Antifungals

 Beta-Glucan Synthesis Blockers

• Echinocandins
Membrane Permeability Agents
• Azoles
o Systemic infections
o Oral bioavailability, some IV
o Cytochrome inducers: Decrease bioavailability
o Toxicity
• Vomiting, diarrhea, rash, hepatoxicity
• Ketoconazole: bad for drug interactions and steroid blocking effects
(Gynecomastia)
o Mechanism
• Inhibit ergosterol formation
• Reduces membrane permeability
▪ Increased leak of cations and nutrients
o Resistance
• Resistance developing due to widespread use
• Reduction of susceptible enzymes to azoles
o Ketoconazole
• Narrow spectrum antifungal
• More adverse than others
• Against chronic candidiasis and derm fungal infections
• Strong inhibitor of Cyt 450 (increase level of other drugs)
• Gynecomastia
o Fluconazole
• Drug of choice in esophageal/oropharyngeal candidiasis
• Oral dose eliminate vaginal candidiasis
• Cryptococcal meningitis (drug of choice)
o Miconazole, Clotrimazole
• Topical
• Well with topical/vaginal, not much systematically
• Combined with steroid; to treat
▪ Tinea corporis
▪ Tinea cruris
▪ Tinea pedis
o Itraconazole
• Wide spectrum
▪ Drug of choice for Blastomyces and Sporothrix
▪ Choice for chromoblastomycosis
▪ Alternate: aspergillus, coccidiosis, Cryptococcus, histoplasma
o Variconazole
• Wider than Itraconazole
▪ Possibly better than amphotericin B
• 30% visual blurring or unknown cause
o Posaconazole
• Widest spectrum
▪ Most species of Candida and Aspergillus
• Only one with activity against Rhizopus
• Terbinafine
• Oral ingestion for skin infection
• Distributed to stratum corneum
 • Not be used in patients with porphyria
o Mechanism
• Inhibits microtubule formation in dermatophytes
• Fungistatic: Absorbed into fungal cells through active transport
o Toxicity
• Headache, GI distress
• Fever, rash, flushing from histamine release
• Interference with warfarin levels
 
• Polyenes
o Superficial infections
o Topically to suppress candida infections
• "Swish and swallow"
o Mechanism
• Bind to ergosterol and cause artificial pores
▪ Leakage of H, K, Cl, Na thourgh pore
▪ Increases free radical in cell
o Amphotericin B
• Related to nystatin
▪ Usually IV (Nystatin: Oral)
• Elimination through slow hepatic metabolism
▪ 2 weeks
▪ Minimal renal excretion
• Systemic mycoses
• Widest antifungal spectrum
• Aspergillus, blastomyces, candida, cryptococcus, histoplasma, mucor
• IV or intrathecal (rarely)
• Mycotic corneal ulcers and keratitis
• Toxicity
▪ Infusion related chills, nauseas, muscle spasms, vomiting
▪ Shocking fall in B
• Premedicated with antihistamines/glucocorticoids
▪ Renal tubule acidosis, Mg and K wasting
▪ Anemia (Decreased EPO production)
▪ Nephrotoxic
▪ Liposomal version: reduce renal toxicity
▪ Intrathecal: associated with seizures and neurologic damage
Nucleic Acid Synthesis Blocker
• Flucytosine
• Antimetabolite, also in cancer chemotherapy
• Eliminated intact in urine (dosage adjustment necessary)
• Narrow spectrum: Used in cryptococcus neoformans infections
o Mechanism
• Accumulated in fungal cells by membrane permease
• Converted by cytosine deaminase (Flucocytosine->5FC
• 5-FC: Blocks production of thymidine through inhibiting thymidylate synthase
• Fungal cells stop producing DNA and RNA
• Synergy occurs when combined with Amphotericin B or itraconazole (strong
effect)
o Toxicity
• Reversible bone marrow depression 
 
Microtubule Function Inhibitors
• Griseofulvin