Should I switch to another intravenous (IV) antibiotic for a patient with acute altered mental status, leukocytosis, and impaired renal function, currently being treated with cefepime (Cefepime)?

Cefepime-Induced Neurotoxicity: Immediate Antibiotic Switch Required

You should immediately discontinue cefepime and switch to meropenem 1 g IV every 12 hours (adjusted for renal function) for this patient with acute altered mental status, leukocytosis, and impaired renal function. The clinical presentation strongly suggests cefepime-induced neurotoxicity, a serious and underrecognized complication that occurs in up to 15% of ICU patients treated with this antibiotic, particularly those with renal dysfunction 1, 2.

Why Cefepime is the Likely Culprit

Your patient exhibits the classic triad of risk factors for cefepime neurotoxicity:

• Impaired renal function: Present in 80-84% of neurotoxicity cases, as cefepime is predominantly renally excreted and accumulates to toxic levels when clearance is reduced 1, 2, 3
• Altered mental status: The most common manifestation (100% of cases), occurring as depressed consciousness, encephalopathy, confusion, or aphasia 1, 2
• Leukocytosis with systemic infection: Critical illness itself is an independent risk factor, likely due to blood-brain barrier disruption 1, 3

The neurotoxicity mechanism involves cefepime crossing the blood-brain barrier and exhibiting concentration-dependent GABA antagonism, leading to symptoms ranging from confusion to non-convulsive status epilepticus 1, 2. Median time to symptom onset is 4 days after starting the drug, though it can occur throughout treatment 1.

Recommended Antibiotic Switch

Switch to meropenem 1 g IV every 12 hours (adjust to every 24 hours if creatinine clearance <30 mL/min) 4. Meropenem provides equivalent broad-spectrum coverage for hospital-acquired infections, including Pseudomonas aeruginosa and other gram-negative pathogens, while having significantly lower neurotoxicity risk 4.

Alternative options if meropenem is contraindicated:

• Piperacillin-tazobactam 4.5 g IV every 6 hours (extended infusion over 4 hours preferred), adjusted for renal function 4
• Imipenem 500 mg IV every 6 hours, though seizure risk increases in patients <70 kg 4

Do not use ceftazidime as a cefepime substitute—it has poor gram-positive coverage and is no longer reliable for empirical therapy due to increasing resistance 4.

Critical Diagnostic Steps

Obtain an electroencephalogram (EEG) immediately if altered mental status persists beyond 24-48 hours after cefepime discontinuation 1, 2, 5. In published case series, 98% of patients with cefepime neurotoxicity had EEG abnormalities, including:

• Non-convulsive status epilepticus (25% of cases) 1, 2, 5
• Triphasic waves (40% of cases) 1, 2
• Myoclonic status epilepticus (7% of cases) 1
• Focal sharp waves (39% of cases) 1

Check serum cefepime levels if available (median toxic concentration: 45 mg/L) 1. However, neurotoxicity can occur even with appropriate dosing in 26% of cases, so normal levels do not exclude the diagnosis 1, 2.

Expected Clinical Course After Switch

Symptom improvement occurs in 89% of patients after cefepime discontinuation, with median resolution time of 2 days 1. If mental status does not improve within 48-72 hours:

• Consider hemodialysis or continuous veno-venous hemofiltration to accelerate cefepime removal, particularly if serum levels are elevated or renal function is severely impaired 6, 3
• Add antiepileptic therapy (levetiracetam 500-1000 mg IV twice daily preferred over valproic acid, which interacts with carbapenems) if EEG shows seizure activity 6, 2

Coverage Considerations for the Underlying Infection

The 2016 IDSA/ATS guidelines for hospital-acquired pneumonia recommend empirical coverage based on mortality risk and local resistance patterns 4:

For patients NOT at high risk of mortality (no septic shock, no mechanical ventilation):

• Meropenem 1 g IV every 8 hours OR piperacillin-tazobactam 4.5 g IV every 6 hours as monotherapy 4

For patients at HIGH risk of mortality (septic shock, mechanical ventilation, or recent IV antibiotics within 90 days):

• Meropenem 1 g IV every 8 hours PLUS ciprofloxacin 400 mg IV every 8 hours OR aminoglycoside (gentamicin 5-7 mg/kg IV daily) for dual gram-negative coverage 4
• ADD vancomycin 15 mg/kg IV every 8-12 hours (target trough 15-20 mg/mL) OR linezolid 600 mg IV every 12 hours if MRSA risk factors present (prior MRSA, recent hospitalization, prevalence >20%) 4

Common Pitfalls to Avoid

Do not assume altered mental status is solely due to sepsis or metabolic derangements without considering cefepime neurotoxicity—this diagnosis is frequently missed because symptoms overlap with critical illness 1, 2, 5. The median delay to recognition is 4 days, during which ongoing cefepime exposure worsens outcomes 1.

Do not restart cefepime after symptom resolution, even with dose adjustment—rechallenge carries high risk of recurrent neurotoxicity 2, 3.

Do not use cefepime in patients with chronic kidney disease (present in 67% of neurotoxicity cases vs. 35% of unaffected patients, p=0.04) unless no alternative exists 2. If cefepime is unavoidable, reduce dose to 1 g IV every 12-24 hours based on creatinine clearance and monitor closely for neurologic changes 7, 2.

Avoid meropenem if the patient is on valproic acid—this combination causes dangerous drug interactions with precipitous drops in valproic acid levels, leading to breakthrough seizures 6. Use piperacillin-tazobactam or aztreonam instead 6.