Clinical and pharmacological characteristics of antifungal and antiviral agents. Pharmacology

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Antifungal and Antiviral Agents: Clinical and Pharmacological Characteristics

PART I: ANTIFUNGAL AGENTS

Classification

Antifungal drugs are grouped by mechanism of action:

Class	Examples
Polyenes	Amphotericin B, Nystatin
Azoles	Fluconazole, Itraconazole, Voriconazole, Posaconazole, Isavuconazole
Echinocandins	Caspofungin, Anidulafungin, Micafungin
Pyrimidine analogs	Flucytosine (5-FC)
Allylamines	Terbinafine

1. Polyenes — Amphotericin B

Mechanism: Binds to ergosterol in the fungal cell membrane → forms transmembrane channels → leakage of intracellular ions (K⁺, Mg²⁺) → cell death. Also causes oxidative damage to the membrane.

Spectrum: Broad — active against Candida, Aspergillus, Cryptococcus neoformans, Histoplasma, Coccidioides, Blastomyces, Mucor.

Formulations:

Deoxycholate (conventional): IV infusion; nephrotoxic (dose-limiting)
Lipid formulations (liposomal, lipid complex, colloidal dispersion): less nephrotoxic, allow higher dosing; preferred when renal impairment is present

Clinical uses:

Cryptococcal meningitis: induction with amphotericin B (0.7–1 mg/kg/day) + flucytosine × ≥2 weeks
Invasive candidiasis, invasive aspergillosis (second-line), mucormycosis
Empirical therapy in febrile neutropenia

Adverse effects:

Nephrotoxicity (most significant; renal tubular acidosis, hypokalemia, hypomagnesemia)
Infusion reactions: fever, chills, rigors, hypotension (can premedicate with antipyretics, antihistamines, meperidine for rigors)
Anemia (reduced erythropoietin), thrombophlebitis

Note: Liposomal amphotericin B (L-AmB) at 3 mg/kg/day is comparable in efficacy to 10 mg/kg/day for invasive aspergillosis while reducing toxicity. — Goldman-Cecil Medicine

2. Azoles

Mechanism: Inhibit 14α-demethylase (CYP51), a fungal cytochrome P450 enzyme → block conversion of lanosterol to ergosterol → depleted ergosterol + accumulation of toxic methylated sterols → membrane disruption.

Fluconazole

Spectrum: Candida spp. (not C. krusei, reduced activity vs. C. glabrata), Cryptococcus
PK: Excellent oral bioavailability (~90%), good CSF penetration, renal excretion
Uses: Oropharyngeal/esophageal/vulvovaginal candidiasis; consolidation/suppression in cryptococcal meningitis (400 mg/day then 200 mg/day); prophylaxis in immunocompromised
Adverse effects: Hepatotoxicity, nausea, rash; teratogenic in high doses; QT prolongation; inhibits CYP2C9/CYP3A4 → multiple drug interactions

Itraconazole

Spectrum: Broader than fluconazole; adds Aspergillus, endemic fungi (Histoplasma, Blastomyces, Sporothrix)
PK: Variable oral absorption (capsule requires acidic environment; solution better absorbed); does not penetrate CSF well; hepatic metabolism
Uses: Histoplasmosis, blastomycosis, paracoccidioidomycosis, onychomycosis, dermatophytosis
Adverse effects: Negative inotropic effect (contraindicated in heart failure), peripheral edema, hepatotoxicity, drug interactions via CYP3A4

Voriconazole

Spectrum: Broad; excellent anti-Aspergillus activity; active vs. Fusarium, Scedosporium; not active vs. Mucor
PK: IV and oral; non-linear pharmacokinetics; hepatic metabolism (CYP2C19 polymorphisms cause wide inter-individual variation); TDM recommended
Uses: Drug of choice for invasive aspergillosis (superior to deoxycholate amphotericin B in RCT)
Adverse effects: Visual disturbances (transient photopsia — very common), hepatotoxicity, photosensitivity/squamous cell carcinoma with prolonged use, QT prolongation; avoid in severe hepatic dysfunction and significantly elevated transaminases
Note: Should not be used in Mucor infections — Goldman-Cecil Medicine

Posaconazole

Spectrum: Broadest azole; active vs. Aspergillus, Mucor, Fusarium, Candida
Uses: Prophylaxis in neutropenic patients and HSCT recipients; salvage therapy for invasive aspergillosis; mucormycosis
PK: Oral (suspension requires fatty meal for absorption; tablet/delayed-release formulation more reliable); IV available
Adverse effects: Generally well tolerated; QT prolongation; hepatotoxicity; less CYP3A4 inhibition than itraconazole
Noninferior to voriconazole for all-cause mortality in invasive aspergillosis with less toxicity — Goldman-Cecil Medicine

Isavuconazole

Spectrum: Similar to voriconazole + active vs. Mucor
Uses: Invasive aspergillosis (non-inferior to voriconazole); mucormycosis
Advantages: More predictable pharmacokinetics, fewer adverse effects, no QT prolongation (actually shortens QTc slightly), available IV and oral
Increasingly considered as potential first-line treatment for invasive aspergillosis — Goldman-Cecil Medicine

3. Echinocandins

Mechanism: Inhibit β-(1,3)-glucan synthase → impair synthesis of β-glucan, an essential fungal cell wall component → osmotic instability → cell lysis. This target is absent in mammalian cells → excellent tolerability.

Drugs: Caspofungin, anidulafungin, micafungin

Spectrum: Candida spp. (including azole-resistant strains, C. glabrata, C. krusei), Aspergillus (fungistatic); not active vs. Cryptococcus neoformans, Fusarium, or Mucor

PK: IV only (poor oral bioavailability); do not penetrate CSF

Clinical uses:

Invasive candidiasis / candidemia (first-line in critically ill)
Salvage therapy for invasive aspergillosis (caspofungin is the only echinocandin licensed for this)
Combination voriconazole + anidulafungin may reduce 6-week mortality in aspergillosis in hematologic malignancy patients — Goldman-Cecil Medicine

Adverse effects: Generally very well tolerated; mild hepatic enzyme elevations; histamine-mediated infusion reactions (rare); minimal drug interactions

4. Flucytosine (5-Fluorocytosine)

Mechanism: Prodrug → converted intracellularly to 5-fluorouracil (5-FU) by fungal cytosine deaminase → inhibits thymidylate synthase (DNA synthesis) and RNA synthesis. Selective for fungi because mammalian cells lack cytosine deaminase.

Spectrum: Candida, Cryptococcus; not used as monotherapy (rapid resistance emergence)

Uses: Always in combination — primarily with amphotericin B for cryptococcal meningitis (induction phase); used with fluconazole in resource-limited settings

Adverse effects: Bone marrow suppression (leukopenia, thrombocytopenia), hepatotoxicity, GI toxicity (nausea, diarrhea); dose-adjust in renal impairment; monitor serum levels

5. Allylamines — Terbinafine

Mechanism: Inhibits squalene epoxidase → blocks ergosterol biosynthesis at an earlier step than azoles → accumulation of toxic squalene + ergosterol depletion → fungal cell death

Spectrum: Excellent against dermatophytes (Trichophyton, Microsporum, Epidermophyton); variable vs. Candida

Uses: Onychomycosis (drug of choice — 250 mg/day × 6–12 weeks), tinea corporis, tinea pedis, tinea capitis

Adverse effects: GI symptoms, taste disturbances, headache; rare: hepatotoxicity (monitor LFTs), serious skin reactions (SJS/TEN); no CYP3A4 inhibition (unlike azoles)

Antifungal Drug Resistance

Azole resistance in Aspergillus: Emerging resistance to triazoles (voriconazole, isavuconazole, posaconazole) — a growing threat to anti-Aspergillus therapy
Candida auris: Intrinsically resistant to fluconazole, sometimes multi-drug resistant including echinocandins

PART II: ANTIVIRAL AGENTS

Classification

Class	Examples
Neuraminidase inhibitors	Oseltamivir, Zanamivir, Peramivir
Nucleoside analogs (herpes)	Acyclovir, Valacyclovir, Famciclovir/Penciclovir, Ganciclovir, Valganciclovir
Pyrophosphate analogs	Foscarnet
Nucleotide analogs	Cidofovir, Brincidofovir
Antiretrovirals (HIV)	NRTIs, NNRTIs, PIs, INSTIs, Entry Inhibitors
Anti-influenza	Baloxavir, Amantadine/Rimantadine
Anti-HBV/HCV	Entecavir, Tenofovir, DAAs (Sofosbuvir, etc.)
COVID-19	Nirmatrelvir/ritonavir, Remdesivir, Molnupiravir

1. Neuraminidase Inhibitors (Influenza)

Drugs: Oseltamivir (Tamiflu), Zanamivir (Relenza), Peramivir (Rapivab)

Mechanism: Influenza neuraminidase cleaves sialic acid residues on the host cell surface, allowing release of new virions. These drugs selectively inhibit neuraminidase → virions remain trapped on cell surface → block cell-to-cell spread — Lippincott Pharmacology

Active against: Influenza A and B; do not interfere with influenza vaccine immunogenicity

Pharmacokinetics:

Drug	Route	Notes
Oseltamivir	Oral (prodrug)	Rapidly hydrolyzed by liver to active form; renal elimination
Zanamivir	Inhaled	Not orally active; renal elimination
Peramivir	IV infusion	Single dose; renal elimination

Clinical use: Reduce symptom duration by ~1 day when given within 24–48 hours of symptom onset; important for high-risk patients (elderly, immunocompromised, cardiopulmonary disease)

Adverse effects:

Oseltamivir: nausea, vomiting (take with food)
Zanamivir: bronchospasm (avoid in asthma/COPD)
Peramivir: diarrhea

Resistance: Mutations in neuraminidase (H275Y in H1N1 for oseltamivir)

2. Baloxavir Marboxil (Cap-Snatching Inhibitor)

Mechanism: Inhibits cap-dependent endonuclease of influenza polymerase acidic (PA) protein → blocks viral mRNA transcription — distinct mechanism from neuraminidase inhibitors

Use: Single oral dose for uncomplicated influenza A or B; active against some oseltamivir-resistant strains

3. Nucleoside Analogs — Herpesvirus Agents

Acyclovir (and Valacyclovir)

Mechanism (3-step activation):

Viral thymidine kinase (TK) phosphorylates acyclovir → acyclovir monophosphate (selective activation in infected cells only)
Cellular kinases → acyclovir triphosphate
Acyclovir-TP inhibits viral DNA polymerase (competitive inhibitor + chain terminator — lacks 3'-OH) — Lippincott Pharmacology

Selectivity key: Acyclovir is a poor substrate for cellular thymidine kinase → not activated in uninfected cells → low host toxicity

Spectrum: HSV-1, HSV-2, VZV (VZV ~10× less sensitive than HSV); EBV (limited); CMV (limited — lacks efficient TK)

PK: Oral bioavailability ~20%; IV form for severe infections; distributes well including CSF; renal excretion (dose-adjust in renal failure)

Valacyclovir: L-valine ester prodrug → converted to acyclovir after absorption; oral bioavailability ~55% (3× higher than acyclovir) → achieves IV-like levels orally

Uses:

Genital HSV (treatment and suppression)
HSV encephalitis (high-dose IV acyclovir)
VZV (herpes zoster, varicella in immunocompromised)
HSV prophylaxis in immunocompromised
Valacyclovir preferred over acyclovir for VZV (better PK, VZV less sensitive to acyclovir) — Fitzpatrick's Dermatology

Adverse effects: Oral — headache, nausea, diarrhea; IV — transient renal dysfunction (crystalluria; hydrate well), neurotoxicity at high doses

Resistance: Mutations in viral TK gene → cross-resistant to valacyclovir, famciclovir, penciclovir, ganciclovir; use foscarnet for resistant strains — Fitzpatrick's Dermatology

Famciclovir / Penciclovir

Mechanism: Famciclovir is a prodrug converted to penciclovir after absorption. Penciclovir is a guanosine analog; same activation mechanism as acyclovir (viral TK → cellular kinases → triphosphate → viral DNA polymerase inhibition)

Advantages over acyclovir:

Superior oral bioavailability (famciclovir)
Higher intracellular concentration of penciclovir-TP with longer intracellular half-life
Preferred for oral VZV treatment — Fitzpatrick's Dermatology

Uses: Herpes zoster, genital HSV

Ganciclovir / Valganciclovir

Mechanism: Same as acyclovir but phosphorylated by CMV-encoded UL97 kinase (instead of viral TK) → active vs. CMV

Spectrum: CMV (primary indication), HSV, VZV

Uses: CMV retinitis, CMV disease in transplant recipients; CMV prophylaxis

Valganciclovir: oral prodrug of ganciclovir; largely replaced IV ganciclovir for CMV treatment/prophylaxis

Adverse effects (major):

Myelosuppression (neutropenia, thrombocytopenia) — dose-limiting; monitor CBC
Nephrotoxicity; teratogenic and carcinogenic in animals
Avoid with zidovudine (additive bone marrow suppression)

4. Foscarnet

Mechanism: Pyrophosphate analog; does NOT require phosphorylation by viral TK. Directly inhibits viral DNA polymerases and reverse transcriptases at the pyrophosphate-binding site at concentrations that spare cellular DNA polymerases — Lippincott Pharmacology / Fitzpatrick's

Spectrum: All herpesviruses (HSV, VZV, CMV, EBV, HHV-6); HIV reverse transcriptase

Critical use: TK-deficient/acyclovir-resistant HSV and VZV (since these strains have mutant TK, foscarnet remains active) — Fitzpatrick's Dermatology; CMV retinitis (alternative to ganciclovir)

PK: IV only; excreted renally unchanged; deposits in bone

Adverse effects:

Nephrotoxicity (major; reversible; hydrate aggressively)
Electrolyte abnormalities: hypocalcemia, hypomagnesemia, hypokalemia, hypophosphatemia → seizures, cardiac arrhythmias
Penile/vulvar ulceration (due to high urine concentration)
More toxic than nucleoside analogs → reserved for resistant infections

5. Cidofovir

Mechanism: Nucleotide analog of cytosine; does NOT require viral kinase activation (already phosphorylated) → direct inhibition of viral DNA polymerase

Spectrum: CMV, HSV (including acyclovir-resistant), adenovirus, poxvirus

Uses: CMV retinitis in AIDS patients; acyclovir-resistant HSV/VZV

PK: IV; active metabolite has very long intracellular half-life → weekly or biweekly dosing

Adverse effects:

Severe nephrotoxicity (proximal tubular injury) — contraindicated with pre-existing renal impairment or other nephrotoxic drugs
Neutropenia, metabolic acidosis
Probenecid + IV saline coadministered to reduce nephrotoxicity — Lippincott Pharmacology

6. Antiretrovirals (HIV)

HIV therapy employs combination antiretroviral therapy (ART). Key classes:

NRTIs (Nucleoside/Nucleotide Reverse Transcriptase Inhibitors)

Examples: Zidovudine (AZT), Lamivudine, Emtricitabine, Tenofovir, Abacavir, Stavudine
Mechanism: After intracellular phosphorylation → compete with natural dNTPs → incorporated into viral DNA → chain termination (lack 3'-OH) → inhibit HIV reverse transcriptase
Key toxicities:
- Zidovudine: bone marrow suppression, myopathy, lactic acidosis
- Tenofovir (TDF): nephrotoxicity, bone density loss
- Abacavir: hypersensitivity reaction (HLA-B*5701 screening required)
- Class effect: mitochondrial toxicity (lactic acidosis/hepatic steatosis)

NNRTIs (Non-Nucleoside RTIs)

Examples: Efavirenz, Nevirapine, Rilpivirine, Doravirine
Mechanism: Bind allosteric site on reverse transcriptase (non-competitive) → conformational change → inhibit RT without requiring phosphorylation; no chain termination
Key toxicities:
- Efavirenz: CNS effects (vivid dreams, dizziness), teratogenic (avoid 1st trimester), induces CYP3A4
- Nevirapine: severe hepatotoxicity, Stevens-Johnson syndrome
- CYP450 interactions: nevirapine/efavirenz are inducers; rilpivirine is a substrate

PIs (Protease Inhibitors)

Examples: Atazanavir, Darunavir, Lopinavir/ritonavir
Mechanism: Bind HIV aspartyl protease → prevent cleavage of gag-pol polyprotein → immature, non-infectious virions
Key toxicities:
- Metabolic: lipodystrophy, hyperlipidemia, insulin resistance
- GI: nausea, diarrhea
- Atazanavir: hyperbilirubinemia (benign, indirect via UGT inhibition)
- Tipranavir: severe hepatotoxicity, intracranial hemorrhage
- Ritonavir: potent CYP3A4 inhibitor → used as pharmacokinetic "booster" for other PIs at sub-therapeutic doses — Lippincott Pharmacology

INSTIs (Integrase Strand Transfer Inhibitors)

Examples: Raltegravir, Elvitegravir, Dolutegravir, Bictegravir
Mechanism: Block HIV integrase → prevent integration of viral cDNA into host genome
Advantages: Excellent tolerability, high barrier to resistance (dolutegravir, bictegravir), minimal drug interactions
Dolutegravir: preferred in current WHO first-line regimens

Entry Inhibitors

Maraviroc (CCR5 antagonist): Blocks CCR5 coreceptor on host T cells → prevents HIV gp120 binding; only for CCR5-tropic virus (tropism testing required)
Enfuvirtide (T-20): Fusion inhibitor; binds HIV gp41 → prevents membrane fusion; SC injection only; injection site reactions
Fostemsavir (attachment inhibitor): Prodrug → temsavir binds HIV gp120 → prevents CD4 receptor attachment; for multi-drug resistant HIV

7. Brivudin

Thymidine analog; activated by VZV TK; very high activity against VZV (superior to acyclovir for herpes zoster)
Not licensed in the US
Contraindication: potentially lethal interaction with 5-fluorouracil (both metabolized by dihydropyrimidine dehydrogenase; enzyme saturation) — Fitzpatrick's Dermatology

8. Newer Agents

Amenamevir

Mechanism: Helicase-primase inhibitor → inhibits viral DNA unwinding/replication; distinct from nucleoside analogs
Active against acyclovir-resistant VZV and HSV (different target — does not depend on TK)
Single daily dose 400 mg — non-inferior to valacyclovir 1 g TID for herpes zoster — Fitzpatrick's Dermatology

COVID-19 Antivirals

Nirmatrelvir/ritonavir (Paxlovid): Nirmatrelvir inhibits SARS-CoV-2 main protease (Mpro) → prevents viral polyprotein processing; ritonavir boosts levels via CYP3A4 inhibition
Remdesivir: Nucleotide analog → inhibits RNA-dependent RNA polymerase → premature chain termination; IV
Molnupiravir: Induces viral RNA mutagenesis via ribonucleoside analog incorporation

Summary Comparison Table

Antifungals

Drug	Target	Spectrum	Key Toxicity
Amphotericin B	Ergosterol (membrane)	Broad (most fungi)	Nephrotoxicity, infusion reactions
Fluconazole	14α-demethylase	Candida, Crypto	Hepatotoxicity, drug interactions
Voriconazole	14α-demethylase	Aspergillus, Candida, Fusarium	Visual disturbances, hepatotoxicity, QT
Posaconazole	14α-demethylase	Broadest azole + Mucor	QT prolongation
Isavuconazole	14α-demethylase	Aspergillus + Mucor	Shortens QTc; fewer adverse effects
Echinocandins	β-1,3-glucan synthase	Candida, Aspergillus	Excellent tolerability
Flucytosine	DNA/RNA synthesis	Candida, Crypto	Bone marrow suppression (always combine)
Terbinafine	Squalene epoxidase	Dermatophytes	GI, taste, hepatotoxicity

Antivirals

Drug	Target	Spectrum	Key Toxicity
Acyclovir/Valacyclovir	Viral DNA polymerase (TK-dependent)	HSV, VZV	Renal crystalluria (IV)
Ganciclovir/Valganciclovir	Viral DNA polymerase (UL97-dependent)	CMV	Myelosuppression
Foscarnet	DNA pol / RT (pyrophosphate site)	HSV, VZV, CMV, HIV	Nephrotoxicity, electrolyte disturbances
Cidofovir	Viral DNA polymerase (no kinase needed)	CMV, HSV	Severe nephrotoxicity
Oseltamivir	Neuraminidase	Influenza A+B	Nausea/vomiting
NRTIs	HIV reverse transcriptase	HIV	Mitochondrial toxicity
NNRTIs	HIV RT (allosteric)	HIV	CNS (efavirenz), hepatotoxicity
PIs	HIV protease	HIV	Metabolic syndrome, drug interactions
INSTIs	HIV integrase	HIV	Well tolerated; drug of choice
Maraviroc	CCR5 coreceptor	HIV (CCR5-tropic)	Hepatotoxicity, tropism test required

Sources:

Lippincott Illustrated Reviews: Pharmacology
Goldman-Cecil Medicine, International Edition
Fitzpatrick's Dermatology, Volume 1–2

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