Antifungals: Mahfouz

Learning objectives: define and classify mycoses, identify pathogenic fungi and the diseases they cause, explain structural differences between human and fungal cells and identify the antifungal targets, explain the indications and MOA, explain the resistance mechanisms, explain the pharmacokinetic properties, explain contra-indications/adverse effects and the underlying mechanisms, determine best treatment choice for fungal infections

define superficial mycoses

cosmetic fungal infections of the stratum corneum or the hair shaft

superficial mycoses properties

• no living tissue invaded

• does not illicit inflammatory response from the host

• ex: tinea versicolor

define cutaneous mycoses

fungal infections of the living layer of the skin, hair, or nails

cutaneous mycoses properties

• inflammatory responses are elicited to the fungus and its metabolic products

• ex: athletes foot

define subcutaneous mycoses

chronic, localized infections of the dermis and subcutaneous tissue following the traumatic implantation of the fungus

three types of pathogenic fungi

unicellular fungi, multicellular fungi, and dimorphic fungi

unicellular fungi characteristics

• yeasts (candida)

• opportunists: cause systemic infections in immunocompromised patients

multicellular fungi characteristics

• dermatophytes (mold)

• produce keratinase

• dermatophytoses (skin infection)

dimorphic fungi characteristics

can overcome host defense by changing the mold to yeast

what two pathogenic families cause yeast infections

• Candida albicans (ascomycetes)

• Cryptococcus neoformans (basidomycetes)

common name for dermatophytoses

ringworm

what pathogenic family most commonly causes dimorphic fungi

Histoplasma capsulatum (histoplasmosis)

what are the five chemical classes of antifungal drugs

polyenes, azoles: imidazoles and triazoles, echinocandins, allylamines, and morpholines

what is the major component of the fungal cell wall

Glucan: polysaccharides made up of B-1,3 or B-1,6; made by glucan synthase

echinocandins MOA

inhibit glucan synthase- weaken cell wall causing lysis of fungal cells; fungicidal

echinocandin resistance

resistance is rare

echinocandin pharmacokinetics

• IV (poor oral availability)

• no BBB or eye penetration

• excreted in feces

echinocandin adverse effects

• embryotoxic and teratogenic effects

• fewer toxicities than polyenes and azoles

echinocandins drug interactions

cyclosporine, rifampin, HIV meds

echinocandin medications

caspofungin, micafungin, anidulafungin

caspofungin uses

candidiasis (yeast)
salvage therapy for invasive aspergillosis (dermatophyte)

caspofungin adverse effects

increased liver enzymes
phlebitis at the site of infusion

caspofungin contraindications

hypersensitivity, precaution in liver impairment and pregnancy

micafungin uses

• invasive candidiasis

• candida prophylaxis in stem cell transplant (superior to fluconazole for this)

micafungin adverse effects

• hyperbilirubinemia

• phlebitis

• rash

• abdominal discomfort

• hypersensitivity

micafungin drug interactions

less than caspofungin

anidulafungin uses

• resistant candida and aspergillus

• candidemia and candidiasis and intra-abdominal abscesses due to candida

anidulafungin adverse effects

DVT, liver toxicity, hypokelemia (caution in impaired cardiac function)

polyenes MOA

hind ergosterol forming cylindrical channels, leading to alterations in membrane permeability and cell death
*fungicidal

polyenes spectrum

broad spectrum with rare resistance, emergency/short term treatment regimens due to toxicity

polyenes toxicity and side effects

oran (specifically kidney) toxicity, caused by binding cholesterol when used in high concentrations (selective for ergosterol but also binds cholesterol), may also increase liver enzymes

polyenes resistance

uncommon

mutations in ergosterol biosynthetic pathway that leads to the the biosynthesis of sterols other than ergosterol

polyenes pharmacokinetics

poorly absorbed in GIT, given IV

(sometimes given orally to treat GIT infections)

polyene medications

amphotericin B, nystatin

amphotericin B indications

servere fungal infections including: histoplasmosis, coccidioidomycosis, blastomycosis, cryptococcal meningitis, disseminated candidiasis

amphotericin B adverse effects

• anemia and loss of ions (K, Na, Mg)

• release of inflammatory cytokines (fever, chills, rigor, nausea, vomiting, myalgia, arthralgia, headache)

• nephrotoxicity (dose limiting)

  • monitor liver and kidney function
    **lipid formulations have less nephrotoxicity

amphotericin B formulations

• liposomal amphotericin B

• amphotericin B lipid complex

• amphotericin B colloidal dispersion

*liposomal amphotericin B is the safest

amphotericin B pharmacokinetics

• IV only (poor oral absorption)

• only free drug is active

• elimination half life is 15 days

• not cleared by dialysis

nystatin pharmacokinetics

IV or topical (poor oral absorption)

liposomal formulation for oral use

nystatin inidcations

oropharyngeal or intestinal candidiasis

nystatin adverse effects

parenteral administration results in dose limiting toxicities and harmful infusion related reactions

allylamines MOA

potent selective inhibitor of fungal squalene eqoxidase (weakly inhibitory towards human)

fungicidal (dermatophytes and dimorphic fungi)

fungistatic (candida)

allylamines drug interactions

some drugs in this class inhibit CYP450

allylamine medications

terbinafine and naftifine

terbinafine inidcations

treatment of onychomycoses

• topical and systemic

• no effect on mammalian cholesterol

terbinafine pharmacokinetics

binds strongly to plasma proteins

• lipophilic compound

  • well absorbed after oral admin

  • concentrates in sebum

  • elimination half life 3-5 days

naftifine indications

topical treatment for dermatophytoses

no effect on mammalian cholesterol

azole indications

systemic life threatening fungal infections

• broad spectrum activities against most yeasts and filamentous fungi

• orally active

• fungistatic

azole MOA

inhibit fungal enzyme 14-alpha demethylase (also binds to heme)

azoles dietary considerations

do not take with dairy, separate from calcium containing vitamins and Tums (metal ions binding to azoles)

azole interactions

• interactions with cyclosporine, benzodiazepines, statins, and HIV meds

• all azoles are reversible inhibitors of CYP enzymes in humans

• drugs that increase gastric pH decrease the bioavailability of azoles

• metal containing drugs decrease absorption of azoles through chelation

azole resistance

• mutations in the enzyme 14-alpha demethylase 

• overexpression of membrane efflux pumps that export the antifungal from the cell

combination of both mechanisms detected in C. albicans isolates

azole medications

ketoconazole, itrazonazole, fluconazole, voriconazole, posaconazole, ravuconazole

ketoconazole indications

candidiasis, histoplasmosis, dermatophytoses, and cutaneous fungal infections

orally bioavailable, no BBB

ketoconazole interactions

antacids reduce bioavailability

ketoconazole adverse effects

• GIT disturbances

• fatal toxic hepatitis

triazole medcations

itraconazole, fluconazole, voriconazole, posaconazole, ravuconazole

itrazonazole indications

chronic pulmonary aspergillosis, onychomycosis, mucosal candida infections, blastomycosis, and histoplasmosis

**fluconazole is better for cryptococcal

itraconazole pharmacokinetics

• orally bioavailable

• poor CNS penetrations

• metabolized by liver

• excreted by kidneys

itraconazole adverse effects

rash, diarrhea, nausea

uncommon but serious: worsening of congestive heart failure, hepatotoxicity, and nephrotoxicity

itraconazole drug interactions

PPIs and antacids should be avoided with capsules, CYP3A4 substrates

fluconazole indications

• superficial and systemic Candida infections

• single oral dose for vaginal candidiasis

• fungal meningitis and systemic cryptococcal infections

fluconazole bioavailability

very high, independent of pH

voriconazole indication

• first line: invasive aspergillosis and other mold infections including fluconazole resistant species

**crosses BBB

voriconazole side effects

• peripheral edema

• rash, N/V

• transaminase elevation (liver dysfunction)

• encephalopathy, hallucinations, visual distrubances

voriconazole contraindications

patients receiving CYP3A4 substrates (fexofenadine, astemizole, pimozide, quinidine) cause QT prolongation

avoid withrifampin, carbemazepine, barbiturates, ritonavir, and efavirenz

posaconazole indications

prophylaxis against invasive fungal infections in severe immunocompromised patients

oropharyngeal candidiasis, Coccidioidomycetes and Zygomycetes

posaconazole pharmacokinetics

poor CNS and eye penetration

posaconazole adverse effects

common: elevation of liver enzymes, diarrhea/abdominal discomfort, headache, skin rash

serious: occasional hepatic dysfunction, QT ptolongation

ravuconazole indication

wide range of fungi including Candida spp, even isolates that are resistant to fluconazole

morpholines MOA

inhibit enzyle delta 14 reductase in ergosterol biosynthetic pathway

amorolfine indication

fungistatic and fungicidal

topical treatment of nail infection

amorolfine preparations

only topical preparations: superficial mycoses

nucleic acid synthesis inhibitors MOA

interfere with nucleic acid (DNA and RNA) biosynthesis as well as protein synthesis

drawbacks of nucleic acid synthesis inhibitors

narrow spectrum of activity, resistance develops easily

nucleic acid medications

flucytosine

flucytosine indications

pathogenic yeasts: candida and cryptococcus neoformans

adjunctive therapy with amphotericin B due to high resistance frequency

flucytocystine - amphotericin B synergism

flucytosine pharmacokinetics

good oral bioavailability

good CNS penetration

flucytosine resistance

high frequency: mutations in permease, deaminase, and phosphoribosyl transferase

flucytosine adverse effects

bone marrow suppression, N/V/D

microtubule synthesis inhibitors MOA

dynamic polymers of a and b tubulin dimers

form highly organized skeleton in all eukaryotic cells

microtubule synthesis inhibitors medications

griseofulvin

griseofulvin indication

only active against dermatophytes 

used to treat tinea (ringworm)

fungistatis

griseofulvin MOA

selectively inhibits fungal cell mitosis by disrupting mitotic spindle formation, interacts with beta tubulin, selective for fungal tubulin

griseofulvin adverse effects

liver toxicity