What is the recommended antifungal treatment and dosing for a child with suspected or confirmed invasive fungal infection?

Antifungal Treatment for Pediatric Invasive Fungal Infections

For pediatric patients with invasive fungal infections, treatment selection depends critically on the type of infection (Candida vs. Aspergillus), patient age, and clinical severity, with echinocandins (micafungin, caspofungin) as first-line for invasive candidiasis and voriconazole for invasive aspergillosis.

Invasive Candidiasis in Children

First-Line Treatment Options

Echinocandins are the preferred first-line agents for invasive candidiasis in pediatric patients, including candidemia, acute disseminated candidiasis, and Candida peritonitis. 1

• Micafungin: 2-4 mg/kg/day IV (maximum 100 mg daily for patients ≤30 kg) 1, 2

  • Supported by randomized controlled trials in both adults and children with extensive pharmacokinetic data 1
  • FDA-approved for patients ≥4 months of age 2

• Caspofungin: Loading dose 70 mg/m²/day, followed by 50 mg/m²/day IV (maximum 70 mg/day) 1

  • Can increase to 70 mg/m²/day if clinically indicated 1
  • Well-established efficacy with documented safety profile in children 1

• Anidulafungin: 3 mg/kg loading dose, followed by 1.5 mg/kg/day IV 1

  • More limited pediatric pharmacokinetic data compared to other echinocandins 1

Alternative Agents for Invasive Candidiasis

• Liposomal amphotericin B: 3 mg/kg/day IV 1

  • Preferred over conventional amphotericin B due to significantly reduced nephrotoxicity (RR 0.43,95% CI 0.21-0.90) 3
  • Less infusion-related reactions (chills) compared to conventional formulation (RR 0.37,95% CI 0.21-0.64) 3

• Fluconazole: 8-12 mg/kg/day IV or orally (maximum 400 mg) 1, 4

  • Fungistatic activity limits use as first-line in severe infections 1
  • Appropriate for step-down therapy in stable patients or less severe infections 1

• Voriconazole: For children 2-14 years: 9 mg/kg every 12 hours orally (maximum 350 mg every 12 hours); IV: day 1 loading 9 mg/kg every 12 hours, then 8 mg/kg every 12 hours 1, 5

  • Requires therapeutic drug monitoring with target trough ≥1 mg/L 1, 4
  • Reserved for selected situations, particularly when Candida glabrata or C. krusei suspected 1

Site-Specific Candida Infections

Neonatal Candidiasis (age <1 month):

• Amphotericin B deoxycholate: 1.0 mg/kg/day IV 1, 6
• Fluconazole: 12 mg/kg/day IV 1, 6
• Echinocandin: Appropriate option with limited data for anidulafungin 1
• Mandatory lumbar puncture and ophthalmoscopic examination for all neonates with positive sterile body fluid or urine cultures 1
• Duration: 3 weeks for candidemia without persistent fungemia or metastatic complications 1

CNS Candidiasis:

• Amphotericin B deoxycholate with or without 5-flucytosine 1
• Fluconazole: 6-12 mg/kg/day (400-800 mg) for patients unable to tolerate amphotericin B 1
• Remove intraventricular devices 1
• Treat until complete resolution of symptoms, CSF abnormalities, and radiologic findings 1

Candida Endophthalmitis:

• Amphotericin B deoxycholate: 0.7-1 mg/kg with 5-flucytosine 1
• Alternatives: fluconazole, liposomal amphotericin B, voriconazole, or echinocandin 1
• Surgical intervention required for severe endophthalmitis or vitreitis 1
• Duration: minimum 4-6 weeks with repeated examinations to verify resolution 1

Invasive Aspergillosis in Children

First-Line Treatment

Voriconazole is the preferred first-line agent for invasive aspergillosis in pediatric patients. 1

• Children 2 to <12 years and 12-14 years weighing <50 kg:

  • IV: Loading dose 9 mg/kg every 12 hours for first 24 hours, then 8 mg/kg every 12 hours 1, 5
  • Oral: 9 mg/kg every 12 hours (maximum 350 mg every 12 hours) 1, 5

• Children ≥15 years or 12-14 years weighing ≥50 kg: Use adult dosing 1, 5

  • IV: Loading dose 6 mg/kg every 12 hours for first 24 hours, then 4 mg/kg every 12 hours 5
  • Oral: 200 mg every 12 hours 5

• Therapeutic drug monitoring is mandatory with target trough concentration ≥1 mg/L 1, 4

• Beware of drug interactions with anticonvulsants when treating CNS aspergillosis 1

Alternative Agents for Invasive Aspergillosis

• Liposomal amphotericin B: 3 mg/kg/day IV 1

  • Preferred for patients at risk of invasive zygomycosis 1

• Echinocandins (micafungin, caspofungin): Appropriate alternatives with no data available for anidulafungin 1

• Itraconazole: 5 mg/kg/day oral suspension in children ≥2 years in two divided doses, with therapeutic drug monitoring (target trough ≥0.5 mg/L) 1

  • Not approved in EU for patients <18 years 1

• Posaconazole: For adolescents ≥13 years 1, 4

  • Gastro-resistant tablet (preferred): 300 mg/day in 1 dose (day 1: two doses of 300 mg) 1
  • Oral suspension: 600 mg/day in three divided doses with therapeutic drug monitoring (target trough ≥0.7 mg/L) 1, 4
  • Not approved in EU for patients <18 years 1

Site-Specific Aspergillosis

Pulmonary Aspergillosis:

• Surgical intervention indicated for lesions in proximity to great vessels or pericardium, chest wall invasion, emphysema, or persistent hemoptysis from cavitary lesion 1

CNS Aspergillosis:

• Surgical resection of infected tissue if possible 1
• Monitor for drug interactions between voriconazole and anticonvulsants 1

Duration: Treat until resolution or stabilization of all clinical and radiographic manifestations 1

Empirical Antifungal Therapy

For febrile neutropenic children with prolonged neutropenia (ANC <500 for ≥10 days) and persistent or new fever despite broad-spectrum antibacterial therapy, empirical antifungal therapy is standard of care. 1

Recommended Options:

• Liposomal amphotericin B: 1-3 mg/kg/day IV 1
• Caspofungin: Loading dose 70 mg/m²/day, followed by 50 mg/m²/day IV 1
• Voriconazole: Age-appropriate dosing with therapeutic drug monitoring 1
• Amphotericin B deoxycholate: 0.7-1.0 mg/kg/day IV (favor for patients at risk of zygomycosis) 1

Prophylaxis in High-Risk Pediatric Populations

Allogeneic Hematopoietic Stem Cell Transplant (HSCT)

Primary prophylaxis is indicated from conditioning through engraftment and during graft-versus-host disease with augmented immunosuppression. 1

• Fluconazole: 8-12 mg/kg/day IV or orally (studied day 0 to day +75 post-transplant) 1

  • Only use if institutional incidence of invasive mold infections is low 1

• Micafungin: 1 mg/kg/day IV (studied from start of preparative regimen until day +30) 1

  • Provides coverage against Aspergillus species 1

• Voriconazole: 8 mg/kg every 12 hours (day 1: 9 mg/kg every 12 hours) for ages 2-14 years; adult dose for ≥15 years (studied day 0 to at least day +100) 1

  • Requires therapeutic drug monitoring with target trough ≥1 mg/L 1, 4

• Posaconazole: 200 mg every 8 hours orally for patients ≥13 years with ≥grade II graft-versus-host disease 1

  • Requires therapeutic drug monitoring with target trough ≥0.7 mg/L 1, 4

Acute Myeloid Leukemia (AML) and Recurrent Leukemia

• Fluconazole: 8-12 mg/kg/day IV or orally after last chemotherapy dose until neutrophil recovery 1
• Posaconazole: 200 mg every 8 hours following chemotherapy completion until neutrophil recovery (adolescents >12 years) with therapeutic drug monitoring 1
• Micafungin: 1 mg/kg/day IV 1
• Liposomal amphotericin B: 1 mg/kg every other day IV 1

Solid Organ Transplant Recipients

• Fluconazole: 8-12 mg/kg/day IV or orally if institutional incidence of invasive aspergillosis is low 1
• Lung transplant recipients: Prophylaxis for 12 months duration 1

Chronic Granulomatous Disease

Lifelong antifungal prophylaxis is indicated due to highest lifetime incidence of invasive aspergillosis. 1

Critical Management Principles

General Treatment Considerations

1. Administer antifungal therapy as quickly as possible upon suspicion or confirmation of invasive fungal infection 1

2. Duration: Continue for 14 days after blood cultures are sterile, provided no unresolved deep infection or severe persistent immunological deficit 1

3. Clinical evaluation for deep sites of infection is mandatory, including ophthalmological examination in all cases of candidemia 1

4. Remove or replace intravenous catheters and implanted prosthetic devices in a timely manner 1

5. Consider combination antifungal therapy for severe life-threatening infections or compromised drug penetration (CNS infection, osteomyelitis, complicated urinary tract infections, complicated intra-abdominal infections) 1

Therapeutic Drug Monitoring Requirements

Therapeutic drug monitoring is strongly recommended for all azole antifungals to ensure therapeutic levels and avoid toxicity. 4

• Voriconazole: Target trough ≥1 mg/L 1, 4
• Posaconazole: Target trough ≥0.7 mg/L 1, 4
• Itraconazole: Target trough ≥0.5 mg/L 1, 4

Drug Interactions

All azole antifungals have significant interactions with immunosuppressants (cyclosporine, tacrolimus, sirolimus), necessitating careful medication reconciliation and potential dose adjustments. 4

• Monitor for sirolimus, itraconazole, or nifedipine toxicity when co-administered with micafungin; reduce doses if necessary 2

Common Pitfalls to Avoid

1. Do not use topical antifungals (clotrimazole, ketoconazole shampoo) for systemic or invasive fungal infections - these require systemic therapy 7, 6

2. Do not prematurely discontinue therapy even if symptoms improve quickly; complete the full treatment course to prevent relapse 6

3. Do not use fluconazole as first-line for severe invasive candidiasis due to fungistatic activity; reserve for step-down therapy or less severe infections 1

4. Avoid intravenous voriconazole in patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) due to accumulation of cyclodextrin vehicle 5

5. Do not extrapolate adult dosing to children - pediatric patients require higher weight-based doses due to different pharmacokinetics 8