hour period, you will find that your concentration above the MIC would be potentially 100%  if you're achieving the accurate concentration. So the time of the MIC would be easily obtained  with continuous infusion. One of the challenges here is that potentially that concentration above the MIC would not be achieved with a continuous infusion. And so this has been  studied actually quite a bit in critically ill patient populations, because this is one of the easiest things that we can do clinically and implement immediately into our practices.  How do we give these antibiotics for patients?  So this is one of the larger meta-analyses available to help us understand the role of continuous and prolonged infusion beta-lactam antibiotics  in improving some of these outcomes, including mortality. So this was a 2018 meta-analysis  of 22 randomized controlled trials and evaluated the impact of infusion strategy. So prolonged  infusion strategy was defined as administering over three hours or more versus short term. So  that would be like a 30-minute bolus on various outcomes. And overall, we can see in this  figure two forest plot was that the prolonged infusion did decrease sepsis-related mortality,  and it overall was decreased by around 30%. However, the prolonged infusion was not associated  with improved clinical cure or microbiologic cure in some of the other analyses conducted in this paper. And one of the limitations to this is these outcomes are often not reported  in these studies, and some of these are also subjectively defined. So they're difficult to  extrapolate and really summarize in the meta-analysis type setting, as you can potentially  have heterogeneity among studies with different outcome definitions. All of these patients in  these studies had normal renal function, so it's hard to extrapolate what this would look like in  patients with acute kidney injury or chronic kidney disease. And again, in this paper,  as I'll state multiple times throughout the talk today, the use of concomitant antibiotics or dual  anti-pseudomotor coverage was really not evaluated well in these studies. And so that's an unmeasured confounder that we're not able to really fully assess the impact on these  outcomes. But overall, this meta-analysis is consistent with other meta-analysis in the  literature that providing continuous infusion or prolonged infusion beta-lactam antibiotics can  improve mortality in patients with sepsis. So the final approach we're going to talk about  for the rest of today is the role of therapeutic drug monitoring for beta-lactam antibiotics.  Therapeutic drug monitoring is considered a fundamental pharmacist activity. It's something  that pharmacists have been doing for hospitalized patients for over 50 years now. It's appropriate  for any therapeutic agent that has a narrow therapeutic index. And so drugs that, you know,  the difference between efficacy and toxicity is very narrow or substantial interpatient variability  with standard dosing. And really our beta-lactams fall into that latter category because we've  already demonstrated these widely erratic pharmacokinetic parameters that our critically  ill patients produce. The therapeutic index is relatively wide for beta-lactam, so it's maybe less important for toxicity and minimizing toxicity, but more important for maximizing  efficacy. So you have to have a known pharmacodynamic target, which hopefully today we've already  established that there are a couple of pharmacodynamic targets available for beta-lactams,  but what's really being emphasized in literature and showing to improve outcomes is the more aggressive target of four-fold above the MIC for 100 percent of the dosing interval.  And this activity can optimize efficacy to improve outcomes. And this has been shown throughout the literature with different antibiotics, aminoglycosides, vancomycin,  for example, antifungal agents, etc. It can reduce adverse drug events. However, it does  require a validated assay for measurement. And this is one of the biggest limitations right now,  at least in the United States, for implementing therapeutic drug monitoring of these agents is that there is no FDA-approved and widely available assay in order to perform these  measurements. And the clinical literature that is surrounding the role of beta-lactam therapeutic drug monitoring in critically ill patients is growing, and this is still  an underdeveloped field, I would say, and really the bulk of the data is coming out of Australia,  New Zealand, and Europe, and they're really leading the way for what we know as how to implement some of these strategies in order to improve antibiotic concentrations and hopefully  affect outcomes. And so, this is the target trial that was just published a little bit ago in 2022.  This study was a randomized controlled trial of 254 patients. They had to have had sepsis or septic shock. Patients were randomized to continuous infusion of piperacillin-tazobactam  with dosing guided by daily therapeutic drug monitoring or the piperacillin dose as a continuous infusion with a fixed dose. And so, the primary study outcome was actually change  in SOFA score from day one to day 10. And what I'll highlight here first is this figure three.  They also looked at the ability to achieve target attainment. And so, they did target the more  aggressive pharmacodynamic goal that we've been discussing. And so, the bars on the left  were the patients in the control group, so without therapeutic drug monitoring. And you can see that the bars highlighted in red, these are the number of concentrations on each day,  day one through five, that were below that pharmacodynamic target. The bars in green were  at target and the bars in blue were above. And so, we actually see both ends of the extreme in  patients who are unmonitored. So, many patients exceeded the pharmacodynamic target and many  patients were below. Really, not many patients were in the green here who did not have therapeutic drug monitoring-based dose adjustments. Versus the bars on the right-hand side,  which we do see that more of these patients actually achieved their therapeutic concentrations.  And so, 30 to 40 percent of these patients were perfectly within the goal. And still, there's  about 30 percent of these patients that were above goal. But it did minimize the patients who  were below that pharmacokinetic target, which is probably the most important takeaway message from  this slide, is that there was much less red in the TDM section of this. And so, again, the primary  outcome of this study was SOFA score change at day 10. And there was no difference between the two  groups with regards to this primary outcome. They did collect and look at other outcomes, however.  So, they found a non-significant reduction in IC mortality with the patients that did receive therapeutic drug monitoring-based dosing adjustments. And this was about a 4 percent  reduction, however, did not meet statistical significance. There was also a non-statistically  significant increase in clinical and microbiologic cure in the patients who received therapeutic  drug monitoring-based dose adjustments. And what they found also in multivariable regression  was that after adjusting for APACHE score, the patients who received TDM-based dose adjustments  did have better resolution of organ dysfunction defined by the SOFA score at day two. And so,  within the first couple of days, achieving that pharmacokinetic dynamic goal was associated with  improved organ dysfunction. However, overall, this study still has left the door open a little bit  with the role of therapeutic drug monitoring for ICU patients. Because, again, we did not see  the study outcome meet that primary outcome of SOFA score at day 10.  But some of the other outcomes that were established in this study are provocative and really start to help us understand maybe a better outcome to be measuring is just directly  measuring ICU mortality for patients receiving therapeutic drug monitoring-based dose adjustments  and or clinical and microbiologic cure. And so, some of the limitations of this study,  you know, they really did have low rates of target attainment. You know, the patients in the green  and in the blue really reflects about 75 percent of patients achieve target attainment, even though  they were guided by therapeutic drug monitoring. And that's something that highlights the real  world application and the challenge of therapeutic drug monitoring. I'm speaking from personal  experience. I do this every day in my job. It can be very challenging to do this, even though you  have the tools, all the tools at your disposal. And so, getting it right, even with the best  circumstances, is really challenging in these dynamic ICU patients. The bacteria that were  isolated in this study had very low MICs. And so, if we were to study, apply these methods in a  population with more resistance, we might actually see incremental benefit, as we know that the  higher concentrations are more efficacious with higher MICs. Again, the impact of dual gram-negative  rod coverage was not restricted. Of course, that's not something they'd be able to restrict in a  study like this, but they did do, however, I think a really good job with this data. So, they collected data on it and they did a sensitivity analysis. And so, the primary dual  agent of patients received in this study was a fluoroquinolone. And again, there was no difference  in any of these outcomes, but I think it was a nice sensitivity analysis looking at this real  world confounder that, you know, when these patients are really sick, we know oftentimes  we're going to pull the trigger on aminoglycoside or fluoroquinolone for these patients. And again,  this study was performed in Germany at centers with therapeutic drug monitoring available.  So, this really restricts the external validity of this study, especially to centers in the United  States where an FDA approved assay is not readily available. And most of the centers doing  therapeutic drug monitoring in the United States are doing it in research labs. So, taking our  measurements out of the research lab and into clinical patient care is a very heavy lift for an  institution. And, you know, there are some labs around the United States that you can send your  levels out to, but often are not available with a turnaround time that would be considered ideal  for making dose decisions in ICU patients. And so, overall, the target trial was the biggest randomized control trial of therapeutic drug monitoring beta-lactam antibiotics in ICU  patients. Mixed results in this trial, and I think it still leaves the opportunity to really find  what is the ideal patient population potentially, and adjusting some of these limitations  in future studies, I think, will be warranted.  The application of therapeutic drug monitoring to the beta-lactam class of antibiotics  and really finding the ideal patient population has been a point of controversy in the literature.  And so, there are certain pros and cons to consider, certainly. Some of the pros are, you know, these beta-lactams exhibit widely variable pharmacokinetic parameters, and we  really don't have the ability to predict who is going to have that large volume distribution,  who is going to have augmented renal clearance. We didn't really get into it very much today, but  using creatinine-based equations to diagnose and identify patients with augmented renal clearance is really challenging, and it typically under-recognizes augmented  renal clearance in these patients. But these patients also have a lot of other variations  that we didn't get to talk to today, because we are out of time, including hyperproteinemia,  the impacts of volume overload, and subsequent aggressive diuresis all changes the way these  drugs will behave in the body. There is a known pharmacokinetic dynamic parameter to target,  however, and we do have stepwise increments of this as well. And so, the less aggressive and  more aggressive target that we've been discussing today. There's plenty of evidence that suggests that current label dosings are providing sub-exposure for these patients. And so,  patients with augmented renal clearance experience suboptimal drug levels 20% of the time,  therapeutic failure 16% of the time, and it's associated with resistant isolates developing.  And then moving on to some of the cons, and I think it's, you know, something to consider and  potentially might really guide the population that we apply therapeutic drug monitoring to for  beta-lactam antibiotics. There's a lack of safety data, and I think a lot of people would be rightly  concerned for the additive toxicity, potentially cefepime-induced neurotoxicity and beta-lactam  induced neurotoxicity, which is getting a lot of traction in the literature and across expert  circles these days. And so, the rate of cefepime neurotoxicity is almost 26% reported during  recommended dosing, which is probably inflated when you're looking for it, but I think it's, you know, nonetheless still an important adverse drug effect that could potentially  be increased if we're increasing the doses of these drugs, although that remains to be seen.  The role of dual antibiotic coverage, and so why, you know, why don't we just use double coverage  more often, and I think that's a very valid point. So, you know, that literature is a whole  another hour-long session by itself, but controlling for this certainly in clinical trials moving  forward is going to be important, but, you know, utilizing this is another tool in the toolbox.  And there is a known dilemma and issue with therapeutic drug monitoring in general is that  serum concentrations or concentrations at the site of infection do not equate to concentrations at the site of infection, and so they're not the same as your tissue concentrations,  and there's plenty of data to support this, especially in critically ill patients really might have trouble getting the drug to the site of infection. Drug distribution into the  periphery might be impaired because blood flow might be impaired, and there's edema present preventing this, and so we don't have the ability to monitor directly the concentration  of these drugs at the site of infection, and that would be the most ideal way to do this.  So, we're extrapolating the concentration in the blood and assuming and hoping that it's getting  to where we need it to go. There are a lot of limitations related to MIC-based dose adjustments  and the one to two-fold dilution difference in potential MIC changes, and we don't have time to  get into that today, but that is just a limitation of utilizing MIC for anything is that there is  that open for interpretation. And then maybe one of the biggest cons right now is just the lack of  available of a reliable method, and so again, at least in the United States, there's not  an FDA-approved assay for beta-lactam measurements, so that really limits the ability of applying this tool to patients locally, for me at least, in the United States.  And so, I presented a three-fold approach to a solution to the problem for us today, and then I want to also mention, what are some of the challenges to the implementation?  And so, with the first point of aggressive dosing, and so I think that there is sometimes  reluctance among clinicians to provide aggressive dosing, and so the talk should really be labeled  not only how slow can you go, but how high can you go, right? So, we know that the Cary paper  that we've discussed earlier, that piperacillin dosing sometimes requires 20 grams a day to  achieve the ideal pharmacokinetic pharmacodynamic target in certain patients with augmented renal  clearance. And then again, literature surrounding renal dose adjustments within the first 48 hours,  it's really not well characterized and not well studied, and you know, an area for potential  future research in this field. But transient acute kidney injury in the setting of altered  pharmacokinetic parameters, such as this really large volume of distribution, really could set  the stage for underdosing in the first 48 hours. And we do know that subtherapeutic antibiotic  concentrations in the first 48 hours is associated with therapy failure and poor outcomes in ICU  patients. And so, putting two and two together here would really suggest that it might be a  good practice in certain patients to not provide a renal dose adjustment within that time frame.  And then the continuous infusion or prolonged infusion dosing strategy,  you know, this requires a multidisciplinary approach, probably looking at some institutional  protocol changes, you know, engaging our nursing colleagues as well. So, we need to have a dedicated IV line, and it might pose problems with IV access for certain patients. It also  could interfere with any type of drug sampling if it's pulled from the line. And so, there's just  a lot of potential logistic issues with using continuous infusion, especially in patients who  only have one IV line. And that's probably more of an issue with our pediatric patients, but a lot of this literature does extend into that patient population as well,  although really we were discussing the data for adults. But that's something to consider,  certainly the impact on our nursing colleagues, but tying up their one IV line with our continuous  infusion beta-lactam. And then therapeutic drug monitoring, which should just be the holy grail  to this whole clinical controversy. But, you know, it's just, it's not yet. And I think we're still  trying to find the best way to provide this service to patients and what patient population  would most benefit, what are the best outcomes to look at, et cetera. Again, there's not a widely  available assay, but the clinical data is growing. There are very few actual randomized  controlled trials. And then the variation in the PKAPD target, you know, is something to consider  as well. And then overall, I think the reluctance to go above package insert label dosing could be  causing some clinical inertia in this field as well. But that is something that probably,  as centers and folks and clinicians gain more experience with these different strategies to help overcome some of these issues with beta-lactam dosing and sharing their experience  with others. You know, I think once upon a time, everyone got the same dose of vancomycin.  And what are we doing now? We're monitoring vancomycin levels and we're tailoring the drug to the patient. I do believe beta-lactams will be going in that same direction.  We just have a few hurdles to kind of cross over before we get there.  So, in conclusion, our beta-lactam pharmacokinetics are altered in sepsis, resulting in variable target attainment. Standard FDA-labeled doses providing to these patients,  in many cases, fail to reach the optimal pharmacokinetic and pharmacodynamic target. And a couple of approaches have been proposed to overcome this, including aggressive dosing,  prolonged or continuous infusions, and utilizing therapeutic drug monitoring to improve the ability of reaching this optimal pharmacokinetic pharmacodynamic target  and ultimately improving patient outcomes. And with that, I want to thank you for listening today and for the opportunity to speak on this topic.

Video Summary

In this video, Melissa Thompson-Baston, a clinical pharmacist and researcher, discusses optimizing antibiotic dosing in critically ill patients. She focuses on the dosing strategies for beta-lactam antibiotics like piperacillin, ceftazidime, and meropenem. <br /><br />Thompson-Baston explains that sepsis, a devastating diagnosis, affects millions of patients worldwide and early administration of appropriate antibiotics can reduce mortality. However, the FDA-labeled doses for beta-lactam antibiotics were not studied in critically ill patients. The volume of distribution and renal clearance can be drastically altered in critically ill patients, leading to suboptimal drug concentrations. <br /><br />To improve outcomes, Thompson-Baston suggests alternative dosing strategies such as aggressive dosing, prolonged or continuous infusions, and therapeutic drug monitoring. Aggressive dosing involves using higher doses of antibiotics to overcome the altered pharmacokinetics in critically ill patients. Prolonged or continuous infusions increase the time above the minimum inhibitory concentration (MIC) of the bacterial pathogen, improving bactericidal effects. Therapeutic drug monitoring allows for individualized dosing based on drug concentration measurements, although challenges such as the lack of an FDA-approved assay remain.<br /><br />Thompson-Baston presents several studies that support these strategies, showing improved pharmacokinetic target attainment, decreased mortality, and higher clinical and microbiological cure rates. However, some limitations include the lack of safety data, the difficulty in accurately measuring tissue concentrations, and the need for institutional protocol changes and multidisciplinary collaboration.<br /><br />Overall, optimizing antibiotic dosing in critically ill patients requires a personalized approach to ensure adequate drug concentrations and improve outcomes.

Asset Subtitle

Pharmacology, 2022

Asset Caption

Guidelines for vancomycin area under the curve (AUC)/minimum inhibitory concentration (MIC) monitoring were published by the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists in March 2020. Many institutions are developing new protocols for monitoring vancomycin, including the updated recommendation from the guidelines to use AUC/MIC monitoring in place of traditional trough monitoring. In addition, recent literature has promoted the use of continuous infusion beta-lactam dosing. In this flipped classroom session, attendees will bring local protocols and dosing schemes to launch a comparison with the newly published guidance and compare strategies by using audience polling. This session will also review the advantages and disadvantages of 2 level AUC pharmacokinetics and more advanced Bayesian AUC pharmacokinetics in an interactive session using simulated patient data, including initial dosing schemes and dosage revisions. A similar approach will be taken to determine time > MIC dosing for beta-lactam antibiotics using therapeutic drug monitoring techniques and extended/continuous infusion dosing approaches.

Meta Tag

Content Type Presentation

Knowledge Area Pharmacology

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Tag Antibiotics

Tag Pharmacokinetics Pharmacodynamics

Year 2022

Keywords

antibiotic dosing

critically ill patients

beta-lactam antibiotics

sepsis

aggressive dosing

prolonged infusions

therapeutic drug monitoring

pharmacokinetic target attainment

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