What is the recommended treatment for oral syphilis?

Treatment Guidelines for Oral Syphilis

Oral syphilis is treated identically to syphilis at any other anatomic site using the same stage-based treatment protocols, with benzathine penicillin G 2.4 million units intramuscularly as a single dose for early-stage disease. 1, 2

Understanding Oral Syphilis

• Oral syphilis manifests as painless ulcers (chancres) in the mouth during primary syphilis or mucous patches during secondary syphilis, but the anatomic location does not change treatment approach 3
• The stage of infection (primary, secondary, early latent, late latent, or tertiary) determines treatment duration, not the site of lesions 1, 2

First-Line Treatment by Stage

Early Syphilis (Primary, Secondary, or Early Latent)

• Benzathine penicillin G 2.4 million units intramuscularly as a single injection is the definitive treatment 1, 2
• This applies regardless of whether lesions are oral, genital, or elsewhere 1
• HIV-infected patients receive the same single-dose regimen, though some specialists historically recommended three weekly doses—however, recent evidence shows no benefit to multiple doses over single-dose therapy in terms of serologic outcomes 4

Late Latent or Tertiary Syphilis

• Benzathine penicillin G 2.4 million units intramuscularly once weekly for 3 consecutive weeks (total 7.2 million units) 2, 5
• Before treating tertiary syphilis, cerebrospinal fluid examination is mandatory to exclude neurosyphilis, as the standard regimen is inadequate for central nervous system involvement 5

Neurosyphilis (Any Stage)

• If neurosyphilis is diagnosed, switch to aqueous crystalline penicillin G 18-24 million units daily intravenously (administered as 3-4 million units every 4 hours) for 10-14 days 2, 5

Alternative Treatments for Penicillin Allergy

For Early Syphilis

• Doxycycline 100 mg orally twice daily for 14 days is the preferred alternative 1, 2, 6
• Tetracycline 500 mg orally four times daily for 14 days is acceptable but compliance is worse due to frequent dosing 1
• Ceftriaxone 1 g daily (intramuscular or intravenous) for 8-10 days is a reasonable alternative based on randomized trial data showing comparable efficacy 4

For Late Latent Syphilis

• Doxycycline 100 mg orally twice daily for 28 days 2, 6

Critical Caveat About Azithromycin

• Azithromycin should NOT be used for syphilis treatment in the United States despite some evidence of efficacy, because widespread macrolide resistance in Treponema pallidum and documented treatment failures make it unreliable 4
• While older studies showed comparable efficacy of azithromycin 2 g as a single oral dose 7, 8, chromosomal mutations conferring macrolide resistance are now highly prevalent in the US 4

Penicillin Desensitization

• For patients whose compliance cannot be ensured or who are pregnant, penicillin desensitization followed by penicillin treatment is strongly recommended over alternative antibiotics 1, 2
• Pregnant patients must receive penicillin, as it is the only proven effective treatment for preventing maternal-fetal transmission 2, 5

Special Populations

HIV-Infected Patients

• Use the same penicillin regimen as HIV-negative patients (single dose for early syphilis, three weekly doses for late latent) 4, 1, 2
• Closer follow-up is mandatory: every 3 months rather than every 6 months 4, 1
• Some HIV-infected patients may have slower serologic response, but this does not warrant routine use of enhanced regimens 4

Pregnant Patients

• Only penicillin is proven effective for preventing congenital syphilis 2, 5
• Penicillin-allergic pregnant patients must undergo desensitization—no alternatives are acceptable 1, 2, 5

Follow-Up Protocol

Standard Monitoring

• Clinical and serologic evaluation (quantitative nontreponemal tests like RPR or VDRL) at 6 and 12 months after treatment 1, 2
• Expect a 4-fold (2-dilution) decline in titers within 6 months for primary/secondary syphilis 2
• For late syphilis, expect 4-fold decline within 12-24 months 2, 5

HIV-Infected Patients

• More frequent monitoring every 3 months 4, 1

Treatment Failure Criteria

• Persistent or recurring clinical signs/symptoms 1, 5
• Sustained 4-fold increase in nontreponemal test titers 1, 5
• Failure of titers to decline 4-fold within expected timeframes 2, 5

Management of Treatment Failure

• Re-evaluate for HIV infection if not previously tested 5
• Perform cerebrospinal fluid examination to exclude neurosyphilis 2, 5
• Retreat with three weekly injections of benzathine penicillin G 2.4 million units unless neurosyphilis is diagnosed 2, 5

Critical Pitfalls to Avoid

• Never use oral penicillin preparations—they are completely ineffective for syphilis 5
• Do not switch between different serologic test methods (RPR vs VDRL) when monitoring response, as results cannot be directly compared 5
• Jarisch-Herxheimer reaction (acute fever, headache, myalgia) may occur within 24 hours of treatment, especially in early syphilis—this is not an allergic reaction and does not contraindicate continued penicillin use 1, 5
• Do not skip cerebrospinal fluid examination before treating tertiary syphilis, as missing neurosyphilis leads to inadequate treatment 5
• Serologic tests may decline more slowly in patients with previous syphilis infections 1
• Older age is associated with lower likelihood of serologic cure and seroreversion 4

Screening and Prevention

• Screen all sexually active persons aged 15-44 years at least once, with annual screening for those at increased risk 3
• Screen pregnant patients three times: at first prenatal visit, during third trimester, and at delivery 3
• For men who have sex with men and transgender women with a sexually transmitted infection in the past year, offer doxycycline 200 mg within 72 hours after sex as postexposure prophylaxis 3