Chap 48: Antifungal agent

Introduction
- human fungal infection increasing
- advances in surgery, cancer treatment, ICU, AIDS
- divided into

1. Systemic drugs (oral/parenteral) for systemic infections
2. Oral drugs for mucocutaneous infection
3. Topical drugs for mucocutaneous infection

SYSTEMIC ANTIFUNGALS FOR SYSTEMIC INFECTIONS
Amphotericin B
- produced Streptomyces nodosus --> both A + B --> only B in use
- polyene macrolide
- poorly absorbed orally unless intestinal infection
- no effect with renal/liver/dialysis pt
- MOA

• difference in lipid composition of fungal and mammalian cell membranes
• human: cholesterol; fungi: ergosterol
• amp B binds to ergosterol only --> creates pores in cell membrane --> leakage of intracellular ions and molecules --> cell death

- Resistance

• ergosterol binding is impaired by decreasing membrane concentration of ergosterol/mutation by modification of sterol molecule

- SE

• infusion related toxicity: very common - fever, chills, m spasm, vomiting, headache, hypoTN - slow down infusion rate/reduce daily dose or use pre-meds (PCM, antiH1, steroids)
• slower toxicity: renal damage happens in all pt with clinically significant dose of drug, abnorm LFT

- Clinical uses

• broadest spectrum antifungal - drug of choice of all life-threatening mycotic infection
• against all clinically significant yeasts - Candida, Cryptococcus neoformans
• endemic mycoses - H capsulatum, Blastomyces dermatitidis, Coccidiodes immitis
• pathogenic moulds - Aspergillus fumigatus, mocor

Liposomal amphotericin B
- due to SE --> this aim to bind more selectively to fungal ergosterol by being morel lipid soluble
AZOLES
General
- synthetic compounds
- depending on number of N atoms in zole ring - divided into

1. imidazole: ketoconazole, miconazole, clotrimazole
2. triazole: itraconazole, fluconazole, voriconazole

MOA
- inhibit fungal c-P450 enzyme --> inhibit ergosterol systhesis
- more selective to fungal one than human c-P450 --> causes SE

Clinical uses
- Candida, C. neoformans, endemic mycosis, dermatophytes
- Itraconazole + voriconazole --> aspergillus

SE
- nontoxic
- minor GI upset, liver abnormalities, hepatitis

Ketoconazole
- 1st oral azole
- hepatitis - less selective to c-P450 than other azoles

Itraconazole
- oral and IV form
- needs gastric acid for better drug absorption --> take it with coke!
- used in dermatophytoses and onychomycosis
- azole of choice in dimorphic fungi histoplasma, blastomyces, sporothrix

Fluconazole
- high water solubility --> hence better oral absorption
- better GI and hepatic tolerance --> widest therapeutic index
- for mucocutaneous candidiasis
- no activity against aspergillus + filamentous fungi

Voriconazole
- similar to itraconazole in activity
- less toxic than amphotericin B --> drug of choice in invasive aspergillosis

ECHINOCANDINS (capsofungin)
- newest class --> inhibit fungal cell wall synthesis
- IV form - extremely well tolerated in GIT and hepatitis
- indicated for salvage therapy with invasive aspergillosis that failed to response with amphotericin B

- Horvath - advantage of capsofungin over amphotericin

• very narrow spectrum
• has best coverage for candida and aspergillus but nothing else
• not as nephrotoxic as amphotericin
• ampho has broader coverage but nephrotoxic is a problem
  

ORAL ANTIFUNGALS FOR MUCOCUTANEOUS INFECTION
Griseofulvin
- from penicillium
- very insoluble fungostatic --> only use in dermatophytoses
- exact MOA unknown --> deposited in newly forming skin --> binds to keratin --> protect skin from new infection
- hence to be given 2-6 wks for hair/skin infection to replacement of infected keratin
- nail infection --> longer

Terbinafine
- systhetic allylamine
- keratophilic medication like griseo; but unlike griseo: fungicidal
- inhibit fungal enzyme (squalene epoxidase) --> accummulate sterol squalene (toxic to fungi)
- cure rate up to 90% for onychomycosis for 12wks duration --> better than itroconazole/griseo

TOPICAL ANTIFUNGALS
Nystatin
- polyene macroline (like amphotericin B)
- too toxic for parenteral admin --> only orals
- active against candida ==> for suppression of local candidal infection

Topical Azoles
- clotrimazole, miconazole
- shampoo form of ketoconazole for seborrheic dermatitis, pityriasis versicolor

Topical allylamines (terbinafine)
- tinea cruris and corporis