Transcript Antifungals

ANTIFUNGALS
When to think fungus?
Diabetes
 Immunosuppresed
 Acidosis
 Neutropenic
 Already on broad spectrum antibiotics.
 Travel to location with an endemic fungal
pathogen.
 Disturbances in the GI mucosa either by
inflammation or mechanical.
 Burns
 Trauma
 Neonatal
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Fungal Cell Structure and Targets
Fungal Cell Structure and Targets
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Several antifungals such as polyenes, azoles, and
allylamines take advantage of the difference in
sterol content
CLASSES OF ANTIFUNGALS
Azoles
Echinocandins
Polyenes
Fungal Death
Immune Modulation
and Other Fungal
Treatments
Antimetabolites
and Other
Allylamines
POLYENES
Natamycin
 Rimocidin
 Filipin
 Nystatin
 Amphotericin B
 Candicin
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MECHANISM OF ACTION FOR
POLYENES
Polyenes act by binding to ergosterol in the
fungal cell membrane.
 This forms pores that increase the permeability
to protiens and monovalent and divalent cations
depolarizing the membrane.
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MECHANISM OF ACTION FOR POLYENES
AMPHOTERICIN B
Produced by Streptomyces nodosus
 First available in the US in 1959
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ANITFUNGAL SPECTRUM FOR
AMPHOTERICIN B
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Drug of Choice for:
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Invasive Fungal Infections
Cryptococcal meningitis (in combo with 5-FC)
Blastomycosis (followed by itraconazole)
Fungal Endocarditis (plus 5-FC)
Endophthalmitis
Severe disseminated coccidioidomycosis
Severe Histoplasmosis +/- steroids
Mucormycosis/Zygomycosis
Penicilliosis (followed by itraconazole)
ANITFUNGAL SPECTRUM FOR
AMPHOTERICIN B
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Active against almost all fungi except:
Apergillus terreus
 Scedosporium apiospermum, prolificans
 Trichosporon spp.
 Candida lusitaniae
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Antiprotozoan Activity
Viseral Leishamniasis
 Primary Amoebic Meningoencephalitis
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Toxicities of Amphotericin
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Fever, Rigor, Hypotension, Nausea, Vomiting
Usually subsides with repeated infusions.
 Alleviated with narcotics, usually meperidine.
 Premedication with Tylenol, diphenhydramine,
hydrocortisone, or heparin has little influence on
rigors/fever.
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Anorexia, Wasting
Nephrotoxicity
Electrolyte Imbalances and Acidosis (RTA)
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Hepatotoxicity
Anemia and blood dyscrasias
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Hypokalemia, hypocalcemia, hypomagnesemia, low bicarb
Leukopenia, thrombopenia, anemia (decreases
erythropoietin)
Cardiac arrhythmias
Drug Interactions of Amphotericin
Flucytosine increases toxicity and vice versa.
 Diuretics or Cisplatin increase renal toxicity and
risk of hypokalemia.
 Corticosteroids increase risk of hypokalemia.
 In general combination with nephrotoxic drugs
increases the risk of serious renal damage.
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Deferent preparations for
Amphotericin B
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Amphotericin B Deoxycholate
Oral Preparations
 Bladder Irrigations
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Cholesteryl sulfate complex (Colloidal
Dispersion)
 Lipid complex (Abelcet)
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Ampho B complexed with 2 lipid bilayer ribbons.
 Larger volume distribution and clearance from the
blood.
 Achieves higher tissue concentrations in liver, spleen,
lung.
 Less renal toxicity.
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Deferent preparations for
Amphotericin B
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Liposomal formulation (AmBisome
Vesicular bilayer liposome with ampho B intercalated
within the membrane
 Same advantages as the lipid complex.
 Acute infusion-related reactions common (20-40%)
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86% Occur in the 1st 5 minutes with chest
pain, dyspnea, hypoxia, severe abdominal,
flank, or leg pain.
 Responds to holding the infusion and
diphenhydramine (1mg/kg).
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To use Amphotericin B
Would prefer to use lipid formulations in most all
situations to limit renal toxicity.
 Has to be infused slowly and with pre/post
hydration.
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May pre-medication with Tylenol and an
antihistamine but more important to infuse slowly.
 Given most patients with invasive fungal disease are
immunosupressed would not pre-medicate with
steroids.
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Must follow electrolytes and renal function.
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May continue to use with mild elevations in renal
function and may spread out the dosing interval to
maintain renal function.
Nystatin
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Drug of Choice
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Thrush
Formulations
Swish and Swallow
 Troches
 No IV formulation and is not absorbed.
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Toxicity
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Virtually no adverse effects.
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AZOLES
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Imidazoles
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Miconazole*
Ketoconazole
Clotrimazole
Econazole*
Bifonazole
Butoconazole
Fenticonazole
Isoconazole
Oxiconazole*
Sertaconazole*
Sulconazole
Tioconazole
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Triazoles
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* Used solely as topical formulations.
Fluconazole
Itraconazole
Isavuconazole
Ravuconazole
Posaconazole
Voriconazole
Terconazole
Thiazoles
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Abafungin
MECHANISM OF ACTION FOR
AZOLES
Azoles inhibit the fungal cytochrome P-450 3-A
dependent enzyme 14-alpha demethylase which
is needed to synthesize ergosterol.
 This leads to depletion of ergosterol in the cell
membrane and accumulation of toxic
intermediate sterols leading to increased
membrane permeability and inhibition of fungal
cell growth.
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MECHANISM OF ACTION FOR AZOLES
Toxicities of Azoles
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Also inhibit mammalian cytochrome P450dependent enzymes causing multiple drug
interactions.
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Itraconazole inhibits CYP 3A4 the most.
Class C in pregnancy with only fluconazole
considered safe with breast feeding.
Itraconazole
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Drug of choice for:
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Bone involvement by Coccidioidiomycosis.
Bastomycosis after primary treatment with
amphotericin.
Chromoblastomycosis
Mild-mod Histoplasmosis
Sporotrichosis
Pharmacology
99% protein-bond and does not penetrate the CSF.
 Recommended taking with food and acidic drinks.
 May need to check drug levels given multiple drug
interactions.
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Itraconazole
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Drug Interactions
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Contraindicated with cisapride, dofetilide, ergot alkaloids,
lovastatin, midazolam, pomozide, quinidine, simvastatin,
triazolam.
Decreased absorption with antacids, PPI, H2 blockers, or
achlorhydria.
Increases adverse effects with trazadone.
Do not use with CrCl <30 ml/min
Inhibits P450 3A4 metabolism and has multiple more
interations.
Toxicities
Negative inotrope (may cause heart failure)
 Hepatotoxicity
 Nausea, Vomiting, and Diarrhea are the most common side
effects.
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Ketoconazole
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Drug of choice:
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Tinea versicolor (instructed to sweat after taking)
Pharmacology
Does not cross into the CSF.
 Gastric acid required for absorption.
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Avoid Antacids, H2 blockers, PPI, buffered
didanosine
 Achlorhydria (need to drink with HCl acid)
 Coca Cola increased absorption by 65%
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Ketoconazole
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Drug Interactions
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Do not use with cisapride, midazolam, pimozide,
trazolam.
Levels reduced by isoniazid, rifampin, efavirenz.
Avoid >200mg/day with ritonavir.
Inhibits P450 3A4 and has many drug interactions.
Need to reduce trazodone dose.
Toxicities
Hepatotoxicity
 High doses (>800mg/day) may case adrenal
deficiency.
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Fluconazole
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Drug of choice for:
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Spectrum of coverage:
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Vaginal candidiasis
Candidemia (unless C. glabrada or C. krusei)
Thrush (non-AIDS)
Candidal Peritonitis
Mild to Mod Coccidioidomycosis, CNS Cocci
Non-meningeal Cryptococcosis (non-AIDS)
Candida
Cryptococcus
Coccidioidiomycosis
Does not cover:
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Aspergillus
C. glabrada, C. tropicalis
Scedosporium
Zygomycetes
Dematiaceous molds
Fluconazole
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Pharmacology
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Excellent bioavailability with CNS penetration.
Drug Interactions
Reduce dose by 50% with CrCl 11-50ml/50
 Many drug interactions due to P-450
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Increases levels of cyclosporine, phenytoin,
theophylline and INR on warfarin.
 May increase levels of statins
 Toxicity
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Side effects uncommon, mild nausea
Hepatotoxicity
May cause alopecia at high doses for long periods.
Voriconazole
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Drug of choice for:
Invasive pulmonary aspergillosis
 Scedosporium apiospermum infection
 Fusarium infection
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Spectrum of coverage:
Aspergillus to include A. terreus
 Candida to include C. krusei
 Fusarium and some molds
 Dimorphic Fungi except Sporothrix
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Does not cover:
Zygomcetes
 Scedosporium prolificans
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Voriconazole
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Drug Interactions
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Substrate and inhibitor of CYP2C9, 2C19, 3A4.
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Check levels with treatment failures.
Ritonivir decreases voriconazole levels.
Will need dose adjustment for cyclosporine,
omeprazole, phenytoin, tacrolimus. Avoid using
sirolimus.
Avoid rifampin, rifabutin, and sirolimus.
Inhibits metabolism of benzodiazpines, CCB, statins,
and methadone.
Increases level of estrogen and progestin with oral
contraceptives
Reduce maintenance dose by 50% with Child-Pugh
class A/B.
Voriconazole
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Toxicities
Type IV anaphylactoid reactions.
 Rare severe skin reaction and photosensitivity.
 Rare hepatotoxicity.
 Transient visual disturbances common.
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Advise against night driving and strong
sunlight.
Vehicle in IV form may accumulate in renal
impairment and would use oral form with CrCl
<50mL/min.
Posaconazole
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Drug of choice:
2nd line for Mucormycosis/Zygomycosis
 Salvage therapy.
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Broadest range of antifungal coverage.
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Aspergillosis
Zygomycosis
Fusarosis
Ssscedosporium
Phaeohyphomycosis
Dimorphic fungi (Histo, Blasto, Cocci)
Refractor Candidiasis
Refractory Cryptococcosis
Refractory Chromoblastomycosis
Dermatiaceous molds
Posaconazole
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Drug Interactions
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Must take with fatty meals for absorption.
Metabolized by glucuronidation.
CYP 34A inhibitor
Contraindicated with ergot alkaloids and other CYP 3A4
substrates which increase QT interval such as cisapride,
pimozide, halofantrine, and quinidine.
Reduce dose with vinca alkaloids, CCB, and statins.
Reduce cyclosporine dose by 25% and tacrolimus dose by
66%.
May need to reduce benzodiazepines
Levels reduced by rifabutin, phenytoin, and cimetidine.
Toxicities
Toxicities similar to other azoles.
 Hepatotoxicity
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Clotrimazole
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Formulations
Vaginal Creams
 Oral Troches
 Dermal Creams
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ECHINOCANDINS
Anidulafungin
 Caspofungin
 Micafungin
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MECHANISM OF ACTION FOR
ECHINOCANDINS
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Glucan Synthesis Inhibitors
Inhibits the enzyme 1,3-beta glucan synthase
resulting in the depletion of glucan polymer in the
fungal cell wall.
 The weakened cell wall is unable to withstand
osmotic stress.
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MECHANISM OF ACTION FOR
ECHINOCANDINS
Echinocandin B
Spectrum of Coverage for
Echinoocandins
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Spectrum of coverage:
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Cidal against Candida and Aspergillus sp.
Including ampho B and triazole resistant
strains.
 Does not cover:
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Dimorphic fungi
 Zygomycetes
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Anidulafungin
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Drug of choice for:
Candidemia and candidal systemic infecitons.
 Candida Esophagitis
 Bloodstream infections with C. glabrata or C. krusei.
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Anidulafungin
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Pharmacology
No CSF penetration.
 Not excreted in the urine.
 No dose adjustment in renal or hepatic insufficiency.
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Side effects:
Slow infusion rate to prevent histamine reactions.
 Diluent contains dehydrated alcohol.
 Overall remarkably non-toxic, like other
echinocandins.
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Caspofungin
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Drug of choice for:
Candidemia and candidal systemic infecitons.
 Bloodstream infections with C. glabrata or C. krusei.
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Pharmacology
No drug in CSF or Urine
 Metabolized in the liver.
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Toxicity
Also remarkable non-toxic.
 Puritis at infusion site or N/V/F/C/diarrhea/headache
rarely report during it infusion.
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Caspofungin
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Drug Interactions:
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Must increase the daily dose to 70mg when using
concurrently with rifampin.
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May need to increase the dose with other
enzyme inducers such as carbamazepine,
dexamethasone, efavirenz, nevirapine,
phenytoin.
Multiple interactions with immunosuppressants.
Cyclosporine will increase caspofungin levels
 Caspofungin with decrease tacrolimus levels
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May need to adjust dose with liver dysfunction.
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Reduce daily dose to 35mg QD with ChildPugh score 7-9.
Micafungin
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Drug of choice for:
Candidemia and candidal systemic infecitons.
 Candidal Esophagitis
 Bloodstream infections with C. glabrata or C. krusei.
Pharmacology
 No antagonism seen when used with other
antifungals.
 No dose adjustment need with severe renal
impairment or moderate hepatic impairment.
 No CSF or Urine penetration.
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Micafungin
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Drug Interactions
Increases levels of sirolimus and nifedipine.
 Not dialysed.
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Toxicities
Histamine-medicated reactions possible with rapid
infusions.
 Again well tolerated like all echinocandins.
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ALLYLAMINES
Terbinafine – Lamisil
 Amorolfine
 Naftifine – Naftin
 Butenafine – Lotrimin Ultra
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MECHANISM OF ACTION FOR
ALLYLAMINES
Works similar to azoles by inhibiting synthesis of
ergosterol but at an earlier step in the pathway.
 Inhibits squalene epoxidase.
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Terbinafine
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Drug of choice:
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Onychomycosis
Toxicity
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Hepatotoxicity (monitor LFT’s)
Neutropenia
May exacerbate lupus.
Do not use with liver disease or CrCl <50 mL/min.
Inhibits CYP 2D6.
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Multiple drug interaction.
Rifampin with increase its clearance.
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ANTIMETABOLITES AND OTHER
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Benzoic acid
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Ciclopirox – (ciclopirox olamine)
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Unsaturated fatty acid derived from natural castor oil;
fungistatic as well as anti-bacterial and anti-viral
Flucytosine or 5-fluorocytosine
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Topical used against Tinea versicolour, Tinea
corporis/cruris, Seborrheic dermatitis
Tolnaftate – Tinactin, Desenex, Aftate, or other names
Undecylenic acid
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Has antifugal properties but must be combined with a
keratolytic agent such as in Whitfield's Ointment
Antimetabolite
Griseofulvin
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Binds to polymerized microtubules and inhibits fungal
mitosis
Flucytosine
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Drug of Choice:
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Drug Interactions:
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Cryptococcal meningitis (plus amphotericin B)
Reduce in renal dysfunction
Toxicity
Myelosuppression
 Nausea
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Must use in combination therapy to prevent
resistance from rapidly developing.
Loss of cytosine permease to cross membrane.
 Altered enzyme for 5FC conversion.
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Griseofulvin
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Drug of choice
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Tinea capitis
Drug Interactions
Do not use in liver failure or porphyria.
 Decreases INR with warfarin.
 Reduced oral contraceptive efficacy.
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Toxicity
Photosensitivity
 Lupus like syndrome / exacerbation of Lupus
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Septra
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Drug of Choice:
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Paracoccidioidomycosis
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NOVEL ANTIFUNGALS AND IMMUNE
MODULATION
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Gamma Interferon
Cryptococcosis
 Coccidioidomycosis
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New azole compounds to with broader spectrums
of activity and less resistance.
 Isavuconazole
 Vibunazole
Surgery
Aspergilloma (Fungus Ball)
 Chromoblastomycosis (if small and few)
 Lobomycosis
 Phaeohyphomycosis (black molds)
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Plus itraconazole
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