Safety concern with high continuous dose of cefepime among critically ill patients with impaired to augmented renal clearance at a level 1 trauma center: CEFTOX Study

Position du problème et objectif(s) de l’étude

Cefepime is commonly used for severe infections in critically ill patients. Despite the obvious advantages of its broad spectrum and efficacy, cefepime overdose and cefepime-induced neurotoxicity (CIN) are common. Renal impairment is a well-established risk factor for CIN resulting from supratherapeutic concentrations. In intensive care unit (ICU), high continuous doses at 6 grams per day are recommended to achieve PK/PD targets in patients with creatinine clearance above 60 ml/min. CEFTOX study aimed to investigate the impact of high continuous doses of cefepime in a cohort of severe trauma and neurosurgical patients in ICU with different level of creatinine clearance on cefepime plasma concentration.

Matériel et méthodes

Retrospective cohort study of patients admitted to ICU from May 1, 2021 to December 31, 2024, treated for a documented infection with continuous high dosing regimen of cefepime, with a single therapeutic drug monitoring (TDM) between 24 and 48 hours after treatment initiation. Patients were stratified into three groups, based on concurrent creatinine clearance using UV/P: impaired (60 - 90 ml/min), normal (between 90 and 150 ml/min), or augmented renal clearance (ARC) ( > 150 ml/min). The primary outcome was cefepime plasma overdose defined by a concentration greater than 35 mg/L. One of the secondary outcome was CIN.

Résultats & Discussion

In this study 162 critically ill patients were included : 84 with ARC, 62 with normal renal clearance, 16 with impaired renal clearance. Cefepime overdose was encountered in 44,4% of the patients included. The prevalence was significantly different across these groups (p=0,0005) : cefepime overdose occurred in 87,5% of patients with impaired renal clearance, 50% with normal renal clearance, and 32,1% with ARC. Among the 119 patients (74,7%) clinically evaluable, 43 patients (36,1%) developed CIN. The prevalence of CIN varied significantly across the groups (p=0,01). The highest rate of CIN was observed in the impaired renal clearance group (60%), followed by the normal renal clearance group (36,7%), and the lowest rate in the ARC group (28,1%). In the ARC group, sepsis was a protective factor against cefepime overdose (OR 0,30 95% CI [0,11 - 0,83] p=0,02), while age older than 33 years was identified as a significant risk factor for cefepime overdose (OR 3,76 95% CI [1,30 - 10,95] p<0,001). Patients with creatinine clearance between 60-90 mL/min were at significant risk of overdose with high continuous dose. There were seven times more likely to experience cefepime overdose. A finding that reinforces the critical need for immediate dosage adjustments in patients with creatinine clearance below 90 mL/min. Whereas current guidelines recommend high continuous dose of cefepime for critically ill patients with creatinine clearance above 60 ml/min. This finding compounded by the fact that over half of the impaired renal clearance patients exhibited CIN. This proves that overdose plays an important role in the occurrence of symptoms and therefore there is an interest in reducing doses to avoid CIN. Moreover, even patients exhibiting normal or ARC are not exempt from these risks. Our results indicate that continuous infusions of high dose of cefepime at 6 grams per day exceeds PK/PD targets even in the ARC group.

Conclusion

High continuous doses at treatment initiation should be avoided in patients with creatinine clearance below 90 mL/min. Cefepime overdose can occur despite normal or ARC highlighting the importance of TDM and tailoring doses

Auteurs

Myriam LAMAMRI, Caroline JEANTRELLE, Stéphanie SIGAUT, Anais CODORNIU, Emmanuel WEISS - (1)Hôpital Beaujon, Aphp Nord, Clichy, France

Orateur(s)

Myriam LAMAMRI (Clichy)