What is the management of febrile neutropenia (low white blood cell count with fever) after chemotherapy?

Management of Febrile Neutropenia After Chemotherapy

Initiate broad-spectrum intravenous antibiotics with antipseudomonal activity immediately upon diagnosis of febrile neutropenia, defined as fever >38.5°C (or two readings >38.0°C for 2 hours) with absolute neutrophil count <0.5 × 10⁹/L. 1

Initial Assessment and Risk Stratification

Upon presentation, perform the following critical evaluations:

• Obtain blood cultures from peripheral sites and all lumens of central venous catheters before antibiotic administration 1
• Document vital signs including temperature, blood pressure, heart rate, respiratory rate, and oxygen saturation 1
• Assess for infection sources: examine skin (especially catheter sites), oral cavity, lungs, abdomen, and perianal area 1
• Order baseline laboratory tests: complete blood count with differential, renal function, liver function, and C-reactive protein 1
• Calculate MASCC risk score to stratify patients: scores >21 indicate low risk (mortality ~3%), while scores <15 indicate high risk (mortality up to 36%) 1

Immediate Empiric Antibiotic Therapy

First-Line Treatment

Start broad-spectrum monotherapy with an antipseudomonal beta-lactam agent immediately (within 1 hour of presentation): 1

• Cefepime 2g IV every 8 hours, OR 2, 3
• Piperacillin-tazobactam 4.5g IV every 6 hours, OR 1
• Meropenem or imipenem-cilastatin (reserve for patients with beta-lactam allergies or resistant organisms) 1

Common pitfall: Do not delay antibiotic administration while awaiting culture results—mortality increases significantly with each hour of delay. 1

When to Add Glycopeptide Coverage

Add vancomycin or teicoplanin if: 1

• Hemodynamic instability or septic shock present
• Suspected catheter-related infection (erythema, tenderness at insertion site)
• Skin or soft tissue infection clinically evident
• Known colonization with MRSA or high local MRSA prevalence
• Mucositis severe enough to suggest viridans streptococci infection

When to Add Gram-Negative Coverage

Add an aminoglycoside (gentamicin or amikacin) if: 1

• Septic shock or hemodynamic instability at presentation
• Suspected resistant Gram-negative infection based on local epidemiology
• Previous infection with ESBL-producing organisms

Assessment at 48-72 Hours

If Patient is Afebrile and Neutrophil Count ≥0.5 × 10⁹/L

• Low-risk patients: Consider switching to oral fluoroquinolone plus amoxicillin-clavulanate for outpatient management 1
• High-risk patients: If on dual therapy, discontinue aminoglycoside; continue beta-lactam monotherapy 1
• If pathogen identified: Tailor antibiotics to culture sensitivities and continue appropriate therapy 1

If Patient Remains Febrile at 48-72 Hours

Clinically stable patients: Continue initial antibacterial regimen and reassess daily 1

Clinically unstable or deteriorating patients: 1

• Broaden antibacterial coverage or rotate to alternative agents (e.g., switch to carbapenem plus glycopeptide)
• Obtain chest CT scan to evaluate for fungal infection, especially if fever persists >4-6 days 1
• Consult infectious disease specialist immediately 1

Antifungal Therapy

When to Initiate Empiric Antifungal Treatment

Start antifungal therapy if: 1

• Persistent fever after 4-6 days of appropriate antibacterial therapy
• High-risk patients (acute leukemia, allogeneic stem cell transplant, prolonged neutropenia >7 days)
• CT findings suggestive of invasive fungal infection (nodules with halos, ground-glass opacities)

First-Line Antifungal Agents

For suspected invasive aspergillosis or mold infection: 1

• Voriconazole (loading dose 6 mg/kg IV every 12 hours for 2 doses, then 4 mg/kg every 12 hours), OR
• Liposomal amphotericin B (3-5 mg/kg IV daily)

For suspected candidemia in patients not on azole prophylaxis: 1

• Fluconazole 400-800 mg IV daily (if low risk for resistant Candida species), OR
• Caspofungin 70 mg IV loading dose, then 50 mg IV daily (if azole-resistant Candida suspected or prior azole exposure)

Critical caveat: If patient is already on azole prophylaxis (voriconazole or posaconazole), switch to liposomal amphotericin B to avoid resistance. 1

Special Clinical Scenarios

Pneumocystis Pneumonia (PCP) Suspected

If patient presents with: 1

• Bilateral interstitial infiltrates on imaging
• Elevated LDH with new onset
• Hypoxemia or desaturation on exertion
• History of corticosteroid use or purine analogue exposure

Treatment: High-dose trimethoprim-sulfamethoxazole (15-20 mg/kg/day of trimethoprim component) IV divided every 6-8 hours 1

Alternative: Clindamycin 600-900 mg IV every 6-8 hours plus primaquine 15-30 mg PO daily if TMP-SMX intolerant 1

Intra-Abdominal or Pelvic Sepsis

Add metronidazole 500 mg IV every 8 hours if clinical or imaging evidence suggests anaerobic involvement 1

Suspected Meningitis or Encephalitis

• Perform lumbar puncture immediately (if no contraindications) 1
• Bacterial meningitis: Ceftazidime or meropenem PLUS ampicillin 2g IV every 4 hours (for Listeria coverage) 1
• Viral encephalitis: Acyclovir 10 mg/kg IV every 8 hours 1

Lung Infiltrates Without Response

• Obtain high-resolution chest CT immediately 1
• Perform bronchoalveolar lavage if safe to do so 1
• Send BAL for: bacterial culture, fungal culture, Aspergillus galactomannan (cutoff ≥1.0), quantitative Pneumocystis PCR (>1450 copies/mL is diagnostic), viral PCR panel 1

Duration of Antibiotic Therapy

Neutrophil Count ≥0.5 × 10⁹/L

Discontinue antibiotics if: 1

• Patient has been afebrile for 48 hours
• No symptoms of active infection
• Blood cultures negative

Neutrophil Count <0.5 × 10⁹/L

Discontinue antibiotics if: 1

• Patient has been afebrile for 5-7 days
• No complications have occurred
• Exception: Continue antibiotics for up to 10 days or until neutrophil recovery in high-risk patients with acute leukemia or post-high-dose chemotherapy

Persistent Fever Despite Neutrophil Recovery

• Reassess for non-infectious causes (drug fever, malignancy)
• Consider antifungal therapy if not already initiated 1
• Obtain infectious disease consultation 1

Role of Growth Factors

Filgrastim (G-CSF) 5 mcg/kg/day subcutaneously can be considered in established febrile neutropenia, though evidence shows modest benefit: 4, 5

• Reduces median duration of neutropenia by approximately 1 day (4 vs 3 days) 5
• Shortens time to resolution of febrile neutropenia (6 vs 5 days) 5
• Does not reduce fever duration itself 5
• Greatest benefit appears in patients with documented infection and presenting neutrophil counts <0.1 × 10⁹/L 5

Note: G-CSF is more commonly used prophylactically to prevent febrile neutropenia rather than therapeutically once it occurs. 4

Monitoring and Follow-Up

• Assess clinical status every 2-4 hours if critically ill, otherwise daily 1
• Monitor fever trends and vital signs daily 1
• Check complete blood count daily until neutrophil recovery 1
• Monitor renal function daily (many antibiotics require dose adjustment) 1
• Repeat imaging if fever persists beyond 4-6 days or clinical deterioration occurs 1

Critical pitfall: Patients may not mount typical inflammatory responses due to neutropenia—fever may be the only sign of serious infection, so maintain high clinical suspicion even with minimal findings. 1, 6