Amantadine and rimantadine block M2 proton channel → prevent viral uncoating. Influenza A only — B lacks M2. OBSOLETE: S31N resistance is universal in current H3N2 and pandemic H1N1 strains. Do not use for influenza treatment or prophylaxis. Amantadine retains non-antiviral uses: Parkinson's disease, drug-induced extrapyramidal symptoms.
Transition-state analogues — competitively inhibit NA active site → virions remain tethered to cell surface. Active against influenza A and B. Oseltamivir: oral prodrug, renal dose adjustment (CrCl <30). Zanamivir: inhaled; avoid in asthma/COPD (bronchospasm risk). Peramivir: IV single dose for hospitalized patients. Start within 48 hours of symptom onset.
Baloxavir acid inhibits cap-dependent endonuclease (CEN) of PA subunit → blocks cap-snatching → halts all viral mRNA transcription. Single oral dose (40 mg <80 kg; 80 mg >80 kg). Active against influenza A and B. Active against oseltamivir-resistant strains (H275Y). Resistance: PA-I38T/F/M → reduces baloxavir binding. Approved treatment and post-exposure prophylaxis.
H275Y in N1 neuraminidase: high-level oseltamivir resistance, largely preserved zanamivir susceptibility. Structural basis: oseltamivir requires rotation of Glu276 in the N1 binding pocket; H275Y sterically blocks this rotation while zanamivir does not depend on it. Spread globally without drug selection pressure (2008–2009 seasonal H1N1 epidemic) — demonstrates resistant strains can transmit efficiently.
Management of H275Y oseltamivir resistance: switch to zanamivir (inhaled) or IV peramivir. Baloxavir retains full activity.
PA-I38T/F/M: reduce baloxavir acid affinity for CEN active site → prolonged shedding, slower symptom resolution. Emergence rate: ~2–9% in adults, up to 23% in children in some studies. PA-I38 variants retain full neuraminidase inhibitor susceptibility. Fitness cost: moderate → limits but does not prevent community spread. Management: neuraminidase inhibitors if baloxavir resistance confirmed or suspected. Combination baloxavir + oseltamivir: under investigation for severe influenza.
Nirsevimab (Beyfortus): long-acting mAb targeting prefusion F protein epitope; single IM injection per RSV season; ~74–83% efficacy. ACIP-recommended for all infants <8 months entering first RSV season. Extended half-life Fc engineering provides season-long protection from one dose.
Palivizumab: now reserved for high-risk groups — gestational age ≤28 weeks (first year), chronic lung disease of prematurity, hemodynamically significant congenital heart disease. Monthly IM injections (15 mg/kg) during RSV season; ~55% reduction in RSV hospitalization.
Ribavirin: broad-spectrum nucleoside analogue; inhibits IMPDH (depletes GTP), inhibits viral RdRp, lethal mutagenesis. Inhaled via SPAG-2 device. Weak evidence of benefit in otherwise healthy infants → largely abandoned in pediatric RSV. Reserved for immunocompromised patients with severe RSV lower respiratory tract disease (especially HSCT recipients — observational benefit). Teratogenic: healthcare workers of childbearing potential require respiratory protection.
Nirmatrelvir: peptidomimetic inhibitor of SARS-CoV-2 main protease (Mpro/3CLpro) → blocks polyprotein cleavage → halts viral replication. Ritonavir: CYP3A4/P-gp inhibitor — pharmacokinetic booster only; no antiviral activity at this dose. Oral 5-day course. EPIC-HR trial: 89% reduction in hospitalization or death in high-risk unvaccinated adults treated within 3 days. Critical interactions: raises concentrations of all CYP3A4 substrates — tacrolimus, cyclosporine, simvastatin, lovastatin, many anticoagulants. COVID-19 rebound reported after completing course.
Phosphoramidate prodrug of adenosine analogue → activated to triphosphate → delayed chain termination of viral RdRp. Broad-spectrum RNA virus activity. IV administration only (except 3-day outpatient course for high-risk COVID-19). Clinical benefit in COVID-19: greatest in hospitalized patients on low-flow oxygen not yet requiring mechanical ventilation. Also investigated for RSV and other RNA respiratory virus infections.
RNA respiratory viruses (influenza, SARS-CoV-2) use error-prone RdRp → every possible single-nucleotide mutation generated many times daily within one infected host. Resistant variants pre-exist before drug exposure; selection amplifies them. Fitness cost of resistance mutation determines whether resistant strains spread in the community. Low fitness cost (influenza S31N) → global spread without drug pressure. Moderate fitness cost (baloxavir PA-I38T) → limited spread. Implication: stockpile mechanistically diverse agents; establish resistance surveillance before widespread deployment.