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Antifungal prophylaxis in immunocompromised adults

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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 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 or moulds are the main causative pathogens. Other factors that affect drug selection include: host risk-stratification; and the effectiveness, toxicity, drug-drug interactions and therapeutic drug monitoring capacity of the antifungal agents being considered. Advice from local infectious diseases, microbiology or infection control experts should be sought regarding these issues. 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.

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 the use and dosing of specific antifungal agents for prophylaxis (grade of evidence). rr

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)

© Internal Medicine Journal 2014.r
*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.
Agent Recommended dose for adult patients Notes
Posaconazole
Oral
  • Noxafil® modified-release tablets 300 mg twice a day on day 1 (loading dose) followed by 300 mg once daily on day 2 and thereafter. Taken with or without food.
  • Noxafil® oral liquid: 200 mg orally, 8-hourly. Taken with or immediately after food (with high fat meal or nutritional supplement or an acidic beverage) - avoid PPI or H2 antagonists.
Intravenous infusion
  • Noxafil® IV 300 mg twice a day (loading dose) on day 1 followed by 300 mg once daily on day 2 and thereafter.
 Oral administration is first line.
Oral preparations of posaconazole 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 200 mg orally or IV, 12-hourly
Tablets: taken at least one hour before, or one hour after a meal		  
Fluconazole 200 – 400 mg orally or IV, daily
Tablets: taken with or without food, as absorption not affected by the presence of food or gastric pH		  
Itraconazole

Sporanox® capsules 200 mg orally, 12-hourly. To be taken with food (but not a rice meal) for best absorption. Avoid PPI or H2 antagonists within 2 hours of Sporanox® capsules as they will interfere with its absorption.

Sporanox® liquid 200 mg orally, 12-hourly. To be taken on an empty stomach, at least 1 hour before food.

Lozanoc® capsules 100 mg orally, 12-hourly.
Can be taken with or without foodr (dose based on dose equivalence with Sporanox® and not on clinical trial data)

 Brands and formulations of oral itraconazole (Lozanoc® capsules, Sporanox® capsules and Sporanox® oral liquid) are NOT interchangeable.r
Amphotericin B AmBisome® nebulized 12.5 mg (2.5 mL of a 5 mg/mL solutionr) daily on two sequential days each week; OR intravenous 100 mg  three times a week or 50 mg on alternate days. TDM not required
Echinocandins Lack broad spectrum anti-mould activity (active against Candida species); only available as IV and high cost.
  • Caspofungin 50 mg daily 
  • Micafungin 50 mg daily
  • Anidulafungin 100 mg dailyr
 TDM not required

IV, intravenous; TDM, therapeutic drug monitoring.

Duration of prophylaxisr

  • Allogeneic BMT:
    • start prophylaxis on the day of stem cell infusion (if indicated pre-engraftment) and continue until the neutrophil count recovers (more than 0.5 x 109/L).
    • start at onset of severe GVHD; continue until day 100 or until prednisolone dose is less than 15 mg daily, whichever is later.
  • Acute leukaemia induction: start prophylaxis on day 1 of chemotherapy (avoiding drug interactions particularly itraconazole and cyclophosphamide) and continue until the neutrophil count recovers (more than 0.5 x 109/L).

Azole antifungal dosing information - practice points

  • No two azole agents (fluconazole, posaconazole, voriconazole, itraconazole) 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. Reference 3 is a highly recommended summary of many of these issues.r
  • A loading dose is not recommended for most patients receiving azoles for prophylaxis (although see posaconazole).
  • The major drug-drug interactions associated with the azole antifungal agents involve oxidative drug metabolism via the cytochrome P450 enzyme system. The potential for drug-drug interactions is higher for itraconazole and voriconazole, as these are metabolised to a greater extent by cytochrome isoenzymes than and posaconazole. Fluconazole appears to have the lowest propensity for drug-drug interactions within the azole class.r For further information regarding interaction between azoles and drugs commonly used in haematology refer to Chau et al.r
  • Azole use with 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: 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. The optimal dosing regimen is also unclear although some Australian centres have used a dose of 100 mg three times a week based on older studies discussed in the previous guideline.rr Penack et alr suggested a benefit of administering low dose IV liposomal amphotericin, 50 mg on alternate days, compared with no prophylaxis in patients with haematological malignancy (predominately AML). Prophylaxis reduced the incidence of IFI, including invasive aspergillosis, although most of the Aspergillus infections in the placebo arm were probable, not proven. No survival benefit was demonstrated. As the clinical trial was unblinded, ascertainment bias represents a significant concern to its validity.
  • Aerosolized liposomal amphotericin: In a placebo controlled RCT,r aerosolised liposomal amphotericin reduced invasive pulmonary aspergillosis incidence by 74%, but 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.
  Activityr Renal impairment Hepatic impairment Drug monitoringrr Comments
Fluconazole
  • Candida
  • Cryptococcus.neoformans
  • Coccidioidomycosis
Inactive against moulds		 Predominantly renally cleared. For CrCl less than 50 mL/min increase dosage interval or reduce dose (seek expert advice and/or consider TDM)r No recommendations

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.

 Oral bioavailability is reported to be over 90%r
Itraconazole
  • Candida, Aspergillus species and some of the rarer moulds
  • Dimorphic fungi and C.neoformans
 Oral formulation- no dose adjustment No recommendations, however predominantly hepatically cleared, may require dose adjustment

Recommended to ensure adequate absorption, as absorption is unpredictable. Timing of first sample 7-15 days. Aim for target trough level >0.5 mg/L for prophylaxis.

If plasma concentration is inadequate in patients taking the capsule, consider switching to the oral solution and rechecking the concentration after 5 days.r

Bioavailability of Sporanox® oral liquid taken in the fasting state is ~ 60% higher than from a Sporanox® capsule taken with a meal, i.e. Sporanox® 100 mg capsule is roughly equivalent to 50 mg Sporanox® oral liquid.r
One 50 mg Lozanoc® capsule is therapeutically equivalent to one 100 mg Sporanox® capsule.r 

Itraconazole IV is not marketed in Australia but may be available through the SAS.
Posaconazole
  • Candida, Aspergillus sp.
  • some Zygomycete sp and some of the rarer moulds
  • Dimorphic fungi and C.neoformans
 Oral formulations- no dose adjustment necessary.
IV- if possible, avoid IV route if CrCl < 50 mL /min as the injection solvent (a cyclodextrin) accumulates		 May increase half-life, consider dose adjustment.
Monitor liver function; manufacturer advises caution

Data on the importance and value of monitoring posaconazole are emerging.

Consider monitoring the plasma concentration, particularly if poor absorption is likely (e.g. in patients with severe mucositis or diarrhoea).r

Timing of first sample 5-7 days.

Aim for a target trough level > 0.7 mg/L for prophylaxis.

  
Voriconazole
  • Candida, Aspergillus species and some of the rarer moulds
  • Dimorphic fungi and C. neoformans
 Oral formulations- no dose adjustment necessary.
IV- if possible, avoid IV route if CrCl < 50 mL /min as the injection solvent (a cyclodextrin) accumulates		 Mild to moderate impairment: following standard loading dose, reduce maintenance dose by 50%.
No data for severe hepatic impairment – monitor for toxicity.

Recommended to monitor the plasma concentration in patients with leukaemia and BMT recipients. Also, consider monitoring the plasma concentration, particularly if poor absorption is likely (e.g. in patients with severe mucositis or diarrhoea).r

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.

Trough levels > 5-6 mg/L associated with increased toxicity i.e. ocular toxicity and encephalopathyr

 Oral formulation has a bioavailability of > 90%, which is reduced by ~ 30% when taken with a high fat meal. Levels may be boosted by concurrent use of proton pump inhibitors. Although there is more experience with voriconazole than posaconazole in lung and heart transplantation, voriconazole may increase the risk of skin cancer.r
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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 consenus guidelines have been updated/published.
31/05/2017 Transferred to new eviQ website. Version number changed to V.2
23/08/2018 Reviewed at BMT reference committee meeting. Minor changes including table formating and content. Version number changed to V.3. Review in 2 years.

This document reflects what is currently regarded as safe practice. While every effort has been made to ensure the accuracy of the content at the time of publication, the Cancer Institute NSW does not accept any liability, with respect to loss, damage, injury or expense arising from any such errors or omission in the contents of this work. Any reference throughout the document to specific pharmaceuticals and/or medical products as examples does not imply endorsement of any of these products. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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20 Feb 2020