How should I manage a patient who develops altered mental status after initiating meropenem, particularly in the setting of reduced renal clearance, advanced age, or pre‑existing central nervous system disease?

Management of Meropenem-Induced Altered Mental Status

Immediately discontinue meropenem and consider therapeutic drug monitoring if available; in patients with renal impairment, the risk of neurotoxicity is substantially elevated even at appropriately dose-adjusted regimens, and symptoms typically resolve within 2–4 days of drug cessation. 1

Recognize the Clinical Syndrome

Meropenem-induced neurotoxicity presents with altered mental status as the hallmark feature, though it is relatively less pro-convulsive compared to other beta-lactams (relative activity = 16 versus penicillin G = 100). 1 The syndrome shares clinical features with other beta-lactam neurotoxicities:

• Altered consciousness ranging from confusion to coma is universal 2
• Myoclonus occurs in approximately 42% of cases 2
• Seizures or non-convulsive status epilepticus may develop 2
• Encephalopathy with or without focal neurologic deficits 3, 4

Critical distinction: Not all altered mental status in hospitalized patients is hepatic encephalopathy or septic delirium—drug-related causes must be systematically excluded. 1

Identify High-Risk Patients

The primary risk factor is renal dysfunction, which causes rapid beta-lactam accumulation. 1 Meropenem is predominantly renally excreted with a half-life of approximately 1 hour in healthy individuals but prolonged up to 13.7 hours in anuric patients. 5

Specific risk factors include:

• Creatinine clearance < 50 mL/min requiring dose adjustment 5
• Advanced age (median age 69 years in neurotoxicity cases) 2
• Pre-existing CNS disease or structural brain injury 2
• Critical illness requiring ICU-level care 1
• Inappropriately high dosing for renal function (occurs in 48% of neurotoxicity cases, though 26% occur despite appropriate dosing) 2

Threshold concentrations: Meropenem trough concentrations above 64 mg/L are associated with neurotoxicity in 50% of patients, and when the free drug concentration-to-MIC ratio (fCmin/MIC) exceeds 8, approximately two-thirds of ICU patients develop neurological deterioration. 1

Immediate Management Steps

1. Discontinue Meropenem Immediately

Stop the drug as soon as neurotoxicity is suspected—do not wait for confirmatory testing. 2 Symptom resolution occurs a median of 2 days after intervention (drug discontinuation, antiepileptic administration, or hemodialysis). 2

2. Obtain Electroencephalography (EEG)

Order EEG urgently if the patient has altered mental status, as 98% of patients with beta-lactam neurotoxicity have EEG abnormalities. 2 Common findings include:

• Non-convulsive status epilepticus (25%) 2
• Triphasic waves (40%) 2
• Focal sharp waves (39%) 2
• Myoclonic status epilepticus (7%) 2

3. Consider Therapeutic Drug Monitoring (TDM)

If available, measure serum meropenem concentrations. 1 Median serum levels in neurotoxicity cases are 45 mg/L (well above the 64 mg/L threshold associated with 50% neurotoxicity risk). 2

4. Assess Renal Function and Adjust for Dialysis

In patients with renal impairment:

• Meropenem half-life is prolonged up to 13.7 hours in anuric patients 5
• Approximately 50% is removed by intermittent hemodialysis 5
• 25–50% is removed by continuous venovenous hemofiltration (CVVHF) 5
• 13–53% is removed by continuous venovenous hemodiafiltration (CVVHDF) 5

Consider hemodialysis in severe cases with refractory symptoms, particularly if serum concentrations are markedly elevated or renal function is severely impaired. 2

5. Administer Antiepileptic Drugs if Seizures Present

If seizures or non-convulsive status epilepticus are documented on EEG, initiate antiepileptic therapy. 2 Short-acting benzodiazepines such as lorazepam are preferred in the acute setting due to rapid onset and lack of active metabolites. 6, 7

Avoid long-acting benzodiazepines (e.g., diazepam) in patients with renal impairment, as active metabolites accumulate and prolong sedation. 6, 8

Exclude Alternative Diagnoses

Altered mental status in critically ill patients has a broad differential. Systematically evaluate for: 1

• Hepatic encephalopathy (if cirrhosis present)
• Septic encephalopathy or systemic infection
• Electrolyte disturbances (hyponatremia, hypercalcemia, uremia)
• Alcohol intoxication or withdrawal
• Intracranial pathology (hemorrhage, stroke, seizures)
• Other drug-related causes (opioids, sedatives, anticholinergics)
• Metabolic derangements (hypoglycemia, diabetic ketoacidosis)

Obtain head CT or MRI if focal neurologic deficits are present or if the diagnosis remains unclear after initial evaluation. 3

Select Alternative Antibiotic Therapy

When switching from meropenem, consider the original indication and pathogen:

• For Pseudomonas aeruginosa coverage: Consider piperacillin-tazobactam (though it also carries neurotoxicity risk at high concentrations, with a threshold of 157 mg/L steady-state concentration) 1
• For ESBL-producing organisms: Consider ceftazidime-avibactam or aztreonam
• For other Gram-negative infections: Consider fluoroquinolones (if susceptible) or aminoglycosides (with renal function monitoring)

Avoid cefepime in patients with renal impairment or CNS disease, as it has the highest pro-convulsive activity among beta-lactams (relative activity = 160) and causes neurotoxicity in up to 15% of ICU patients. 1, 3, 4, 2

Monitor for Resolution

Expected timeline:

• Median delay from drug initiation to symptom onset: 4 days 2
• Median time to symptom resolution after intervention: 2 days 2
• Overall survival to hospital discharge: 87% 2
• Symptom improvement rate: 89% 2

If symptoms do not improve within 2–4 days of meropenem discontinuation, reassess for alternative diagnoses or consider hemodialysis to accelerate drug clearance. 2

Common Pitfalls to Avoid

• Assuming appropriate dosing excludes neurotoxicity: 26% of cases occur despite FDA-approved dosing for renal function 2
• Delaying diagnosis due to multiple possible causes: Maintain high suspicion in any patient on meropenem with altered mental status 3, 4
• Failing to obtain EEG: Non-convulsive status epilepticus is present in 25% of cases and requires specific treatment 2
• Using long-acting benzodiazepines in renal failure: Diazepam and clonazepam have prolonged half-lives and active metabolites that accumulate 6, 8
• Overlooking propylene glycol toxicity from IV lorazepam: Doses as low as 1 mg/kg/day can cause metabolic acidosis and acute kidney injury in critically ill patients 7