SCCM Resource Library-46-Population Pharmacokinetic Evaluation of Cefepime in Critically Ill Adults

Video Transcription

Thank you very much for the opportunity to be here. My name is Erin Barreto. I'm an associate professor of medicine and pharmacy and a current scholar in the Center  for the Science of Healthcare Delivery at Mayo Clinic in Rochester and a practicing critical care pharmacist.  I'm excited to present on behalf of our team the population pharmacokinetics of cefepime in critically ill adults. These are my disclosures.  Beta-lactam antibiotics are assuredly the most commonly used antibiotic class in critically ill patients.  In a multi-center study of more than 35,000 hospitalized patients with sepsis, Lewin colleagues  showed that 75% of the critically ill were treated with a penicillin, a cephalosporin, or a carbapenem.  These drugs are the backbone of all major treatment algorithms, especially anti-pseudomonal drugs in the critically ill patients with sepsis or septic shock.  Pneumonia, bacteremia, UTIs, intra-abdominal infections, skin and soft tissue infections, and CNS infections typically all recommend beta-lactams as the first-line agent, barring  any contraindications. Beta-lactams are time-dependent antimicrobials, so this is a very traditional concentration  versus time curve, and you can see that this window here where the fraction of time that the free drug concentration exceeds the minimum inhibitory concentration of the organism is  the target pharmacodynamic index. Drug concentrations that are in excess of the ceiling for a prolonged period of time  could theoretically contribute to toxicity, which in the case of beta-lactams may be CNS toxicity, and drug concentrations that are below the floor or the minimum inhibitory  concentration for a substantial part of the dosing interval lead to a risk for antimicrobial resistance and clinical failure.  While we know the pharmacokinetic and pharmacodynamic indices that are preferred in the critically  ill patients for beta-lactams, what unfortunately persists is that there is widespread pharmacokinetic  variability in critically ill patients, making the observed beta-lactam concentrations unpredictable.  If you look here at some data from the DALI study, this is data that's about six years old but is very elegantly done.  It's a multicenter study that looked at beta-lactam concentrations across a variety of different drugs here, and I want to direct your attention to the panel B on the right.  This is showing the trough concentrations of beta-lactams that are observed in the ICU. What I hope you can appreciate is that on this logarithmic scale here, there is substantial  variability across patients in the observed beta-lactam levels. If we take cefepime here, you can see that some patients had a trough concentration of  one milligram per liter, whereas others had in excess of 60 milligrams per liter. So even with customary routine dosing, you can see that we're getting very different  levels for the patients, and for this reason, the Surviving Substance Campaign in their most recent iteration suggested that dosing strategies be optimized based on PKPD principles  and specific drug properties, in so much as they suggest evaluating ways to optimize the fraction of time above MIC for beta-lactams in the ICU patient population, whether that  be through initial dosing models or through therapeutic drug monitoring. So in this case, our objective for this study was to develop an optimized pharmacokinetic  model for cefepime in critically ill patients. And what makes this unique is that we sought to do it using opportunistically sampled data  as opposed to conducting a rich pharmacokinetic study using traditional sampling methods. This is a prospective cohort study of patients at Mayo Clinic in Rochester, Minnesota from  2018 to 2020. We included any adult who is admitted to the ICU who is treated with cefepime, and in our  institution it is quite customary to bolus the drug in as opposed to use extended infusion. So all of these patients had bolus drug over 30 minutes.  We excluded anybody with dynamic renal function, either recovering acute kidney injury or worsening,  dialysis dependence, or those who were on extracorporeal membrane oxygenation at the outset of beta-lactam therapy.  To give you an idea of our methods, what we did was we sampled at least three samples for each patient.  So here on the curve, you can see the orange dot representing a given patient. So we maybe have a sample prior to the beta-lactam concentration, maybe something after the second  dose and something after the fourth dose. For a different patient, again, prior to the first beta-lactam dose, but then maybe after the third and after the fourth.  And again, for another patient, maybe we have something after the first dose and after the third, and so on and so forth.  The purpose for this then is across patients, we start to develop insights into what the population distribution looks like for the beta-lactam concentrations.  In our sample of 84 patients, we had an average age of 64 years, about half men and half women, the predominant race ethnicity was Caucasian, which is customary for our institution.  We had a mean weight of 84 kilograms and a baseline estimated cramming clearance of 112 using the Cockroft-Gall formula.  43% of these infections were culture positive, of which 56% of those were considered gram negative infections.  And 74% of these patients were admitted for a non-operative indication, particularly respiratory distress or hypotension or cardiac complications.  And when you look at the pharmacokinetic models that we developed, the optimal volume of distribution identified was 31.7 liters.  You can see this graphically represented here, it had a 9% relative standard error and a 35% between subject variability.  And you can see that there are some patients here on the x-axis in the left pane who had substantially larger volumes of distribution.  Clearance was 5.6 liters per hour with a 4.5% relative standard error and 29% between subject variability.  And we demonstrated that it varied with estimated creatinine clearance, which is not unexpected  as we know that a kidney function primarily is the determinant of cephapene elimination. This study does have some limitations.  It's a single drug, single center study of a relatively homogenous population. However, we do have ongoing studies of Piptazone and Meropenem using similar methods.  We use total cephapene concentrations rather than free drug concentrations, which is an area of controversy.  However, in the case of cephapene, this is less consequential given the drug overall has a relatively low protein binding.  While use of remnant samples or clinical residual specimens is an attractive option in enhancing the feasibility of the study completion, there are some limitations of it.  As we have fewer samples for a given patient to use, we can only model a select number of parameters.  We also, because of the limitations, observed greater shrinkage than we would like. We saw 66% shrinkage for volume distribution, 36% for clearance.  This suggests that there is some issues with the individual estimates shrinking towards the population estimates that we developed. Ideally, you would have less than 20 to 30%.  But what we did demonstrate here is that it is feasible to use stored specimens to develop a population PK model for adults treated with beta-lactams.  This is important as it opens the door to future modeling studies using already existing data as opposed to having to conduct a whole host of very richly sampled pharmacokinetic  studies. Consistent with other literature, we demonstrated that the cephapene volume of distribution  in the critically ill is about two-fold higher than what has been represented in non-critically ill patients in the literature.  And this is not unexpected as we know that cephapene is a hydrophilic small molecule which is expected to have expanded volume of distribution in the ICU patients.  Additional studies are needed to further understand these pharmacokinetic parameters for beta-lactams and to develop optimized model.  Our next steps are to evaluate correlations between individual predictions and other elements of the patient characteristics including their severity of illness, fluid balance,  and other estimating tools for kidney function. I'd like to acknowledge our excellent study team and in particular call out Drs. Ruhl  and Sheets, Matt Bjergum, our development technologist, and Lori Mead, our study coordinator. And I'd like to thank SCCM for this great honor as well as specifically the NIAID for  support of this research study. I'm happy to take any questions so please do enter them into the system or send me an email and I'll get back to you as soon as I can. Thank you.

Video Summary

Dr. Erin Barreto, an associate professor of medicine and pharmacy at Mayo Clinic, presents a study on population pharmacokinetics of the antibiotic cefepime in critically ill adults. Beta-lactam antibiotics are commonly used in intensive care units (ICUs), but there is significant variability in their levels in critically ill patients, which can affect efficacy and toxicity. Using opportunistically sampled data from 84 patients, Dr. Barreto and her team developed an optimized pharmacokinetic model for cefepime in critically ill patients. The study found that the volume of distribution of cefepime in critically ill patients is about twice as high as in non-critically ill patients. Further studies are needed to better understand the pharmacokinetics of beta-lactams in this patient population.

Asset Subtitle

Pharmacology, 2021

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2021 Critical Care Congress held virtually from January 31-February 12, 2021.

Erin Frazee Barreto

Introduction/Hypothesis: Anti-pseudmonal beta-lactams such as cefepime are the cornerstone of antibiotic regimens for intensive care unit (ICU) patients. Significant variability exists in the pharmacokinetics (PK) of cefepime in ICU patients. The objective of this study was to develop an optimized PK model for cefepime in this population using opportunistic sampling from remnant serum samples collected as part of routine care.

Methods: A prospective cohort of adults admitted to the ICU at Mayo Clinic, Rochester, MN from November 2018 to March 2020 treated with cefepime (bolus over 30 minutes) were studied. Patients with acute kidney injury, dialysis dependence or exposed to ECMO were excluded. We performed a PK evaluation based on the total cefepime concentrations obtained from 3 serum samples per patient (residual specimen from blood obtained during ICU care). Samples were stored refrigerated before assaying for approximately 3-days. A 1-compartment non-linear mixed effects model was fit using Monolix. Model inputs included dose, interval, concentration, body surface area (BSA) and estimated creatinine clearance (eCrCl) based on the Cockcroft-Gault equation.

Results: There were 84 ICU patients included with a mean Â± SD weight of 84 Â± 23 kg, BSA of 1.94 Â± 0.28 m^2, and eCrCl of 112 Â± 67 mL/min. Final parameter estimates (relative standard errors) in the population included a Vd of 31.7 L (9.0%) with a between subject variability (BSV) of 35% and a clearance of 5.6 L/h (4.5%) with a BSV of 28.5%. Volume of distribution (Vd) varied with BSA, while drug clearance varied with eCrCl. Individual predictions for observed concentrations were appropriate at the patient level, with only 3.7% outliers for the 90% predictive interval.

Conclusions: This study demonstrated the feasibility of using stored specimens to develop a population PK model for adults treated with cefepime in the ICU. The cefepime Vd observed was approximately 2-fold higher than that reported in the literature for non-ICU patients. Understanding the nuances of an individual patient's PK variability in critical illness is a first step toward precision dosing. Additional studies are needed to test optimized cefepime models more broadly for therapeutic individiualization.

Meta Tag

Content Type Presentation

Knowledge Area Pharmacology

Knowledge Level Advanced

Membership Level Select

Tag Antibiotics

Tag Pharmacokinetics Pharmacodynamics

Year 2021

Keywords

cefepime

critically ill adults

pharmacokinetics

Mayo Clinic

antibiotics

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