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Antifungal and Antiviral Agents: Clinical & Pharmacological Characteristics

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PART I — ANTIFUNGAL AGENTS

Mechanisms of Action

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1. Polyenes (Amphotericin B, Nystatin)

• Broad-spectrum: active against Candida, Aspergillus, Cryptococcus, endemic mycoses (histoplasmosis, coccidioidomycosis, blastomycosis)
• IV administration only for systemic infection
• Toxicity: Nephrotoxicity (dose-limiting), infusion-related reactions (fever, rigors, hypotension), hypokalemia, hypomagnesemia, anemia
• Lipid formulations (liposomal AmB, AmB lipid complex, AmB colloidal dispersion) are equally or more effective with significantly less nephrotoxicity; preferred when renal function is compromised
• Cryptococcal meningitis induction: 0.7–1 mg/kg/day IV + flucytosine 100 mg/kg/day for ≥2 weeks (AIDS), or 3 mg/kg/day liposomal formulation

• Topical only (too toxic for systemic use); used for oropharyngeal and cutaneous candidiasis

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2. Azoles

Imidazoles (topical)

Triazoles (systemic) — preferred over imidazoles for systemic infections due to better selectivity

• Water-soluble; oral bioavailability nearly 100% (unaffected by food or gastric pH)
• Good CNS penetration — drug of choice for cryptococcal meningitis consolidation (400 mg/day × 8 weeks) and maintenance (200 mg/day × 6–12 months)
• Metabolized via CYP3A; inhibits CYP3A4 and CYP2C9 — multiple drug interactions (warfarin, phenytoin, cisapride, astemizole → risk of fatal arrhythmias)
• Adverse effects: Headache, GI upset, prolonged QTc, rare Stevens-Johnson syndrome/toxic epidermal necrolysis, neutropenia
• Pregnancy Category C

• Highly lipophilic; capsules require gastric acidity (take with food); cyclodextrin solution absorbed on empty stomach
• Accumulates in nails (reservoir 6–9 months post-treatment) — useful for onychomycosis
• Half-life ~21 hours; metabolized by CYP3A4 (dose adjust in liver disease)
• Broad-spectrum including Aspergillus, dimorphic fungi, dermatophytes
• Drug interactions: Major CYP3A4 inhibitor

• First-line for invasive aspergillosis (superior to D-AmB in randomized trials)
• Active against Aspergillus, Candida (including fluconazole-resistant spp.), Fusarium, dimorphic fungi
• Visual disturbances (transient photopsia) common; hepatotoxicity, QTc prolongation
• Avoid if substantially elevated aminotransferases or prolonged QTc
• Not recommended in patients <2 years; unpredictable PK in children

• Equally effective as voriconazole for invasive aspergillosis with fewer adverse effects and more predictable pharmacokinetics — increasingly considered treatment of choice
• Also active against mucormycosis (advantage over voriconazole)

• Noninferior to voriconazole for invasive aspergillosis (all-cause mortality); less toxic
• Extended-spectrum: only triazole with activity against Mucor
• Used for prophylaxis in high-risk neutropenic patients and GVHD patients

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3. Allylamines (Terbinafine, Naftifine)

• Oral: excellent for onychomycosis and tinea capitis (first-line)
• Highly lipophilic → concentrates in skin, nails, hair follicles; half-life ~17 hours
• Oral absorption not affected by food; metabolized by CYP2D6; eliminated in urine
• Dose adjustment required in renal or hepatic impairment
• Topical form: 3–5% systemic absorption
• Adverse effects: GI upset, taste disturbance (dysgeusia), rare hepatotoxicity, rare severe skin reactions

• Topical only; persists in stratum corneum up to 5 days after single application; 3–6% systemic absorption
• Indications: tinea pedis, cruris, corporis, versicolor, cutaneous candidiasis
• Side effects: local dryness, pruritus, irritation, erythema

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4. Benzylamines (Butenafine)

• Topical; OTC (Lotrimin Ultra); once–twice daily for tinea infections and tinea versicolor

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5. Echinocandins (Caspofungin, Micafungin, Anidulafungin)

• IV only; active against Candida (including azole-resistant) and Aspergillus
• Caspofungin is the only echinocandin licensed for salvage treatment of invasive aspergillosis
• Anidulafungin + voriconazole combination may reduce 6-week mortality in invasive aspergillosis (hematologic malignancy patients)
• Not active against Cryptococcus neoformans — should not be used for cryptococcal meningitis
• Generally well-tolerated; liver enzyme elevation possible
• Minimal drug interactions (not CYP substrates)

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6. Flucytosine (5-FC)

• Used almost exclusively in combination (with amphotericin B) to prevent resistance
• Key use: cryptococcal meningitis induction (100 mg/kg/day in 4 divided doses)
• Adverse effects: Bone marrow suppression (leukopenia, thrombocytopenia), GI toxicity, hepatotoxicity — monitor levels and CBC
• Requires renal dose adjustment

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7. Griseofulvin

• Oral; only for dermatophyte infections (tinea capitis, tinea corporis, onychomycosis)
• Fungistatic; requires prolonged treatment
• Induces CYP450 (reduces effectiveness of warfarin, oral contraceptives)

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8. Ciclopiroxamine

• Topical for dermatophytoses; also available as nail lacquer for onychomycosis

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9. Tavaborole

• Topical solution for onychomycosis

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PART II — ANTIVIRAL AGENTS

General Principles

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1. Antiherpesvirus Agents

Nucleoside Analogues (Acyclovir Class)

• Mechanism: Guanosine analog; selectively phosphorylated by HSV/VZV thymidine kinase (TK) to acyclovir-monophosphate → then by cellular enzymes to triphosphate → inhibits viral DNA polymerase and terminates DNA chain. Not activated in uninfected cells → excellent selectivity
• Active against HSV-1, HSV-2, VZV (VZV ~10× less sensitive than HSV)
• IV for severe/disseminated infections; oral for moderate disease
• Varicella dosing:
  • Immunocompetent child: 20 mg/kg PO 4× daily × 5 days (if initiated within 24h)
  • Immunocompromised (severe): 10 mg/kg IV q8h × 7–10 days
  • Acyclovir-resistant VZV: foscarnet 40 mg/kg IV q8h until healed
• Resistance mechanism: Mutations in viral TK gene → cross-resistance to ganciclovir, valacyclovir, famciclovir, penciclovir

• Prodrug (valine ester of acyclovir); converted to acyclovir after intestinal absorption
• Superior oral bioavailability vs. acyclovir → higher plasma levels, less frequent dosing (3× vs. 5× daily)
• Standard for herpes zoster in adults: 1 g PO q8h × 7 days

• Prodrug of penciclovir (structurally similar to acyclovir; guanosine analog)
• Same mechanism: activated by viral TK → inhibits viral DNA polymerase
• Better oral absorption than acyclovir; similar antiviral activity against VZV and HSV
• Standard for herpes zoster: 500 mg PO q8h × 7 days
• Contraindication: Do NOT combine with 5-fluorouracil (brivudin only — potentially lethal interaction; famciclovir caution)

• Active form of famciclovir; available as topical cream for orolabial HSV
• Same mechanism as acyclovir; similar resistance profile

• Active against CMV (primary indication); also HSV, VZV, EBV
• Mechanism: phosphorylated by CMV-encoded kinase (UL97) → triphosphate inhibits CMV DNA polymerase
• Valganciclovir = oral prodrug with high bioavailability; replaces IV ganciclovir for most CMV indications
• Toxicity: Myelosuppression (neutropenia, thrombocytopenia — dose-limiting); use with caution with other myelosuppressants

Pyrophosphate Analogue

• Mechanism: Inorganic pyrophosphate analog; directly inhibits viral DNA polymerases (and HIV reverse transcriptase) at the pyrophosphate-binding site without requiring TK phosphorylation
• Active against all herpesviruses including TK-deficient (acyclovir-resistant) mutants
• Second-line agent — more toxic than nucleoside analogs
• Indications: acyclovir-resistant HSV/VZV (especially in advanced AIDS), CMV retinitis, ganciclovir-resistant CMV
• Toxicity: Nephrotoxicity (most common, requires aggressive hydration), electrolyte disturbances (hypocalcemia, hypomagnesemia, hypo/hyperphosphatemia), genital ulceration

Other Herpesvirals

• Nucleotide analog; directly inhibits viral DNA polymerase (does not require TK activation)
• Third-line; significant nephrotoxicity limits use
• Indicated for CMV retinitis in AIDS patients

• Novel helicase-primase inhibitor — new class; inhibits viral DNA replication upstream of DNA polymerase
• Potent activity against acyclovir-resistant VZV and HSV
• Single dose 400 mg/day as effective and well-tolerated as valacyclovir 1 g TID for herpes zoster (Japanese trial)
• Licensed in Japan; investigational in USA

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2. Antiviral Agents for Influenza

• Mechanism: Inhibit neuraminidase (sialidase) — a surface enzyme that cleaves sialic acid from host cell receptors, preventing release and spread of new viral particles
• Active against influenza A and B
• Oseltamivir: oral; Zanamivir: inhaled
• Most effective if started within 48 hours of symptom onset

• Mechanism: Inhibits cap-dependent endonuclease (polymerase acidic/PA subunit) — blocks viral mRNA transcription; novel class
• Single oral dose; active against influenza A and B including oseltamivir-resistant strains

• Mechanism: Block M2 ion channel of influenza A, preventing viral uncoating
• Active only against influenza A; widespread resistance limits current use
• CNS side effects (amantadine); rimantadine better tolerated

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3. Antiretrovirals (HIV) — Overview of Classes

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4. Antivirals for Hepatitis

• Combination DAA regimens achieve >95% sustained virologic response (SVR/cure)
• Sofosbuvir-based combinations (e.g., Sofosbuvir/Ledipasvir, Glecaprevir/Pibrentasvir) are pangenotypic

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5. Antiviral Resistance

• Arises from mutations in viral targets (polymerase, TK, protease, integrase)
• Acyclovir resistance in HSV/VZV: usually TK mutations → cross-resistance to penciclovir/famciclovir/valacyclovir; foscarnet (TK-independent) remains active
• CMV resistance to ganciclovir: UL97 kinase mutations (most common) or UL54 DNA polymerase mutations
• Influenza resistance to oseltamivir: neuraminidase H275Y mutation — baloxavir remains active
• HIV resistance: Prevented by combination therapy; single-drug use rapidly selects resistant virus
• Azole resistance in Aspergillus: Emerging CYP51 mutations threaten utility of voriconazole, isavuconazole, posaconazole

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Summary Table: Antifungal Drug Classes

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