AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

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.

Zygomycosis is an infection caused by the fungi of the orders Mucorales and Entomophthorales. Mucormycosis is another common name applied to this same group of diseases. This designation reflected the predominance of the Mucorales in causing disease in humans. This term, however, ignored the role of the Entomophthorales (Conidiobolus species and Basidiobolus species). The currently accepted designation is zygomycosis, reflecting all disease processes caused by the members of the class Zygomycetes. The 2 orders of Zygomycetes include Mucorales and Entomophthorales. In the Mucorales order, 2 families exist—Mucoraceae and Cunninghamellaceae.

These organisms are ubiquitous and generally saprophytic, rarely causing disease in an immunocompetent host, but they are the third most frequent cause of invasive fungal infection in immunocompromised patients.

The agents of zygomycosis commonly are found in the environment on fruit, bread, and in soil. The organisms are common components of decaying organic debris.

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 of zygomycosis is Rhizopus arrhizus (Rhizopus oryzae).

The infection produced by this species is acute and rapidly fatal despite early diagnosis and treatment. These organisms have a particular predilection to invade major blood vessels, with ensuing ischemia, necrosis, and infarction of adjacent tissues, resulting in the production of black pus. Particularly at risk are granulocytopenic and acidotic patients. The Zygomycetes, for unknown reasons, have a propensity to affect acidotic patients—in particular, patients with diabetes. They also will infect patients with acidosis secondary to renal insufficiency, diarrhea, and aspirin intake. Patients on glucocorticoid or deferoxamine therapy and those who had previous splenectomy also are at risk.

Frequency

International

The distribution of the various forms of zygomycosis internationally or in the United States is not based on age, sex, geography, or race.

Mortality/Morbidity

The mortality rate is approximately 85% for patients with the rhinocerebral form, and the overall mortality rate is approximately 50%. Mortality rates are very high because, by the time the disease is suspected and diagnosed, it frequently has spread diffusely and caused extensive tissue destruction.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Zygomycosis presents as a spectrum of diseases, depending on the portal of entry and the predisposing risk factors of the patient. The 5 major clinical forms are as follows: (1) rhinocerebral, (2) pulmonary, (3) abdominal-pelvic and gastric (gastrointestinal), (4) primary cutaneous, and (5) disseminated.

• Rhinocerebral zygomycosis
• • Rhinocerebral is the most frequently encountered form of the disease, observed primarily in patients with diabetic acidosis. The characteristic presentation generally involves the nose, followed by the eyes, brain, and, occasionally, the meninges.
  • Patients 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 (see Image 1). These lesions frequently are accompanied by cranial nerve palsy of the II, III, IV, and VI nerves.
  • Black necrotic lesions generally are observed on the hard palate or nasal mucosa of these extremely ill patients.
• Pulmonary zygomycosis
• • Patients 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 zygomycosis tends to occur in patients with hematological malignancy or profound neutropenia and in those who have been on steroid therapy.
• Gastrointestinal zygomycosis
• • Patients 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 zygomycosis usually results when a patient who is malnourished or experiencing renal failure ingests the organism. Infection results in necrotic ulcerations, with ischemia and gangrene of the stomach and colon.
• Cutaneous zygomycosis
• • Primary disease is due to local trauma or inoculation; secondary disease is due to hematogenous dissemination to the skin.
  • Patients 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 zygomycosis 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 infection generally is observed with widely disseminated zygomycosis because of hematogenous seeding.
• Disseminated zygomycosis
• • The disseminated form generally arises from the lungs and spreads hematogenously to the central nervous system.
  • Patients 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.
  • Disseminated zygomycosis in patients 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 physical examination findings paired with clinical syndromes above.

Causes

The majority of affected patients are immunocompromised, although sporadic cases in noncompromised hosts have been described. The most common risk factors include the following:

• Poorly controlled diabetes mellitus
• Hematologic malignancy (eg, leukemias, lymphomas)
• Solid organ or bone marrow transplant
• Steroid use
• Metabolic acidosis
• Deferoxamine therapy
• Severe and prolonged neutropenia

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Rhinocerebral zygomycosis
Aspergillosis of the nasal cavity
Infection due to Pseudallescheria boydii and other filamentous molds
Cavernous sinus thrombosis
Bacterial sinusitis
Periorbital cellulitis

Pulmonary zygomycosis
Pulmonary aspergillosis
Pulmonary infection with Pseudallescheria boydii and other filamentous molds
Pulmonary infection with Pseudomonas aeruginosa

Gastrointestinal zygomycosis
Peptic ulcer disease
Gastrointestinal carcinoma
Gastrointestinal infection with Aspergillus or other filamentous molds
Mesenteric ischemia

Cutaneous zygomycosis
Ecthyma gangrenosum
Cutaneous aspergillosis
Cutaneous infections with other molds

Disseminated zygomycosis
Disseminated aspergillosis
Nocardiosis
Cryptococcosis
Toxoplasmosis
CNS lymphoma or other CNS malignancies
Bacterial brain abscess

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Unfortunately, findings from laboratory studies are nonspecific. 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. No serologic tests are available, and blood cultures are of no benefit.
• Rhinocerebral zygomycosis
• • Discharge scrapings may be examined with potassium hydroxide (KOH) to reveal broad, irregularly shaped hyphae with right-angle branching (see Image 2).
  • 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 zygomycosis
• • Sputum smear and cultures rarely are helpful.
  • Lung tissue biopsy generally is needed for diagnosis.
• Gastrointestinal zygomycosis
• • In most cases, diagnosis is made at surgery or postmortem.
  • Fungal stains and cultures of biopsy material are needed for definitive diagnosis.
• Cutaneous zygomycosis requires fungal stains and cultures of a skin biopsy for diagnosis.
• Disseminated zygomycosis
• • 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 generally is nonspecific, even in the presence of brain involvement.
  • Cerebrospinal fluid abnormalities include slightly increased pressure, modest pleocytosis with predominant polymorphonuclear cells, and slight protein elevation. Hypoglycorrhachia is unusual. Erythrocytosis occasionally is observed. Fungal stains and culture results rarely are positive.

Imaging Studies

• Rhinocerebral zygomycosis
• • 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 (see Image 3).
• Pulmonary zygomycosis
• • Chest radiographs may demonstrate single or multiple large masslike infiltrates, pulmonary nodules, and cavitary lesions. These lesions, however, are indistinguishable from aspergillosis.
  • CT scan with contrast may help delineate the extent of disease.
• Gastrointestinal zygomycosis
• • Abdominal radiographs may demonstrate air under the diaphragm if a perforation has occurred.
  • Barium studies of the upper GI tract or colon may demonstrate a filling defect or a masslike effect that suggests zygomycosis.
• Disseminated zygomycosis
• • 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 make a diagnosis of pulmonary infection.
• 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 of gastrointestinal zygomycosis.
• 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 classic appearance demonstrates the fungus as broad, nonseptate hyphae with acute right-angle branching.

TREATMENT

Section 6 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• Take aggressive surgical measures to debride affected tissue. Without early and aggressive therapy, zygomycosis almost always is fatal.
• Take aggressive measures to control the underlying condition.
• • 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 steroids or deferoxamine.

Surgical Care

• The mainstay of treatment for any form of zygomycosis is early and aggressive surgical removal of all infected tissue.
• Remove as much devitalized tissue as possible, and consider wide surgical debridement if feasible.

Consultations

• Infectious disease specialist
• Surgeon
• Otorhinolaryngologist
• Gastroenterologist
• Pulmonary medicine specialist
• Ophthalmologist
• Neurosurgeon

MEDICATION

Section 7 of 11  

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• Differentials
• Workup
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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Start antifungal therapy as early as possible. Amphotericin B is the mainstay of therapy and is the only available antifungal that is effective against Zygomycetes. Because of drug toxicity, monitor for adverse effects and toxicity. Liposomal amphotericin B derivatives are utilized more frequently because they deliver higher doses of the parent compound, amphotericin B, and associated renal insufficiency is not as severe. Although still investigational, several reports demonstrate a successful outcome in patients administered combination therapy with either amphotericin B or a liposomal derivative and G-CSF.

In addition, a new triazole, posaconazole, was recently approved by the US Food and Drug Administration (FDA). It was approved with an indication for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression. It may possibly replace amphotericin B compounds as the drug of choice for zygomycosis. Posaconazole is available only in an oral suspension form and must be administered 2-4 times a day. It has shown encouraging results in open-labeled clinical trials in the difficult-to-treat infections due to the various Zygomycetes.

Drug Category: Antifungals

Polyene antifungals. Only antifungal class with known activity against Zygomycetes.

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

Drug Category: Antifungal agents, triazoles

Posaconazole has shown encouraging results in clinical trials for difficult-to-treat infections due to the various Zygomycetes.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Inpatient care frequently is prolonged due to the severe nature of the illness.
• Patients frequently will undergo multiple surgical procedures in an attempt to eradicate devitalized tissue.
• Antifungals generally are provided parenterally for a period of several months to achieve cure.

Further Outpatient Care

• Once the zygomycosis 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, electrolytes, BUN, serum creatinine).

In/Out Patient Meds

• Due to the severity of the infection, the majority of patients will undergo inpatient care for most of their treatment; however, if patients are stable, discharge them home on parenteral antifungal therapy with close monitoring for 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 diabetes mellitus.
• Control metabolic acidosis.
• Eliminate risk factors such as neutropenia and immune modulators.

Complications

• Invasive zygomycosis generally will spread to adjacent organ systems (ie, osteomyelitis), including sinuses and adjacent bones.
• The ocular globe frequently is 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 lead to peritonitis and sepsis.

Prognosis

• Prognosis depends on several factors, such as infection site, rapidity of diagnosis, and type and severity of immunosuppression.
• The mortality rate is approximately 85% for patients with the rhinocerebral form of infection, and the overall mortality rate is approximately 50%. Mortality rates are elevated because, by the time disease is suspected and diagnosed, it frequently has spread diffusely and produced extensive tissue destruction.

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.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• The major pitfall in treating zygomycosis is differentiating it from more common bacterial infections, which may delay diagnosis, surgical resection, and appropriate antifungal therapy.
• Rule out invasive zygomycosis early in patients with appropriate risk factors by using fungal stains and cultures of affected tissues.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  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.
	View Full Size Image
Media type:  Photo

Media file 2:  Material from the periorbital tissue of a woman with poorly controlled diabetes mellitus with facial and periorbital swelling due to zygomycosis (see Image 1) 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).
	View Full Size Image
Media type:  Photo

Media file 3:  A CT scan of the head of a patient with zygomycosis shows involvement of the paranasal sinuses and periorbital soft tissues.
	View Full Size Image
Media type:  CT

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Dannaoui E, Meletiadis J, Mouton JW, et al. In vitro susceptibilities of zygomycetes to conventional and new antifungals. J Antimicrob Chemother. Jan 2003;51(1):45-52. [Medline].
• Gonzalez CE, Rinaldi MG, Sugar AM. Zygomycosis. Infect Dis Clin North Am. Dec 2002;16(4):895-914, vi. [Medline].
• Greenberg RN, Scott LJ, Vaughn HH, Ribes JA. Zygomycosis (mucormycosis): emerging clinical importance and new treatments. Curr Opin Infect Dis. Dec 2004;17(6):517-25. [Medline].
• Herbrecht R. Posaconazole: a potent, extended-spectrum triazole anti-fungal for the treatment of serious fungal infections. Int J Clin Pract. Jun 2004;58(6):612-24. [Medline].
• Ibrahim AS, Edwards JE, Filler SG. Zygomycosis. In: Dismukes WE, Pappas PG, Sobel JD, eds. Clinical Mycology. 1st edition. New York, Oxford University Press; 2003:241-251.
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• Kontoyiannis DP, Wessel VC, Bodey GP. Zygomycosis in the 1990s in a tertiary-care cancer center. Clin Infect Dis. Jun 2000;30(6):851-6. [Medline].
• Kwon-Chung KJ, Bennett JE. Mucormycosis. In: Cann C, ed. Medical Mycology. Lea & Febiger;1992:524-59.
• Petrikkos G, Skiada A, Sambatakou H, et al. Mucormycosis: ten-year experience at a tertiary-care center in Greece. Eur J Clin Microbiol Infect Dis. Dec 2003;22(12):753-6. [Medline].
• Ribes JA, Vanover-Sams CL, Baker DJ. Zygomycetes in human disease. Clin Microbiol Rev. Apr 2000;13(2):236-301. [Medline].
• Rippon JW. The new opportunistic fungal infection: diagnosis, isolation, identification and impact on mycology. Fear of fungi. Mycopathologia. Sep 1987;99(3):143-6. [Medline].
• Rippon JW. Zygomycosis. In: Wonsiewicz M, ed. Medical Mycology. The pathogenic fungi and the pathogenic actinomycetes. 3rd ed. Philadelphia, Pa:. W.B. Saunders;1998:681-713.
• Sugar AM. Agents of mucormycosis and related species. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, Pa. Churchill Livingstone;2000:2685-2694.
• Sun QN, Fothergill AW, McCarthy DI, et al. In vitro activities of posaconazole, itraconazole, voriconazole, amphotericin B, and fluconazole against 37 clinical isolates of zygomycetes. Antimicrob Agents Chemother. May 2002;46(5):1581-2. [Medline].
• Thomson SR, Bade PG, Taams M, et al. Gastrointestinal mucormycosis. Br J Surg. Aug 1991;78(8):952-4. [Medline].

Article Last Updated: Nov 7, 2006