Mucormycosis is caused by fungi of the order Mucorales. It is an opportunistic infection seen in immunocompromised patients. The rhino-orbito-cerebral form presents as sinusitis that can invade the orbit and brain. Pulmonary mucormycosis is the second most common type seen in cancer and transplant patients. Diagnosis requires tissue biopsy demonstrating wide, ribbon-like hyphae. Treatment involves antifungal therapy with amphotericin B and surgical debridement of infected tissues. Prognosis depends on early diagnosis and treatment.

1. Mucormycosis
Dr. UTKARSH TRIPATHI
DNB GENERAL MEDICINE
JLN HOSPITAL & RC, BHILAI

2. Overview
Introduction
Etiology
Predisposing factors
Pathogenesis
Clinical menifestation
Diagnosis
Treatment
Prophylaxis
Prognosis

3. Introduction
Mucormycosis belong to order Mucorales of subphylum
mucormycotina(formerly Zygomycosis) – present freely in
soil and environment
Highly invasive and progressive infection resulting in high
mortality and morbidity
Important opportunistic mycosis in severely
immunocompromised state
Early initiation of treatment based on suspicion is
critical in prognosis

4. Etiology
Among mucorales, Rhizopus oryzae and Rhizopus delemer
are most common in western world & Apophysomyces
elegans in india

5. Causes
Predisposing factors

6. Pathogenesis
Sporangiospores enters through nose and reach sinuses
and lungs
Neutrophils and macrophages block their replication so in
neutropenia other immunodeficient state, fungal growth
prospers
Fungal growth also enhances in Iron overload condition
Undetected fungal growth lead to angioinvasion and
necrosis follwed by dissemination to various site

7. Clinical menifestation
Rhino-orbito-cerebral (MC)
Pulmonary
Disseminated
Cutaneous/Soft tissue
Gastro Intestinal
Miscellaneous

8. Rhino-orbital-cerebral disease
• Acute sinusitis with fever, nasal congestion, purulent nasal discharge, headache, and
sinus pain.
• Can lead to destruction of the turbinates, perinasal swelling, and erythema and
cyanosis of the facial skin overlying the involved sinuses and/or orbit.
• Signs of orbital involvement include periorbital edema, proptosis, chemosis blindness
and opthalmoplegia s/o cavernous sinus thrombosis
• Infection progress from being normal visual inspection findings to erythrmatous phase
with/withot edema to finally black necrotic eschar
• Most cases occur in uncontrolled diabetes, steroid induced diabetes in covid &
transplant setting

9. Pulmonary mucormycosis (2nd mc)
• most common type of mucormycosis in people with cancer and in people
who have had an organ transplant or a stem cell transplant.
• present with Fever, cough, pleuritic chest pain and massive hemoptysis due
to angioinvasion
• It is critical to differentiate mucormycosis from aspergillosis as rapidly as
possible because treatment differs
Gastrointestinal mucormycosis
• More common in neonates
• Present with nonspecific Abdominal pain with nausea,vomiting and
hematemesis, perforation and peritonitis, Bowel infarctions and
hemorrhagic shock in severe cases maybe seen in endoscpy

10. Cutaneous mucormycosis
Single, painful, indurated area of cellulitis rapidly progressing to
necrotic tissue.
occur due to soil exposure from trauma, penetration injury, catheter
insertion, drugs injection
Disseminated and miscellaneous form
the mc site of dissemination is brain haing 100% mortality and can
disseminate to any site through hematological route

11. DAIGNOSIS
• A high index of suspicion is must for dignosis
• DEFINITE DAIGNOSIS requires a positive culture from sterile
site(needle aspirate, tissue biopsy, pleural fluid) or histopathologic
evidence
• Biopsy with histopathological test is most sensitive and specific test
• BIOPSY reveals characteristic wide (>6-30um) thick walled, ribbon like,
aseptate hyphae element that branch at right angle while other fungi
like aspergillus, fusarium are septate, thinner and branch at acute
angles
• The width and ribbon like shape is most imp in distinguishing
mucormycosis with other fungi

13. DAIGNOSIS - HISTOPATHOLOGY
WET PREPARATIONS
• KOH mount
• India ink stain
• Nigrosin stain
• Calcoflour white stain
• Lactophenol Cotton blue
• Neutral RED stain
DIFFERENTIAL STAINS
• Grams stain
• H and E stain
• Giemsa
• PAS
• Gomori’s methamine
stain
• Acridine orange stain
• Fluorescent antibody
staining

14. 1. KOH wet mount – contains 10% KOH with gycerol and distilled water
glycerol accentuated yeast and hyphae while koh dissolves protein

15. 2. INDIA INK STAIN
Used to negatively stain
background and repel
polysacchride cell wall of
cryptococcal infection
3. Calcoflour white stain
Superior to koh mount as
calcoflour is water soluble bind to
cellulose while Evans blue give
flouroscent illumination

16. GOMORI METHAMINE
SILVER STAIN
Fungi are black to brown in
color due to deposition of silver
PAS stain
1% pas solution with basic fuschin
and conc. Hcl
Fungi are magenta red in color

17. DAIGNOSIS – FUNGAL CULTURE
Culture
Tissue swabs, sputum, or BALcultures are usually nondiagnostic
Direct microscopy of bronchoalveolar lavage & transbronchial
biopsy may increase the yield
Rapid growth (48-72 hrs) on Sabouraud agar
and potato dextrose agar incubated at 37◦C
Specimens should be chopped to prevent killing of mucorales
during preparation

18. Mucormycosis
candida
Blastomycosis
mucormycosis

19. Diagnosis - others
Genus and species identification
Molecular based methods (ECMM 2013)
PCR,RFLP
,DNA sequencing that targets the 18S ribosomal DNA of
Mucorales
Antigen Detection & Specific Tcells
Galactomannan and ß-D Glucan – If negative likely
invasive mucormycosis than Aspergillosis.
Mucorales-specific Tcells - enzyme-linked immunospot(ELISpot) assay
Sequencing of Internal Transcribed Spacer (ITS)of rRNA is the best
technique

20. DAIGNOSIS - APPROACH
Three-step analysis of CTguided biopsy specimens
of lung lesions to differentate pulmonary mucor and
Aspergillosis:
1. Calcofluor-white staining - septated versus aseptae
hyphae
2. Aspergillus Galactomannan and PCRtesting for
rapid testing
3. PCRtesting of DNA in specimens where aseptate
hyphae were observed and Aspergillus
markers were negative

21. Diagnosis - Radiology
Mc finding in CT/MRI of rhino-orbital mucormycosis is sinusitis that is
indistinguishable from bacterial sinusitis
MRI (godolinium enhanced) is more sensitive than CT but high risk
patient should always undergo endoscopy and/or surgical exploration
with biopsy
Black turbinate sign in MRI refers to non enhancement of nasal
turbinates in invasive fungal rhinosinusitis
Fungi shows dark hyperintensity of
mucosa on T2WI and hypointense on
T1 while godolinium enhances the
Inflamed mucosal lining

22. Pulmonary mucormycosis – HRCT thorax is best method
Infilteration, wedge consolidation, multiple nodule>10, cavitation and rarely pleural effusion in
Pulmonary mucormycosis > Aspergillosis
Reverse Halo sign
Air Crescent sign
crescent of air seen in lungs mc in
Invasive aspergillosis >>
mucormycosis in HRCT thorax
Focal area of GGO
surrounded by ring of
consolidation in HRCT thorax
~20 to 90 %of pulmonary
mucormycosis & 6% with IPA

23. Treatment
General principles
Early diagnosis is critical and associated with increased survival
Early administration of active antifungal agents primarily polyenes when
mucormycosis is suspected and confirmation is awaited
Reversal of underlying predisposing factors like daibetes control, normal
acid base status, stoppage of immunosuppressive drugs
Complete surgical removal of all infected tissues is imp for iradication of
disease due to poor penetration of antifungal in necrotic tissue
Use of adjunctive therapy and team approach

24. Treatment
First Line Antifungal Therapy
 Should be polyene systemic antifungal agent except in mild localized infection
where surgery is best option
 Polyenes bind to ergosterol in cell membrane of fungi and form pores in it lead
to cell death having widest antifungal spectrum and drug of choice for most of
systemic mycosis except fusarium
 Obtained from streptomyces nodosus, a bacteria having antifungal activity
 Drugs include AmphoterecinB, Nystatin, Hamycin
 Different formulations of Amphoterecin include
1. AmphotericinB deoxycholate
2.Liposomal AmphoterecinB(Lamb)
3.AmphoterecinB lipid complex(ABLC)
4.AmphoterecinB colloidal dispersion (ABCD)

25. AmphoterecinB deoxycholate
given in doses of 1-1.5mg/kg/day IV infusion over 4-6hrs
To avoid infusion related immidiate complication
1. Pre-infusion of 500-1000ml of normal saline
2. NSAIDS and/or inj diphenhydramine 25mg iv or hydrocortisone 25mg iv
ADMINISTRATION? Available 50mg of lypholized powder should be
reconstituted with 50ml of sterile water,shaked well, leading to conc of
1mg/ml; TEST DOSE of 1ml solution in 50ml of 5%dextrose is infused over 60
min via central catheter; if no reaction like fever, hypersensitivity, hypotension
then remaining 49 ml of soln. in 500ml of 5% dextrose infused over 4-5 hrs in
well dark setup(to be covered in black sheet) as amB is highly photosensitive
DISADVANTAGE? Highly toxic preferably renotoxic and poor cns penetration
ADVANTAGE? Low cost

26. ADVERSE REACTION? MC is hypersenstivity rxn like fever, chills,
rash after 1-3 hrs
Febrile reaction subside over subsequent transfusions
OTHERS; hypotension, hypokalemia, hypomagnesemia, anaemia(low
erythropoietin), dairrhoea, abdominal pain, anorexia, tachypnoea, bone
marrow suppression
Dose limited toxicity is NEPHROTOXICITY including azotemia(80%
pt), renal tubular acidosis, nephocalcinosis(>0.1mg/ml) and renal
insufficiency
MONITORING? Daily monitor Urine output and renal function tests
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

27. Liposomal amphoterecinB (Lamb)
DOSE? Started at 5mg/kg/day escalated upto 10mg/kg/day in cns infection
ADVANTAGE? Less nephrotoxic than amB deoxycholate
Best cns penetration among polyene with better clinical outcome
Excreted by liver macrophages but hepatotoxicity is not more than
deoxycholate
Do not require major dose adjustment in critical patient with poor renal
function
DISADVANTAGE? Expensive
ADMINISTRATION? Same as amB deoxycholate
Reconstituted soln. can be used upto 24 hr when refrigerated and infusion
should begin within 6 hr after dilution

28. AmphoterecinB liposomal complex (ABLC)
DOSE? upto 5mg/kg/day
ADVANTAGE? Less nephrotoxic than amB deoxycholate, more responsive to
candidiasis
DISADVANTAGE? Expensive and less efficacious than Lamb
ADMINISTRATION? Available as 100mg/20ml suspension, approx dose is
diluted with 5% dextrose to final conc of 1mg/ml administered as 2.5mg/kg/hr
over 2 hr.
Diluted soln. is stable over 15 hr when refrigerated and placed in dark

29. AmphoterecinB colloidal dispersion (ABCD)
DOSE? 3-4mg/kg/day upto 6mg/kg/day for majority fungal infection
ADVANTAGE? Less nephrotoxic than deoxycholate variant; more effective for invasive
aspergillosis; also metabolized through liver macrophages but hepatotoxicity is equal to
deoxycholate; it can be fungostatic in low doses and fungicidal in higher doses
DISADVANTAGE? more expensive and less efficacious than Lamb; also having more
infusion related anaphylaxis than Lamb
ADMINISTRATION? Available as 50/100mg lypholized powder reconstituted with
sterile water having conc. of 5mg/ml diluted in 5% dextrose and infused at rate of
1mg/kg/hr in dark environment
Should be used within 48hrs after reconstitution

30. Second line/Salvage Therapy
• Consist of AZOLES which includes Posaconazole and
Isavuconazole
• Both are FDA approved azoles against mucorales but lesser
efficacy than amb
• MOA? Act by inhibiting conversion of lanosterol to ergosterol so,
decreasing cell membrane formation
• Posaconazole-polyene therapy combination is not superior to
polyene monotherapy
• Patients receiving antifungal prophylaxis with itraconazole and
voriconazole have increased risk of disseminated mucormycosis

31. ISAVUCONAZOLE
DOSE - 200mg(372mg of isavuconazole sulphate) oral q8h*6 days then od
ADVERSE EFFECTS – dairrhoea, rash, hepatotoxicity, QT prolongation and
long term use lead to skin disorders and maybe SCC
Best reserved drug for oral step-down therapy in pt whose condition has been
improved with polyenes therapy or Salvage therapy in pt who are intolerant to
polyene based therapy or infection is still refractory
Emperically, lipid polyenes and azoles therapy is preffered in invasive mould
infection when septate and aseptate moulds are both in differentials
POSACONAZOLE
DOSE – Oral Posaconazole – 18-24 mg/kg/day in 3-4 divided doses(200mg q4d)
IV doses – 18-24 mg/kg/day in 2-3 divided doses

32. COMBINATION THERAPY
1. Echinocandin and polyene: Echinocandins basically Indicated for
candidal infections mainly esophageal and peritoneal abcess
It consists of caspofungin, anidulafungin and micafungin in which caspofungin
having standard iv dose of 200mg loading and 100mg/day for maintenance dose
14 days upto last positive culture along with standard dose of polyenes improve
survival rate and having better outcome than polyene monotherapy in
disseminated mucormycosis however definitive trials are needed to confirm
efficacy
2. Lipid polyene and azole; limited safety profile, definitive trials needed
3. Triple therapy; limited safety profile, definitive trials needed

33. Treatment – Adjunctive
Hyperbaric Oxygen – 100% O2 at 2atm pressure for 90
min twice a day (C)
Cytokine therapy in hematological malignancy –
GCSF(A),Granulocyte transfusion +/- IFNγ (C)
Lovastatin
VT-1161(otesaconazole) – Inhibits fungal CYP51
Nivolumumab and IFNγ

34. Treatment – Adjunctive
IRON CHELATOR - DEFERASIROX
Deferasirox-AmBisome Therapy for Mucormycosis (DEFEATMucor)
study
It is contraindicated as therapy in pt with active malignancy
Deferasirox cannot be recommended aspart of an initial
combination regimen for the
treatment of mucormycosis.

35. DURATION OF MEDICAL
MANAGEMENT
Highly individualized but minimun 2-3 week of injectable amb
therapy upto 6 week depending upon clinical/radiological severity
then stepdown therapy with oral azoles for 3-6 months depending
upon clinical severity upto near normalization of radiograph,
negative biopsy specimens and cultures, recovery from
immunosuppression

36. Treatment - Surgery
Removal of necrotic tissue – Increases penetration of
antifungals
Lobectomy, Pneumonectomy or wedge resection
Surrounding infected healthy-looking tissues should
be removed
Mortality reduced by 79%

37. 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 earlylocalised 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 indicationof exenteration
Exenteration of eye
• 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
3

38. Prophylaxis
Neutropenic or GvHD with immunosuppressive
outbreaks – Posaconazole 600mg/day acc to
European confederation of medical mycology
(ECMM)
No role of antifungals in prophylaxis

39. PREVENTION IN COVID ERA
• Judicious use of systemic steroids in strict complaince – Right time of
initiation, right dose and right duration
• Aggressive monitoring and control of diabetes mellitus and DKA
• Systemic steroides should only used in hypoxemic pt
• Oral steroides are contraindicated in pt with normal oxygen level
• The dose and duration of steroid therapy should be limited to
dexamethasone (0.1mg/kg/day) for 5-10 days

40. • Judicious use and strict aseptic precautions while administering
oxygen such as sterile water for humidifier, regular change of
humidifier and tubes without any exposure of organic decaying
matter
• Personel and environmental hygiene
• Betadine mouth gargle twice a day
• Barrier mask covering nose and mouth reduce exposure to
mucorales
• During discharge of pt, advice about early sign and symptoms of
mucormycosis and avoidance of construction sites
• Regular follow up with ENT specialist for nasal endoscopy (for
higher risk pt)

41. Prognosis
Overall mortality in pulmonary mucormycosis 50-70% ,if disseminated
with cns involvement >90%
The key factor is strict control of predisposing factors but a balanced
approach is needed with other life threatening diseases and
mucormycosis in long term

42. Major fungals and management

43. More common in immunocompromised pt
Antifungals should be used cautiously
No specific clinical or radiological features making
diagnosis more difficult and challenging
Diagnostic options are limited with variable results
Invasive diagnostics have more yield
Take Home Message

44. Early diagnosis means early treatment and leading to less mortality
rates
Reversal of underlying factors, Surgery and Liposomal amphotericin
B increases cure rates
Duration of treatment is highly individualized
Posaconazole, Isuvaconazole can also be tried
Salvage therapy in refractory or intolerant pts
Adjunctive therapies need to proved in large trials and standardized

45. References
Fishman's Pulmonary Diseases and Disorders, 5th edition
Pilmis B,Lanternier F
.Recent advances in understanding and management of
mucormycosis 2018, F1000 research
Challenges in the diagnosis and treatment of mucormycosis
A. Skiada. Medical Mycology, 2018
ESCMID and ECMM joint clinical guidelines for the diagnosis and management
of mucormycosis 2013, Clin Microbiol Infect 2014
Mucormycosis and entomophthoramycosis: a review of the clinical
manifestations, diagnosis and treatment, R.M. Prabhu and R.Patel,Mayo clinic of
medicine, Clin Microbiol Infect 2004