Medication Summary
Although aggressive surgical intervention for rhinocerebral mucormycosis is required, patients also should receive adjuvant antifungal therapy. While the currently approved azoles are active against the phaeohyphomycoses that cause fungal sinusitis, they have no activity against Mucor molds. Amphotericin B is fungistatic for Mucor molds but is the only reliable systemic antifungal agent. Amphotericin is a highly toxic agent that is administered intravenously in its conventional form or in 1 of 3 lipid-complex formulations.
Amphotericin has also been administered via intracavitary (ie, via catheter into the space), interstitial, and intrathecal routes. [44] Reports document the use of nebulized amphotericin B for sinonasal disease. Large doses of amphotericin are required for cure of rhinocerebral mucormycosis; use the drug at the maximum dose tolerated for this life-threatening infection.
Only conventional amphotericin B is approved by the US Food and Drug Administration (FDA) as initial therapy for rhinocerebral mucormycosis (RCM); thus, it is considered the standard therapy for invasive mucormycosis. Lipid formulations are approved if the creatinine level rises to greater than 2.5 mg/dL, if adverse events are severe and persistent, or if the disease progresses despite a total dose greater than 500 mg. Experience with the lipid formulations is growing, but no head-to-head studies have been performed.
Many experts initiate therapy with a lipid-complex formulation in patients with preexisting renal impairment. Some experts argue that lipid-formulation amphotericin offers better penetration across the blood-brain barrier and into the sinus.
Isavuconazole (Cresemba) is a triazole antifungal agent. Isavuconazole is the active moiety of the prodrug isavuconazonium sulfate. It is indicated for invasive mucormycosis infection caused by Mucorales fungi (eg, R oryzae, Mucormycetes species).
Isavuconazole’s approval in March 2015 was based on an open-label noncomparative study in adult patients with invasive aspergillosis and renal impairment or in patients with invasive fungal disease caused by other rare fungi. A subpopulation of 37 patients with invasive mucormycosis treated with isavuconazole showed all-cause mortality was 38%. The efficacy of isavuconazole in the treatment of invasive mucormycosis has not been evaluated in concurrent, controlled clinical trials. [45]
Experimental antifungal agents have demonstrated in vitro activity against the Mucor molds and may offer additional treatment options in the future. The evidence for iron chelators (ie, deferoxamine) as a potential therapeutic intervention has been increasing in animal studies. While deferoxamine is an iron chelator from the perspective of the human host, it actually serves as a siderophore, delivering free iron to Mucor. Animal studies have shown that administration of iron chelators to mice with Rhizopus infection markedly improved survival and may be just as effective as liposomal amphotericin B.
Antifungal agents
Class Summary
The mechanism of action for these agents may involve the inhibition of fungal cell membrane formation and the impairment of the integrity of fungal cell membrane. The antifungals may give rise to an alteration of RNA and deoxyribonucleic acid (DNA) metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.
Amphotericin B (conventional)
Liposomal amphotericin B is a polyene antibiotic with poor oral availability. It is produced by a strain of Streptomyces nodosus and can be fungistatic or fungicidal. This agent binds to sterols (eg, ergosterol) in the fungal cell membrane, causing leakage of intracellular components and fungal cell death. Toxicity to human cells may occur via this same mechanism.
Amphotericin B lipid complex (Abelcet)
This agent is amphotericin B in phospholipid complexed form; it is a polyene antibiotic with poor oral availability. Amphotericin B is produced by a strain of Streptomyces nodosus; it can be fungistatic or fungicidal. The drug binds to sterols (eg, ergosterol) in the fungal cell membrane, causing leakage of intracellular components and fungal cell death. Toxicity to human cells may occur via this same mechanism.
Amphotericin B, Liposomal (AmBisome)
This is a lipid preparation consisting of amphotericin B within unilamellar liposomes. It delivers higher concentrations of the drug, with a theoretical increase in therapeutic potential and decreased nephrotoxicity.
Amphotericin B is a polyene antibiotic with poor oral availability. It is produced by a strain of Streptomyces nodosus, and it can be fungistatic or fungicidal. The drug binds to sterols (eg, ergosterol) in the fungal cell membrane, causing leakage of intracellular components and fungal cell death. Toxicity to human cells may occur via this same mechanism.
Amphotericin B colloidal dispersion (Amphotec)
Amphotericin B colloidal dispersion is a lipid preparation consisting of amphotericin B attached to lipid discoid structures. Amphotericin B is a polyene antibiotic with poor oral availability. It is produced by a strain of Streptomyces nodosus, and it can be fungistatic or fungicidal. The drug binds to sterols (eg, ergosterol) in the fungal cell membrane, causing leakage of intracellular components and fungal cell death. Toxicity to human cells may occur via this same mechanism.
Posaconazole (Noxafil)
Triazole antifungal agent. Blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption. Available as oral susp (200 mg/5 mL). Indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression.
Isavuconazole (Cresemba)
Triazole antifungal agent. Isavuconazole is the active moiety of the prodrug isavuconazonium sulfate. It is indicated for invasive mucormycosis infection caused by Mucorales fungi (eg, R oryzae, Mucormycetes species).
Caspofungin (Cancidas)
Shown to be effective in the treatment of rhinocerebral mucormycosis. First of a new class of antifungal drugs (glucan synthesis inhibitors). Inhibits synthesis of beta-(1,3)-D-glucan, an essential component of fungal cell wall.
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Clinical view of the face of a patient with rhinocerebral mucormycosis. Notice the cutaneous hemorrhagic ulcer on the right anterior cheek resulting from perforation of the fungus through the sinus cavity.
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A cotton blue preparation of Rhizopus species.
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A tissue hematoxylin and eosin stain of Rhizopus species.
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The appearance of a culture slant of Rhizopus species.
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Culture plates of Rhizopus species.
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Low-power photomicrograph of a Gomori methenamine silver stain of Rhizopus species.
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High-power photomicrograph of a Gomori methenamine silver stain of Rhizopus species.
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CT brain scan illustrating the appearance of cavernous sinus thrombosis.
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CT brain scan showing the appearance of a cerebral infarct.
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CT scan of a patient who is suspected of having mucormycosis shows extensive involvement of the right orbit and adjacent sinuses.
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This diabetic patient with mucormycosis presented with complete ophthalmoplegia and proptosis. Note the complete ptosis and periorbital edema on the right side.
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Characteristic appearance of mucormycosis under the microscope.
