What is the best course of action for a pediatric patient with B-cell Acute Lymphoblastic Leukemia (B-ALL) on induction chemotherapy, presenting with fever, chills, fatigue, poor oral intake, and emesis, with a history of a tunneled Central Venous Catheter (CVC) placement and prophylactic trimethoprim-sulfamethoxazole (TMP-SMX) for Pneumocystis jirovecii pneumonia (PCP)?

Management of Febrile Neutropenia in Pediatric B-ALL During Induction

This child requires immediate hospital admission for empirical broad-spectrum intravenous antibiotics covering Pseudomonas aeruginosa and other gram-negative organisms, along with comprehensive evaluation for infection source including blood cultures from both the central line and peripheral sites. 1

Immediate Actions Required

Risk Stratification

• This patient is HIGH RISK for serious bacterial infection and invasive fungal disease based on multiple factors: B-ALL diagnosis, day 14 of induction chemotherapy (expected profound neutropenia), fever >39°C, presence of central venous catheter, and poor oral intake suggesting inability to tolerate oral medications. 1
• High-risk ALL patients (which includes those on induction therapy) are at elevated risk for invasive fungal disease, particularly with prolonged neutropenia and high-dose corticosteroids. 1
• The presence of a tunneled CVC increases risk for catheter-related bloodstream infections, including viridans group streptococci, coagulase-negative staphylococci, and gram-negative organisms. 1

Urgent Diagnostic Workup

• Obtain blood cultures from BOTH the central line (each lumen if multi-lumen) AND a peripheral venipuncture site before initiating antibiotics. 1
• Complete blood count with differential to document absolute neutrophil count (ANC) and assess for profound neutropenia (expected <500/μL on day 14 of induction). 1
• Comprehensive metabolic panel including liver and renal function tests. 1
• Chest radiography even in the absence of respiratory symptoms, as immunocompromised patients may have atypical presentations. 1
• Urinalysis and urine culture if any genitourinary symptoms or if no other source identified. 1

Empirical Antibiotic Management

Initial Antibiotic Selection

Initiate antipseudomonal beta-lactam monotherapy immediately after obtaining cultures: 1

• Cefepime (fourth-generation cephalosporin) 50 mg/kg/dose IV every 8 hours (maximum 2 g/dose) is the preferred empirical monotherapy for high-risk febrile neutropenia in pediatric oncology patients. 1
• Alternative: Piperacillin-tazobactam 100 mg/kg/dose (piperacillin component) IV every 6 hours (maximum 4 g/dose) if institutional resistance patterns favor this agent. 1

Aminoglycoside Consideration

• Do NOT routinely add an aminoglycoside to initial empirical therapy, as combination therapy with aminoglycosides does not improve outcomes compared to monotherapy and increases nephrotoxicity and ototoxicity risk. 1
• Consider adding gentamicin or amikacin only if: (1) hemodynamic instability/septic shock present, (2) suspected resistant gram-negative infection based on local epidemiology, or (3) patient deteriorates on monotherapy. 1

Vancomycin Consideration

Add vancomycin 15 mg/kg/dose IV every 6 hours (target trough 10-15 mcg/mL) if ANY of the following present: 1

• Hemodynamic instability or septic shock
• Suspected catheter-related infection (CVC site erythema, tenderness, or purulence)
• Skin or soft tissue infection
• Pneumonia on chest imaging
• Known colonization with methicillin-resistant Staphylococcus aureus (MRSA)
• High institutional prevalence of MRSA or viridans group streptococci with penicillin resistance
• Blood culture gram-positive cocci pending speciation

In this case, given the tunneled CVC and fever without clear source, empirical vancomycin addition is reasonable while awaiting culture results. 1

Antifungal Considerations

When to Add Empirical Antifungal Therapy

Do NOT initiate empirical antifungal therapy immediately unless specific high-risk features present. 1

Add empirical antifungal coverage if: 1

• Persistent fever after 4-7 days of appropriate broad-spectrum antibacterial therapy despite negative cultures
• Clinical deterioration or new pulmonary infiltrates develop
• High suspicion for invasive fungal disease based on imaging (nodules, halo sign, air crescent sign on CT chest)
• Prolonged neutropenia expected (>7-10 days from presentation)

This patient did NOT receive antifungal prophylaxis, which increases concern for invasive fungal disease if fever persists beyond 4-7 days. 1

Pneumocystis jirovecii Considerations

• The weekend-only TMP-SMX prophylaxis regimen is adequate for PCP prevention during induction therapy, with studies showing 2 consecutive days per week is effective. 2
• PCP typically presents with dry cough, dyspnea, and hypoxemia—this patient has NO respiratory symptoms, making PCP unlikely at this presentation. 3
• Continue TMP-SMX prophylaxis once patient is stable and tolerating oral intake, as it may also have antibacterial and potential antileukemic effects. 4

Supportive Care Measures

Immediate Supportive Interventions

• Aggressive IV hydration with isotonic crystalloid to maintain adequate perfusion and support renal function during antibiotic therapy. 1
• Antiemetics (ondansetron 0.15 mg/kg IV every 8 hours) for nausea/vomiting to improve oral intake once stable. 1
• Nutritional support: If poor oral intake persists >48-72 hours, consider nasogastric feeding or parenteral nutrition to maintain nutritional status during critical illness. 1
• Avoid rectal temperatures, suppositories, and intramuscular injections due to risk of introducing bacteria in neutropenic patient. 1

Growth Factor Consideration

• Granulocyte colony-stimulating factor (G-CSF) is NOT routinely recommended during induction chemotherapy for ALL, as it does not improve survival and may interfere with chemotherapy efficacy. 1
• Consider G-CSF only if life-threatening infection with profound neutropenia and slow expected recovery. 1

Duration of Antibiotic Therapy

For This High-Risk Patient

Continue IV antibiotics until ALL of the following criteria met: 1

• Afebrile for at least 24-48 hours
• Hemodynamically stable
• ANC recovery to >500/μL (or >200/μL with rising trend if clinically stable)
• Resolution of any identified infection source
• Negative blood cultures for at least 48 hours

If blood cultures remain negative and patient becomes afebrile but neutropenia persists, continue antibiotics until neutrophil recovery given high-risk status. 1

If specific pathogen identified, tailor antibiotics to susceptibility results but maintain broad-spectrum coverage until neutrophil recovery. 1

Critical Pitfalls to Avoid

• Never delay antibiotic administration while awaiting culture results—febrile neutropenia is a medical emergency with potential for rapid deterioration to septic shock. 1
• Do not discontinue antibiotics prematurely in high-risk patients even if afebrile, as relapse of infection is common without neutrophil recovery. 1
• Do not assume TMP-SMX prophylaxis prevents all bacterial infections—it primarily targets PCP and may reduce some bacterial infections but does not eliminate risk during profound neutropenia. 5
• Monitor closely for clinical deterioration in first 48-72 hours, as viridans group streptococci (common in ALL patients with mucositis) can cause fulminant sepsis and acute respiratory distress syndrome. 1
• Reassess daily for new infection sources, medication toxicities (renal function with vancomycin, hepatotoxicity with antifungals if added), and need to escalate or modify therapy. 1