Cefepime neurotoxicity: thresholds and risk factors. A retrospective cohort study

Boschung-Pasquier, Léna; Atkinson, Andrew; Kastner, Leonie Kassandra; Banholzer, Sarah; Haschke, Manuel; Buetti, Niccolò; Furrer, Dominique Isabel; Hauser, Christoph; Jent, Philipp; Que, Yok-Ai; Furrer, Hansjakob; Flury, Bernhard

doi:10.1016/j.cmi.2019.06.028

Cited by 105 publications

(108 citation statements)

References 24 publications

(27 reference statements)

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“…Although trough concentrations have primarily been studied, peak concentrations and AUC have also been investigated as potential parameters for neurotoxicity. Overall, the data are limited, and a definitive threshold for toxicity has not been defined . Empiric dose reduction due to concern for causing neurotoxicity is a consideration; however, lower doses may result in failure to attain the pharmacodynamic target and expose the patient to risk of treatment failure or bacterial resistance .…”

Section: Discussionmentioning

confidence: 99%

“…Overall, the data are limited, and a definitive threshold for toxicity has not been defined. [41][42][43][44][45] Empiric dose reduction due to concern for causing neurotoxicity is a consideration; however, lower doses may result in failure to attain the pharmacodynamic target and expose the patient to risk of treatment failure or bacterial resistance. 8,46 Our results support the use of EI cefepime in patients receiving CRRT to optimize pharmacodynamic target attainment in critically ill patients who are at risk for resistant organisms.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics and Pharmacodynamics of Extended‐Infusion Cefepime in Critically Ill Patients Receiving Continuous Renal Replacement Therapy: A Prospective, Open‐Label Study

et al. 2019

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Study Objective To evaluate extended‐infusion (EI) cefepime pharmacokinetics (PK) and pharmacodynamic target attainment in critically ill patients receiving continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodialysis (CVVHD). Design Prospective, open‐label, PK study. Setting Intensive care units at a large, academic, tertiary‐care medical center. Patients Ten critically ill adults who were receiving cefepime 2 g intravenously every 8 hours as a 4‐hour infusion while receiving CVVH (eight patients) or CVVHD (two patients). Intervention Two sets of five serum cefepime concentrations were collected for each patient to assess pharmacokinetics before and during presumed steady state. Concurrent serum and CRRT effluent samples were collected at hours 1, 2, 3, 4, and 8 after the first cefepime dose and after either the fourth, fifth, or sixth (steady‐state) cefepime doses. Measurements and Main Results Reversed‐phase high‐performance liquid chromatography was used to determine free cefepime concentrations. PK analyses included CRRT clearance, half‐life, and sieving coefficient or saturation coefficient. Cefepime peak (4 hrs) concentrations, trough (8 hrs) concentrations (Cmin), and minimum inhibitory concentration breakpoint of 8 µg/ml for the pathogen (MIC8) were used to evaluate attainment of pharmacodynamic targets: 100% of the dosing interval that free drug remains above MIC8 (100% fT > MIC8), 100% fT > 4 × MIC8 (optimal), percentage of time fT > 4 × MIC8 (%fT > 4 × MIC8) at steady state, and ratio of Cmin to MIC8 (fCmin/MIC8). Total CRRT effluent flow rate was a mean ± SD of 30.1 ± 5.4 ml/kg/hr, CRRT clearance was 39.6 ± 9.9 ml/min, and half‐life was 5.3 ± 1.7 hours. Sieving coefficient or saturation coefficient were 0.83 ± 0.13 and 0.69 ± 0.22, respectively. First and steady‐state dose Cmin were 23.4 ± 10.1 µg/ml and 45.2 ± 14.6 µg/ml, respectively. All patients achieved 100% fT > MIC8 on first and steady‐state doses. First and steady‐state dose 100% fT > 4 × MIC8 were achieved in 22% (2/9 patients) and 87.5% (7/8 patients) of patients, respectively. The mean %fT > 4 × MIC8 at steady state was 97.5%. The fCmin/MIC8 was 2.92 ± 1.26 for the first dose and 5.65 ± 1.83 at steady state. Conclusion Extended‐infusion cefepime dosing in critically ill patients receiving CRRT successfully attained 100% fT > MIC8 in all patients and an appropriate fCmin/MIC8 for both first and steady‐state doses. All but one patient achieved 100% fT > 4 × MIC8 at steady state. No significant differences were observed in PK properties between first and steady‐state doses among or between patients. It may be reasonable to initiate an empiric or definitive regimen of EI cefepime in critically ill patients receiving concurrent CRRT who are at risk for resistant organisms. Further research is needed to identify the optimal dosing regimen of EI cefepime in this patient population.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Extended‐Infusion Cefepime in Critically Ill Patients Receiving Continuous Renal Replacement Therapy: A Prospective, Open‐Label Study

et al. 2019

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“…Therapeutic drug monitoring (TDM) studies show that the incidence of CIN has increased, from 11% to 23.2% [26][27][28]. In the French pharmacovigilance database on serious CNS adverse effects, cefepime was the most common drug among cephalosporins to be associated with CNS adverse effects [29].…”

Section: Incidencementioning

confidence: 99%

“…Some investigators measured serum cefepime concentrations and demonstrated the association between serum cefepime concentrations and the occurrence of CIN [28,45,51]. Others described that clinical improvement of CIN was associated with a decrease in the blood concentration of cefepime [2,26,45,46].…”

Section: Serum Cefepime Concentrationmentioning

confidence: 99%

Cefepime-induced neurotoxicity

Lee

2019

J Neurocrit Care

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Cefepime, a fourth-generation cephalosporin antibiotic, was approved for use in 1996. It is widely used to treat severe bacterial infections because it acts against both gram-negative and gram-positive bacterial strains, and has antipseudomonal activity. Safety data of cefepime in clinical trials were relatively favorable when initially approved. Approximately 3% of 2,032 patients treated with cefepime experienced adverse central nervous system (CNS) effects including headache (2.4%), dizziness (0.7%), and

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“…A recent retrospective study conducted by Boschung-Pasquier et al assessed serum cefepime trough concentrations in 319 adult patients. 18 Cefepime serum trough concentrations were measured to determine correlation with neurotoxicity. Probability of neurotoxicity was determined to be 25% in patients with trough concentrations !12 mg/L and 50% in patients with trough concentrations !16 mg/L, with 100% of patients exhibiting signs of neurotoxicity with trough concentrations !38.1 mg/L.…”

Section: Future Perspectivementioning

confidence: 99%

Cefepime Dosing in Neonates: What is the Evidence?

McDonald

Shah

2019

Am J Perinatol

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Objective Recommended cefepime dosing strategies in neonates varies in commonly utilized dosing references with regard to dose and frequency. The objective of this review is to summarize and evaluate the available literature describing cefepime dosing in neonatal patients. Study Design We performed a literature review in MEDLINE using the keyword cefepime. The search was limited to the English language, humans, and patients <2 months of age. We evaluated four pharmacokinetic studies and two studies describing the use of cefepime in clinical practice. Results The available studies assessing cefepime serum concentrations in neonatal patients demonstrated maintenance of adequate pharmacokinetic parameters when utilizing a dosing frequency of every 12 hours, specifically for organisms with a minimum inhibitory concentration (MIC) ≤ 8 mg/L. In studies evaluating clinical outcomes of cefepime use in neonates, the most frequent adverse effects reported included seizures and hypophosphatemia. Microbiologic cure was demonstrated with a dosing regimen of 50 mg/kg per dose every 12 hours. Conclusion Cefepime dosed 30 to 50 mg/kg per dose every 12 hours may be appropriate to achieve a concentration two to four times above an MIC ≤ 8 mg/L for at least 60% of the dosing interval in neonatal patients.

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Cefepime neurotoxicity: thresholds and risk factors. A retrospective cohort study

Cited by 105 publications

References 24 publications

Pharmacokinetics and Pharmacodynamics of Extended‐Infusion Cefepime in Critically Ill Patients Receiving Continuous Renal Replacement Therapy: A Prospective, Open‐Label Study

Pharmacokinetics and Pharmacodynamics of Extended‐Infusion Cefepime in Critically Ill Patients Receiving Continuous Renal Replacement Therapy: A Prospective, Open‐Label Study

Cefepime-induced neurotoxicity

Cefepime Dosing in Neonates: What is the Evidence?

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