In a patient with persistent fever and a decline in Glasgow Coma Scale to 14/15 while receiving ceftriaxone, and a normal non‑contrast CT brain, what are the likely causes and recommended next diagnostic and therapeutic steps?

Proceed Urgently with Lumbar Puncture and Consider Ceftriaxone-Induced Encephalopathy

In a patient with persistent fever and declining GCS (14/15) on ceftriaxone with a normal CT brain, you must immediately perform a lumbar puncture to rule out bacterial meningitis, while simultaneously considering ceftriaxone-induced encephalopathy as a potential cause of the altered mental status.

Immediate Diagnostic Steps

Lumbar Puncture is Essential

• Normal CT does not exclude meningitis or raised intracranial pressure 1, 2
• With GCS 14/15 and no focal neurological deficits or papilledema, LP is not contraindicated 2
• Obtain CSF for: cell count with differential, glucose, protein, Gram stain, culture, and PCR for bacterial pathogens (pneumococcus, meningococcus) 1, 3
• Opening pressure should be measured 2

Consider MRI Brain

• MRI is superior to CT for detecting meningitis/encephalitis and can identify complications like cerebral edema, ischemia, or leptomeningitis 4, 5
• MRI may reveal findings not visible on CT, particularly in early or atypical presentations 6

Likely Differential Diagnoses

1. Bacterial Meningitis (Despite Ceftriaxone)

Possible scenarios:

• Inadequate CSF penetration if meningeal inflammation has resolved
• Resistant organism (though uncommon with ceftriaxone) 1
• Wrong pathogen coverage: If patient is >50 years or immunocompromised, Listeria monocytogenes is not covered by ceftriaxone alone and requires ampicillin addition 3
• Intracranial complications: subdural empyema, brain abscess, ventriculitis, or cerebral ischemia occur in 57% of ICU patients with meningitis 7, 4

2. Ceftriaxone-Induced Encephalopathy (Critical to Consider)

This is an emerging and underrecognized adverse effect 8, 9:

• Presents with altered consciousness, confusion, lethargy, seizures, myoclonus, or nonconvulsive status epilepticus 8, 9
• Can occur even with normal renal function, though more common in renal impairment 9, 10
• Typically begins 4-8 days after starting ceftriaxone 9, 11
• High ceftriaxone levels in blood and CSF are causative 10, 11
• Symptoms resolve within 3-7 days after discontinuation 9, 12, 13

3. Viral Encephalitis

• HSV, CMV (even in immunocompetent hosts), or other viral pathogens 4, 6
• CSF PCR for HSV-1, HSV-2, VZV, enterovirus should be sent 4

4. Non-Infectious Causes

• Cerebral edema, ischemia, or metabolic encephalopathy 7, 5

Therapeutic Algorithm

Step 1: Optimize Antibiotic Coverage Immediately

While awaiting LP results:

• If patient is >50 years or immunocompromised: Add ampicillin 2g IV every 4 hours to cover Listeria 1, 3
• If penicillin/cephalosporin resistance suspected: Add vancomycin 15-20 mg/kg IV every 12 hours (target trough 15-20 μg/mL) 1, 3
• Continue ceftriaxone 2g IV every 12 hours unless encephalopathy is strongly suspected 1

Step 2: Add Aciclovir for Possible Viral Encephalitis

• Start aciclovir 10 mg/kg IV every 8 hours if any suspicion of HSV encephalitis 4
• Do not delay while awaiting confirmatory tests

Step 3: Consider Dexamethasone

• Dexamethasone 10mg IV every 6 hours should be given with or just before antibiotics in suspected bacterial meningitis 3
• Can be started up to 4 hours after first antibiotic dose 3
• Discontinue if Listeria is identified (associated with increased mortality) 3

Step 4: Evaluate for Ceftriaxone Encephalopathy

If LP shows normal or improving CSF parameters:

• Strongly consider discontinuing ceftriaxone and switching to an alternative antibiotic 8, 9
• Alternative options: meropenem 2g IV every 8 hours or cefotaxime 2g IV every 4-6 hours 1
• Expect neurological improvement within 3 days if ceftriaxone was the cause 9, 12
• Consider measuring ceftriaxone levels in blood/CSF if available 10, 11

Step 5: Obtain EEG

• Rule out nonconvulsive status epilepticus, which can occur with both meningitis and ceftriaxone toxicity 7, 8

Critical Pitfalls to Avoid

1. Do not assume normal CT excludes serious CNS pathology - LP and MRI are essential 2, 4
2. Do not overlook Listeria coverage in older/immunocompromised patients - ceftriaxone alone is insufficient 3
3. Do not dismiss ceftriaxone encephalopathy - it can occur with normal renal function and is reversible 9
4. Do not delay LP for imaging unless there are specific contraindications (GCS ≤9, focal signs, papilledema) 1, 2
5. Do not continue ineffective antibiotics - if no improvement after 48-72 hours, reassess coverage and consider complications 7

Duration of Treatment (If Bacterial Meningitis Confirmed)

• Meningococcal: 5 days if recovered 1
• Pneumococcal: 10 days if stable, up to 14 days if slow response 1
• Listeria: 21 days 1
• No pathogen identified: 10 days if clinically recovered 1