Cefepime Safety in Kidney Disease
Cefepime can be used in patients with kidney disease, but requires mandatory dose adjustment based on creatinine clearance and carries significant risk of neurotoxicity, particularly in those with chronic kidney disease—even when doses are appropriately adjusted.
Dose Adjustment Requirements
The FDA label explicitly requires dose adjustment in patients with creatinine clearance ≤60 mL/min to compensate for slower renal elimination 1. The risk of toxic reactions is substantially greater in patients with impaired renal function because cefepime is primarily renally excreted 1.
Specific Dosing Considerations
- Maintain the milligram dose per administration while extending the dosing interval (rather than reducing the dose amount) to preserve concentration-dependent bactericidal effects 2
- Cefepime is effectively removed by hemodialysis, making post-dialysis administration timing critical 2
- For hemodialysis patients, administer cefepime after dialysis sessions to facilitate directly observed therapy and avoid premature drug removal 2
Neurotoxicity Risk Profile
Serious adverse events including life-threatening or fatal encephalopathy, myoclonus, and seizures have occurred in geriatric patients with renal impairment given unadjusted doses 1. However, the critical caveat is that neurotoxicity can occur even with appropriate renal dose adjustments.
Clinical Manifestations
The predominant neurologic symptoms include 3:
- Impaired consciousness (most common)
- Myoclonus
- Disorientation
- Nonconvulsive status epilepticus
- Agitation and tremor 4
High-Risk Populations
Patients with chronic kidney disease are particularly susceptible to cefepime neurotoxicity 3. In one ICU study, chronic kidney disease was present in 66.7% of patients who developed neurotoxicity versus only 35.3% without neurotoxicity (P = 0.04) 3.
Neurotoxicity occurred more frequently when doses were not adjusted for renal function (only 28.6% of neurotoxic cases had appropriate dose adjustment versus 75.3% of non-neurotoxic cases, P = 0.001) 3. However, neurotoxic symptoms can still occur despite proper dose modifications 3, 5.
Monitoring Requirements
Essential Monitoring Parameters
- Renal function monitoring is mandatory, particularly in elderly patients who are more likely to have decreased renal function 1
- Monitor for neurological symptoms including confusion, encephalopathy, myoclonus, and seizures 6
- Serum drug concentrations should be monitored to avoid toxicity in patients with severe renal impairment 2
- Therapeutic drug monitoring in patients with kidney dysfunction or baseline neurologic abnormalities may help inform appropriate dosing and avoid toxicity 4
Diagnostic Approach When Neurotoxicity Suspected
- Obtain electroencephalogram (EEG) to assist in establishing diagnosis, particularly when therapeutic drug monitoring is unavailable 7
- EEG may show sharply contoured triphasic waves suggestive of nonconvulsive status epilepticus 5
- Serial assessment of any residual renal function is critical, as further deterioration can occur 6
Management of Cefepime Neurotoxicity
Once identified, immediate discontinuation of cefepime is essential 5. Treatment includes:
- Benzodiazepines for seizure activity 5
- Hemodialysis for effective clearance of cefepime 5, 8
- At least one session of intermittent hemodialysis may shorten time to return to nontoxic range and should be considered early, even in frail elderly patients 8
- Pharmacokinetic modeling demonstrates hemodialysis can allow serum concentrations to return to nontoxic range 15 hours earlier than without intervention 8
Pediatric Considerations
Safety and effectiveness are established for children aged 2 months to 16 years for specific indications 1. However:
- Safety and effectiveness in pediatric patients below 2 months have not been established 1
- Pediatric patients with acute and chronic kidney disease are at risk of cefepime-related neurologic changes 4
- A 2-year-old with chronic kidney disease experienced agitation, tremor, and inconsolability with elevated cefepime trough that improved with discontinuation alone 4
Critical Pitfalls to Avoid
- Do not assume proper dose adjustment eliminates neurotoxicity risk—cases occur despite appropriate renal dosing 3, 5
- Be aware that glomerular filtration rate may be overestimated, leading to inadvertent overdosing 7
- Maintain high index of suspicion in patients with impaired renal function, as diagnosis may be challenging due to multiple potential causes of encephalopathy in critically ill patients 7
- Consider electronic health record alerts about risk constellations for potential overdosing 7
Pregnancy and Lactation
- Published data over several decades have not identified an association with cephalosporin use during pregnancy and major birth defects, miscarriage, or adverse maternal/fetal outcomes, though available studies have methodologic limitations 1
- Cefepime is present in human milk at low concentration (0.5 mcg/mL); a nursing infant consuming 1000 mL/day would receive approximately 0.5 mg of cefepime daily 1