In this section
Fever and suspected or confirmed neutropenia
Children with cancer are at varying risk of invasive fungal infection (IFI). Factors that influence this risk include type of cancer, chemotherapy protocol, depth and duration of neutropaenia, steroid exposure and previous history of IFI. Antifungal prophylaxis has been shown to reduce the
risk of developing an IFI and can be broadly divided into mould-active (ie against Aspergillus spp.) and non-mould active (ie against Candida spp.) prophylaxis.
Primary antifungal prophylaxis is recommended when the underlying incidence of IFI exceeds 10%. When implementing prophylaxis regimens, consideration must also be given to institutional epidemiology and relevant adjustments made.
1: Stratification of risk of IFI in children with cancer/Haematopoietic Stem Cell Transplant (HSCT)
High risk/very high risk acute lymphoblastic leukaemia (ALL) in intensive treatment phases
Acute myeloid leukaemia (AML)
Relapsed acute leukaemia (ALL and AML)
Allogeneic HSCT with acute Grade II-IV GvHD
Allogeneic HSCT chronic extensive GvHD
Severe aplastic anaemia
Allogeneic HSCT (pre-engraftment phase)
Non-relapse ALL (excluding high-risk ALL in intensive phases)
Lymphoma (excluding autologous HSCT)
Solid tumours (excluding autologous HSCT)
Paediatric solid tumours
If a child has a suspected IFI (ie prolonged or recurrent fever), evaluation and empiric treatment should follow the
Fever and suspected or confirmed neutropenia recommendations.
Recommended prophylaxis regimens according to patient population
Note: Refer to Table 3 for dose and monitoring recommendations.
3: Antifungal prophylaxis dose, therapeutic drug monitoring (TDM) targets, important food-drug interactions and monitoring recommendations
6-12 mg/kg (max 400 mg) oral/IV daily
oral: round to nearest 50 mg capsules
Administer with or without food
Monitor for rash (rare) and hepatotoxicity (rare)
Monitor for QT prolongation if other risk factors or pro-arrhythmic drugs
Adjust in renal impairment (speak to pharmacy)
≥13 years: 200 mg oral TDS
≥13 years OR
≥10 years and weighing
≥30 kg: 300 mg oral daily
Trough level >0.7 µg/mL
Take trough level 5-7 days after starting drug or changing dose or formulation
Administer with food.
(absorption ↑with high fat meal)
Monitor for rash (rare), hepatotoxicity (rare), neurotoxicity and GI upset
Caution in renal impairment as solubilizer may accumulate, consult pharmacy
<2 years: discuss with ID and pharmacy
2 years to
<12 years or 12-14 years and weighing <50 kg: 9 mg/kg (max 350 mg) oral BD
2 years to
<12 years or 12-14 years and weighing <50 kg: 8 mg/kg (day 1, 9 mg/kg) IV BD
Trough level 1-3 µg/mL**
Take trough level 2-5 days after starting drug or changing dose or formulation
Dose should not be altered if level is 4-6 mg/L and clinical signs of toxicity are not present
Oral: administer 1 h before or after food (absorption ↓ with high fat meals)
Caution in renal impairment as IV solubilizer may accumulate. Significance is not known, consult pharmacy
(Sporonox®): 2.5 mg/kg oral BD (max 200 mg daily)
and capsules are not interchangeable. The oral solution is preferred due to improved bioavailability and as there is limited experience with capsules in children. If conversion is required, consult pharmacy.
Trough level >0.5 µg/mL
Take trough level 10-15 days after starting drug or changing dose
Liquid (Sporanox®): administer on an empty stomach at least 1h before food. Absorption not affected by H2-anagonists
Monitor for rash, hepatotoxicity, neurotoxicity and GI upset.
3 mg/kg IV three times per week (max 100 mg daily)
Ambsiome is available in 50 mg vials (max 100 mg). Where possible round dose to 50 mg ensuring dose is at least 2 mg/kg (max 100 mg)
Monitor for renal toxicity, electrolyte disturbances (esp. hypokalaemia and hypomagnesaemia) and hepatotoxicity
Consider pre/concurrent hydration with 10 mL/kg normal saline
Consider premedication if infusion related adverse effects (inc. fever, chills, rigors)
1 to 3 months: 25 mg/m2 (max 50mg) IV daily
≥3 months: 50 mg/m2 (max 50mg) IV daily
<4 months age: 2 mg/kg IV daily
>4 months age: 1 mg/kg (max 50 mg) IV daily
*Trough levels for voriconazole, itraconazole and posaconazole are sent to the Alfred hospital and run on a Monday, Tuesday and Thursday (must arrive at The Alfred by 11am). Samples require minimum 1 mL in an EDTA tube.
**A voriconazole trough level >5–6 mg/L is associated with an increased probability of neurological toxicity, including visual disturbances, hallucinations and encephalopathy
Itraconazole, voriconazole and posaconazole require TDM
Indications for repeat TDM include
Dose adjustments should be discussed with oncology pharmacy and/or local infectious diseases unit
Prior to any dose adjustment, repeat drug level and ensure the following:
In children with a documented history of proven or probable IFI, secondary prophylaxis is required for further cycles of chemotherapy
The azole class of antifungal agents are metabolised by the cytochrome P450 (CYP450) system. The potential for drug-drug interactions is higher for itraconazole and voriconazole than posaconazole and, in particular, fluconazole.
Table 4: Important drug interactions for azole antifungal agents and management recommendations.
(vincristine and vinblastine)
Vinca alkaloid metabolism reduced leading to excess vinca alkaloid exposure
Cases of neurotoxicity (peripheral neuropathy, autonomic neuropathy and seizures) have been reported with vincristine and vinblastine and itraconazole, voriconazole and posaconazole. Concurrent use with itraconazole leads to earlier and more severe toxicity
Electrolyte abnormalities, hyponatraemia associated with SIADH and GI upset have also been reported
Fluconazole is a weaker CYP3A4 inhibitor so toxicity is rare.
Concurrent use of itraconazole is strictly contraindicated
Avoid concurrent use of posaconazole where possible (unless advised by infectious diseases and oncology pharmacy)
For weekly IV vinca alkaloid: non-azole agent is preferred
For fortnightly or monthly IV vinca alkaloid: withhold voriconazole the day before, the day of and the day after vinca alkaloid dose. Monitor for toxicity.
TKI metabolism reduced, increasing risk of toxicity including QT prolongation and cardiac arrhythmias
Refer to chemotherapy protocols for detailed management
Concurrent use of itraconazole, voriconazole and posaconazole is not recommended in most protocols.
Fluconazole can be used in most instances except in combination with sorafenib. A non-azole agent is mandated for all children receiving sorafenib.
If unavoidable speak to oncology pharmacy and oncology consultant (venetoclax dose reduction may be required)
Bortezomib metabolism reduced.
Cases of new or worsening peripheral neurotoxicity have been reported with itraconazole and voriconazole.
All azoles should be stopped 72 hours prior to bortezomib dosing and recommenced 72 hours (24 hours for fluconazole) after final dose in course. A non-azole agent should be substituted during this period.
For example, in children with AML receiving bortezomib on D1 and D8 in a 28-day curse, substitute fluconazole for an echinocandin on D(-3) to D(+12)
Metabolism reduced, leading to significant increases in levels of these drugs
Reports of significantly increased trough concentrations despite dose reduction, due to combination of itraconazole and sirolimus
Monitor sirolimus, tacrolimus or cyclosporine levels. Dose reduction usually required
Itraconazole should be used with extreme caution in children on sirolimus
Use combination in caution. Obtain an ECG prior to starting treatment and weekly thereafter
Azoles should not be used in children with additional cardiac risk factors including reduced left ventricular fraction and electrolyte disturbances
All decisions to start and stop antifungal prophylaxis as well as issues with tolerability or side effects should be discussed with the child’s primary treating team.
All suspected or confirmed fungal infections should be discussed with the child’s primary treating team and consideration given to transfer to a tertiary paediatric cancer centre for investigation and management.
For emergency advice and paediatric or neonatal ICU transfers, call the Paediatric Infant Perinatal Emergency Retrieval (PIPER) Service: 1300 137 650.
Last Updated May 2021