Ophthalmology Notes @ OphthalNotes.blogspot.com

Ophthalmology Notes @ OphthalNotes.blogspot.com
A comprehensive collection of ophthalmology revision notes that cover a broad range of topics.

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

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


Test

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

Frozen section

Saline

Extension of disease/ fungus intraoperatively if available

Squash and imprint cytology preparation

Saline

Presence of fungi

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



1. Harrison’s Principles of Internal Medicine – 20th Edition. 213: Mucormycosis: Page no:1537
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)



SITUATION

APPROACH

SURGICAL DEBRIDEMENT

RECONSTRUCTION

INTERVENTION BY

1) If nasal and sinus involvement is present without bony erosion of maxilla/ zygoma and orbital floor

-

Endoscopic sinus surgery (ESS) by ENT surgeon

----

2) Maxilla involvement without involvement of intraoral soft tissue


Intraoral crevicular incision


Maxillectomy (partial/ total)


Primary closure

Surgical debridement of the involved structures by Maxillofacial surgeon/ Plastic surgeon


Endoscopic clearance of sinuses (ESS) by ENT

3) Maxilla involvement with involvement of intraoral soft tissue


Intraoral crevicular incision


Maxillectomy (partial/ total)

Depending on size of the defect:

1 or 2 teeth involvement - Buccal fat pad


More than 2 teeth or central portion of palate- Temporalis muscle/ other flaps


Involvement of Infra temporal fossa/ necrosis of Temporalis muscle- STG/ other flaps


Obturator/ Zygomatic implants

Surgical debridement of the involved structures by Maxillofacial surgeon/ Plastic surgeon


Endoscopic clearance of sinuses (ESS) by ENT

3) Maxilla + Minimal zygoma involvement

Intraoral crevicular incision

Maxillectomy (partial/ total) +

Zygoma debridement

          As above

Intra oral surgical debridement by Maxillofacial surgeon/ Plastic surgeon


Endoscopic clearance of sinuses (ESS) by ENT

4) Maxilla

+zygoma +orbit

A) Weber ferguson with Dieffenbach's modification incision

Maxillectomy (partial/ total)

+

Zygoma debridement

+

Debridement of Orbital floor/ walls

+

Localised debridement of necrosed tissue in early


As above










Reconstruction of floor of orbit+ walls of orbit and


Surgical debridement of the involved structures by Maxillofacial surgeon/ Plastic surgeon


Endoscopic clearance of sinuses by ENT


Orbital region debridement/ exenteration by Ophthalmologist


B) Trans- conjunctival approach

localised orbital disease

Exenteration of eye in case of:

.Vision loss

.Total ophthalmople gia

.Chemosis

.Necrosis of orbital tissues 

NOTE:- Loss of vision in not always the indication of exenteration

orbital shelf with temporalis muscle/ other flaps


5) Frontal bone and skull base

Coronal approach

A) Anterior table:- Debridement Posterior table:- Cranialization 

B) Debridement if Osteomyelitic skull bone and involvement of the cerebral parenchyma


-

Endoscopic clearance of sinuses & skull base by ENT and neurosurgeon


Safe maximum resection by Neurosurgeon




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