What are the dosing considerations for cefepime in patients with End-Stage Renal Disease (ESRD)?

Cefepime Dosing in End-Stage Renal Disease

In patients with ESRD, cefepime requires substantial dose reduction to prevent life-threatening neurotoxicity, with recommended dosing of 250-500 mg every 24 hours for most infections (or 1g every 24 hours for severe infections like febrile neutropenia), administered after hemodialysis sessions. 1

Renal-Adjusted Dosing Protocol

The FDA-approved dosing schedule for ESRD patients (creatinine clearance <11 mL/min) depends on infection severity 1:

• Mild-moderate UTI: 250 mg every 24 hours 1
• Pneumonia or moderate infections: 250 mg every 24 hours 1
• Severe infections: 500 mg every 24 hours 1
• Febrile neutropenia: 1 g every 24 hours 1

For patients on hemodialysis, the specific regimen is 1 g loading dose on day 1, then 500 mg every 24 hours thereafter (except febrile neutropenia which requires 1 g every 24 hours), with all doses administered after dialysis completion 1. Hemodialysis removes approximately 68% of cefepime during a 3-hour session, necessitating post-dialysis dosing 1, 2.

For continuous ambulatory peritoneal dialysis (CAPD), dosing intervals extend to every 48 hours at the same milligram amounts 1.

Critical Neurotoxicity Risk

Despite appropriate renal dose adjustments, ESRD patients remain at substantial risk for cefepime-induced encephalopathy, with reported incidence rates of 7.5% in this population. 3 This represents a significantly higher risk compared to the 1.4% incidence in the general population receiving cefepime 3.

Neurotoxicity Manifestations

Monitor vigilantly for these neurological complications 4, 5:

• Altered mental status, confusion, or delirium 6, 4
• Global aphasia (particularly concerning sign) 4
• Myoclonus and chorea-athetosis 4
• Seizures or non-convulsive status epilepticus 7, 5
• Encephalopathy progressing to coma 4

The latency period averages 4.75 days (range 1-10 days) from treatment initiation to symptom onset 4. Neurotoxicity can occur even with doses as low as 0.5 g/day in ESRD patients 3.

High-Risk Patient Identification

Pre-existing CNS pathology significantly increases neurotoxicity risk in ESRD patients. 3 Patients with prior stroke, dementia, seizure disorders, or metabolic encephalopathy from chronic uremia are particularly vulnerable 7. Advanced age compounds this risk 7.

Management of Suspected Neurotoxicity

If neurological deterioration occurs 7, 4:

1. Immediately discontinue cefepime 7, 4
2. Initiate urgent hemodialysis to enhance drug clearance 7
3. Perform EEG if available (typically shows diffuse slow-wave delta activity and triphasic waves) 4
4. Clinical improvement usually occurs within 24-48 hours after discontinuation and dialysis 7

Pharmacokinetic Considerations

Cefepime elimination half-life increases from 2.3 hours in normal renal function to approximately 13.5 hours in ESRD patients 2. The volume of distribution remains unchanged at approximately 20.5 liters regardless of renal function 2. Total body clearance correlates linearly with creatinine clearance 2.

Alternative Antibiotic Considerations

Given the substantial neurotoxicity risk, consider alternative cephalosporins with dual hepatic and renal excretion (cefotaxime, ceftriaxone) or other broad-spectrum agents like meropenem that lack neurological toxicity in ESRD patients 7. This is particularly important for elderly patients with pre-existing CNS disease or chronic uremia 7.

Common Pitfalls

• Assuming renal-adjusted dosing eliminates neurotoxicity risk: Even appropriately dosed cefepime causes encephalopathy in 7.5% of ESRD patients 3
• Missing the diagnosis: Neurotoxicity may present atypically, and the frequency is likely underestimated 4, 5
• Dosing before dialysis: Always administer after hemodialysis to prevent premature drug removal 1
• Using standard dosing intervals: ESRD requires 24-48 hour intervals, not the standard 8-12 hour dosing 1