Neutropenic Fever Empiric Therapy Overview

Neutropenic Fever Empiric Therapy

• Neutropenia Definition: Absolute neutrophil count (ANC) less than 500/μL, or less than 1000/μL with anticipated decline to less than 500/μL in 48 hours.
• Neutropenic Fever Definition: Single oral temperature of 38.3°C (101°F) or sustained temperature above 38.0°C (100.4°F) for over an hour in a neutropenic patient.
• Patient Risk Assessment: Crucial for determining appropriate therapy (oral vs. IV), duration, and inpatient/outpatient management. High-risk vs. low-risk classification.
• High-Risk Patients: Characteristics include; anticipated, prolonged (>7 days), profound neutropenia (ANC < 100/μL) following cytotoxic chemo; significant medical comorbidities (hypotension, pneumonia, new-onset abdominal pain, neurologic changes).
• Low-Risk Patients: Characteristics include; anticipated brief (<7 days) neutropenia; ANC > 100/μL and absolute monocyte count > 100/μL; normal chest X-ray; outpatient status at fever onset; no acute comorbidity; no hepatic/renal insufficiency; early bone marrow recovery.

Low-Risk Patient Regimens

• Oral Empiric Therapy: Amoxicillin-clavulanate (500 mg/125 mg PO q8h) + ciprofloxacin (500 mg PO q12h).
• Alternative: Moxifloxacin (400 mg PO daily).
• Penicillin Allergy Substitution: Clindamycin (300 mg PO q6h) for amoxicillin-clavulanate.
• Outpatient Monitoring: Daily office visits for at least 72 hours.

High-Risk Patient Regimens (Hospitalized)

• First-Line Monotherapy (anti-pseudomonal required): Piperacillin-tazobactam (4.5 g IV q6h), Cefepime (2 g IV q8h), Meropenem (1 g IV q8h), Imipenem-cilastatin (500 mg IV q6h) are suitable.
• Second-Line Dual Therapy (complications/resistance): Piperacillin-tazobactam + aminoglycoside; Cefepime + aminoglycoside; Meropenem + aminoglycoside; Imipenem-cilastatin + aminoglycoside.
• Aminoglycoside Options: Gentamicin (2 mg/kg IV q8h or 5 mg/kg q24h), Amikacin (15 mg/kg/day), Tobramycin (2 mg/kg q8h).

Vancomycin Considerations

• Indications: Clinically suspected serious catheter-related infections, known colonization with penicillin/cephalosporin-resistant pneumococci or methicillin-resistant Staphylococcus aureus (MRSA), blood culture positive for gram-positive bacteria, hypotension, severe mucositis (if prior fluoroquinolone prophylaxis).

Additional Considerations for Antibiotic-Resistant Organisms

• MRSA: Vancomycin, linezolid, or daptomycin.
• Vancomycin-resistant enterococcus (VRE): Linezolid or daptomycin.
• ESBL-producing gram-negative bacteria: Carbapenem (e.g., meropenem).
• Carbapenemase-producing organisms: Polymyxin-colistin or tigecycline.

Fever Resolution (3-5 days or More)

• Identified Organism: Adjust antibiotics based on organism & infection site; 7+ days of therapy until negative cultures and clinical improvement.
• No Organism Identified, ANC > 500/μL for 2 Consecutive Days: Change to amoxicillin-clavulanate + ciprofloxacin; discontinue after 5-7 days of afebrile period.
• No Organism Identified, ANC < 500/μL: Continue current regimen until day 7; low-risk/stable at day 7, discontinue antibiotics; high-risk, continue for 2 weeks or until neutropenia resolves.
• Fever Persists > 3-5 Days (ANC > 500/μL): Continue current regimen, stop after ANC > 500/μL. Assess for undiagnosed fungal infection.
• Fever Persists > 3-5 Days (ANC < 500/μL): Add vancomycin (if not already on) per criteria. Consider discontinuing vancomycin if MRSA cultures are negative. Add empiric antifungal therapy if needed.

Antifungal Agents (Empiric)

• Options: Amphotericin B liposomal, voriconazole, posaconazole, itraconazole IV/PO, caspofungin, micafungin, anidulafungin.
• Considerations: Withhold in specific high-risk stable patients without fungal signs after 4-7 days of broad-spectrum antibiotics. Avoid routine use in low-risk patients.
• Duration: 2 weeks if stable and no infectious nidus is found, switching classes if fever persists is needed.

Special Considerations

• Colony-stimulating factors (CSFs): Prophylactic use can reduce neutropenic fever incidence; consider when risk is high. Chemotherapy dose reduction is considered for palliative chemo intent. Use of CSFs for established fever and neutropenia is not generally recommended.