Antifungal prophylaxis for children with cancer or undergoing haematopoietic stem cell transplant

  • See also:

    Fever and suspected or confirmed neutropenia 

    In this guideline:

    Background
    Prophylaxis regimens based on risk groups
    Drug information
    Dose adjustment based on TDM
    Timing and duration of prophylaxis
    Secondary prophylaxis
    Important drug interactions

    Background

    Children with cancer are at varying risk of invasive fungal infection (IFI). Factors that influence this risk include type of cancer, chemotherapy protocol 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.

    Table 1: Stratification of risk of IFI in paediatric cancer/HSCT patients

    Risk Stratum

    Risk of IFI with

    Patient Population

    High Risk (≥10%)

    Mould > Yeast

    Relapsed acute leukaemia
    Allogeneic HSCT with acute Grade II-IV GvHD
    Allogeneic HSCT chronic extensive GvHD
    Severe aplastic anaemia

    Yeast > Mould

    Non-relapse Acute Myeloid Leukaemia (AML)
    Allogeneic HSCT (pre-engraftment phase)
    Very high-risk Acute Lymphoblastic Leukaemia (ALL) induction phase

    Intermediate Risk

    Yeast > Mould

    Autologous HSCT (neutropenic phase)

    Low Risk (≤5%)


    Non-relapse ALL (excluding very-high risk ALL in induction phase)
    Lymphoma (excluding autologous HSCT)
    Solid tumours (excluding autologous HSCT)

    Sporadic occurrence


    Paediatric solid tumours
    Brain tumours
    Hodgkin’s lymphoma

    *Very high-risk ALL includes T-cell, age >13y and high MRD, Philadelphia positive

    Recommendations for primary prophylaxis based on risk groups

    Table 2: Recommended prophylaxis regimens according to patient population.
    See 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

    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

    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 7-15 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 patients 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

    Voriconazole

    Oral tablets/suspension:
    2 years to <12 years or 12-14 years and weighing <50kg: 9mg/kg (max 350mg) oral BD

    ≥15 years or aged 12-14 years and weighing ≥ 50kg: 200mg oral BD

    Intravenous solution:
    2 years to <12 years or 12-14 years and weighing <50kg: 8mg/kg (day 1, 9mg/kg) IV BD

    ≥15 years or aged 12-14 years and weighing ≥ 50kg: 4mg/kg (day 1, 6 mg/kg) IV BD

     

    Trough level 1-2 µg/mL**

    Take trough level 2-5 days after starting drug or changing dose

    Dose should not be altered if level is 4-6 mg/L and clinical signs of toxicity are not present

     

    Administer 1 h before or after food (absorption with high fat meals)

    Council on avoidance sun exposure. Reports of skin cancer with prolonged (>1yr) use.

    Caution in renal impairment as 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 therapy.

    Monitor for QT prolongation if other risk factors or pro-arrhythmic drugs

    Posaconazole

     

    Oral suspension:
    ≥13 years: 200 mg oral TDS

    Oral tablets:
    ≥13 years: 300 mg oral daily

    Trough level >0.7 µg/mL

    Take trough level 5-7 days after starting drug or changing dose

    Administer with food.
    (absorption ↑with high fat meal)

    Safety and efficacy in paediatric patients below the age of 13 years has not been well established.

    Monitor for rash (rare), hepatotoxicity (rare), neurotoxicity and GI upset.

    Monitor for QT prolongation if other risk factors or pro-arrhythmic drugs

    Liposomal amphotericin (Ambisome®)

    3mg/kg IV three times per week

    Not required

    Monitor for renal toxicity, electrolyte disturbances (esp hypokalaemia and hypomagnesaemia) and hepatotoxicity.

    Consider premedication if infusion related adverse effects (inc. fever, chills, rigors)

    Caspofungin

    1 to 3 months: 25mg/m2 (max 50mg) IV daily

    ≥3 months: 50mg/m2 (max 50mg) IV daily

    Not required

    May cause histamine induced reaction (rash, facial swelling, pruritus and/or bronchospasm)

    Micafungin

    1mg/kg (max 50mg) 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 Tuesday and Thursday (must arrive at The Alfred by 11am). Samples require minimum 1ml 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 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 (i) dose adjustment or iv/oral switch; (ii) introduction of new drug with potential interactions (iii) suspected toxicity (always do level before withholding or adjusting dose); or (iv) diagnosis of a proven, probable or possible IFI.

    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. 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:

    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 III)
    • 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.

     

    Timing and duration of prophylaxis

    For allogeneic HSCT, commence agent in conditioning phase and continue until at least day 75 (in the absence of GvHD), unless precluded by toxicity. For patients with GvHD continue for until corticosteroid dose is less than 0.3 mg/kg daily prednisolone equivalent. For all other patients, commence prophylaxis during administration of chemotherapy (unless contraindicated due to chemotherapy-azole interaction) and cease when neutrophil count is expected to be greater than 1.0x109/L for 7-14 days.

    Secondary prophylaxis

    In patients 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

     

    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.

    For weekly IV vinca alkaloid: non-azole agent is preferred

    For monthlyIV vinca alkaloid: consider withholding voriconazole or posaconazole 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)

    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 patients receiving sorafenib.

    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 patients with AML receiving bortezomib on D1 and D8 in a 28-day curse, substitute fluconazole for an echinocandin on D(-3) to D(+12)

    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 patients on sirolimus.

    Diazepam, midazolam

    Metabolism reduced, increasing risk of toxicity including respiratory depression

    Monitor for signs of toxicity

     

    Prolonged QT interval

    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 patients with additional cardiac risk factors including reduced left ventricular fraction and electrolyte disturbances.

    References

    Chau MM et al. Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014. Intern Med J. 2014; v44

    Fleming S. et al. Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation, 2014. Intern Med J. 2014; v44