## Mechanism and Clinical Use **Key Point:** Acyclovir is a guanosine analogue that requires viral thymidine kinase (TK) for activation, making it highly selective for HSV-infected cells. ### Activation Pathway 1. Acyclovir enters the cell 2. Viral thymidine kinase phosphorylates it to acyclovir monophosphate 3. Cellular enzymes convert it to acyclovir triphosphate 4. Triphosphate inhibits viral DNA polymerase and causes chain termination **High-Yield:** Acyclovir is the **gold standard** for HSV encephalitis because: - Excellent CNS penetration (crosses blood-brain barrier) - High selectivity for HSV-infected cells - Low toxicity profile - Intravenous formulation available for severe infections **Clinical Pearl:** HSV encephalitis is a medical emergency requiring immediate IV acyclovir 10–15 mg/kg every 8 hours. Delay in treatment increases morbidity and mortality. ### Why Other Agents Are Not First-Line | Agent | Limitation | |-------|------------| | Ganciclovir | Used for CMV; requires TK activation; more toxic | | Foscarnet | Reserved for TK-deficient HSV; requires dose adjustment in renal impairment | | Cidofovir | Used for CMV retinitis; nephrotoxic; not first-line for HSV | **Mnemonic:** **ACY-clovir for HSV** — think "Acyclic" guanosine for herpes simplex.
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