What is the best course of action for a patient with acute altered mental status, leukocytosis (elevated White Blood Cell (WBC) count with neutrophilia), and elevated Erythrocyte Sedimentation Rate (ESR), who recently completed a course of antibiotics (ceftriaxone then cefuroxime) and is now on empiric broad-spectrum Intravenous (IV) cefepime plus vancomycin, with impaired renal function (eGFR 41.2) and coagulopathy (mildly prolonged Prothrombin Time (PT) and Partial Thromboplastin Time (PTT))?

Management of Acute Altered Mental Status in a Patient on Empiric Cefepime Plus Vancomycin with Renal Impairment

The current empiric regimen of cefepime plus vancomycin is appropriate for this septic-appearing patient, but immediate priorities include aggressive monitoring for cefepime-induced neurotoxicity given the altered mental status and renal dysfunction (eGFR 41.2), with plans to discontinue vancomycin within 48-72 hours if blood cultures remain negative, and to de-escalate or switch antibiotics based on culture results while closely monitoring renal function and coagulation parameters. 1, 2

Immediate Assessment and Monitoring Priorities

Cefepime Neurotoxicity Surveillance

• Cefepime-induced neurotoxicity is a critical concern in this patient given the combination of altered mental status, renal impairment (eGFR 41.2), and recent antibiotic exposure. 3, 4
• Neurotoxic symptoms include depressed consciousness, encephalopathy, aphasia, myoclonus, seizures, and coma, occurring in up to 15% of ICU patients treated with cefepime. 3
• Risk factors present in this patient include renal dysfunction, older age (if applicable), and critical illness with possible sepsis. 3, 4, 5
• Obtain an urgent electroencephalogram (EEG) to evaluate for non-convulsive status epilepticus (NCSE), which occurs in 25% of cefepime neurotoxicity cases and presents with triphasic waves (40%) or focal sharp waves (39%). 3, 4
• Cefepime neurotoxicity can occur despite appropriate renal dosing (26% of cases), though 48% of cases involve overdosing. 3
• If cefepime neurotoxicity is confirmed or strongly suspected, immediately discontinue cefepime and consider hemodialysis if symptoms are severe or life-threatening, as this can shorten time to recovery by approximately 15 hours. 6, 7

Vancomycin Management and Hematologic Monitoring

• Vancomycin should be discontinued after 48-72 hours if blood cultures remain negative for gram-positive organisms, as empiric vancomycin has not shown mortality benefit in randomized trials and increases risk of resistance and toxicity. 1, 2
• The current leukocytosis (WBC 18.91) requires close monitoring, as vancomycin-induced leukopenia is a recognized adverse effect. 8
• Obtain weekly complete blood count (CBC) monitoring given prolonged antibiotic therapy, especially as vancomycin therapy risk of cytopenia increases after 1 week or cumulative doses exceeding 25 grams. 8
• If WBC falls below 3,000/mm³ or absolute neutrophil count below 1,500/mm³, discontinue vancomycin immediately and monitor daily CBC. 8

Antibiotic De-escalation Strategy

Culture-Guided Modifications (48-72 Hours)

• Persistent fever alone in a hemodynamically stable patient is not an indication to alter antibiotics; modifications should be guided by clinical change or culture results rather than fever pattern. 1
• If blood cultures remain negative at 48-72 hours, discontinue vancomycin to reduce cost and toxicity. 1, 2
• For documented gram-negative bacteremia (excluding Pseudomonas aeruginosa), transition to monotherapy with cefepime if susceptible, as combination therapy provides no additional benefit. 1
• For Pseudomonas bacteremia, maintain combination therapy with cefepime plus an aminoglycoside and check serum bactericidal titers. 1

Alternative Antibiotic Considerations

• If cefepime must be discontinued due to neurotoxicity, consider switching to a carbapenem (meropenem or imipenem) or piperacillin-tazobactam, which provide similar broad-spectrum coverage without the same neurotoxicity risk. 1, 7
• In patients with advanced renal insufficiency, cefotaxime or ceftriaxone (with both hepatic and renal excretion) may be safer alternatives to cefepime. 7
• Meropenem is recommended as an alternative with the same spectrum but without neurological toxicity in renally impaired patients. 7

Management of Persistent Fever Beyond 4-7 Days

Empiric Antifungal Coverage

• If fever persists beyond 4-7 days despite broad-spectrum antibiotics, initiate empiric amphotericin B for fungal coverage, as disseminated fungal infections (Candida or Aspergillus) are common in prolonged neutropenia and present as protracted fever with negative blood cultures. 1, 2
• Continue broad-spectrum antibiotics during antifungal therapy, as discontinuation may be associated with fatal bacteremia in febrile patients. 1, 2

Evaluation for Non-Infectious Causes

• Investigate non-infectious sources including drug-related fever, thrombophlebitis, underlying malignancy, or blood resorption from hematoma. 1
• Assess for Clostridioides difficile infection given recent antibiotic exposure (ceftriaxone, cefuroxime) by testing stool for C. difficile toxin. 1
• Evaluate for catheter-related infections if indwelling venous access is present. 1

Renal Function and Coagulation Monitoring

Renal Dosing Adjustments

• Continue renal-adjusted dosing of both cefepime and vancomycin based on eGFR 41.2, with frequent reassessment as renal function may fluctuate in sepsis. 9, 10
• Monitor creatinine clearance closely, as calculated values overestimate actual clearance in conditions with decreasing renal function, shock, severe heart failure, or oliguria. 10
• Consider measuring serum cefepime levels if available, as median toxic concentrations are 45 mg/L (serum) and 13 mg/L (CSF). 3

Coagulopathy Management

• Trend PT (currently 14.6) and PTT (currently 42.2) closely, as mild prolongation may reflect sepsis-associated coagulopathy, antibiotic effects, or vitamin K deficiency. 2
• Vancomycin does not typically cause coagulopathy, but cephalosporins can interfere with vitamin K metabolism; consider vitamin K supplementation if PT remains elevated without other explanation.

Duration of Therapy

Treatment Course

• Plan for a total of 7 days of antibiotic therapy for patients responding to empiric treatment without microbiological documentation. 1, 2
• Aminoglycosides (if added for documented gram-negative bacteremia) can be discontinued earlier than 7 days once clinical improvement is evident. 1
• Avoid prolonged antimicrobial treatment without clear indication, as this significantly increases risk of superinfections, particularly fungemia. 1, 2

Critical Pitfalls to Avoid

• Do not add or switch antibiotics empirically for persistent fever alone in a hemodynamically stable patient without clinical deterioration or positive cultures. 1
• Do not continue vancomycin beyond 48-72 hours if blood cultures are negative, as this increases resistance risk without proven benefit. 1
• Do not overlook cefepime neurotoxicity as a cause of altered mental status in patients with renal dysfunction, even with appropriate dosing. 3, 4
• Do not discontinue broad-spectrum antibiotics prematurely in patients with persistent fever and leukocytosis, as this may lead to breakthrough bacteremia. 1