Antifungal prophylaxis in immunocompromised adults

The purpose of this document is to provide guidance regarding antifungal prophylaxis in patients with haematological malignancy or profound neutropenia > 10 days, and is intended to be used as a guide only.

Antifungal prophylaxis should not be used routinely in all patients with neutropenia. The rationale for antifungal prophylaxis is to prevent fungal infections in a targeted group of high risk patients, especially those with AML, longer durations of neutropenia or with graft versus host disease (GVHD) post allogeneic blood or marrow transplant (BMT).

Consideration for antifungal prophylaxis should be determined, where possible, by local rates of invasive fungal infection (IFI) in specific patient populations. If prophylaxis is to be used, the choice of antifungal agent should be guided by institutional types of invasive fungal infection in specific groups, in particular whether Candida species or moulds are the primary causative pathogens. Other factors that affect drug selection include:

• host risk-stratification
• antifungal agent characteristics, e.g. efficacy, toxicity, drug-drug interactions and therapeutic drug monitoring (TDM) availability

As a result of such issues, there may be wide variations in institutional practice regarding antifungal prophylaxis, and thus recommendations in this document may differ from those of specific institutions. Advice from local infectious diseases or microbiology experts should be sought regarding these issues for tailored policy best suited to each institution.

The following recommendations are from the Australian and New Zealand consensus guidelines for the use of antifungal agents in the haematology/oncology setting, 2014 update.^r

Classification of risk and recommended prophylaxis for adults

Risk classification	Clinical examples (level of evidence, grade of recommendation)	Recommended prophylaxis
High risk	Acute leukaemia or myelodysplasia, with remission induction and re-induction chemotherapy (ll, A) Severe GVHD: steroid dependent or refractory or grade 3 or 4 (ll, A) Extensive chronic GVHD (ll, A) Allogeneic HSCT with expected neutropenia > 14 days (lll, C)	Mould-active prophylaxis
Low risk	Selected autologous HSCT* (ll, C) Allogeneic HSCT with expected neutropenia < 14 days (ll, A) Patients receiving intensive/dose escalated therapy for lymphoma (lV, D)	Anti-Candida prophylaxis
Very low risk	Standard chemotherapy for lymphoma (lll, C) Chronic myeloid leukaemia (lll, C) Other myeloproliferative neoplasms(lll,C)	No prophylaxis
* 'Selected' refers to autologous HSCT with higher risk of mucositis and thus Candida infection (e.g. those with recent aggressive salvage chemotherapy or receiving multi-agent regimens). ​ GVHD, graft-versus-host disease; HSCT, haemopoietic stem cell transplant. Read more about the National health and medical research council (NHMRC) evidence hierarchy and grades of recommendations.

© Internal Medicine Journal 2014

Prophylaxis recommendations for specific antifungal agents (grade of evidence)^r

Risk group	Agent	Alternative agents
High risk	Posaconazole (A)	Voriconazole (B) Itraconazole (B) Liposomal amphotericin B (C) *Micafungin (B) Caspofungin (C)
Low risk	Fluconazole (B)	Itraconazole (B) Echinocandins (B)
*Although a randomised controlled trial has compared micafungin and fluconazole prophylaxis, this study was not adequately powered to establish anti-mould efficacy.r Read more about the National Health and Medical Research Council (NHMRC) evidence hierarchy and grades of recommendations.

© Internal Medicine Journal 2014

Duration of prophylaxis^rr

• Refer to local or institutional protocols for duration of antifungal prophylaxis.
• Allogeneic BMT:
  • Start prophylaxis from Day +1 of transplant
    • For mould prophylaxis, continue up until Day +75 or prednisolone dose < 15mg daily, whichever is later.
    • For yeast prophylaxis, continue up until Day +75 or corticosteroids have ceased, whichever is later.
  • Patients with GVHD prophylaxis should be continued for 16 weeks or until corticosteroid dose is less than 10 mg daily (prednisolone equivalent).
• Acute leukaemia induction: start prophylaxis on day 1 of chemotherapy and continue until the neutrophil count recovers (more than 0.5 x 10⁹/L). Some institutions may continue throughout induction and consolidation periods.
• Low risk groups: continue until the neutrophil count recovers (more than 0.5 x 10⁹/L).

Recommendations for the use and dosing of specific antifungal agents for prophylaxis ^rr

Activityr	Recommended Adult dose	Therapeutic Drug Monitoring (TDM)rr	Dose Modification	Notes
Posaconazole
Candida, Aspergillus sp. some Zygomycete sp and some of the rarer moulds Dimorphic fungi and C.neoformans	Oral Noxafil® modified-release tablets 300 mg twice a day on day 1 (loading dose) followed by 300 mg once daily from day 2. Swallowed whole, with or without food. Noxafil® oral liquid: 200 mg orally, 8-hourly. Taken with or immediately after food (full meal or nutritional supplement or an acidic beverage) - avoid PPI or H2 antagonists. Intravenous (IV) infusion Noxafil® 300 mg IV twice a day (loading dose) on day 1 followed by 300 mg once daily from day 2.	TDM recommended. Timing of first sample 5-7 days. Aim for a target trough level > 0.7 mg/L for prophylaxis (C).	If possible avoid IV formulation if CrCl < 50 ml/min as the injection solvent (a cyclodextrin) accumulates. Hepatic impairment may increase half-life, consider dose adjustment. Monitor liver function; manufacturer advises caution.	Oral administration is first line. Oral preparations are not bioequivalent; appropriate dosing and administration depends on the preparation. Where possible, posaconazole tablets should be used in preference to the suspension because the tablets have a higher bioavailability. Only consider intravenous administration if oral route is unavailable or absorption may be impaired and benefits outweigh risks.
Voriconazole
Candida, Aspergillus species and some of the rarer moulds Dimorphic fungi and C. neoformans	Oral 400 mg orally, 12-hourly for 2 doses then 200 mg orally, 12- hourly Oral: take at least one hour before, or one hour after a meal Intravenous (IV) infusion 6mg/kg IV 12-hourly for 2 doses then 4 mg/kg IV 12-hourlyr	TDM recommended in patients with leukaemia and BMT recipients (B). Consider monitoring, in other patients with haematological malignancy who require prophylaxis (D), particularly if poor absorption is likely (e.g. in patients with severe mucositis or diarrhoea). First sample 2-5 days and repeat sample should be collected to ensure stability. Aim for a target trough level between 1 and 5 mg/L – commonly recommended for clinical efficacy (C). Trough levels > 5-6 mg/L associated with increased toxicity i.e. ocular toxicity and encephalopathy (C).	If possible avoid IV formulation if CrCl < 50 ml/min as the injection solvent (a cyclodextrin) accumulates. For mild to moderate hepatic impairment: follow standard loading dose, but reduce maintenance dose by 50%. No data for sever hepatic impairment – monitor for toxicity.	Oral formulation has a bioavailability of > 90%, which is reduced by ~ 30% when taken with a high fat meal.  Long term complications resulting from metabolic irregularities may include increased risk of squamous cell carcinoma and hyperphosphataemia.r With prolonged use, fluoride in drug can cause a painful periostitis. Correlates with elevated serum fluoride levels. ​Resolves with discontinuation of drug.r
Fluconazole
Candida Cryptococcus.neoformans Coccidioidomycosis Inactive against moulds ​	200 mg – 400 mg orally or IV, daily Tablets: taken with or without food	TDM not recommended. Routine monitoring is not indicated in most patients. Consider in those that have severely compromised renal function, for those who are undergoing dialysis, or for those where absorption may be impacted.	Predominantly renally cleared. For CrCl less than 50 mL/min increase dosage interval or reduce doser (seek expert advice and/or consider TDM).	Oral bioavailability is reported to be over 90%.r
Itraconazole
Candida, Aspergillus species and some of the rarer moulds Dimorphic fungi and C.neoformans	Conventional itraconazole capsules 200 mg orally, 12-hourly. To be taken with food (but not a rice meal) and acidic beverage for best absorption. Avoid PPI or H2 antagonists within 2 hours of conventional itraconazole capsules as they will interfere with its absorption. Itraconazole liquid 200 mg orally, 12-hourly. To be taken on an empty stomach, at least 1 hour before food. SUBA-itraconazole capsules (Lozanoc®)  200 mg orally, 12-hourly. Can be taken with or without foodr	TDM recommended to ensure adequate absorption, as absorption is unpredictable. Timing of first sample 7-15 days. Aim for target trough level > 0.5 - 1.0 mg/L.	No dose adjustment required for renal impairment with oral formulation. Predominately hepatically cleared. May require dose adjustment, limited data.	Brands and formulations of oral itraconazole are NOT interchangeable.r Bioavailability of Sporanox® oral liquid taken in the fasting state is ~ 60% higher than from a conventional itraconazole capsule taken with a meal,r i.e.  conventional 100 mg capsule is roughly equivalent to 50 mg Sporanox® oral liquid. One 50 mg Lozanoc® capsule (SUBA-itraconazole) is therapeutically equivalent to one 100 mg conventional itraconazole capsule,r with less inter-patient variability, however starting dose should remain the same for rapid attainment of therapeutic levels.r  Itraconazole IV is not marketed in Australia but may be available via Special Access Scheme.
Isavuconazole (Isavuconazonium sulfate)
Invasive Aspergillosis sp. Mucormycosis	Oral Initial: 372 mg (isavuconazole 200 mg) 8-hourly for 6 doses; Maintenance: 372 mg (isavuconazole 200 mg) once daily. Start maintenance dose 12 to 24 hours after the last loading dose. Given with or without food. Intravenous (IV) infusion Initial: 372 mg (isavuconazole 200 mg) 8-hourly for 6 doses; Maintenance: 372 mg (isavuconazole 200 mg) once daily. Start maintenance dose 12 to 24 hours after the last loading dose.	TDM may not be accessible in Australia	No dose adjustment required for renal impairment with oral formulation. Predominately hepatically cleared. May require dose adjustment, limited data.	Can be considered in patients intolerant or refractory to first-line anti-mould therapy. May shorten QTc. Duration of therapy: 6 to 12 weeks (minimum), although duration is highly dependent on degree/duration of immunosuppression, disease site, and evidence of disease improvement.r
Amphotericin B
Candida Aspergillus sp. (excluding Aspergillus terreus) Zygomycetes​ Dimorphic fungi and C.neoformans Rarer moulds	Various dosing schedules have been used: 100 mg IV three times a weekr  50 mg IV on alternate daysr  3 mg/kg IV three times a weekr  5 mg/kg IV twice a weekr	TDM not recommended	Manufacturer recommends close monitoring of patients with renal or hepatic dysfunction.	Although the level of evidence for liposomal amphotericin B prophylaxis is weak and an azole should be used if possible in high risk patients, it is often used for prophylaxis in settings where an azole cannot be used due to drug interactions.
Echinocandins
Primary therapy for candidemia and invasive candidiasis C. auris may be resistant to echinocandins May be used as part of second-line or subsequent regimen for invasive aspergillosis Not reliable or effective against other fungal pathogens	Caspofungin 50 mg IV daily  Micafungin 50 mg IV daily Anidulafungin 100 mg IV dailyr	TDM not recommended	Caspofungin: For moderate hepatic impairment: reduce dose to 35mg IV dailyr   Micafungin and anidulafungin: No dose adjustment is required for renal or hepatic impairment	Good safety profile. Echinocandins have poor CNS penetration. Lack broad spectrum anti-mould activity.r Only available as IV.
Read more about the National Health and Medical Research Council (NHMRC) evidence hierarchy and grades of recommendations.

Azole antifungal dosing information - practice points

• No two azole agents (fluconazole, posaconazole, voriconazole, itraconazole, isavuconazole) offer the same pharmacokinetic profile. In addition, these agents are increasingly available in formulations which may not be bio-equivalent. It is important to understand the differences in spectrum, bioavailability, metabolism, elimination and toxicities among these agents. Chau et al is a highly recommended summary of many of these issues.^r
• Loading dose is generally recommended for patients receiving voriconazole, posaconazole or isavuconazole for prophylaxis.
• The major drug-drug interactions associated with the azole antifungal agents involve oxidative drug metabolism via the cytochrome P450 enzyme system, both as inhibitors and substrates of this pathway. The potential for drug-drug interactions to affect the azole is higher for itraconazole, voriconazole and isavuconazole, as these are metabolised to a greater extent by cytochrome isoenzymes than posaconazole. Fluconazole appears to have the lowest propensity for drug-drug interactions within the azole class. However, all mould active azoles are moderate to strong inhibitors of CYP3A4 and care must be taken when administering CYP3A4 substrates (e.g. ibrutinib and venetoclax). For further information regarding interaction between azoles and drugs commonly used in haematology refer to Chau et al and Lindsay et al.^rr
• Azole use with vinca alkaloids (especially vincristine) or high doses of cyclophosphamide: Given the potential for serious drug interactions, concomitant administration of extended-spectrum azole (posaconazole, voriconazole, itraconazole) prophylaxis should be avoided in patients at the time they are receiving vincristine or high doses of cyclophosphamide, and an appropriate washout period allowed after azole discontinuation before administration of these drugs.^r 
• Hepatic function abnormalities are associated with all of the azoles. These range from mild elevations in transaminases to severe hepatic reactions including hepatitis, cholestasis, and fulminant hepatic failure. High-dose therapy, drug interactions, and genetic polymorphisms may increase the risk of hepatotoxicity. Close monitoring of transaminases is recommended, particularly in the first weeks of therapy.^r The less severe forms of hepatotoxicity are usually reversible with drug cessation, and do not preclude careful administration of alternative azole drugs.

Amphotericin compounds – practice points

• Liposomal amphotericin B: While IV liposomal amphotericin B is often used for prophylaxis in settings where an azole cannot be used due to toxicity or drug interactions, it remains uncertain whether it is as effective as azole prophylaxis. Optimal dosing also remains unclear. Some Australian centres have used a dose of 100 mg three times a week based on older studies discussed in the previous guideline.^rr Other dosing schedules used in studies evaluating the efficacy of IV liposomal amphotericin B prophylaxis with varying outcomes include 50mg on alternate days,^r 3mg/kg three times a week^r and 5mg/kg twice a week.^r Overall, optimal dose and timing is not well evaluated and warrants further investigation.^r
• Aerosolized liposomal amphotericin B for invasive pulmonary aspergillosis: In a placebo controlled RCT of patients with haematological disease with expected neutropenia of ≥ 10 days, aerosolised liposomal amphotericin B 12.5 mg (2.5 mL of a 5 mg/mL solution) daily on two sequential days each week; reduced invasive pulmonary aspergillosis incidence by 74%.^r However, the study was underpowered to show a survival benefit. In addition, it has not been directly compared to systemic antifungal prophylaxis. The delivery also has significant practical issues, as the droplet size may be crucial to ensure delivery of the drug to the lower respiratory tract and may vary from one delivery device to another. Seek expert advice if use of this modality is contemplated.

Prophylaxis with chimeric antigen (CAR) T-cell therapy

• CAR T-cell products are an emerging treatment for ALL, NHL and CLL. The first product registered in Australia is tisagenlecleucel, a CD19-targeted product. Fungal risk in patients receiving CAR T-cell products is due to a number of factors, including immunodeficiency secondary to prior multiple lines of chemotherapy, lymphodepleting chemotherapy administered prior to the CAR T-cell infusion and depletion of normal B cells, leading to prolonged hypogammaglobulinemia.  Treatment of common toxicities of CAR T-cells such as the cytokine release syndrome (CRS) and immune effector-associated neurotoxicity syndrome also increases fungal risk, often involving treatment with corticosteroids and tocilizumab.^r
• Recommendations for antifungal prophylaxis with CAR T-cells is yeast prophylaxis with fluconazole or micafungin starting after lymphodepleting chemotherapy, for at least 30 days post CAR T-cell infusion. Mould active prophylaxis is recommended in the setting of prolonged neutropenia or if additional treatments for high grade CRS following CAR T-cell therapy are initiated, including corticosteroids and tocilizumab. Previous therapies including recent allogeneic or autologous HSCT should be taken into account when assessing initial antifungal prophylaxis.^rr

Secondary prophylaxis

• Secondary prophylaxis is recommended in patient with a documented history of suspected or confirmed IFI, with the same agent to treat the initial infection provided it was well tolerated and effective.^r
• Therapeutic dosing should be used.^r
• Consult institutional infectious disease team for further recommendations. 

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Version 4

Date	Summary of changes
20/10/2020	Reviewed at BMT and Cellular Therapies reference committee meeting on 31/07/2020. Version number changed to V.4. Review in 1 year. Added - isavuconazole, prophylaxis in CAR T-cell therapy. Updated - duration of prophylaxis, amphotericin B dosing options, references.

Version 3

Date	Summary of changes
23/08/2018	Reviewed at BMT reference committee meeting. Minor changes including table formatting and content. Version number changed to V.3. Review in 2 years.

Version 2

Date	Summary of changes
01/08/2014	Transferred from ACI to a Resource Document. Interim update and review by haematologists and infectious disease physicians. To be reviewed February 2015 once Australian consensus guidelines have been updated/published.
31/05/2017	Transferred to new eviQ website. Version number changed to V.2