Institutional Strategies
1. All mucormycosis cases will be primarily admitted and managed pre & post operatively in respective surgical specialty (ENT, Oral and maxillofacial surgery, Ophthalmology, Neurosurgery etc.)
After admission every patient is to be examined by Department of Medicine, ENT, and Oral and Maxillofacial Surgery; and by Ophthalmology & Neurosurgery as and when indicated.
2. Uncontrolled medical illness would be managed by respective medical units.
3. Independent second opinion of senior / another faculty from respective emergency unit may be taken if required.
4. Separate ward, OT or extra OT day are to be managed as per clinical load.
5. Day care treatment may be offered even post operatively whenever feasible.
6. The focus will be on early diagnosis & rapid initiation of antifungal therapy and aggressive “early” surgical debridement of necrotic lesions with optimal correction of co- morbidities.
Introduction:
• Mucormycosis or Zygomycosis is a fungal disease caused by fungi of order Mucorales.
• High risk group- Diabetes mellitus, diabetic ketoacidosis, steroid, cytotoxic drug therapy, HIV, immunosuppression, malignancy or haematological disorder including iron overload states.
• New corona virus SARS COV 2 itself may serve as a risk factor - chronic respiratory disease, corticosteroid therapy, intubation /mechanical ventilation, deranged glucose metabolism, which may lead to secondary fungal infection.
• Overall mortality: Pulmonary mucormycosis: 50-70%, Rhinocerebral: 30 - 70%, CNS involvement: >80%, Disseminated: > 90%, AIDS: almost 100%
Presenting features:
Facial findings:
Facial swelling / Paresthesia / Sinus tract on face/ Discolouration of skin (necrosis)/
Infection in dangerous area of face
Nasal findings:
Foul smelling nasal discharge/Nasal congestion/ Sinusitis/ Erythematous to violaceous
to black necrotic eschar in nasal cavity
Intraoral findings:
Halitosis/ Intraoral pus discharge/ Ulceration & Blackening of mucosa/ Exposed palatal
bone/ Sinus tract/ Loosening of teeth/ Unhealed tooth socket/ Mobility of maxilla
Orbital findings:
Vision loss/ Peri orbital cellulitis/ Chemosis/ Exophthalmos(Proptosis)/ Opthalmoplegia
CNS findings:
Headache/ Cranial nerve involvement/ Rapidly progressive neurological deficit
Pulmonary findings:
Fever/ Cough/ Chest pain/ Dyspnea/ Hemoptysis
Gastrointestinal findings:
Abdominal pain/ Nausea/ Vomiting/ Gastrointestinal bleeding
Specific points to be observed in history:
- H/o COVID infection (Immunosuppressive drugs/ Ventilatory care, etc.)
- Co morbid conditions: Diabetes mellitus/ Malignancy/ HIV/ Chronic kidney disease /
Obesity/ Other systemic illness
- Local factors (H/O tooth extraction or any other oral/surgical procedure/ Head injury)
Investigations:
1) Lab parameters:
CBC/ ESR/ FBS, PPBS, HbA1C/ LFT/ RFT with electrolytes/ HIV, HbsAg / CSF (if indicated)
2) Nasal endoscopic examination:
Black necrotic eschar tissue
3) Radiographic Examination:
X- Ray PNS and OPG may be normal
Contrast enhanced CT scan with 3D Reconstruction findings:
Erosion and thinning of Hard tissues Enlargement of masticatory muscle
Mucosal thickening of sinuses Changes in Fat Planes
MRI with contrast findings:
Optic neuritis Intracranial involvement
Cavernous sinus thrombosis Infratemporal fossa involvement
4) Biopsy:
Oral cavity: Biopsy from deeper portion of extracted tooth socket/exposed bone
Nasal Cavity: Nasal endoscopy and crust sampling
Direct microscopy of bronchoalveolar lavage & transbronchial biopsy
Treatment:
Medical management:
1. Mucormycosis should be treated with antifungal Injectable Amphotericin B for 2-3 weeks on clinical suspicion & as per severity even while awaiting diagnostic and culture reports.
2. Duration of pre operative Amphotericin therapy may be considered as per clinical severity and early need for surgical intervention.
3. Oral antifungal: Overlap with Injectable for 3-4 days before step down and to be continued 1 week after endoscopic biopsy is negative.
4. Liposomal amphotericin is preferred in cases having Renal complication due to Amphotericin and in case of cerebral parenchymal involvement.
1) First line antifungal therapy:
Inj Amphotericin B Deoxycholate(C-AmB):
Dose: 1.0-1.5 mg/kg once per day, IV: infused over 4 - 6 hours
- Half-life:
Biphasic: Initial 15 to 48 hr, Terminal 15 days
- Disadvantages:
Highly toxic, Poor CNS penetration
To avoid infusion-related immediate reactions, premedicate with:
1. NSAID and/or diphenhydramine or acetaminophen with diphenhydramine or hydrocortisone
2. Pre-infusion administration of 500 to 1,000 mL of normal saline
- Dosing:
1) Renal Impairment: Daily total dose can be decreased by 50% or the dose can be given every other day- Haemodialysis or CRRT.
2) Hepatic Impairment: No dosage adjustment
Adverse Reactions:
Systemic: >10%:
Hypersensitivity: Anaphylaxis, Infusion reactions
Cardiovascular: Hypotension
Central nervous system: Chills, malaise, pain & headache (less frequent with I.T.)
Endocrine & metabolic: Hypokalemia, hypomagnesemia
Gastrointestinal: Anorexia, diarrhoea, epigastric pain, heartburn, nausea (less frequent with I.T.), stomach cramps, vomiting (less frequent with I.T.)
Hematologic & oncologic: Anemia (normochromic-normocytic)
Local: Pain at injection site (with or without phlebitis/ thrombophlebitis –incidence may increase with peripheral infusion of admixtures)
Renal: Renal function abnormality (including azotemia, renal tubular acidosis, nephrocalcinosis [>0.1 mg/ml]), renal insufficiency
Respiratory: Tachypnea
Miscellaneous: Fever 1% to 10%:
Cardiovascular: Flushing, hypertension
Central nervous system: Arachnoiditis, delirium, neuralgia (lumbar; especially with Intrathecal therapy), paresthesia (especially with intrathecal therapy)
Genitourinary: Urinary retention
Hematologic & oncologic: Leukocytosis
- Watch for: Urine output , Renal function Test (pH, Bl. Urea, S. Creatinine, Electrolytes)
Cockcroft-Gault formula for estimating creatinine clearance (CrCl)
CrCl (male) = ([140-age] × weight in kg)/(serum creatinine × 72)
CrCl (female) =([140-age] × weight in kg)/(serum creatinine × 72) × 0.85
In case of nephrotoxicity
Crcl <10 ml/min: 0.5-0.7 mg/kg IV q24-48hr
Consider other antifungal agents that may be less nephrotoxic
Intermittent hemodialysis: 0.5-1 mg/kg IV q24hr after dialysis session
Continuous renal replacement therapy: 0.5-1 mg/kg IV q24hr
Inj Liposomal amphotericin B (LAmB):
- Dosage: 5 mg/kg per day and in CNS mucormycosis dose is 7.5 – 10 mg/kg per day
- Advantages: Less nephrotoxic, better CNS penetration than AmB or ABLC
- Disadvantage: Expensive
- Contraindication : Hypersensitivity
Inj Amphotericin B lipid complex (ABLC) :
- Dosages:5 mg/kg/day
- Advantages and Supporting Studies: Less nephrotoxic than AmB deoxycholate
- Disadvantage: Expensive, Possibly less efficacious than LAmB for CNS infection
2) Second line- AZOLE Derivatives (Step Down or Salvage Therapy)
Step-down therapy — Posaconazole and isavuconazole are broad-spectrum azoles
available in both parenteral and oral formulations
Posaconazole or isavuconazole for oral step-down therapy. Alternatively IV parenteral formulations can be used as salvage regimen in case of unresponsiveness to AmB
Isavuconazole:
Dosage:
- 200 mg of isavuconazole (372 mg of isavuconazonium sulfate), load q8h * 6
followed by once-daily dosing
Advantages and Supporting Studies:
- Efficacy similar to that of LAmB in mouse models
- FDA-approved
- Rational empirical option when septate mold vs mucormycosis is not yet
established
Disadvantage:
- Much less clinical experience
- Clinical study supporting approval is small and historically controlled
Posaconazole:
Dosage:
- 200 mg four times per day
- Alternatively, posaconazole delayed-release tablets (300 mg every 12 hours on
first day, then 300 mg once daily) taken with food.
Advantages and Supporting Studies:
- In vitro activity against the Mucorales
- Lower MICs than isavuconazole
- Retrospective data for salvage therapy in mucormycosis
Disadvantage:
- Substantially lower blood levels than isavuconazole,
- No data on initial therapy for mucormycosis
- No evidence for combination therapy with posaconazole
- Limited use for salvage therapy, hyperglycemia, hypokalemia, pruritus
- Contraindicated with Statin group of drugs
3) Combination therapy
a. Lipid polyenes (both ABLC and LAmB) plus echinocandins( e.g. caspofungin, micafungin, and anidulafungin) :
- Improves survival rate among disseminated mucormycosis including CNS disease
better outcome than monotherapy with polyenes.
Advantages and Supporting Studies:
- Favorable toxicity profile
- Synergistic in murne disseminated mucormycosis
- superior outcomes for rhino-orbial-cerebral mucormycosis.
Disadvantage: Limited data
b. Lipid polyenes plus azole (Posaconazole or Isavuconazole)
Advantages and Supporting Studies:
- Favorable toxicity profile
Disadvantage:
- No convincing data to support any form of combination therapy
- Not recommended in major treatment guidelines.
c. Triple therapy (Lipid polyene plus echinocandin plus azole)
Advantages and Supporting Studies:
- Maximal Aggressiveness
Disadvantage:
- No available evidence of superiority vs. monotherapy or dual therapy
Duration of therapy:
• Inj antifungal 2-3 weeks or more depending on clinical severity
• Liposomal antifungal may be used if AmB toxicity develops
• Overlap of injectable and oral antifungals for 3-4 days followed by oral antifungals.
• Oral antifungal to be continued 1 week after biopsy is negative.
• Regular follow up initially monthly for 3 months then SOS.
4) Treatment of comorbidities
5) Other treatment:
- Use of blood & blood components should be judicious to maintain the hemoglobin level >10 gm%.
- Iron chelating agent may be useful in iron overload conditions like patient on multiple blood transfusion
Surgical Management:
ENT surgeon/ Oral and Maxillofacial surgeon/ Ophthalmologist/ Plastic surgeon/ Neuro surgeon
2. Cornely OA al: ESCMID and ECMM joint clinical guidelines for the diagnosis and management of
mucormycosis 2013.Clin Microbiol Infect 20(S3):5, 2014
3. Kontoyiannis DP et al: Prospective antifungal therapy (PATH) alliance: Focus on mucormycosis
Mycoses 57:240, 2014
4. Spellberg B et al: Novel Perspective on mucormycosis: Pathophysiology, Presentation, and
management. Clin Microbiol Rev 18:556, 2005
5. Spellberg B et al: Combination therapy for mucormycosis: Why, what, and how? Clin infect Dis
54(S1):S73, 2012
6. Spellberg B et al: Risk factor for mortality in patients with mucormycosis. Med Mycol 50:611, 2012
7. www.cdc.gov
8. Clin Infect Dis. 2009;48(12):1743
9. Am J Transplant. 2009;9(9):2166. Epub 2009 Jul 22. Transplantation. 2010;90(1):85
10. Theory and Practice of Histological techniques; Bancroft 6TH Edition; Chap 9; Pg 121 – 134.
11. District laboratory practice in tropical countries”, Monica Cheesbrough 2003 (part-1 & 2)
12. Koss’s Diagnostic Cytology& its Histopathologic Bases, 1616, 5th edition
13. Comprehensive Cytology, Marluce Bibbo 32:881-906, 1991
14. Theory and Practice of Histological techniques; Bancroft 6TH Edition
15. Vankatesh Anehosur- JOMS 2019
16. Dimitrios P Kontoyiannis, How I treat mucormycosis BLOOD (2011)
17. B.Rammaert, Diabetes and mucormycosis: A complex interplay, Diabetes & Metabolism (2012)
18. Kiran Bala, International society for human and medical mycology, Medical Mycology (2015)
Faculties in the Expert Committee:
1) Dr. Kamlesh Upadhyay: (Professor and Head, General medicine)
2) Dr. Ila Upadhya: (Professor and Head, ENT)
3) Dr. Sonal Anchlia: (Professor and Head, Oral and maxillofacial surgery)
4) Dr. Hansa Thakkar: (Professor and Head, Ophthalmology)
5) Dr. Jaimin Shah: (Professor and Head, Neurosurgery)
6) Dr. Jayesh Sachde: (Professor and Head, Plastic surgery)
7) Dr. Pranay Shah: (Professor and Head, Microbiology)
8) Dr. Hansa Goswami: (Professor and Head, Pathology)
