How is febrile neutropenia treated?

Management of Febrile Neutropenia

Febrile neutropenia requires immediate empirical broad-spectrum antibiotics within 1 hour of presentation, with treatment intensity determined by risk stratification using the MASCC score. 1, 2

Immediate Assessment and Resuscitation

Assess circulatory and respiratory function immediately upon presentation, with vigorous resuscitation if hypotension (systolic BP <90 mmHg) or respiratory distress is present. 1, 2

• Obtain urgent full blood count to confirm neutrophil level (ANC <1,000/mm³ or <500/mm³ defines severity) 1
• Measure vital signs, renal and liver function, coagulation screen, and C-reactive protein 1, 3
• Critical pitfall: Signs of infection may be minimal or absent in neutropenic patients, especially those on corticosteroids—maintain high suspicion even with low-grade fever or afebrile presentation 1, 4
• Patients presenting unwell, hypotensive, or afebrile may be developing Gram-negative septicemia requiring immediate treatment 1

Risk Stratification Using MASCC Score

Calculate the MASCC score immediately to determine treatment intensity—scores ≥21 indicate low risk (6% complication rate, 1% mortality), while scores <21 indicate high risk. 1, 3

The MASCC scoring criteria include: 1

• Burden of illness: no/mild symptoms (5 points), moderate symptoms (3 points), severe symptoms (0 points)
• No hypotension/systolic BP >90 mmHg (5 points)
• No chronic obstructive pulmonary disease (4 points)
• Solid tumor/lymphoma with no previous fungal infection (4 points)
• No dehydration (3 points)
• Outpatient status at fever onset (3 points)
• Age <60 years (2 points)

Microbiologic Sampling Before Antibiotics

Obtain two sets of blood cultures from peripheral vein and all indwelling catheters before starting antibiotics, but do not delay antibiotic administration. 1, 2

• Collect sputum, urine, skin swabs, and stool specimens where clinically indicated 1
• Review clinical records for previous positive microbiology, particularly antibiotic-resistant organisms or prior bacteremia 1
• Document presence of indwelling IV catheters and examine for potential infection foci (respiratory, gastrointestinal, skin, perineal, oropharynx, CNS) 1

Antibiotic Selection Based on Risk

High-Risk Patients (MASCC <21)

Start IV monotherapy with anti-pseudomonal beta-lactam (cefepime 2g IV every 8 hours or piperacillin-tazobactam) within 1 hour of presentation. 2, 3, 5

• Cefepime is FDA-approved as monotherapy for empiric treatment of febrile neutropenic patients 5
• Important caveat: In patients at highest risk (recent bone marrow transplantation, hypotension at presentation, underlying hematologic malignancy, severe/prolonged neutropenia), monotherapy may not be appropriate—consider combination therapy with beta-lactam plus aminoglycoside 5
• Add vancomycin only if specific indications exist: suspected catheter-related infection, skin/soft tissue infection, pneumonia, or hemodynamic instability 2, 3

Low-Risk Patients (MASCC ≥21)

Low-risk patients who are hemodynamically stable, without acute leukemia, organ failure, pneumonia, indwelling catheter, or severe soft tissue infection can receive oral antibiotics (quinolone plus amoxicillin-clavulanate). 1, 3

• These patients may be treated as outpatients or with early hospital discharge 1, 3
• Exclude patients with acute leukemia, evidence of organ failure, pneumonia, indwelling venous catheter, or severe soft tissue infection from oral therapy 1

Site-Specific Antibiotic Modifications

• Central line infections: Add vancomycin and administer antibiotics through the line when possible 2
• Cellulitis: Add vancomycin to broaden coverage against skin pathogens 2
• Community-acquired pneumonia: May not be adequately covered by standard empirical antibiotics—tailor therapy accordingly 1

Assessment of Response at 48-72 Hours

Reassess clinical status, culture results, and fever trends at 48-72 hours to guide subsequent management. 2, 3

If Afebrile and ANC ≥0.5×10⁹/L at 48 Hours:

• Consider changing to oral antibiotics for low-risk patients 2
• Discontinue aminoglycoside for high-risk patients on dual therapy 2

If Still Febrile at 48 Hours:

• Continue initial antibacterial therapy if patient is clinically stable 2
• Broaden antibiotic coverage and seek infectious disease consultation if clinically unstable 2

Management of Persistent Fever Beyond 4-6 Days

If fever persists for >4-6 days despite appropriate antibiotics, obtain high-resolution chest CT to exclude invasive fungal infection and consider empiric antifungal therapy. 1, 4, 2, 3

• Suspect invasive aspergillosis in patients with acute myeloid leukemia during induction chemotherapy or allogeneic stem cell transplantation 4
• Look for nodules with haloes or ground-glass changes on chest CT 4
• Consider candidemia, particularly in patients with central venous catheters or previous azole prophylaxis 4
• Start fluconazole for suspected candidosis, with early switch to alternative antifungal if inadequate response 2

Duration of Antibiotic Therapy

Discontinue antibiotics if neutrophil count ≥0.5×10⁹/L, patient is asymptomatic, afebrile for 48 hours, and blood cultures are negative. 2, 3

• Exception: High-risk cases with acute leukemia or post-high-dose chemotherapy may continue antibiotics for up to 10 days or until neutrophil recovery 2
• For patients with ANC ≤0.5×10⁹/L, continue antibiotics until ANC recovers or for at least 5-7 days if afebrile without complications 3

Additional Diagnostic Considerations for Persistent Symptoms

• Herpes simplex virus reactivation: Initiate aciclovir after obtaining appropriate samples 4
• Cytomegalovirus infection: Consider ganciclovir substitution with high clinical suspicion 4
• Bacterial meningitis: Perform lumbar puncture and treat with ceftazidime plus ampicillin or meropenem to cover Listeria monocytogenes 4
• Typhlitis: Obtain CT imaging of abdomen in patients with abdominal pain and fever 4
• Clostridium difficile colitis: Consider in patients with diarrhea and recent antibiotic exposure 4

Critical Pitfalls to Avoid

• Never delay antibiotic administration while awaiting diagnostic workup—obtain cultures then immediately start empiric antibiotics 4, 2
• Do not use oral antibiotics in high-risk patients with significant neutropenia following chemotherapy, as this may not provide adequate coverage 3
• Do not underestimate infection severity due to minimal signs—fever may be the only clinical indicator in neutropenic patients 3
• Thrombocytopenia may preclude invasive diagnostic procedures, requiring risk-benefit assessment and potential platelet transfusion 4
• Frequent clinical assessment (every 2-4 hours in severe cases) is crucial, with daily evaluation of fever trends and laboratory parameters 2