What is the recommended management of febrile neutropenia in a chemotherapy patient (fever ≥38.3 °C, absolute neutrophil count <500/µL), including initial empiric anti‑pseudomonal β‑lactam therapy, criteria for outpatient oral therapy using the MASCC (Multinational Association for Supportive Care in Cancer) score, indications for adding vancomycin, duration of treatment, when to start empiric antifungal therapy, use of granulocyte colony‑stimulating factor prophylaxis, and steps for escalation if the initial regimen fails?

Management of Febrile Neutropenia

Immediately initiate empiric monotherapy with an antipseudomonal β-lactam (cefepime, piperacillin-tazobactam, or a carbapenem) within 1 hour of presentation for any patient with fever ≥38.3°C and ANC <500/µL. 1, 2, 3

Initial Assessment and Risk Stratification

Before administering antibiotics, obtain at least 2 sets of blood cultures (peripheral and from central line if present), perform focused physical examination looking specifically for skin/soft tissue lesions, respiratory symptoms, catheter site inflammation, and abdominal tenderness. 1

Use the MASCC score to stratify risk:

• **High-risk patients (MASCC score <21):** Require hospitalization and IV antibiotics. This includes patients with AML, relapsed leukemia, allogeneic HSCT recipients, profound neutropenia expected >7 days, hemodynamic instability, or significant comorbidities. 1, 3
• Low-risk patients (MASCC score ≥21): May be candidates for outpatient oral therapy after initial observation, provided they have solid tumors, expected brief neutropenia, no organ dysfunction, and reliable home support with 24/7 access to medical care within 1 hour. 1

First-Line Empiric Antibiotic Selection

For high-risk patients, choose ONE of the following antipseudomonal β-lactam monotherapy options:

• Piperacillin-tazobactam 4.5g IV every 6 hours (preferred based on mortality data showing RR 0.56 compared to other antibiotics) 4, 5
• Meropenem 1g IV every 8 hours or imipenem-cilastatin 500mg IV every 6 hours (carbapenems result in fewer treatment modifications but higher rates of C. difficile diarrhea) 1, 4, 5
• Ceftazidime 2g IV every 8 hours (acceptable alternative) 1, 3

Do NOT use cefepime as monotherapy—it is associated with significantly increased all-cause mortality (RR 1.39,95% CI 1.04-1.86) compared to other β-lactams. 4, 5

When to Add Vancomycin

Do NOT routinely add vancomycin to initial empiric therapy. 1, 3

Add vancomycin 15-20mg/kg IV every 8-12 hours ONLY if one or more of these specific indications are present:

• Hemodynamic instability or severe sepsis/septic shock 1, 2
• Suspected catheter-related bloodstream infection (erythema, tenderness, purulence at insertion site) 1, 2, 6
• Skin or soft tissue infection with visible cellulitis 1
• Pneumonia documented on chest imaging 1
• Blood cultures growing gram-positive cocci before speciation 1, 2
• Known colonization with MRSA 1

If vancomycin was added empirically and blood cultures remain negative at 48-72 hours, discontinue vancomycin to reduce toxicity, cost, and resistance. 1, 6

Reassessment at 48-72 Hours

Perform clinical reassessment after 2-4 days of therapy. 1

If the patient is clinically stable and improving:

• Continue the same antibiotic regimen 1
• Persistent fever alone (without clinical deterioration) is NOT an indication to modify antibiotics—median time to defervescence is 5 days in high-risk patients 1, 6
• Low-risk patients who are afebrile and stable may transition to oral antibiotics (ciprofloxacin 750mg PO twice daily plus amoxicillin-clavulanate 875mg PO twice daily) for outpatient completion 1

If the patient has clinical deterioration, new symptoms, or hemodynamic instability:

• Broaden coverage by adding vancomycin if not already included 1
• Consider adding an aminoglycoside (gentamicin or amikacin) for double gram-negative coverage if septic or documented resistant gram-negative bacteremia 1, 7
• Obtain targeted imaging: chest CT for respiratory symptoms, abdominal CT for abdominal pain/diarrhea, sinus CT for facial pain/headache 1

Empiric Antifungal Therapy

If fever persists for 4-7 days despite appropriate broad-spectrum antibacterial therapy in high-risk patients, initiate empiric antifungal therapy. 1, 2, 6, 8

This is critical because up to one-third of patients with persistent fever have invasive fungal infections (invasive aspergillosis or disseminated candidiasis), and blood cultures are often negative even with disseminated disease. 6

Before starting antifungals, obtain high-resolution chest CT (including liver and spleen) to look for:

• Nodules with halo sign (aspergillosis) 1, 6
• Ground-glass opacities 1
• Hepatosplenic candidiasis 6

First-line empiric antifungal options:

• Liposomal amphotericin B 3-5mg/kg IV daily (preferred for suspected aspergillosis) 1, 6
• Voriconazole 6mg/kg IV every 12 hours × 2 doses, then 4mg/kg IV every 12 hours (alternative for aspergillosis) 6
• Caspofungin 70mg IV loading dose, then 50mg IV daily (preferred if prior azole exposure or suspected resistant Candida) 6

Duration of Antibiotic Therapy

Continue antibiotics until ALL of the following criteria are met:

• Patient afebrile for ≥48 hours 1, 2
• ANC recovered to >500 cells/µL with rising trend 1, 2
• All signs/symptoms of infection resolved 1
• Minimum duration of 7-10 days for high-risk patients 2

For documented infections (bacteremia, pneumonia, soft tissue infection), continue antibiotics for the full treatment course appropriate to that infection (typically 10-14 days), even if neutrophil count recovers earlier. 1

Granulocyte Colony-Stimulating Factor (G-CSF)

G-CSF prophylaxis (filgrastim 5mcg/kg/day or pegfilgrastim 6mg once per cycle) should be administered with chemotherapy regimens that carry ≥20% risk of febrile neutropenia. 8

G-CSF does NOT replace antimicrobial therapy and should not be used as treatment for active febrile neutropenia. 2 It may shorten neutropenia duration but cannot treat established infection. 2

Critical Pitfalls to Avoid

• Never delay antibiotics—febrile neutropenia is an oncologic emergency requiring treatment within 1 hour of presentation. 3, 6
• Do not use cefepime as monotherapy due to increased mortality risk. 4, 5
• Do not add vancomycin empirically for persistent fever alone in stable patients—this does not improve outcomes and promotes resistance. 1
• Do not delay antifungal therapy beyond 7 days of persistent fever—this increases mortality from untreated invasive fungal infections. 6
• Do not use oral antibiotics or fluoroquinolone monotherapy in high-risk patients—these are insufficient for empiric coverage. 3
• Do not rely on blood cultures alone to diagnose fungal infections—obtain CT imaging and consider BAL if infiltrates present. 6
• Do not use antibiotics lacking antipseudomonal activity (such as ceftriaxone) in neutropenic patients. 6