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Antifungals
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Fungal pathogens
Superficial mycoses are the most
common infections. Oral candidiasis/candidosis with themajority of these infections are causedby Candida albicans.
Risk factors: corticosteroid therapy,broad-spectrum antibiotic, diabetesand immunosuppression.
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C. albicans, normal component of GIflora, compete with bacteria and arekept in check by the immune system.
Candida, dimorphous fungi, live in ayeast state,
replicate by budding (C).
U
nder appropriate conditions,Candida can chan e into an invasive
C D
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Systemic fungal infections
Fungal infections arecharacteristic ofHIV, cancer,and patients receiving broad-
spectrum antibiotics orimmunosuppressive agents.
Are a major cause of death.
The fungi involved in includeCandida, Histoplasma,
Aspergillus, and Cryptococcus
species.3
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Antifungal Pharmacotherapy:
All drugs known to
humans are poisons, onlythe amountordose
determine the effects.
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Paracelsus
14931541
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Main classes of antifungals
A.Azoles inhibit Erg11:block the production ofergosterol and causethe accumulation of a
toxic sterolintermediate, whichresults in cellmembrane stress.
B.Polyenes bind to
ergosterol, formingpores in cellmembranes.
C. 5-flucytosine inhibits DNA 5
Antifungal mechanisms
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SUMMARY ofAntifungalMechanisms:
The majority of
antifungalsinhibitbiosynthesis orstability ofergosterol,
a majorcomponent of
fungal cellmembrane.
Ergosterol servesthe same
functions in6
Antifungals affect
ergosterol by:1. Bind to ergosterol
and block its
function.
2. Block ergosterolsynthesis by
inhibiting enzymelanosterol
demethylase.
3. Block ergosterolsynthesis by
inhibiting proteinsqualene synthase.
HO
CH3 H H3C
CH3
H3C
H
H
HO
CH3 H3C
CH3
H3C
H
H
CH3
CH3
CH3
H
H
Cholesterol
Ergosterol
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Resistance to antifungal drugs
esistance: mutations in expression
of the target protein, lanosteroldemethylase
drug transport: Efflux pumps
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Azoles inhibit lanosterol 14-a demethylase (ERG11) (pinkcircle), blocking the formation of ergosterol.efflux transportproteins : encoded by either MDR or CDR
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Candidiasis pharmacotherapy
Oral candidiasis is treatedtopically with topicalnystatin
Azoles is an alternative
treatment, with oral fluconazoleas the next line of therapy.
In extreme cases, intravaneousamphotericin with flucytosinemay be considered.
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Q: Bacteria and fungi infect some of the same
areas of the body. How can you distinguish
bacterial and fungal infections?
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Drug Classes:
Polyenes: nystatin (topical),amphotericin (topical,systemic)
Imidazoles: clotrimazole,ketoconazole
Triazoles: fluconazole
Routes of Administration:
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Polyene: NystatinBinds to sterols(preferentially
ergosterol)
Disruption osmoticintegrity
of fungal membraneLeakage ofintracellularcomponents
Fungal death
Amphotericin B: conc-dependent fungicidal:Cmax/MIC
against Candida, Cryptococcusand A. fumigatus
PK/PD relationship in vivo :
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-clinical treatment with AMB is
limited by
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Polyenes
Nystatin (NY laboratory) acts by binding to the fungal
cell membrane sterol resultingin permeability changes and cell
lysis.a) Uses: similar to amphotericin Bexcept that it is used only fortopical treatment or oral candidosis
b) Administration:There is minimalabsorption orally, but can be used fororal candidiasis. It has an extremelybitter taste which limits its use.
c)Side effects: minimal when used 11
Not absorbed from skin, mucous membranes,or GI tract.
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Topical Antifungals for Thrush
For topical agents, successdepends on contact time
(minimum of2 minutes)
Treat 4-5 times per day
Treatment duration varies (7-14
d)2-3 days beyond last clinicalsymptoms
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Old Standard: Nystatin
Polyene antifungalw
ith broadspectrum
Concentration-dependent fungicidalactivity
Increased concentrations results inincreased rate and/or extent of
killing
Fungistatic at 0.5 2 x MIC
Fungicidal at >2 x MIC (C. kruseirequired 4x MIC)
Rate of kill de endent s onGunderson SM, et al. AntimicrobAgents Chemother 2000;44:2887-90.
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Azoles
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Description: Azoles are named for ringstructures within the drug.
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Azole drugs- inhibit ergosterol synthesis
Mechanism: by inhibitingfungalcytochrome p450 enzyme
activity, thus inhibitingconversion of methylsterol to
ergosterol, leading to cellulardisruption.
Side effects: Lanosterol
demethylase is a cytochromeP450 protein, related to humanlanosterol demethylase andother P450 proteins. As a result,
azole drugs inhibit human P450 15
lanosterol
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Azoles PK/PD
Conc-independent fungistatic agents Dosage escalation may be necessary when faced with
more resistant fungal species (e.g. Candida glabrata)
Goal of dosing is to maintain AUC:MIC >50effective therapy: AUC/MIC 25 (Candida spp.)
maintain concentrations 1-2 x MIC for the entire dosing
interval
Time-dependent and conc-dependent for
fungicidal activity against A. fumigatus
in
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Ketoconazole
The first oral azole introduced
into clinical use.
Less selective for fungal P450
Inhibition of human P450 interfereswith biosynthesis of adrenal andgonadal steroid hormones;
Alter the metabolism of other
drugs.
Best absorbed at a low gastricpH.
Miconazole, Econazole, Clotrimazole
Bioavailability is low by takingorally.
Used topically.17
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Clotrimazole
a)Uses: use for a number offungal infections, oropharyngeal
candidosis. It can also be used
cutaneously and intravaginally.b)Application: administered as a10 mg oral troche.
Its effects are purely topical.Clotrimazole = Lotrimin.
c)Side effects: Patients taking
oral troche experience gastric18