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Fungal infections
Superficial mycoses hair, skin, mucous membranes eg
dermatophytosis (ringworm), candida (thrush, intertrigo)
and malassezia furfur (pityriasis versicolor)
Systemic mycoses
1. Inhalation =>pulmonary infection=>disseminated (eg
histoplasmosis, coccidioidomycosis, blastomycosis)
2. Opportunist aspergillus, candida, crytococcus. Patients
compromised by disease, drugs
Fungal infections
Background
3 main groups:
Moulds reproduce by spores, which may produce
mycotoxins
Facts on Fungi
Fungal cell membranes have a unique sterol,
ergosterol, which replaces cholesterol found in
mammalian cell membranes
Tubule proteinproduction of a different type in
microtubules
formed during nuclear division.
Fungal cell
Background - fungi
May be:
= pathogenic in all exposed patients (eg
histoplasma capsulatum, coccidioides immitis)
Fungal infections
Risks:
FUNGAL INFECTIONS
SYSTEMIC
HISTOPLASMOSIS
ASPERGILLOSIS
CRYPTOCOCCOSIS
BLASTOMYCOSIS
MUCORMYCOSIS
CANDIDIASIS
LOCAL
DERMATOPHYTOSIS
SPOROTRICHIOSIS
ZYGOMYCOSIS
CHROMOMYCOSIS
RHINOSPOIDIOSIS
Histoplasmosis
coccidoiomycosis
blastomycosis
cryptococcosis
aspergillosis
mucormicosis
mycetoma
Classification in GeneMedRx
Antifungals
Polyenes
Imidazoles
nystatin
amphotericin
B
Triazole
-3-glucan
Allylamines synthase
inhibitors
miconazole
fluconazole
clotrimazole
itraconazole terbinafine
ketoconazole
naftifine
voriconazole butenafine
posaconazole
Other
caspofungin
griseofulvin
micafungin
flucytosine
anidulafungin
tolnaftate
ANTIFUNGAL AGENTS
How do they work?
Polyenes, triazoles, and
imidazoles target ergosterol
destroying the cell
membranes integrity.
Allylamines inhibit
ergosterol synthesis.
-3-glucan synthase
inhibitor block the
production of the -(1,3)glucan protein damaging
the cell wall.
ANTIFUNGAL AGENTS
How do they work?
Every component of the cell
wall and membrane can be
targeted. Drugs not available
in the market such as
Nikkomycin and Polyoxin
target chitin synthase.
Mannoproteins are another
potential target.
ANTIFUNGAL AGENTS
SYSTEMIC ANTIFUNGALS
TOPICAL ANTIFUNGALS
Systemic antifungals
1.
2.
3.
4.
5.
PATKI
GRISEOFULVIN
AMPHOTERICIN- B
FLUCYTOSINE
IMIDAZOLES
TRIAZOLES
18
GRISEOFULVIN
A heterocyclic benzofuran antibiotic
Most commonly used for fungal infections of skin
caused by dermatophytes
Indications
Tinea capitis
Tinea pedis & tinea manuum(optional)
Tinea corporis that is either
Widespread, or
Has underlying predisposing factor like DM, HIV,
Immunosuppresive therapy
Is not responding to topical antifungals
GRISEOFLFULVIN
DOSE
250mg twice a day (micronized) or
375mg once a day (ultramicronized) for an
ordinary adult
10mg/kg/day (micronized) for children
PREGNANCYCategory C
Body skin
Hair
Palms & soles
Finger nails
Toe nails
4 weeks
4-6 weeks
6-8 weeks
6-12 months
12-18 months
Adverse Effects
Systemic
Headache (commonest)
GIT disturbances
Transient leukopenia
Peripheral neuritis
Albuminuria (without renal damage)
Cutaneous
Fixed drug eruptions, photoallergic dermatitis, & lichenoid
drug eruption
Precipitation of acute intermittent porphyria or lupus
erythematosus
KEY POINTS
Duration of treatment depends upon the site of
infection, thickness of SC, its turnover rate, &
immunological status
Since it is fungistatic drug, fungus persists in
already infected keratin till it is shed off
KEY POINTS
Griseofulvin can cause alcohol intolerance
FLUCONAZOLE
Broad-spectrum triazole antifungal;
It is also somewhat effective against some Grampositive & anaerobic bacteria
MOA==Fungicidal drug, inhibits fungal ergosterol
synthesis by blocking fungal enzyme lanosterol
14-demethylase.
Mechanism of antibacterial action remains
unexplained
FLUCONAZOLE
Cryptococcal meningitis & coccidioidal meningitis
Disseminated candidiasis
Candidiasis including oropharyngeal, vaginal, &
mucocutaneous (except C. krusei)
Histoplasmosis, paracoccidiodomycosis, &
sporotrichosis
Pityrosporum ovale infections
Fungal keratitis
Dermatophyte infections of the skin, hair, & nail
Pityriasis versicolor
Onychomycosis
FLUCONAZOLE
Systemic: Well tolerated; side effects may
occur like nausea, vomiting, abdominal pain,
headache, thrombocytopenia, & raised
creatinine levels.
Cutaneous: Maculopapular rash (rare)
Pregnancy=== Category C
KEY POINTS
Of the orally administered fluconazole 94% is
absorbed;
KEY POINTS
Unlike ketoconazole, it does not inhibit steroid
synthesis & hence is not antiandrogenic
(no gynecomastia)
Plasma levels of drug is reduced by rifampicin
& enhanced by zidovudine
Fluconazole potentiates hypoglycemic effects
of tolbutamide & glipizide.
Can cause elevation of hepatic transaminases
in HIV pts (due to high doses for prolong period)
ITRACONAZOLE
Broad-spectrum antifungal with fungistatic
action that also includes Aspergillus & Mucor
MOA=== Inhibits fungal ergosterol synthesis
like other azoles
ITRACONAZOLE
Subcutaneous mycoses like eumycetoma &
chromoblastomycosis (DOC)
Systemic mycoses not associated with
meningitis like blastomycosis &
paracoccidiomycosis (DOC)
Aspergillosis & mucormycosis (partially
effective & 2nd DOC)
ITRACONAZOLE
Pityrosporum ovale infections
Vaginal candidiasis
Oral candidiasis
Pityriasis versicolor
200 mg BD for 7
consecutive days/per
month x 2 months
200 mg BD for 7
consecutive days/per
month x 3 months
Seborrhec dermatitis
(experimental
indication)
ADVERSE EFFECTS
Systemic: More side effects as compared to fluconazole,
nausea, dizziness, headache, abdominal pain, constipation,
hypokalemia, & impotence.
Cutaneous: skin rash & cutaneous vasculitis
Pregnancy=== Category C
Drug Interactions
Phenytoin , rifampicin, H2 blockers decrease plasma
concentration of drug.
KEY POINTS
KETOCONAZOLE
First oral broad-spectrum antifungal with mechanism of
action similar to that of other azoles.
Drug Interactions
H2 blockers, proton pump inhibitors, & antacids decrease oral
absorption.
ADVERSE EFFECTS
Systemic
Cutaneous
KEY POINTS
TERBINAFINE
Oral & topical broad-spectrum allylamine
antifungal.
MOA=== Inhibits the squalene epoxidase, leading
to accumulation of intrcellular squalene &
deficient ergosterol synthesis with subseqent
fungal cell death.
Drug reaches the body surface through diffusion
from dermal vasculature and via sebum to the
hair follicle.
TERBINAFINE
Widespread dermatophytosis (as an effective
alternative to griseofulvin).
Candidiasis (less effective than other alternative
anticandidial drugs like fluconazole).
Adult 250mg OD ,
Children <20kg : 62.5 mg/day in divided doses, QID
Children >20kg : 125 mg/day in divided doses, QID
Pregnancy== Category B
Cutaneous candidiasis
250 mg once daily for 2-4 weeks
(not routinely
recommended)
Toe nail
onychomycosis
ADVERSE EFFECTS
Systemic
Mild gastrointestinal
distrabances
Dreanged hepatic & renal
function
Cutaneous
Skin rash
Autoimmune hepatitis
Precipitation of lupus
erythematosus
Acute exanthematous
pustulosis & dyschromatosis
are also reported
KEY POINTS
70-80% oral absorption, not significantly affected by presence
of food.
Being liphophilic, it accumulates in keratinous tissues & is
present in the tissues long after it is withdrawn. This is the
basis of terbinafine pulse therapy.
Less effective against candida & pityrosporum infections
particularly when used topically.
AMPHOTERICIN B (AMB)
Broad-spectrum polyene macrolide antibiotic is the most
potent antifungal agent for systemic mycosis.
Fungicidal drug at higher concentrations & static at lower
levels.
MOA=== High affinity for fungal ergosterol, forms
micropore in fungal cell membrane through which ions,
amino acids, & other water soluble substances move out.
Markedly increases cell permeability.
Cholestrol, present in host cell membranes, closely resembles
fungal ergosterol & thus explains the high toxicity of AMB in
humans.
AMPHOTERICIN B (AMB)
Disseminated candidiasis, cryptococcosis, &
coccidioidomycosis (in combination with 5-FC)
AMPHOTERICIN B (AMB)
0.4 -0.6 mg/kg OD for 6-12 weeks
(available in powdered form to be dissolved in 5% dextrose)
Pregnancy== Category B
Liposomal AMB
New lipid formulations (DOSE: 3-5mg/kg/day)
AMB is incorporated into lipid formulations to reduce toxicity
& enhance efficacy. This allows higher dose to be used
without increasing the toxicity.
Much more expensive than ordinary AMB.
ADVERSE EFFECTS
Systemic
Cutaneous
Hypersensitivity
KEY POINTS
AMB is not absorbed enterally; hence can be given orally for
intestinal candidiasis.
Drug concentration achieved in infected skin is very low, &
hence ineffective against superficial fungal infections.
Penetration in brain & CSF is poor (but extremely effective in
fungal meningitis when combined with 5-FC)
Drug should be preferably given through CVP line due to risk
of thrombophlebitis.
KEY POINTS
Antihistamines & IV Hydrocortisone 100mg is routinely given prior
to the administration of AMB to avoid hypersensitivity reactions.
IV or oral K+ supplementation is necessary with monitoring of
serum potasium levels.
Daily monitoring of BUN & Crt is mandatory.
Start with test dose of 1mg on day 1. If there is no hypersensitivity,
increase to 0.5mg/kg/day. If no other side effects, the dose can be
steadily increased (except in candidiasis) to reach a maximum of
1mg/kg/day
For serious infections, one can dispense with the test dose & start
with higher dose.
FLUCYTOSINE (5-FC)
Pyrimidine antimetabolite, narrow-spectrum fungistatic
FLUCYTOSINE (5-FC)
Indications
Chromoblastomycosis
Meningeal & nonmeningeal cryptococcosis and disseminated
candidiasis (synergistic action with AMB)
Dose
100-150 mg/kg/day in four divided doses orally
Pregnancy== Category B
FLUCYTOSINE (5-FC)
Adverse Effects
Mylosuppression
GI disturbances
Mild & reversible liver dysfunction
KEY POINTS
Since this is a narrow-spectrum fungistatic, it is mainly used as
an adjuvant drug & not used as a sole therapy.
CSF penetration is excellent, hence it is combined with AMB in
fungal meningitis.
Mammalian bone marrow cell have the capacity to convert 5FC to 5-FU, and this explains marrow toxicity with flucytosine.
Concurrent use of other mylosuppressive drugs should be
avoided.
TOPICAL ANTIFUNGAL
AZOLES - CLOTRIMAZOLE,ECONAZOLE,
MICONAZOLE,TERCONAZOLE
.BUTOCONAZOLE
CICLOPIROX OLAMINE
HALOPROGIN,BENZOIC+SALICYLIC,
TOLNAFTATE,TERBINAFINE, NYSTATIN
UNDECYLENIC ACID,
PATKI
62
CLOTRIMAZOLE
PATKI
63
Local antifungals
MICONAZOLE
Cream,powder,lotion
,100mg Pessaries,
Teniasis,vulvovaginitis,-80%
Success.
Terconazole Butoconazole-
CICLOPIROX OLAMINE,
HALOPROGIN ,
TOLNAFTATETRICHOPHYTONS AND
MICROSPORUM.
TERBINAFINE CREAM
NYSTATIN
similar to amphotericin B
used topically and for GI use
used against candida and dermatophytes
(Epidermophyton, Trichophyton, Microsporum).
ADRs- RARE
PATKI
65
66
Alternatives
Research conducted in 1996 indicated that the following
substances or essential oils had anti-fungal properties:[12]
Allicin - created from crushing garlic
Tea tree oil - ISO 4730 ("Oil of Melaleuca, Terpinen-4-ol
type")
Citronella oil - obtained from the leaves and stems of
different species of Cymbopogon (Lemon grass)
Iodine - Lugol's iodine
olive leaf
orange oil
palmarosa oil
Alternatives
patchouli
lemon myrtle
Neem Seed Oil
Coconut Oil - medium
chain triglycerides in the oil have
antifungal activities
Zinc - in dietary supplements or natural
food sources, including pumpkin
seeds and chick peas
Alternatives
Selenium - in dietary supplements or natural food
sources, particularly Brazil nuts
Horopito (Pseudowintera colorata) leaf - contains
the anti-fungal compound polygodial[5]
Israeli researchers at Tel Aviv University's
Department of Plant Sciences published a study in
2009 indicating that carnivorous plants like the
Venus flytrap contain compounds that may be
useful in providing a new class of anti-fungal drugs
for use in humans, for fungal infections that are
resistant to current anti-fungal drugs
ANY QUESTION ??
Thank you