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

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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