Antifungals:

Fungi and mycosis

 Eucaryotes
 Defined nucleus with nuclear membrane
 Cell membrane (lipids, glycoprotein, sterols)
 Cytoskeleton (microtubules, filaments)
 Difficult to give therapeutic agent: similar with host cells

Classification:

1) Superficial mycoses-mild, readily diagnose, response well to tx

2) Cutaneous mycoses-athlete’s foot & ringworm = dermatophytes
3) Subcutaneous mycoses
4) Systemic mycoses-infx with invasion of internal organ
- Healthy person: H.capsulatum
- Opportunistic: candida albicans

Damage:

 Direct invasion and displacement

-mass of cellfungus ballocclude organs (bronchi, tubules, ureter)obstruct
outflow2nd infxtissue damage

Infection:
Systemic infx Mucocutaneous infx
Amphotericin B Griseofulvin
Flucytosine Terbinafine
Azoles
Echinocandins

Topical antifungal therapy:

 Nystatin
 Topical azoles
 Topical allylamines
Systemic antifungal drugs for systemic infections:

Drugs/ features Amphotericin B Flucytosine (5-FC) Azoles Echinocandins

Properties -Polyene macrolides -synthetic compound Drug= caspofung
-Streptomyces nodosus -imidazole (KMC)
-triazole (IVF)
Pharmacokinetics -Poorly absorbed ~Oral- well absorbed IV
-Oral- GIT infx ~poor protein bound
-IV- 90% bound ~ penetration +
-Most metabolized CSF
-Wide distribution ~measure peak
-t½= 15 days serum periodically
-in CSF ~ intrathecal
MOC -Fungicidal ~taken by fungal -reduce ergosterol Affect cell wall
-Bind w enzyme cytosine synthesis by inhibiting formationcell d
ergosterolporeleakage permease5-FU fungal cytochrome p450
intracellular ionscell death intracellularly5-
dUMP +
FUTPinhibit DNA
& RNA synthesis
~synergy w amp. B=
enhance 5-FC
penetration & dev
resistance
Clinical use -Mycotic infx( if chronic- azole) Not use alone- Quite broad spectrum Invasive aspergil
-cancer synergism + reduce
-conjunctival infx resistance
development

Targets -broad spectrum - broad spectrum -candida sp.

-c.albicans -crytococcus -cryptococcus neoformans
-cryptococcus neoformans neoformans -endemic mycoses
-H.capsulatum -candida sp. -dermatophyte
-blastomyces dermatidis -aspergillus
-coccidiodes immitis -pseudoallescheria boydii
-aspergillus fumigatus
Adverse effects -immediate rxn= ~renal toxicity -relatively non-toxic -Well tolerated
fever,chills,spasm,vomit,headache ~BM toxicity -minor GIT upset -minor GIT upse
,hypotension (anemia, leucopenia, -abnormal liver enzymes -flush
-slower= renal damage,liver thrombocytopenia) -hepatits
damage,seizures(intrathecal) ~derangement of
LFT
~toxic enterocolitis
~narrow therapeutic
index
 Azoles:

Features/ drugs Ketoconazole Itraconazole Fluconazole Voriconazol

Pharmacokinetics Less selective for -Oral & IV -ly water soluble -oral & IV
fungal p450 -absorption:  by food,  by -good ! CSF penetration -well absorb orally
low gastric pH - oral bioavailability -hepatic metabolism
-interact w hepatic microsomal - effect w hepatic - inhibition of
enzyme microsomal enzyme mammalian p450
-rifamycin  its concentration -highest therapeutic index
-poor penetration to CSF =( -oral & IV

Adverse effects -Rash

- liver enzyme
-transient visual
disturbances

Targets -histoplasma - x active for aspergillus / -candida sp.

-blastomyces filamentous fungi -dimorphic fungi
-sporothrix -active against
aspergilloses
Clinical use -dermatophytoses -prophylaxis of cryptococcal
-onychomycosis meningitis
-candidemia in ICU patient
-mucocutaneous candidiasis
-coccidiodal disease
-meningitis

Systemic antifungals drugs for mucocutaneous infections:

Features/ drugs Griseofulvin (penicillium) Terbinafine

pharmacokinetics -very insoluble fungistatic drug synthetic
-absorption improved by fatty food
MOC -unclear -fungicidal
-deposit in newly formed skinbound to -interfere w ergosterol biosynthesis by inhibiting
keratinprotect skin from further infx enzyme squalene epoxidaseaccumulation of toxic
sterol squalene
Clinical use Systemic infx of dermatophytosis -Dermatophytoses
-keratophilic medication
DDI Warfarin, phenobarbitol
Adverse effect Allergic syndrome Rare- GIT upset, headache

Topical antifungal therapy:

 Nystatin
- Too toxic
- Skin & mucous membrane
- Little toxicity
- Active: candida sp.
- Clinical use: oropharyngeal trush/ vaginal candidiasis/ intertriginous candidal infection
 Topical azoles ( clotrimazole/ miconazole)
- Clinical use: vulvovaginal candidiasis/ oral trush/ dermatophytic infx( tinea corporis, pedia, cruris)/
seborrhoeic dermatitis, pityriasis versicolor
- Negligible absorption
- Rare AE