Drug
Dose
Advantages
Disadvantages
Special precautions
AmBD
1–1.5 mg/kg/day
Inexpensive
Nephrotoxicity
Test dose, premedication to prevent hypersensitivity reaction
Maximum experience
Poor CNS penetration
LAmB
5–10 mg/kg/day
Less nephrotoxicity
Expensive
Good CNS penetration
Amphotericin B lipid complex (ABLC)
5–7.5 mg/kg/day
Less nephrotoxicity
Expensive
Clinical studies suggest benefit with combination therapy with echinocandins
Less efficacious than LAmB for CNS infections
Caspofungin plus lipid polyene
70-mg IV loading dose, then 50 mg/day for 2 weeks
Favourable toxicity profile
Limited data on combination therapy
Synergistic in murine disseminated mucormycosis
Limited penetration into CNS
Retrospective clinical data suggest superior outcomes for rhino-orbital-cerebral mucormycosis
Posaconazole
800 mg/day PO in 4 divided doses
Oral administration for salvage, maintenance/ secondary prophylaxis
Uncertain bioavailability
Must be co-administered with fatty foods, acidic beverages
Requires drug level monitoring
Avoid proton pump inhibitors
Breakthrough infections reported, not to be used as primary treatment
7 days to reach steady-state concentration
Adjunctive Treatments
1.
Hyperbaric oxygen therapy has been found to be a beneficial adjunctive therapy for mucormycosis, particularly diabetic patients with rhinocerebral disease [9]. Specifically, the increased partial pressure of oxygen achieved with hyperbaric therapy seems to improve neutrophil activity and oxidative killing by amphotericin B. In addition, high concentrations of oxygen can inhibit the growth of Mucorales in vitro and improve the rate of wound healing by increasing the release of tissue growth factors [10]. There are no clinical data to suggest appropriate pressures and duration of therapy. It is usually started during the acute phase of the illness and not as salvage therapy at 2.4–3.0 ATA range of pressures, twice daily depending on the patient’s general condition and ability to tolerate the pressures. In some successful cases up to 30 treatments have been reported [11].
2.
Iron plays a pivotal role in the pathogenesis of mucormycosis, its proliferative and angioinvasive properties. The role of deferasirox, an iron chelator without xenosiderophore activity in Mucorales, was emphasised in a recent case series from our centre. Deferasirox starves the fungus of iron which is critical for its growth and pathogenicity [12].
3.
Immune augmentation strategies are also considered in patients with refractory mucormycosis, including administration of cytokines (e.g. granulocyte-macrophage colony-stimulating factor, interferon). In select neutropenic patients, granulocyte transfusion may be a useful bridge until neutrophil recovery, although the clinical benefit remains unproven; and serious adverse effects, including pulmonary toxicity and accelerated cavitation/bleeding, have been reported in patients with opportunistic lung mycoses [5].
4.
Research reveals that both yeast and moulds have homologues of calcineurin and mTOR that play a significant part in fungal growth and proliferation. Hence, in addition to their immunosuppressive effects, the calcineurin inhibitors (tacrolimus, cyclosporin) and mTOR inhibitors (sirolimus, everolimus) have been found to have antifungal activity against both yeast and moulds [5]. The potential clinical relevance of this development needs to be further explored as knowledge of interactions between antifungal agents and immunosuppressants could improve outcomes.
5.
Another potential adjunctive agent currently under study is colistin which has been shown to exert fungicidal activity in vitro against R. oryzae by damaging cytoplasmic and vacuolar membranes, leading to the leakage of intracellular contents [13].
6.
Statins have been found to have fungicidal activity against Glomeromycota and act synergistically with other antifungal agents, such as voriconazole [14].
Management of Invasive Sinonasal Aspergillosis
Several studies involving immunocompromised patients indicate that sinonasal aspergillosis may be associated with invasive pulmonary aspergillosis or complicated by CNS or orbital invasion [15]. Despite appropriate host factors and strong clinical suspicion of possible aspergillosis, if the identification of the aetiological organism is unknown or pending, an AmB formulation should be initiated to also cover possible mucormycosis. When the diagnosis of confirmed or probable invasive aspergillosis has been established, voriconazole is considered to be the drug of choice. AmBD has also been approved for primary treatment; however, due to high rates of nephrotoxicity and excess mortality attributed to it, use of lipid formulations or alternative agents is preferred. Lipid formulations of AmB, itraconazole, posaconazole and caspofungin are advocated as salvage therapy for patients who are refractory to or intolerant of primary therapy [16, 17]. Posaconazole has been approved in the European Union for treatment of invasive aspergillosis that is refractory to an AmB formulation or to itraconazole. Micafungin and anidulafungin have shown in vitro, in vivo and clinical activity against aspergillosis but are not licensed in the USA for this indication as yet [17]. Posaconazole has also been licensed for use as prophylaxis in neutropenic patients with haematological malignancies and in allogenic haematopoietic stem cell transplant (HSCT) patients with graft-versus-host disease GVHD [16]. Table 2 shows the indications, doses and characteristics of anti-fungal agents used in the treatment of invasive aspergillosis.
The duration of therapy for invasive aspergillosis has not been clearly defined and may have to be continued for at least 3 months. Most experts prefer to continue treatment until resolution or stabilisation of all clinical and radiographic manifestations. Other factors involved in deciding treatment duration include the site of infection, level of ongoing immunosuppression and extent of disease.
A growing body of evidence suggests patient-to-patient variability in the pharmacokinetics of triazoles used for treatment or prophylaxis in invasive aspergillosis. Absorption issues (for itraconazole and posaconazole), drug-drug interactions (for all triazoles) and pharmacogenetic differences (for voriconazole) all contribute in various degrees to this variability, and hence plasma drug level monitoring may play an important role in optimising the safety and efficacy of the triazole antifungals [17].
Voriconazole is extensively metabolised in the liver by CYP2C19 drug-metabolising enzyme. This enzyme has various genetic polymorphisms which affect the rate of drug metabolism, leading to a considerable impact on the dose of drug required to achieve therapeutic plasma levels [17]. Studies reveal that 12–14 % of Indians have CYP2 C19 polymorphisms [18], and hence it may be prudent to check for these mutations especially in critical patients where attaining therapeutic drug levels may significantly affect outcome.
Table 2
Indications, doses and characteristics of antifungal agents in the management of invasive aspergillosis [17]
Drug | Dosage | Indication | Advantages | Disadvantages |
|---|---|---|---|---|
Voriconazole | 6 mg/kg IV 12hrly on day1, followed by 4 mg/kg 12hrly | Primary therapy | Oral formulation may be used as step down therapy after initial stabilisation with IV preparation | IV formulation not to be used if GFR <50. (Oral formulation may be used) |
6 mg/kg 12hrly on day1 followed by 3 mg/kg 12hrly (Oral dose 200 mg BID)
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