AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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

Section 2 of 11  

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• Follow-up
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Background

Mucormycosis refers to several different diseases caused by infection with fungi in the order of Mucorales. Rhizopus species are the most common causative organisms. In descending order, the other genera with mucormycosis-causing species include Rhizomucor, Cunninghamella, Apophysomyces, Saksenaea, Absidia, Mucor, Syncephalastrum, Cokeromyces, and Mortierella. Most infections are life-threatening, and risk factors, such as diabetic ketoacidosis and neutropenia, are present in most cases. Severe infection of the facial sinuses, which may extend into the brain, is the most common presentation. Pulmonary, cutaneous, and Gi infections are also recognized. Successful treatment requires correction of the underlying risk factor or factors, antifungal therapy with amphotericin B, and aggressive surgery.

Pathophysiology

Mucoraceae are ubiquitous fungi that are commonly found in soil and in decaying matter. Rhizopus can be found in moldy bread. Given the ubiquitous nature of these fungi, most humans are exposed to these organisms on a daily or weekly basis. Nonetheless, they rarely cause disease because of the low virulence of the organisms and mainly affect individuals with immunocompromising conditions. Immunocompromised hosts with poorly controlled diabetes mellitus (especially with ketoacidosis), who are receiving glucocorticosteroids, who have neutropenia in the setting of hematological or solid malignancy, who have undergone transplantation, who have iron overload, and who have burns are at risk for disease.

The major route of infection is via inhalation of conida; other routes include ingestion and traumatic inoculation. For instance, nonsterile tape and contaminated wooden splints have caused wound infections. Such cases are associated with trauma, the presence of a pre-existing wound, or both. When spores are deposited in the nasal turbinates, rhinocerebral disease develops (see Rhinocerebral Mucormycosis); when spores are inhaled into the lungs, pulmonary disease develops. When the agents are introduced through abraded skin, cutaneous disease develops. Ingestion leads to GI disease, primarily among malnourished patients.

Mucoraceae are molds in the environment that become hyphal forms in tissues. Once the spores begin to grow, fungal hyphae invade blood vessels, producing tissue infarction, necrosis, and thrombosis. Neutrophils are the key host defense against these fungi; thus, individuals with neutropenia or neutrophil dysfunction (diabetes, steroid use) are at highest risk. Few cases of mucormycosis have been reported in patients with AIDS, suggesting that the host defense against this infection is not primarily mediated by cellular immunity.

Frequency

United States

Mucormycosis is extremely rare, and its incidence is difficult to calculate accurately. Rhinocerebral disease is the most common form, accounting for more than half of the cases. Other major syndromes include pulmonary, cutaneous, and disseminated diseases; rarer forms involve the GI tract and kidneys. Mucormycosis has been reported in immunocompetent individuals, mostly after traumatic inoculation of fungal spores, but this is extremely rare. A recent review of mucormycosis cases at one US cancer center found that 0.7% of patients were found to have mucormycosis at autopsy and that 20 patients per 100,000 admissions had the disease.¹ The incidence of the mucormycosis appears to be increasing secondary to rising numbers of immunocompromised persons.

International

Mucormycosis was found in 1% of patients with acute leukemia in an Italian multicenter review.²

A related disease, entomophthoramycosis, is rare in the United States; it is most commonly found in Africa, Southeast Asia, Australia, and Central America. Entomophthoramycosis consists of 2 diseases: conidiobolomycosis (caused by Conidiobolus infection) and basidiobolomycosis (caused by Basidiobolus infection). The former presents as a painless, firm, subcutaneous mass that primarily involves the head and face, whereas the latter involves the trunk and/or extremities. In contrast with mucormycosis, entomophthoramycosis is associated with a lower mortality rate and usually affects immunocompetent hosts.

Mortality/Morbidity

Mucormycosis carries a very high mortality rate (50-85%). Pulmonary and GI diseases carry an even higher mortality rate because these forms are typically diagnosed late in the disease course. Rhinocerebral disease causes significant morbidity in patients who survive because treatment usually requires extensive, and often disfiguring, facial surgery.

Race

No racial factors that predispose people to mucormycosis exist.

Sex

Sex is not likely to affect the occurrence of mucormycosis because the underlying conditions are the major predisposing factors. Reviews of cases from single institutions show an equal sex distribution. However, a recent review of all published cases of pulmonary mucormycosis performed by Lee et al (1999) showed a male-to-female ratio of 3:1.³

Age

Mucormycosis is found in patients of a wide age range.

CLINICAL

Section 3 of 11  

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

History

Manifestations of mucormycosis depend on the location of involvement.

• Rhinocerebral disease may manifest as unilateral, retro-orbital headache, facial pain, numbness, fever, and nasal stuffiness that progresses to black discharge. Initially, mucormycosis may mimic sinusitis.⁴ Late symptoms that indicate invasion of the orbital nerves and vessels include diplopia and visual loss. These late symptoms indicate a poor prognosis and are usually followed by reduced consciousness. Most patients with rhinocerebral disease have diabetes (especially with ketoacidosis) or have malignancies in combination with neutropenia and who may be receiving broad-spectrum antibiotics.
• Pulmonary mucormycosis manifests nonspecifically as fever, dyspnea, and cough. Hemoptysis may occur in the presence of necrosis. Most patients with pulmonary disease have malignancies and a history of neutropenia.
• Cutaneous disease manifests as cellulitis that progresses to dermal necrosis and black eschar formation. Patients with skin disease may have had prior trauma or have been exposed to contaminated medical equipment, such as bandages. Rare cases have occurred at catheter sites or insulin injection sites.
• GI mucormycosis usually affects severely malnourished individuals. Some case reports have described GI mucormycosis in transplant patients (eg, renal transplant). This may occur throughout the GI tract but most commonly affects the stomach, ileum, and colon. Again, the presentation is nonspecific, with abdominal pain, distension, nausea, and vomiting. Hematochezia may occur.
• CNS disease manifests as headache, decreasing consciousness, and focal neurologic symptoms. Patients with CNS involvement may have a history of open head trauma, drug use, or malignancy.
• Other disseminated forms may involve the kidneys, bones, and heart, with symptoms attributed to these organ systems.

Physical

The physical signs of mucormycosis depend on the location of involvement.

• Rhinocerebral
• • Orbital swelling and facial cellulitis are progressive. Black pus discharges from the necrotic palatine or nasal eschars.
  • Proptosis, ptosis, chemosis, and ophthalmoplegias indicate retro-orbital extension. Cranial nerves V and VII are the most commonly affected. Loss of vision can occur with retinal artery thrombosis.
  • A reduced conscious state denotes brain involvement.
• Pulmonary: The signs of pulmonary disease are nonspecific. Fevers are often noted. Lung examination may reveal decreased breath sounds and rales.
• Cutaneous: The progressive black necrotic lesion of cutaneous mucormycosis reflects the vessel invasion characteristic of all forms of the disease.
• Gastrointestinal: These manifestations are nonspecific; some patients have tenderness to palpation or a mass; rupture may lead to signs of peritonitis.
• Central nervous system: This manifests as decreasing consciousness and focal neurologic signs, including cranial nerve deficits.

Causes

Immunocompromising conditions are the main risk factor for mucormycosis. Patients with uncontrolled diabetes mellitus, especially with ketoacidosis, are at high risk. Patients with cancer, especially those who are neutropenic and have received broad-spectrum antibiotics, are also at risk. Patients receiving immunosuppressive agents, including oral or intravenous steroids, as well as tumor necrosis factor (TNF)–alpha blockers, are at risk. Extreme malnutrition is also linked to mucormycosis, especially the GI form. Iron is a growth stimulant for Mucorales, and deferoxamine acts as a siderophore that delivers iron to the fungi. Deferoxamine therapy and all causes of iron overload are additional risk factors for mucormycosis. Trauma and the use of contaminated medical supplies over wounds are associated with cutaneous mucormycosis. In addition, patients with burns and those who use intravenous drugs are at a higher risk.

Some patients with mucormycosis have no identifiable risk factors.⁵

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Rhinocerebral
Bacterial orbital cellulitis
Cavernous sinus thrombosis
Aspergillosis
Pseudallescheria boydii infection (Pseudallescheriasis)
Rapidly growing orbital tumor

Pulmonary
Aspergillosis
P boydii infection (pseudallescheriasis)
Pulmonary embolism

Skin
Ecthyma gangrenosa associated with pseudomonal infection
Anthrax

Gastrointestinal
Bowel obstruction
Ileocecal tuberculosis

WORKUP

Section 5 of 11  

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• Follow-up
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• Multimedia
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Lab Studies

• The diagnosis of mucormycosis is established by obtaining a biopsy specimen of the involved tissue. Swabs of tissue or discharge are unreliable.
• A complete blood cell count should be obtained to assess for neutropenia. A chemistry panel that includes blood glucose, bicarbonate, and electrolytes is useful to monitor homeostasis and direct correction of acidosis. An arterial blood gases study can help determine the degree of acidosis and direct corrective treatments.
• Iron studies: Assess the presence of iron overload as shown by high ferritin levels and a low total iron-binding capacity.

Imaging Studies

• Plain films may show sinus involvement with mucosal thickening, air-fluid levels, or bony erosions.
• Head and facial CT scanning: This should be used as the initial investigation in rhinocerebral infections. CT scans may show sinusitis of the ethmoid and sphenoid sinuses, as well as orbital and intracranial extension. As the disease progresses, the bone may erode and the infection may spread into the brain or orbits. In addition, because these organisms have a predilection for vascular involvement, thromboses of the cavernous sinus or internal carotid artery may occur.⁶ All of the areas of involvement must be understood in order to plan the extent of surgical debridement.
• MRI of the facial sinuses and brain: This is superior to a CT scan in assessing the need for ongoing surgery.
• Chest radiography and chest CT scanning: The most common finding is consolidation, usually unilobar; with disease progression, multilobar involvement may develop. Cavitation, especially producing an air crescent, is highly suggestive of fungal infection but does not distinguish from aspergillosis. Nodular lesions and pleural effusions may be present.
• Abdominal CT scanning: In GI disease, abdominal CT scan may show a mass associated with the GI tract.

Other Tests

• In cases of CNS involvement, cerebrospinal fluid (CSF) findings may include elevated protein levels and a modest mononuclear pleocytosis. CSF cultures are sterile. A CT scan should precede a lumbar puncture to ensure that this procedure is safe.
• For pulmonary disease, a bronchoalveolar lavage (BAL), biopsy, or both may assist in the diagnosis.

Procedures

The critical test procedure is obtaining a biopsy of involved tissue. Act promptly on the histological appearances of mucormycosis.

• Biopsy of necrotic tissue (nasal, palatine, lung, cutaneous, GI, abscess wall)
• • Stains of fixed tissues with hematoxylin and eosin (H&E) or specialized fungal stains, such as Grocott methenamine-silver or periodic acid-Schiff (PAS) stains, show broad-based (10- to 20-µm diameter), ribbonlike, nonseptate hyphae with right-angle branching. Neutrophil infiltration, vessel invasion, and tissue infarction are often observed.
  • Culture of biopsy samples is required to determine the species of Mucorales. Do not crush or grind the specimen because the nonseptate hyphae are prone to damage. Growth usually occurs in 2-3 days. The genus and species are determined via examination of the fungal morphology (eg, the presence and location of the rhizoids).

Histologic Findings

Pathognomonic changes of broad, irregular, nonseptate, right-angled, branching hyphae are demonstrated by H&E and by specialized fungal stains. Vascular invasion and necrosis are the characteristic consequences of the infective process. A neutrophil infiltrate is typical, and a granulomatous reaction may be observed.

TREATMENT

Section 6 of 11  

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Medical Care

Correction of the underlying abnormality and prompt institution of amphotericin B therapy and surgical resection are critical.

• Diabetic ketoacidosis requires insulin, correction of acidosis with sodium bicarbonate, and rehydration.
• Neutropenia in association with hematological malignancy and its treatment should be reversed, if possible, with the use of colony-stimulating factors and the withdrawal of cytotoxic chemotherapy.
• Wean glucocorticosteroids and other immunosuppressive drugs.
• Interrupt deferoxamine therapy. Hydroxypyridine chelators may be substituted for deferoxamine.

Surgical Care

Debridement of necrotic tissue in combination with medical therapy is mandatory for survival.

• In rhinocerebral disease, surgical care includes drainage of the sinuses and may require excision of the orbital contents and involved brain. Repeated surgery may be required, especially for rhinocerebral mucormycosis.
• Excise pulmonary lesions if they are localized to a single lobe.
• Excise cutaneous lesions entirely.
• Resect any GI masses.

Consultations

• Infectious diseases consultation - For management of antifungal therapy and coordination of medical care
• Surgical specialties consultations depending on location of disease
• • Ear, nose, and throat consultation and neurosurgery consultation for rhinocerebral mucormycosis
  • Thoracic surgery consultation for pulmonary involvement
  • GI surgery consultation for GI involvement
  • Plastic surgery consultation for cutaneous involvement
• Endocrinology consultation - For the management of unstable diabetes
• Hemato-oncology consultation - For the management of issues related to hematology and solid tumors
• Surgical ICU consultation - For supportive care

MEDICATION

Section 7 of 11  

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Antifungal treatment consists of amphotericin B, lipid formulations of amphotericin, or posaconazole. Although most clinical experience has focused on amphotericin agents, data on the efficacy of posaconazole are promising. This may eventually become the drug of choice, but more evaluation is needed.

Amphotericin agents

Amphotericin B has proven efficacy in the treatment of mucormycosis. Amphotericin B is typically administered at 1-1.5 mg/kg/d. The total dose given over the course of therapy is usually 2.5-3 g. High doses of this drug are required, and nephrotoxicity may result. Lipid formulations of amphotericin B allow for very high doses to be administered while better protecting renal function. Whether lipid formulations of amphotericin B provide better therapeutic outcomes is not clear, and the high cost necessitates careful consideration of use.

Renal impairment and failed treatment with conventional amphotericin B are appropriate indications for the use of the lipid formulations. Lipid preparations of amphotericin B are used at 5 mg/kg/d. Some have doses of up to 15 mg/kg/d to treat mucormycosis.

Posaconazole

Posaconazole, a new triazole, has recently been approved by the US Food and Drug Administration (FDA). Posaconazole is indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression. Posaconazole 400 mg twice daily is the typical dose used in the treatment of mucormycosis.

Studies have reported that posaconazole yielded a 50-70% success rate, while the comparator (typically amphotericin B or lipid-based amphotericin, in many cases used as salvage therapy) yielded a success rate of only 25%, suggesting that posaconazole may become the preferred drug for mucormycosis. However, further studies are needed.^{7, 8}

Posaconazole has also been studied in several case reports,⁶ including as salvage therapy after failure of amphotericin.⁹ Rickerts et al (2006) reported that liposomal amphotericin B plus posaconazole was successful in the treatment of disseminated mucormycosis in a patient who could not undergo surgery.¹⁰

Other medications

Other azoles (eg, fluconazole, voriconazole) and the echinocandins have not shown significant activity against these fungi. Of note, despite the use of voriconazole prophylaxis in high-risk patients (eg, transplant recipients), breakthrough zygomycosis has been reported.^{11, 12}

Drug Category: Antifungals

These agents are used to treat Mucorales infection. The mechanism of action may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.

FOLLOW-UP

Section 8 of 11  

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Further Inpatient Care

• Successful courses of therapy typically last 4-6 weeks and require cumulative doses of greater than 2 g of amphotericin B. Posaconazole offers another option. Repeated surgical debridement of necrotic tissue identified by follow-up head CT scan or MRI is often indicated.
• Monitor renal function of patients taking amphotericin B; doubling of serum creatinine over the baseline levels is an indication for changing to liposomal amphotericin B.

Further Outpatient Care

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

Transfer

• Treat patients with mucormycosis in a tertiary referral center with subspecialty units experienced in the care of the condition and the underlying causes.

Deterrence/Prevention

• Place patients with severe prolonged neutropenia in rooms equipped with high-efficiency particulate air (HEPA) filters, where practicable.
• Avoid the use of contaminated medical bandages and other equipment to prevent cutaneous disease; frequently check the wound or wounds.

Prognosis

• Surviving mucormycosis requires rapid diagnosis and aggressive coordinated medical and surgical therapy.
• Mucormycosis carries a mortality rate of 50-85%. The mortality rate associated with rhinocerebral disease is 50-70%. Disseminated disease carries a mortality rate that approaches 100%. Cutaneous disease carries the lowest mortality rate (15%). The advent of novel antifungals, such as posaconazole, may offer improvement in these mortality rates; further studies are needed.

Patient Education

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

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Failure to recognize the typical clinical presentation of rhinocerebral mucormycosis or act on the characteristic histological features of the disease may lead to poor patient outcomes and litigation.
• The use of contaminated bandages and other dressings has caused cutaneous mucormycosis. Failure to examine area under dressings or to recognize the significance of deterioration in preexisting wounds may produce severe cutaneous and, ultimately, disseminated disease.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Postmortem photograph of a woman with diabetes and left rhinocerebral mucormycosis complicating ketoacidosis. Rhizopus oryzae was the causative organism. Note the orbital and facial cellulitis and the black nasal discharge. (Courtesy of A. Allworth, MD, Brisbane, Australia)
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Media file 2:  The right eye of an immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. Note the proptosis. (Courtesy of A. Allworth, MD, Brisbane, Australia)
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Media file 3:  The right eye of an immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. A picture of chemosis is shown. Internal and external ophthalmoplegia, no light perception, and afferent pupil defect were present, which is consistent with orbital apex syndrome. (Courtesy of A. Allworth, MD, Brisbane, Australia)
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Media file 4:  An immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. A surgical field of this patient is shown. Excision of the right orbit, maxillary antrum, nasal cavity, sphenoid sinus, and infratemporal fossa has taken place. The tissue was infarcted. (Courtesy of A. Allworth, MD, Brisbane, Australia)
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Media file 5:  Histologic findings from an immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. Findings show the typical Mucorales hyphae on Grocott methenamine-silver staining. The hyphae are the dark structures with budlike, right-angle hyphae. (Courtesy of A. Allworth, MD, Brisbane, Australia)
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Media file 6:  An immunocompetent man who sustained a high-pressure water jet injury, resulting in rhinocerebral mucormycosis. Traumatic inoculation of Apophysomyces elegans was the pathogenetic mechanism. Picture of the patient after successful treatment with repeated surgical debridement and high-dose liposomal amphotericin B. (Courtesy of A. Allworth, MD, Brisbane, Australia)
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Media file 7:  Chest CT scan showing pulmonary mucormycosis with left basal consolidation and widespread nodules due to Rhizopus oryzae infection. The patient was receiving cytotoxic chemotherapy for myelodysplastic syndrome and had iron overload from numerous blood transfusions.
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Media file 8:  Chest CT scan showing pulmonary mucormycosis with left basal consolidation and widespread nodules due to Rhizopus oryzae infection. The patient was receiving cytotoxic chemotherapy for myelodysplastic syndrome and had iron overload from numerous blood transfusions. Chest CT scan of patient shows resolution of pulmonary mucormycosis after 5 months of antifungal treatment.
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Media type:  CT

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
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• Differentials
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• Follow-up
• Miscellaneous
• Multimedia
• References

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10. Rickerts V, Atta J, Herrmann S, et al. Successful treatment of disseminated mucormycosis with a combination of liposomal amphotericin B and posaconazole in a patient with acute myeloid leukaemia. Mycoses. 2006;49 Suppl 1:27-30. [Medline].
11. van Well GT, van Groeningen I, Debets-Ossenkopp YJ, et al. Zygomycete infection following voriconazole prophylaxis. Lancet Infect Dis. Sep 2005;5(9):594. [Medline].
12. Trifilio SM, Bennett CL, Yarnold PR, et al. Breakthrough zygomycosis after voriconazole administration among patients with hematologic malignancies who receive hematopoietic stem-cell transplants or intensive chemotherapy. Bone Marrow Transplant. Apr 2007;39(7):425-9. [Medline].
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15. Maertens J, Demuynck H, Verbeken EK, et al. Mucormycosis in allogeneic bone marrow transplant recipients: report of five cases and review of the role of iron overload in the pathogenesis. Bone Marrow Transplant. Aug 1999;24(3):307-12. [Medline].
16. McAdams HP, Rosado de Christenson M, Strollo DC, et al. Pulmonary mucormycosis: radiologic findings in 32 cases. AJR Am J Roentgenol. Jun 1997;168(6):1541-8. [Medline].
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19. Sugar AM. Agents of mucormycosis and related species. In: Mandell GL, Bennett GE, Dolin R, eds. Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases. 5^th ed. Philadelphia, Pa: Churchill Livingstone; 2005:2973-2984.
20. Tobon AM, Arango M, Fernandez D, et al. Mucormycosis (zygomycosis) in a heart-kidney transplant recipient: recovery after posaconazole therapy. Clin Infect Dis. Jun 1 2003;36(11):1488-91. [Medline].
21. Van Cutsem J, Boelaert JR. Effects of deferoxamine, feroxamine and iron on experimental mucormycosis (zygomycosis). Kidney Int. Dec 1989;36(6):1061-8. [Medline].
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23. Wingard JR, White MH, Anaissie E, et al. A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. L Amph/ABLC Collaborative Study Group. Clin Infect Dis. Nov 2000;31(5):1155-63. [Medline].

Article Last Updated: Jul 1, 2008