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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
M e d ic a l M y c o lo g y :T h e L a s t 5 0 Y e a r s
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5 - F CM ic o n a z o le
K e t o c o n a z o leF lu c o n a z o le
I t r a c o n a z o l e
L - A m BA B C DA B L C
T e r b in a f in e
# o f drugs
Fungal Cell Structure and Targets
Fungal Cell Structure and Targets
Several antifungals such as polyenes, azoles, and allylamines take advantage of the difference in sterol content
CLASSES OF ANTIFUNGALS
Fungal Death
Azoles
EchinocandinsPolyenes
Immune Modulation and Other Fungal Treatments
Antimetabolites and Other
Allylamines
POLYENES
Natamycin Rimocidin Filipin Nystatin Amphotericin B Candicin
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.
MECHANISM OF ACTION FOR POLYENES
AMPHOTERICIN B
Produced by Streptomyces nodosus First available in the US in 1959
ANITFUNGAL SPECTRUM FOR AMPHOTERICIN B
Drug of Choice for: 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
Active against almost all fungi except: Apergillus terreus Scedosporium apiospermum, prolificans Trichosporon spp. Candida lusitaniae
Antiprotozoan Activity Viseral Leishamniasis Primary Amoebic Meningoencephalitis
Toxicities of Amphotericin 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.
Anorexia, Wasting Nephrotoxicity Electrolyte Imbalances and Acidosis (RTA)
Hypokalemia, hypocalcemia, hypomagnesemia, low bicarb
Hepatotoxicity Anemia and blood dyscrasias
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.
Deferent preparations for Amphotericin B
Amphotericin B Deoxycholate Oral Preparations Bladder Irrigations
Cholesteryl sulfate complex (Colloidal Dispersion)
Lipid complex (Abelcet) 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.
Deferent preparations for Amphotericin B
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%)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).
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. 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.
Must follow electrolytes and renal function. May continue to use with mild elevations in renal
function and may spread out the dosing interval to maintain renal function.
Nystatin
Drug of Choice Thrush
Formulations Swish and Swallow Troches No IV formulation and is not absorbed.
Toxicity Virtually no adverse effects.
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AZOLES Imidazoles
Miconazole* Ketoconazole Clotrimazole Econazole* Bifonazole Butoconazole Fenticonazole Isoconazole Oxiconazole* Sertaconazole* Sulconazole Tioconazole
Triazoles Fluconazole Itraconazole Isavuconazole Ravuconazole Posaconazole Voriconazole Terconazole
Thiazoles Abafungin
* Used solely as topical formulations.
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.
MECHANISM OF ACTION FOR AZOLES
Toxicities of Azoles
Also inhibit mammalian cytochrome P450-dependent enzymes causing multiple drug interactions.
Itraconazole inhibits CYP 3A4 the most. Class C in pregnancy with only fluconazole
considered safe with breast feeding.
Itraconazole
Drug of choice for: 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.
Itraconazole Drug Interactions
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.
Ketoconazole
Drug of choice: Tinea versicolor (instructed to sweat after taking)
Pharmacology Does not cross into the CSF. Gastric acid required for absorption.
Avoid Antacids, H2 blockers, PPI, buffered didanosine
Achlorhydria (need to drink with HCl acid)
Coca Cola increased absorption by 65%
Ketoconazole
Drug Interactions 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.
Fluconazole Drug of choice for:
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)
Spectrum of coverage: Candida Cryptococcus Coccidioidiomycosis
Does not cover: Aspergillus C. glabrada, C. tropicalis Scedosporium Zygomycetes Dematiaceous molds
Fluconazole Pharmacology
Excellent bioavailability with CNS penetration. Drug Interactions
Reduce dose by 50% with CrCl 11-50ml/50 Many drug interactions due to P-450
Increases levels of cyclosporine, phenytoin, theophylline and INR on warfarin.
May increase levels of statins Toxicity
Side effects uncommon, mild nausea Hepatotoxicity May cause alopecia at high doses for long
periods.
Voriconazole
Drug of choice for: Invasive pulmonary aspergillosis Scedosporium apiospermum infection Fusarium infection
Spectrum of coverage: Aspergillus to include A. terreus Candida to include C. krusei Fusarium and some molds Dimorphic Fungi except Sporothrix
Does not cover: Zygomcetes Scedosporium prolificans
Voriconazole Drug Interactions
Substrate and inhibitor of CYP2C9, 2C19, 3A4. 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
Toxicities Type IV anaphylactoid reactions. Rare severe skin reaction and photosensitivity. Rare hepatotoxicity. Transient visual disturbances common.
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 Drug of choice:
2nd line for Mucormycosis/Zygomycosis Salvage therapy.
Broadest range of antifungal coverage. Aspergillosis Zygomycosis Fusarosis Ssscedosporium Phaeohyphomycosis Dimorphic fungi (Histo, Blasto, Cocci) Refractor Candidiasis Refractory Cryptococcosis Refractory Chromoblastomycosis Dermatiaceous molds
Posaconazole Drug Interactions
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
Clotrimazole
Formulations Vaginal Creams Oral Troches Dermal Creams
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ECHINOCANDINS
Anidulafungin Caspofungin Micafungin
MECHANISM OF ACTION FOR ECHINOCANDINS
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.
MECHANISM OF ACTION FOR ECHINOCANDINS
Echinocandin B
Spectrum of Coverage for Echinoocandins
Spectrum of coverage: Cidal against Candida and Aspergillus sp.
Including ampho B and triazole resistant strains.
Does not cover: Dimorphic fungi Zygomycetes
Anidulafungin
Drug of choice for: Candidemia and candidal systemic infecitons. Candida Esophagitis Bloodstream infections with C. glabrata or C.
krusei.
Anidulafungin
Pharmacology No CSF penetration. Not excreted in the urine. No dose adjustment in renal or hepatic
insufficiency. Side effects:
Slow infusion rate to prevent histamine reactions.
Diluent contains dehydrated alcohol. Overall remarkably non-toxic, like other
echinocandins.
Caspofungin
Drug of choice for: Candidemia and candidal systemic infecitons. Bloodstream infections with C. glabrata or C.
krusei. Pharmacology
No drug in CSF or Urine Metabolized in the liver.
Toxicity Also remarkable non-toxic. Puritis at infusion site or
N/V/F/C/diarrhea/headache rarely report during it infusion.
Caspofungin Drug Interactions:
Must increase the daily dose to 70mg when using concurrently with rifampin.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
May need to adjust dose with liver dysfunction.Reduce daily dose to 35mg QD with Child-Pugh score 7-9.
Micafungin
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.
Micafungin
Drug Interactions Increases levels of sirolimus and nifedipine. Not dialysed.
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
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.
Terbinafine
Drug of choice: Onychomycosis
Toxicity Hepatotoxicity (monitor LFT’s) Neutropenia May exacerbate lupus. Do not use with liver disease or CrCl <50
mL/min. Inhibits CYP 2D6.
Multiple drug interaction. Rifampin with increase its clearance.
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ANTIMETABOLITES AND OTHER Benzoic acid
Has antifugal properties but must be combined with a keratolytic agent such as in Whitfield's Ointment
Ciclopirox – (ciclopirox olamine) Topical used against Tinea versicolour, Tinea
corporis/cruris, Seborrheic dermatitis Tolnaftate – Tinactin, Desenex, Aftate, or other names Undecylenic acid
Unsaturated fatty acid derived from natural castor oil; fungistatic as well as anti-bacterial and anti-viral
Flucytosine or 5-fluorocytosine Antimetabolite
Griseofulvin Binds to polymerized microtubules and inhibits fungal
mitosis
Flucytosine
Drug of Choice: Cryptococcal meningitis (plus amphotericin B)
Drug Interactions: Reduce in renal dysfunction
Toxicity Myelosuppression Nausea
Must use in combination therapy to prevent resistance from rapidly developing. Loss of cytosine permease to cross membrane. Altered enzyme for 5FC conversion.
Griseofulvin
Drug of choice Tinea capitis
Drug Interactions Do not use in liver failure or porphyria. Decreases INR with warfarin. Reduced oral contraceptive efficacy.
Toxicity Photosensitivity Lupus like syndrome / exacerbation of Lupus
Septra
Drug of Choice: Paracoccidioidomycosis
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NOVEL ANTIFUNGALS AND IMMUNE MODULATION
Gamma Interferon Cryptococcosis Coccidioidomycosis
New azole compounds to with broader spectrums of activity and less resistance.IsavuconazoleVibunazole
Surgery
Aspergilloma (Fungus Ball) Chromoblastomycosis (if small and few) Lobomycosis Phaeohyphomycosis (black molds)
Plus itraconazole
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