MG - infectious diseases and oncology 5

Antifungal drugs

fungi

eukaryotes

both plant-like and animal-like properties

two main life forms

• yeast

• mold

fungal infections

categorized by

• tissue type

• degree of infection/severity

• immune response

five major groups with increasing severity

• skin, hair and nail infection

• mucosal infection

• allergic fungal disease

• chronic or deep tissue infections

• invasive fungal infections

risk factors that influence the susceptibility of fungal infections

• environmental

• disruption of natural flora and local immune responses

• hereditary factors

• weakened immune system

superficial cutaneous mycoses

mild superficial infections of the skin, hair and nails

yeast

• candida albicans (red spots with flakey edges)

• malessezia furfur(small, discolored patches)

dermatophytes

• epidermophyton(skin and nails)

• microsporum(hair, skin)

• trichophyton(hair, skin, nails

• onychomycosis

• ringworm

• athlete’s foot

mucosal infection

mostly caused by Candida

oral cavity: thrush

• risk factors: neonates, poorly fitting prosthesis, antibiotic treatment, inhalation of anti-inflammatory drugs

vagina: vulvo-vaginal yeast infection

• risk factors: antibiotic treatment, pregnancy, genetic predisposition

deep tissue mycoses

often only after tissue damage

• sporotrichosis

• mycetoma

• chromoblastomycosis

• fungal keratitis

invasive (systemic mycoses

usually only occurs in immunocompromised agents

• immune-paralysis phase after severe infection

• chemotherapy patients

• AIDS patients

• receivers of stem cell/organ transplants

widely known mycoses

• invasive candidiasis

• fusariosis and mucormycosis

• invasive aspergillosis (immune system fails to clear spores > germination and hyphae formation)

• cryptococcal meningitis (pneumonia-like symptoms > often not properly diagnosed)

endemic mycoses

restricted to

• specific ecological niche and therefore

• geographical area or climate zone

resulting in recent travel stays being important in the diagnosis of the pathogen

cellular targets for antimycotics

cell membrane, cell wall and intracellular(RNA/DNA synthesis and mitosis)

polyene macrolide

amphotericin B

MOA: disrupting the ergosterol binding and pore formation resulting in membrane permeabilization

broad-spectrum antimycotics with enhanced affinity to ergosterol but some bind to cholesterol

SE: injection-related, fever, headache, hypotension, nephrotoxic

often used as induction therapy

Azoles

inhibition of the ergosterol synthesis, resulting in membrane leakage and blockage of electron transport

the P450 enzymes are inhibited

these inhibit dermatophytes and yeasts: broad spectrum fingicidal

few side effects but prone to drug interactions

itraconazole: topical, oral, iv, increased absorption with food, dermatophytosis, onychomycosis

fluconazole: oral, iv, widest spectrum, least interactions, CNS penetration, cryptococcal meningitis

voriconazole: oral, iv, interacts with CYP3A4, fewer side effects than Amp B indicated for aspergillosis

increasing resistance is becoming an issue

nafrifine, butenafine, terbinafine

allylamines

dual effect with ergosterol depletion and squaline accumulation

terbinafine: inhibits the biosynthesis of lanosterol and ergosterol, fungicidal. oral and topical, good GI resportion, degraded in liver, SE=GI

amorolfine - inhibits two drugs in the biosynthesis, not effective for chronic infections, no systemic use

echinocandins

target: cell wall

inhibition of the glucan synthase activity

chemical properties: peptide backbones, cyclic, long hydrophobic side chains

caspofungin: iv only, degraded by liver.

• fungicidal: candida

• fungistatic: aspergillus

micafungin: invasive or esophageal candida infection

anidulafungin: invasive candida infection used in patients with liver or kidney problems

advantages: few IA, few SE, little resistance

disadvantages: no oral, more expensive than azoles

flucytosine

depletes thymidine pool and stalls translation

prodrug: two modes of action

• incorporated into RNA as 5-FUTP and thereby inhibits the protein biosynthesis

• inhibits thymidylate synthase and thereby the DNA synthesis

PK: good GI resorption > oral administration, for systemic mycoses often iv with AmpB, good distribution

narrow spectrum: good inhibition of Candida and Cryptococcus

resistance very frequent: altered metabolism(occurs mainly in monotherapy)

griseofulvin

binds to tubulin and arrests mitosis

works well against dermatophytes, oral administration, long therapy

many side effects : possible teratogenic and carcinogenic