211. Defining Optimal Sampling Times for Cefepime Therapeutic Drug Monitoring in Clinical Practice
Authors: Rhodes Nathaniel J , Smith Brandon , Shields Ryan K , Pan Samantha , Weslander Erin , Galvin Shannon , Hughes Jasmine , Hughes Maria-Stephanie , Sime Fekade B , Roberts Jason A , Kiel Patrick J , Neely Michael N , Scheetz Marc H 
Published: January 2025

Background

Clinicians performing beta-lactam therapeutic drug monitoring (TDM) lack evidence on when levels should ideally be drawn after a dose. Herein, we define the optimal timing (i.e., optimal sampling) for cefepime using real-world TDM data to validate our approach.Figure 1.External validation of the Bayesian prior non-parametric population PK model

Methods

De-identified data from two centers performing routine cefepime TDM were extracted by InsightRX and served as an external validation cohort. Plasma cefepime was quantified using validated LC-MS/MS assays for TDM and dosing was protocolized at each site. CRRT and ECMO patients were included but other dialysis patients were not. Bias (MPE) and precision (RMSE) of a non-parametric prior were assessed. Multiple-model optimal (MM-opt) sampling strategies were estimated for the first 24 hours of treatment. To mirror clinical practice, one- and two-sample designs were evaluated. Dose and covariate values informed optimal sampling times. Bayesian PK exposures were compared using all samples, trough-only sampling, or using a single optimally timed sample. AUCs were calculated from the posteriors. For fT &gt;MIC analysis, the MIC was fixed at 8 mg/L. We used Pmetrics 2.1.1 for R.Figure 2.Distribution of MM-optimal sampling times in external validation data using n=1 sample

Results

116 patients (42% female; median age, CRCL, and weight: 62 years, 76 mL/min, and 80 kg, respectively) contributed 235 levels. The PK model demonstrated acceptable bias and precision (-6% MPE, 30.9 RMSE) as a prior for estimating exposures from the TDM data (Fig1). For a one-sample approach, the most common MM-opt sampling times varied (Fig2) but were often a mid-point or trough. In the two-sample approach, sample one was often a mid-point and sample two was often a trough (Fig3). First 24-hr AUC and fT&gt;MIC did not significantly differ using all available samples for analysis vs. limiting sampling to a single optimized time point vs. limiting sampling to a trough-only approach (P &gt;0.05 for all comparisons; Fig4).Figure 3.Distribution of MM-optimal sampling times in external validation data using n=2 samples

Conclusion

Optimal cefepime sampling times depended on dosing regimen, and renal disposition. When limited to a single sample, optimal sampling times for cefepime TDM were often midpoint/trough levels, but when two samples were obtained the optimal sampling times were often a mid-point followed by a trough. Estimation of PK and PK/PD exposures was not significantly worse when using a validated Bayesian prior and a trough-only sampling approach.Figure 4.First 24 hours PK and PK/PD exposure estimates from Bayesian analysis of all external validation data and Bayesian analysis of n=1 optimally timed samples from the same population

Disclosures

Nathaniel J. Rhodes, PharmD MS, Apothecademy, LLC: Advisor/Consultant Brandon Smith, MD, PharmD, Melinta Therapeutics: Advisor/Consultant|Shionogi, INC: Advisor/Consultant Ryan K. Shields, PharmD, MS, Allergan: Advisor/Consultant|Cidara: Advisor/Consultant|Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Menarini: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Utility: Advisor/Consultant|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support Jasmine Hughes, PhD, InsightRX: Employee|InsightRX: Stocks/Bonds (Private Company) Maria-Stephanie Hughes, PharmD, InsightRX: Employee of company|InsightRX: Stocks/Bonds (Private Company) Fekade B. Sime, PhD, S.Aust., Gilead: Grant/Research Support|Pfizer: Grant/Research Support Patrick J. Kiel, PharmD, Amgen: Employee|Amgen: Stocks/Bonds (Public Company) Marc H. Scheetz, PharmD, MSc, Abbvie: Advisor/Consultant|Basilea: Advisor/Consultant|Cidara: Advisor/Consultant|DoseMe: Advisor/Consultant|Entasis: Advisor/Consultant|F2G: Advisor/Consultant|GSK: Advisor/Consultant|Lykos: Advisor/Consultant|Roche: Advisor/Consultant|Third Pole Therapeutics: Advisor/Consultant|Xelia: Advisor/Consultant