What is the recommended treatment for syphilis using Penicillin G (PCN G)?

Syphilis Treatment with Penicillin G

Primary Recommendation

Benzathine penicillin G remains the definitive treatment of choice for all stages of syphilis, with specific dosing determined by disease stage. 1, 2, 3

Treatment Regimens by Stage

Early Syphilis (Primary, Secondary, and Early Latent)

• Administer benzathine penicillin G 2.4 million units intramuscularly as a single dose for primary, secondary, or early latent syphilis (acquired within the preceding year). 4, 1, 2

• Early latent syphilis is defined by documented seroconversion, fourfold increase in nontreponemal titer, history of primary/secondary symptoms, or sexual partner with documented early syphilis within the past year. 1

• For HIV-infected patients with early syphilis, the same single 2.4 million unit dose is recommended, though some specialists advocate for two additional weekly doses (total of three weekly injections)—however, this enhanced approach remains unproven and is not standard. 4

Late Latent Syphilis and Latent Syphilis of Unknown Duration

• Administer benzathine penicillin G 7.2 million units total as three separate doses of 2.4 million units intramuscularly, given at weekly intervals (weeks 0,1, and 2). 4, 1, 2

• This regimen applies when CSF examination has excluded neurosyphilis. 4

• HIV-infected patients receive the same three-dose regimen. 4

Neurosyphilis

• Administer aqueous crystalline penicillin G 18-24 million units daily intravenously, given as 3-4 million units every 4 hours (or continuous infusion) for 10-14 days. 1, 2, 5, 6

• Many experts recommend supplementing this with benzathine penicillin G 2.4 million units intramuscularly weekly for three doses after completing IV therapy. 6

• CSF examination is mandatory before treatment in patients with neurologic/ocular symptoms, tertiary syphilis manifestations, treatment failure, or HIV-infected patients with late-latent disease. 5

Tertiary Syphilis (Non-Neurologic)

• Administer benzathine penicillin G 7.2 million units total as three doses of 2.4 million units intramuscularly at weekly intervals. 1, 2

• CSF examination must be performed before treatment to exclude neurosyphilis, as cardiovascular and gummatous syphilis require different management considerations. 4

Alternative Regimens for Penicillin Allergy

Non-Pregnant Adults with Early Syphilis

• Doxycycline 100 mg orally twice daily for 14 days is the preferred alternative for penicillin-allergic patients with primary, secondary, or early latent syphilis. 1, 2, 7, 8

• Recent comparative studies demonstrate serological success rates of 82.9-92.4% with doxycycline versus 91.4-96.2% with penicillin—differences that are not statistically significant. 7, 8

Non-Pregnant Adults with Late Latent Syphilis

• Doxycycline 100 mg orally twice daily for 28 days for penicillin-allergic patients after CSF examination excludes neurosyphilis. 4, 1

• Tetracycline 500 mg orally four times daily for 28 days is an alternative if doxycycline is unavailable. 4

Critical Caveat: Pregnancy and Neurosyphilis

• Penicillin is the ONLY proven effective therapy for preventing maternal-fetal transmission and treating neurosyphilis—penicillin-allergic pregnant women and all neurosyphilis patients must undergo desensitization. 4, 1, 5

• Alternative antibiotics (doxycycline, tetracycline, ceftriaxone, azithromycin) have insufficient evidence in these populations and should never be used. 4

Important Clinical Considerations

Azithromycin Concerns

• While a single 2-gram oral dose of azithromycin showed 94% serological response in one pilot study 9, widespread molecular resistance of T. pallidum to macrolides and documented clinical failures make this unreliable. 4

• Azithromycin should only be considered when no other options exist and requires intensive clinical and serologic monitoring. 4

Enhanced Penicillin Regimens

• Adding high-dose oral amoxicillin and probenecid to standard benzathine penicillin does not improve outcomes and is not recommended. 4

Jarisch-Herxheimer Reaction

• An acute febrile reaction may occur within 24 hours of initiating any syphilis therapy, particularly in early-stage disease, manifesting as fever, headache, and myalgias. 1, 5

• Patients should be counseled about this self-limited reaction before treatment. 1

Follow-Up and Treatment Response Monitoring

Serologic Monitoring Schedule

• Repeat quantitative nontreponemal tests (RPR or VDRL) at 3,6,12, and 24 months after treatment. 1, 2

• For primary/secondary syphilis, expect a fourfold decline in titer within 6 months. 1, 2

• For late syphilis, expect a fourfold decline within 12-24 months. 1

Defining Treatment Failure

• Treatment failure is defined as failure of nontreponemal titers to decline fourfold within 6 months for primary/secondary syphilis, or a fourfold increase in titers at any time. 1, 2

• If treatment failure occurs, re-evaluate for HIV infection, perform CSF examination, and re-treat appropriately. 1

Neurosyphilis Follow-Up

• Repeat CSF examination at 6-month intervals until CSF white blood cell count normalizes. 5

• CSF-VDRL should become nonreactive; if it remains reactive after 2 years despite normalized cell count, consider re-treatment. 5

Critical Pitfalls to Avoid

• Never use oral penicillin preparations for syphilis treatment—they are completely ineffective. 1

• Do not switch between different nontreponemal tests (RPR vs. VDRL) when monitoring treatment response, as results cannot be directly compared. 1

• Do not rely on treponemal antibody titers (FTA-ABS, MHA-TP) to assess treatment response—they remain positive for life and correlate poorly with disease activity. 1

• If a weekly benzathine penicillin dose is missed, an interval of 10-14 days between doses may be acceptable before restarting the sequence, but avoid longer gaps. 1

• In HIV-infected patients, atypical serologic responses may occur, but standard treatment regimens remain appropriate with closer follow-up. 4

Partner Management

• Persons exposed within 90 days before diagnosis of primary, secondary, or early latent syphilis should receive presumptive treatment (benzathine penicillin G 2.4 million units IM) even if seronegative. 1

• Those exposed more than 90 days before diagnosis should be treated presumptively if serologic results are not immediately available and follow-up is uncertain. 1