See also
Fever and suspected or confirmed neutropenia
Key points
- Appropriate antifungal prophylaxis is an important component of cancer care
- Antifungal prophylaxis has been shown to reduce the risk of invasive fungal infection (IFI) in selected high-risk children.
- Where possible, an azole agent is preferred and therapeutic drug monitoring should be done for posaconazole, voriconazole and itraconazole.
Background
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.
Assessment
- Prophylaxis recommendations are based on underlying risk of IFI
- The type of prophylaxis (mould versus non-mould active) varies according to cancer diagnosis associated complications and/or treatment phases
- Children at high and intermediate risk for IFI should receive appropriate prophylaxis
Table
1: Stratification of risk of IFI in children with cancer/Haematopoietic Stem Cell Transplant (HSCT)
| Risk Stratum |
Risk of IFI with |
Patient Population |
| High Risk (≥10%) |
Mould > Yeast |
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 |
| Yeast > Mould |
Allogeneic HSCT (pre-engraftment phase) |
| Intermediate Risk |
Yeast > Mould |
Autologous HSCT (neutropenic phase) |
| Low Risk (≤5%) |
- |
Non-relapse ALL (excluding high-risk ALL in intensive phases)
Lymphoma (excluding autologous HSCT)
Solid tumours (excluding autologous HSCT) |
| Sporadic occurrence |
- |
Paediatric solid tumours
Brain tumours
Hodgkin lymphoma |
Management
Investigations
Nil
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.
Primary prophylaxis
Table 2:
Recommended prophylaxis regimens according to patient population
Note: Refer to Table 3 for dose and monitoring recommendations.
Drug information
Table
3: Antifungal prophylaxis dose, therapeutic drug monitoring (TDM) targets, important food-drug interactions and monitoring recommendations
| Antifungal |
Dose |
Target trough* for prophylaxis |
Notes |
| Fluconazole |
6-12 mg/kg (max 400 mg) oral/IV daily oral: round to nearest 50 mg capsules |
Not routinely required |
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) |
| Posaconazole |
Oral suspension:
≥13 years: 200 mg oral TDS
Oral tablets:
≥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) Safety and efficacy in children below the age of 13 years has not been well established. Variable doses for posaconazole tablets for children <13 years and <30 kg have been described including 200 mg oral daily. Discuss with ID and pharmacy if required
Monitor for rash (rare), hepatotoxicity (rare), neurotoxicity and GI upset Monitor for QT prolongation if other risk factors or pro-arrhythmic drugs Caution in renal impairment as solubilizer may accumulate, consult pharmacy |
| Voriconazole |
Oral tablets/suspension:
<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 ≥15 years or aged 12-14 years and weighing ≥50 kg: 200 mg oral BD
Intravenous solution:
<2 years: discuss with ID and pharmacy 2 years to
<12 years or 12-14 years and weighing <50 kg: 8 mg/kg (day 1, 9 mg/kg) IV BD ≥15 years or aged 12-14 years and weighing ≥50 kg: 4 mg/kg (day 1, 6 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) Council on avoidance sun exposure. Reports of skin cancer with prolonged (>1 year) use
Caution in renal impairment as IV solubilizer may accumulate. Significance is not known, consult pharmacy Monitor for rash, hepatotoxicity, neurotoxicity and visual disturbances (NB. a trough level >5-6 is associated with an increased probability of neurological and ocular toxicity). Visual disturbances are dose related, self-limiting and rarely require cessation of treatment.
Monitor for QT prolongation if other risk factors or pro-arrhythmic drugs |
| Itraconazole |
Oral solution
(Sporonox®): 2.5 mg/kg oral BD (max 200 mg daily)
Oral solution
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 Capsules (Sporanox®): administer with or after food. For children on gastric acid suppressant medications, separate administration by at least 2 hours and administer with an acidic beverage (e.g. cola).
Monitor for rash, hepatotoxicity, neurotoxicity and GI upset. Monitor for QT prolongation if other risk factors or pro-arrhythmic drugs
|
| Liposomal amphotericin (Ambisome®) |
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) |
Not required |
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) |
| Caspofungin |
1 to 3 months: 25 mg/m2 (max 50mg) IV daily
≥3 months: 50 mg/m2 (max 50mg) IV daily |
Not required |
May cause histamine induced reaction (rash, facial swelling, pruritus and/or bronchospasm) |
| Micafungin |
<4 months age: 2 mg/kg IV daily >4 months age: 1 mg/kg (max 50 mg) IV daily |
Not required |
May cause histamine induced reaction (rash, facial swelling, pruritus and/or bronchospasm) |
*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
Therapeutic
drug monitoring (TDM)
Itraconazole, voriconazole and posaconazole require TDM
- All children must have TDM
- All patients should have one repeat TDM to confirm stability
- Once target trough levels are confirmed, repeat TDM is not routinely required
Indications for repeat TDM include
- dose or formulation adjustment (ie iv/oral switch)
- introduction of new drug with potential interactions
- suspected toxicity (always do level before withholding or adjusting dose)
- diagnosis of proven, probable or possible IFI
Dose adjustments should be discussed with oncology pharmacy and/or local infectious diseases unit
- Depending on the age of the child, azoles may exhibit nonlinear or linear pharmacokinetics
- There is also significant INTER- and INTRA- patient variability with these agents
Prior to any dose adjustment, repeat drug level and ensure the following:
| Low azole levels |
High azole levels |
- Confirm true trough sample was taken
- Confirm adherence
- Exclude poor absorption (absorption reduced with severe mucositis and diarrhoea). Depending on agent, diet may also affect absorption (see Table 3)
- Investigate potential drug-drug interactions (see below and discuss with pharmacy)
|
- Confirm a true trough sample was taken
- Investigate potential drug-drug interactions (see below and discuss with pharmacy)
- If clinical signs of toxicity are not present, consider leaving dose regimen unchanged and monitor potential toxicity carefully.
|
Secondary prophylaxis
In children with a documented history of proven or probable IFI, secondary prophylaxis is required for further cycles of chemotherapy
- The agent that was used to treat the initial infection may be used for prophylaxis, provided it was well tolerated and effective
- Discuss with local infectious diseases unit
Important drug interactions for azole antifungal agents
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.
| Medication |
Interaction |
Management |
| Decreased plasma concentration of
azoles |
| Rifampicin, rifabutin |
Induces azole metabolism. |
Avoid combination where possible. An increase in azole dose may be required |
| Carbamazepine |
Induces azole metabolism (fluconazole, itraconazole, voriconazole) |
| Phenobarbitone |
| Phenytoin |
Induces azole metabolism (itraconazole, voriconazole and posaconazole). Phenytoin metabolism reduced. |
Avoid combination where possible. Monitoring of phenytoin and azole levels recommended. An increase in azole dose may be required |
| Omeprazole and esomeprazole (oral formulations) | Liquid posaconazole: PPIs affect gastric pH and reduce posaconazole liquid absorption (less effect on tablets) | Avoid if possible or monitor posaconazole levels |
| Increased plasma concentration of
co-administered drug |
|
Vinca alkaloids
(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. |
| Tyrosine kinase inhibitors (TKI): (sorafenib,
imatinib, dasatinib, nioltinib, ceritinib, carfizomib, ruxolitnib) |
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. |
| Venetoclax | Venetoclax metabolism reduced increasing risk of toxicity | Avoid combination If unavoidable speak to oncology pharmacy and oncology consultant (venetoclax dose reduction may be required) |
| Bortezomib |
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) |
| Busulfan, Thiotepa | Biosulfan and thiotepa reduced (CYP3A4), leading to significant increases in levels of these drugs | Avoid voriconazole, posaconazole or itraconazole 7 days prior to starting HSCT conditioning (not fluconazole) |
| Proton pump inhibitors (omeprazole and esomeprazole) | Reduced metabolism of voriconazole (CYP2C19), increasing voriconazole levels | Monitor voriconazole levels and signs of toxicity. In particular when starting or stopping the PPI |
| Sirolimus, Tacrolimus Cyclosporin |
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 |
| Diazepam, midazolam |
Metabolism reduced, increasing risk of toxicity including respiratory depression |
Monitor for signs of toxicity |
| Prolonged QT interval |
| Gemtuzumab, macrolide & quinolone antibiotics,
conventional antipsychotics |
Additive risk of QT prolongation in setting of azole prophylaxis |
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 |
Consider consultation with local paediatric
team when
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.
Consider transfer when
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