mucormicosis (zygomicosis)

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Official reprint from UpToDatewww.uptodate.com ©2015 UpToDate

Author

Gary M Cox, MD

Section Editor

Carol A Kauffman, MD

Deputy Editor

Anna R Thorner, MD

Mucormycosis (zygomycosis)

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2015. | This topic last updated: Jul 27, 2015.

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, that 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].

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rmycosis (zygomycosis) http://www.uptodate.com.wdg.biblio.udg.mx:2048/contents/muco

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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

[5,18-29]:

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 [35].

Malignancy and hematopoietic cell transplantation — Among patients with malignancy, hematologic malignanciesare 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 [36]. 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 [31].

Reports from several countries have noted an increase in mucormycosis in patients with hematologic malignancies

[1,30,37]. Most of these patients had undergone HCT, many had graft-versus-host disease, and almost all were on

voriconazole for prophylaxis or treatment [1,30]. 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].

Diabetes mellitus, particularly with ketoacidosis●

Treatment with glucocorticoids [25]●

Hematologic malignancies [1,27,30]●

Hematopoietic stem cell transplantation [5,25,31]●

Solid organ transplantation [31-34]●

Treatment with deferoxamine [9-11,13] (see 'Deferoxamine and iron overload' above and "Chelation therapy for

thalassemia and other iron overload states")

●

Iron overload [13]●

AIDS●

Injection drug use●

Trauma/burns [35]●

Malnutrition●


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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 [38].

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 [31,39]. Among solid organ transplant recipients, risk factors for mucormycosisinclude renal transplantation [32], renal failure, diabetes, and prior voriconazole or caspofungin use [34].

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 [37] or in developing countries [28,40]. 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)

[41]. 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 [41-43]. 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 [44]. (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 [45-49]. 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 [45]. 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 [48]. 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 [50]. 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)

[50]. 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).


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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 [51,52].

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-cerebralmucormycosis in the absence of any apparent risk factors [18,52-55].

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 [51].

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. A

black eschar, which results from necrosis of tissues after vascular invasion by the fungus, may be visible in the nasal

mucosa or the palate [56].

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 [57]:

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 [58,59], or disseminate hematogenously to

other organs [60,61].

Most patients have fever with hemoptysis that can sometimes be massive [60,61]. 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 [19,60-65]. 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) [66]. The ileum and esophagus were rare sites of involvement.

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●


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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 [20,66-69]. 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

[70], 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 entrysite for an intravenous catheter, spider bites, and insulin injection sites [21,22,71-75]. Infection has also been

associated with contaminated traumatic wounds, dressings and splints, burns, and surgical sites

[21,22,41,45,46,48,50,71-75].

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 [5,75].

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 [21,22,46,48,50,72,74,75].

Dissemination and deep tissue involvement are unusual complications of cutaneous mucormycosis [73,75].

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 [23,24,76-78].

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 [24,79-81]. Infection was 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 had HIV infection in addition to drug use. However, it is not clear

whether HIV infection is an independent risk factor [24,80,82].

Most of the patients presented with lethargy and focal neurologic deficits, with the vast majority having involvement of

the basal ganglia [79-81]. Isolated involvement of the frontal lobe has also been described [79].

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 — 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.

Investigational studies have demonstrated the feasibility of using polymerase chain reaction (PCR)-based techniques

on histologic specimens [83-85]. In one study of patients with proven mucormycosis, among 12 cases that were


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positive by culture, 10 were also positive by PCR and sequencing was concordant with culture results to the genus

level in 9 [84]. 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.

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 [86].

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 [62,87]. 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 [ 88-90]. Mucormycosis appears to be the most common

condition to cause the reversed halo sign in immunocompromised hosts [89]. 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 [88]. Radiographic evidence of infarction with cavitary lesions and an air crescent sign is unusual [62]. 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 [87].

Sputum or bronchoalveolar lavage (BAL) specimens can show the characteristic broad nonseptate hyphae, which is

often the first indicator of mucormycosis [63]. 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 ultrasound or CT can

demonstrate enhancement and 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]. 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 [91]. Posaconazole is used as

step-down therapy for patients who have responded to amphotericin B; in most cases, the extended-release tablet

formulation can be used. Posaconazole 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 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. Isavuconazole, available in both an IV and an oral formulation, can be used


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if the patient cannot tolerate posaconazole.

Surgery — Aggressive surgical debridement of involved tissues should be undertaken as soon as the diagnosis of

rhino-orbital-cerebral mucormycosis is suspected. The debridement to remove all necrotic tissue will often be

disfiguring, requiring removal of the palate, nasal cartilages, and the orbit. There are reports of patients with early

pulmonary infection who were cured with lobectomies [60,61,92]. However, many patients present with multilobar

involvement that precludes surgical resection.

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) [93].

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 up 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 have been apparent cures of isolated renal mucormycosis using amphotericin B deoxycholate alone [ 23,76] 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 oral azoles that are active in vitro

against the agents of mucormycosis [94-96]. For patients who have responded to a lipid formulation of amphotericin B,

posaconazole can be used for oral step-down therapy. Isavuconazole is an alternative for patients who cannot take

posaconazole. 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 [ 97]. 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 of at least 0.7

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 [98]. 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 an open-label non-comparative

study that included 37 patients with proven or probable mucormycosis [98]. Patients were treated with isavuconazoleIV 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 success rate at the end of treatment was 31 percent. These data suggest

that isavuconazole has some clinical efficacy in treating mucormycosis, although how it compares to amphotericin B or

posaconazole is unknown.

Salvage therapy — We use posaconazole as salvage therapy for patients who do not respond to or cannot

tolerate amphotericin B [97]. The IV formulation 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 oral formulations) is given as a loading dose of 300 mg every 12 hours on the first day,


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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 is an alternative to posaconazole in patients who are intolerant of posaconazole or who cannot achieve

a therapeutic serum level of posaconazole. 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. 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.

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 [99]. 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.

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 [100]. Therapy often extends for months.

Other possible adjunctive therapies

Antifungals — Although the echinocandins (eg, caspofungin) have no in vitro activity against the agents of

mucormycosis [101-103], Rhizopus oryzae, the most common cause of mucormycosis, expresses the target enzymefor echinocandins, suggesting that these agents may have clinical utility [104]. 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 [105]. 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 [106,107].

At this time, larger studies are needed to establish whether combination therapy is beneficial [108]. 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) [94].

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


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'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 [109]. 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 [110]. 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 hematologicmalignancy, 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 [57,111,112].

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 [57]. 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 [ 113-115].

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 [5,32,60]. 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 growthand 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

●


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Treatment of mucormycosis involves a combination of surgical debridement of involved tissues and antifungal

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The drug of choice for initial therapy of mucormycosis is a lipid formulation of amphotericin B. The usual starting

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●

For patients who have responded to a lipid formulation of amphotericin B, posaconazole can be used for oral

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●

We use intravenous (IV) posaconazole as salvage therapy for patients who do not respond to or cannot tolerate

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●

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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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human polymorphonuclear neutrophil activity against Aspergillus and non-Aspergillus hyphae. J Infect Dis 2008;

198:186.

107.

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Topic 2465 Version 28.0


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Pulmonary mucormycosis in a lung transplant

recipient

(A) Computed tomography (CT) scan of lung showing pulmonary nodule

and (B) fine needle aspiration of right lower lobe of lung showing

aseptate hyphae (Papanicolaou stain, x400).

Reproduced with permission from: Silveira FP, Husain S. Fungal infections in

lung transplant recipients. Curr Opin Pulm Med 2008; 14:211. Copyright ©

2008 Lippincott Williams & Wilkins.



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In vitro susceptibility of filamentous fungi to systemically active

antifungal agents determined by CLSI M38-A2 broth microdilution

methods

OrganismAntifungal

agentNumber tested

MIC (mcg/mL)

50

percent*

90

percent*

Aspergillus fumigatus Amphotericin B 1119 0.5 1

Itraconazole 1119 0.5 1

Isavuconazole 855 0.5 1

Posaconazole 1119 0.12 0.5

Voriconazole 1119 0.25 0.5

Caspofungin 256 0.03 0.06

A. flavus Amphotericin B 89 1 2

Itraconazole 89 0.5 1

Isavuconazole 444 0.5 1


Voriconazole 89 0.5 1


A. niger Amphotericin B 101 0.12 1

Itraconazole 101 1 2

Isavuconazole 207 1 2




A. versicolor Amphotericin B 20 1 2

Itraconazole 20 1 2

Isavuconazole 75 0.25 0.5

Posaconazole 20 0.5 1



A. terreus Amphotericin B 22 2 2

Itraconazole 22 0.5 0.5

Isavuconazole 384 0.5 0.5




¶

¶

¶

¶

¶


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Fusarium spp Amphotericin B 67 8 32


Isavuconazole 20 16 >16

Posaconazole 67 16 32

Voriconazole 67 16 32

Caspofungin 13 >8 >8

Scedosporium

apiospermum

Amphotericin B 26 2 8





Micafungin 36 >16 >16

S. prolificans Amphotericin B 80 16 32


Isavuconazole 6 16 -

Posaconazole 80 16 32

Voriconazole 55 4 4

Micafungin 17 >32 >32

Mucorales Amphotericin B 86 0.25 2




Voriconazole 86 16 128

CLSI: Clinical and Laboratory Standards Institute; MIC: minimum inhibitory concentration.

* 50 percent and 90 percent; MIC encompassing 50 percent and 90 percent of isolates tested, respectively.

¶ Amphotericin B MICs determined by Etest.

Data from:

Sabatelli F, Patel R, Mann PA, et al. In vitro activities of posaconazole, fluconazole, itraconazole,

voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts.

Antimicrob Agents Chemother 2006; 50:2009.

1.

Diekema DJ, Messer SA, Hollis RJ, et al. Activities of caspofungin, itraconazole, posaconazole,

ravuconazole, voriconazole, and amphotericin B against 448 recent clinical isolates of filamentousfungi. J Clin Microbiol 2003; 41:3623.

2.

Pfaller MA, Messer SA, Boyken L, et al. In vitro survey of triazole cross-resistance among more than

700 clinical isolates of Aspergillus species. J Clin Microbiol 2008; 46:2568.

3.

Cortez KJ, Roilides E, Quiroz-Telles F, et al. Infections caused by Scedosporium spp. Clin Microbiol

Rev 2008; 21:157.

4.

Espinel-Ingroff A, Chowdhary A, Gonzalez GM, et al. Multicenter study of isavuconazole MIC

distributions and epidemiological cutoff values for Aspergillus spp. for the CLSI M38-A2 broth

microdilution method. Antimicrob Agents Chemother 2013; 57:3823.

5.

Guinea J, Pelaez T, Recio S, et al. In vitro antifungal activities of isavuconazole (BAL4815),

voriconazole, and fluconazole against 1,007 isolates of zygomycete, Candida, Aspergillus, Fusarium,

6.

¶

¶

¶

¶


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and Scedosporium species. Antimicrob Agents Chemother 2008; 52: 1396.



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Disclosures: Gary M Cox, MD Nothing to disclose. Carol A Kauffman, MD Nothing to disclose. Anna R Thorner, MD Nothing to disclose.

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Disclosures


mucormicosis (zygomicosis)

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