Management Protocol For Mucormycosis

अखिल भारतीय आयरु्विज्ञान ससं्थान, एम्स ऋर्िकेश

All India Institute of Medical Sciences Rishikesh, Uttarakhand, India, 249203

@Multidisciplinary Mucor management team_Version 1.0_16.05.2021 (AIIMS Rishikesh) 1

Management Protocol For Mucormycosis

A diagnosis we cannot afford to miss

Institutional Strategies: 1. A multidisciplinary team is constituted for managing mucormycosis cases with following

responsibilities:

Assessing time to time situations

Providing guidelines for prevention and treatment

Managing patients admitted at AIIMS Rishikesh

To give public-oriented messages for awareness

2. All mucormycosis cases will be admitted in a separate Mucor ward (having CCU beds, HDU,

general beds) and it will be managed by multidisciplinary team comprising department of ENT,

Medicine, Oral and maxillofacial surgery, Ophthalmology, Neurosurgery, Pediatrics, Paediatric

surgery, Microbiology, Pharmacology, Community and Family Medicine, and other departments as

per organ involvement.

4. Separate ward, OT, or extra OT are to be arranged as per clinical load.

5. Multidisciplinary team will facilitate steps for prevention and early diagnosis with rapid initiation

of antifungal therapy and aggressive early surgical debridement with optimal correction of co-

morbidities.




Types and symptoms:

Mucormycosis is an aggressive, angioinvasive fungal infection, acquired primarily vial inhalation of

environmental sporangiospores (3-11micron) in immunocompromised hosts or direct entry during

trauma, and affects these hosts with severe metabolic conditions.

1. Rhino-orbito-

cerebral

mucormycosis

(ROCM)

Nasal stuffiness, foul smell, epistaxis, nasal discharge, unilateral

facial oedema, diplopia, proptosis, pain and redness around eyes

and/or nose, loss of vision, restriction of eye movements, palatal or

palpebral fistula, blackish discolouration over bridge of nose/palate,

prolonged Fever, headache, toothache, loosening of teeth, jaw

involvement, altered mental status

2. Cutaneous and soft

tissue

mucormycosis

Erythema, induration, then black eschar at trauma/puncture site,

muscle pain with deeper involvement

3. Pulmonary

mucormycosis

Refractory fever on broad-spectrum antibiotics, non-productive

cough, progressive dyspnea, pleuritic chest pain

4. Gastrointestinal

mucormycosis

Fever, bleeding per anus, masslike lesions, then perforation of gut

5. Mucormycosis of

bones and joints

Local pain and tenderness, cellulitis, fever is rare

6. Disseminated

mucormycosis

Symptoms vary as per site of involvement, mostly associated with

pneumonia

RISK FACTORS-

1. Case of concurrent or recently (<6 weeks) treated Severe COVID-19

2. Uncontrolled diabetes mellitus, Chronic granulomatous diseases, HIV/AIDS, or primary

immunodeficiency states

3. Use of Immunosuppression by steroids (any dose use for >3weeks or high dose >1week),

Tocilizumab, other immunomodulators, or therapy used with transplantation

4. Prolonged neutropenia

5. Trauma, Burns, IV drug abusers

6. Prolonged ICU stay

7. Post-transplant/malignancy (solid or Hemopoietic)

8. Voriconazole therapy, Deferoxamine or other iron overloading therapy

9. Contaminated adhesive bandages, wooden tongue depressors, adjacent building construction,

and hospital linens

10. Renal failure, diarrhea, and malnutrition in low-birth-weight infants/even children/adults




DIAGNOSIS- Symptoms + Investigations

Investigations 1) Lab parameters:

CBC, ESR, FBS, PPBS, HbA1C, LFT, KFT with electrolytes, Viral markers (HIV/HBV/HCV)

2) Diagnostic nasal endoscopy: crusting, debris, scabbing, granulation, discoloured mucosa

(either darkened or pale), decreased bleeding and insensate mucosa

3) Imaging:

CECT Nose and PNS: Erosion and thinning of bones, Enlargement of masticatory muscle,

Mucosal thickening of sinuses Changes in Fat Planes

CEMRI Brain Orbit and Face: Optic neuritis, Intracranial involvement, Cavernous sinus

thrombosis, Infratemporal fossa involvement

4) KOH staining & microscopy - Direct microscopy using fluorescent brightener and

histopathology with special stains (e.g. PAS and GMS)

Typical findings: non-septate/pauci-septate, ribbon-like hyphae (at least 6–16μm wide), Vessel

occlusion

5) Histopathology- haemorrhagic infarction, coagulation necrosis, angioinvasion, infiltration by

neutrophils (in non-neutropenic hosts), and perineural invasion.

6) Fungal culture- Routine media at 30°C and 37°C

Typical findings: cotton white or greyish black colony

Sample collection and transportation:

Test (all endoscope

assisted)

Sample to be collected in To diagnose

KOH

Saline Presence of Fungi

Fungal culture

Saline Type of Fungi

Histopathology

10% Formalin Fungus/Bony lesions/

malignancy

Specimens should be collected aseptically in sterile containers and transported to the laboratory

within 2 hours.

Avoid sending swabs if pus or sterile body fluid can be aspirated or when tissue can be

obtained. Swabs may give false negative reports.

Never use dry swabs to collect specimen.

Completely filled TRF is required for accurate reporting.

Please write the Name & mobile number of the attending physician (JR/SR/Faculty) in legible

handwriting to facilitate prompt communication regarding reports




Sample collection according to the site of Mucormycosis

Specimen Collection Unacceptable specimen

ROCM Scraping or exudate from nares, hard palatal lesions, sinus material, biopsy from extracted tooth socket area. Endoscopic collection of debrided tissue/biopsy

Nasal dry swabs

Cutaneous Aspirations collected with sterile needle and syringe from undrained abscess. Pus expressed from abscess opened with scalpel; transported to laboratory either in sterile container/syringe and needle Tissue should be collected from both centre and edge of the lesion.

Swab or materials from open wound dry swabs

Pulmonary Sputum

Bronchial brush washing/ broncho-alveolar lavage (BAL) Lung biopsy- Collected by bronchoscope, Fluoroscope guided trans-thoracic needle aspiration or open lung biopsy

Saliva Saline wash

Gastrointestinal mucormycosis

Endoscopic biopsy of the lesions Faeces

Renal mucormycosis

Biopsy of the lesions Urine

TREATMENT-

Possible or Proven ROCM

Urgent surgical debridement

Strict glycemic control

Inj Amphotericin B (1.0-1.5 mg/kg/day)

or

Inj Liposomal amphotericin B

5-10mg/kg/day (intra cranial involvement-10 mg/kg /day)

or

Inj Amphotericin B lipid complex 5mg /kg/day

Continue treatment till resolution of initially indicative findings on imaging and reconstitution

of host immune system.




Second line- AZOLE Derivatives (Step Down or Salvage Therapy) Posaconazole is broad-spectrum azoles available in both parenteral and oral formulations.

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.

Amphotericin B administration and monitoring protocol

Drugs Recommended Dose

Duration

Inj Amphotericin B

Deoxycholate (C-

AmB):

1.0-1.5 mg/kg/day

14 to 21 days depending on severity/till clinical resolution and radiological stabilization; after 14days of therapy, shift to oral Posaconazole if clinically stable.

Inj Liposomal

amphotericin B

(LAmB):

5-10mg/kg/day

Inj Amphotericin B

lipid complex (ABLC)

5mg/kg/day

Inj Liposomal amphotericin B (LAmB):

Premedication Complications K + correction

Urea Creatinine Na K Mg

Amphotericin Monitoring Chart(To be filled daily) Patient name : …………………………………..

Serum ElectrolytesCumulative

dose

Dose

givenName of the drug Date

Starting

time

Ending

timeSr. No.

Test dose

•Inj. Liposomal Amphotericin- B 1 vial (50 mg) to be diluted in 12 ml of the diluent and 0.25ml (1 mg) of solution made, to be mixed in 100ml Dextrose and to be infused in 30 minutes.

•Observe for fever and reactions

Pre-hydration

•500 mL NS over 30 minutes

•To reduce the risk of renal toxicity and hypokalaemia :- 500ml Normal Saline + 1 Amp (20mmol) KCL

Therapeutic dose

•5mg-10 mg /kg/day Amphotericin B in 500 mL D5 with 10 Units HIR over 3 hrs (To be covered in black sheet)

Post Hydration


Post dose

•KFT with Serum electrolytes after Every dose of Amphotericin B

•Fill Amphotericin monitoring chart




Inj Amphotericin B Deoxycholate(C-AmB)

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

Pediatric conversions (<30kg):

Dose of amphotericin B is same

Fluid dilution – 10-12mg/Kg

Oral Posaconazole – 18-24 mg/kg/day in 3-4 divided doses; IV doses – 18-24 mg/kg/day in 2-3

divided doses

Inj Amphotericin B lipid complex (ABLC)

Test dose

• 1 mg in 100 mL D5 over 20 minutes

Pre-hydratio

n

• 500 mL NS over 30 minutes

Therapeutic dose

• 1.0-1.5 mg/kg/day Amphotericin B in 500 mL D5 with 10 Units HIR over 3 hrs (To be covered in black sheet)

Post Hydratio

n

• 500 mL NS over 30 minutes

Watch for:

• Urine output , Renal function Test (pH, Bl. Urea, S. Creatinine, Electrolytes)

• Fill Amphotericin monitoring chart

Test dose

•1 mg in 100 mL D5 over 20 minutes

Pre-hydration


Therapeutic dose

•5mg /kg/day Amphotericin B in 500 mL D5 with 10 Units HIR (Human Insulin Regular) over 3 hrs (To be covered in black sheet)

Post Hydration


Post dose

•KFT Serum electrolytes after Every dose of Amphotericin B

•Fill Amphotericin monitoring chart




SURGICAL MANAGEMENT

Early surgical debridement (all patients)

Transcutaneous retrobulbar

Amphotericin B (TRAMB) 1 ml of 3.5 mg/ml (select cases

only)

Orbital Exenteration

(patients with extensive

orbital involvement)

• Endoscopic sinus surgery debridement

Nasal and sinus involvement is present without bony

erosion of maxilla/ zygoma and orbital floor

• Maxillectomy(partial/ total)Maxilla involvement

• Maxillectomy(partial/ total) with

• Zygoma debridement

Maxilla + Minimal zygoma involvement

•Maxillectomy(partial/ total),Zygoma debridement

•Debridement of Orbital floor/ walls,Localised debridement of necrosed tissue in early localised orbital disease

Maxilla+ Zygoma+ orbit

•1) Vision loss 2) Total ophthalmoplegia 3) Chemosis 4) Necrosis of orbital tissues

•NOTE:- Loss of vision in not always the indication of exenterationExenteration of eye in

case of

• Anterior table:- Debridement

• Posterior table:- Cranialization

• Debridement of Osteomyelitic skull bone and involvement of the cerebral parenchyma (Safe maximum resection)

Frontal bone and skull base




PREVENTION-

SOP for strict adherence of humidifiers

Always use distilled or sterile water

Never use un-boiled tap water nor mineral water

Fill up to about 10 mm below the maximum fill line

Do not let the water level pass below the maximum fill line

Water level should be checked twice daily and topped up when required

Water in the humidifier should be changed daily

Humidifier should be washed in mild soapy water, rinsed with clean water and dried in air

before reuse

Once a week (for the same patient) and in between patients, all the components of the

humidifier should be soaked in mild antiseptic solution for 30 minutes, rinsed with clean

water and dried in air.

Enviromental cleanliness to have NO exposure to decaying organic matters like breads/fruits/vegetables/soil/compost/excreta/etc

Control hyperglycemia

Glucose monitoring in COVID-19 patients requiring steroid therapy

Optimally steroid usage - right timing of initiation, right dose, and right duration

Use clean distilled water for humidifiers during oxygen therapy

Use antibiotics/antifungals only and only when indicated

Do not consider all the cases with blocked nose as cases of bacterial sinusitis, particularly in the context of immunosuppression and/or COVID-19 patients on immunomodulators

Simple tests like pupillary reaction, ocular motility, sinus tenderness and palatal examination should be a part of routine physical evaluation of a COVID-19 patient.




REFERENCES-

1. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases - 9th Edition. 2020. E-Book

2. Oliver A Cornely, Ana Alastruey-Izquierdo, Dorothee Arenz, Sharon C A Chen, Eric Dannaoui, Bruno Hochhegger et al. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium.The Lancet Infectious Diseases. 2019;19 (12):e405-e421. Available from: https://doi.org/10.1016/S1473-3099(19)30312-3.

3. Mucormycosis (zygomycosis): Available from: https://www.uptodate.com/contents/mucormycosis-zygomycosis?source=history_widget.

4. Evidence Based Advisory In The Time Of Covid-19: Available from: https://www.icmr.gov.in/pdf/covid/techdoc/Mucormycosis_ADVISORY_FROM_ICMR_In_COVID19_time.pdf

5. Honavar SG. Code Mucor: Guidelines for the Diagnosis, Staging and Management of Rhino-Orbito-Cerebral Mucormycosis in the Setting of COVID-19. Indian J Ophthalmol 2021;69:1361-5.

6. Treatment Protocol For Mucormycosis In Adult Patients- By Expert Committee of Civil Hospital, Ahmedabad

ACKNOWLEDGMENT

I would like to thank Director and CEO Padmashri Prof Ravi Kant for providing me opportunity to be part of

institute MUCOR management team as Team leader. I would like to thank MS Prof Binaya Kumar Bastiya

DHA Prof U.B.Mishra, and Dean (A) Prof Manoj Gupta for their invaluable support. I would like to thank Dr

PK Panda, COVID nodal officer, Department of internal medicine for his invaluable support. I would like to

thank my faculty colleagues in various departments. I would like to thank the Senior Residents and Junior

Residents of Department of ENT and other departments and Nursing officers, ward attendants, Guards, and

housekeeping staffs posted in MUCOR ward for their role in management of the patients. Last I would like

to acknowledge the role of the following departments in preparing the institute protocol for MUCOR

management at present:

1. Department of ENT, AIIMS Rishikesh 2. Department of Internal Medicine, AIIMS Rishikesh 3. Department of Ophthalmology, AIIMS Rishikesh 4. Department of Maxillofacial Surgery, AIIMS Rishikesh 5. Department of Neurosurgery, AIIMS Rishikesh 6. Department of Microbiology, AIIMS Rishikesh 7. Department of Anaesthesia, AIIMS Rishikesh 8. Department of Pediatrics, AIIMS Rishikesh 9. Department of Pediatric Surgery, AIIMS Rishikesh 10. Department of Pharmacology, AIIMS Rishikesh 11. Department of CFM, AIIMS Rishikesh

Management Protocol For Mucormycosis

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