Systemic fungal infections venkat

Systemic fungal infections
N Venkateshwarlu MBBS (Kurnool), MD(AIIMS/Lady Hardinge)
Monday, 10 October 2016
Nandyala Venkateshwarlu SVS Medial College Mahabubnagar,
Telangana India
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N Venkateshwarlu MBBS (Kurnool), MD(AIIMS/Lady Hardinge)
Professor,
Department of Internal Medicine
SVS Medical College Mahabubnagar A.P.

Fungi
• Molds and yeasts are widely distributed in air, dust, fomites and normal flora.
• Humans are relatively resistant.
• Fungi are relatively nonpathogenic.
• Of the 100,000 fungal species, only 300 have been linked to disease in animals.
• Fungi are the most common plant pathogens.
• Human mycoses are caused by true fungal pathogens and opportunistic
pathogens.
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Fungi

Fungal infections
1. Superficial
2. Cutaneous
3. Subcutaneous
4. Systemic
5. Opportunistic
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• May result from breathing in the spores of fungi, which normally live in the
soil or rotting vegetation or as opportunistic disease in immune
compromised individuals.
A. Inhaled fungal infection (By True pathogens)
• Although uncommon, some may infect healthy individuals. The result is
most often a mild infection and long lasting resistance to further attack,
but occasionally these infections are more serious and chronic (especially
in the immune suppressed). The organisms causing systemic fungal
infections include:
1. Histoplasmosis
2. Coccidioidomycosis (North and South America).
3. Blasomycosis
4. Para-coccidiodomycosis
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B. Fungal infections of intermediate virulence
1. Sporothrex schenckii – Sporotrichosis
2. Genera dermatophytes [Microsporan,
Trichophoton,
Epidedermophyton]
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C. Opportunistic infections
• Other systemic mycoses only infect those who are already sick or with an
immunodeficiency disorder i.e. they are ‘opportunists’. Repeated infection
may occur. Risks for systemic mycoses include:
1. Serious illness and debility
2. Cancer or leukemia
3. Diabetes mellitus
4. Transplant
5. Massive doses of antibiotics
6. Parenteral nutrition
7. Drug addiction
8. Infection with human immunodeficiency virus (HIV)
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C. Opportunistic infections
Opportunistic fungal infections include:
1. Aspergillosis (found everywhere)
2. Zygomycosis
3. Cryptococcosis (where there are pigeon droppings)
4. Trichosporon beigelii
5. Pseudallescheria boydii
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Opportunistic fungal diseases
• Opportunistic mycosis a fungal or fungus-like disease occurring in an animal /
human’s with a compromised immune system.
• Opportunistic organisms are normal resident flora that become pathogenic only
when the host's immune defences are altered, as in immunosuppressive therapy,
in a chronic disease, such as diabetes mellitus, or during steroid or antibacterial
therapy that upsets the balance of bacterial flora in the body.
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Systemic fungal infections – clinical
suspicion
1. Fever with severe neutropenia or immunosuppresion
2. Fever resistant to broad spectrum antibiotics in neutropenic patient
3. Symptoms and signs of new resistant or progressive lower
respiratory tract infection
4. Prolonged severe lymphocytopenia in chronic graft versus host
disease [GVHD] and immunosuppression
5. Periorbital or maxillary swelling with tenderness
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Systemic fungal infections – clinical
suspicion
6. Palatal necrosis or perforation
7. Features of focal neurologic deficit or meningeal irritation
with fever
8. Unexplained mental changes with fever
9. Papular or nodular skin lesions
10.Intra-ocular evidence of systemic fungal infection
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Systemic Fungal infections
• The highest frequency of opportunistic fungal infections come in the following
order:
1.Candidiasis
2.Aspergillosis
3.Cryptococcosis
• Candidiasis
• Deep fungal infections
• Mucormycosis
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Transmission
• Portal of entry
– primary mycoses – respiratory portal; inhaled spores
– subcutaneous - inoculated skin; trauma
– cutaneous and superficial – contamination of skin surface
• Virulence factors – thermal dimorphism, toxin production, capsules and
adhesion factors, hydrolytic enzymes, inflammatory stimulants
• Antifungal defenses are the integrity of the barriers and respiratory cilia.
• Most important defenses are cell-mediated immunity, phagocytosis, and
inflammation.
• Long-term immunity can only develop for some.
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Diagnosis of invasive fungal infections
• High degree of suspicion depending upon
1. The risk factor
2. Clinical situation
3. Immune status of the patient
4. Pneumonia
5. Sinusitis
6. Radiological and histological diagnosis
7. Microbiological serological abnormality
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1. Microscopy
2. Culture
3. Serology
4. Histopathology
5. Imaging
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Microscopy
1. Readily available easy, simple and cheap
2. Respiratory secretions like sputum, broncho-alveolar lavage [BAL]
fluid
3. Microscopy differentiate septate and nonseptate molds
4. A positive India ink preparation of CSF – cryptococcal meningitis
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Culture
• Samples can be Blood, CSF, Urine, sputum, Intracath tip, Endo-
tracheal tube tip,
• Automated cultures
• Candida species is most common organism – can be contamination
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Serology
• A variety of serological tests are available with different degree of
specificity and sensitivity are available for example…
1. Detection of Cryptococcal polysaccharide antigen in serum and CSF.
Positivity is >90% as against India ink preparation – 70% Culture in
CSF – 50%
2. Detection of Histoplasma antigen in urine and serum
3. Detection of antibodies to Coccidoides immitis and Histoplasma
capsulatum in serum and CSF
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Serology
• Serological markers – Galactomannan and (1,3)-β-D-glucan [BG]
• For diagnosis of IPA [invasive pulmonary Aspergillosis] in patients
with neutropenia
• Galactomannan is released from Aspergillosis during growth
• Multiple tests to be done in order to lessen the false positive results
• Sensitivity is much higher if respiratory secretions are used in stead
of serum
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Histopathology
• Definitive
• Stained with Periodic acid Schiff [PAS] stain, Gomri methenamine
silver or fluroscent stain,
• Candida is seen in Gram’s stain
• Evidence of inflammatory cells along with fungus is highly
diagnostic as it eleminates contaminants
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Imaging
1. Pulmonary fungal infections
2. Fungal sinusitis
3. Fungal meningitis
4. Fungal IE
5. Disseminated candidiasis
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Imaging
HRCT Scan of chest is diagnostic of IPA – Presence of halo-crescent sign
– a localized ground glass appearance representing hemorrhagic
infarction surrounds a nodule suggestive of IPA
Immunocompramized patient with a new neurologic feature [
headache – new persistent, seizures, stroke or meningitis – MRI/CT
BRAIN
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Systemic anti-fungal drugs
1. Polyenes [Amphotericin B deoxycholate]
2. Azoles [Flucanazole etc.]
3. Echinocandins
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Classification of antifungal infection according
to site of action
1. Fungal cell wall synthesis inhibition: Caspofungin.
2. Bind to fungal cell membrane ergosterol: Amphotercin–B, Nystatin.
3. Inhibition of ergosterol + lanosterol synthesis: Terbinafine, Naftifine,
Butenafine.
4. Inhibition of ergosterol synthesis: Azoles
5. Inhibition of nucleic acid synthesis: 5–Flucytosine.
6. Disruption of mitotic spindle and inhibition of fungal mitosis: Griseofulvin.
7. Miscellaneous:
• Ciclopirox, Tolnaftate, Haloprogin, Undecylenic acid, Topical azoles.
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Site of
action
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Site of
action
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Site of
action
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FLUCYTOSINE
IMIDAZOLES
TRIAZOLES
POLYENES
CANDINS
GRISEOFULVIN
OTHERS
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ANTI FUNGAL DRUGS MECHANISAM

Classification of antifungal drugs – according
to chemical structures
A. ANTIBIOTICS
Polyene: Amphotericin, Nystatin, Hamycin
Heterocyclic benzofuran: Griseofulvin
B. ANTIMETABOLITE : Flucytosine
C. AZOLES
1. Imidazoles: Ketoconazole, clotrimazole, oxiconazole,
miconazole,
2. Triazoles: Fluconazole, itraconazole, voriconazole,
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Classification of antifungal drugs
D. ALLYLAMINES
• Terbinafine, Butenafine
E. ECHINOCANDINS
• Caspofungin, Anidulafungin, Micafungin
F. OTHER TOPICAL AGENTS
• Tolnaftate, Undecyclinic acid, Benzoic acid
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Polyenes
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Antibiotics
1. Amphotericin B
2. Liposomal Amphotericin B [LAB]
3. Nystatin
4. Hamycin
5. Natamycin
6. Griseofulvin
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Polyenes
• Fundamental prototype [Amphotericin B] for
1. Aspergillosis
2. Cryptococcosis
3. Systemic candidiasis
4. Histoplasmosis
5. Blastomycosis
6. Coccidiodomycosis
7. Zygomycosis
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Site of action
• Several amphotericin B molecules bind to
ergosterol in the plasma membranes of
sensitive fungal cells.
• There, they form pores (channels) that
require hydrophobic interactions between
the lipophilic segment of the polyene
antibiotic and the sterol.
• The pores disrupt membrane function,
allowing electrolytes (particularly potassium)
and small molecules to leak from the cell,
resulting in cell death.
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Amphotericin B
• Late 1950’s
• Amphoterecin deoxylate
• Fungicidal
• Acts on ergosterol of the fungal cell wall membrane
• 0.6 – 1 mg/kg/day
• Broad specrtum
• Significant nephrotoxicity
• No oral
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Amphotericin B
- Aspergillus
- Blastomyces dermatitidis
- Candida albicans
- Cryptococcus neoformans
- Coccidioides immitis
- Histoplasma capsulatum
- Mucor spp.
• Also active against Leshmania
• Broadest spectrum of action
• Fungicidal at high & static at low conc.
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Mechanism of resistance – Amphotericin
• Resistance:
• Replacement of ergosterol by other sterols in fungal plasma membrane.
• Resistance is not a problem clinically.
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Pharmacokinetics
• Poorly absorbed orally
• Insoluble in water so colloidal suspension prepared
with sodium deoxycholate(1:1 complex)
• 90% bound to plasma proteins
• Metabolized in liver slowly excreted in urine
• t ½ = 15 days
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Administration – dose
• Systemic mycosis: IV
• Available as 50mg vial – suspended in 10 ml water and then diluted with 500
ml glucose
• 0.5mg/kg to 1 mg/kg
• Total dose- 3-4 gm over 2-3 months
• Intestinal Monoliasis: 50-100 mg QID Orally
• Vaginitis: topical
• Otomycosis: 3 % drops
• Intrathecal: 0.5 mg BD in fungal meningitis
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Amphotericin B
• Useful drug in nearly all life threatening mycotic infections
• Treatment of invasive aspergillosis
• Rapidly progressive Blastomycosis & Coccidiomycosis
• Cryptococcus neoformans
• Mucormycosis.
• Disseminated rapidly progressing Histoplasmosis
• Reserve drugs for resistant kala azar
• Topical uses:
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Amphotericin B
• Adverse events:
– Acute reaction:
– Chills, fever, headache, pain all over, nausea, vomiting,
dyspnoea lasting 2-5 hrs because of release of IL & TNF
– can be treated with hydrocortisone 0.6mg/kg
– Long term toxicity:
– Nephrotoxicity: Azotemia, Hypokalemia,
acidosis, ↓ GFR
– anemia
– CNS toxicity : intrathecal administration, headache,
vomiting, nerve palsies
– Hepatotoxicity rarely
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Amphotericin B
• Intravenous infusion related reactions – fever, chills, nausea and
vomiting, hypotension and hypoxemia – 4-6 hours
• Rapid infusion – life threatening hyperkalemia and arrhythmias
• Shock
• Should not be administered simultaneously with leukocytes as this
may precipitate pulmonary toxicity
• Infusion related reactions can be reduced by infusing for 24 hours
continuously with normal saline
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Amphotericin B
• Risk factors for nephrotoxicity
1. Male
2. Body weight greater than 90 kg
3. C.K.D.
4. Treatment with aminoglycosides and cyclosporine
5. Dose of Amphotericin B > 35 mg/ day
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Lipid formulations of Amphotericin B
• Amphotericin B Lipid Complex
• Amphotericin B Colloidal Dispersion
• Liposomal Amphotericin B
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Amphotericin B Lipid Complex [ABLC]
• Amphotericin B Lipid Complex [ABLC]
• 35% AMB incorporated in ribbon like
particles of dimyristoyl phospholipids
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Amphotericin B Colloidal Dispersion [ ABCD]
• Amphotericin B Colloidal
Dispersion [ABCD]
• Disc shaped particles
containing 50% each of AMB
& cholesteryl ester in aqueos
dispersion
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Liposomal Amphotericin B [LAB]
• Liposomal Amphotericin B
[LAB] ( Small unilamellar
vesicles)
•10% AMB
incorporated in SUV
made up of lecithin
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Major advantages of lipid amphotericin B
Milder acute reaction
Can be used in intolerance to conventional preparations
Lower nephrotoxicity & anemia
Deliver AMB to RES of liver spleen so useful in leshmania & immuno-
compromised
Can be used in higher doses
20 – 50 times costlier than Amphotericin B
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Antibiotics – Nystatin
Obtained from S. Noursei
Similar to AMB in antifungal properties, high systemic toxicity so used locally
only
Poorly absorbed from mucus membrane
Available as ointment ,cream , powder, tablet
Uses:
 5 lac U in intestinal moniliasis TDS
 1 lac U in vaginitis
 Prevention of oral candidiasis
 Can be used in oral, cutaneous, conjunctival candidiasis
Adverse events:
 Gastointestinal disturbances with oral tablets
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Antibiotics
 Hamycin:
 S. Pimprina
 Hindustan antibiotics pimpri
 More water soluble, fraction absorbed orally but unreliable in systemic
infections
 Topical use in thrush, cutaneous candidiasis, trichomonas & monilial vaginitis,
otomycosis by aspergillus
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Antibiotics
 Natamycin:
 Similar to nystatin, broad spectrum
 Used topically 1%, 3% ointment
 Fusarium solani keratitis, trichomonas & monilial vaginitis
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Griseofulvin
• One of early antibiotics from penicillium griseofulvum
• Fungistatic, systemic drug for superficial fungal infections
• Active against most dermatophytes
• Dermatophytes concentrate it actively hence selective toxicity
• Resistance: loss of concentrating ability
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Griseofuvin
• Mechanism of action:
• Griseofulvin interacts with polymerized
microtubules and disrupts the mitotic spindles
thus arresting fungal mitosis
• Pharmacokinetics:
• Oral administration, irregular absorption,
increased by fatty food and microfine particles
• Gets conc in keratinized tissue
• Metabolized in liver, excreted in urine,t1/2=24 hrs
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Griseofulvin
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Griseofulvin
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• Adverse events:
• Headache most common
• GIT disturbances
• CNS symptoms: confusion, fatigue, vertigo
• Peripheral neuritis
• Rashes, photoallergy
• Transient leukopenia, albuminuria

Griseofulvin
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• Uses:
• Systemically only for dermatophytosis, ineffective topically
• Systemic azoles more effective and preferred
• Duration of treatment depends on site, thickness of keratin and
turnover of keratin.
• Treatment must be continued till infected tissue is completely
replaced by normal skin,hair, nail.
• Dose: 125-250 mg QID

Griseofulvin
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• Body skin = 3 weeks
• Palm, soles = 4- 6 weeks
• Finger nails = 4- 6months
• Toe nails = 8 – 12 months
• Griseofulvin should be reserved for nail hair or larger body surface
involvement
• Interactions:
– Warfarin , OCP
– Phenobarbitone, Disulfiram like reaction

Imidazoles
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Triazole Allymines
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β-1-3-Glucan symthase inhibitors
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Grisofulvin
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Flucytosine

Azoles
• Azoles:
• Synthetic antifungals
• Broad spectrum
• Fungistatic or fungicidal depending on concentration of
drug
• Most commonly used
• Classified as imidazoles & triazoles
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Azoles
• Imidazoles: Two nitrogen in structure
• Topical: econazole, miconazole, clotrimazole
• Systemic : ketoconazole
• Newer : butaconazole, oxiconazole, sulconazole
• Triazoles : Three nitrogen in structure
• Fluconazole, itraconazole, voriconazole
• Terconazole: Topical for superficial infections
• Both these groups are
• Structurally related compounds
• Have same mechanism of action
• Have similar antifungal spectrum
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Ergosterol
14 α demethylase
Ѳ
Azoles
squalene 2,3 epoxide
Ѳ
Lanosterol
Squalene
Terbinafine
Mechanism of action:

Micanazole Clotrimazole
• Topical use:
• Miconazole 2 % and clotrimazole 1 % applied BD for 2 weeks in pityriasis
versicolor, 4 weeks in cruris, capitis and corporis
• Uses:
• Dermatophyte infections
• Candida: oral pharyngeal, vaginal, cutaneous
• Adverse events:
• Local irritation , itching or burning
• Miconazole shows higher incidence of vaginal irritation & pelvic cramps
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Ketaconazole
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–First orally effective broad spectrum antifungal
–Effective against
• Dermatophytosis, Deep mycosis , Candidiasis
• Most toxic among azoles so not used so much
triazoles preferred
• Acidic environment favours absorption so
orange juice increases absorption and proton
pump inhibitors decrease absorption.
• But saturation of metabolism occurs shortly
which prolongs the its half life and permits
once daily dosing , since small amount of drug
appears in urine.

Ketaconazole – Pharmacokinetics
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• Effective orally
• Acidic environment favours absorption
• High protein binding
• Readily distributed, not to BBB
• Metabolized in liver, excreted in bile
• t1/2 = 8- 10 hrs
• Dose : 200 mg OD or BD

Ketaconazole – Adverse effects
• Nausea , vomiting , anorexia
• Headache , paresthesia, alopecia
• ↓ steroid, testosterone & estrogen synthesis
• Gynaecomastia, oligospermia , loss of libido & impotence in males
• Menstrual irregularities & amenorrhoea in females
• Elevation of liver enzymes
• Hypersensitivity reaction - skin rashes, itching
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Ketaconazole – Drug reactions
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Ketaconazole
• Dermatophytosis: concentrated in stratum corneum
• Monilial vaginitis : 5-7 days
• Systemic mycosis: blastomycosis, histoplasmosis, coccidiodomycosis
• Less efficacy than AMB & slower response
• ↓Efficacy in immuno-compromized and meningitis
• Lower toxicity than AMB higher than triazoles
• High dose used in Cushing’s syndrome
• Topical: T. pedis, cruris, corporis, versicolor
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Fluconazole
• Newer water soluble triazole
• Oral, IV as well as topical
• Broad spectrum antifungal activity
• Candida, cryptococcosis, coccidiodomycosis
• Dermatophytosis
• Blastomycosis
• Histoplasmosis
• Sporotrichosis
• Not effective against aspergillosis & mucormycosis
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Fluconazole
Pharmacokinetics
• 94% oral bioavailability
Not affected by food or gastric pH
Primarily excreted unchanged in urine t1/2 = 25 -30 hrs
Poor protein binding
Widely distributed crosses BBB
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Fluconazole
Adverse effects
GIT upset
Headache, alopecia, skin rashes, hepatic necrosis
Teratogenic effect
CYP450 Enzyme inhibiting property less Interactions:
 Effects hepatic drug metabolism to lesser extent than Ketoconazole
 H2 blockers & PPI do not effect its absorption
No anti androgenic & other endocrine effects
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Fluconazole – Uses
 Candida:
 150 mg oral dose can cure vaginal candidiasis with few relapse
 Oral candidiasis- 2 weeks treatment required
Tinea infections & cutaneous candidiasis: 150 mg weekly for 4 weeks,
tinea unguim : 12 months
systemic fungal infections: Disseminated candidiasis, cryptococcal,
coccidiodal meningitis 200-400 mg / day 4- 12 weeks or longer
Meningitis: preferred drug
Eye drops for fungal keratitis
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Itraconazole
 Broadest spectrum of activity also against aspergillus
Fungistatic but effective in immunocompromised
Does not inhibit steroid hormone synthesis and no
serious hepatoxicity
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Itraconazole – Pharmacokinetics
 50-60% bioavailability, absorption is variable, enhanced by food &
gastric acidity
High protein binding 99 %
Well distributed accumulates in vaginal mucosa, skin, nails but CNS
penetration is poor
Metabolized in liver CYP3A4 excreted in feces t1/2= 30- 64hr
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Itraconazole
 DOC for paracoccidomycosis & chromoblastomycosis
DOC for histoplasmosis & blastomycosis
Esophageal, oropharyngeal vaginal candidiasis
 Not superior to fluconazole : 200 mg OD X 3 days
Dermatophytosis: less effective than fluconazole
 100- 200 mg OD X 15 days
Onychomycosis : 200 mg / day for 3 months
 Intermittent pulse regime 200 BD once a week / month for 3 months equally
effective
Aspergillosis: 200 mg OD/ BD with meals for 3 months or more
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Itraconazole – Uses
• Capsule form of drug better absorbed in fed state , invasive
aspergillosis outside the CNS
• In treating deep mycosis two 100 mg capsules given twice daily with
food , divided doses increase the AUC
• WHY PULSE THERAPY: retention of active drug in nail keratin . Daily
therapy preferred for recurring infection.
• Terbinbafine 250 mg OD better in onychomycosis than itraconazole
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Itraconazole – Adverse effects
• GI Intolerance
• Dizziness, pruritis , headache , hypokalemia
• Increase plasma transaminase
• Rarely hepatotoxicity
• Drug interactions:
• Oral absorption ↓by antacids, H2 blockers
• Rifampicin, phenytoin induce metabolism
• Inhibits CYP3A4 drug interaction profile similar to ketoconazole
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Triazoles
• Itraconazole
- Varied absorption.
Metabolized by cyt P450
- less endocrine effects but
occur at high doses
- Less penetration in CSF
- Many drug interactions (due to
inhibition of CYT P450/ 3A4)
• Fluconazole
- Completely absorbed and
better tolerated, Renal
excretion
- Less endocrine effects
- Penetrates well into CSF
- Drug Interactions
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Voriconazole
 II generation triazole
 High oral bioavailability, low protein binding
 Good CSF penetration
 Metabolized by CYP2C19
 Doesn’t require gastric acidity for absorption
 T1/2= 6 hrs
 Uses:
 DOC for invasive aspergillosis
 Most useful for esophageal candidiasis
 First line for moulds like fusarium
 Useful in resistant candida infections
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Voriconazole
• Dose : 200 mg BD
• Adverse events:
• Transient visual changes like blurred vision , altered color perception &
photophobia
• Rashes in 5 -6 %
• Elevated hepatic enzymes
• Prolongation of QT
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Posaconazole
• Broad spectrum antifungal
1. Candida
2. Aspergillosis
3. Zygomycetes
4. Fusarium
• Oral preparation
• Variable bioavailabilty
• Better after food
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Posaconazole
• Prophylaxis against aspergillosis [200mg t.i.d PO]
• Prophylaxis against candidiasis [ 100 – 400 mg PO q12 –
q24h]; in severely immunocompramized individuals
• Treatment of oropharyngeal candidiasis refractory to
flucanazole and itraconazole
• In combination therapy in Mucor mycosis – 400 mg b.i.d
PO
• As a salvage therapy in severely immuno-compramized
patients in refractory patients with aspergillosis
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Terbinafine
 Orally & topically effective drug against candida & dermatophytes
Fungicidal : shorter courses of therapy required & low relapse rates
 Mechanism of action:
 Pharmacokinetics:
 Well absorbed orally 75%
 Highly keratophilic & lipophilic
 High protein bound , poor BBB permeability
 t1/2- 15 days
 Negligible effect on CYP450
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Terbinafine
 Adverse events:
 Nausea , vomiting , Diarrhoea
 Taste disturbances
 Rarely hepatic dysfunction
 Topical: erythema , itching , dryness , urticaria, rashes
 Uses:
 Dermatophytosis: topically/ orally 2- 6 weeks
 Onychomycosis: first line drug 3- 12 months
 Candidiasis: less effective 2- 4 weeks therapy may be used as alternative 250
mg OD
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Spectrum of azoles
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Echinocandins
• New parenteral antifungal agents
• Mechanism of action: Inhibits B (1,3) D glucan an
essential component of fungal cell wall
1. Capsofungin
2. Micafungin
3. Anidulafungin
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Echinocandins
Pharmacokinetics
• No renal or hepatic toxicity
• Do not cross B.B.B
• Fungicidal against Candida albicans and non-albicans
Candida species
• Fungistatic against Aspergillus species
• Greatest use against Candida infection
• No cross resistance with Azoles
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Capsofungin acetate
 Semisynthetic antifungal
MOA: Inhibits B (1,3) D glucan an essential component of fungal cell
wall
Uses: Treatment of
1. Refractory Invasive aspergillosis
2. Candidiasis (esophageal, intraperitoneal),
3. Empiric therapy in neutropenic patients
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Capsofungin acetate
Pharmacokinetics: It is metabolized in liver and is slowly degraded by
hydrolysis and N-acetylation
Dose: IV 70 mg slowly [Loading dose] then 50 mg daily infusion
Dose should be reduced to 35 mg/day in hepatic dysfunction
Dose adjustment is not advised in renal insufficiency
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Capsofungin acetate
Adverse events: safe medicine
1. Flushing rashes,
2. Nausea and/or vomiting,
3. Phlebitis,
4. Elevation of transaminases
5. Histamine like reaction
Drug – Drug interaction with Rifampicin, Anticonvulsants, Tarcolimus,
Cyclosporine, Protease inhibitors, NNRTI
Telangana India
95

Micafungin
• Approved for treatment of esophageal candidiasis
•Prophylaxis in patients with hematopoetic stem cell
transplant [HSCT]
•Simultaneous administration of Micafungin and
Cyclosporin do not require any dose adjusted for either
drug
•As or more effacacious as flucanazole
•Indicated in deep seated Aspergillosis and candidiasis
Telangana India
96

Anidulafungin
1. Indicated in candidemia
2. Candida esophagitis
3. Candida peritonitis and deep seated candidiasis
4. Refractory to flucanazole
5. H I V positive patients
Telangana India
97

5 flucytosine
Telangana India
98
• Prodrug, pyrimidine analog, antimetabolite
• Converted to 5 FU
• Human cells cant convert it to 5FU
• Adverse events:
• Bone marrow toxicity , GIT , Alopecia, skin rashes, itching , rarely hepatitis
• Uses: in combination with AMB in cryptococcal meningitis
• Narrow spectrum of action

5 flucytosine
Telangana India
99

Amphotericin B &
5 flucytosine
Telangana India
100
• Advantages of combination:
–Entry of 5 FC
–Reduced toxicity
–Rapid culture conversion
–Reduced duration of therapy
–Decreased resistance

Amphotericine and 5 flucytosine combination
Telangana India
101
• Differences between AMB & 5 FC
• AMB = Active drug, broad spectrum, antibiotic, fungicidal
• Not absorbed, high protein binding, no BBB, metabolized in
liver, highly efficacious, IV, Intrathecal, topical

Telangana India
102
Systemic
administration
Topical
Griseofulvin Ketoconazole
Ketoconazole Miconazole
Fluconazole Clotrimazole
Itraconazole Terbinafine
Terbinafine Nystatin

Telangana India
103
AMB 5FC KTZ FLU ITR
Aspergillus -- -- -- Y
Blastomycosis -- Y Y Y
Cryptococcus Y -- Y Y
Coccidiodo -- Y Y Y
Candida Y Y Y Y
Histoplasma -- Y Y Y
Mucor -- -- -- --
Sporotrichosis -- -- Y Y
Chromoblast Dermatophyte Fusarium

Source of action
• Nystatin: Candidiasis only
• Griseofulvin: Dermatophytosis only
• Terbinafine : Dermatophytosis & candidiasis
• Caspofungin: Aspergillosis & candidiasis
Telangana India
104

Important characteristics
• Broad spectrum: AMB, KTZ, FLU, ITR
• Resistance: 5 FC
• Nephrotoxic/ Anemia: AMB
• Leucopenia: 5 FC
• GIT upset: All
• Over all toxicity: highest for AMB lowest for fluconazole, itraconazole
Telangana India
105

Therapeutic options for invasive Cadidiasis
• Flucanazole is DOC for empirical therapy in patients with candidemia
without sepsis or septic shock or recent exposure to azoles
• Amphotericin B or Capsofungin in patients with previous exposure to
azoles and in patients with Neutropenia
• In severe sepsis and septic shock Capsofungin is DOC.
• Microbiologically documented candidiasis [ C. Albicans, C. Tropicalis,
C. Parapsiliosis] Flucanazole is DOC
• C glabrata or C krusei – Capsofungin or Amphorecin B are DOC
Telangana India
106

Therapeutic options for invasive Aspergillosis
• Primary therapy – Voriconazole
• Salvage therapy – Capsofungin, Voriconazole [if not used earlier]
liposomal Amphoterecin B – refractory cases
• Combination therapy – Capsofungin + Voriconazole or liposomal
Amphoterecin B – critically ill patients
• Empirical therapy – Amphotericin B deoxylate – patients with
neutropenia and persistent fever
Telangana India
107

Therapeutic options for cryptococcosis
• CNS /disseminated Cryptococcosis in HIV patients: Amphotericin B
0.7-1.0 mg/KG/ + Flucytosine 100mg /KG/day PO for 2 weeks;
followed by Flucanazole or Itraconazole 400mg PO for 8 weeks;
followed by secondary prophylaxis with 200 mg of Flucanazole.
Flucanazole prophylaxis is discontinued after starting of HAART,
Symptom free, and CD count > 200/cu.mm.
• Asymptomatic or mild disease: Flucanazole 400mg/d or Itraconazole
400 mg/d for 6 – 12 months followed by secondary prophylaxis
Telangana India
108

Therapeutic options for Mucor mycosis
• Surgical resection and debridement
• Followed by high doses of Liposomal Amphotericin B 5-10 mg/KG/d
or Amphotricin B deoxylate 0.7-1.0mg/KG/day for 6 months
• In patients who can not tolerate are refractory – Poscanazole 200 mg
PO four times a day
• Prognosis is poor
Telangana India
109

Telangana India
110
INDICATION PRIMARY THERAPY SECONDARY THERAPY
Disseminated candidiasis Flucanazole or Voricanazole Amphotericin B, Capsofungin
Invasive Aspergillosis Voricanazole Itraconazole, Amphotericin B,
Capsofungin, Poscanazole
CNS Apergillosis Voricanazole Amphotericin B
Cryptococcal meningitis Liposomal Amphotericin B +
Flucytosin
Flucanazole
Mucor mycosis
Persistent neutropenic
patient not responding to
antibiotics
Amphotericin B, Capsofungin Poscanizole, Amphotericin B

Antifungal prophylaxis
NAME of DRUG DOSE for PROPHYLAXIS ROUTE of ADMINISTRATION
Flucanazole 50 – 400 mg / day PO
Itraconizole 10 mg / KG/ day PO
Voriconazole 200 mg B.I.D. PO
Posaconazole 200 mg T.I.D. PO
Micafungin 50 mg/day Intravenous
Capsofungin 50 mg/ day Intravenous
Telangana India
111

Telangana India
112

Telangana India
113

Think a while
• Each patient is a Book !
• Each Day is a Learning Opportunity!!
• Learning has More Relevance
today than ever !!!
Wards are temples of MEDICINE
Telangana India
114

Take home message
Telangana India
115
Eyes see only
what brain
thinks
Common
things are
common
Think “horses”
not “zebras”
Analysis
improves
patient care

Telangana India
116

Systemic fungal infections venkat

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