Mucormycosis and Treatment

 

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 sk in (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

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