Muhammad Bilal(1, 2), Michael Zoller(3), Uwe Fuhr(1), Ulrich Jaehde(2), Sami Ullah(1), Uwe Liebchen(3), Johannes Zander(4), Max Taubert(1)
(1)Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Cologne, Germany, (2) Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, Bonn, Germany, (3) Department of Anaesthesiology, Hospital of the Ludwig Maximilians University of Munich, Munich, Germany (4) Institute of Laboratory Medicine, Hospital of the Ludwig Maximilians University of Munich, Munich, Germany
Introduction: Cefepime is a fourth-generation cephalosporin antibiotic with a broad antibacterial spectrum[1] and exhibits time-dependent bactericidal activity like other beta-lactams[2]. Pathophysiological changes in severely ill patients may cause high pharmacokinetic (PK) variability, which may result in under-or over-exposure to the drug. Cefepime has been reported to cause neurotoxicity, especially in critically ill patients with renal failure[3]. German Federal Institute for Drugs and Medical Devices (BfArM) suggests dosing of cefepime in severe infections based on creatinine clearance estimated by the Cockcroft-Gault equation.
Objectives:
- To quantify pharmacokinetic variability of cefepime in critically ill patients
- To identify predictors of cefepime pharmacokinetics
- To identify a dosing regimen providing a sufficient probability of target attainment (PTA) and acceptable risk of neurotoxicity (PNT)
Methods: 344 plasma concentrations (median 58.5 mg/L [range 0.60 – 228]) were collected from 14 medical/surgical ICU patients for a period of four consecutive days. The median age and bodyweight of the patients were 62 [range 22-94] years and 70 [45-120] kg, respectively. Four out of 14 patients were on continuous venovenous hemodialysis (CVVHD). The patients received a median daily dose of 2000 mg cefepime by 30-minute intravenous infusions. NONMEM 7.4.3 was used for non-linear mixed-effects modeling. For patients on CVVHD, a separate clearance was estimated. IIV and IOV were evaluated on clearance.Covariates were selected also based on physiological plausibility and were evaluated on cefepime clearance and volume of distribution. Simulations were performed for 2000 virtual subjects using the final covariate model for 7 days. The PTA was based on the time during which the total concentration exceeded the minimum inhibitory concentrations (T>MIC) target of 65% and a MIC of up to 16 mg/L was simulated with doses ranging from 100 to 5000 mg for four CRCL groups (CRCL >50 mL/min, 30-50 mL/ 11-29 mL/min and ≤ 10 mL/min) with an infusion rate of 30 minutes. The probability of neurotoxicity was calculated via a logistic regression model reported by Boschung-Pasquier et al, 2019 based on plasma trough concentrations of cefepime. Trough concentrations above 7.5 mg/L may be linked to a high risk of neurotoxicity[3].
Results: A two-compartment model with linear elimination best described the data. Creatinine clearance estimated by the Cockcroft-Gault equation (eCRCL) was significantly related to clearance using a power model. Point estimates (relative standard error[RSE]) of the final model were: 2.74 L/h (13%), clearance of dialysis patients (CLD); 2.94 L/h (10%), clearance of non-dialysis patients (CLND); 8.88 L (38%), central volume of distribution (V1); 27.4 L/h (54%), inter-compartmental clearance (Q); 18.7 L (22%), peripheral volume of distribution (V2); and 0.896 (17%), eCRCL effect on CLND, respectively. Inter-individual variability (coefficient of variation [RSE]) was: 22.7% (15%); on CLD 31.3% (20%) on CLND; 47.3% (25%) on V1; and 19.3% (26%), on V2, respectively. Inter-occasion (IOV) variability on CL was 22.4% (23%). Based on simulations of a dosing regimen suggested by the BfArM all the four groups (CRCL >50 mL/min [2000 mg BID], 30-50 mL/min [2000 mg OD], 11-29 mL/min [1000 OD], and ≤ 10 mL/min [500 mg OD]) achieved >90% PTA for MIC of 8 mg/L. However, the risk of neurotoxicity was found to be very high. For CRCL >50 mL/min and 30-50 mL/min, the median PNT for both was around 40% on day 7, for 11-29 the median PNT was around 80% on day 7, and for ≤ 10 mL/min the median PNT was 100% on day 5. We found that the median PNT can be decreased to less than 20% by decreasing doses to 1400 mg BID, 500 mg BID, and 500 mg BID given a CRCL of >50 mL/min, 30-50 mL/min, and 11-29 mL/min respectively while achieving PTA of 90% for MIC of 8 mg/L. For CRCL ≤ 10 mL/min the dose of 250 OD achieved the MIC target but the risk of neurotoxicity was found to be gradually increasing and reached around 90% on day 7. The recommended dose (2 g once daily) for CVVHD reported in the literature resulted in a PTA of almost 90% for a MIC of 8 mg/L and the median PNT estimated was less than 10%.
Conclusions: This evaluation suggests that the probability of neurotoxicity can be decreased via dose adjustment without relevantly reducing PTA.
References:
[1] Shahid SK. Cefepime and its role in pediatric infections. Recent Pat Antiinfect Drug Discov. 2008; 3(2):145-148. doi:10.2174/157489108784746614
[2] Nicasio AM, Ariano RE, Zelenitsky SA, et al. Population pharmacokinetics of high-dose, prolonged-infusion cefepime in adult critically 111 patients with ventilator-associated pneumonia. Antimicrob Agents Chemother. 2009; 53(4):1476-1481. doi:10.1128/AAC.01141-08
[3] Boschung-Pasquier L, Atkinson A, Kastner LK, et al. Cefepime neurotoxicity: thresholds and risk factors. A retrospective cohort study. Clin Microbiol Infect. 2019; 26(3):333-339. doi:10.1016/j.cmi.2019.06.028
Reference: PAGE 30 (2022) Abstr 10205 [www.page-meeting.org/?abstract=10205]
Poster: Drug/Disease Modelling - Infection