241.1 🎓 醫孞生版

241.1.0.1 📌 䞀頁重點

241.1.0.1.1 5 Major Antifungal Classes
Class Drug Examples Mechanism Target Spectrum
Polyenes Amphotericin B (lipid + conventional) Binds ergosterol → membrane disruption Broad (Candida, Aspergillus, Crypto, Mucor, dimorphic, Histo, Blasto)
Azoles Fluconazole, voriconazole, posaconazole, isavuconazole, itraconazole Inhibits cytochrome P450 14α-demethylase → ↓ ergosterol synthesis Broad spectrum varies by agent
Echinocandins Caspofungin, micafungin, anidulafungin, rezafungin (2023) Inhibits β-1,3-glucan synthase → cell wall disruption Candida + Aspergillus; NOT Crypto/Mucor
Pyrimidine Flucytosine (5-FC) Inhibits DNA synthesis Cryptococcus (combination); Candida (synergy)
Allylamines Terbinafine Inhibits squalene epoxidase Dermatophytes (skin/nails)
241.1.0.1.2 Newer Agents (2021-2024)
  • Rezafungin (Rezzayo) — echinocandin, FDA 2023, once-weekly IV
  • Ibrexafungerp (Brexafemme) — oral triterpenoid, FDA 2021, vulvovaginal candidiasis + emerging invasive
  • Olorofim — orotomide, Phase 3 (DHODH inhibitor; targets molds including azole-resistant Aspergillus + Lomentospora + Scedosporium)
  • Fosmanogepix — Gwt1 inhibitor, broad-spectrum, Phase 3
241.1.0.1.3 Amphotericin B
241.1.0.1.3.1 Forms
  • Conventional (deoxycholate): severe nephrotoxicity (infusion reactions, dose-limiting)
  • Liposomal (AmBisome): less toxic, preferred
  • Lipid complex (Abelcet), ABLC: alternative
  • Amphotericin B colloidal dispersion (ABCD): rarely used
241.1.0.1.3.2 Indications
  • Severe invasive fungal infections
  • Cryptococcal meningitis (with flucytosine)
  • Mucormycosis
  • Severe histoplasmosis, blastomycosis
  • Empirical in neutropenic fever
  • Visceral Leishmaniasis (Ch 229)
241.1.0.1.3.3 Toxicity
  • Renal: nephrotoxicity (especially conventional), electrolyte wasting (K+, Mg2+)
  • Infusion reactions: fever, chills, rigors (pre-medicate acetaminophen + diphenhydramine + hydrocortisone)
  • Anemia (chronic)
  • Liposomal less toxic but expensive
241.1.0.1.4 Azoles
241.1.0.1.4.1 Fluconazole
  • Best CNS + urine penetration of azoles
  • Active against: Candida (except C. krusei intrinsic R; C. glabrata variable R); Cryptococcus (consolidation/maintenance); some dimorphic fungi
  • Not active: Mucor, Aspergillus (very limited)
  • Oral + IV
  • Cheap, well-tolerated
  • Pregnancy: avoid high-dose 1st trimester (teratogenic)
241.1.0.1.4.2 Voriconazole
  • First-line for invasive aspergillosis
  • Active against: Aspergillus, Scedosporium, Fusarium, Candida; not Mucor
  • Severe side effects: visual disturbances (transient), hepatotoxicity, periostitis (long-term), skin (cutaneous SCC risk with chronic use + photosensitivity)
  • TDM (therapeutic drug monitoring) recommended
  • Drug interactions extensive (CYP3A4 inhibition)
241.1.0.1.4.3 Posaconazole
  • Broadest azole spectrum (Aspergillus, Mucor, Fusarium, Scedosporium, dimorphic)
  • Prophylaxis for high-risk neutropenia + HSCT
  • Treatment of invasive mucormycosis (salvage)
  • Oral + IV (delayed-release tablet preferred over suspension)
241.1.0.1.4.4 Isavuconazole
  • Broad spectrum: Aspergillus + Mucor (first-line alternative), Candida, Cryptococcus
  • Lower toxicity than voriconazole
  • Linear pharmacokinetics (vs voriconazole non-linear)
  • Less drug interactions
241.1.0.1.4.5 Itraconazole
  • Dimorphic fungi (Histoplasma, Blastomyces, Sporothrix, Coccidioides — alternative)
  • ABPA
  • Onychomycosis
  • Older, less used invasive now (less reliable absorption)
241.1.0.1.5 Echinocandins
241.1.0.1.5.1 Caspofungin, Micafungin, Anidulafungin
  • First-line invasive Candida infections
  • Fungicidal vs Candida; fungistatic vs Aspergillus
  • IV only (no oral)
  • Daily dosing
  • Less drug interactions (no CYP interactions significantly)
  • Generally safe; mild liver enzyme elevation
241.1.0.1.5.2 Rezafungin (Rezzayo, FDA 2023)
  • Once-weekly IV dosing
  • For invasive candidiasis
  • Equivalent efficacy to caspofungin
  • Convenience advantage (outpatient, fewer line access)
241.1.0.1.6 Flucytosine (5-FC)
  • Synergy with Amphotericin B for cryptococcal meningitis (induction phase)
  • Synergy with azole for Candida (rare clinical use alone)
  • Always combined (resistance emerges fast with monotherapy)
  • Toxicity: bone marrow suppression (dose-related, monitor TDM)
241.1.0.1.7 Terbinafine
  • Allylamine
  • Dermatophytes (onychomycosis, tinea pedis, cruris, capitis)
  • Oral or topical
  • Hepatic monitoring
241.1.0.1.8 Other / Topical
  • Nystatin (polyene, topical): oral thrush, vaginal Candida
  • Clotrimazole, miconazole, ketoconazole (azole, topical): dermatophytes + Candida
  • Ciclopirox (broad topical): dermatophytes
  • Tavaborole, efinaconazole (newer onychomycosis topical)

241.1.0.2 1⃣ Amphotericin B Detail

241.1.0.2.1 Mechanism
  • Binds ergosterol in fungal cell membrane → forms pores → membrane disruption + cell death
  • Concentration-dependent killing
241.1.0.2.2 Spectrum
  • Broadest antifungal spectrum
  • Candida (including resistant), Cryptococcus, Aspergillus, Mucor, dimorphic fungi (Histo, Blasto, Cocci, Paracocci), Sporothrix
  • Not active: Pseudallescheria, Lomentospora prolificans (resistant)
241.1.0.2.3 Forms
241.1.0.2.3.1 Conventional (Deoxycholate)
  • Original formulation
  • Severe nephrotoxicity (50%+ in courses)
  • Severe infusion reactions
  • Cheap; rarely used in developed countries now
241.1.0.2.3.2 Liposomal Amphotericin B (AmBisome)
  • Preferred for most indications
  • Less nephrotoxic, less infusion reactions
  • 3-5 mg/kg/day IV typical
  • More expensive
241.1.0.2.3.3 Lipid Complex (Abelcet)
  • Alternative
  • Similar efficacy + lower toxicity than conventional
  • 5 mg/kg/day
241.1.0.2.3.4 Amphotericin B Colloidal Dispersion (ABCD)
  • Rarely used
241.1.0.2.4 Toxicity
241.1.0.2.4.1 Nephrotoxicity
  • Most common dose-limiting (especially conventional)
  • Tubular damage, ATN
  • Sodium loading + hydration before infusion reduces
  • Electrolyte wasting: K+, Mg2+ (replete)
  • Liposomal much less
241.1.0.2.4.2 Infusion Reactions
  • Fever, chills, rigors during infusion
  • Pre-medicate: acetaminophen + diphenhydramine
  • Add hydrocortisone for severe / breakthrough
  • Hydration before infusion
  • Test dose historically (less needed with liposomal)
241.1.0.2.4.3 Hematologic
  • Anemia (suppressed EPO + hemolysis)
  • Less marrow toxicity than flucytosine
241.1.0.2.4.4 Hepatic
  • Mild transaminitis
241.1.0.2.5 Dosing
  • Conventional: 0.5-1 mg/kg/day IV
  • Liposomal: 3-5 mg/kg/day IV (higher for CNS — 6 mg/kg/day)
  • Test dose + escalation (conventional)
  • Duration variable by indication
241.1.0.2.6 Indications
  • Severe / invasive fungal infections
  • Cryptococcal meningitis (with flucytosine)
  • Mucormycosis (high-dose liposomal)
  • Severe histoplasmosis, blastomycosis
  • Empirical neutropenic fever
  • Visceral Leishmaniasis (Ch 229)
241.1.0.2.7 Resistance
  • Rare; selected with prolonged use

241.1.0.3 2⃣ Azoles Detail

241.1.0.3.1 Mechanism
  • Inhibit cytochrome P450 14α-demethylase (CYP51)
  • Block ergosterol synthesis → membrane defects + accumulation of toxic sterols
  • Fungistatic for most yeasts; fungicidal for some molds at high concentrations
241.1.0.3.2 Fluconazole
241.1.0.3.2.1 Pharmacokinetics
  • Oral bioavailability > 90%
  • Best CNS penetration (50%+ of plasma)
  • Best urinary penetration (Candida UTI treatment)
  • Renal clearance (adjust for CrCl)
241.1.0.3.2.2 Indications
  • Mucosal Candidiasis (oropharyngeal, esophageal, vulvovaginal)
  • Invasive Candidiasis (susceptible species)
  • Cryptococcal meningitis (consolidation + maintenance)
  • Coccidioidomycosis (chronic / disseminated)
  • Prophylaxis HSCT
241.1.0.3.2.3 Resistance
  • C. krusei intrinsic R
  • C. glabrata variable R (often need higher dose or alternative)
  • C. auris often R (Ch 252)
  • Acquired resistance with prolonged use
241.1.0.3.2.4 Side Effects
  • Generally well-tolerated
  • Hepatotoxicity
  • QTc prolongation (high doses)
  • Pregnancy: avoid high-dose 1st trimester (teratogenic — craniofacial, cardiac); single low-dose OK for VVC
241.1.0.3.3 Voriconazole
241.1.0.3.3.1 Indications
  • First-line invasive aspergillosis
  • Scedosporium, Fusarium
  • Refractory Candida (severe)
  • Esophageal candidiasis
241.1.0.3.3.2 Side Effects
  • Visual disturbances (transient blurring + brightness changes — 30%; mostly mild + resolves)
  • Hepatotoxicity (monitor LFTs)
  • Photosensitivity + cutaneous SCC risk (chronic use)
  • Periostitis (long-term — bone pain)
  • QTc prolongation
  • Hallucinations / encephalopathy (rare high levels)
241.1.0.3.3.3 TDM
  • Therapeutic Drug Monitoring (TDM) recommended
  • Trough 1-5.5 mg/L target
  • Non-linear pharmacokinetics
  • Sub-therapeutic = treatment failure; supra = toxicity
241.1.0.3.3.4 Drug Interactions
  • CYP3A4 substrate + inhibitor (extensive interactions)
  • Coumarins, statins, immunosuppressants, etc.
241.1.0.3.4 Posaconazole
241.1.0.3.4.1 Indications
  • Prophylaxis for high-risk neutropenia + HSCT
  • Mucormycosis (salvage / step-down)
  • Aspergillosis (alternative)
  • Fusarium
241.1.0.3.4.2 Formulations
  • Delayed-release tablet (preferred — predictable absorption)
  • Oral suspension (taken with food, less reliable absorption)
  • IV
241.1.0.3.4.3 Side Effects
  • GI, hepatotoxicity
  • QTc prolongation
  • Hypertension (rare)
241.1.0.3.4.4 TDM
  • Trough 1.0 mg/L+ for prophylaxis; > 1.5 mg/L for treatment
241.1.0.3.5 Isavuconazole
241.1.0.3.5.1 Indications
  • Invasive aspergillosis (first-line alternative)
  • Mucormycosis (FDA approved 2015)
  • Candida (limited use)
241.1.0.3.5.2 Advantages
  • Lower hepatotoxicity than voriconazole
  • Linear pharmacokinetics (less TDM)
  • Less drug interactions (vs voriconazole)
  • Shorter QTc (vs voriconazole)
  • Oral + IV
241.1.0.3.5.3 Loading Dose
  • Loading × 6 doses then maintenance
241.1.0.3.6 Itraconazole
241.1.0.3.6.1 Indications
  • Histoplasmosis (mild-moderate)
  • Blastomycosis (mild-moderate)
  • Sporotrichosis (cutaneous + lymphocutaneous)
  • ABPA (allergic bronchopulmonary aspergillosis)
  • Onychomycosis (pulse dosing)
241.1.0.3.6.2 Side Effects
  • Negative inotrope (caution in CHF)
  • Hepatotoxicity
  • Drug interactions (CYP3A4)
241.1.0.3.7 Newer Azoles
241.1.0.3.7.1 Olorofim (Phase 3)
  • Dihydroorotate dehydrogenase (DHODH) inhibitor
  • Active against azole-resistant Aspergillus + Lomentospora + Scedosporium + Fusarium
  • Anticipated approval 2025+
241.1.0.3.7.2 Encochleated Amphotericin (Phase 3)
  • Oral bioavailable
  • For cryptococcal meningitis (improves access in resource-limited)

241.1.0.4 3⃣ Echinocandins Detail

241.1.0.4.1 Mechanism
  • Inhibit β-1,3-D-glucan synthase → cell wall disruption
  • Fungal-specific target (no human ortholog) → favorable safety profile
241.1.0.4.2 Spectrum
241.1.0.4.2.1 Active
  • Candida species (fungicidal — including most azole-resistant)
  • Aspergillus (fungistatic)
  • Pneumocystis (limited)
  • Endemic dimorphic (limited)
241.1.0.4.2.2 Not Active
  • Cryptococcus (cell wall structure different)
  • Mucor / Rhizopus / Rhizomucor (no glucan)
  • Trichosporon, Rhodotorula (limited)
  • Fusarium
241.1.0.4.3 Drug Choice
241.1.0.4.3.1 Caspofungin
  • 70 mg loading, then 50 mg/day IV
  • Hepatic adjustment
241.1.0.4.3.2 Micafungin
  • 100-150 mg/day IV
  • No major dose adjustments
241.1.0.4.3.3 Anidulafungin
  • 200 mg loading, 100 mg/day IV
  • No metabolism (degraded), good for hepatic insufficiency
241.1.0.4.3.4 Rezafungin (Rezzayo, FDA 2023)
  • Once-weekly IV (400 mg load → 200 mg/wk)
  • For invasive candidiasis + candidemia
  • Outpatient convenience advantage
  • Same spectrum as other echinocandins
241.1.0.4.4 Indications
  • First-line for invasive Candida infections (per IDSA, especially when species unknown)
  • Candidemia
  • Empirical neutropenic fever
  • Aspergillosis (alternative)
241.1.0.4.5 Toxicity
  • Generally safe; well-tolerated
  • Mild transaminitis
  • Histamine-related reactions (rare)
  • No significant drug interactions (no CYP metabolism)
  • Hepatic dose adjustment (caspofungin)
241.1.0.4.6 Pregnancy
  • Limited data; use if necessary

241.1.0.5 4⃣ Flucytosine (5-FC)

241.1.0.5.1 Mechanism
  • Cytosine analog → DNA + RNA synthesis inhibition
  • Selective fungal uptake (cytosine permease)
241.1.0.5.2 Indications
  • Cryptococcal meningitis (induction phase combination with amphotericin B)
  • Candida combination (rare clinical use)
  • Synergy with amphotericin B
241.1.0.5.3 Side Effects
  • Bone marrow suppression (cytopenia — dose-related)
  • TDM essential: target peak 50-100 mg/L
  • Hepatotoxicity
  • GI
241.1.0.5.4 Combination Therapy
  • Always combined (resistance emerges quickly with monotherapy)
  • Standard: amphotericin B + flucytosine for cryptococcal meningitis induction
241.1.0.5.5 Dosing
  • 100 mg/kg/day PO divided q6h
  • Renal adjustment

241.1.0.6 5⃣ Terbinafine (Allylamine)

241.1.0.6.1 Mechanism
  • Inhibits squalene epoxidase
  • Blocks ergosterol synthesis
  • Fungicidal
241.1.0.6.2 Indications
  • Dermatophytes (onychomycosis, tinea pedis/cruris/capitis)
  • Oral 250 mg/day × 6 wk (fingernails) or 12 wk (toenails)
  • Topical for skin infections
241.1.0.6.3 Side Effects
  • Hepatotoxicity (monitor LFTs — rare but serious)
  • Taste disturbances
  • Headache

241.1.0.7 6⃣ Other Antifungals

241.1.0.7.1 Nystatin
  • Polyene, topical
  • Oral thrush, vaginal Candida
  • “Swish and swallow” oral
  • Not absorbed systemically
241.1.0.7.2 Topical Azoles
  • Clotrimazole, miconazole, ketoconazole, econazole
  • Dermatophytes + Candida
  • OTC + prescription
241.1.0.7.3 Ciclopirox
  • Broad-spectrum topical
  • Onychomycosis (nail lacquer)
241.1.0.7.4 Newer Topicals (Onychomycosis)
  • Tavaborole
  • Efinaconazole
241.1.0.7.5 Griseofulvin
  • Old anti-dermatophyte
  • Pediatric tinea capitis (still used)
  • Hepatotoxicity, photosensitivity
241.1.0.7.6 Ibrexafungerp (Brexafemme, FDA 2021)
  • Oral triterpenoid (glucan synthase inhibitor; similar mechanism echinocandins but oral)
  • Vulvovaginal candidiasis (FDA approval)
  • Emerging invasive fungal use (under investigation)
241.1.0.7.7 Fosmanogepix (Phase 3)
  • Inhibits Gwt1 (GPI anchor biosynthesis)
  • Broad-spectrum
  • Active against fluconazole-resistant Candida, Candida auris, Aspergillus

241.1.0.8 7⃣ Therapeutic Drug Monitoring (TDM)

241.1.0.8.2 Not Routinely TDM
  • Echinocandins
  • Liposomal AmB
  • Fluconazole (predictable PK)
  • Isavuconazole (linear PK)
241.1.0.8.3 Targets
  • Voriconazole trough: 1-5.5 mg/L
  • Posaconazole trough: > 1.0 (prophylaxis), > 1.5 (treatment)
  • 5-FC peak: 50-100 mg/L

241.1.0.9 8⃣ Drug Interactions

241.1.0.9.1 Azoles (CYP3A4 Inhibitors)
  • Significant interactions with:
    • Calcineurin inhibitors (tacrolimus, cyclosporine) — major dose reduction
    • Statins (simvastatin contraindicated; rosuvastatin some interaction)
    • Anticoagulants (warfarin, DOACs)
    • Anti-arrhythmics (amiodarone, etc.)
    • Anti-cancer drugs (vincristine)
    • HIV ART (variable)
    • Benzodiazepines (lorazepam, midazolam)
  • Liverpool Drug Interactions / UpToDate for review
241.1.0.9.2 Voriconazole vs Isavuconazole
  • Voriconazole = more interactions, more variable PK
  • Isavuconazole = fewer interactions, linear PK (preferred in some settings)
241.1.0.9.3 Echinocandins
  • Minimal drug interactions (no CYP metabolism significantly)
  • Useful in complex polypharmacy