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Mucormycosis (zygomycosis)
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Mucormycosis (zygomycosis)
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Literature review current through: Oct 2017. | This topic last updated: Jan 25, 2017.

INTRODUCTION — Mucormycosis is manifested by a variety of different syndromes in humans, particularly in immunocompromised patients and those with diabetes mellitus [1]. Devastating rhino-orbital-cerebral and pulmonary infections are the most common syndromes caused by these fungi.

There is some controversy over the terminology used to refer to infections due to this group of fungi. The term "mucormycosis" was used for years and then was supplanted by "zygomycosis" for several decades. Based on molecular studies, "mucormycosis" is currently again the appropriate term [1-4].

The microbiology, clinical manifestations, diagnosis, and therapy of mucormycosis will be reviewed here. Several specific syndromes that can be caused by these fungi are discussed separately. (See "Fungal rhinosinusitis" and "Non-access-related infections in chronic dialysis patients".)

MYCOLOGY — The genera in the order Mucorales cause most human infection. These organisms are ubiquitous in nature and can be found on decaying vegetation and in the soil. These fungi grow rapidly and release large numbers of spores that can become airborne. Because the agents of mucormycosis are common in the environment, they are relatively frequent contaminants in the clinical microbiology laboratory; all humans have ample exposure to these fungi during day-to-day activities. The fact that mucormycosis is a rare human infection reflects the effectiveness of the intact human immune system. This is further supported by the finding that almost all human infections due to the agents of mucormycosis occur in the presence of some underlying compromising condition.

The genera most commonly found in human infections are Rhizopus, Mucor, and Rhizomucor; Cunninghamella, Absidia, Saksenaea, and Apophysomyces are genera that are less commonly implicated in infection [5].

The hyphae of the Mucorales are distinct and allow for a presumptive identification from clinical specimens. The hyphae are broad (5 to 15 micron diameter), irregularly branched, and have rare septations (picture 1). This is in contrast to the hyphae of ascomycetous molds, such as Aspergillus, which are narrower (2 to 5 micron diameter), exhibit regular branching, and have many septations.

The lack of regular septations may contribute to the fragile nature of the hyphae and the difficulty of growing the agents of mucormycosis from clinical specimens. Grinding clinical specimens can cause excessive damage to the hyphae. Thus, finely mincing tissues is preferred for culturing tissue samples that may contain molds.

PATHOGENESIS — Rhizopus organisms have an enzyme, ketone reductase, which allows them to thrive in high glucose, acidic conditions. Serum from healthy individuals inhibits growth of Rhizopus, whereas serum from individuals in diabetic ketoacidosis stimulates growth [6].

Rhino-orbital-cerebral and pulmonary mucormycosis are acquired by the inhalation of spores. In healthy individuals, cilia transport these spores to the pharynx and they are cleared through the gastrointestinal tract. In susceptible individuals, infection usually begins in the nasal turbinates or the alveoli [7]. The agents of mucormycosis are angioinvasive; thus, infarction of infected tissues is a hallmark of invasive disease [8].

Deferoxamine and iron overload — Deferoxamine, which chelates both iron and aluminum, increases the risk of mucormycosis by enhancing growth and pathogenicity [7,9-11]. The deferoxamine-iron chelate, called feroxamine, is a siderophore for the species Rhizopus, increasing iron uptake by the fungus, which stimulates fungal growth and leads to tissue invasion [8,12].

Iron overload itself may predispose to mucormycosis in the absence of deferoxamine therapy [13]. In addition, individuals with diabetic ketoacidosis have elevated concentrations of free iron in their serum, which supports the growth of Rhizopus oryzae at an acidic, but not at an alkaline, pH [14,15].

Deferoxamine was once used commonly as an aluminum chelator in patients with renal failure; however, aluminum excess is rarely seen today. Currently, patients at risk for deferoxamine-associated mucormycosis are those who have received multiple blood transfusions and are treated with this chelating agent for iron overload. The majority of patients with deferoxamine-associated infection present with disseminated disease that is rapidly fatal, with a mortality rate that approaches 90 percent [11]. (See "Aluminum toxicity in chronic kidney disease", section on 'Adverse effects of deferoxamine'.)

In contrast with deferoxamine, other iron chelating agents, such as deferasirox and deferiprone, do not act as siderophores and therefore do not increase the risk of mucormycosis. To the contrary, studies in mice with mucormycosis found that these agents might actually be beneficial (eg, improve survival and reduce the tissue fungal burden) [16,17]. The use of deferasirox for the treatment of mucormycosis has not been adequately studied in humans. (See 'Deferasirox' below.)

RISK FACTORS — Almost all patients with invasive mucormycosis have some underlying disease that both predisposes to the infection and influences the clinical presentation. The most common underlying diseases are [5,18-30]:

Diabetes mellitus, particularly with ketoacidosis

Treatment with glucocorticoids [25]

Hematologic malignancies [1,27,31]

Hematopoietic cell transplantation [5,25,32]

Solid organ transplantation [32-35]

Treatment with deferoxamine [9-11,13] (see 'Deferoxamine and iron overload' above and "Iron chelators: Choice of agent, dosing, and adverse effects")

Iron overload [13]

AIDS

Injection drug use

Trauma/burns [36-38]

Malnutrition

EPIDEMIOLOGY — The incidence of mucormycosis is difficult to estimate since it is not a reportable disease and the risk varies widely in different populations. A review of 929 cases of mucormycosis that were reported between 1940 and 2003 noted that diabetes mellitus was the most common risk factor, found in 36 percent of cases, followed by hematologic malignancies (17 percent) and solid organ or hematopoietic cell transplantation (12 percent) [5]. In some patients, mucormycosis was the diabetes-defining illness. In a later study of 101 patients diagnosed with mucormycosis between 2005 and 2007 in France, hematologic malignancy was the most common risk factor, occurring in 50 percent of patients, followed by diabetes in 23 percent and trauma in 18 percent of cases [36].

Malignancy and hematopoietic cell transplantation — Among patients with malignancy, hematologic malignancies are much more frequently associated with mucormycosis than solid tumors [5,25-27]. However, even in patients with hematologic malignancies, mucormycosis appears to occur in less than 1 percent of patients [39]. Among hematopoietic cell transplant (HCT) recipients, the reported incidence has ranged from 0.1 to 2 percent, with the highest incidence in patients with graft-versus-host disease [32].

Reports from several countries have noted an increase in mucormycosis in patients with hematologic malignancies [1,31,40]. Most of these patients had undergone HCT, many had graft-versus-host disease, and almost all were on voriconazole for prophylaxis or treatment [1,31]. A case-control study in a population of patients with hematologic malignancies compared patients with mucormycosis to those who had no fungal infection; voriconazole prophylaxis was an independent risk factor for mucormycosis (odds ratio 10.4, 95% CI 2.1-39) [27].

Although the possible causes of the increase in mucormycosis in patients with hematologic malignancies continue to be debated, reasons that have been proposed include selection of the agents of mucormycosis caused by voriconazole use, increasing use and intensity of immunosuppressive agents, and a decrease in invasive aspergillosis-related mortality following HCT, resulting in the emergence of rare fungi during the late posttransplant period [41].

Solid organ transplantation — In a multicenter prospective study of invasive fungal infections in transplant recipients in the United States between 2001 and 2006, the 12-month cumulative incidence of mucormycosis was less than 1 percent among solid organ transplant recipients; only 2 percent of invasive fungal infections in such patients were caused by the agents of mucormycosis [32,42]. Among solid organ transplant recipients, risk factors for mucormycosis include renal transplantation [33], renal failure, diabetes, and prior voriconazole or caspofungin use [35].

Diabetes — As noted above, diabetes is a common predisposing condition [5]. The number of reported cases of mucormycosis in diabetic patients in the United States has declined since the 1990s, a trend that has not been noted in France [40] or in developing countries [28,43]. One hypothesis that has been suggested to explain the decline in the United States is the widespread use of statins, which have inhibitory activity in vitro against a wide range of the agents of mucormycosis [28].

Healthcare-associated — Healthcare-associated cases of mucormycosis have been reported. In a study of 169 healthcare-associated cases of mucormycosis in Europe between 1970 and 2008, the major underlying diseases were solid organ transplantation (in 24 percent), diabetes mellitus (in 22 percent), and severe prematurity (in 21 percent) [44]. Skin was the most common site of infection (in 57 percent), followed by the gastrointestinal tract (15 percent). Portals of entry included surgery, catheters (especially intravascular catheters), and adhesive tape. Outbreaks and clusters have been associated with adhesive bandages, wooden tongue depressors, adjacent building construction, and hospital linens [44-47]. Fatal gastrointestinal mucormycosis has also been reported in a premature neonate who received a probiotic that was contaminated with Rhizopus oryzae; probiotics were being given in an attempt to prevent necrotizing enterocolitis [48]. (See "Prevention of necrotizing enterocolitis in newborns", section on 'Probiotics'.)

Natural disaster-associated — Cases of mucormycosis have occurred following a tornado, a tsunami, and a volcanic eruption [49-53]. As an example, in 2011, an outbreak of necrotizing soft tissue infections causes by Apophysomyces trapeziformis occurred in patients with traumatic injuries resulting from a tornado in Joplin, Missouri, in the United States [49]. A total of 18 suspected cases were identified, of which 13 were confirmed. Two patients had diabetes and none were immunocompromised. Ten patients required intensive care unit admission and five died.

In a case-control study of patients injured during the tornado in Joplin, Missouri, the 13 patients with confirmed infection each had a median of five wounds (range one to seven); 11 patients (85 percent) had ≥1 fracture, nine patients (69 percent) had blunt trauma, and five patients (38 percent) had penetrating trauma [52]. All case patients had been located in the zone that sustained the most severe damage during the tornado. On multivariate analysis, infection was associated with penetrating trauma (adjusted odds ratio [aOR] 8.8, 95% CI 1.1-69.2) and an increased number of wounds (aOR 2.0 for each additional wound; 95% CI 1.2-3.2). Whole genome sequencing showed that the Apophysomyces trapeziformis isolates represented four separate strains.

Combat-associated — Invasive fungal infections, including mucormycosis, have been reported in United States military personnel who sustained blast injuries during combat in Afghanistan [54]. Between June 2009 and through December 2010, a total of 37 cases were identified, including 20 proven cases (with histopathologic evidence of angioinvasion), 4 probable cases (with histopathologic evidence of nonvascular tissue invasion), and 13 possible cases (with a positive fungal culture, but without histopathologic evidence). All injuries occurred secondary to explosive blasts, and most injuries occurred during foot patrol (in 34 patients; 92 percent). All patients had extremity injuries and 29 patients (78 percent) had lower extremity amputation either at the time of the injury or during the first surgery following the injury. Thirty-six patients (97 percent) required large-volume blood transfusion.

Mold isolates were recovered from the wounds of 31 patients (83 percent); the most commonly detected fungi belonged to the order Mucorales (in 16 patients), Aspergillus spp (in 16 patients), and Fusarium spp (in 9 patients) [54]. Multiple mold species were isolated from 28 percent of infected wounds. Frequent debridements or amputation revisions were required and three deaths were thought to be related to the infection (8 percent).

CLINICAL PRESENTATION — Mucormycosis is characterized by infarction and necrosis of host tissues that results from invasion of the vasculature by hyphae [29]. The pace is usually fast, but there are rare descriptions of infections with an indolent course [55,56].

Rhino-orbital-cerebral mucormycosis — The most common clinical presentation of mucormycosis is rhino-orbital-cerebral infection, which is presumed to start with inhalation of spores into the paranasal sinuses of a susceptible host. Hyperglycemia, usually with an associated metabolic acidosis, is the most common underlying condition [5]. A review of 179 cases of rhino-orbital-cerebral mucormycosis found that 126 (70 percent) of the patients had diabetes mellitus and that most had ketoacidosis at the time of presentation [18]. There are rare reports of rhino-orbital-cerebral mucormycosis in the absence of any apparent risk factors [18,56-59].

The infection usually presents as acute sinusitis with fever, nasal congestion, purulent nasal discharge, headache, and sinus pain. All of the sinuses become involved, and spread to contiguous structures, such as the palate, orbit, and brain, usually progresses rapidly. However, there have been some reports of rhino-orbital-cerebral mucormycosis with an indolent course [55].

The hallmarks of spread beyond the sinuses are tissue necrosis of the palate resulting in palatal eschars, destruction of the turbinates, perinasal swelling, and erythema and cyanosis of the facial skin overlying the involved sinuses and/or orbit (picture 2). A black eschar, which results from necrosis of tissues after vascular invasion by the fungus, may be visible in the nasal mucosa, palate, or skin overlying the orbit (picture 3) [60,61].

Signs of orbital involvement include periorbital edema, proptosis, and blindness. Facial numbness is frequent and results from infarction of sensory branches of the fifth cranial nerve. Spread of the infection from the ethmoid sinus to the frontal lobe results in obtundation. Spread from the sphenoid sinuses to the adjacent cavernous sinus can result in cranial nerve palsies, thrombosis of the sinus, and involvement of the carotid artery. Hematogenous spread to other organs is rare unless the patient has an underlying hematologic malignancy with neutropenia.

A review of 208 cases of rhino-orbital-cerebral mucormycosis published in the literature between 1970 and 1993 found the following frequency of symptoms and signs [62]:

Fever – 44 percent

Nasal ulceration or necrosis – 38 percent

Periorbital or facial swelling – 34 percent

Decreased vision – 30 percent

Ophthalmoplegia – 29 percent

Sinusitis – 26 percent

Headache – 25 percent

Rhino-orbital-cerebral mucormycosis is most commonly caused by Rhizopus oryzae.

Pulmonary mucormycosis — Pulmonary mucormycosis is a rapidly progressive infection that occurs after inhalation of spores into the bronchioles and alveoli (image 1). Pneumonia with infarction and necrosis results, and the infection can spread to contiguous structures, such as the mediastinum and heart [63,64], or disseminate hematogenously to other organs [65,66].

Most patients have fever with hemoptysis that can sometimes be massive [65,66]. The most common underlying conditions have been hematologic malignancies, treatment with glucocorticoids or deferoxamine, and solid organ transplantation; pulmonary infection is less common than rhino-orbital-cerebral infection in diabetics [19,65-70]. In a series of 24 patients with mucormycosis and hematologic malignancy, 71 percent had pulmonary involvement and only one had rhino-orbital-cerebral involvement; 7 of 12 patients who underwent autopsy had disseminated disease in addition to pulmonary infection [25].

Gastrointestinal mucormycosis — Although unusual, mucormycosis of the gastrointestinal tract may occur as the result of ingestion of spores. One review of 87 cases found that the stomach was the most common site (58 percent), followed by the colon (32 percent) [71]. The ileum and esophagus were rare sites of involvement.

The underlying diseases of patients with gastrointestinal mucormycosis have been diabetes mellitus, solid organ transplantation, treatment with glucocorticoids, and prematurity and/or malnutrition in infants [20,71-74]. Patients present with abdominal pain and hematemesis. The gastrointestinal lesions are necrotic ulcers that can lead to perforation and peritonitis [20]. Bowel infarctions and hemorrhagic shock can result from gastrointestinal mucormycosis [75], and the prognosis for all patients is poor.

Cutaneous mucormycosis — Infection of the skin and soft tissues with the agents of mucormycosis usually results from inoculation of the spores into the dermis. Thus, cutaneous mucormycosis is almost always associated with trauma or wounds. The entry of the fungi into the dermis can result from seemingly innocuous insults, such as the entry site for an intravenous catheter, spider bites, and insulin injection sites [21,22,76-80]. Infection has also been associated with contaminated traumatic wounds, dressings and splints, burns, and surgical sites [21,22,44,49,50,52,54,76-80].

When infection is associated with relatively minor breaks in the skin, the host usually has some underlying disease, such as diabetes mellitus, organ transplantation, neutropenia, or severe prematurity. Infections associated with major trauma or contaminated dressings have been found in otherwise immunocompetent patients [5,80].

Healthcare-associated, natural disaster–associated, and combat-associated cases of mucormycosis are discussed above. (See 'Healthcare-associated' above and 'Natural disaster-associated' above and 'Combat-associated' above.)

Cutaneous mucormycosis usually appears as a single, painful, indurated area of cellulitis that develops into an ecthyma-like lesion. Patients who have suffered trauma with an open wound that was contaminated with spores can develop rapidly progressive tissue necrosis reflecting the presence of ischemic infarction [21,22,50,52,54,77,79,80]. Dissemination and deep tissue involvement are unusual complications of cutaneous mucormycosis [78,80].

Renal mucormycosis — Isolated involvement of the kidneys with mucormycosis has been reported and is presumed to occur via seeding of the kidneys during an episode of fungemia. Almost all patients with isolated renal mucormycosis have risk factors for fungemia, including an intravenous catheter, intravenous drug use, or AIDS [23,24,81-83].

Patients with renal mucormycosis usually present with flank pain and fever. Involvement can be either unilateral or bilateral.

Isolated CNS involvement — Central nervous system (CNS) mucormycosis typically arises from an adjacent paranasal sinus infection. However, there have been more than 30 cases of isolated CNS mucormycosis described in the literature [24,84-88]. Infection is thought to result from seeding of the brain during an episode of fungemia, analogous to renal involvement. Over two-thirds of the patients with isolated CNS mucormycosis have been intravenous drug users who presumably have injected material contaminated with fungi directly into the bloodstream. Some of the patients with isolated CNS mucormycosis have had HIV infection in addition to drug use [24,85,89]. However, it is not clear whether HIV infection is an independent risk factor.

Most of the patients with isolated CNS mucormycosis have presented with lethargy and focal neurologic deficits, with the vast majority having involvement of the basal ganglia [84-86]. Isolated involvement of the frontal lobe has also been described [84].

Disseminated disease — Disseminated mucormycosis is rare and occurs most commonly in severely immunocompromised patients, burn patients, premature infants, and individuals who have received deferoxamine [1,5]. In the series of 929 cases of mucormycosis described above, disseminated disease was present in 40 to 50 percent of patients with cerebral or pulmonary mucormycosis [5]. The mortality rate in patients with disseminated mucormycosis was 96 percent.

DIAGNOSIS

Approach to diagnosis — The diagnosis of mucormycosis relies upon the identification of organisms in tissue by histopathology with culture confirmation. However, culture often yields no growth, and histopathologic identification of an organism with a structure typical of Mucorales may provide the only evidence of infection. A clinician must think of this entity in the appropriate clinical setting and pursue invasive testing in order to establish a diagnosis as early as possible. On the other hand, the agents of mucormycosis can colonize the airways or be contaminants in cultures, and the isolation of these fungi in a culture does not necessarily prove infection. Interpreting the culture results in the context of the patient's signs and symptoms and underlying disease are necessary to determine whether antifungal therapy should be given.

Serum tests, such as the 1,3-beta-D-glucan assay and the Aspergillus galactomannan assay, are being used with increased frequency in patients suspected of having an invasive fungal infection. The agents of mucormycosis do not share these cell wall components and neither test is positive in patients with mucormycosis. (See "Diagnosis of invasive aspergillosis", section on 'Beta-D-glucan assay' and "Diagnosis of invasive aspergillosis", section on 'Galactomannan antigen detection'.)

Investigational studies have demonstrated the feasibility of using polymerase chain reaction (PCR)-based techniques on histologic specimens [90-92]. In one study of patients with proven mucormycosis, among 12 cases that were positive by culture, 10 were also positive by PCR and sequencing was concordant with culture results to the genus level in 9 [91]. Among 15 culture-negative cases, PCR was positive and sequencing allowed genus identification in 12. The PCR-based technique used in this study appears promising for establishing the diagnosis of mucormycosis when cultures are negative.

In addition to traditional culture techniques and PCR with sequencing, matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry can be used to identify the causative species from culture specimens [93-95].

Rhino-orbital-cerebral infection — The presence of mucormycosis should be suspected in high-risk patients, especially those who have diabetes and metabolic acidosis and who present with sinusitis, altered mentation, and/or infarcted tissue in the nose or palate.

Endoscopic evaluation of the sinuses should be performed to look for tissue necrosis and to obtain specimens. The specimens should be inspected for characteristic broad, nonseptate hyphae with right-angle branching using calcofluor white and methenamine silver stains. The presence of the characteristic hyphae in a clinical specimen provides a presumptive diagnosis that should prompt further evaluation (picture 1). However, the absence of hyphae should not dissuade clinicians from the diagnosis of mucormycosis when the clinical picture is highly suggestive.

Further evaluation includes imaging of the head with either computed tomography (CT) or magnetic resonance imaging (MRI) to gauge sinus involvement and to evaluate contiguous structures such as the eyes and brain [96]. In a study of 23 immunocompromised patients with fungal sinusitis, CT findings included severe soft tissue edema of the nasal cavity mucosa (turbinates, lateral nasal wall and floor, and septum) in 21 patients, sinus mucoperiosteal thickening in 21 patients, bone erosion in 8 patients, orbital invasion in 6 patients, facial soft tissue swelling in 5 patients, and retroantral fat pad thickening in 2 patients [97].

Pulmonary infection — The diagnosis of pulmonary mucormycosis is difficult since the presentation does not differ from pneumonia due to other angioinvasive molds. Chest radiographs or CT scans may demonstrate focal consolidation, masses, pleural effusions, or multiple nodules [67,98]. A halo sign (ground glass attenuation surrounding a nodule) is characteristic of angioinvasive fungi, but a reversed halo sign, a focal area of ground glass attenuation surrounded by a ring of consolidation, has also been reported [99-101]. Mucormycosis appears to be the most common condition to cause the reversed halo sign in immunocompromised hosts [100]. In a retrospective study that included 189 patients with proven or probable fungal pneumonia, the reversed halo sign was seen in 7 of 37 patients with mucormycosis (19 percent), 1 of 132 patients with invasive aspergillosis (<1 percent), and none of 20 patients with fusariosis [99]. Radiographic evidence of infarction with cavitary lesions and an air crescent sign is unusual [67]. In a series of 45 cases, the following radiographic features were independent predictors of mucormycosis and helped to differentiate it from aspergillosis: concomitant sinusitis, >10 pulmonary nodules on CT scan, pleural effusion, and prior voriconazole prophylaxis [98].

Sputum or bronchoalveolar lavage (BAL) specimens can show the characteristic broad nonseptate hyphae, which is often the first indicator of mucormycosis [68]. However, in one case series, only 25 percent of sputum or BAL specimens were positive premortem [25]. Hyphae can also be demonstrated on lung biopsy (picture 1).

Other syndromes — The diagnosis of gastrointestinal mucormycosis can be made with endoscopic biopsy of the lesions that show the characteristic hyphae. For isolated renal involvement, percutaneous biopsy or nephrectomy can establish a diagnosis [23]. Urine cultures are almost always sterile. Imaging of the kidneys with CT can demonstrate either ill-defined areas of low attenuation and diminished enhancement suggestive of pyelonephritis or multiple small foci suggestive of abscesses.

In isolated central nervous system (CNS) involvement, CT scan usually shows poorly enhancing lesions; cerebrospinal fluid cultures are negative. Diagnosis can be made with biopsy or resection of the involved areas.

TREATMENT

Approach to treatment — Treatment of mucormycosis involves a combination of surgical debridement of involved tissues and antifungal therapy [2,30]. Elimination of predisposing factors for infection, such as hyperglycemia, metabolic acidosis, deferoxamine administration, immunosuppressive drugs, and neutropenia, is also critical.

Intravenous (IV) amphotericin B (lipid formulation) is the drug of choice for initial therapy [102]. Posaconazole or isavuconazole is used as step-down therapy for patients who have responded to amphotericin B. Posaconazole or isavuconazole can also be used as salvage therapy for patients who don't respond to or cannot tolerate amphotericin B; for salvage therapy, the decision to use oral or intravenous posaconazole or isavuconazole depends on how ill the patient is, whether an initial course of amphotericin B was able to be administered, and whether the patient has a functioning gastrointestinal (GI) tract.

Surgery — Aggressive surgical debridement of involved tissues should be undertaken as soon as the diagnosis of any form of mucormycosis is suspected. In the case of rhinocerebral infection, debridement to remove all necrotic tissue will often be disfiguring, requiring removal of the palate, nasal cartilage, and the orbit. There are reports of patients with early pulmonary infection who were cured with lobectomies [65,66,103]. However, many patients present with multilobar involvement that precludes surgical resection. Isolated soft tissue infection should be debrided if the clinical situation allows.

Antifungal drugs — Early initiation of antifungal therapy improves the outcome of infection with mucormycosis. This was illustrated in a retrospective study of 70 patients with hematologic malignancy who had mucormycosis in which delayed amphotericin B therapy (starting treatment ≥6 days after diagnosis) resulted in an almost twofold increase in mortality at 12 weeks after diagnosis (83 versus 49 percent) [104].

There are no randomized trials assessing the efficacy of antifungal regimens for mucormycosis because the disease is rare.

Initial therapy — As noted above, amphotericin B is the drug of choice for initial therapy; most clinicians use a lipid formulation of amphotericin B (rather than amphotericin B deoxycholate) in order to deliver a high dose with less nephrotoxicity. The usual starting dose is 5 mg/kg daily of liposomal amphotericin B or amphotericin B lipid complex, and many clinicians will increase the dose as high as 10 mg/kg daily in an attempt to control this infection. The total dosage of lipid amphotericin B that should be administered has not been studied.

There are anecdotal reports of using combination therapy with amphotericin B and either posaconazole or an echinocandin. However, there are no convincing data to support any form of combination therapy, and combination therapy is not recommended in the major treatment guidelines. One review of 101 cases of invasive mucormycosis showed no difference in 90-day survival when the group of patients diagnosed between 1995 and 2003 (a period when 5 percent received combination amphotericin B plus an echinocandin) was compared with the group diagnosed between 2004 and 2011 (a period when 31 percent received combination therapy with amphotericin B plus an echinocandin) [105]. Another retrospective review of 106 patients with invasive mucormycosis and hematologic malignancies found that there was no difference in six-week mortality in patients treated with amphotericin B monotherapy versus combination therapy using amphotericin B plus either an azole or an echinocandin [106].

There have been apparent cures of isolated renal mucormycosis using amphotericin B deoxycholate alone [23,81] or combined with nephrectomy [23]. In severe cases in which there is little residual renal function, nephrectomy with a short course of amphotericin B deoxycholate (1 mg/kg daily for one to two weeks) appears to be a reasonable course of action.

Step-down therapy — Posaconazole and isavuconazole are broad-spectrum azoles that are active in vitro against the agents of mucormycosis and that are available in both parenteral and oral formulations [107-110]. For patients who have responded to a lipid formulation of amphotericin B, posaconazole or isavuconazole can be used for oral step-down therapy. We continue amphotericin B until the patient has shown signs of improvement; this usually takes several weeks.

When switching to oral posaconazole, we favor the use of posaconazole delayed-release tablets (300 mg every 12 hours on the first day, then 300 mg once daily) taken with food if possible [111]. We do not use the oral suspension of posaconazole since it is not highly bioavailable and requires fatty food for absorption. A serum trough concentration of posaconazole should be checked after one week of therapy; we suggest a goal trough concentration >1 mcg/mL, but higher levels are preferred for treatment of this serious infection (see "Pharmacology of azoles", section on 'Posaconazole'). The data supporting the use of posaconazole for mucormycosis are discussed below. (See 'Salvage therapy' below.)

When using isavuconazole, loading doses are necessary for the first 48 hours. Loading doses of 200 mg (ie, two capsules) of oral isavuconazole (equivalent to 372 mg of the prodrug isavuconazonium sulfate) should be given every 8 hours for six doses, followed by 200 mg orally once daily starting 12 to 24 hours after the last loading dose [112]. An IV formulation of isavuconazole is also available. (See "Pharmacology of azoles", section on 'Isavuconazole'.)

Isavuconazole has not been studied in randomized trials, but it has been evaluated in a multicenter open-label single-arm study (the VITAL study) that included 37 patients with proven or probable mucormycosis [113]. Patients were treated with isavuconazole IV or orally. Median treatment duration was 102 days for patients with primary mucormycosis, 33 days for those with refractory mucormycosis, and 85 days for those with intolerance to other antifungal therapy. All-cause mortality through day 42 was 38 percent, and overall complete or partial response rate at the end of treatment was 32 percent for primary treatment and 36 percent for treatment of mucormycosis refractory to other antifungals. In a matched case-control analysis that compared patients who received isavuconazole for primary therapy of mucormycosis with contemporary controls who received amphotericin B (the majority received a lipid formulation), day 42 crude all-cause mortality was similar in those who received isavuconazole (7 of 21 patients; 33 percent) versus amphotericin B followed by posaconazole (13 of 33 patients; 39 percent) [113]. Weighted all-cause mortality was also similar in those who received isavuconazole versus amphotericin B followed by posaconazole (33 versus 41 percent). These data suggest that isavuconazole has some clinical efficacy in treating mucormycosis, but it is not possible to draw firm conclusions given the nonrandomized study design and the small study size.

Salvage therapy — We use posaconazole or isavuconazole as salvage therapy for patients who do not respond to or cannot tolerate amphotericin B [111,112]. The IV formulation of posaconazole or isavuconazole should be used in patients who have to be switched from amphotericin B before they have had a favorable response and in patients who have an inability to absorb oral medications.

Posaconazole (both IV and delayed-release formulations) is given as a loading dose of 300 mg every 12 hours on the first day, followed by a maintenance dose of 300 mg every 24 hours thereafter. The IV formulation should be avoided in patients with moderate or severe renal impairment (CrCl <50 mL/min) due to the potential for accumulation of the betadex sulfobutyl ether sodium (SBECD) vehicle, unless an assessment of the possible benefits and risks to the patient justifies its use. If it is used in patients with renal impairment, serum creatinine should be monitored closely, and, if increases occur, consideration should be given to changing to the extended-release tablet formulation of posaconazole or to IV or oral isavuconazole. In patients who are able to take medications orally, we use posaconazole delayed-release tablets, usually given with food, rather than the oral suspension because bioavailability with the tablets is much better and it is easier for patients to take.

Isavuconazole should be given as a loading dose of 200 mg (equivalent to 372 mg of the prodrug isavuconazonium sulfate) IV or orally every 8 hours for the first six doses followed by 200 mg IV or orally every 24 hours thereafter. Because the IV formulation of isavuconazole is highly water soluble and does not contain the SBECD vehicle, there are no known concerns about administering the IV formulation to patients with renal impairment.

The clinical efficacy of the oral suspension of posaconazole was shown in a salvage study that enrolled 91 patients who had failed or could not tolerate standard therapy [114]. Posaconazole led to complete or partial response in 60 percent of patients; 21 percent had stable disease. Although there are limitations to this salvage study, this series supports a potential role for oral posaconazole for the treatment of mucormycosis refractory to standard therapy.

The data supporting the use of isavuconazole are discussed above. (See 'Initial therapy' above.)

Duration of therapy — As noted above, patients can be switched from a lipid formulation of amphotericin B to delayed-release posaconazole tablets for oral step-down therapy once a favorable clinical response has been achieved, which usually takes several weeks.

Therapy should continue until there is clinical resolution of the signs and symptoms of infection, as well as resolution of radiographic signs of active disease; therapy should also continue until reversal of underlying immunosuppression has been achieved, when feasible [115]. Therapy often extends for months.

Adverse effects — The adverse effects of amphotericin B formulations, posaconazole, and isavuconazole are discussed in detail separately. (See "Pharmacology of amphotericin B", section on 'Adverse effects' and "Amphotericin B nephrotoxicity" and "Pharmacology of azoles", section on 'Adverse effects' and "Pharmacology of azoles", section on 'Posaconazole' and "Pharmacology of azoles", section on 'Isavuconazole'.)

Other possible adjunctive therapies

Antifungals — Although the echinocandins (eg, caspofungin) have no in vitro activity against the agents of mucormycosis [116-118], Rhizopus oryzae, the most common cause of mucormycosis, expresses the target enzyme for echinocandins, suggesting that these agents may have clinical utility [119]. In a retrospective study of 21 patients with rhino-orbital mucormycosis and 20 patients with rhino-orbital-cerebral mucormycosis, all six patients who received combination therapy with amphotericin B and an echinocandin had successful outcomes, defined as surviving and not requiring hospice care, compared with only 14 of 31 patients who received amphotericin B monotherapy [120]. The benefit of combination therapy was most pronounced among patients with cerebral involvement; all four patients who received combination therapy survived compared with 4 of 16 patients who received amphotericin B monotherapy.

However, there are several limitations to the above observations. In addition to the limited number of patients, all underwent surgical debridement, making it difficult to assess the impact of antifungal therapy on outcomes. The patients who received an echinocandin were seen more recently than most of those who were treated with amphotericin B alone. In addition, the patients were predominantly nonneutropenic. This may have influenced the response to antifungal therapy because modulation of the host neutrophil response is postulated to occur when echinocandins are used to treat infections with filamentous fungi [121,122].

At this time, larger studies are needed to establish whether combination therapy is beneficial [123]. We do not recommend using the combination of a polyene and an echinocandin for the treatment of mucormycosis.

Other antifungal agents, including voriconazole, fluconazole, and flucytosine, are not effective against the Mucorales (table 1) [107].

Deferasirox — In contrast with the iron chelator, deferoxamine, which increases the risk of mucormycosis, the oral iron chelating agent, deferasirox, showed a possible benefit when used to treat mucormycosis in murine models. (See 'Deferoxamine and iron overload' above.)

The possible utility of deferasirox as an adjunctive therapy for mucormycosis has been evaluated in small studies, with mixed results. In an open-label study of deferasirox in combination with antifungal therapy, seven of eight patients survived [124]. In a small trial, 20 patients with proven or probable mucormycosis were randomly assigned to receive either liposomal amphotericin B plus either deferasirox or placebo for the first 14 days of therapy [125]. Death at 90 days after therapy was initiated was significantly more frequent in those who received deferasirox than in those who received placebo (82 versus 22 percent). Reported adverse events were similar between the groups. One possible reason for the worse outcomes in the patients who received deferasirox is that more patients with hematologic malignancy, neutropenia, and/or pulmonary involvement received this agent; all of these conditions are associated with poor outcomes. Further study is necessary to determine the possible benefits or harms of deferasirox.

Hyperbaric oxygen — Hyperbaric oxygen has been used in some patients with mucormycosis, but the benefit of this therapy has not been established [62,126,127].

OUTCOMES — Despite early diagnosis and aggressive combined surgical and medical therapy, the prognosis for recovery from mucormycosis is poor (table 1). An exception is cutaneous involvement, which rarely disseminates. Independent risk factors for mortality include disseminated infection, renal failure, and infection with Cunninghamella species, while the use of surgery and administration of any antifungal agent were associated with a better outcome [5].

Rhino-orbital-cerebral infection — A review of 208 patients with rhino-orbital-cerebral infection showed that the most significant factors associated with death were delayed diagnosis, the presence of hemiparesis/hemiplegia, bilateral sinus involvement, leukemia, renal disease, and treatment with deferoxamine [62]. Overall mortality from rhino-orbital-cerebral mucormycosis ranges from 25 to 62 percent, with the best prognosis in patients with infection confined to the sinuses [5]. The prognosis is especially poor for patients with brain, cavernous sinus, or carotid involvement, although some patients with these complications have been cured of the infection [128-130].

Pulmonary mucormycosis — The outcome in patients with pulmonary mucormycosis is worse than for patients with rhino-orbital-cerebral involvement, with mortality rates as high as 87 percent [5,33,65]. This may be in part due to the underlying conditions and to the inability to widely excise the involved tissues. Widely disseminated mucormycosis carries a mortality rate of 90 to 100 percent [5].

SUMMARY AND RECOMMENDATIONS

Mucormycosis is manifested by a variety of syndromes, particularly in immunocompromised patients and those with diabetes mellitus. Devastating rhino-orbital-cerebral and pulmonary infections are the major syndromes caused by these fungi. (See 'Introduction' above.)

Organisms in the order Mucorales are ubiquitous in nature and can be found on decaying vegetation and in the soil. The genera most commonly found in human infections are Rhizopus, Mucor, and Rhizomucor; Cunninghamella, Saksenaea, and Apophysomyces are less commonly implicated in infection. (See 'Mycology' above.)

Deferoxamine, which chelates both iron and aluminum, increases the risk of mucormycosis by enhancing growth and pathogenicity. The deferoxamine-iron chelate, called feroxamine, is a siderophore for the species Rhizopus, increasing iron uptake by the fungus, which stimulates fungal growth and leads to tissue invasion. (See 'Deferoxamine and iron overload' above.)

Mucormycosis is characterized by infarction and necrosis of host tissues that results from invasion of the vasculature by hyphae. The most common clinical presentation of mucormycosis is rhino-orbital-cerebral infection, which is presumed to start with inhalation of spores into the paranasal sinuses of a susceptible host. (See 'Clinical presentation' above and 'Rhino-orbital-cerebral mucormycosis' above.)

Pulmonary mucormycosis is a rapidly progressive infection that occurs after inhalation of spores into the bronchioles and alveoli. Pneumonia with infarction and necrosis results, and the infection can spread to contiguous structures, such as the mediastinum and heart, or disseminate hematogenously to other organs. Mucormycosis can also cause gastrointestinal, cutaneous, renal, and disseminated disease. (See 'Pulmonary mucormycosis' above and 'Clinical presentation' above.)

The diagnosis of mucormycosis relies upon the identification of organisms in tissue by histopathology with culture confirmation. However, culture often yields no growth, and histopathologic identification of an organism with a structure typical of Mucorales may provide the only evidence of infection. A clinician must think of this entity in the appropriate clinical setting and pursue invasive testing in order to establish a diagnosis as early as possible. The polymerase chain reaction with sequencing may be useful for identifying the causative species when histopathology is positive but cultures are negative. (See 'Diagnosis' above.)

Treatment of mucormycosis involves a combination of surgical debridement of involved tissues and antifungal therapy. Aggressive surgical debridement of involved tissues should be undertaken as soon as the diagnosis of rhino-orbital-cerebral mucormycosis is suspected. Elimination of predisposing factors for infection, such as hyperglycemia, metabolic acidosis, deferoxamine administration, and neutropenia, is also critical. (See 'Treatment' above and 'Surgery' above.)

The drug of choice for initial therapy of mucormycosis is a lipid formulation of amphotericin B. The usual starting dose is 5 mg/kg daily of liposomal amphotericin B or amphotericin B lipid complex, and many clinicians will increase the dose up as high as 10 mg/kg daily in an attempt to control this infection. (See 'Initial therapy' above.)

For patients who have responded to a lipid formulation of amphotericin B, posaconazole or isavuconazole can be used for oral step-down therapy. We continue amphotericin B until the patient has shown signs of improvement; this usually takes several weeks. When switching to oral posaconazole, we favor the use of posaconazole delayed-release tablets (300 mg every 12 hours on the first day, then 300 mg once daily) taken with food. We do not use the oral suspension of posaconazole since it is not highly bioavailable and requires fatty food for absorption. Loading doses of 200 mg (ie, two capsules) of oral isavuconazole (equivalent to 372 mg of isavuconazonium sulfate) should be given every 8 hours for six doses, followed by 200 mg orally once daily starting 12 to 24 hours after the last loading dose. (See 'Step-down therapy' above.)

We use intravenous (IV) posaconazole or isavuconazole as salvage therapy for patients who do not respond to or cannot tolerate amphotericin B. IV posaconazole should be given as a loading dose of 300 mg IV every 12 hours on the first day, followed by a maintenance dose of 300 mg every 24 hours thereafter. The IV formulation should be avoided in patients with moderate or severe renal impairment (CrCl <50 mL/min) due to the potential for accumulation of the cyclodextrin vehicle. In patients who are able to take medications orally, we use posaconazole delayed-release tablets. The dose is 300 mg every 12 hours on the first day and then 300 mg once daily thereafter, taken with food if possible. Isavuconazole should be given as a loading dose of 200 mg (equivalent to 372 mg of the prodrug isavuconazonium sulfate) IV or orally every 8 hours for the first six doses followed by 200 mg IV or orally every 24 hours thereafter. (See 'Salvage therapy' above.)

Overall mortality from rhino-orbital-cerebral mucormycosis ranges from 25 to 62 percent, with the best prognosis in patients with infection confined to the sinuses. The prognosis is especially poor for patients with brain, cavernous sinus, or carotid involvement, although some patients with these complications have been cured of the infection. The outcome in patients with pulmonary mucormycosis is worse than for patients with rhino-orbital-cerebral involvement, with mortality rates as high as 87 percent. (See 'Outcomes' above.)

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