What is the appropriate management for a severe herpes simplex outbreak that has not responded to oral acyclovir 800 mg five times daily for seven days, with persistent vesicles and crusting?

Management of Acyclovir-Resistant Severe Herpes Simplex Outbreak

Switch immediately to intravenous foscarnet 40 mg/kg every 8 hours until complete clinical resolution, as this patient has failed high-dose oral acyclovir and likely has acyclovir-resistant HSV. 1

Immediate Assessment and Treatment Escalation

Confirm Treatment Failure and Resistance

• After 7 days of acyclovir 800 mg five times daily with continued vesicle formation and no symptom improvement, this represents clear treatment failure requiring escalation 2
• Obtain viral culture with acyclovir susceptibility testing immediately to confirm resistance, though treatment should not be delayed pending results 1, 2
• Increasing the oral acyclovir dose further (beyond 800 mg five times daily) is unlikely to be effective if the patient has already failed this regimen 2

First-Line Treatment for Acyclovir-Resistant HSV

• Foscarnet 40 mg/kg IV every 8 hours (or 60 mg/kg IV twice daily) for 10 days or until complete lesion resolution is the treatment of choice for acyclovir-resistant HSV 1, 2
• All acyclovir-resistant strains are also resistant to valacyclovir, and most are resistant to famciclovir, making these alternatives ineffective 3
• Intravenous therapy is mandatory—oral alternatives do not exist for proven resistance 2

Alternative Therapies if Foscarnet Fails or Is Contraindicated

• If lesions are accessible, topical trifluridine (as ophthalmic solution) applied 3-4 times daily can be used adjunctively or as monotherapy for localized disease 2
• Intravenous cidofovir (or compounded 1-3% topical cidofovir) is reserved for foscarnet failure 3, 2
• Vidarabine is the last-resort option when all other therapies have failed 2

Critical Monitoring During Foscarnet Therapy

Renal Function and Electrolytes

• Obtain baseline renal function (creatinine, BUN, creatinine clearance) before initiating foscarnet 1
• Monitor renal function at least twice weekly during treatment, as foscarnet is nephrotoxic 1
• Ensure aggressive hydration (2-3 liters daily) to minimize nephrotoxicity 3

Electrolyte Disturbances

• Monitor serum calcium, magnesium, phosphate, and potassium at least twice weekly 1
• Foscarnet causes hypocalcemia, hypomagnesemia, and hypokalemia requiring frequent replacement 1

Assess for Immunocompromise

Identify Underlying Risk Factors

• Acyclovir resistance is extremely rare in immunocompetent patients but occurs in up to 7% of immunocompromised patients 3, 2
• Obtain HIV testing, CD4 count if HIV-positive, and assess for other causes of immunosuppression (chemotherapy, organ transplant, chronic corticosteroids, autoimmune disease on immunosuppressants) 1, 2
• Immunocompromised patients may have prolonged episodes with extensive disease and are at risk for disseminated infection requiring more aggressive management 1, 4

Adjust Immunosuppression if Feasible

• Consider temporarily reducing or discontinuing immunosuppressive medications if clinically safe 1
• For HIV-infected patients, ensure antiretroviral therapy is optimized 1

Treatment Duration and Endpoints

Continue Until Complete Resolution

• Treat with foscarnet for a minimum of 10 days and continue until all lesions have completely healed—not just crusted 2
• Do not discontinue therapy at an arbitrary timepoint if active vesicles or ulcers remain 2

Suppressive Therapy After Acute Episode

• Once acute infection resolves, initiate high-dose oral acyclovir 800 mg five times daily as suppressive therapy to prevent recurrence in the same location 2
• If lesions recur in a different location, restart standard-dose acyclovir (200 mg five times daily) and escalate per the resistance protocol if treatment fails 2

Common Pitfalls to Avoid

• Do not continue escalating oral acyclovir doses indefinitely—if 800 mg five times daily fails after 5-7 days, resistance is likely and IV foscarnet is required 2
• Do not use topical acyclovir—it is substantially less effective than systemic therapy and is explicitly discouraged 1, 4
• Do not assume valacyclovir or famciclovir will work if acyclovir has failed—cross-resistance is the rule 3
• Do not delay foscarnet while awaiting susceptibility testing—clinical treatment failure after 7 days of appropriate therapy is sufficient to warrant empiric foscarnet 2