Rhinocerebral Mucormycosis

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Background

Rhinocerebral mucormycosis is an uncommon infection caused by the ubiquitous saprophytic fungi of the Mucorales genus. These fungi also are known as the Zygomycetes, hence the sometime name of rhinocerebral zygomycosis. Under certain conditions, the fungi can invade the sinuses, nasal passages, oral cavity, orbit, and rapidly make their way to the brain, with the result often being fatal.[1, 2, 3]

Poorly controlled diabetes is the most common underlying condition in rhinocerebral mucormycosis. Poor glucose control may lead to chronic low-grade ketoacidosis. Iron is a potent stimulator of fungal growth. In serum, with a normal pH, iron is bound and unavailable to the fungal metabolism. However, with a lower pH, iron is released from its protein carrier and becomes available to the fungi.[4]

Besides patients with poorly controlled diabetes, individuals with iron overload states, neutropenia, organ transplants, and those receiving corticosteroids are at risk. Corticosteroids hinder both glucose metabolism and neutrophil function.

Fungi of the of the Mucorales genus are angio-invasive with destruction of the endothelial cells, leading to thrombosis of blood vessels with resulting tissue necrosis. The rapidity of the fungal invasion through tissue is measured in hours and a few days.

Without rapid intervention consisting of both surgery and antifungal treatment, the prognosis is very poor.

Occurrence

The true incidence of rhinocerebral mucormycosis is unknown and varies from region to region. In the United States it is estimated to be 1.7 cases per one million population to 140 per one million in India and Pakistan. These figures may represent the state of control of underlying diabetes.

Etiology

Etiology & Pathophysiology

The saprophytic (feeding on dead and decaying organic matter) fungi of the Mucorales order are responsible for the infection. The 3 most common genera of the order are Rhizopus, Absidia, and Mucor.  However, other genera also are known to cause disease. These fungal organisms are non-septate (coenocytic) with broad and bizarre shapes.

Sustained hyperglycemia impairs glutathione activity, which results in decreased phagocytic activity of neutrophils and decreased number of neutrophils. This, combined with the chronic low level ketoacidosis releasing iron, contributes to the capacity for these fungi to become pathogenic.  In particular, Rhizopus species have a ketone reductase system enabling them thrive in an acidic and glucose rich environment. Rhizopus species, more than the other species, thrive in an iron rich milieu making them more common in iron overload states and in those receiving deferoxamine therapy.

Being ubiquitous in nature, and rapid growers, the fungi release airborne spores that are inhaled into the upper respiratory tract of the sinuses and oral cavity. In the correct physiologic and immune environment, these spores will germinate into the hyphal form and invade blood vessels, nerves, cartilage, bone, and meninges. Direct invasion of blood vessels leads to thrombosis with downstream tissue necrosis. The fungi also invade contiguous tissue and erode through bone, spread into the orbit and retro-orbital area, and then into the brain.[5, 6, 7]

Risk Factors

The majority (70%) of cases occur in individuals with diabetes mellitus. An underlying risk factor is recognized in nearly 96% of mucormycosis cases. Risk factors for rhinocerebral mucormycosis include the following[8, 9, 10] :

Especially in India, numerous cases and outbreaks of rhino-cerebral mucormycosis were noted in patients undergoing treatment for Covid. This appears to be the result of the use of high doses of corticosteroids in these patients, leading to poor glycemic control.

Iron overload

For reasons stated above, iron overload states, as seen with hemochromatosis and deferoxamine treatment in patients receiving dialysis, are risk factors.

Burns

In individuals with burns the ubiquitous spores settle onto the skin and wounds leading to localized infections. Mucormycosis generally involves only the skin and rarely results in rhinocerebral infection.

Blood dyscrasias

These are an uncommon setting for rhinocerebral mucormycosis and if seen are usually the result of prolonged neutropenia and/or treatment with high dose corticosteroids.

Transplantation

Mucormycosis has been seen in patients with solid organ or bone marrow transplantation. Most of these cases do not involve the central nervous system.

 

Prognosis

Rhinocerebral mucormycosis carries a prognosis of high morbidity and mortality (85%). Survival depends on the reversibility of underlying risk factors and the rapidity of early surgical intervention.[11, 12, 13]

Complications

Complications include the following:



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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 ke....



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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.

The infection spreads rapidly and with thromboses of the various blood vessels may lead to hemiparesis, hemiplegia, coma, and death. Also seen are CNS hemorrhage, abscess formation, and cerebritis. Orbital involvement may lead to blindness and spread to the neck may lead to airway obstruction.  In survivors, a permanent residual effect is present 70% of the time. Due to the extensive surgery often required, post-surgical disfigurement is common.

Mortality

Rhinocerebral mucormycosis has a fulminant fata clinical pattern. The mortality is directly dependent upon rapid diagnosis with early surgical debridement and exenteration. The survival rate also is improved if the infection has not progressed to cerebral involvement. If the infection reaches the brain the fatality rate can exceed 80%.

Patients who have been treated with amphotericin B and who have had orbital exenterations are more likely to survive. Patients with frontal sinus involvement and older patients have lower rates of survival.

A meta-analysis by Yohai et al indicated that the survival rate declines when interval from diagnosis to treatment is longer than 6 days.[13]

Epidemiology

The occurrence of rhinocerebral mucormycosis is dependent upon the prevalence of the different risk factors and high-risk populations. In countries and regions where there is better widespread control of diabetes, the incidence of the infection is lower. This also holds true for hematologic malignancies and organ and bone marrow transplantation.

Pathophysiology

See Etiology.

History

Presentation

The early symptoms of rhinocerebral mucormycosis are nonspecific and relate to those associated with the sinuses. As it progresses there is facial pain, headache, lethargy, and visual loss.  Findings may include proptosis or a palatal ulcer.

General symptoms of rhinocerebral mucormycosis include the following:

Facial symptoms of the disease include the following:

Nasal symptoms of rhinocerebral mucormycosis include:

Ocular symptoms include the following:

CNS symptoms include the following:

Physical Examination

Whenever a diabetic patient presents with ketoacidosis a search for the precipitating cause must be undertaken, especially if there is no or slow improvement in the first 24 hours. Particular attention must be paid to the eye and neck, oral cavity, cranial nerves, eyes and sinuses.

Nasal and palatal findings of rhinocerebral mucormycosis include the following:

Ocular findings include the following:

Neurologic findings include the following:

Approach Considerations

Workup & Evaluation

The key to a more successful outcome is an early and immediate diagnosis. Routine laboratory work is only suggestive with perhaps hyperglycemia and a mild acidosis. Blood cultures are negative in mucormycosis. Cerebrospinal fluid (CSF) may or may not be abnormal and generally is not helpful.

Finding the typical fungal organisms on direct smear, or biopsy is the cornerstone of diagnosis.



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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 ....



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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 ....

With biopsy material perform a frozen section and ask for a Gomori-methenamine silver stain (GMS) to increase the yield of observing the organisms. Permanent sections should also be done, but these take a few days to process, and time is of the essence.

Do not wait for culture results before interceding. If cultures do grow, it may take up to 48-72 hours to appear, and this may be to late. If tissue is sent for culture, the laboratory often grinds the material with a mortar and pestle before plating the sample. This grinding may damage the coenocytic hyphae leading to loss of cell contents resulting in a sterile culture. Tell the laboratory to plate the tissue directly and not grind it.

Although cultures are not useful for the early diagnosis, they may be helpful in order to perform antifungal susceptibility testing.

Direct microscopic examination can be performed to identify the hyphae of infectious agents. The following tissue preparations can be used (see the images below):



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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.

Imaging

CT scanning

Imaging studies do not make the diagnosis of rhinocerebral mucormycosis; only the observation of the hyphae on smear or histology does that.  However, imaging studies are very useful for determining the extent and involvement of the infection. This is critical preoperatively for the surgeons to plan the approach and type of surgery needed.



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CT scan of the same patient showing left eye proptosis and involvement of the orbit and sinuses.

MRI

Contrast-enhanced magnetic resonance imaging (MRI) shows findings similar to those on a CT scan. MRI also helps to define early vascular intracranial invasion and infection along peripheral nerves before clinical signs develop.

Sinus radiography

Sinus radiography reveals mucosal thickening with or without air-fluid levels. Sinus opacification, especially ethmoid or sphenoid, may be observed.

Histologic Findings

Direct microscopic examination can be performed to identify the hyphae of infectious agents. The following tissue preparations can be used (see the images below):

Frozen-tissue biopsy at the time of surgery should demonstrate tissue invasion by nonseptate hyphae with right- or obtuse-angle branching. In contrast, Aspergillus hyphae are thinner and less septated and can cause granulomas. The tissue culture result is positive for the fungus. Histology demonstrates invasion along the elastic lamina of blood vessels with subsequent thrombosis and tissue necrosis.



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Characteristic appearance of mucormycosis under the microscope.

Approach Considerations

Treatment includes the following:



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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.

Treatment of rhinocerebral mucormycosis requires a multipronged approach consisting mainly of surgical interventions, systemic antifungals, and reversal of any underlying predisposing factors (e.g. diabetic ketoacidosis).[1, 4, 7, 9, 15, 16]  Antifungals alone are inadequate for the treatment of mucormycosis. Surgical evaluation should be pursued urgently when concerned for mucormycosis in a patient, as aggressive debridement and even resection or exenteration of affected tissues is required for adequate source control.[7, 13, 17, 16]  Local tissue irrigation with Amphotericin B lipid-based formulations may also be beneficial during surgical interventions.[7]

In the treatment of mucormycosis, particular attention should be given to correcting any predisposing factors. Chief of these factors discussed in the literature are often diabetic ketoacidosis (DKA) and hyperglycemia.[18, 19, 17]  DKA poses a significant risk to affected patients as acidosis increases circulating iron which the Mucorales feed off of and decreases neutrophil activity against fungi, broadly speaking.[20] Additionally, ketones, particularly beta-hydroxybutyrate, impair phagocytosis and T cell proliferation.[17, 21, 22, 23, 24]

Hyperglycemia on its own also impairs phagocytosis, T cell proliferation, and interferon gamma production, all of which are integral parts of the body's defenses against bacterial and fungal pathogens.[23]

Other Antifungal Therapies

The Mucorales are largely resistant to other antifungal agents but more recent case reports and series have demonstrated efficacy with the use of azole agents isavuconazole or posaconazole.[25, 26]  These come in both intravenous (IV) and oral formulations and have been used as step down therapies after initial treatment with amphotericin B formulations and surgical interventions.[27] There is emerging data on the use of these agents as initial therapies when amphotericin cannot be used due to renal compromise but amphotericin remains the initial antifungal of choice.[27] Additionally, case reports and series have shown possible benefit with combination therapy of amphotericin with isavuconazonium sulfate or posaconazole in patients with extensive disease or rapid progression but again further studies are needed.[28]  

Isavuconazonium sulfate is indicated for invasive mucormycosis caused by Mucorales fungi (eg, Rhizopus oryzae, Mucormycestes species) in patients aged 1 year and older. 

The Mucorales have throughout the available literature largely been considered resistant to echinocandins (eg, anidulafungin, caspofungin), however both animal studies and human case series have suggested a potential benefit to combination treatment with an echinocandin and amphotericin.[29] ) It is thought that the echinocandin may help disrupt beta glucan cross linking in the fungal cell wall allowing better delivery of amphotericin B but further studies are needed to compare amphotericin treatment alone to combination therapy.

Debridement and Exenteration

Surgical evaluation is a mainstay of treatment for mucormycosis and must be pursued urgently early in the treatment course. The Mucorales can induce a vasculitis picture in affected tissues and cause occlusion of larger blood vessels leading to necrotic tissues that must be extensively debrided.[21, 30, 31, 15, 32]  No clear guidelines exist as to the extent of debridement indicated in cases of mucormycosis other than that debridement should occur until normal tissues with good blood flow and clear margins on pathology evaluation are observed.[19, 16, 33]  Multiple debridements are often required and the number and extent of debridements should be individualized to each patient and based on serial imaging, often on a weekly basis, to assess depth and extent of infection as well as overall clinical response to antifungals as well.[27, 16, 33]  Often, exenteration of an affected orbit, oral, or sinus structures may be required. Craniectomies and lobectomies may also be indicated based on the extent of infection. These can be very disfiguring procedures and once clear margins are obtained, patients should be evaluated for reconstruction with plastic surgery.[33]

Inpatient Care

Patients with rhinocerebral mucormycosis often require initial intensive care such as intubation. Close attention must also be paid to renal function when using amphotericin B and to liver function when using azoles, although overall isavuconazole is less hepatotoxic.[34, 35]  Metabolic derangements such as hypokalemia, hypomagnesemia, and metabolic acidosis are common during treatment with amphotericin B and require aggressive electrolyte repletion and temporizing measures.[34, 35]  Azoles are also known to prolong Qtc, but isavuconazole has been reported to shorten Qtc.[28]   Periodic electrocardiogram evaluations should be done for monitoring.[25]

Outpatient and Follow-Up Care

Once patients have been discharged, they will require continued treatment for months to years. There are no clearly defined endpoints to antifungal treatment and the total course duration must be individualized to each patient.[27]   Because of the extent of debridement and resection of affected tissues, establishing end points of antifungal treatment can be difficult and this decision making should continue to involve a multidisciplinary team of infectious disease physicians and surgeons. Various durations of antifungal treatment have been reported in case studies with some courses as long as 2-3 years, however most of the literature suggests at least 6 months of antifungal therapy after stabilization and discharge from the hospital.

Patients will also need close follow up with wound care teams and surgeons for continued monitoring of wounds and areas that were debrided. Reconstruction with plastic surgery and fitting for facial prosthetics should also be offered.

It is also important to recognize that mucormycosis can recur so frequent follow up and correction of any underlying predisposing factors such as poorly controlled diabetes is important.[18, 19, 17]  Antifungal salvage therapies discussed in the literature mainly consist of switching to a different antifungal class than was last used.[27] For instance, if Isavuconazole was primarily used in the initial treatment, amphotericin B formulations should be used for salvage and vice versa. Any further guidelines for medical salvage therapy are not well defined in the literature.

Consultations

A multidisciplinary approach is the best. Specialties to consider include the following:

Additional Considerations

 

 

Treatments of Unclear Benefit

Because of the high morbidity and mortality of mucormycosis infections, multiple other supplemental therapies have been pursued mostly in small cohorts of patients or individual case reports. Because many of these additional treatments have not been well studied, they are of uncertain benefit but can be considered, particularly in rapidly progressive cases.

Hyperbaric oxygen therapy has been suggested as a treatment that can be fungistatic at lower pressures of 1-3 atmospheres and fungicidal at higher pressures of 10 atmospheres. It also reduces tissue hypoxia and acidosis and has been theorized to potentially increase the efficacy of amphotericin B, but further studies are required to evaluate this potential.[23, 36]

Colony stimulating factors have been used in cases of neutropenic patients with mucormycosis to correct the neutropenia but there is limited evidence to recommend this in all cases.[26, 16]

Iron chelation has also been theorized at various times as a therapy that should theoretically reduce circulating iron for use by the Mucorales but several studies have shown that various chelating agents, mainly deferoxamine and some reports of deferasirox, may actually paradoxically increase available circulating iron.[20, 35, 37, 38]  As such iron chelation should not be used at this time and correction of other factors that may promote increased circulating iron, such as hyperglycemia and DKA, should be done.[39]    

Guidelines Summary

There are no definitive guidelines within the United States on the treatment of rhinocerebral mucormycosis. However, the Infectious Disease Society of America did give some guidance in 2014 on skin and soft tissue infections in the setting of primary cellular immunodeficiencies and neutropenic patients in the setting of malignancy.[40]  These recommendations include the use of lipid-based formulations of amphotericin as first line therapy, potential role for posaconazole as an adjunctive or alternative anti-fungal if toxicity or intolerance with amphotericin arises, and the recommendation for dermatology and surgery consultations.[40]

In terms of more definitive guidelines available elsewhere in the world, in 2019 the European Confederation of Medical Mycology and the Mycoses Study Group Education and Research Consortium published global guidelines in The Lancet for treatment of mucormycosis. This document includes multiple recommended treatment algorithms depending on availability of certain anti-fungal agents in different areas of the world. The main guidelines herein state that urgent surgical evaluation and debridement of affected areas is required for adequate treatment. Anti-fungal treatment alone is inadequate. Of the available antifungals, liposomal amphotericin B is the initial treatment of choice and should be dosed at 5-10 mg/kg/day. A starting dose of 10 mg/kg/day is recommended for brain involvement and for patients with a history of solid organ transplant. In patients with renal compromise or intolerance to amphotericin formulations, isavuconazole IV 200 mg every 8 hours on Days 1 and 2, followed by 200 mg per day starting on Day 3 can be used.

Additionally, posaconazole IV 300 mg every 12 hours on Day 1, followed by 300 mg per day starting on Day 2 is another alternative to amphotericin if isavuconazole is unavailable. No definitive answer as to treatment duration has been established in any articles or guidelines thus far and should be individualized to each patient. However, de-escalation of treatment to an oral regimen should be based on follow up imaging which should be done typically on a weekly basis. More urgent imaging should be done if there are concerns for worsening disease. If the burden of disease appears stable or there is evidence of response to treatment on follow up imaging studies, then patients can be considered for de-escalation of therapy to oral formulations of isavuconazole or posaconazole (if isavuconazole is unavailable). Again, de-escalation of therapy should be individualized to each patient.[27]

It is important to note that in the United States, Isavuconazole is approved by the FDA in a different dose of 372 mg oral or intravenous every 8 hours for 6 doses (loading dose) and then 372 mg daily thereafter.

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 carries 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.

Amphotericin B liposomal (AmBisome)

Clinical Context:  Consists of a mixture of phosphatidylcholine, cholesterol, and distearoyl phosphatidylglycerol that arrange into amphotericin B–containing unilamellar vesicles in aqueous media. Considered first-line therapy for mucormycosis. 

Amphotericin B phospholipid complex (Abelcet)

Clinical Context:  Amphotericin B lipid complex is amphotericin B in phospholipid complexed form. This is an alternate therapy to liposomal amphotericin B.

Amphotericin B deoxycholate (Amphotericin B (conventional))

Clinical Context:  Less commonly used than the lipid formulations because of higher rates of nephrotoxicity but less costly and more widely available.

Isavuconazonium sulfate (Cresemba, Isavuconazole)

Clinical Context:  Isavuconazole is a triazole antifungal agent. Isavuconazole is the active moiety of the prodrug isavuconazonium sulfate. It is indicated in patients aged 1 year and older for invasive mucormycosis caused by Mucorales fungi such as Rhizopus oryzae and Mucormycetes species. 

Posaconazole (Noxafil)

Clinical Context:  Used off-label for salvage therapy in patients intolerant to amphotericin B or as step-down therapy after initial polyene treatment. 

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 also can 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 United States 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 also is an azole antifungal that binds to lanosterol 14-alpha-demethylase, inhibiting ergosterol formation, and thereby disrupts the integrity of the fungal cell wall.[25] It can be used as an alternative regimen in the treatment of mucormycosis but is not strictly FDA approved for this indication and only should be used if amphotericin B or isavuconazole are unavailable or for stepdown 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 1 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]

Author

Thomas M Kerkering, MD, FACP, FIDSA, Professor of Medicine with Tenure, Division of Infectious Diseases, Virginia Tech Carilion School of Medicine; Adjunct Professor, Department of Population Studies, Masters of Public Health Program, Virginia Tech University, School of Veterinary Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Sydney A Stayrook, DO, Fellow, Division of Infectious Diseases, Virginia Tech Carilion School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Pranatharthi Haran Chandrasekar, MBBS, MD, Professor, Chief of Infectious Disease, Department of Internal Medicine, Wayne State University School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Cynthia C Lazzaro, DO, Physician

Disclosure: Nothing to disclose.

Michael T Yen, MD, Professor and The Sarah Campbell Blaffer Chair in Ophthalmology, Division of Ophthalmic Plastic, Lacrimal, and Orbital Surgery, Cullen Eye Institute, Medical Director, Alkek Eye Center, Co-Director, BCM Aesthetics, Program Director, ASOPRS Fellowship, Baylor College of Medicine

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Sling Therapeutics; Ipsen Innovation<br/>Received research grant from: Viridian Therapeutics.

Natalie Ana Baugh, California State University, Long Beach

Disclosure: Nothing to disclose.

William P Baugh, MD, Assistant Clinical Professor of Dermatology, Western University of Health Sciences; Medical Director, Full Spectrum Dermatology; Consulting Staff, Department of Dermatology, St Jude Medical Center

Disclosure: Nothing to disclose.

Acknowledgements

Kenneth C Earhart, MD Deputy Head, Disease Surveillance Program, United States Naval Medical Research Unit #3

Kenneth C Earhart, MD is a member of the following medical societies: American College of Physicians, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, and Undersea and Hyperbaric Medical Society

Disclosure: Nothing to disclose.

Thomas M Kerkering, MD Chief of Infectious Diseases, Virginia Tech Carilion School of Medicine

Thomas M Kerkering, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Public Health Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Medical Society of Virginia, and Wilderness Medical Society

Disclosure: Nothing to disclose.

John M Leedom, MD Professor Emeritus of Medicine, Keck School of Medicine of the University of Southern California

John M Leedom, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society for Microbiology, Infectious Diseases Society of America, International AIDS Society, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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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.

Upon looking to the right, the patient's left eye is fixed and dilated secondary to occlusion of the ophthalmic artery.

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.

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.

PAS stain of an arteriole showing hyphae thrombosing the lumen.

GMS stain showing mucor in tissue. The arrow points to a hypha that looks like a dental root. The organism is Rhizopus.

CT scan of the same patient showing left eye proptosis and involvement of the orbit and sinuses.

A tissue hematoxylin and eosin stain of Rhizopus species.

A cotton blue preparation of Rhizopus species.

The appearance of a culture slant of Rhizopus species.

Culture plates of Rhizopus species.

Low-power photomicrograph of a Gomori methenamine silver stain of Rhizopus species.

High-power photomicrograph of a Gomori methenamine silver stain of Rhizopus species.

Characteristic appearance of mucormycosis under the microscope.

Tissue that needed to be removed from the patient to get to fully viable tissue and beyond the progress of the fungus.

Post-operative appearance of the same patient. The patient recovered, was fitted with a cosmetic prosthesis, and went on to resume a normal life.

A cotton blue preparation of Rhizopus species.

A tissue hematoxylin and eosin stain of Rhizopus species.

The appearance of a culture slant of Rhizopus species.

Culture plates of Rhizopus species.

Low-power photomicrograph of a Gomori methenamine silver stain of Rhizopus species.

High-power photomicrograph of a Gomori methenamine silver stain of Rhizopus species.

Characteristic appearance of mucormycosis under the microscope.

Patient presenting with a 10-day history of a worsening presumed bacterial sinusitis. At presentation, he was discovered to have diabetes with mild ketoacidosis.

Upon looking to the right, the patient's left eye is fixed and dilated secondary to occlusion of the ophthalmic artery.

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.

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.

PAS stain of an arteriole showing hyphae thrombosing the lumen.

GMS stain showing mucor in tissue. The arrow points to a hypha that looks like a dental root. The organism is Rhizopus.

CT scan of the same patient showing left eye proptosis and involvement of the orbit and sinuses.

Tissue that needed to be removed from the patient to get to fully viable tissue and beyond the progress of the fungus.

Post-operative appearance of the same patient. The patient recovered, was fitted with a cosmetic prosthesis, and went on to resume a normal life.