What is the recommended approach to managing febrile neutropenia in an adult patient who presents with a fever ≥38.3 °C (101 °F) or a sustained fever ≥38.0 °C (100.4 °F) for more than one hour and an absolute neutrophil count (ANC) <500 cells/µL (or expected to fall below 500 cells/µL within 48 hours)?

Febrile Neutropenia Management

Initiate empirical broad-spectrum intravenous antibiotics within 2 hours of presentation for any patient with fever (≥38.3°C single reading or ≥38.0°C sustained for ≥1 hour) and ANC <500 cells/µL, because infection can progress rapidly and delay increases mortality. 1, 2

Immediate Assessment (Within 2 Hours)

Define Fever and Neutropenia

• Fever is a single oral temperature ≥38.3°C (101°F) or temperature ≥38.0°C (100.4°F) sustained over 1 hour. 1, 2
• Neutropenia is ANC <500 cells/µL or expected to fall below 500 cells/µL within 48 hours. 1, 2
• Avoid rectal temperatures and rectal examinations during neutropenia. 1
• Any fever in severe neutropenia is a medical emergency, even at 38.0–38.5°C. 2

Obtain Cultures Before Antibiotics

• Draw two sets of blood cultures: one from a peripheral vein and one from each lumen of any central venous catheter. 1, 2
• Collect urine culture and obtain chest radiograph. 1, 2
• Order complete blood count, comprehensive metabolic panel, liver enzymes, coagulation panel, C-reactive protein, and lactate dehydrogenase. 2
• Add respiratory viral screening and chest CT if pulmonary symptoms are present. 2

Risk Stratification

High-Risk Features (Require Inpatient IV Antibiotics)

• Anticipated prolonged neutropenia >7 days. 1, 2, 3
• ANC <100 cells/µL (profound neutropenia). 2, 3
• Hemodynamic instability or hypotension. 2
• Significant comorbidities (cardiac disease, COPD, diabetes). 4
• MASCC score <21. 2, 4
• Underlying hematologic malignancy or allogeneic stem-cell transplant. 3
• Significant mucositis or organ dysfunction. 2, 4

Low-Risk Features (May Qualify for Outpatient Oral Therapy)

• Anticipated brief neutropenia <7 days. 2, 4
• MASCC score ≥21. 1, 2, 4
• No significant comorbidities. 2, 4
• Hemodynamically stable with adequate oral intake. 4
• Reliable follow-up available. 4

Empirical Antibiotic Therapy

High-Risk Patients (Inpatient IV Therapy)

• Start an antipseudomonal β-lactam within 2 hours: cefepime is the preferred first-line agent. 1, 2, 5
• Cefepime dosing: 2 g IV every 8 hours for empiric therapy of febrile neutropenia; continue for 7 days or until resolution of neutropenia. 5
• Alternative antipseudomonal β-lactams: piperacillin-tazobactam, ceftazidime, meropenem, or imipenem. 2
• Add vancomycin only when specific indications are present: suspected catheter-related infection, hemodynamic instability, known MRSA colonization, skin/soft-tissue infection, or severe mucositis. 1, 2
• Consider adding an aminoglycoside for severe sepsis or hemodynamic instability. 2

Low-Risk Patients (Outpatient Oral Therapy)

• Oral regimen: ciprofloxacin 500 mg twice daily plus amoxicillin-clavulanate. 1, 2, 4
• Alternative oral regimens: levofloxacin monotherapy or ciprofloxacin plus clindamycin. 4
• Do not use fluoroquinolone empiric therapy if the patient is already receiving fluoroquinolone prophylaxis. 4
• Outpatient therapy requires all low-risk criteria to be met and daily follow-up capability. 1, 4

Supportive Care

• Initiate or continue filgrastim (G-CSF) 5 µg/kg/day subcutaneously in septic neutropenic patients; continue until ANC ≥500 cells/µL for two consecutive days. 2, 3
• Transfuse platelets when count <30 × 10⁹/L and packed red blood cells when hemoglobin <7 g/dL. 2
• Give normal saline bolus 10–20 mL/kg (maximum 1,000 mL) if hypotension develops, but avoid additional boluses in patients with cardiac dysfunction or volume overload. 2
• Use only irradiated blood products in severely immunocompromised patients. 3

Reassessment and Modification of Therapy

If Afebrile by Day 3–5

• When a pathogen is identified: de-escalate to the most appropriate targeted antibiotic and continue until ANC >500 cells/µL. 1, 2
• When no pathogen is identified and ANC is recovering (>500 cells/µL): continue antibiotics until the patient is afebrile for ≥48 hours and ANC >500 cells/µL for two consecutive days. 1, 2
• When no pathogen is identified and ANC remains <500 cells/µL:
  • Low-risk patients: complete 5–7 days of IV antibiotics, then may stop if afebrile. 2
  • High-risk patients: continue IV antibiotics until ANC recovery. 1, 2

If Fever Persists Beyond Day 3

• Re-evaluate for occult infection sites (sinuses, lungs, catheter sites, perineum, oral cavity) and continue the current antibiotic regimen. 1, 2
• Do not attribute fever solely to cytokine effects without first ruling out infection. 2

If Fever Persists Beyond Day 4–7

• Add empiric antifungal therapy (fluconazole, micafungin, or amphotericin B). 1, 2
• Obtain CT of chest and sinuses; consider galactomannan or β-D-glucan testing. 4
• Reassess for resistant organisms (MRSA, VRE, ESBL, carbapenem-resistant Enterobacteriaceae). 2, 4

If Clinical Deterioration or Hypotension Occurs

• Transfer to ICU-level care immediately. 2
• Broaden antimicrobial coverage and consider anti-IL-6 therapy when cytokine-release syndrome is suspected (e.g., CAR-T recipients). 2

Duration of Antibiotic Therapy

• ANC ≥500 cells/µL: Stop antibiotics 4–5 days after ANC recovery if the patient is afebrile and cultures are negative. 1, 2
• ANC <500 cells/µL with persistent fever: Continue antibiotics for a minimum of 2 weeks, then reassess. 2
• ANC <500 cells/µL, afebrile, no identified infection (high-risk): Continue antibiotics until ANC recovery. 1, 2
• Documented infections: Continue appropriate antibiotics for at least the duration of neutropenia or longer if clinically indicated. 4

Antimicrobial Prophylaxis for Anticipated Prolonged Neutropenia (>7 Days)

Antibacterial Prophylaxis

• Levofloxacin 500 mg orally daily (preferred) or ciprofloxacin 500 mg orally daily (alternative). 1, 3, 4
• Levofloxacin is preferred when mucositis risk is high due to better coverage of viridans group streptococci. 3
• Continue until ANC >500 cells/µL. 1, 3, 4

Antifungal Prophylaxis

• Fluconazole 400 mg orally daily starting at anticipated nadir. 1, 3, 4
• Continue until ANC >1,000 cells/µL. 3, 4

Antiviral Prophylaxis

• Acyclovir 400 mg orally daily or valacyclovir 500 mg orally twice daily. 1, 3, 4
• Continue for up to 6 months post-recovery or until CD4 >200 cells/µL. 3, 4

Pneumocystis jirovecii Prophylaxis

• Trimethoprim-sulfamethoxazole three times weekly. 1, 3, 4
• Continue for up to 6 months or until CD4 >200 cells/µL. 3, 4

Critical Pitfalls to Avoid

• Never delay antibiotics while awaiting the "classic" 38.3°C threshold or culture results in severe neutropenia. 1, 2
• Do not overlook relative hypotension; establish each patient's baseline blood pressure before labeling values as normal. 2
• Do not add vancomycin empirically unless specific risk factors (catheter infection, MRSA colonization, hemodynamic instability) are present. 1, 2
• Do not stop antibiotics prematurely in persistently neutropenic patients; therapy must continue until ANC recovery. 1, 2
• Do not use fluoroquinolone empiric therapy in patients already receiving fluoroquinolone prophylaxis. 4
• Do not use G-CSF during active chest radiotherapy due to increased pulmonary complications and mortality. 3
• Recognize that inflammatory signs may be minimal; localized pain at common infection sites may be the only clue. 2