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Antifungal and Antiviral Agents: Clinical and Pharmacological Characteristics

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PART I — ANTIFUNGAL AGENTS

Drug Classes Overview

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1. Polyenes

Amphotericin B Deoxycholate (D-AmB)

• Mechanism: Binds ergosterol in the fungal cell membrane, forming pores that cause K⁺/Mg²⁺ leakage and cell death. Broad-spectrum fungicidal.
• Spectrum: Active against most Candida spp., Aspergillus, Cryptococcus, endemic fungi (histoplasma, coccidioides, blastomyces, paracoccidioides), Mucorales.
• Clinical uses: Induction therapy for cryptococcal meningitis (0.7–1 mg/kg/day IV + flucytosine for ≥2 weeks), invasive candidiasis, mucormycosis, salvage therapy.
• Pharmacokinetics: IV only; poor CSF penetration (intrathecal use occasionally needed); renal excretion.
• Toxicity: Infusion reactions (fever, rigors, hypotension), nephrotoxicity (dose-limiting), hypokalemia, hypomagnesemia, anemia. Premedication with diphenhydramine/acetaminophen and normal saline hydration reduce toxicity.

Lipid Formulations (L-AmB, ABLC, ABCD)

• Rationale: Preferential delivery to reticuloendothelial tissues; dramatically reduced nephrotoxicity.
• L-AmB (AmBisome): 3–5 mg/kg/day IV. Used as first-line alternative for aspergillosis, first-line in mucormycosis, and when renal toxicity precludes D-AmB. Single-dose L-AmB (10 mg/kg) plus flucytosine + fluconazole is as effective as longer D-AmB courses in cryptococcal meningitis in HIV patients.
• ABLC (Amphotericin B lipid complex): 5 mg/kg/day IV; used for salvage in aspergillosis and mucormycosis.

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2. Azoles

Fluconazole

• Spectrum: Candida albicans, C. parapsilosis, C. tropicalis, Cryptococcus spp. Intrinsically resistant: C. krusei; variable C. glabrata.
• Clinical uses: Oropharyngeal/esophageal/vaginal candidiasis; consolidation and suppression of cryptococcal meningitis (400 mg/day consolidation ×8 weeks, then 200 mg/day suppression ×6–12 months); step-down after amphotericin B in invasive candidiasis.
• Pharmacokinetics: Excellent oral bioavailability (~90%); good CNS penetration; renal excretion; minimal CYP3A4 interaction (mainly CYP2C9).
• Toxicity: Generally well tolerated. Hepatotoxicity (rare); QTc prolongation at high doses.

Itraconazole

• Spectrum: Broader than fluconazole; active against Aspergillus, endemic fungi (histoplasma, blastomyces, sporotrichosis, onychomycosis), Candida.
• Clinical uses: Endemic mycoses (histoplasmosis, blastomycosis, sporotrichosis), onychomycosis, ABPA (allergic bronchopulmonary aspergillosis), salvage aspergillosis (400 mg/day capsule or 2.5 mg/kg/day solution q12h).
• Pharmacokinetics: Capsule absorption requires food and acid; oral solution has better bioavailability (taken fasted). Poor CNS penetration. Strongly inhibits CYP3A4.
• Toxicity: Hepatotoxicity, negative inotropy (heart failure), peripheral neuropathy, hypertension, hypokalemia.

Voriconazole

• Spectrum: Broadest azole: Aspergillus (including many triazole-susceptible strains), Candida spp., Fusarium, Scedosporium, Cryptococcus, endemic fungi. Not active against Mucorales (potential antagonism).
• Clinical uses: Drug of choice for invasive aspergillosis (IV 6 mg/kg q12h × 2 doses loading, then 4 mg/kg q12h; oral 4 mg/kg or 200–300 mg BID). Also used in Fusarium, Scedosporium, and salvage CNS fungal infections.
• Pharmacokinetics: Non-linear kinetics; hepatic metabolism (CYP2C19 polymorphisms affect levels significantly). Oral bioavailability ~96%; good CNS penetration. IV formulation contains cyclodextrin vehicle — avoid in renal failure.
• Toxicity: Visual disturbances (photopsia, color changes — most distinctive side effect), hepatotoxicity (avoid in elevated LFTs), phototoxicity/squamous cell skin cancer with prolonged use, QTc prolongation, hallucinations/encephalopathy.
• Contraindications: Prolonged QTc; substantially elevated hepatic aminotransferases.

Isavuconazole (Isavuconazonium prodrug)

• Spectrum: Similar to voriconazole + active against Mucorales (making it unique among azoles for mucormycosis).
• Clinical uses: First-line alternative or equivalent to voriconazole for invasive aspergillosis (IV/oral 372 mg q8h × 6 doses, then 372 mg q24h). Approved for mucormycosis.
• Advantages over voriconazole: More predictable pharmacokinetics (no CYP2C19 polymorphism effect), fewer drug-related adverse events, no cyclodextrin vehicle (safer in renal failure), shortens the QTc (does not prolong it).
• Toxicity: Hepatotoxicity; generally better tolerated than voriconazole.

Posaconazole

• Spectrum: Broadest of all azoles: Aspergillus, Candida, Mucorales, endemic fungi, Fusarium.
• Clinical uses: Prophylaxis in hematological malignancy/HSCT (high-risk neutropenia); invasive aspergillosis (non-inferior to voriconazole, less toxic); mucormycosis (with or after amphotericin B). Dose: 300 mg IV/oral delayed-release tablet q12h day 1, then 300 mg daily.
• Toxicity: Hepatotoxicity; QTc prolongation.

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3. Echinocandins

• Mechanism: Inhibit β-1,3-glucan synthase (encoded by FKS genes) → disruption of cell wall synthesis. Fungicidal against Candida, fungistatic against Aspergillus.
• Spectrum: Candida spp. (including C. glabrata, C. krusei, C. auris), Aspergillus spp. Not active: Cryptococcus neoformans, Mucorales, endemic dimorphic fungi.
• Resistance: FKS mutations → reduced susceptibility (relevant in C. glabrata).

• Pharmacokinetics: IV only (no oral form); minimal renal excretion (important advantage in azotemia); extensive protein binding; poor CNS penetration.
• Toxicity: Among the safest antifungals. Elevated LFTs (caspofungin, micafungin), histamine-like infusion reactions (anidulafungin at rapid infusion). Caspofungin dose-reduce in hepatic impairment.
• Clinical note: For invasive aspergillosis, combination of voriconazole + anidulafungin may reduce all-cause mortality vs. voriconazole monotherapy in hematologic malignancy/HSCT patients.

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4. Flucytosine (5-FC)

• Mechanism: Converted intracellularly to 5-fluorouracil → inhibits thymidylate synthase and incorporates into RNA, blocking DNA/RNA synthesis.
• Spectrum: Candida, Cryptococcus. Never used as monotherapy (rapid resistance emerges).
• Clinical uses: Combined with amphotericin B for cryptococcal meningitis (100 mg/kg/day in 4 divided doses). Adding flucytosine to amphotericin B significantly improves survival in HIV-positive cryptococcal meningitis compared to amphotericin B alone.
• Pharmacokinetics: Excellent oral bioavailability; excellent CSF penetration; renal excretion — dose-reduce in renal failure.
• Toxicity: Myelosuppression (leukopenia, thrombocytopenia — monitor CBC), hepatotoxicity, GI intolerance. Toxicity increases with elevated serum levels (target trough 25–100 µg/mL).

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Triazole Resistance

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PART II — ANTIVIRAL AGENTS

Drug Classes Overview

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1. Nucleoside Analogs — Herpesvirus Group

Acyclovir

• Mechanism: Guanosine analog. Selectively phosphorylated by viral thymidine kinase (TK) to acyclovir-monophosphate → then by cellular kinases to acyclovir-triphosphate → inhibits viral DNA polymerase and acts as a chain terminator. Minimal activation in uninfected cells → low host toxicity.
• Spectrum: HSV-1, HSV-2, VZV (10× less sensitive to acyclovir than HSV), EBV (partially).
• Clinical uses: Herpes labialis, genital herpes (treatment + suppression), herpes encephalitis (IV 10 mg/kg q8h), herpes zoster in immunocompromised, varicella prophylaxis/treatment.
• Pharmacokinetics: Oral bioavailability low (~20%) — limited by poor absorption. IV used for severe infection. Renal excretion — crystalluria/nephrotoxicity at high IV doses without adequate hydration.
• Toxicity: Generally safe. IV: crystalluria, nephrotoxicity, neurotoxicity (encephalopathy) at high doses. Teratogenicity low.

Valacyclovir

• Mechanism: L-valyl ester prodrug of acyclovir. Converted to acyclovir post-absorption by intestinal/hepatic valacyclovirase.
• Advantage: Oral bioavailability ~55% (3× that of acyclovir) → higher, sustained plasma acyclovir levels → less frequent dosing (BID or TID vs. 5× daily).
• Uses: Preferred over oral acyclovir for herpes zoster, recurrent genital herpes, and HSV suppression. Dose: 1 g TID × 7 days for zoster; 500 mg BID for genital herpes suppression.
• Toxicity: Similar to acyclovir. Thrombotic thrombocytopenic purpura (TTP)/HUS at very high doses in immunocompromised (rare).

Famciclovir / Penciclovir

• Famciclovir is the oral prodrug of penciclovir (a nucleoside analog similar to acyclovir). Converted enzymatically after absorption.
• Mechanism: Activated by viral TK → penciclovir-triphosphate inhibits viral DNA polymerase.
• Advantages: Higher intracellular stability (longer half-life in infected cells than acyclovir-TP); equivalent antiviral efficacy. Superior to oral acyclovir for VZV (VZV is 10× less sensitive to acyclovir than HSV).
• Preferred over acyclovir for oral therapy of VZV (herpes zoster, varicella in immunocompromised).

Resistance Pattern (HSV/VZV)

• Foscarnet (does not require TK activation — first choice)
• Amenamevir (helicase-primase inhibitor — active against TK-mutant strains)
• Cidofovir (direct DNA polymerase inhibitor; third-line due to toxicity)

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2. Foscarnet (Pyrophosphate Analog)

• Mechanism: Analog of inorganic pyrophosphate. Directly inhibits viral DNA polymerase at the pyrophosphate-binding site without requiring phosphorylation by TK. Does not need cellular activation.
• Spectrum: All herpesviruses (HSV-1, HSV-2, VZV, CMV, EBV, HHV-6, HHV-8). Active against acyclovir-resistant VZV/HSV (TK-mutants). Also active against HIV.
• Clinical uses: Acyclovir-resistant HSV/VZV (especially in HIV/immunocompromised); CMV retinitis/disease in HIV; ganciclovir-resistant CMV.
• Pharmacokinetics: IV only; renal excretion; penetrates CSF.
• Toxicity: Nephrotoxicity (major dose-limiting — requires aggressive IV hydration); electrolyte dysregulation (↓Ca²⁺, ↓Mg²⁺, ↓PO₄, ↓K⁺ — can cause seizures); penile/vulvar ulceration; anemia.

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3. Anti-Influenza Agents

Neuraminidase Inhibitors (NAIs)

• Agents: Oseltamivir (oral), Zanamivir (inhaled), Peramivir (IV)
• Mechanism: Inhibit viral neuraminidase → prevent cleavage of sialic acid → block release of newly formed virions from infected cells → limit viral spread.
• Spectrum: Influenza A and B (unlike adamantanes).
• Clinical use: Treatment (within 48 hours of symptom onset) and prophylaxis of influenza A and B. Oseltamivir 75 mg BID × 5 days (treatment); 75 mg daily × 10 days (prophylaxis). Zanamivir is inhaled BID — avoid in asthma/COPD.
• Resistance: Mutations in the neuraminidase gene (H275Y in H1N1 → oseltamivir resistance). Zanamivir remains active against many oseltamivir-resistant strains.
• Toxicity: Oseltamivir: nausea/vomiting (take with food). Zanamivir: bronchospasm.

Adamantanes

• Agents: Amantadine, Rimantadine
• Mechanism: Block the M2 ion channel of influenza A → prevent viral uncoating and entry into host cell cytoplasm. M2 channel facilitates proton influx needed for ribonucleoprotein release. Not active against influenza B (which lacks M2 protein).
• Resistance: Emerges rapidly (especially in children; prolonged shedding in immunocompromised). Near-universal resistance in influenza A/H3N2 since early 2000s — no longer recommended for influenza A treatment in most guidelines.
• Toxicity: Amantadine: CNS effects (insomnia, confusion, dizziness — especially in elderly); anticholinergic effects; renal excretion — reduce dose in renal failure. Rimantadine: fewer CNS effects.

Baloxavir Marboxil

• Mechanism: Cap-dependent endonuclease inhibitor — interferes with viral RNA transcription by blocking the "cap-snatching" step essential for viral mRNA synthesis. Active against influenza A and B.
• Clinical use: Single oral dose (40 mg if <80 kg; 80 mg if ≥80 kg) within 48 hours of symptoms. As effective as oseltamivir with single-dose convenience.
• Resistance: I38T/F mutations in PA gene; cross-resistance does not affect NAIs or adamantanes.

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4. Anti-Herpetic Agents — CMV

Ganciclovir / Valganciclovir

• Mechanism: Guanosine analog; phosphorylated by CMV UL97 kinase (and then cellular kinases) → inhibits CMV DNA polymerase. Also activated by HSV TK. More active against CMV than acyclovir.
• Clinical uses: CMV retinitis, pneumonitis, colitis, encephalitis in immunocompromised (transplant, AIDS); CMV prophylaxis in HSCT/solid organ transplant.
• Valganciclovir: Oral prodrug with ~60% bioavailability → equivalent to IV ganciclovir.
• Toxicity: Bone marrow suppression (neutropenia, thrombocytopenia — major dose-limiting); nephrotoxicity; teratogenic/carcinogenic in animals (use caution in reproductive-age patients).
• Resistance: UL97 mutations (most common) or UL54 (DNA polymerase) mutations. UL97 mutants remain susceptible to foscarnet/cidofovir.

Cidofovir

• Mechanism: Nucleotide analog of cytosine; directly inhibits viral DNA polymerase (does not require viral TK activation — active against TK-mutant strains).
• Uses: CMV retinitis (when ganciclovir/foscarnet fail); acyclovir-resistant HSV (third-line); BK virus nephropathy in renal transplant.
• Toxicity: Severe nephrotoxicity (requires probenecid + IV saline prehydration); uveitis; neutropenia.

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5. Novel Antiviral Agent — Amenamevir

• Mechanism: Helicase-primase inhibitor — blocks the viral helicase-primase complex essential for HSV/VZV DNA replication. Does not require TK activation.
• Key advantage: Active against acyclovir-resistant VZV and HSV (TK-mutant strains). Single dose 400 mg/day for herpes zoster was as effective and well-tolerated as valacyclovir 1 g TID in Japanese trials.
• Status: Approved in Japan; investigational in the US.

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Summary Comparison Table

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• Amphotericin B remains the cornerstone induction agent for cryptococcal meningitis and mucormycosis; lipid formulations are preferred when renal function is compromised.
• Voriconazole or isavuconazole is first-line for invasive aspergillosis; isavuconazole is preferred in patients with QTc prolongation or renal failure.
• Echinocandins are the safest class and preferred empiric/first-line therapy for invasive candidiasis, but have no role in cryptococcosis.
• Flucytosine must always be combined with amphotericin B (never monotherapy) for cryptococcal meningitis.
• Acyclovir resistance in HSV/VZV is treated with foscarnet (which bypasses TK requirement); amenamevir is a promising alternative.
• Adamantanes are no longer clinically useful for influenza due to widespread resistance; NAIs (oseltamivir) and baloxavir are the current standard of care.