Cefepime Dosing in Renal Impairment
Cefepime requires dose reduction in patients with creatinine clearance ≤60 mL/min, with specific adjustments based on the degree of renal impairment, and carries significant risk of neurotoxicity in end-stage renal disease patients even with appropriate dose adjustments. 1
Dose Adjustment Algorithm by Creatinine Clearance
The FDA-approved dosing schedule mandates the following adjustments based on creatinine clearance 1:
For CrCl 30-60 mL/min:
- Standard 500 mg dose → 500 mg every 24 hours
- Standard 1 g dose → 1 g every 24 hours
- Standard 2 g every 12 hours → 2 g every 24 hours
- Standard 2 g every 8 hours → 2 g every 12 hours 1
For CrCl 11-29 mL/min:
- Standard 500 mg dose → 500 mg every 24 hours
- Standard 1 g dose → 500 mg every 24 hours
- Standard 2 g every 12 hours → 1 g every 24 hours
- Standard 2 g every 8 hours → 2 g every 24 hours 1
For CrCl <11 mL/min:
- Standard 500 mg dose → 250 mg every 24 hours
- Standard 1 g dose → 250 mg every 24 hours
- Standard 2 g every 12 hours → 500 mg every 24 hours
- Standard 2 g every 8 hours → 1 g every 24 hours 1
Special Populations Requiring Additional Considerations
Hemodialysis Patients
Administer cefepime after hemodialysis sessions, not before. 1 Hemodialysis removes approximately 68% of cefepime during a 3-hour dialysis period, dramatically shortening the elimination half-life from 13.5 hours to 2.3 hours 2. The recommended dosing is 1 g on Day 1, followed by 500 mg every 24 hours for most infections (or 1 g every 24 hours for febrile neutropenia), administered following completion of hemodialysis 1. This timing facilitates directly observed therapy and prevents premature drug removal 3.
Continuous Ambulatory Peritoneal Dialysis (CAPD)
Extend the dosing interval to every 48 hours while maintaining the milligram dose amount 1. This approach preserves the concentration-dependent bactericidal effect that would be compromised by reducing the actual dose 4.
Critical Neurotoxicity Risk in Renal Impairment
Even with appropriate renal dose adjustments, cefepime carries a 7.5% incidence of neurotoxicity in end-stage renal disease patients. 5 This represents a substantially elevated risk compared to the 1.4% incidence in patients with normal renal function 5.
High-Risk Features for Neurotoxicity
Pre-existing central nervous system morbidity significantly increases the risk of cefepime-induced encephalopathy in ESRD patients 5. Neurotoxicity can occur even with doses as low as 0.5 g/day in ESRD patients, and no clear dose-response relationship exists in this population 5.
Clinical Manifestations to Monitor
Watch for subtle neurological symptoms including 6, 7, 8:
- Confusion and altered mental status
- Muscle jerks or myoclonus
- Non-convulsive status epilepticus (may present as confusion without obvious seizure activity)
- Delirium
- Inability to tolerate oral intake
These symptoms may not be immediately attributed to cefepime toxicity by clinicians, leading to delayed recognition. 7 In two documented cases, symptoms were only recognized as drug-related after plasma levels were disclosed, and resolved promptly after drug discontinuation 7.
Pharmacokinetic Principles Underlying Dose Adjustments
Cefepime's half-life increases from approximately 2 hours in normal renal function to 13.5 hours in severe renal impairment 2. Peak plasma concentrations (63.5-73.9 mcg/mL) remain unaffected by renal dysfunction, but trough concentrations can vary up to 40-fold between individuals 7. The volume of distribution (approximately 20.5 liters) remains stable regardless of renal function 2.
Total body clearance and renal clearance demonstrate significant linear relationships with creatinine clearance, necessitating proportional dose reductions. 2
Common Pitfalls to Avoid
Do not reduce the loading dose in acute infections. While maintenance doses require adjustment, the initial dose should achieve therapeutic concentrations rapidly 3.
Do not assume adequate coverage for pathogens with MIC ≥8 mg/L using standard renal-adjusted doses. Only 45-65% of ICU patients achieve appropriate pharmacokinetic/pharmacodynamic parameters (T>MIC ≥50%) for organisms at the upper susceptibility limits, even with appropriate dosing 7.
Monitor for drug accumulation even with dose adjustment. Ten percent of patients with CrCl <30 mL/min demonstrated plasma accumulation (trough concentrations 20-30 mg/L) despite following recommended dose adjustments 7.
Monitoring Requirements
Serum drug concentration monitoring should be considered in 3, 7:
- Patients with CrCl <30 mL/min
- ESRD patients, particularly those with pre-existing CNS disease
- Infections caused by pathogens with cefepime MIC ≥8 mg/L
- Any patient developing unexplained neurological symptoms
Maintain heightened vigilance for neurological changes throughout the treatment course, as neurotoxicity can develop despite appropriate renal dosing. 8, 5