Zygomycosis 

Updated: Aug 12, 2015
Author: Jose A Vazquez, MD, FACP, FIDSA; Chief Editor: Mark R Wallace, MD, FACP, FIDSA 

Overview

Background

Mucormycosis is an infection caused by fungi in the orders Mucorales and Entomophthorales. Previously, the term zygomycosis was used to denote invasive fungal infections (IFIs) caused by the fungi belonging to the phylum Zygomycota, class Zygomycetes, orders Mucorales and Entomophthorales. The Mucorales order contains 2 families—Mucoraceae and Cunninghamellaceae.[1] Since the majority of human infections are caused by Mucorales fungi, the term Mucormycosis is now used to designate this infection.[2]

The terms mucormycosis and zygomycosis are used interchangeably here. The Entomophthorales constitute the second order and includes (Conidiobolus species and Basidiobolus species).[1, 3] During the past decade, mucormycosis has emerged as a common causes of IFI.[4, 3, 5, 6, 7]

The pathogens that cause mucormycosis are commonly found in the environment on fruit, on bread, and in soil and are common components of decaying organic debris.[1] These organisms are ubiquitous and generally saprophytic, rarely causing disease in immunocompetent hosts, but they are the third-most-common cause of invasive fungal infection in immunocompromised patients, especially stem cell transplant recipients and patients with underlying hematologic malignancies.[4, 8, 9, 10, 11]

Fungi are ubiquitous in the natural world, often found in association with plants, mammals, and insects. Accordingly, humans are continually exposed to multiple genera of fungi via various routes, including the respiratory and gastrointestinal routes, which allow the possibility of colonization. Depending on the interaction between host mucosal defense mechanisms and fungal virulence factors, colonization may be transient or persistent, or local disease may ensue.

Pathophysiology

Overall, Rhizopus species from the Mucoraceae family are the most commonly identified etiologic agents of zygomycosis in humans. Of the Rhizopus species, the most common agent associated with zygomycosis is Rhizopus arrhizus (Rhizopus oryzae), followed by Rhizopus rhizopodiformis. Other causes include Mucor species, Cunninghamella bertholletiae, Apophysomyces elegans, Lichtheimia (Absidia species), Saksenaea species, Rhizomucor pusillus, Entomophthora species, Conidiobolus species, and Basidiobolus species.[4, 11, 12, 7]

Infections caused by R arrhizus are frequently acute and rapidly fatal despite early diagnosis and treatment. These organisms have a particular predilection for invading major blood vessels, with ensuing ischemia, necrosis, and infarction of adjacent tissues, resulting in the production of black pus. Persons at particular risk include patients with granulocytopenia, hematopoietic stem cell transplant and solid organ transplant recipients, and patients with underlying acidosis.[13] For unknown reasons, agents of mucormycosis have a propensity to affect patients with acidosis, particularly those with diabetes. In addition, they also infect patients with acidosis secondary to renal insufficiency, diarrhea, and aspirin intake. Patients who are receiving glucocorticoids or deferoxamine and those who have undergone splenectomy also are at risk.[10, 11, 12, 14]

Epidemiology

Frequency

International

The distribution of the various forms of zygomycosis is uniform regardless of age, geography, or race.

Mortality/Morbidity

The overall mortality rate associated with zygomycosis is approximately 50% and has remained at this level for the past 50 years. Rhinocerebral zygomycosis carries a mortality rate of approximately 85%. Mortality rates are very high because, by the time zygomycosis is suspected and diagnosed, it has frequently spread diffusely and caused extensive tissue destruction. However, the risk of mortality varies depending on the characteristics of the host, the type of infection, the site of infection, and the use of surgical intervention. In general, antifungal therapy and surgical management independently decrease the likelihood of death.[11]

Sex

According to the latest epidemiologic surveys, approximately two thirds of all zygomycosis cases occur in males. The reason for this discrepancy is poorly understood.

 

Presentation

History

Mucormycosis can manifests as a spectrum of diseases, depending on the portal of entry and the predisposing risk factors of the patient. The 5 major clinical forms include rhinocerebral mucormycosis, pulmonary mucormycosis, abdominopelvic and gastric (gastrointestinal) mucormycosis, primary cutaneous mucormycosis, and disseminated mucormycosis.[3, 15, 12, 14]

Rhinocerebral mucormycosis

Rhinocerebral mucormycosis is the most frequently encountered form of the disease. Approximately 50% of mucormycosis cases in persons with diabetes are of the rhinocerebral type. Rhinocerebral mucormycosis is frequently observed in patients presenting with diabetic ketoacidosis. The typical presentation of rhinocerebral zygomycosis generally involves the nose, followed by the eyes, brain, and, occasionally, the meninges.

Patients with rhinocerebral mucormycosis typically present with a history of fever, unilateral facial pain or headaches, nasal congestion, epistaxis, visual disturbances, and lethargy.

Physical examination may reveal periorbital cellulitis, proptosis, and loss of extraocular muscle movement (as seen in the image below). These lesions are frequently accompanied by cranial nerve palsy of the II, III, IV, and VI nerves.

A 45-year-old woman with poorly controlled diabete A 45-year-old woman with poorly controlled diabetes mellitus with facial and periorbital swelling due to zygomycosis. She was unable to open her right eye upon admission.

Black necrotic lesions are generally observed on the hard palate or nasal mucosa of these extremely ill patients.

Pulmonary mucormycosis

Patients with pulmonary mucormycosis typically present with a history of fever, cough, hemoptysis, chest pain, and increasing shortness of breath.

Physical examination may reveal pleuritic rub and rhonchi over the affected area.

Primary pulmonary mucormycosis is the second most common form of the infection and tends to occur in patients with hematological malignancy, those with profound neutropenia, stem cell transplant recipients, and in those who have been receiving high-dose steroid therapy.

Gastrointestinal mucormycosis

Patients with gastrointestinal infection typically present with a history of abdominal pain or distention, dyspepsia, nausea and vomiting, diarrhea, and hematochezia.

Physical examination may reveal decreased bowel sounds, guarding or rebound tenderness, and localized-to-diffuse abdominal tenderness.

Gastrointestinal mucormycosis is the least common form of the infection, accounting for less than 10% of all cases of mucormycosis.[11]

Gastrointestinal mucormycosis tends to develop in malnourished individuals, low birth weight infants, or in patients with renal failure who are on peritoneal dialysis. Infection is caused by ingestion of the organism and results in necrotic ulcerations, with ischemia and gangrene of the stomach and colon. Gastrointestinal mucormycosis carries an extremely high mortality rate because of the high incidence of bowel perforation and the difficulty in establishing the diagnosis.[16]

Cutaneous mucormycosis

Cutaneous mucormycosis accounts for approximately 20% of all zygomycosis cases.

Primary cutaneous zygomycosis is generally due to local trauma or inoculation, while secondary infection is due to hematogenous dissemination of the organisms to the skin.

Patients with cutaneous infection typically present with a history of previous local trauma, with pain around the trauma site.

Physical examination may reveal single skin lesions that begin with induration and erythema and gradually develop into a necrotic ulcer with a characteristic dark central area. The margins of the ulcer are sharply demarcated.

Cutaneous mucormycosis may be primary, resulting from direct inoculation of the organism into disrupted integument. It also has been associated with the use of Elastoplast bandages over biopsy sites and in burn patients with prior colonization. Secondary cutaneous mucormycosis is generally seen in association with widely disseminated infection due to hematogenous seeding.

Disseminated mucormycosis

Disseminated mucormycosis generally arises from the lungs and spreads hematogenously to the central nervous system.

Patients with disseminated mucormycosis typically present with a history of headaches, fever, visual disturbances, and changes in mental status.

Physical examination may reveal lethargy, obtundation, coma, sudden onset of focal neurologic deficits, and necrotic ulcerations on the respiratory-tract mucosa or the skin.

Deferoxamine therapy appears to be the most significant risk factor for disseminated mucormycosis. This underscores the importance of iron availability as a virulence factor for these infections.

Disseminated mucormycosis in individuals with hematological malignancies begins in the lungs and spreads to the CNS, producing infarction and abscess. It also can spread to the liver, spleen, kidney, heart, and skin.

Physical

See History.

Causes

Most persons who develop mucormycosis are immunocompromised, although 15-20% of patients have no evidence of any underlying condition at the time of the diagnosis.[6, 10, 11, 12, 14] Thus, sporadic cases in immunocompetent hosts are not uncommon. The most common risk factors include the following:

  • Stem cell transplantation

  • Poorly controlled diabetes mellitus, either type 1 or type 2

  • Hematologic malignancy (eg, leukemias, lymphomas)

  • Solid organ transplants

  • Steroid use

  • Metabolic acidosis

  • Deferoxamine therapy

  • Severe and prolonged neutropenia

  • Intravenous drug use

  • Renal failure

  • Peritoneal dialysis

  • Burns

  • Penetrating trauma (rare)

 

DDx

 

Workup

Laboratory Studies

Unfortunately, findings from laboratory studies are nonspecific for zygomycosis.[9, 15] Diagnosis requires a high index of suspicion, a host with appropriate risk factors, and evidence of tissue invasion with the characteristic appearance of broad nonseptate hyphae with right-angle branches.[12, 14] No serologic tests are available, and blood cultures are of no benefit.[1]

Rhinocerebral mucormycosis

Discharge scrapings may be examined with potassium hydroxide (KOH) to reveal broad irregularly shaped hyphae with right-angle branching (as seen in the image below).

Material from the periorbital tissue of a woman wi Material from the periorbital tissue of a woman with poorly controlled diabetes mellitus with facial and periorbital swelling due to zygomycosis is stained with periodic acid-Schiff stain (X 560). The material demonstrates the classic appearance of irregularly shaped broad hyphae with right-angle branching (arrow).

Fungal stains of biopsy material obtained from affected tissue remains the mainstay for a definitive diagnosis.

Fungal culture of biopsy tissue also may be helpful, but results frequently are negative despite positive histopathology. In fact, fungal culture results are only positive in 15-25% of cases.

Pulmonary mucormycosis

Sputum smear and cultures are rarely helpful.

Lung tissue biopsy is generally needed for diagnosis.

Gastrointestinal mucormycosis

Most cases of gastrointestinal infection are diagnosed at surgery or postmortem.

Fungal stains and cultures of biopsy material are needed for definitive diagnosis.

Cutaneous mucormycosis

Diagnosis of this type requires fungal stains and cultures of a skin biopsy.

Disseminated mucormycosis

Blood cultures are of no benefit.

Fungal stains and cultures of affected tissue and histopathologic identification of the fungus are needed.

Brain biopsy may be helpful.

Cerebrospinal fluid analysis is generally nonspecific, even in the presence of brain involvement.

Cerebrospinal fluid abnormalities include slightly increased pressure, modest pleocytosis with predominant polymorphonuclear cells, and slightly elevated protein levels. Hypoglycorrhachia is unusual. Erythrocytosis is occasionally observed. Fungal stains and culture results are rarely positive.

Imaging Studies

Rhinocerebral mucormycosis

Plain radiographs of sinuses and orbits may demonstrate sinus mucosal thickening, with or without air-fluid levels, but this is nonspecific.

CT scans with contrast or MRI may demonstrate erosion or destruction of bone or sinuses and delineate the extent of disease (as seen in the image below).

A CT scan of the head of a patient with zygomycosi A CT scan of the head of a patient with zygomycosis shows involvement of the paranasal sinuses and periorbital soft tissues.

Pulmonary mucormycosis

Chest radiographs may demonstrate single or multiple large masslike infiltrates, pulmonary nodules, and cavitary lesions. These lesions, however, are indistinguishable from those caused by aspergillosis.

CT scan with contrast may help delineate the extent of disease.

Gastrointestinal mucormycosis

Abdominal radiographs may demonstrate air under the diaphragm in patients with perforation.

Barium studies of the upper GI tract or colon may demonstrate a filling defect or a masslike effect that suggests zygomycosis.

Disseminated mucormycosis

CT scan of the chest and head may demonstrate invasive disease and delineate the extent of disease.

CT scan of the abdomen and pelvis may demonstrate lesions in the liver, spleen, kidney, pancreas, stomach, and omentum.

Procedures

Bronchoscopy with bronchoalveolar lavage and transbronchial biopsy provides adequate tissue to diagnose pulmonary mucormycosis.

CT-guided percutaneous lung biopsy may also be beneficial.[17]

Open lung biopsy may be required if bronchoscopy findings are negative.

Endoscopy provides direct examination of the esophagus and stomach, the most commonly affected organs in patients with gastrointestinal mucormycosis.

Brain biopsy may be required to establish a diagnosis.

Histologic Findings

Fixed tissue can be stained with hematoxylin and eosin (H&E). Fungal hyphae may be demonstrated with Grocott methenamine-silver stain or periodic acid-Schiff (PAS) staining. The typical appearance demonstrates the fungus as broad, nonseptate hyphae with acute right-angle branching.

 

Treatment

Medical Care

Take aggressive surgical measures to débride affected tissue. Without early and aggressive therapy, mucormycosis is almost always fatal.

Take aggressive measures to control the underlying condition, as follows:

  • Correct hyperglycemia and ketoacidosis to improve outcome.
  • Correct neutropenia with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) to improve outcome.

Institute early and appropriate antifungal administration.

If possible, discontinue any immunosuppressant agents, including chemotherapy and steroids.

Surgical Care

The mainstay of treatment for any form of mucormycosis is early and aggressive surgical removal of all infected tissue.

Remove as much devitalized tissue as possible and consider wide surgical debridement, if feasible.

Patients with mucormycosis frequently require numerous surgical procedures to eradicate all infected and necrotic material.

Consultations

See the list below:

  • Infectious disease specialist

  • Surgeon

  • Otorhinolaryngologist

  • Gastroenterologist

  • Pulmonologist

  • Ophthalmologist

  • Neurosurgeon

 

Medication

Medication Summary

Start antifungal therapy as early as possible.[18, 14] Until recently, amphotericin B was the only available antifungal with some proven efficacy against most of the Zygomycetes. Recently, a novel azole antifungal, isavuconazonium sulfate (isavuconazole) has been approved for the treatment of invasive mucormycosis.[19, 20]

Lipid preparations of amphotericin B have been the current mainstay of therapy for all forms of mucormycosis.[5, 18, 21] The lipid preparations of amphotericin B are used more frequently because they allow the delivery of higher doses of the parent compound, amphotericin B. In addition, lipid preparations cause milder renal insufficiency typically associated with amphotericin B. Although investigational, combination therapy with lipid preparations of amphotericin B and G-CSF have been successful in several small-scale clinical trials.[22] Additionally, other combinations that have shown some synergistic activity include amphotericin B and echinocandins, amphotericin B and posaconazole, and amphotericin B and isavuconazole.[23]

Isavuconazole, a newer triazole, was recently approved by the FDA for the treatment of invasive aspergillosis and invasive mucormycosis.[19, 20] It has quickly become a viable alternative as primary therapy for invasive mucormycosis. The antifungal is available in capsule form, 186 mg of isavuconazonium sulfate (equivalent to 100 mg isavuconazole), and parenteral form, 372 mg of isavuconazonium sulfate (equivalent to 200 mg isavuconazole). The drug has demonstrated excellent results in a large multicenter, open-label study.

Posaconazole is also a triazole with proven efficacy against most Zygomycetes in vitro and in vivo.[24, 25, 26] Posaconazole was approved with an indication for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression.[26] Currently, posaconazole is available in an oral suspension, a tablet, and, most recently, in parenteral form and must be administered 2-4 times per day. It has shown encouraging results in open-labeled clinical trials involving complicated Zygomycetes infections.[27] In addition, posaconazole is frequently used as the oral de-escalation therapy in patients in whom amphotericin B has elicited an initial response and are clinically stable or improving.

Antifungals

Class Summary

These agents are polyene antifungals.[28] They represent the only antifungal class with known activity against Zygomycetes.

The FDA has approved 3 novel lipid formulations of amphotericin B. The advantage of the lipid preparation over standard amphotericin B deoxycholate is that it delivers higher concentrations of amphotericin B, resulting in a theoretical increase in therapeutic potential and causes decreased nephrotoxicity (25%). The 3 lipid formulations include amphotericin B lipid complex (ABLC; Abelcet), amphotericin B colloidal dispersion (ABCD; Amphotec), and liposomal amphotericin B (L-AMB; AmBisome).

Amphotericin B (Amphocin, Fungizone)

The only available antifungal agent effective against Zygomycetes. Because of the drug toxicity, monitoring for side effects and toxicity is extremely important. Dose aggressively. A polyene antibiotic synthesized by Streptomyces nodosus. Binds irreversibly to ergosterol in fungal cell membrane. This increases permeability and causes extracellular leak of cations and eventual cellular death.

Amphotericin B lipid complex (Abelcet)

Mainstay of therapy in any form of zygomycosis. Approved for treating adults and children with fungal infections refractory to, or intolerant of, conventional amphotericin B.

Amphotericin B colloidal dispersion (Amphotec)

Approved for treating adults and children with aspergillosis refractory to, or intolerant of, conventional amphotericin B.

Liposomal amphotericin B (AmBisome)

Mainstay of therapy for any form of zygomycosis. It is approved for the treatment of adults and children with aspergillosis, candidiasis, and cryptococcosis refractory to, or intolerant of, conventional amphotericin B. Also approved for empiric antifungal therapy of persistently febrile neutropenic patients.

Antifungal agents, triazoles

Class Summary

Posaconazole has shown encouraging results in clinical trials for complicated Zygomycetes infections.

Posaconazole (Noxafil)

Triazole antifungal agent. Blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. In vitro, posaconazole has demonstrated activity against most Zygomycetes. This mechanism of action results in the disruption of the cellular membrane. Available as oral susp (200 mg/5 mL). Indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression and for the treatment of oropharyngeal candidiasis and antifungal refractory oropharyngeal candidiasis.

Systemic, Antifungal agent, triazole

Isavuconazonium sulfate (Cresemba, Isavuconazole)

Triazole antifungal agent. Blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. In vitro, isavuconazole has demonstrated excellent activity against the Mucormycetes. This mechanism of action results in the disruption of the cellular membrane. Available as a capsule (186 mg isavuconazonium sulfate, equivalent to 100 mg of isavuconazole) and parenteral formulation (372 mg isavuconazonium sulfate, equivalent to 200 mg isavuconazole). It is approved for invasive mucormycosis and invasive aspergillosis.

 

Follow-up

Further Outpatient Care

Once the patient is stabilized and no further surgical procedures are planned, discharge the patient home on antifungal therapy with follow-up visits every 2-4 weeks.

Monitor patients on amphotericin B products at least biweekly for adverse effects and toxicity (eg, CBC counts, electrolytes, BUN, serum creatinine).

Further Inpatient Care

Inpatient care of mucormycosis is frequently prolonged because of the severe nature of the illness.

Patients with mucormycosis frequently undergo multiple surgical procedures in an attempt to eradicate devitalized tissue.

Antifungals are generally provided parenterally for a period of several months to achieve cure.

Inpatient & Outpatient Medications

Because of the severity of the infection, most patients with mucormycosis undergo inpatient care for most of their treatment. If patient is clinically stable, the infection appears controlled, and the gastrointestinal tract is functional, he or she may be switched to oral posaconazole and discharged home with close monitoring for efficacy and toxicity.

Transfer

Transfer patients to the service that can care for serious infections (eg, neurosurgery, otorhinolaryngology, infectious diseases, ophthalmology).

Transfer patients with altered mental status to an appropriate critical care unit.

Deterrence/Prevention

Control blood sugar in patients with diabetes mellitus.

Control metabolic acidosis.

Eliminate risk factors such as neutropenia and immune modulators.

Closely monitor patients on deferoxamine therapy.

Complications

Invasive mucormycosis frequently spreads to adjacent organ systems (ie, osteomyelitis), including sinuses and adjacent bones.

The ocular globe is frequently affected, which may cause blindness.

Cavernous sinus thrombosis with cranial nerve palsies and extension of infection into the brain and meningitis is a possibility.

Brain abscess and CNS infarction with ischemia and necrosis may occur.

Pulmonary infiltrates, cavitary lesions, and life-threatening pulmonary hemorrhages are possible.

Gastrointestinal hemorrhages may result from gastrointestinal perforation and may lead to peritonitis and sepsis.

Prognosis

The prognosis of mucormycosis depends on several factors, including the infection site, rapidity of diagnosis, and type and severity of immunosuppression.

The overall mortality rate among patients with mucormycosis is approximately 50%, although rhinocerebral and gastrointestinal forms of the infection carry a mortality rate of approximately 85%. Mortality rates are high because of the difficulty in establishing the diagnosis and the lack of adequate antifungal therapy. By the time a diagnosis of mucormycosis is confirmed, it has frequently spread via either local invasion with extensive tissue destruction or widely disseminated infection.

Patient Education

Inform patients and family members that this is an extremely serious condition with a poor prognosis (high morbidity and mortality rate) unless aggressive action is taken early.