Decreasing Incidence of Diabetes-Related Mucormycosis Since the 1990’s
May Be Related to the Widespread Use of Statins
Statins Have In Vitro Inhibitory Activity Against Organisms Which Cause Mucormycosis
Environmental Risk Factors for Mucormycosis
Combat-Associated Mucormycosis
Cases Have Been Reported in Association with Blast Injuries in Aghanistan
Healthcare-Associated Mucormycosis
Cases Have Been Reported in Association with Intravenous and Other Catheters, Adhesive Tape, surgical wounds, Wooden Tongue Depressors, Adjacent Building Construction, and Hospital Linens
Natural Disaster-Associated Mucormycosis
Cases Have Been Reported in Association with Tornado, Tsunami, and Volcanic Eruption
Clinical Risk Factors
General Comments
All Human Mucormycosis Infections Occur in the Presence of Some Underlying Immunocompromising Condition
Malignancy
General Comments
Hematologic Malignancy is a Common Risk Factor for Mucormycosis
Voriconazole Prophylaxis Appears to Increase the Risk of Mucormycosis
Possibly Due to Increased Selective Pressure for the Organisms Which Cause Mucormycosis
Deferoxamine-Iron Chelate Acts as Siderophore for Rhizopus: increases Rhizopus iron uptake, stimulating fungal growth and tissue invasion
In Contrast, Deferasirox and Deferipone Do Not Act as Siderophores for Rhizopus and Do Not Increase the Risk of Mucormycosis
Highest Risk for Deferoxamine-Related Mucormycosis is Observed in Those Who Have Received Multiple Blood Transfusions with Subsequent Deferoxamine Treatment
Mortality rate is almost 90% in deferoxamine-associated mucormycosis cases
Diabetes Mellitus (DM) (see Diabetes Mellitus, [[Diabetes Mellitus]])
Diabetes Mellitus is Probably the Most Common Risk Factor for Mucormycosis
Risk of Mucormycosis is Especially High with Diabetic Ketoacidosis (DKA): due to impaired neutrophil function and elevated free iron present in diabetic ketoacidosis
Free Iron Enhances the Growth of Rhizopus at Acidic (But Not Alkaline) pH
Mucormycosis May Occur as the Initial Presentation of Diabetes Mellitus
Mucor (see Mucor, [[Mucor]]): one of the most common genera responsible for human infection
Rhizomucor: one of the most common genera responsible for human infection
Rhizopus (see Rhizopus, [[Rhizopus]]): one of the most common genera responsible for human infection
Saksenaea
Syncephalastrum
Order: Entomophthorales
Basidiobolus
Conidiobolus
Physiology
Entry and Infection
Inhalation of Spores is the Portal of Entry for Rhino-Orbital-Cerebral and Pulmonary Mucormycosis
In Normal Patients, Spores Undergo Ciliary Transport to the Gastrointestinal Tract with Excretion in the Stool
Characteristic Angioinvasion with Thrombosis and Distal Infarction
Characteristic Perineural Invasion
Unique Features of Rhizopus
Possesses Ketone Reductase Enzyme: allows this organism to grow in high glucose, acidic conditions (such as diabetic ketoacidosis)
Diagnosis
Direct Microscopy/Histopathology (Preferably with Optical Brighteners)
Characteristics of Mucorales
Hyphae are Morphologically Distinctive from Those of Aspergillus: hyphae of Aspergillus are narrower, 2-5 μm in diameter, exhibit regular branching, and have regular septations
Broad Hyphae: 5-15 μm in diameter
Irregular Right Angle (90°) Branching
Irregular Ribbon-Like Appearance
Rare Hyphal Septations
No Pseudohyphae or Budding Yeasts
May Stain Better with Hematoxylin + Eosin (H+E) Stain than Fungal Stains (Calcofluor White, Methenamine Silver)
Blankophor and Calcofluor Bind to Chitin and Cellulose and Fluoresce in Ultraviolet Light
Direct Microscopy (Preferably Using Optical Brighteners) is Recommended to Diagnose Mucormycosis (Strength of Recommendation A, Quality of Evidence IIu)
May Be Used to Monitor Treatment in Populations with Hematologic Malignancy (Strength of Recommendation C, Quality of Evidence IIu)
No Commercial Assay Available
Clinical Manifestations
Central Nervous System (Isolated) Mucormycosis
Epidemiology
While Central Nervous System Involvement is Usually Due to Contiguous Extension from the Paranasal Sinuses, Multiple Cases Have Been Reported with Isolated Central nervous System Mucormycosis
Halo Sign (Focal Ground-Glass Infiltrate Surrounding a Lung Nodule, Which is Characteristic of Infection with an Angioinvasive Fungus): may be observed
Reversed Halo Sign (Atoll Sign) (Focal Ground-Glass Infiltrate Surrounded by a Ring of Consolidation): has also been observed (in fact, mucormycosis is the most common condition to cause a reversed halo sign in an immunocompromised host)
Pleural Effusions
Sputum Gram Stain/Culture (see Sputum Culture, [[Sputum Culture]]): low sensitivity (probably around 25%)
Bronchoscopy with Bronchoalveolar Lavage (BAL) (see Bronchoscopy, [[Bronchoscopy]]): low sensitivity (probably around 25%)
Transbronchial Biopsy (TBB): organism may be demonstrated by methenamine silver stain
Open Lung Biopsy (see Lung Biopsy, [[Lung Biopsy]]): diagnostic
Clinical: usually subacute or slowly progressive (but may be rapidly progressive in some cases)
Deferoxamine Use (see Deferoxamine, [[Deferoxamine]])
Severely Immunocompromised State
Prematurity (Neonate)
Prognosis: mortality rate is 96%
Treatment
Elimination of Predisposing Factors
Crucial
Surgery
Indications
Rhino-Orbital-Cerebral Mucormycosis: aggressive surgical debridement is usually necessary
Localized Pulmonary Disease: lobectomy may be attempted in select cases with isolated pulmonary disease
Hemoptysis may necessitate resection
Antifungal Treatment
General Comments
Early Anti-Fungal Therapy Improves Mortality Rate in Mucormycosis
Liposomal Amphotericin (see Amphotericin, [[Amphotericin]]): drug of choice for initial treatment
Initial Dose: 5 mg/kg IV qday (may go as high as 10 mg/kg qday, as required to control the infection)
The Total Cumulative Dose of Amphotericin Has Not Been Studied in Mucormycosis
Posaconazole (Noxafil, Posanol) (see Posaconazole, [[Posaconazole]])
Oral Posaconazole Step-Down Therapy: step-down to oral posaconazole after initial clinical response to amphotericin (which has been given for at least a period of several weeks)
Dose: posaconazole delayed-release tablets 300 mg PO BID x 1 day, then 300 mg PO qday thereafter
Posaconazole Oral Suspension Has Poor Bioavailability and Requires Fatty Food for Absorption: therefore, it is not the preferred oral formulation
Intravenous Posaconazole Salvage Therapy: posaconazole can be used in patients with lack of response to amphotericin or poor amphotericin tolerance
Dose: 300 mg q12hrs IV x 1 day, then 300 mg IV qday thereafter
Avoid Intravenous Posaconazole Formulation with CrCl <50 mL/min: due to potential accumulation of the SBECD vehicle
Oral Posaconazole Salvage Therapy: posaconazole delayed-release tablets may be used when intravenous posaconazole cannot be used
Although Oral Posaconazole Suspension Has Also Been Studied as Salvage Therapy, its Current Role is Unclear
Isavuconazole (Cresemba) (see Isavuconazole, [[Isavuconazole]])
May Be Used as an Alternative to Posaconazole
Duration of Anti-Fungal Therapy
Continue Antifungal therapy Until There is Resolution in Signs/Symptoms/Radiographic Findings and Until There is Resolution of the Underlying Immunosuppression
Anti-Fungal Therapy is Usually Continued for a Period of Months
Other
General Comments
Voriconazole/Fluconazole/Flucytosine are Not Active Against the Organisms Which Cause Mucormycosis
Deferasirox (Exjade) (see Deferasirox, [[Deferasirox]]): possible benefit has been observed in mouse studies -> currently, not recommended
Echinocandins (Caspofungin, Micafungin)
Although Echinocandins Have No In Vitro Activity Against Mucormycosis, Rhizopus Oryzae Possesses the Target Enzyme for the Echinocandins
Based on this Observation and Studies, Echinocandins May Be Added onto Amphotericin Therapy: without further data, this cannot be recommended though
Hyperbaric Oxygen (HBO) (see Hyperbaric Oxygen, [[Hyperbaric Oxygen]]): unclear benefit
References
The diagnostic value of halo and reversed halo signs for invasive mold infections in compromised hosts. Clin Infect Dis. 2011 May;52(9):1144-55. doi: 10.1093/cid/cir122 [MEDLINE]
Epidemiology and clinical manifestations of mucormycosis. Clin Infect Dis. 2012 Feb;54 Suppl 1:S23-34. doi: 10.1093/cid/cir866 [MEDLINE]
ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis 2013. Clin Microbiol Infect. 2014 Apr;20 Suppl 3:5-26. doi: 10.1111/1469-0691.12371 [MEDLINE]
Our 2014 approach to mucormycosis. Mycoses. 2014 Sep;57(9):519-24. doi: 10.1111/myc.12203. Epub 2014 May 15 [MEDLINE]
Consensus guidelines for the treatment of invasive mould infections in haematological malignancy and haemopoietic stem cell transplantation, 2014. Intern Med J. 2014 Dec;44(12b):1333-49. doi: 10.1111/imj.12598 [MEDLINE]
Isavuconazole: A New Option for the Management of Invasive Fungal Infections. Ann Pharmacother. 2015 Jul;49(7):825-42. doi: 10.1177/1060028015581679. Epub 2015 May 4 [MEDLINE]
