In a hemodynamically stable adult with undifferentiated fever that occurs only at night, marked neutrophilic leukocytosis, normal renal function and no drug allergies, what is the appropriate empiric antibiotic regimen—should intravenous antipseudomonal β‑lactam therapy (e.g., cefepime or piperacillin‑tazobactam) be started instead of oral antibiotics alone?

Intravenous Antipseudomonal β-Lactam Therapy is Required

For a hemodynamically stable adult with undifferentiated fever occurring only at night and marked neutrophilic leukocytosis, intravenous antipseudomonal β-lactam therapy (cefepime 2 g IV every 8 hours or piperacillin-tazobactam 4.5 g IV every 6-8 hours) must be initiated immediately—oral antibiotics alone are insufficient and contraindicate established febrile neutropenia guidelines. 1

Critical Distinction: This is NOT Febrile Neutropenia

The clinical scenario describes neutrophilic leukocytosis (elevated neutrophils), not neutropenia (low neutrophils < 500 cells/mm³). 1 This fundamentally changes the management approach:

• Febrile neutropenia guidelines do not apply here because the patient has high neutrophils, not low neutrophils 1
• The pattern of fever only at night with marked neutrophilia suggests either occult bacterial infection, inflammatory process, or malignancy-related fever 2
• Oral antibiotics are only appropriate for LOW-RISK febrile neutropenic patients (neutrophils < 500/mm³) who meet strict criteria including MASCC score ≥ 21, no hemodynamic instability, no pneumonia, and expected brief neutropenia 1, 3

Why IV Antipseudomonal Therapy is NOT Indicated

In a hemodynamically stable adult with normal neutrophil counts (or elevated neutrophils) and undifferentiated fever, empiric broad-spectrum IV antibiotics should NOT be started without evidence of serious bacterial infection. 1

The appropriate workup includes:

• Complete infectious workup: Blood cultures (two sets from peripheral sites), urinalysis and culture, chest radiograph, and targeted cultures based on symptoms 1, 3
• Assessment for infection source: Respiratory symptoms, urinary symptoms, skin/soft tissue infection, catheter-related infection, or intra-abdominal process 1, 3
• Evaluation for non-infectious causes: Malignancy (lymphoma, leukemia), drug fever, connective tissue disease, or thromboembolic disease 1

When to initiate IV antibiotics in this scenario:

Start IV antipseudomonal β-lactam therapy ONLY if any of the following develop: 1, 3

• Hemodynamic instability (hypotension, tachycardia, altered mental status) 1, 3
• Documented or highly suspected serious bacterial infection (pneumonia on imaging, complicated UTI, bacteremia, soft tissue infection) 1, 3
• Clinical deterioration or development of sepsis criteria 1, 3
• Neutrophil count drops to < 500 cells/mm³ (converting to true febrile neutropenia) 1

Management Algorithm for This Patient

Step 1: Confirm this is NOT febrile neutropenia

• Verify absolute neutrophil count is > 500 cells/mm³ (the patient has neutrophilia, not neutropenia) 1
• If ANC < 500 cells/mm³, immediately start IV cefepime or piperacillin-tazobactam per febrile neutropenia protocols 1, 3

Step 2: Comprehensive infectious evaluation

• Obtain blood cultures, urinalysis/culture, chest X-ray before any antibiotics 1, 3
• Examine for focal infection: skin, oropharynx, perirectal area, catheter sites 1
• Review medication list for drug-induced fever 1

Step 3: Risk stratification

• If hemodynamically stable with no identified source: Observe with close monitoring, repeat cultures if fever persists, consider CT imaging of chest/abdomen/pelvis after 48-72 hours 1
• If focal infection identified: Treat with targeted antibiotics appropriate for the specific infection site and likely pathogens 1
• If hemodynamically unstable or septic: Immediately start IV piperacillin-tazobactam 4.5 g every 6 hours or cefepime 2 g every 8 hours 1, 3

Step 4: Consider non-infectious etiologies

• Malignancy workup if no infection found: peripheral smear, LDH, uric acid, imaging 1
• Drug fever: temporal relationship to medication initiation 1
• Connective tissue disease markers if clinically indicated 1

Critical Pitfalls to Avoid

Do not reflexively start broad-spectrum IV antibiotics for fever and leukocytosis without evidence of serious infection—this promotes antimicrobial resistance, increases costs, and exposes patients to unnecessary adverse effects including Clostridioides difficile infection. 1

Do not apply febrile neutropenia protocols to patients with normal or elevated neutrophil counts—these are fundamentally different clinical scenarios with different risk profiles and management strategies. 1, 2

Do not use oral fluoroquinolones as monotherapy for empiric treatment if serious infection is suspected—ciprofloxacin has inadequate gram-positive coverage and should be combined with amoxicillin-clavulanate only in low-risk febrile neutropenic patients. 1

If the patient develops hemodynamic instability, do not delay IV antibiotics—administration within 1 hour of presentation is critical for sepsis outcomes. 3, 4