611,000 species of fungus have been identified, and 600 of these are known human pathogens. In the environment all around us, these pathogens pose little risk to people unless they are immunocompromised in some way. Colonisation of the skin and mucosal surfaces with Candida is the first step in the process of systemic candidiasis. The other main pathogens isolated in invasive fungal disease (IFD) are Aspergillus species. Without proper treatment, systemic Aspergillus poses a risk of mortality of almost 100%, and candidaemia mortality rates are estimated to be between 30% and 55%.

The latest Australian guidelines published in 2014 for the prophylaxis of fungal infections in haematology patients stratify the risk of IFD to treatment and disease. Neutrophil count, knowledge of local fungal epidemiology, and individual patient characteristics such as antibiotic usage, older age, central venous catheter use, lower respiratory tract infection and environmental exposure to mould also should be taken into consideration when determining patient risk level. Since the introduction of fluconazole and itraconazole for prophylaxis in haematology patients, there has been a shift towards Aspergillus in epidemiological studies.

Clinical risk factors identify the following two groups of patients as those at highest risk of developing IFD:

  • Patients receiving intensive chemotherapy for acute myeloid leukaemia (AML) or myelodysplastic syndrome; and
  • Patients with corticosteroid-requiring graft-versus-host disease (GVHD) following allogeneic haemopoietic stem cell transplantation (HSCT). Steroid refractory GVHD, high grade (grade 3-4) GVHD, or chronic GVHD pose the greatest risk.

Other risk factors include HSCT with cord-blood, mismatched donors, cytomegalovirus (CMV), iron overload, and acute leukaemia with active disease at the time of transplant.

Patients undergoing intensive regimens for other haematological malignancies such as HyperCVAD (hyperfractionated therapy with cyclophosphamide, vincristine, doxorubicin [Adriamycin®], and dexamethasone plus methotrexate and cytarabine) for acute lymphoblastic leukaemia (ALL) are considered high risk also. It is important to keep in mind patient characteristics as patient status can change, and IFD risk is dynamic throughout the patient’s treatment cycle.

Table 1: Risk classification and recommended prophylaxis (adapted from Fleming et al.)

Risk Classification Clinical Examples Recommended Prophylaxis
High Risk Acute leukaemia or myelodysplasia, with remission induction and re-induction chemotherapy Mould prophylaxis
(posaconazole first line)
Severe GVHD: steroid dependent, refractory, or grade 3 or 4
Extensive chronic GVHD
Allogeneic HSCT with expected neutropenia > 14 days
Low risk Selected autologous HSCT Candida prophylaxis
(fluconazole first line)
Allogeneic HSCT with expected neutropenia < 14 days
Patients receiving intensive/dose-escalated therapy for lymphoma

The decision to give prophylaxis for mould fungi or candidiasis depends on the risk factors described above. If neutropenia is less protracted and mucosal integrity is compromised, then the patient should receive Candida prophylaxis.

Cessation of prophylaxis is recommended following the resolution of risk. For acute leukaemia, this risk is reduced upon neutrophil resolution (>0.5 or 1.0 x 109/L). For allogeneic patients at high risk of IFD, treatment should be continued until at least day 75 and for patients with GVHD, prophylaxis should be continued for 16 weeks or until corticosteroid dose is less than 10mg/day of prednisolone or equivalent.

The azoles are the main arsenal in the prophylaxis of fungal infections in haematology due to their high efficacy and bioavailability when given orally. Liposomal amphotericin B is another option commonly used in Australia while the echinocandins are rarely used. Drug interactions and individual patient co-morbidities will influence drug selection.

Posaconazole is the preferred agent for prophylaxis in high-risk patients. The recommended dosage for prophylaxis in adults is 200mg three times daily when the oral liquid is supplied. However, posaconazole is also available as sustained-release tablets that may be administered daily after an initial loading dose. It has been shown to have a survival benefit in AML and broad activity against moulds which makes it the agent of choice. Saturable absorption limits the effectiveness in patients with GVHD of the digestive tract, mucositis, diarrhoea, or colitis. Therapeutic drug monitoring (TDM) can be used to optimise therapy, and the guidelines recommend a minimum plasma level of 0.7mg/L in patients receiving prophylaxis. It is important to note that posaconazole undergoes glucuronidation rather than being metabolised via the CYP450 enzyme system. It does, however, inhibit CYP3A4.

Voriconazole showed a trend towards fewer IFDs, fewer Aspergillus infections, and less empirical antifungal therapy when compared with fluconazole for HSCT recipients. This study shows bias for those at low-risk of Aspergillus infections however and does not provide sufficient evidence over fluconazole. Due to the susceptibility of Aspergillus, voriconazole is a good alternative if posaconazole is not tolerated. The recommended dosage is 200mg twice each day. Voriconazole undergoes metabolism through the CYP2C19 enzyme that is subject to polymorphism. TDM may assist optimisation of therapy with a target trough level of 1-2mg/L and greater toxicity associated with trough levels greater than 5-6mg/L. Due to the non-linear pharmacokinetics of voriconazole, TDM should be performed after dose modification.

Itraconazole, when compared with voriconazole, was shown to have more intolerance and the same efficacy. It especially has greater gastrointestinal toxicity when compared with the other azoles, and loading doses are often not tolerated. It is sometimes recommended to start one to two weeks before prophylaxis is required to avoid the need for a loading dose. There is variability between the pharmacokinetics of different brands of itraconazole and they are not directly interchangeable. If used for prophylaxis, a dose of 2.5mg/kg every 12 hours is recommended for the oral liquid.

As a class, the azoles are generally well tolerated. Rash, headache and gastrointestinal upset are common side-effects and usually self-limiting. Hepatotoxicity is a more serious side-effect that can occur and is most commonly seen with voriconazole. It has also been associated with a photo-sensitive skin rash that can lead to malignancy in prolonged use. The azoles are associated with QT prolongation, and monitoring should occur in at-risk patients.

Aerosolised liposomal amphotericin B has been shown to be effective in AML patients who are neutropenic. The need for an advanced nebuliser has limited the adoption of the aerosolised form though. Intravenously administered liposomal amphotericin B has been studied, and the high risk of nephrotoxicity has prevented it from being recommended. A recent trial in patients with ALL that normally require vinca-alkaloid therapy, and therefore are at significant risk of drug interactions with azole therapy, showed no statistical difference in the rate of IFD between IV liposomal amphotericin B (5mg/kg, twice weekly) and placebo. A recent survey showed this is used for prophylaxis in some hospitals, despite evidence to the contrary and no standardised dosing is recommended.

The echinocandins show a favourable safety profile. However, due to higher breakthrough rates of IFD when compared with voriconazole/posaconazole and the lack of broad-spectrum mould activity, these agents are generally not recommended for prophylaxis. A recent retrospective trial, however, showed comparable prophylactic activity to posaconazole in neutropenic haematological patients. This may be an alternative if intolerance or drug interactions prevent the use of other agents.

Table 2: Antifungal prophylaxis in high and low-risk patient groups (Adapted from Fleming et al.)

Risk Group Agent Alternative Agents
High Risk Posaconazole Voriconazole
Itraconazole
Liposomal amphotericin B
Micafungin
Low Risk Fluconazole Itraconazole
Echinocandins

Fungal spores are present in the environment and minimising the risk of exposure to these pathogens should be a part of high-risk patient management. In-patients may be required to utilise high-efficiency particulate air filtration and positive pressured rooms. Outpatients should minimise their exposure to environmental pathogens through avoidance of activities with a high risk of exposure to soils and dust.

It is important to note this review is for adult patients and due to the complex pharmacokinetics of these drugs, recommendations will differ significantly for paediatric patients.

References:

  1. Antibiotic Expert Group. Therapeutic Guidelines: Antibiotic (ver 15). Melbourne: Therapeutic Guidelines; 2014.
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  4. Fleming S, Yannakou CK, Haeusler GM, Clark J, Grigg A, Heath CH, et al. Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation, 2014. Internal Medicine Journal 2014; 44: 1283-97
  5. Mellinghoff SC, Panse J, Alakel N, Behre G, Buchheidt D, Christopeit M, et al. Primary prophylaxis of invasive fungal infections in patients with haematological malignancies: 2017 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO). Ann Hematol. 2018; 97(2): 197-207.
  6. Nett JE, Andes DR. Antifungal Agents: Spectrum of Activity, Pharmacology and Clinical Indications. Infect Dis Clin North Am. 2015; 1-33.
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  8. Van Hal SJ, Gilroy NM, Morrissey CO, Worth LJ, Szer J, Tam CS, et al. Survey of antifungal prophylaxis and fungal diagnostic tests employed in malignant haematology and haemopoietic stem cell transplantation (HSCT) in Australia and New Zealand. Internal Medicine Journal 2014; 44: 1277-82.

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