Medication Summary
Although aggressive surgical intervention for rhinocerebral mucormycosis is required, patients also should receive adjuvant antifungal therapy. Amphotericin B is fungistatic for Mucor molds but it carry significant risk for toxicity particularly in relation to renal function.
Amphotericin has been administered via intracavitary (ie, via catheter into the space), interstitial, and intrathecal routes. [41] 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. [42]
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
Amphotericin B is a polyene antifungal that has high affinity for ergosterol in fungal cell walls. It is the initial treatment of choice in most cases of rhinocerebral mucormycosis. [43] Lipid-based formulations should be used over amphotericin B deoxycholate due to their less nephrotoxic properties. These lipid-based formulations are liposomal amphotericin B, amphotericin B lipid complex, and amphotericin B colloidal dispersion. [44, 41] There have been reports of infusion reactions with various amphotericin B formulations but of the lipid formulations the colloidal dispersion may be most likely to cause an infusion reaction and premedication can be considered. Liposomal amphotericin B is generally more widely available of the lipid-based formulations and dosing should be 5-10 mg/kg/day. [27, 42, 45] If using amphotericin B deoxycholate, dosing should be 1 mg/kg/day. [44, 41, 42] Amphotericin B can also be applied topically to affected areas during surgical debridement. [19, 46] If this is desired treatment it should be done in concert with surgical experts. When treating with any formulation of amphotericin B renal function and electrolytes should be monitored frequently. Some of the most common electrolyte derangements are hypokalemia and hypomagnesemia.
Isavuconazole is an azole antifungal that binds to lanosterol 14-alpha-demethylase, inhibiting ergosterol formation and thereby integrity of the fungal cell well. [25] It is approved in the US for invasive mucormycosis. It can be used alone in the initial treatment of mucormycosis in cases where amphotericin is unavailable or cannot be used due to renal function. [27, 28] It also has been used in combination with amphotericin B formulations in cases of rapid progression or extensive disease. [28] Dosing consists of 372 mg daily (in PO or IV formulations) after an initial loading dose of 372 mg every 8 hours for 6 doses. Of the azoles it is less likely to cause hepatotoxicity and can actually shorten the Qtc. [27, 28]
Posaconazole is also an azole antifungal that binds to lanosterol 14-alpha-demethylase, inhibiting ergosterol formation and thereby disrupts the integrity of the fungal cell well. [25] It can be used as an alternative regimen in the treatment of mucormycosis but is not strictly FDA approved for this indication and should only be used if amphotericin B or isavuconazole are unavailable or for step down oral therapy after initial inpatient treatment. [27, 38, 47] It comes in IV, delayed release tablets and oral suspension. Tablet and IV dosing usually consists of two 300 mg doses 12 hours apart on day one and then 300 mg daily thereafter. [27] Oral suspension dosing consists of 200 mg 4 times daily until disease stabilization or improvement and then 200 mg twice daily thereafter. Posaconazole can cause hepatoxicity and QTc prolongation so these should be monitored regularly while on treatment. [27, 47]
Echinocandins, particularly caspofungin have been reported in the available case report literature as a potential combination therapy with amphotericin B. [48] They inhibit the synthesis of 1,3-beta-D-glucan thereby inhibiting fungal cell wall creation. Echinocandins should not be used on their own for mucormycosis as the Mucorales are generally resistant to them but there may be synergistic effect with amphotericin B and combination therapy can be considered in cases of rapid progression or extensive disease although further study is needed. [26, 48]
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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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Characteristic appearance of mucormycosis under the microscope.
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Patient presenting with a 10-day history of a worsening presumed bacterial sinusitis. At presentation, he was discovered to have diabetes with mild ketoacidosis.
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Upon looking to the right, the patient's left eye is fixed and dilated secondary to occlusion of the ophthalmic artery.
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In this patient, the arrow points to necrotic debris at the opening of the left nostril. The clinician can take some of this debris and place it on a slide, add a drop of KOH and examine under the microscope.
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The KOH prep from the necrotic debris of the same patient reveals the broad, nonseptate hyphae of a Mucorales species. In this case, the organism was a Rhizopus. This made the diagnosis and was accomplished within an hour of admission.
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PAS stain of an arteriole showing hyphae thrombosing the lumen.
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GMS stain showing mucor in tissue. The arrow points to a hypha that looks like a dental root. The organism is Rhizopus.
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CT scan of the same patient showing left eye proptosis and involvement of the orbit and sinuses.
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Tissue that needed to be removed from the patient to get to fully viable tissue and beyond the progress of the fungus.
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Post-operative appearance of the same patient. The patient recovered, was fitted with a cosmetic prosthesis, and went on to resume a normal life.
