2. Introduction
Mucormycosis is a rare opportunistic fungal
infection with high morbidity & mortality
3rd most common Angio-invasive fungal infection
(after candidiasis and aspergillosis)
Majority of the patient has underlying risk factor
Immuno-compromised Patient
2
3. Mucormycosis is caused by the fungal
organisms of the family of Mucorale
(Mucor, Rhizopus and Absida).
3
4. • Represents 8.3%–13% of all fungal infections
• In developed countries, the disease remains uncommon is
mostly seen in patients with diabetes mellitus and
hematological malignancies undergoing chemotherapy
• In developing countries, especially in India, mucormycosis
cases, although sporadic, occur mainly in patients with
uncontrolled diabetes or trauma
Epidemiology
Chakrabarti A, Singh R. Mucormycosis in India: unique features. Mycoses. 2014 Dec 1;57(s3):85-90.
5. • An upsurge of mucormycosis is being reported
throughout the world over the past two decades.
• With an alarming rise in the number of cases from
developing countries including India.
• Rhino-orbito-cerebral presentation associated
with uncontrolled diabetes is the predominant
characteristic in Indian mucormycosis.
Incidence
Chakrabarti A, Singh R. Mucormycosis in India: unique features. Mycoses. 2014 Dec 1;57(s3):85-90.
6. Host Defence
• Polymorphonuclear phagocytes -kill Mucorales by the
generation of oxidative metabolites
•Neutropenic patients - risk of developing mucormycosis
•Hyperglycemia and acidosis are known to impair the ability of
phagocytes
• Though its exact mechanism is not known
6
7. • Increased susceptibility to mucormycosis of patients with
elevated available serum iron
• Patients treated with the iron chelator deferoxamine have a
markedly increased incidence of invasive mucormycosis
• Rhizopus actually utilize deferoxamine as a siderophore to
supply previously unavailable iron to the fungus
• Rhizous grows rapidly in free iron available
Role of Iron in pathogenesis
Spellberg B, Edwards J, Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation, and
management. Clinical microbiology reviews. 2005 Jul 1;18(3):556-69.
8. • Patients in systemic acidosis have elevated levels of available
serum iron, likely due to release of iron from binding proteins
in the presence of acidosis
• Hence patients in diabetic ketoacidosis are at high risk of
developing rhinocerebral mucormycosis
Role of Iron in pathogenesis
Spellberg B, Edwards J, Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation, and
management. Clinical microbiology reviews. 2005 Jul 1;18(3):556-69.
10. RISK FACTORS
M.Mignogna, G.Fortuna et al. Mucormycosis in immunocompetent patients: a case-series of patients with
maxillary sinus involvement and a critical review of the literature. Int jour Infec Dis. 2011;15
Underlying
Disease
Therapy
Transplantation
Local
Condition
General
Condition
• Leukemia
• Lymphoma
• DM type
• Acute Renal Failure
• Cirrhosis
• Corticosteorieds
• Antibiotics
• Antineoplastic agents
• Bone Marrow
• Solid organ
• Burns
• Trauma
• Malnutrition
10
11. Rising Incidence in immunocompetent patients
M.Mignogna, G.Fortuna et al. Mucormycosis in immunocompetent patients: a case-series of patients with
maxillary sinus involvement and a critical review of the literature. Int jour Infec Dis. 2011;15
11
42%
38%
9%
5%
3%
2% 1%
Cutaneous
Rhino-orbito-
cerebral
Genitourinary
Disseminated
Pumnonary
Gestrointestinal
vascular
January 1978 to June 2009 showed a total of 212 patients of mucormycosis in
immunocompetent/ otherwise healthy individuals
12. Clinical Forms
M.Mignogna, G.Fortuna et al. Mucormycosis in immunocompetent patients: a case-series of patients with
maxillary sinus involvement and a critical review of the literature. Int jour Infec Dis. 2011;15
12
• Rhino-orbitocerebral
• Cutaneous/Subcutaneous
• Gastrointestinal
• Pulmonary
• Dissiminated
• Uncommon Presentation
14. • Sinusitis
• Unilateral facial swelling
• periorbital cellulitis
• eye or facial pain and facial numbness
• conjunctival suffusion
• Blurred vision
• Low-grade fever
• white blood cell counts
• Ophthalmoplegia
• Chemosis
Clinical features
15. • The nasal turbinates on the affected side
may be dusky red or a necrotic black.
• Palatal involvement is usually the result
of direct extension of disease from the
maxillary sinus and in the distribution of
the nasopalatine and greater palatine
arteries.
Clinical features
16. • Oral and skin ulcerations are present with Pain and swelling
Clinical features
18. As the disease progresses to the orbit and skull, the patient
may become confused, irritable, and comatose.
Chemosis, and proptosis result from vascular compromise
and infection of the orbital contents.
Fungal invasion of the globe or retinal artery finally leads to
blindness.
Peripheral spread
20. Diagnostics
• Angiography or surgical exploration-
In areas of anatomic complexity, especially the orbit, reactive
inflammation may be difficult to distinguish from true invasion
with either CT or MRI
Diagnosis
21. Broad, Non-septate, Obtuse-angle
Branching Hyphae. diameters
ranging from 6 to 50 μ
They are recognized microscopically
21
•The fungus is difficult to grow away from infected tissue,
but when it grows, it is rapid and profuse on most media at
room temperature.
•It must be distinguished from Aspergillus, which is smaller
and septate, with more acute branching.
Diagnosis
22. KOH
Diagnosis
Potassium hydroxide (KOH) preparation
•Used for the rapid detection of fungal elements in clinical
specimen
•As it clears the specimen making fungal elements more visible
during direct microscopic examination.
23. Success of Mucormycosis treatment
.
• Early Diagnosis
• Prolonged antifungal therapy
• Reversal of underlying cause if possible
• Surgical debridement
23
24. Early diagnosis
• Early diagnosis - small, focal lesions can often be surgically
excised before they progress to involve critical structures
• Unfortunately, there are no serologic tests available to allow
rapid diagnosis
• Initiation of polyene therapy within 5 days after diagnosis of
mucormycosis was associated with improvement in survival,
compared with initiation of polyene therapy at ≥6 days after
diagnosis (83% vs. 49% survival)
24
Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericin B–based frontline therapy significantly increases mortality
among patients with hematologic malignancy who have zygomycosis. Clin Infect Dis 2008; 47:503–9
25. Antifungal therapy
• Amphotericin B deoxycholate has been used as standard
treatment when no alternative was available
• It is a polyene antimicrobial that acts by binding to sterols in
the fungal cell membrane with a resultant change in membrane
permeability.
• It was considered as ‘golden regime’ for about first 45 years
• With period of time other alternatives to Amphotericine B like
lyposomal/ lipid amphotericine came into the picture
25
26. Treatment
• Amphotericin B is highly protein bound (90%) and poorly
dialyzable.
• Initially a test dose –
• 1 mg in 20 mL of 5% dextrose in water is infused intravenously
over 20 to 30 minutes, with careful monitoring for side effects (ie,
chills, fever, and anaphylaxis) every 30 minutes for 2 to 4 hours.
• If this dose is well tolerated-
• An initial dose of 0.1 to 0.3 mg/kg/day is then prepared as a 0.1
mg/mL infusion and delivered slowly over 6 to 24 hours.
Antifungal therapy
27. Treatment
• Gradually increased by 5 to 10 mg per day, up to a total dose
of 0.7 to 1 mg/kg/day.
• Minor side effects occur- the maintenance dose can be
doubled and given on alternate days
• But a single dose should not exceed 1.5 mg/kg/day; as
overdoses can result in cardiorespiratory arrest.
Antifungal therapy
28. Treatment
Creatinine and urea clearance
blood urea - exceeds 40 mg/100 mL or the
serum creatinine - exceeds 3.0 mg/100 mL,
• Temporarily decrease the dosage.
• A total dose of 3 to 4 g should be given over 6 to 12 weeks.
• Small doses administered over a long period -minimize
toxicity and side effects.
Antifungal therapy
29. Antifungal therapy
• Ambhotericin B and its derivatives-
Drug Recommended
Dose
Advantages Limitations
Amphotericin
B(AmB)
1.0-1.5mg/kg/day > 5 Decades clinical
experience
Highly nephrotoxic
Lyposomal
Amphotericin
B(LAmB)
2.5-5mg/kg/day Less nephrotoxic
than AmB and ABLC
Cost
Amphotericin B
Lipid Concentrate
( ABLC)
5-7.7mg/kg/day Less nephrotoxic
than AmB
More nephrotoxic
than LAmB
29
30. Other antifungal drugs
• Posaconazole
broad-spectrum oral antifungal available
Dose- 800 mg/day divided in 4
• Isavuconazole
Another triazole
Available in oral and intravenous formulations
Administered with a loading dose of 200 mg 3 times a
day for 2 days and 200 mg daily thereaftere
Rutar T, Cockerham KP. Periorbital zygomycosis (mucormycosis) treated with posaconazole. American journal of
ophthalmology. 2006 Jul 31;142(1):187-8.
30
31. Other antifungal drugs
• Fluconazole, voriconazole, and itraconazole do not have
reliable activity against mucormycosis
• Novel regimens for the treatment of mucormycosis include a
combination of lipid-based amphotericin plus either an
posaconazole or Isavuconazole
Rutar T, Cockerham KP. Periorbital zygomycosis (mucormycosis) treated with posaconazole. American journal of
ophthalmology. 2006 Jul 31;142(1):187-8.
31
32. Treatment
• Extensive and early surgical debridement is necessary to
remove necrotic tissue
• Repeated surgical exploration of the sinuses and orbit may be
necessary to ensure that all necrotic tissue has been debrided
and the infection has not progressed
Surgical Debridement
33. • Blood vessel thrombosis , resulting in tissue necrosis during
mucormycosis can result in poor penetration of antifungal
agents to the site of infection.
• Therefore, debridement of necrotic tissues may be important
for complete eradication of mucormycosis.
• Patients who did not undergo surgical debridement of
mucormycosis had a far higher mortality rate than did patients
who underwent surgery
Surgical Debridement
34. Treatment
• Surgical Management Include
o Debridement of the necrotic part
o Drainage of the sinuses
o Total and subtotal maxillectomy
o Palatectomy
o Orbital Exenteration
o Sphenoid and ethmoid sinusectomy
Surgical Debridement
35. Treatment
• exerts a fungistatic effect
• aid in neovascularization
Dose-
• exposure to 100% oxygen for 1and
1/2 2 hours at pressures from 2- 2.5
atm with 1 or 2 exposures daily for a
total of 40 treatments.
Management- Hyperbaric oxygen
36. • Immune-augmentation strategies such as
Administration of granulocyte (macrophage)
colony-stimulating factor or interferon-g alone or in
combination with granulocyte transfusions
• have shown promise in vitro and in case reports
Management
37. Why early intervention is necessary?
• High mortality rate
• Poor prognosis
• Progresses rapidly
• Results in carotid artery occlusion or cavernous sinus
thrombosis
• Permanent residual effects of the disease occur up to 70% of
the time.
0%
20%
40%
60%
80%
100%
120%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
Hall WA et al . Rhinocerebral mucormycosis: changing patterns of disease. Surgical neurology. 2005 Feb
28;41(2):152-6.
37
38. Conclusion
• Mucormycosis is a fatal infection
• Early recognition will prevent further dissemination of disease
• Medical as well as surgical management plays equal role in its treatment
• The detection and limitation of underlying cause is necessary
• Overcoming all the medical and surgical difficulties and making the patient
disease free is a challenging task
38
39. • Bitar D, Van Cauteren D, Lanternier F, et al.Increasing incidence of zygomycosis
(mucormycosis), France, 1997–2006. Emerg nfect Dis 2009, 15:1395–1401
• Rutar T, Cockerham KP. Periorbital zygomycosis (mucormycosis) treated with
posaconazole. American journal of ophthalmology. 2006 Jul 31;142(1):187-8
• M.Mignogna et al. Mucormycosis in immunocompetent patients: a case-series of
patients with maxillary sinus involvement and a critical review of the literature. Int jour
Infec Dis. 2011;15
• Chakrabarti A, Singh R. Mucormycosis in India: unique features. Mycoses. 2014 Dec
1;57(s3):85-90.
References
39
40. • Lehrer RI, Howard DH, Sypherd PS, et al. Mucormycosis. Ann Intern Med 93:93, 1990
• McLean FM, Ginsberg LE, Stanton CA. Perineural spread of rhinocerebral
mucormycosis. Am J Neuroradiol 17:114, 1996
• Van Johnson et al. Bilateral cavernous sinus thrombosis due to mucormycosis. Arch
Ophthalmol 106:1089, 1988
• Hong RH, Koch RJ.Possible role of anticoagulation in the treatment of rhinocerebral
mucormycosis. Otolaryngol Head Neck Surg 122:577, 2000
References
40
41. • Paulltauf A. Mycosis mucorina. Virchows Arch [A] 102:543,1885
• Marx RE, Stern D. Oral and Maxillofacial Pathology (Ed 1). Hanover Park, IL,
Quintessence Publishing, 104-106 , 2003
• Fairley C, Sullivan TJ, Bartley P, et al. Survival after rhino-orbitalcerebral
mucormycosis in an immunocompetent patient. Ophthalmology 107:555, 2000
• Topazian RG, Goldberg MH. Oral & Maxillofacial Infections (Ed 3)
• Cordeiro PG and Santamaria E. Plast Reconst Surg 105: 2331 (2000)
References
41
Incidences are different in developed and developing contires
Siderophores are small, high-affinity iron-chelating compounds secreted by microorganisms such as bacteria and fungi and serving to transport iron across cell membranes.
Because polymorphonuclear leukocytes are less effective in removing hyphae, the infection can then become established.
It progresses as the hyphae begin to invade arteries, where they propagate within the vessel walls and lumens causing thrombosis, ischemia, and infarction with dry gangrene of the affected tissues.
stage 1 - infection of nasal mucosa and paranasal sinuses, stage 2 - orbital involvement leading to superior orbital fissure syndrome and orbital apex syndrome; and stage 3 - cerebral involvement leading to cavernous sinus thrombosis, occipital and frontal lobe infarctions
Once established in the paranasal sinuses, the infection can easily spread to and enter the orbit via the nasolacrimal duct and medial orbit.
Factors contributing to the ease of spread include the thinness of the lamina papyracea, congenital dehiscences often present along the medial wall,
and the perforation of the medial wall by
arteries and veins.
Spread to the brain may occur via the
orbital apex, orbital vessels, or via the
cribiform plate.
In cases of cavernous sinus involvement, anticoagulants have been advocated to prevent vessel thrombosis and hence improve amphotericin B delivery.
are frequently nonspecific.
provides a sensitive indicator of the extent of orbital involvement.
, given the susceptibility of vascular and other soft tissue structures to fungal invasion.
They are appropriate for demonstrating intracerebral disease extension, vascular invasion, and response to therapy.
Sabarand agar, potato dextrose agar
Place a drop of KOH solution on a slide.
Transfer the specimen (small pieces) to the drop of KOH, and cover with glass. Place the slide in a petri dish, or other container with a lid, together with a damp piece of filter paper or cotton wool to prevent the preparation from drying out.
As soon as the specimen has cleared, examine it microscopically using the 10X and 40X objectives with the condenser iris diaphragm closed sufficiently to give a good contrast.
Surgical Management depend upon extent of the disease.
has been used as an adjunct to aggressive surgical debridement and amphotericin B therapy.
with subsequent healing in poorly perfused acidotic and hypoxic tissues.
High concentration of oxygen is fungicidal and has many advantages, such as improve neutrophil activity, inhibit growth of mucorales, improve flow of oxygen to ischemic tissues, and improve wound healing by releasing growth factors.4