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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