• Neutropenia can result from decreased production (e.g., drug-induced, infection, malignancy, nutrition deficiency), redistribution (e.g., margination to the spleen), or immune destruction (e.g., autoimmune conditions).
• Due to a muted immune response, fever may be the principal and only sign of invasive infection in neutropenic patients.
• Prompt recognition of a neutropenic fever is prudent to ensure initiation of empiric antimicrobial therapy and to avoid progression to a sepsis syndrome.

Definitions

• Fever: A single oral temperature of ≥ 38.3° C (101° F) OR a temperature ≥ 38° C (100.4° F) which lasts more than 1h.
• Neutropenia: An abnormally low number of neutrophils in the blood (ANC < 1.0 x 10⁹/L). The lower the neutrophil count, the greater the risk of infection.
• Absolute Neutrophil Count (ANC) Calculator https://www.mdcalc.com/calc/19/absolute-neutrophil-count-anc

1. History

• A thorough history should be conducted with emphasis on new site-specific symptoms, recent antibiotic treatment, surgical history, underlying comorbid conditions, and past microbiology records (e., history of antibiotic resistant organisms or bacteremia).

2. Physical Examination

• Focus on identifying a focus of infection including, but not limited to: presence of indwelling IV catheters, skin lesions and lymph nodes, oropharynx, chest and lungs, abdomen, genital and perianal/rectal area^*, central nervous system.
  • * DRE should be avoided in neutropenic or immunocompromised patients.

3. Investigations

Routine Investigations

• CBC with differential
• Creatinine, electrolytes
• Liver function tests, coagulation screen
• CRP
• Blood cultures: two sets – one peripheral and one from CVC
• Microbiologic testing from suspected sites of infection: urinalysis and culture, sputum microscopy and culture, stool microscopy and culture, skin lesion (aspirate, biopsy, swab, culture), chest radiograph, lumbar puncture.

Further Testing

• High-resolution chest CT (if pyrexial despite 72h of appropriate antibiotics)
• Bronchoalveolar lavage

4. Severity Assessment

• A prognosis clinical prediction rule, in addition to clinical judgement, is recommended. Two are commonly used:
  • Multinational Association for Supportive Care in Cancer (MASCC) score
    • https://www.mdcalc.com/calc/3913/mascc-risk-index-febrile-neutropenia
  • Clinical Index of Stable Febrile Neutropenia (CISNE) score
    • https://www.mdcalc.com/calc/3997/clinical-index-stable-febrile-neutropenia-cisne

EMPIRIC OUTPATIENT TREATMENT

Recommended Antibiotics

• Levofloxacin 750mg daily PO or Ciprofloxacin 750 mg PO Q12H AND Amoxicillin/Clavulanate 875/125 mg PO Q12H, or
• Levofloxacin 750mg daily PO or Ciprofloxacin 750 mg PO Q12H AND Clindamycin 600 mg PO Q8H if penicillin allergy.
• Fluoroquinolones are NOT recommended if significant patient exposure in the past 3 months.
• Antimicrobial therapy duration: continue until the infection has resolved AND the patient is no longer neutropenic.

Plan

• Formally re-evaluate patient in 2 to 3 days.
• If AFEBRILE for ≥ 48 hours AND neutrophils ≥ 2 consecutive days and increasing, no positive source of infection identified and patient clinically stable, may discontinue antibiotics and monitor patient.
• If FEBRILE, admit patient for further investigations and initiation of appropriate antimicrobial therapy.

EMPIRIC INPATIENT TREATMENT

Recommended Antibiotics

• Piperacillin-Tazobactam 4.5 g IV QID, or ^[1,2]
• Imipenem 500 mg IV Q6H or Meropenem 1g IV Q8H, or ^[1,2]
• Cefepime 2g IV Q8H or Ceftazidime 2g IV Q8H (NOT recommended as monotherapy in areas at risk for ESBL producing bacteria). ^[1,2]
• If anaphylaxis allergy to beta-lactams, treat with Vancomycin + Aminoglycoside + Ciprofloxacin.
• NOTE: avoid aminoglycosides or other nephrotoxic agents in patients receiving cisplatin or other nephrotoxic chemotherapy.

Adjunct Antibiotics

• If positive blood culture for gram-positive organism, catheter-related infection, skin or soft-tissue infection, known or suspected MRSA, or suspicion for Clostridium difficile, add:
  • Vancomycin 25 mg/kg IV loading dose, followed by 15 mg/kg IV ^[3]
• If anaerobic infection (g., intra-abdominal) suspected, add:
  • Metronidazole 500 mg IV Q12H
• If resistance suspected or there are complications (g., hypotension, persistent fever, pneumonia, etc.), add: ^[3]
  • Tobramycin or Gentamicin 6-7 mg/kg IV Q24H, or
  • Ciprofloxacin 400 mg IV Q8-12H, or
• If atypical pneumonia suspected (g., Legionella or Mycoplasma), add:
  • Azithromycin 500 mg IV daily, or
  • Moxifloxacin 400 mg IV daily or Levofloxacin 750 mg IV daily.

Antifungal therapy

• Consider in those with persistent fevers, despite receiving 3-5 days of broad-spectrum antibiotic therapy.

1. Empiric treatment for febrile neutropenia. (2015). BC Cancer Agency. Available at http://www.bccancer.bc.ca/Documents/BCCA%20Febrile%20Neutropenia%20Guidelines.pdf.

   
   

1. Freifeld, A. G., Bow, E. J., Sepkowitz, K. A., Boeckh, M. J., Ito, J. I., Mullen, C. A., … & Wingard, J. R. (2011). Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clinical infectious diseases, 52(4), e56-e93.

   
   

2. Flowers, C. R., Seidenfeld, J., Bow, E. J., Karten, C., Gleason, C., Hawley, D. K., … & Ramsey, S. D. (2013). Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol, 31(6), 794-810.

   
   

3. Klastersky, J., De Naurois, J., Rolston, K., Rapoport, B., Maschmeyer, G., Aapro, M., & Herrstedt, J. (2016). Management of febrile neutropaenia: ESMO clinical practice guidelines. Annals of Oncology, 27, v111-v118.

   
   

4. Taplitz, R. A., Kennedy, E. B., Bow, E. J., Crews, J., Gleason, C., Hawley, D. K., … & Flowers, C. R. (2018). Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America Clinical Practice Guideline Update. J Clin Oncol, 36(14), 1443-1453.