Approach Considerations
Treatment of rhinocerebral mucormycosis includes the following:
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Reversing underlying immunocompromised states
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Administering systemic antifungals
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Performing urgent surgical débridement
No studies address the appropriate dose or formulation of antifungal therapy; therefore, a wide range of doses and formulations are used until the underlying cause of the immune suppression is under control. Antifungal therapy alone and surgical therapy by itself are ineffective.
Correcting hypoxia, acidosis, hyperglycemia, and electrolyte abnormalities is critical to the successful management of this condition. Discontinuation or maximally reducing chemotherapy and immunosuppressive therapy is desirable if clinically possible. Any steroid medication, antimetabolites, or immunosuppressants that the patient is on should also be addressed and discontinued if appropriate. [3]
Granulocyte colony-stimulating factor (GCSF) can be administered to reconstitute host defenses and to enhance leukocytosis. [27] Dexamethasone has been used to treat brain edema.
Hyperbaric oxygen (HBO) therapy has been used in an attempt to control the infection. Experts suggest that HBO may exercise fungistatic activity by reducing tissue hypoxia and acidosis. However, no studies have addressed its efficacy.
If the disease is limited to the sinus and orbit (ie, sino-orbital), débridement and systemic antifungals, combined with local amphotericin irrigation, may control the process. [28, 29]
Amphotericin B
Promptly initiate antifungal therapy. Amphotericin B is the only reliable systemic antifungal agent approved for the treatment of mucormycosis, and the highest possible tissue levels should be achieved. Remember to assess for nephrotoxicity. Other systemic toxicities include fever, nausea and vomiting, phlebitis, anemia, and electrolyte abnormalities. Liposomal amphotericin B may be more efficacious; it is less toxic, allowing higher doses of the medication to be given. [30, 31]
Consider local irrigation and packing of the areas to aid delivery of amphotericin to necrotic and poorly perfused tissues. Because poor vascular supply may prevent systemic therapy from reaching the fungus, local irrigation of infected tissue has been reported as an important adjunct to treatment and may even prevent disfiguring surgery. [30, 28, 29]
Other Antifungal Therapies
Garner and Machin investigated the use of prophylactic posaconazole (a second-generation azole antifungal) during an outbreak of mucormycosis, reporting that none of 15 children considered to be at high risk who received the drug developed mucormycosis. [32] Several studies have reported salvage therapy with posaconazole in patients with zygomycosis refractory or intolerant to other treatments. Whether posaconazole is superior to amphotericin B is still being studied. [33, 34]
Isavuconazole (Cresemba), another azole antifungal, has also been reported to be efficacious in the treatment of rhinocerebral mucormycosis that is refractory to amphotericin B and posaconazole. [35] In March 2015, it was approved by the FDA for invasive mucormycosis infections caused by Mucorales fungi (eg, Rhizopus oryzae, Mucormycetes species). [45]
Although specifically approved for the treatment of aspergillosis and candidiasis, some studies have reported the efficacy of caspofungin, an echinocandin antifungal, in combination with amphotericin B. [31, 36]
Debridement and Exenteration
The mainstay of therapy is extensive débridement of all infected and necrotic tissue, with drainage of all sinus and abscess fluid collections. Immediately obtain consultation with a surgeon. Conservative attempts to spare tissue may result in retention of the organism and subsequent treatment failure. A delay in surgery may decrease the likelihood of survival in all forms of invasive mucormycosis.
Multiple débridements are sometimes required. Because of the vasoocclusive effect of mucormycosis, the involved tissue rarely bleeds, so débridement until normal, well-perfused, bleeding tissue is encountered is ideal. Intraorbital irrigation of amphotericin B may be considered as an adjunct treatment.
Orbital exenteration, along with removal of the sinuses, may be necessary. No standard exists to guide physicians on the best timing of exenteration. [37, 38, 39]
Intraoperative frozen sections help to determine involved tissues and margins. Wide excision should ideally occur before CNS invasion. The role of endoscopic sinus surgery is unclear, although it may provide an initial diagnostic role. [40]
Surgery often is disfiguring. Consider reconstructive surgery only after complete resolution of infection. [41]
In their discussion on mucormycosis treatment, Bullock and Warwar aptly stated that patients, family members, and all involved health care personnel must understand that the physical and psychological morbidity of wide, disfiguring surgical débridement must be weighed against the life-threatening nature of the mucormycosis. [42]
Inpatient Care
Among patients who survive the initial presentation of rhinocerebral mucormycosis, the extent of the disease dictates additional inpatient care. Further surgical débridement, surgical repair, and wound care may be required. Continued medical therapy with close monitoring for drug toxicity or recurrence of disease is recommended. If eye enucleation is necessary to surgically clear the infection, postoperative reconstruction of the orbit and fitting of an eye prosthesis can be highly valuable in restoring the patient's psychosocial health. [43]
Serial imaging and evaluation is performed as needed to assess the extent of the disease and to decide if reoperation is necessary. After amphotericin B is discontinued, close assessment for recurrence needs to be performed. Treatment often is long term and disfiguring.
Outpatient and Follow-Up Care
Once the patient is stable, continue amphotericin therapy in the outpatient setting, administered either as a home infusion or in an ambulatory infusion center. At this point, the frequency of amphotericin infusion is often reduced to every other day or more, depending on renal function.
Follow-up MRI or CT scanning at the end of therapy should demonstrate significant improvement and lack of inflammation.
Treatment may require 7 months of therapy or more. Moreover, chronic presentations and late sequelae after successful therapy have been observed; therefore, patients require long-term monitoring to detect recurrence or signs of indolent residual infection.
Consultations
A multidisciplinary approach is the best. Specialties to consider include the following:
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Ophthalmology - For evaluation of ophthalmoplegia and optic neuropathy
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Oculoplastic surgery - For orbital evaluation, débridement, and reconstruction
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Otolaryngology - For biopsy or débridement of nasal/sinus cavities
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Infectious disease, internal medicine, and endocrinology - For medical management of underlying systemic etiologies
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Neurosurgery - If intracranial involvement is present
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Pharmacotherapy - Consult to assist with dosing of amphotericin B
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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.
