Antifungal Prophylaxis and Treatment in Paediatric Oncology Patients and other Immunocompromised Children Document ID CHQ-GDL-01075 Version no. 4.0 Approval date 28/04/2022 Executive sponsor Executive Director of Medical Services Effective date 28/04/2022 Author/custodian Director of Infection Management and Prevention Review date 28/04/2024 service, Immunology and Rheumatology Supersedes 3.0 Applicable to All Children’s Health Queensland (CHQ) clinical staff Authorisation Executive Director Clinical Services Purpose This Guideline provides recommendations regarding best practice for Antifungal Prophylaxis and Treatment in paediatric oncology patients and other immunocompromised children. Scope This Guideline provides information for Children’s Health Queensland (CHQ) staff caring for paediatric oncology patients and other immunocompromised children. Related documents • CHQ-GDL-0129 Management of Fever in a Paediatric Oncology Patient- Febrile Neutropaenia and Febrile Non-neutropaenia • CHQ-PROC-01036 Antimicrobial: Prescribing and Management • CHQ Antimicrobial Restriction list Contents • Treatment and prophylaxis guideline – Table 1: Risk stratification and antifungal prophylaxis – Table 2: Treatment of suspected or proven fungal infection – Table 3: Antifungal paediatric dosing and TDM recommendations (normal renal and hepatic function) – prophylaxis and treatment – Table 4: Paediatric Posaconazole dosing and TDM recommendations – Table 5: Antifungal pharmacokinetics and dosing in infants and children on Extracorporeal Membrane Oxygenation (ECMO) – Table 6: Important drug interactions for azole antifungal agents Antifungal Prophylaxis and Treatment in Paediatric Oncology patients and Immunocompromised Children Guideline Summary of prophylaxis options (Table 1) (1) Fluconazole is appropriate prophylaxis in patients at low risk of mould infections (2) Voriconazole, posaconazole micafungin, or liposomal amphotericin B (Ambisome®) are all potential options in patients who are at high risk of a mould infection. There is no data to prove superiority of one agent over the others. Therefore, local practice should take into consideration individual patient circumstances, Pharmaceutical Benefit Scheme (PBS) approved indications, ease of administration and cost. Primary antifungal prophylaxis: Risk for invasive fungal infection (IFI) varies by treatment regimen and underlying diagnosis. Additionally, distinguishing the risk for candida infection versus mould infection warranting anti-mould prophylaxis informs decisions around antifungal choice. Posaconazole Modified Release (MR) tablets are listed on the Pharmaceutical Benefit Scheme (PBS) for antifungal prophylaxis against yeasts and moulds, and this guideline therefore recommends posaconazole as first line in children over 8 years where anti-mould prophylaxis is required. With uncertainties around dosing and variable absorption in younger children with posaconazole, voriconazole is the preferred choice in children under 8 years of age. Secondary antifungal prophylaxis: Risk of subsequent IFI after probable or proven fungal infection remains high. Antifungal therapy should be continued as secondary prophylaxis for duration of each neutropenic episode, until neutropenia has resolved and patient is no longer immunosuppressed. Timing and duration of antifungal prophylaxis: Most studies commence prophylaxis during administration of chemotherapy or estimated 3 days before neutrophils expected to fall to less than 0.5x10^9/L. Cessation is generally recommended following resolution of risk, which in acute leukaemia corresponds with neutrophil reconstitution (more than 1.0 × 10^9/L). ALERT NOTE: Duration of voriconazole prophylaxis If voriconazole prophylaxis (primary or secondary) is necessary for longer than 6 months, in view of the risk of photosensitivity (and recent rare reports of skin malignancies and fluorosis) it may be appropriate to consider switching to another azole, either itraconazole or posaconazole. This should be a consultant-led decision based on the individual patient’s clinical circumstances. CHQ-GDL-01075 Antifungal Prophylaxis and Treatment in Paediatric Oncology and Immunocompromised Children - 2 - Summary of treatment options (Table 2) Empirical anti-fungal therapy in the context of febrile neutropaenia Febrile neutropenia prolonged fever (more than 96 hours) add: • Liposomal Amphotericin (Ambisome®) IV 1 mg/kg once daily and assess as per FN protocol. (CHQ-GDL- 01249 Management of Fever in a Paediaric Oncology Patient - Febrile neutropenia (FN) and Febrile Non- neutropenia protocol.) Treatment of possible, probable and proven fungal infection (discuss with Oncology and Infection Management) (See Table 2) Key considerations: When a yeast or mould is isolated from a sterile site request microbiology lab perform sensitivity testing. Switch to oral therapy (voriconazole/ posaconazole / fluconazole) when no azole drug contraindications, afebrile, clinically stable, tolerating oral feeds and able to maintain therapeutic levels. Duration of treatment is tailored to individual patients, underlying diagnosis and pathogen but is generally 4 to 12 weeks. ALERT Liposomal Amphotericin (Ambisome®) to oral azole switch does not require routine establishment of therapeutic azole levels before stopping Ambisome®. CHQ-GDL-01075 Antifungal Prophylaxis and Treatment in Paediatric Oncology and Immunocompromised Children - 3 - Table 1: Risk stratification: Prophylaxis for invasive fungal infection (IFI) in high risk patient groups Disease Specific subgroup Timing of prophylaxis Recommended prophylaxis Alternative if recommended agent contraindicated (eg weekly vincristine or tyrokinase inhibitor) Under 8 years old 8 years and older All ages ALL Relapsed ALL Start: with relapse diagnosis <1 years of age: Posaconazole PO Micafungin IV – daily (inpatient) (note: if on Itraconazole PO Micafungin IV – three times a week (HITH) immunotherapy treatment or Infant ALL Start: when ANC < 1.0 and >1 years of age: Alternative: Alternative: shorter steroid (< 1 year old at during intensive phase only Voriconazole PO Voriconazole PO Ambisome ®IV courses, mould diagnosis) (induction, consolidation and active delayed intensification) Alternative: prophylaxis VHR/ T-cell ALL Posaconazole PO may not be Stop: when ANC is ≥1.0 for at required at HR ALL (induction only) least 7 days SMO HR ALL consolidation / Fluconazole PO Fluconazole PO Micafungin IV – daily (inpatient) oncologist delayed intensification Micafungin IV – three times a week (HITH) discretion) SR ALL Routine prophylaxis not recommended unless mandated by trial protocol AML Relapsed AML Start: with relapse diagnosis Voriconazole PO Posaconazole PO Micafungin IV – daily (inpatient) (note: mould Micafungin IV – three times a week (HITH) active Alternative: Alternative: prophylaxis AML Start: following last dose of Posaconazole PO Voriconazole PO Alternative: may not always chemotherapy in cycle or Ambisome ®IV be required for Infant AML ANC<1.0 Stop: when ANC is ≥1.0 for at Downs least 7 days syndrome protocols.) Aplastic Severe aplastic anaemia Start when neutrophil count is Voriconazole PO Posaconazole PO Micafungin IV – daily (inpatient) anaemia (while neutropenic < 0.5) less than 0.5 Micafungin IV – three times a week (HITH) Alternative: Alternative: Alternative: Posaconazole PO Voriconazole PO Ambisome ®IV Allogeneic Low risk Start during conditioning Fluconazole PO/IV HSCT High risk Start during conditioning Ambisome ® IV– daily Alternative: Micafungin IV - daily Switch as per HSCT protocol / Voriconazole PO Posaconazole PO when tolerating oral Stop: day + 100 CHQ-GDL-01075 – Antifungal Prophylaxis and Treatment in Paediatric Oncology and Immunocompromised Children - 4 - Table 1: Risk stratification: Prophylaxis for invasive fungal infection (IFI) in high risk patient groups (continued) Disease Specific subgroup Timing of prophylaxis Recommended prophylaxis Alternative if recommended agent contraindicated Under 8 years old 8 years and older All ages Allogeneic HSCT With GvHD requiring Start at GvHD diagnosis Voriconazole PO Posaconazole PO Liposomal Amphotericin prolonged systemic Stop: when corticosteroid dose is (Ambisome ®) IV– daily steroid therapy < 0.5mg/kg or 10 mg daily prednisolone Alternative: Alternative: Alternative: equivalent (whichever is less). Posaconazole PO Voriconazole PO Micafungin IV – daily (inpatient) Micafungin IV – three times a week (HITH) Autologous HSCT Pre-engraftment phase Start: during conditioning Fluconazole PO Fluconazole PO Micafungin IV – daily Stop: when ANC is ≥1.0 for at least 7 Micafungin IV – three days times a week (HITH) Neuroblastoma Stage 4 Start: with or just after chemotherapy is Fluconazole PO Fluconazole PO Micafungin IV – daily Neuroblastoma commenced. Micafungin IV – three Stop: when ANC is ≥1.0 for at least 7 times a week (HITH) days Langerhans Cell LCH Induction therapy Start: with or just after chemotherapy is Fluconazole PO Fluconazole PO Micafungin IV – daily Histiocytosis commenced. Micafungin IV – three (LCH) Stop: when ANC is ≥1.0 for at least times a week (HITH) 7 days Lymphoma Excluding patients Routine prophylaxis not recommended undergoing any HSCT Solid tumours Routine prophylaxis not recommended (receiving chemotherapy) CHQ-GDL-01075 – Antifungal Prophylaxis and Treatment in Paediatric Oncology and Immunocompromised Children - 5 - Table 1: Risk stratification: Prophylaxis for invasive fungal infection (IFI) in high risk patient groups (continued) Disease Specific subgroup Timing of prophylaxis Recommended prophylaxis Alternative if recommended agent contraindicated Under 8 years old 8 years and older All ages Primary immune Severe combined Start at time of diagnosis Fluconazole PO Seek ID advice deficiency with a immunodeficiency high risk of IFI (SCID) DiGeorge Syndrome Start at time of diagnosis As directed by (severe disease) Immunology SMO Chronic mucocutaneous candidiasis Hyper IgE syndromes Chronic Start at time of diagnosis Itraconazole PO Itraconazole PO granulomatous disease (CGD) Alternative: Alternative: Wiskott-Aldrich As per immunology SMO Voriconazole PO Posaconazole PO Syndrome (classic, Itraconazole PO severe) (WAS) Severe phagocyte As per immunology SMO defects eg congenital neutropaenia, LAD CHQ-GDL-01075 Antifungal Prophylaxis and Treatment in Paediatric Oncology and Immunocompromised Children - 6 - Table 2. Treatment of suspected or proven fungal infection (discuss with Oncology and IMPS) Indication Antifungal choice Comment Empirical Treatment* Febrile neutropenia Add Liposomal Amphotericin (Ambisome ®) Assess as per CHQ Febrile neutropenia (FN) prolonged fever IV 1 mg/kg once daily protocol. (more than 96 hours) Invasive fungal infection Ambisome ® IV 3 mg/kg once daily; (IFI) treatment (probable followed by Voriconazole PO or possible, no organism identified) IFI with CNS disease Voriconazole IV suspected (no organism identified) Disseminated First line: Echinocandins# (Caspofungin IV) Tailor to pathogen once spp and sensitivities Candidiasis / Alternatives: Voriconazole; Ambisome® IV candidaemia Candida Pyelonephritis / Fluconazole IV/oral Neither echinocandins nor voriconazole complicated UTI Alternatives: Ambisome® IV concentrate well in urine. Microbiologically Directed Treatment* (tailored individually to child and pathogen) Candida albicans First line: Fluconazole Can be used for infections due to C tropicalis, C kefyr, C dubliniensis, C Alternatives: Caspofungin IV#, lusitaniae, and C guilliermondi. Voriconazole, Ambisome ® IV Candida glabrata First line: Caspofungin IV # Alternatives: Voriconazole, Ambisome® IV. Fluconazole (only if sensitivity confirmed) Candida krusei First line: Caspofungin IV # Alternatives: Posaconazole, Voriconazole Candida parapsilosis First line: Fluconazole Echinocandins have higher MICs against Candida parapsilosis group; however, no Alternatives: Voriconazole, Ambisome® IV, diminished efficacy against these species has Caspofungin IV# been noted in randomised clinical trials Aspergillus spp First line: Voriconazole Alternative: Ambisome® IV Aspergillus terreus Voriconazole Resistant to amphotericin Lomentaspora / First line: Voriconazole and Terbinafine Scedosporium Alternative: Posaconazole Fusarium Ambisome® (5 mg/kg IV once daily) and Voriconazole IV Mucormycoses First line: Ambisome® (5 mg/kg to 7.5 mg/kg IV once daily) Alternative: Posaconazole *See Table 3 and 4 for dosing and monitoring recommendations. #Echinocandins: There are more dosage and safety data for caspofungin and micafungin than anidulafungin in children and for micafungin in neonates and infants. Anidulafungin has no significant drug interactions at all and requires less dose adjustment with moderate to severe liver disease, but is approved for adults only. Choice of echinocandin depends on age of child, potential drug interactions, type of infection and comorbidities as advised by IMPS. CHQ-GDL-01075 – Antifungal Prophylaxis and Treatment in Paediatric Oncology and Immunocompromised Children - 7 - Table 3: Dosing and therapeutic drug monitoring (TDM) recommendations for antifungals (normal renal and hepatic function) – prophylaxis and treatment Antifungal Prophylaxis Treatment TDM Comments Liposomal Infants, children and Infants, children and adolescents: Not Dose based on actual body weight. Amphotericin B adolescents: required 3 mg/kg to 5 mg/kg IV once daily For patients weighing more than 100 kg, fixed dosing (Ambisome ®) 3 mg/kg IV three times per is recommended. See treatment dosing CNS disease/meningitis: week (Mondays, recommendations. Wednesdays and Fridays of 5 mg/kg to 7.5 mg/kg IV once daily on advice from ID specialist Monitor for renal toxicity, electrolyte disturbances each week) (especially hypokalaemia and hypomagnesaemia) (Max 100 mg/dose) Neonates: Limited data. Seek ID specialist advice. and hepatotoxicity. (Conventional amphotericin B (Fungizone®) preferred in OR neonates) Consider premedication if infusion related adverse 1 mg/kg/IV daily effects (inc. fever, chills, rigors) Obesity: For patients weighing more than 100 kg, fixed dosing (Max 100 mg/dose) is recommended. Neonates: Limited data. 3 mg/kg IV daily (Max 300 mg/day) and seek specialist advice Seek ID specialist advice. 5 mg/kg IV daily (Max 500 mg/day) and seek specialist advice. Anidulafungin Infants, children and Infants, children and adolescents: Not No dose adjustment for renal or liver impairment. adolescents: Loading dose: 3mg/kg IV as a single dose on day 1 required Obesity: Increase daily dose by 25-50% of the usual (Maximum 200 mg/day) 1.5 mg/kg IV once daily dose in patients weighing >75 kg. (Max 100mg/day) Maintenance dose: 1.5 mg/kg IV once daily from day 2 onwards (Maximum 100 mg/day) Neonates: Limited data. Seek ID specialist advice. Neonates: Limited data. Seek ID specialist advice. Caspofungin Infants (>3 months), Infants (>3 months), children and adolescents: Not May cause histamine induced reaction (rash, facial children and adolescents: required swelling, pruritus and/or bronchospasm). Monitor for Loading dose: 70 mg/m2 IV on day 1 (Maximum 70 mg/day) hepatotoxicity and electrolyte disturbances (especially 50 mg/m2 IV daily hypokalaemia, hypercalcaemia and Maintenance dose: 50 mg/m2 IV on day 2 onwards (Maximum 50 mg/day) hypomagnesaemia) and hepatotoxicity. (Maximum 50 mg/day) 1 to 3 months of age: No dose adjustment for renal impairment. Hepatic In critically ill patients, maintenance dose can be increased 25 mg/m2 IV daily impairment: For Child-Pugh score of 7-9 (class B; to 70 mg/m2/day (maximum 70 mg/day) (Maximum 25 mg/day) significant functional compromise), after loading dose, 1 to 3 months of age: 25 mg/m2 IV daily reduce maintenance dose by 50%. Neonates: Limited data. (Maximum 25 mg/day) Seek ID specialist advice. Obesity: Increase daily dose by 25-50% of the usual Neonates: Limited data. Seek ID specialist advice. dose in patients weighing >75 kg. CHQ-GDL-01075 – Antifungal Prophylaxis and Treatment in Paediatric Oncology and Immunocompromised Children - 8 - Table 3: Antifungal paediatric dosing and therapeutic drug monitoring (TDM) recommendations (normal renal and hepatic function) – prophylaxis and treatment (CONTINUED) Antifungal Prophylaxis Treatment TDM Comments Fluconazole Infants, children and Infants, children and adolescents: Not routinely required. Obesity: Dose based on total body adolescents: weight. Loading dose: 12 mg/kg (maximum 800 mg) Advisable for patients with severe IFI, 6 mg/kg IV/oral as a single dose on CRRT or ECMO. Seek ID specialist Administer with or without food (maximum 400 mg) advice. Maintenance dose: Monitor for rash (rare) and oral/IV once daily 6 mg/kg (maximum 400 mg) IV/oral once daily An AUC/MIC ratio ≥ 50 for Candida hepatotoxicity (rare) Term Neonates: species with MIC breakpoint ≤ 8 mg/L Use 12 mg/kg (maximum 800 mg) IV/oral once Monitor for QT prolongation if other risk corresponds with a favourable Week 1 of life: daily if Immunocompromised or infection is factors or pro-arrhythmic drugs outcome, requiring an AUC of severe ≥400 mg × h/L. 3 mg/kg/dose to Drug interactions (see Table 5) 6 mg/kg/dose oral/IV Term Neonates: a Higher AUC target of 800 mg × h/L in twice weekly immunocompromised and critically ill Loading dose: 25 mg/kg IV as a single dose patients with invasive Candida may be Week 2 to 4 of life: Maintenance dose: preferred. 6 mg/kg/dose oral/IV Week 1 of life: 12 mg/kg IV/oral every 48 hourly every 72 hourly Week 2 to 4 of life: 12 mg/kg IV/oral once daily Flucytosine Seek ID advice. Administer in combination with susceptible Take trough (30 minutes pre-dose) and Dose based on ideal body weight. antifungal due to development of resistance. peak level (2 hours post dose) on day 3 Monitor FBC, renal and liver function Seek ID advice. after starting drug or changing dose closely (daily initially, then twice a Infants, children and adolescents: Treatment: week) 25 mg/kg oral every 6 hourly Trough level: 25 to 50 mg/L Renal impairment – dose adjustment required if CrCl <40 mL/min Term Neonates: Peak level: 50 to 100 mg/L Hepatic impairment – seek ID specialist Week 1 of life: 25 mg/kg oral every 8 hourly Bone marrow and hepatotoxicity advice. associated with peak levels exceeding Week 2 to 4 of life: 25 mg/kg oral every 6 hourly 100 mg/L CHQ-GDL-01075 Antifungal Prophylaxis and Treatment in Paediatric Oncology and Immunocompromised Children - 9 - Table 3: Antifungal paediatric dosing and therapeutic drug monitoring (TDM) recommendations (normal renal and hepatic function) – prophylaxis and treatment (CONTINUED) Antifungal Prophylaxis Treatment Therapeutic drug monitoring Comments Itraconazole Oral solution (Sporanox®): Take trough level on day 7 to Liquid (Sporanox®): administer on an empty stomach at 10 after starting drug or least 1 hour before food with an acidic beverage (e.g. 1 month to <12 years: 5 mg/kg oral twice daily (maximum 200 changing dose cola, orange juice) mg/dose) Prophylaxis: Capsules (Sporanox®): administer with or after food. Neonates: Limited data. Seek ID specialist advice. For patients on gastric acid suppressant medications, Trough level separate administration by at least 2 hours and Oral capsules (Sporanox ®): 12 to 18 years: administer with an acidic beverage (e.g. cola, orange 2.5 mg/kg oral twice daily (maximum 200 mg/dose) >500 to 1000 microgram/L* juice) Oral solution and capsules are not interchangeable. The oral solution Treatment: Monitor for rash, hepatotoxicity, neurotoxicity and GI is preferred due to improved bioavailability and as there is limited Trough level upset. Monitor for QT prolongation if other risk factors experience with capsules in children. If conversion is required, consult or pro-arrhythmic drugs. Drug interactions (see Table 5) pharmacy. 1000 to 2000 microgram/L* *Itraconazole levels measured using HPLC method Micafungin Infants, children Infants and children up to 2 years: Not required May cause histamine induced reaction (rash, facial and adolescents: swelling, pruritus and/or bronchospasm) 5 mg/kg IV once daily (Max 100 mg/day) Inpatient: Obesity: Increase daily dose by 25-50% of the usual 2 to 16 years (up to 40kg): dose in patients weighing >75kg. 1 mg/kg IV daily 3 mg/kg IV once daily (Max 100 mg/day*) (Max 100 mg/day) No dose adjustment for renal or hepatic impairment. 16 to 18 years (more than 40kg): HITH: 3mg/kg IV once daily (Max 150 mg/day) 3 mg/kg IV three times a week (* Increase to maximum 200 mg once daily if (Max 200 mg/dose) response is inadequate) Neonates: Limited Term Neonates: data. Seek ID specialist advice. General: 4 mg/kg IV once daily CNS infection: 10 mg/kg IV once daily Posaconazole See table 4. CHQ-GDL-01075 Antifungal Prophylaxis and Treatment in Paediatric Oncology and Immunocompromised Children - 10 -