How should we manage a 27-year-old male with possible early syphilis (initial serology insufficient) and a current herpes outbreak, given benzathine penicillin G (Bicillin) is on back‑order, he is on doxycycline, and he requests acyclovir ointment and a prescription for the penicillin injection?

Management of Possible Early Syphilis with Herpes Outbreak During Benzathine Penicillin Shortage

This patient must be retested immediately with quantitative RPR/VDRL and treponemal testing to confirm syphilis diagnosis before any further treatment decisions, and the current herpes outbreak should be treated with oral antiviral therapy (not ointment) while awaiting definitive syphilis management. 1

Immediate Priorities

1. Complete Syphilis Diagnostic Workup

• Order quantitative nontreponemal testing (RPR or VDRL) plus treponemal confirmation (FTA-ABS, TP-PA, or treponemal EIA) – the initial insufficient sample means you have no confirmed diagnosis, and treatment cannot proceed rationally without knowing the baseline titer and confirming true infection versus false-positive. 1

• Both nontreponemal AND treponemal tests must be reactive to diagnose syphilis – a single test type is insufficient, and you need quantitative titers (e.g., 1:4,1:16,1:64) to monitor treatment response, not just "positive/negative." 1

• Test for HIV infection immediately – HIV co-infection alters monitoring frequency (every 3 months instead of 6 months), increases neurosyphilis risk, and may cause atypical serologic responses. 2, 1

2. Herpes Management

• Prescribe oral acyclovir, valacyclovir, or famciclovir for the current herpes outbreak – topical acyclovir ointment has minimal efficacy compared to systemic therapy and should not be used as primary treatment for genital herpes. 3

• The herpes outbreak and syphilis are separate infections requiring distinct management; treating one does not affect the other.

Syphilis Treatment Algorithm

If Benzathine Penicillin G Remains Unavailable

Doxycycline 100 mg orally twice daily for 14 days is the established second-line treatment for early syphilis in non-pregnant, penicillin-allergic patients and is appropriate when benzathine penicillin is unavailable. 2, 1, 4

• Doxycycline achieves 82.9%–100% serological cure rates for early syphilis, comparable to benzathine penicillin's 91.4%–97.4% success rates in multiple studies. 5, 6, 7, 8

• The patient has already been on doxycycline for 2 months – if this was prescribed for presumed syphilis, verify the exact regimen (dose, duration, adherence). If he received the full 14-day course at 100 mg twice daily, he may already be adequately treated for early syphilis. 4, 5

• If doxycycline was incomplete or incorrectly dosed, restart a full 14-day course of doxycycline 100 mg orally twice daily with explicit instructions: take with plenty of water, avoid lying down for 30 minutes after dosing to prevent esophageal irritation, avoid sun exposure due to photosensitivity, and complete the entire course even if symptoms resolve. 4

Critical Medication Instructions for Doxycycline

• Take each dose with a full glass of water and remain upright for at least 30 minutes to reduce risk of esophageal ulceration. 4

• Avoid dairy products, antacids, iron supplements, and multivitamins within 2–3 hours of dosing – these chelate doxycycline and reduce absorption, though food/milk can be used if gastric irritation occurs. 4

• Use strict sun protection (SPF 50+, protective clothing) – doxycycline causes significant photosensitivity and severe sunburn can occur with minimal exposure. 4

If Benzathine Penicillin Becomes Available

• Provide a prescription for benzathine penicillin G 2.4 million units IM as a single dose so the patient can obtain it if he locates a pharmacy or health department with stock. 1

• If the patient receives benzathine penicillin after completing doxycycline, do NOT give additional penicillin – one adequate treatment course is sufficient, and dual therapy is not indicated. 1

Follow-Up and Monitoring

Serologic Monitoring Schedule

• Recheck quantitative nontreponemal titers (same test method, preferably same laboratory) at 6 and 12 months after treatment completion. 1

• Treatment success is defined as a 4-fold decline in titer within 6–12 months for early syphilis (e.g., 1:64 declining to 1:16 or lower). 1

• If HIV-positive, increase monitoring frequency to 3,6,9,12, and 24 months due to higher treatment failure rates and atypical serologic responses. 2, 1

Indications for Treatment Failure or Neurosyphilis Evaluation

• Perform lumbar puncture with CSF examination if any of the following occur: 1

  • Neurologic symptoms (headache, confusion, cranial nerve palsy, stroke-like presentation)
  • Ocular symptoms (vision changes, eye pain, uveitis)
  • Failure of nontreponemal titer to decline 4-fold within 6–12 months
  • Sustained 4-fold increase in titer after initial decline
  • New or recurrent clinical manifestations (chancre, rash, mucocutaneous lesions)

• If neurosyphilis is confirmed, treat with aqueous crystalline penicillin G 18–24 million units per day IV (3–4 million units every 4 hours or continuous infusion) for 10–14 days – oral doxycycline does NOT achieve adequate CSF levels and is contraindicated for neurosyphilis. 2, 1

Assessment of Current Penile Lesion

• Document whether the penile lesion has improved, worsened, or resolved since starting doxycycline – this clinical response helps distinguish between syphilis chancre (which should heal with appropriate treatment) versus herpes ulceration (which recurs episodically regardless of syphilis therapy). 1

• If the lesion persists or worsens despite 2 months of doxycycline, consider alternative diagnoses including treatment-resistant herpes, chancroid, lymphogranuloma venereum, or inadequate doxycycline dosing/adherence. 1

Partner Notification and Prevention

• Identify and notify all sexual contacts from the past 6 months plus duration of symptoms – partners require evaluation and presumptive treatment if syphilis is confirmed. 1

• Counsel on condom use for all sexual encounters and consider offering doxycycline post-exposure prophylaxis (200 mg within 72 hours after sex) if the patient is a man who has sex with men with recurrent STI risk. 3

Common Pitfalls to Avoid

• Do not treat syphilis empirically without confirmed serologic diagnosis – the insufficient initial sample means you have no baseline titer, and you cannot monitor treatment response or distinguish treatment failure from reinfection without quantitative titers. 1

• Do not use topical acyclovir as primary therapy for genital herpes – systemic oral antivirals are far more effective and should be prescribed instead. 3

• Do not assume doxycycline given for another indication (e.g., Descovy PrEP companion therapy) constitutes adequate syphilis treatment – verify the exact dose and duration; syphilis requires 100 mg twice daily for 14 days, not lower doses or shorter courses. 4

• Do not delay HIV testing – HIV status fundamentally changes syphilis management, monitoring frequency, and neurosyphilis risk assessment. 2, 1

• Do not use benzathine penicillin for neurosyphilis – it does not achieve therapeutic CSF levels and is inappropriate for CNS infection. 1