Acyclovir Dosing for Viral Meningitis
Critical Distinction: Meningitis vs. Encephalitis
For immunocompetent adults with confirmed HSV-2 meningitis presenting with isolated headache, photophobia, fever, and meningismus—but normal mental status—supportive care alone (analgesia and IV fluids) is recommended without acyclovir, as these patients recover completely without neurologic sequelae. 1, 2
However, this recommendation diverges sharply from standard practice:
- UK Joint Specialist Societies explicitly state no antiviral treatment is needed for pure HSV meningitis in immunocompetent adults because no evidence supports benefit and outcomes are excellent with supportive care alone 1
- US-based guidelines (IDSA, AAP, CDC) recommend treatment despite acknowledging the same evidence gap, reflecting a more aggressive approach 1
- Immunocompromised patients have significantly worse outcomes and must receive antiviral therapy—neurologic sequelae improved significantly with treatment in this population (P < 0.05) 2
When to Escalate Immediately to Full Encephalitis Treatment
Any patient with meningitis who develops encephalitic features—personality changes, behavioral changes, confusion, cognitive impairment, altered consciousness, seizures, or focal neurological deficits—requires immediate escalation to IV acyclovir 10 mg/kg every 8 hours for 14-21 days. 1 Untreated HSV encephalitis carries 70% mortality versus 20-30% with acyclovir 1, 3, making this distinction life-saving.
Standard Dosing Regimens
Adults (≥12 years)
- 10 mg/kg IV every 8 hours for 14-21 days with normal renal function 1, 4, 3
- Treatment should be started within 6 hours of admission if encephalitis is suspected, even before lumbar puncture results 1
- Early treatment (within 4 days of symptom onset) reduces mortality to 8% compared to 28% with delayed treatment 1
Children (3 months–12 years)
- 500 mg/m² IV every 8 hours (approximately 20 mg/kg) for a minimum of 21 days 1, 5
- The 21-day minimum is critical—shorter courses (10 days) led to relapse rates of 26-29% in children 1
- Body-surface-area dosing (500 mg/m²) is preferred over weight-based dosing in children >1 year 1
Neonates (birth–3 months)
- 20 mg/kg IV every 8 hours for 21 days 1, 4
- Higher dosing is required due to worse outcomes in this age group 1
Renal Dose Adjustments
Acyclovir is 62-91% renally excreted and must be dose-adjusted in renal impairment to prevent nephrotoxicity. 1, 4
Intravenous Dosing Adjustments
| Creatinine Clearance | Adjusted IV Dose |
|---|---|
| >50 mL/min | No adjustment: 10 mg/kg q8h |
| 25-50 mL/min | 10 mg/kg q12h |
| 10-24 mL/min | 10 mg/kg q24h |
| <10 mL/min | 5 mg/kg q24h |
| Hemodialysis | 5 mg/kg q24h; dose after dialysis |
Oral Valacyclovir Adjustments
| Creatinine Clearance | Adjusted Oral Dose |
|---|---|
| >50 mL/min | No adjustment: 1 g TID |
| <10 mL/min | 500 mg q24h |
| Hemodialysis | 500 mg q24h; first dose after dialysis |
Treatment Duration and Monitoring
Standard Course
- Continue IV acyclovir for 14-21 days, then perform repeat lumbar puncture with HSV PCR 6, 1, 3
- If CSF PCR remains positive, continue IV therapy and repeat PCR weekly until negative 6, 1
- CSF PCR can remain positive for 7-10 days after starting treatment, so delayed sampling can still confirm diagnosis 1
Switching to Oral Therapy
- Oral acyclovir is contraindicated for acute CNS infections—it does not achieve adequate CSF concentrations 6, 1
- Valacyclovir 1 g PO three times daily may be used only after 10-14 days of IV acyclovir when IV access is problematic, or to complete therapy after fever and headache resolve in HSV-2 meningitis 1
- A randomized trial showed valacyclovir 500 mg BID does not prevent recurrent HSV-2 meningitis and causes rebound upon discontinuation—prophylaxis is not recommended 1
Nephrotoxicity Prevention and Monitoring
Nephrotoxicity occurs in up to 20% of patients after approximately 4 days of IV therapy, manifesting as crystalluria, rising creatinine, or obstructive nephropathy. 6, 1, 7
Prevention Strategies
- Maintain aggressive IV hydration throughout treatment to prevent crystal precipitation 1, 7
- Monitor renal function (serum creatinine, urine output) at baseline and 1-2 times weekly during high-dose therapy 7
- Infuse acyclovir over 1 hour rather than rapid bolus to reduce crystalluria risk 1
- Adjust dose immediately if creatinine rises 7
Other Adverse Effects
- Rare but serious: hepatitis, bone marrow suppression, thrombocytopenia, encephalopathy 1, 7, 8
- Thrombocytopenia occurred in 33% of patients receiving high-dose oral valacyclovir in one series 8
- Monitor complete blood counts twice weekly during induction, then weekly 7
Common Pitfalls to Avoid
Do Not Use Oral Acyclovir for Acute CNS Infections
Oral acyclovir does not achieve therapeutic CSF levels and is never appropriate for acute viral meningitis or encephalitis requiring hospitalization. 6, 1 Only IV acyclovir or (after initial IV course) oral valacyclovir should be used.
Do Not Stop Treatment Prematurely
The original 10-day regimens led to relapse rates of 26-29% in children—current guidelines mandate 14-21 days in adults and a minimum of 21 days in children 3 months–12 years. 6, 1
Do Not Delay Treatment Waiting for Confirmation
Start IV acyclovir immediately when HSV encephalitis is strongly suspected, even before lumbar puncture or PCR results. 6, 1 Delays beyond 48 hours markedly worsen outcomes. If the patient is deteriorating, start acyclovir concurrently with empirical antibiotics for bacterial meningitis. 6, 1
Do Not Treat All Encephalopathy Empirically
Empirical acyclovir for all patients with altered mental status without regard to likelihood of HSV is not beneficial and delays identification of other etiologies. 6 However, if there is strong clinical suspicion or potential delay in lumbar puncture, start acyclovir immediately. 6
Special Populations
Immunocompromised Patients
- Require antiviral therapy—outcomes are significantly improved compared to supportive care alone (P < 0.05) 2
- May require prolonged courses beyond 21 days if CSF PCR remains positive 1
- If acyclovir resistance is suspected (persistent lesions despite therapy), switch to foscarnet 40 mg/kg IV every 8 hours 1
- HIV-infected patients with severe HSV disease: acyclovir 5 mg/kg IV every 8 hours 1
Recurrent HSV-2 (Mollaret's) Meningitis
- Most recurrent lymphocytic meningitis (78-84%) is caused by HSV-2 1
- Prophylactic valacyclovir 500 mg BID is not recommended—a placebo-controlled RCT showed no reduction in recurrence rates and higher relapse after discontinuation 1
- Recurrent episodes in immunocompetent patients typically resolve without sequelae 9
Pregnancy
The safety of systemic acyclovir and valacyclovir in pregnancy has not been established; women receiving these medications during pregnancy should be reported to registries. 7
Stopping Criteria
Acyclovir can be discontinued in immunocompetent patients if: 6
- An alternative diagnosis has been made, or
- HSV PCR in CSF is negative on two occasions 24-48 hours apart and MRI is not characteristic for HSV encephalitis, or
- HSV PCR in CSF is negative once >72 hours after neurological symptom onset, with unaltered consciousness, normal MRI (performed >72 hours after symptom onset), and CSF white cell count <5 × 10⁶/L 6