What is Febrile Neutropenia?

Febrile Neutropenia (FN): Definition and Clinical Overview

Febrile neutropenia is a medical emergency defined as fever (≥38.3°C orally or ≥38.0°C sustained over 1 hour) occurring in a patient with neutropenia (absolute neutrophil count <500 cells/μL or <1000 cells/μL with predicted decline to ≤500 cells/μL within 48 hours). 1, 2

Pathophysiology and Clinical Significance

FN represents a life-threatening complication of myelosuppressive chemotherapy that requires immediate recognition and treatment. 1, 3 The condition arises because:

• Chemotherapy-induced neutropenia eliminates the primary defense against bacterial and fungal pathogens 4
• Signs and symptoms of infection are often minimal or absent in neutropenic patients, particularly those on corticosteroids, making fever the only indicator of serious infection 1, 2
• Delay in diagnosis and treatment is associated with higher morbidity and mortality 3, 5
• Mortality rates can reach 15%, with profound neutropenia (ANC <100/μL) being the strongest predictor of death 3

Microbiology

The bacterial landscape has shifted significantly over recent decades:

• Approximately 70% of positive blood cultures now show Gram-positive organisms, representing a shift from the historical predominance of Gram-negative bacteria 1
• However, Gram-negative bacteria (72% of positive cultures in some series) remain critical pathogens and are associated with rapid clinical deterioration 3
• Antibiotic-resistant organisms are increasingly common, including ESBL-producing Gram-negatives, MRSA, VRE, and fluconazole-resistant Candida species 1
• Over 70% of FN cases have no identifiable causative pathogen despite thorough evaluation 6

Initial Assessment and Risk Stratification

Immediate Evaluation (Within 1 Hour)

All patients presenting with suspected FN require urgent assessment of circulatory and respiratory function with vigorous resuscitation if needed, followed by systematic evaluation for infection sources. 1, 2

Critical history elements include: 1

• Type and timing of chemotherapy received
• Prior prophylactic antibiotic use
• Concomitant corticosteroid therapy
• Recent surgical procedures
• Previous positive microbiology results, especially antibiotic-resistant organisms
• Presence of indwelling venous catheters

Physical examination must specifically assess: 1

• Respiratory system
• Gastrointestinal tract
• Skin and soft tissues
• Perineal region and genitourinary system
• Oropharynx
• Central nervous system
• All indwelling catheter sites

Essential Laboratory and Microbiological Workup

Before initiating antibiotics, obtain: 1, 2

• Urgent complete blood count to confirm neutrophil level
• Renal and liver function tests
• Coagulation screen
• C-reactive protein
• Two sets of blood cultures from peripheral vein AND all indwelling venous catheters 1, 2
• Sputum, urine, skin swabs, and stool specimens when clinically indicated

MASCC Risk Score

The Multinational Association for Supportive Care in Cancer (MASCC) index is the validated tool for rapid risk stratification, with scores ≥21 indicating low risk (6% complication rate, 1% mortality) and <21 indicating high risk. 1, 2

Management Algorithm

High-Risk Patients (MASCC <21)

High-risk patients must be admitted immediately and started on broad-spectrum intravenous antibiotics within 1 hour of presentation. 1, 2

First-Line Antibiotic Selection

Monotherapy with an anti-pseudomonal beta-lactam (piperacillin-tazobactam, ceftazidime, or carbapenem) is equivalent to combination therapy for most high-risk patients. 1, 2, 7

• Piperacillin-tazobactam provides broad-spectrum coverage against Gram-positive, Gram-negative aerobic, and anaerobic bacteria, including many beta-lactamase producers 2
• Cefepime 2g IV every 8 hours is FDA-approved as monotherapy for empiric treatment of febrile neutropenic patients 7
• Local epidemiological patterns and resistance data must guide initial selection, as coverage for MRSA or resistant Gram-negatives may be required 1

Combination therapy with a beta-lactam plus aminoglycoside is preferable in patients with prolonged neutropenia or documented bacteremia due to bactericidal synergy. 1

Glycopeptide Addition

Do NOT routinely add vancomycin or other glycopeptides empirically. 2 Add glycopeptides only when specific indications exist: 1, 2

• Suspected catheter-related infection
• Skin or soft tissue infection
• Pneumonia
• Hemodynamic instability
• Known colonization with MRSA or VRE

Low-Risk Patients (MASCC ≥21)

Low-risk patients who are hemodynamically stable, without acute leukemia, organ failure, pneumonia, indwelling venous catheter, or severe soft tissue infection may be treated with oral antibiotics (quinolone plus amoxicillin-clavulanate). 1, 2

Early discharge after minimum 24 hours of clinical stability, symptomatic improvement, and fever resolution is supported by evidence, though 20% require readmission. 1

Reassessment at 48-72 Hours

If patient is afebrile and ANC ≥0.5 × 10⁹/L at 48 hours: 1, 2

• Low-risk patients: Consider switching to oral antibiotics
• High-risk patients on dual therapy: Aminoglycoside may be discontinued 1

If fever persists at 48 hours: 1, 2

• Clinically stable: Continue initial antibacterial therapy
• Clinically unstable: Rotate antibacterial therapy or broaden coverage; seek infectious disease consultation immediately 1

If fever persists >4-6 days despite appropriate antibiotics: 1, 2

• Initiate antifungal therapy 1, 2
• Obtain chest and upper abdominal imaging to exclude fungal infection or abscesses 1

Duration of Antibiotic Therapy

Discontinue antibiotics when: 1, 2

• ANC ≥0.5 × 10⁹/L AND patient is asymptomatic, afebrile for 48 hours, with negative blood cultures 1, 2
• ANC ≤0.5 × 10⁹/L BUT patient has been afebrile for 5-7 days without complications (except high-risk cases with acute leukemia or post-high-dose chemotherapy, where antibiotics continue for up to 10 days or until ANC ≥0.5 × 10⁹/L) 1, 2

Recent evidence supports early de-escalation at 72 hours in afebrile patients without documented infection, significantly reducing antibiotic days without compromising outcomes. 8

Special Clinical Scenarios

Catheter-Related Infections

When catheter-related infection is suspected, measure differential time to positivity (DTTP) between catheter and peripheral blood cultures; DTTP ≥2 hours is highly sensitive and specific for catheter-related bacteremia. 1

Administer vancomycin through the catheter when possible to cover Gram-positive organisms. 1

Attempt catheter preservation in stable patients with coagulase-negative Staphylococcus infections (93% success rate reported). 1

Mandatory catheter removal for: 1

• Tunnel or pocket infections
• Persistent bacteremia despite adequate treatment
• Atypical mycobacterial infection
• Candidemia
• S. aureus bacteremia (controversial but recommended when possible due to metastatic seeding risk)

Pneumonia

If pneumonia is diagnosed clinically or radiologically, add a macrolide antibiotic to beta-lactam therapy to cover atypical organisms (Legionella, Mycoplasma). 1

Consider Pneumocystis jirovecii in patients with high respiratory rates or desaturation, particularly those with prior corticosteroid exposure. 1

Critical Pitfalls to Avoid

• Never underestimate infection severity based on minimal clinical signs—fever may be the only indicator of life-threatening sepsis 2
• Never delay antibiotic administration beyond 1 hour from presentation 2, 5
• Never use oral antibiotics in high-risk patients with significant neutropenia 2
• Never remove indwelling catheters without microbiological evidence when patient is stable 1
• Never fail to reassess at 48-72 hours to guide subsequent management 2
• Be vigilant for patients presenting with hypotension or low-grade fever who may be developing Gram-negative septicemia requiring immediate intervention 1

Patient Education and Systems

Successful FN management requires educating outpatients to monitor body temperature and providing clear written instructions on when and how to contact medical services. 1

Effective written local protocols are essential for rapid response, including clear Emergency Department pathways for patients presenting outside oncology services. 1