Mucormycosis (Zygomycosis)

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Background

Mucormycosis, previously called zygomycosis, refers to several different diseases caused by infection with fungi belonging to the order Mucorales. Rhizopus species are the most causative organisms of this group. In descending order, the other genera with mucormycosis-causing species include Mucor, Cunninghamella, Apophysomyces, Lichtheimia (formerly Absidia), Saksenaea, Rhizomucor, and other species.[1, 2]

Most mucormycosis infections are life-threatening. Risk factors such as diabetic ketoacidosis and neutropenia are present in most cases. Severe sinusitis, complicated by brain abscess, is the most common presentation. Pulmonary, cutaneous, and gastrointestinal (GI) infections also are recognized.

Successful mucormycosis treatment requires correction of the underlying risk factor(s), antifungal therapy (traditionally with a polyene), and aggressive surgery.



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Postmortem photograph of a woman with diabetes and left rhinocerebral mucormycosis complicating ketoacidosis. Rhizopus oryzae was the causative organi....

See also Pediatric Mucormycosis and Rhinocerebral Mucormycosis.

Etiology and Pathophysiology

Risk factors

Immunocompromising conditions are the main risk factors for mucormycosis. Patients with uncontrolled diabetes mellitus, especially those with ketoacidosis, are at high risk. Other high-risk groups include patients with cancer, especially those who are neutropenic and those receiving broad-spectrum antibiotics, and individuals receiving immunosuppressive agents, including oral or intravenous steroids and tumor necrosis factor (TNF)-alpha blockers (patients with rheumatoid disorders). In addition, patients with hematologic cancer who have opportunistic cytomegalovirus (CMV) infections and graft versus host disease (GVHD) are at an increased risk. Prior receipt of voriconazole is another risk factor for mucormycosis.[3]

Extreme malnutrition is linked to mucormycosis, especially the gastrointestinal (GI) form. Iron is a growth stimulant for Mucorales; older iron chelators such as deferoxamine and all causes of iron overload are additional risk factors for mucormycosis. Trauma and the use of contaminated medical supplies over wounds are associated with cutaneous mucormycosis. Additionally, nonsterile tape and contaminated wooden splints are other risk factors for cutaneous diseases.[4, 5]  Such cases are associated with trauma/surgery or the presence of a preexisting wound or intravascular line. Patients with burns and those who use intravenous drugs are at a higher risk.

Some patients with mucormycosis have no identifiable risk factors.[6, 7] Invasive mucormycosis also has been associated with health-care associated outbreaks and natural disasters.[8, 9, 10, 11, 12]

Pathophysiology

Mucorales are ubiquitous fungi that are commonly found in soil and in decaying matter. Rhizopus can be found in moldy bread. The major route of infection is via inhalation of conidia; other routes include ingestion and traumatic inoculation (see the images below). Ingestion leads to GI disease and occurs primarily among malnourished patients but also can occur after ingesting non-nutritional substances (pica).

Mucoraceae are molds in the environment that become hyphal forms in tissues. Once the spores begin to grow, fungal hyphae invade blood vessels, producing tissue infarction, necrosis, and thrombosis. When spores are deposited in the nasal turbinates, rhinocerebral disease develops (see Rhinocerebral Mucormycosis); when spores are inhaled into the lungs, pulmonary disease develops; when ingested, GI disease ensues; and when the agents are introduced through interrupted skin, cutaneous disease develops.

The virulence factor involved in the pathogenesis of Mucorales is high affinity iron permease (FTR1), allowing Mucorales survival in iron-poor environments.[13, 14, 15]  Spore coat protein (Cot H) present on the surface of Mucorales results in impaired host defense[13] ; ADP-ribosylation factor plays a significant role in the growth of Mucorales.[13]  Neutrophils are the key host defense against these fungi; thus, individuals with neutropenia or neutrophil dysfunction (eg, diabetes, steroid use) are at highest risk.[16] Few cases of mucormycosis have been reported in patients with acquired immunodeficiency syndrome (AIDS), suggesting that the host defense against this infection is not primarily mediated by cellular immunity.

Mucormycosis should be considered in the differential diagnosis of a necrotic-appearing wound or one with an inadequate response to antibiotic treatment.[17, 18, 19]  External factors, such as toxins produced by bacterial endosymbiosis, can lead to endothelial disruption, resulting in fungal virulence.[13, 20, 21]  Additionally, voriconazole exposure by a unknown mechanism and not due to selective pressure, allows for invasive mucormycosis.[13, 22]



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The right eye of an immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation....



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The right eye of an immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation....



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Brain MRI (sagittal view) in a patient with uncontrolled diabetes who presented with progressive right eye pain and facial swelling. He underwent mult....

Epidemiology

United States

Mucormycosis is rare, and its incidence is difficult to calculate accurately. Further, since mucormycosis is not a reportable disease, the true incidence is unknown. An estimated burden of mucormycosis in United States is 3.0 cases per 1 million people, increased from 1.75 cases per 1 million people in the United States annually.[23, 24, 25]  A retrospective study among 560 hospitals with 104 million patients estimated the prevalence of mucormycosis-related hospitalizations at 0.12 per 10,000 discharges.[25, 26]  A prospective surveillance for invasive fungal infections conducted at 23 transplant centers from 2001-2006 reported an incidence of 0.29% for hematopoietic stem cell transplant (HSCT) and 0.07% for solid organ transplant.[25, 26]  A rise in mucormycosis incidence was seen in patients with hematological malignancy per 100 autopsies, from 0.006 cases (1989-1993) to 0.018 cases in (2004-2008).[25, 27]

The incidence of mucormycosis appears to be increasing secondary to rising numbers of immunocompromised persons. There are also increasing reports of breakthrough mucormycosis in the setting of antifungal prophylaxis or treatment (eg, voriconazole, echinocandins) that is effective against most fungi, such as Aspergillus, but not mucormycosis. With improvements in early diagnosis via modalities such as matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF), polymerase chain reaction (PCR), and 18s rRNA sequencing, it has been suggested that mucormycosis is the cause of more than 10% of invasive fungal infections.[28, 29]

Additionally, several cases of cutaneous mucormycosis due to the mucormycete Apophysomyces trapezi­formis were described among wound-injured victims from a tornado.[18, 30, 31]

International

A rise in mucormycosis cases has been seen globally; the estimate of mucormycosis rose to 910,000 cases globally.[25, 32, 33]  Increased cases were noted in Asia and Europe. A multicenter study from Spain estimating prevalence of mucormycosis reported 0.43 cases per million population/year.[25, 34]  Similarly, a population-based study conducted nationwide in France reported an increase in prevalence in 1997 to 2006, 0.7 cases to 1.2 per million cases, respectively.[25, 35] A single centre study from India reported a rise in mucormycosis cases from 24.7 cases to 89 cases per year.[25, 36]  A study conducted in multiple ICUs in India reported high burden of mucormycosis, detected in 14.4% of patients.[25, 37]

Prognosis

Prognosis and survival depend on early diagnosis and timely initiation of treatment.[38]  Mortality of mucormycosis varies between 40-80%, despite advances in treatment; mortality depends on the site of infection.[39] Higher mortality of 80% is seen in among patients with disseminated disease to CNS[39] ; rhino-orbital-cereberal mucormycosis has a mortality rate of 25-62%. Among patients with orbital involvement, early diagnosis through nasal endoscopic examination and rapid initiation of treatment are important in improving disease specific mortality.[13, 40, 41, 42]  Rapid diagnosis and early surgical debridement lead to lower mortality; this can be achieved among patients with localized sinus and skin disease.[39, 43, 44]

Mortality also is high among patients with gastrointestinal manifestations, as diagnosis often is achieved late due to non-specific presentation.[39, 45]  Pulmonary mucormycosis carries a mortality rate of 57.1%, however mortality has improved over time due to combination of medical and surgical treatment.[46]

COVID-19 and Mucormycosis

The COVID-19 pandemic, caused by severe SARS-CoV-2, has affected 177 million people worldwide and accounted for 3.82 million deaths as of June 2021. COVID-19 disease can be complicated by secondary bacterial infection; however, reports of invasive fungal infection (COVID-19-associated pulmonary aspergillosis, pneumocystosis, and mucormycosis) are rising.[47]  The incidence of COVID-19-associated mucormycosis (CAM) has increased in India, with more than 20,000 cases reported.[48, 49, 50, 51]

COVID-19 has a predisposition to cause extensive lung damage, which promotes colonization and infection of invasive fungi of airway, sinuses, and lung.[48, 52, 53, 54, 55]  Alteration in T cell immunity, use of steroids, and broad-spectrum antibiotics are additional risk factors for acquiring invasive fungal infection.[48, 52, 53, 54, 55]  COVID-19 disrupts iron metabolism, resulting in high ferritin state and increasing intracellular iron, which causes tissue damage. This causes more iron to be released into the circulation, and it is this increase in free iron that is a risk factor for mucormycosis.[47]  

Diabetes mellitus previously has been described in this chapter as a risk factor for mucormycosis. Patients with diabetes and infected with SARS-CoV2 are at increased risk for mucormycosis. High expression of ACE-2 receptors in pancreatic islets caused by SARS-CoV-2 results in insulin resistance leading to poorly controlled diabetes, further increasing the risk for mucormycosis.

A retrospective study conducted in India from September-December 2020 reported a 2.0 fold rise in 2020 compared to 2019 of COVID-19 mucormycosis, with prevalence of 0.27% among hospitalized COVID-19 patients; the most common clinical manifestation was rhino-orbital form.[56]  Case fatality at 12 weeks was 45.7% with no difference in mortality among COVID-19 and non-COVID-19 patients.[56]

Please refer to the Treatment section for details on medication dosing.

History and Physical Examination

Based on anatomic localization, mucormycosis can be classified as 1 of 6 forms: (1) rhinocerebral, (2) pulmonary, (3) cutaneous, (4) gastrointestinal, (5) disseminated, and (6) uncommon presentations.[23] Manifestations of mucormycosis depend on the location of involvement.

Rhinocerebral disease

Rhinocerebral disease may manifest as unilateral, retro-orbital headache, facial pain, numbness, fever, hyposmia, and nasal congestion, which progresses to black discharge. Initially, mucormycosis may mimic bacterial sinusitis.[57, 58]

Late symptoms that indicate invasion of the orbital nerves and vessels include diplopia and visual loss. These late symptoms indicate a poor prognosis and usually are followed by a reduced level of consciousness. Most patients with rhinocerebral disease have diabetes (especially with ketoacidosis) or have malignancies with associated neutropenia and may be receiving broad-spectrum antibiotics.



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An immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces....

Orbital swelling and facial cellulitis are progressive. Necrotic eschars with black purulent discharge can be noted in the nasal cavity, on the hard palate, or on the face. Although these lesions suggest mucormycosis, their absence does not exclude the possibility of this disease.

Proptosis, ptosis, chemosis, and ophthalmoplegias indicate retro-orbital extension. Cranial nerves V and VII are the most commonly affected. Loss of vision can occur with retinal artery thrombosis.

A reduced level of consciousness state denotes brain involvement.

Pulmonary disease

Pulmonary mucormycosis manifests nonspecifically as fever, dyspnea, and cough. Hemoptysis may occur in the presence of necrosis. Most patients with pulmonary disease have hematologic malignancies and a history of neutropenia.[59] Pulmonary disease frequently occurs with concurrent sinus involvement.

The signs of pulmonary disease are nonspecific. Fevers often are noted. The lung examination may reveal decreased breath sounds and rales. Occasionally, chest wall cellulitis can occur adjacent to the underlying parenchymal disease, given the ability of this infection to cross tissue planes.

Cutaneous disease

Cutaneous disease manifests as cellulitis, which progresses to dermal necrosis and black eschar formation. The progressive black necrotic lesion of cutaneous mucormycosis reflects the vascular invasion characteristic of all forms of the disease.

Patients with skin disease may have had previous trauma or been exposed to contaminated medical equipment, such as bandages.[4, 5] Rare cases have occurred at catheter sites or insulin or illicit drug injection sites.

Gastrointestinal

Gastrointestinal (GI) mucormycosis usually affects severely malnourished individuals. Some case reports have described GI mucormycosis in patients who have undergone organ transplant (eg, renal transplant). This infection may occur throughout the GI tract but most commonly affects the stomach, ileum, and colon. Again, the presentation is nonspecific, with abdominal pain, distention, nausea, and vomiting. Hematochezia[60] or obstruction[61] may occur. Some patients have tenderness to palpation or a mass. Rupture may lead to signs of peritonitis.

Disseminated disease

Other disseminated forms of mucormycosis may involve the kidneys, bones, heart, and other locations, with symptoms attributed to these organ systems. Peritonitis in the setting of continuous ambulatory peritoneal dialysis also has been described.[62]

Other forms including central nervous system

Central nervous system (CNS) disease manifests as headache, decreasing level of consciousness, and focal neurologic symptoms/signs including cranial nerve deficits. Patients with CNS involvement may have a history of open head trauma, intravenous drug use, or malignancy.

Approach Considerations

Timely diagnosis is paramount in cases of mucormycosis.[63]  Diagnosis of mucormycosis requires positive culture and histopathological changes. However, there are certain instances where culture may not be available or results may be negative; in such instances, diagnosis is made by histopathology alone.[64]  

Patients with suspected or confirmed mucormycosis should be treated as a medical emergency; they should be referred to institutions that can perform highest level of care.[39]  The European Confederation Medical Mycology (ECMM) society lays out a diagnostic approach based on symptoms and underlying risk factors[39] :

Laboratory Tests

A complete blood cell (CBC) count should be obtained to assess for neutropenia. A chemistry panel that includes blood glucose, bicarbonate, and electrolytes is useful to monitor homeostasis and correction of acidosis. An arterial blood gas (ABG) study can help determine the degree of acidosis and guide corrective therapy. Iron studies may be indicated to assess the presence of iron overload as shown by high ferritin levels and a low total iron-binding capacity. In cases of central nervous system (CNS) involvement, cerebrospinal fluid (CSF) findings may include elevated protein levels and a modest mononuclear pleocytosis. CSF fungal stain and cultures typically are sterile. A CT scan should precede a lumbar puncture to assess for evidence of space occupying lesions, which could lead to herniation.

Blood cultures can be obtained; however, they usually are negative despite the angioinvasive nature of the organism. Blood cultures may be useful to detect bacteremia in addition to Mucorales infection. One study of pulmonary mucormycosis identified concurrent bacteremia as an independent predictor of 28-day mortality.[59] There are no specific biomarkers to identify mucormycosis. Bronchoalveolar lavage (BAL) of fluid culture has a low yield, with a sensitivity of 20-50%. Antigen tests (beta-D-glucan or galactomannan) are not useful for detecting this infection.[28]  Guidelines from the European Confederation of Medical Mycology (ECMM) strongly suggest obtaining a culture of the specimen to identify the organism.[39] Cultures should be incubated at 30°C and 37°C; direct microscopy should be done mainly to identify septation, branching angle, and hyphal width.[39]  The ECMM guidelines strongly recommend susceptibility testing to expand epidemiological knowledge, although general use of standard methods for susceptibility testing for Mucorales are marginally reinforced as there are no cut-off values established by the European Committee on Antimicrobial Susceptibility testing (EUCAST) or Clinical and Laboratory Standards Institute (CLSI).[39]

Molecular-based testing is moderately supported; fresh tissue is preferred over paraffin tissue, as formalin damages DNA.[39]  The use of molecular-based testing has moderate support only, due to lack of standardization. The use of quantitative polymerase chain reaction (qPCR) for detection of circulating DNA from common Mucorales species (Lichtheimia species, Rhizomucor species, and Mucor/Rhizopus species), although not yet commercially available, has been described and appears promising for the early diagnosis of mucormycosis in high-risk patients.[65, 66] In a retrospective analysis of 44 cases, qPCR identification was fully concordant with that of culture. Assay positivity was observed at an average of 9 days, at least 2 days before positive imaging findings. Development of PCR negativity after treatment was associated with higher survival rates (48% vs 4%), suggesting that this modality eventually could be used for treatment monitoring.[67] DNA detection can be looked for in CSF or BAL clinical samples.[68, 69, 70, 71]

 

Radiologic Studies

Imaging should be used to investigate areas of suspected mucormycosis. Because subclinical disease may be present, a thorough history and physical examination are recommended in addition to imaging (CT) of the brain, sinuses, chest, and abdomen.[72]

Rhinocerebral infections

Plain films may show sinus involvement with mucosal thickening, air-fluid levels, and/or bony erosions.[58]

Head and facial CT imaging should be used as the initial investigation in rhinocerebral infections. CT scans may show sinusitis of the ethmoid and sphenoid sinuses, as well as orbital and intracranial extension. As the disease progresses, bony erosion may occur and the infection may spread into the brain or orbits. Additionally, because mucormycosis organisms have a predilection for vascular involvement, thromboses of the cavernous sinus or internal carotid artery may occur.[73] All areas of involvement must be understood, to plan the extent of surgical debridement.

Magnetic resonance imaging (MRI) of the facial sinuses and brain is superior to a CT scan in assessing the degree of tissue invasion and need for ongoing surgery.



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Rhino-orbital-cerebral mucormycosis in a patient with SARS-CoV-2 infection. Courtesy of Dr Sujata Rege.

Pulmonary disease

Chest radiography often is the initial test performed; however, its sensitivity and specificity for mucormycosis are low. Nonenhanced high-resolution CT scanning is the imaging modality of choice.[28] The most common findings include pleural effusion, nodules, consolidation, and ground-glass opacities.[59] With disease progression, consolidation can become multilobar. The reverse halo sign (ie, a nodule with central ground-glass opacity and a ring of peripheral consolidation) strongly suggests pulmonary mucormycosis and rarely is seen in invasive aspergillosis.[74] The halo sign (ie, a nodule surrounded by ground-glass opacity) represents a lung infarct surrounded by alveolar hemorrhage; it is associated with invasive mold infections but can be present in bacterial or viral infections and noninfectious lung disease (eg, Wegener granulomatosis, sarcoidosis, malignancy).[28] Other findings such as the air crescent sign and hypodense sign are less specific and may occur in later stages. 



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Chest computed tomography (CT) scan showing pulmonary mucormycosis with left basal consolidation and widespread nodules due to Rhizopus oryzae infecti....



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Pulmonary mucormycosis in a patient with SARS-CoV-2 infection. Courtesy of Dr Sujata Rege.

Gastrointestinal disease

In gastrointestinal (GI) disease, abdominal CT scans may show a mass associated with the GI tract. Esophagogastroduodenoscopy (EGD) may show areas of tissue necrosis amenable to biopsy.

Central nervous system

CT scanning or MRI of the central nervous system may reveal abscesses (especially in the setting of intravenous drug use) or extension of rhinocerebral disease into the brain. Cavernous and, less commonly, sagittal sinus thrombosis also may be seen. 



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Brain MRI (sagittal view) in a patient with uncontrolled diabetes who presented with progressive right eye pain and facial swelling. He underwent mult....

Biopsy and Histologic Features

Biopsy of the involved tissue is the most definitive means of establishing a diagnosis of mucormycosis. A rapid histologic assessment of a frozen tissue section should be performed to promptly institute surgical and medical management for the infection.

Biopsy of necrotic tissue

Biopsy of necrotic tissue may be obtained from nasal, palatine, lung, cutaneous, gastrointestinal (GI), or abscess wall site.

Stains of fixed tissues with hematoxylin and eosin (H&E) or specialized fungal stains, such as Grocott methenamine-silver (GMS) or periodic acid-Schiff (PAS) stains, show pathognomonic broad (typically 6- to 25-µm diameter), irregular, ribbonlike, nonseptate (or sparsely septate) hyphae with irregular branching occurring at 45-90º.[75] Vascular invasion and necrosis are the characteristic consequences of the infective process. Thus, neutrophil infiltration, vessel invasion, and tissue infarction often are observed. A granulomatous reaction may be seen.



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Histologic findings from an immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic ino....

Culture of biopsy samples generally is required to determine the species of Mucorales. Do not crush or grind the specimen, because the nonseptate hyphae are prone to damage. Growth usually occurs in 2-3 days. The genus and species are determined via examination of the fungal morphology (ie, the presence and location of the rhizoids). Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) also can provide rapid and accurate identification at the species level but requires a reference database. 18s ribosomal RNA (rRNA) sequencing may provide genus-level identification, even if tissue damage precludes fungal growth.[28]

 

Laboratory Studies

A complete blood cell (CBC) count should be obtained to assess for neutropenia. A chemistry panel that includes blood glucose, bicarbonate, and electrolytes is useful to monitor homeostasis and correction of acidosis. An arterial blood gas (ABG) study can help determine the degree of acidosis and guide corrective therapy. Iron studies may be indicated to assess the presence of iron overload as shown by high ferritin levels and a low total iron-binding capacity. In cases of central nervous system (CNS) involvement, cerebrospinal fluid (CSF) findings may include elevated protein levels and a modest mononuclear pleocytosis. CSF fungal stain and cultures typically are sterile. A CT scan should precede a lumbar puncture to assess for evidence of space occupying lesions, which could lead to herniation.

Blood cultures can be obtained; however, they usually are negative despite the angioinvasive nature of the organism. Blood cultures may be useful to detect bacteremia in addition to Mucorales infection. One study of pulmonary mucormycosis identified concurrent bacteremia as an independent predictor of 28-day mortality.[59] There are no specific biomarkers to identify mucormycosis. Bronchoalveolar lavage (BAL) of fluid culture has a low yield, with a sensitivity of 20-50%. Antigen tests (beta-D-glucan or galactomannan) are not useful for detecting this infection.[28] ECMM guidelines strongly recommend obtaining a culture of the specimen to identify the organism.[39] Cultures should be incubated at 30°C and 37°C; direct microscopy should be done mainly to identify septation, branching angle, and hyphal width.[39] European Confederation of Medical Mycology (ECMM) guidelines strongly recommend susceptibility testing to expand epidemiological knowledge, although generally use of standard method for susceptibility testing for Mucorales is marginally reinforced as there are no cut-off values established by European Committee on Antimicrobial Susceptibility testing (EUCAST) or Clinical and Laboratory Standards Institute (CLSI).[39]

Molecular based testing is moderately supported; fresh tissue is preferred over paraffin tissue, as formalin damages DNA.[39]  The use of molecular-based testing has only moderate support due to lack of standardization. The use of quantitative polymerase chain reaction (qPCR) for detection of circulating DNA from common Mucorales species (Lichtheimia species, Rhizomucor species, and Mucor/Rhizopus species), although not yet commercially available, has been described and appears promising for the early diagnosis of mucormycosis in high-risk patients.[65, 66] In a retrospective analysis of 44 cases, qPCR identification was fully concordant with that of culture. Assay positivity was observed at an average of 9 days, at least 2 days prior to positive imaging findings. Development of PCR negativity after treatment was associated with higher survival rates (48% vs 4%), suggesting that this modality could eventually be used for treatment monitoring.[67] DNA detection can be looked for in CSF or BAL clinical samples.[68, 69, 70, 71]

Approach Considerations

Correction of the underlying abnormality, prompt initiation of liposomal amphotericin B therapy, and surgical resection are critical.[1, 72, 76]

Other important considerations in medical management include the following:

The use of contaminated bandages and other dressings has caused cutaneous mucormycosis. Failure to examine areas under dressings or to recognize the significance of deterioration in preexisting wounds may produce severe cutaneous and, ultimately, disseminated disease. Placing patients with severe prolonged neutropenia in rooms equipped with high-efficiency particulate air (HEPA) filters, when feasible, may be beneficial.

Antifungal Therapy

No prospective comparative studies of the primary treatment of mucormycosis have been performed, largely because of the rarity of this disease. In current practice, amphotericin B and isavuconazole are the 2 antifungal agents licensed by the US Food and Drug Administration (FDA) for the primary therapy of mucormycosis. First-line treatment is with an amphotericin derivative, preferably the liposomal form of amphotericin B to minimize nephrotoxicity. Other options include amphotericin B deoxycholate, isavuconazole, and posaconazole. In patients with extensive disease or rapid progression, the addition of posaconazole or isavuconazole to amphotericin B may be considered[77, 78, 39] ; definitive data are not available.

Although some reports have described a combination of different classes of antifungal agents, trials are needed to determine the efficacy of this approach.[79] Potential advantages would include more rapid fungicidal activity and lower risk for resistance. Potential disadvantages would include the risk for antagonism, additive or synergistic toxicity, more drug-drug interactions, and higher cost.[80]

Liposomal and lipid complex amphotericin B

Amphotericin B has proven efficacy in the treatment of mucormycosis. The liposomal formulation (AmBisome) is the drug of choice based on efficacy and safety data.[39, 81, 82] 83 ECMM recommends a  dosage of  5-10 mg/kg of liposomal amphotericin B; the dose need not be slowly increased; instead, a full dose should be given on day 1 of treatment.[39]  High doses of liposomal amphotericin B ≥ 7.5 mg/kg were tested in a pilot study (Ambizygo); the response rate was 43% among patients who received the higher dose during the first week compared with 0% in patients who did not.[83]  A high dose combined with surgery led to an overall response rate of 36% and 45% at Weeks 4 and 12 respectively.[83]  A higher dose of 10mg/kg is recommended in patients with CNS involvement.[39]

The use of higher doses, however, has been associated with rates of nephrotoxicity up to 40% without a concomitant mortality benefit.[72, 79, 83, 84]

Amphotericin B

Amphotericin B deoxycholate also can be used to treat mucormycosis, particularly when other formulations prove too costly. The typical dose is 1-1.5 mg/kg/d. The total dose given over the course of therapy is usually 2.5-3 g. High doses of this drug are required, and nephrotoxicity may result. This is of particular concern because many patients who develop mucormycosis have preexisting renal disease (eg, diabetic patients, transplant recipients). Monitoring the renal function of patients taking amphotericin B is critical; doubling of serum creatinine over the baseline levels is an indication for changing to liposomal amphotericin B.

In addition, careful monitoring and repletion of serum electrolytes (eg, potassium, phosphorus, magnesium) should be performed when administering any formulation of amphotericin B.

Isavuconazonium sulfate

Isavuconazonium sulfate (isavuconazole; Cresemba) is a novel triazole antifungal agent that was approved for the treatment of mucormycosis in March 2015. The prodrug isavuconazonium sulfate is rapidly metabolized by serum butylcholinesterase to the active form, isavuconazole (ISZ).[75]  In 2023, the FDA expanded approval of isavuconazole to include children aged older than 1 year. 

The efficacy of isavuconazole in the treatment of invasive mucormycosis has not been evaluated in randomized controlled trials because of the rarity of this disease. The approval of this medication was based on a noncomparative, single-arm, open-label, matched, case-control trial (VITAL). Of 149 patients enrolled, 37 had proven (86%) or probable (14%) mucormycosis. Twenty-one patients received primary treatment with ISZ, whereas 11 patients received isavuconazole salvage therapy; 5 were intolerant to other antifungals. Controls treated with amphotericin (67% liposomal, 12% lipid complex, 21% deoxycholate) were matched from the Fungiscope Registry. Isavuconazole- and amphotericin-treated patients had similar day-42 weighted all-cause mortality at 33% and 41%, respectively. Patients received isavuconazole for a median of 84 days versus 18 for amphotericin, suggesting more favorable tolerability.[85]  ECMM recommends isavuconazole with moderate strength as first-line treatment.[39] Isavuconazole brain penetration is low in necrotic center, however it is adequate in inflammatory brain tissue, comparable to plasma concentration.[86] Isavuconazole was efficacious in Mucorales CNS infection in a retrospective study.[87]

Isavuconazole offers several advantages over other triazoles (ie, posaconazole, voriconazole), apart from its wider spectrum of antifungal activity. The drug has excellent oral bioavailability not reliant on food intake or gastric pH and also is available in an intravenous formulation, which does not contain the nephrotoxic solubilizing agent cyclodextrin. Switching between oral and IV forms does not require dose adjustment. ISZ displays linear and predictable pharmacokinetics with minimal CYP3A4 interactions, reducing or eliminating the need for therapeutic drug monitoring. Unlike voriconazole, ISZ does not cause phototoxicity, increased risk for squamous cell carcinoma, or visual disturbance. The clinical significance of ISZ-related QTc shortening is unknown, but it is reasonable to avoid this medication in patients with familial short QT syndrome and to avoid co-administrating with sodium channel–blocking antiepileptics.[88]

Given the highly variable, species-dependent susceptibility pattern of the Mucorales to isavuconazole, clinical susceptibility testing may be indicated in some situations.[89]

Posaconazole

Posaconazole, another triazole antifungal, has been shown to be superior to fluconazole or itraconazole as prophylaxis against invasive mold infection (both aspergillosis and mucormycosis) in patients with hematologic malignancy who have neutropenia or GVHD. The number needed to treat (NNT) to prevent one fungal infection was 27 and to prevent one death was 35.[90]

Posaconazole can be used for off-label salvage treatment of mucormycosis in patients intolerant to amphotericin B. Issues with the absorption of the oral suspension of posaconazole, particularly decreased absorption in the setting of proton pump inhibitor (PPI) or antimotility agent (eg, metoclopramide) use have been overcome with the introduction of a delayed-release tablet formulation.[75, 81]  An intravenous formulation also is available. Therapeutic drug monitoring is strongly recommended for patients on posaconazole being treated for mucormycosis.[39]

Several case reports have discussed the use of posaconazole,[73, 91] including as salvage therapy.[92] A review of 96 patients treated with posaconazole found that complete response was achieved in 62 (64.6%), partial response in 7 (7.3%) patients, and stable disease in 1 (1%), with an overall mortality of 24%.[77] Rickerts et al reported that liposomal amphotericin B plus posaconazole was successful in the treatment of disseminated mucormycosis in a patient who could not undergo surgery; however, the benefit of dual antifungal therapy is unclear.[79, 93]

Posaconazole also has been used as step-down therapy after the initial administration and control of the disease with liposomal amphotericin B.[94, 95]

Other agents and combination therapy

Other azoles (ie, fluconazole, voriconazole) are ineffective against Mucorales species. With the use of voriconazole prophylaxis in high-risk patients, such as transplant recipients, mucormycosis has been reported.[96, 97, 98]

Most Mucorales species show moderate in vitro resistance to the echinocandins; these agents cannot be used in the treatment of mucormycosis.[29] Animal and limited clinical data have suggested that combination therapy with amphotericin and an echinocandin may improve survival.[81, 82, 99, 100, 101] However, a recent retrospective cohort study of combination liposomal amphotericin B (L-AmB) with posaconazole, L-AmB with echinocandins, and posaconazole with echinocandins showed no differences in mortality between monotherapy and combination treatment groups.[102] The in vitro combinations of isavuconazole with micafungin or amphotericin resulted in a range of interactions, some concentration-dependent, ranging from antagonism to synergy against various Mucorales.[103]

Further clinical trials are needed before antifungal combination therapy can be definitively recommended. Currently there is a clinical trial assessing the combination of inhaled amphotericin +IV liposomal amphotericin B vs IV amphotericin alone, and other novel therapies are being evaluated out based on medical patent review and in-vitro data.[104, 105]

Surgical Intervention

Debridement of necrotic tissue in combination with medical therapy is mandatory for patient survival. In rhinocerebral disease, surgical care includes drainage of the sinuses and may require excision of the orbital contents and involved brain. Repeated surgery may be required, especially for rhinocerebral mucormycosis.

Excise pulmonary lesions if they are localized to a single lobe, excise cutaneous lesions entirely, and resect any GI masses, for good disease control.



View Image

An immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces....

Adjunctive Therapies

Hyperbaric oxygen therapy after surgical debridement has been used, especially in cases of cutaneous disease and rhinocerebral disease in diabetic patients, but its effectiveness has not been extensively studied. Treatment of mucormycosis is not one of the approved uses of hyperbaric oxygen.[91, 106] High oxygen concentrations may improve neutrophil function, inhibit the growth of Mucorales, and improve wound healing.

Colony-stimulating factors have been used to enhance immune responses, specifically in neutropenic patients, as have interferon-gamma and white blood cell transfusions. The usefulness of these interventions is unclear.

Finally, the use of iron chelators without xenosiderophore activity (eg, deferasirox) has been described in case reports.[106] Older iron chelators, namely deferoxamine, can be exploited as an iron source by Rhizopus, thereby increasing the risk for mucormycosis.[75] Newer agents such as deferasirox were hypothesized to decrease the risk of mucormycosis via iron starvation; however, they have not proven clinically efficacious.[107] In an immunosuppressed murine model of pulmonary mucormycosis, a combination of deferasirox with posaconazole increased the AUC/MIC of posaconazole but failed to demonstrate improved efficacy over monotherapy.[108] In the DEFEAT MUCOR study, 20 patients with mucormycosis were randomly assigned to L-AmB plus deferasirox or L-AmB plus placebo; the deferasirox arm had a higher 90-day mortality rate.[109, 110]

 

Consultations

Patient survival from mucormycosis requires rapid diagnosis and aggressive coordinated medical and surgical therapy. To that effect, consultations with various specialists are critical.

Infectious disease consultation is warranted for management of antifungal therapy and coordination of medical care.

Surgical specialty consultations depend on the location of disease, as follows:

In addition, endocrinology consultation may be necessary for the management of unstable diabetes, hematology/oncology consultation may be needed for the management of issues related to underlying malignancy, and surgical intensive care unit (SICU) consultation is important for perioperative care.

Duration of Therapy and Long-Term Monitoring

There is no definitive guidance on duration of therapy, and weeks to months of therapy usually are given; ECMM strongly suggests treatment until immunosuppression is resolved, diabetes is effectively controlled, and complete response is seen on imaging.[39]

Successful courses of amphotericin B typically last 4-6 weeks. Primary or salvage isavuconazole therapy may be continued for several months given its higher tolerability compared with amphotericin. Repeated surgical debridement of necrotic tissue identified by follow-up head computed tomography (CT) scan or magnetic resonance imaging (MRI) often is indicated.

Ongoing clinical surveillance and diagnostic imaging are required to ensure complete resolution of mucormycosis and to detect relapse.

Educate patients about the signs of disease, such as facial swelling and black nasal discharge, and instruct patients to present promptly for evaluation if these signs occur.

Prevention

Primary Prophylaxis

There is no evidence for primary prophylaxis towards mucormycosis. The ECMM has a moderately strong recommendation regarding primary prophylaxis with oral (B-II) or IV posaconazole (B111), and marginally recommends (C-II) posaconazole oral suspension among patients who are neutropenic or have graft versus host disease (GvHD).[39] Isavuconazole is marginally recommended (C-II) for primary prophylaxis among neutropenic patients; in a study consisting of 147 patients, isavuconazole prophylaxis was less effective than voriconazole or posaconazole for invasive fungal disease as two patients had breakthrough mucormycosis despite being on isavuconzole.[39, 111]  For patients with solid organ transplant (SOT), posaconazole or isavuconazole is marginally (C-II, C111) recommended.[39]

Secondary Prophylaxis

The ECMM strongly recommends secondary prophylaxis for patients with a previous history of mucormycosis who are undergoing immunosuppression.[39]

Medication Summary

The 2 main classes of antifungal medications used to treat mucormycosis are the polyenes (amphotericin formulations) and triazoles (isavuconazole and posaconazole). Amphotericin B and isavuconazole are the 2 agents currently FDA approved for the primary therapy of mucormycosis. Posaconazole can be used off-label for salvage treatment in patients intolerant to amphotericin B. It has also been used as step-down therapy after initial control of the disease with amphotericin.[94, 95]

In patients with hematologic malignancy, posaconazole is superior to other triazoles as prophylaxis for invasive mold infection. Isavuconazole is a novel triazole antifungal agent with many advantages, including excellent oral bioavailability, linear and predictable pharmacokinetics, and minimal CYP450 interactions.[88] Owing to its safety, tolerability, and comparable efficacy to amphotericin B,[85] isavuconazole is promising as a primary and salvage therapy. Further study is needed prior to its use as primary mold prophylaxis in the setting of prolonged neutropenia.

Echinocandin agents, including anidulafungin, caspofungin, and micafungin, competitively inhibit the beta-1,3-D-glucan synthase enzyme complex. In Candida species, beta-glucan depletion causes cell lysis via loss of resistance to osmotic force; in Aspergillus, it is fungistatic owing to impaired growth at hyphal branching points. Echinocandins have minimal activity against the Mucorales, which contain little or no beta-1,3-D-glucan. Some studies have suggested combination therapy with amphotericin and an echinocandin may improve survival; however, a more recent retrospective study showed no such mortality benefit. There is no current evidence-based recommendation for the addition of an echinocandin to amphotericin B or isavuconazole for the treatment of mucormycosis.

The benefit of combination therapy with different classes of antifungals (including echinocandins) is uncertain. Despite advances in medical management, surgical evaluation is essential in the management of mucormycosis, and overall mortality rates remain high.

See the Treatment section for further discussion of individual antifungal agents.

Liposomal amphotericin B (AmBisome)

Clinical Context:  Consists of a mixture of phosphatidylcholine, cholesterol, and distearoyl phosphatidylglycerol that arrange into amphotericin B–containing unilamellar vesicles in aqueous media. First-line therapy for mucormycosis at 5 mg/kg/d. Owing to decreased risk of nephrotoxicity at this dose, it can be used in the setting of preexisting renal dysfunction and when nephrotoxicity develops during amphotericin B deoxycholate therapy. Careful electrolyte monitoring and replacement is required.

Amphotericin B lipid 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

Clinical Context:  Less commonly used than the lipid formulations because of higher rates of nephrotoxicity but less costly and more widely available. The typical dose is 1-1.5 mg/kg/d. The total dose given over the course of therapy is usually 2.5-3 g.

Class Summary

These agents bind irreversibly to ergosterol within the fungal cell membrane. This binding results in disruption of membrane integrity, leakage of intracellular components, and, ultimately, cell death.

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. Administered as one 300-mg tablet twice on day 1 followed by 300 mg orally once daily with or without food. The delayed-release tablet formulation is preferred over the oral suspension because of its more reliable absorption. An intravenous formulation is also available.

Class Summary

These agents inhibit the cytochrome P450-dependent 14-alpha-lanosterol demethylase of the fungal cell membrane. Toxic cell membrane sterols accumulate and ergosterol production is inhibited, leading to impaired growth and replication and, ultimately, cell death.

What is mucormycosis (zygomycosis)?What are the risk factors for mucormycosis (zygomycosis)?What is the pathophysiology of mucormycosis (zygomycosis)?What is the prevalence of mucormycosis (zygomycosis) in the United States and globally??How is mucormycosis involved in some cases of COVID-19?What is the prognosis of mucormycosis (zygomycosis)?What are forms of mucormycosis (zygomycosis)?What are the signs and symptoms of rhinocerebral mucormycosis (zygomycosis)?What are the signs and symptoms of pulmonary mucormycosis (zygomycosis)?What are the signs and symptoms of cutaneous mucormycosis (zygomycosis)?What are the signs and symptoms of GI mucormycosis (zygomycosis)?Which organ systems may be involved in disseminated mucormycosis (zygomycosis)?What are the signs and symptoms of central nervous system mucormycosis (zygomycosis)?Which conditions should be included in the differential diagnoses of mucormycosis (zygomycosis)?What are the differential diagnoses for Mucormycosis (Zygomycosis)?Which tests are performed in the workup of mucormycosis (zygomycosis)?What is the role of lab testing in the workup of mucormycosis (zygomycosis)?What is the role of imaging studies in the workup of mucormycosis (zygomycosis)?What is the role of imaging studies in the workup of rhinocerebral mucormycosis (zygomycosis)?What is the role of imaging studies in the workup of pulmonary mucormycosis (zygomycosis)?What is the role of imaging studies in the workup of GI mucormycosis (zygomycosis)?What is the role of imaging studies in the workup of central nervous system mucormycosis (zygomycosis)?What is the role of biopsy in the workup of mucormycosis (zygomycosis)?How is mucormycosis (zygomycosis) treated?What is the role of antifungal therapy in the treatment of mucormycosis (zygomycosis)?What is the role of amphotericin B in the treatment of mucormycosis (zygomycosis)?What is the role of isavuconazole (Cresemba) in the treatment of mucormycosis (zygomycosis)?What is the role of posaconazole in the treatment of mucormycosis (zygomycosis)?Which azoles are ineffective for the treatment of mucormycosis (zygomycosis)?What is the role of combination therapy in the treatment of mucormycosis (zygomycosis)?What is the role of surgery in the treatment of mucormycosis (zygomycosis)?Which adjunctive therapies are used in the treatment of mucormycosis (zygomycosis)?Which specialist consultations are beneficial to patients with mucormycosis (zygomycosis)?What is included in the long-term monitoring of patients with mucormycosis (zygomycosis)?Which medications are used in the treatment of mucormycosis (zygomycosis)?Which medications in the drug class Antifungal agents, Azole derivatives are used in the treatment of Mucormycosis (Zygomycosis)?Which medications in the drug class Antifungal agents, Polyene are used in the treatment of Mucormycosis (Zygomycosis)?

Author

Avnish Sandhu, DO, Assistant Professor of Infectious Diseases, Department of Internal Medicine, Wayne State University School of Medicine; Hospitalist, Inpatient Consultant Healthcare/Team Health, Barbara Ann Karmanos Cancer Institute

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.

John L Brusch, MD, FACP, Corresponding Faculty Member, Harvard Medical School

Disclosure: Nothing to disclose.

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

Nancy F Crum-Cianflone, MD, MPH, Consulting Staff, Department of Internal Medicine, Division of Infectious Diseases, Naval Medical Center at San Diego

Disclosure: Nothing to disclose.

Philip J McDonald, MD, Fellow, Division of Infectious Diseases, Department of Internal Medicine, Detroit Medical Center, Wayne State University School of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Mark T Duffy, MD, PhD Consulting Staff, Division of Oculoplastic, Orbito-facial, Lacrimal and Reconstructive Surgery, Green Bay Eye Clinic, BayCare Clinic; Medical Director, Advanced Cosmetic Solutions, A BayCare Clinic

Mark T Duffy, MD, PhD is a member of the following medical societies: American Academy of Ophthalmology, American Medical Association, American Society of Ophthalmic Plastic and Reconstructive Surgery, Sigma Xi, and Society for Neuroscience

Disclosure: Allergan - Botox Cosmetic Honoraria Speaking and teaching

Ronald A Greenfield, MD Professor, Department of Internal Medicine, University of Oklahoma College of Medicine

Ronald A Greenfield, MD is a member of the following medical societies: American College of Physicians, American Federation for Medical Research, American Society for Microbiology, Central Society for Clinical Research, Infectious Diseases Society of America, Medical Mycology Society of the Americas, Phi Beta Kappa, Southern Society for Clinical Investigation, and Southwestern Association of Clinical Microbiology

Disclosure: Pfizer Honoraria Speaking and teaching; Gilead Honoraria Speaking and teaching; Ortho McNeil Honoraria Speaking and teaching; Abbott Honoraria Speaking and teaching; Astellas Honoraria Speaking and teaching; Cubist Honoraria Speaking and teaching; Forest Pharmaceuticals Speaking and teaching

Simon K Law, MD, PharmD Clinical Professor of Health Sciences, Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, David Geffen School of Medicine

Simon K Law, MD, PharmD is a member of the following medical societies: American Academy of Ophthalmology, American Glaucoma Society, and Association for Research in Vision and Ophthalmology

Disclosure: Nothing to disclose.

Maria D Mileno, MD Associate Professor of Medicine, Division of Infectious Diseases, The Warren Alpert Medical School of Brown University

Maria D Mileno, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, International Society of Travel Medicine, and Sigma Xi

Disclosure: Nothing to disclose.

Ron W Pelton, MD, PhD Private Practice, Colorado Springs, Colorado

Ron W Pelton, MD, PhD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, American Society of Ophthalmic Plastic and Reconstructive Surgery, AO Foundation, and Colorado Medical Society

Disclosure: Nothing to disclose.

Hampton Roy Sr, MD Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology

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

Kimberly G Yen, MD Associate Professor of Ophthalmology, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine

Kimberly G Yen, MD is a member of the following medical societies: American Academy of Ophthalmology and American Association of Pediatric Ophthalmology & Strabismus (AAPOS)

Disclosure: Nothing to disclose.

Michael T Yen, MD Associate Professor of Ophthalmology, Division of Ophthalmic Plastic, Lacrimal, and Orbital Surgery, Cullen Eye Institute, Medical Director, BCM Ambulatory Surgery Center, Program Director, ASOPRS Fellowship, Baylor College of Medicine

Michael T Yen, MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Ophthalmic Plastic and Reconstructive Surgery, and Association for Research in Vision and Ophthalmology

Disclosure: Nothing to disclose.

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Postmortem photograph of a woman with diabetes and left rhinocerebral mucormycosis complicating ketoacidosis. Rhizopus oryzae was the causative organism. Note the orbital and facial cellulitis and the black nasal discharge. Courtesy of A Allworth, MD, Brisbane, Australia.

The right eye of an immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. Note the proptosis. Courtesy of A Allworth, MD, Brisbane, Australia.

The right eye of an immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. Chemosis is shown in this photograph. Internal and external ophthalmoplegia, no light perception, and afferent pupil defect were present, which is consistent with orbital apex syndrome. Courtesy of A Allworth, MD, Brisbane, Australia.

Brain MRI (sagittal view) in a patient with uncontrolled diabetes who presented with progressive right eye pain and facial swelling. He underwent multiple surgeries to control rhinocerebral Mucor infection, including partial right frontal lobectomy and right orbital exenteration. He was treated with amphotericin B and his diabetes mellitus was controlled. The disease did not progress, and long-term isavuconazole therapy was initiated for salvage/maintenance therapy.

An immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. A surgical field of this patient is shown. Excision of the right orbit, maxillary antrum, nasal cavity, sphenoid sinus, and infratemporal fossa has taken place. The tissue was infarcted. Courtesy of A Allworth, MD, Brisbane, Australia.

Rhino-orbital-cerebral mucormycosis in a patient with SARS-CoV-2 infection. Courtesy of Dr Sujata Rege.

Chest computed tomography (CT) scan showing pulmonary mucormycosis with left basal consolidation and widespread nodules due to Rhizopus oryzae infection. The patient was receiving cytotoxic chemotherapy for myelodysplastic syndrome and had iron overload from numerous blood transfusions.

Pulmonary mucormycosis in a patient with SARS-CoV-2 infection. Courtesy of Dr Sujata Rege.

Brain MRI (sagittal view) in a patient with uncontrolled diabetes who presented with progressive right eye pain and facial swelling. He underwent multiple surgeries to control rhinocerebral Mucor infection, including partial right frontal lobectomy and right orbital exenteration. He was treated with amphotericin B and his diabetes mellitus was controlled. The disease did not progress, and long-term isavuconazole therapy was initiated for salvage/maintenance therapy.

Histologic findings from an immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. Findings show the typical Mucorales hyphae on Grocott methenamine-silver staining. The hyphae are the dark structures with budlike, right-angle hyphae. Courtesy of A Allworth, MD, Brisbane, Australia.

An immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. A surgical field of this patient is shown. Excision of the right orbit, maxillary antrum, nasal cavity, sphenoid sinus, and infratemporal fossa has taken place. The tissue was infarcted. Courtesy of A Allworth, MD, Brisbane, Australia.

Postmortem photograph of a woman with diabetes and left rhinocerebral mucormycosis complicating ketoacidosis. Rhizopus oryzae was the causative organism. Note the orbital and facial cellulitis and the black nasal discharge. Courtesy of A Allworth, MD, Brisbane, Australia.

The right eye of an immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. Note the proptosis. Courtesy of A Allworth, MD, Brisbane, Australia.

The right eye of an immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. Chemosis is shown in this photograph. Internal and external ophthalmoplegia, no light perception, and afferent pupil defect were present, which is consistent with orbital apex syndrome. Courtesy of A Allworth, MD, Brisbane, Australia.

An immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. A surgical field of this patient is shown. Excision of the right orbit, maxillary antrum, nasal cavity, sphenoid sinus, and infratemporal fossa has taken place. The tissue was infarcted. Courtesy of A Allworth, MD, Brisbane, Australia.

An immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. Picture of the patient after successful treatment with repeated surgical debridement and high-dose liposomal amphotericin B. Courtesy of A Allworth, MD, Brisbane, Australia.

Histologic findings from an immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. Findings show the typical Mucorales hyphae on Grocott methenamine-silver staining. The hyphae are the dark structures with budlike, right-angle hyphae. Courtesy of A Allworth, MD, Brisbane, Australia.

Chest computed tomography (CT) scan showing pulmonary mucormycosis with left basal consolidation and widespread nodules due to Rhizopus oryzae infection. The patient was receiving cytotoxic chemotherapy for myelodysplastic syndrome and had iron overload from numerous blood transfusions.

Chest computed tomography (CT) scan showing pulmonary mucormycosis with left basal consolidation and widespread nodules due to Rhizopus oryzae infection. The patient was receiving cytotoxic chemotherapy for myelodysplastic syndrome and had iron overload from numerous blood transfusions. This CT scan of the patient shows resolution of pulmonary mucormycosis after 5 months of antifungal treatment.

Brain MRI (sagittal view) in a patient with uncontrolled diabetes who presented with progressive right eye pain and facial swelling. He underwent multiple surgeries to control rhinocerebral Mucor infection, including partial right frontal lobectomy and right orbital exenteration. He was treated with amphotericin B and his diabetes mellitus was controlled. The disease did not progress, and long-term isavuconazole therapy was initiated for salvage/maintenance therapy.

Rhino-orbital-cerebral mucormycosis in a patient with SARS-CoV-2 infection. Courtesy of Dr Sujata Rege.

Pulmonary mucormycosis in a patient with SARS-CoV-2 infection. Courtesy of Dr Sujata Rege.