What is the recommended treatment for syphilis in [LOCATION]?

Syphilis Treatment

Benzathine penicillin G is the definitive treatment for all stages of syphilis, administered as a single 2.4 million unit intramuscular injection for early syphilis (primary, secondary, and early latent) or three weekly doses of 2.4 million units for late latent syphilis and tertiary syphilis. 1, 2, 3

Treatment by Stage

Primary and Secondary Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose is the recommended regimen for adults 4, 1, 2
• This regimen achieves 90-100% treatment success rates based on four decades of clinical experience 4, 5
• For children with acquired syphilis, administer benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) as a single dose after CSF examination to exclude neurosyphilis 4, 2

Early Latent Syphilis (Duration <1 Year)

• Benzathine penicillin G 2.4 million units IM as a single dose 4, 2, 3
• Early latent syphilis is defined by documented seroconversion, fourfold increase in titer, history of symptoms within the past year, or having a sex partner with documented early syphilis 2

Late Latent Syphilis and Tertiary Syphilis (Duration >1 Year or Unknown)

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals 4, 2, 3
• If a dose is missed, an interval of 10-14 days between doses might be acceptable before restarting the sequence, though 7-9 days is more optimal if feasible 2, 6
• Pregnant women who miss any dose must repeat the full course of therapy—no exceptions 4

Neurosyphilis

• Aqueous crystalline penicillin G 18-24 million units IV daily (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days 2, 3
• CSF examination is mandatory before treatment for patients with neurologic or ophthalmic signs/symptoms, evidence of active tertiary syphilis, treatment failure, HIV infection with late latent syphilis, or nontreponemal titer ≥1:32 4, 2
• Procaine penicillin without probenecid does not achieve adequate CSF levels and is inadequate for neurosyphilis 2

Alternative Regimens for Penicillin Allergy

Non-Pregnant Adults with Early Syphilis

• Doxycycline 100 mg orally twice daily for 14 days is the preferred alternative 4, 1, 2, 3, 7
• Tetracycline 500 mg orally four times daily for 14 days is an alternative, though compliance is better with doxycycline due to less frequent dosing 4, 1, 2
• Ceftriaxone 1 gram IM or IV daily for 10-14 days may be considered, though optimal dosing is not well established 1, 2
• Ceftriaxone should be avoided in patients with severe penicillin allergy (such as Stevens-Johnson syndrome) due to cross-reactivity between beta-lactam antibiotics 2

Non-Pregnant Adults with Late Latent Syphilis

• Doxycycline 100 mg orally twice daily for 28 days 4, 2, 3, 7
• Tetracycline 500 mg orally four times daily for 28 days is an alternative 4, 2
• CSF examination must exclude neurosyphilis before using nonpenicillin therapy 4

Pregnant Women

• All pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no exceptions 4, 2, 3
• Penicillin is the only therapy with documented efficacy for preventing maternal transmission to the fetus and treating fetal infection 2, 8
• Tetracycline, doxycycline, erythromycin, azithromycin, and ceftriaxone are inadequate—erythromycin does not reliably cure fetal infection 2
• Some experts recommend a second dose of benzathine penicillin 2.4 million units IM administered 1 week after the initial dose for women with primary, secondary, or early latent syphilis 2

Special Populations

HIV-Infected Patients

• Use the same penicillin regimens as HIV-negative patients for all stages of syphilis 1, 2, 3
• Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis in HIV-infected patients compared to a single dose 1, 2
• Closer follow-up is mandatory: perform serologic testing every 3 months rather than every 6 months 1, 3
• Patients with penicillin allergy should undergo skin testing and desensitization, then be treated with penicillin 2

Pregnancy Considerations

• Screen all pregnant women for syphilis at first prenatal visit, during third trimester, and at delivery 2, 3
• Women treated during the second half of pregnancy are at risk for premature labor and/or fetal distress from Jarisch-Herxheimer reaction 2
• Patients should seek immediate medical attention if they notice contractions or changes in fetal movements after treatment 2
• The highest risk of fetal treatment failure (5.3%) occurs with maternal secondary syphilis, compared to 0% for primary, 2% for early latent, and 0% for late latent syphilis 8

Follow-Up Protocol

Early Syphilis (Primary, Secondary, Early Latent)

• Perform quantitative nontreponemal serologic tests (RPR or VDRL) at 6 and 12 months after treatment 1, 2, 3
• Expect a fourfold decline in titer within 6 months 2, 3
• For HIV-infected patients, perform serologic testing at 3,6,9,12, and 24 months 1

Late Latent Syphilis

• Perform quantitative nontreponemal tests at 6,12, and 24 months 4, 2
• Expect a fourfold decline in titer within 12-24 months 2

Treatment Failure Criteria

Re-treat and evaluate for HIV if any of the following occur:

• Persistent or recurring signs/symptoms 2
• Sustained fourfold increase in nontreponemal titers 4, 2
• Failure of initially high titer (≥1:32) to decline at least fourfold within 6-12 months for early syphilis or 12-24 months for late syphilis 4, 2
• Unless reinfection is likely, perform lumbar puncture to evaluate for neurosyphilis in cases of treatment failure 2
• Re-treatment typically involves three weekly injections of benzathine penicillin G 2.4 million units IM, unless CSF examination indicates neurosyphilis 2

Management of Sex Partners

Presumptive Treatment Indications

• Treat sex partners presumptively if exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis, even if seronegative 4, 2, 3
• Persons exposed >90 days before diagnosis should be treated presumptively if serologic test results are not immediately available and follow-up is uncertain 4, 2
• Use benzathine penicillin G 2.4 million units IM as a single dose for presumptive treatment 3

Time Periods for At-Risk Partners

• Primary syphilis: 3 months plus duration of symptoms 4, 2
• Secondary syphilis: 6 months plus duration of symptoms 4, 2
• Early latent syphilis: 1 year 4, 2
• Long-term sex partners of patients with late syphilis should be evaluated clinically and serologically 4

Additional Considerations

HIV Testing

• All patients with syphilis should be tested for HIV at the time of diagnosis 4, 1, 2, 3
• In areas with high HIV prevalence, patients with primary syphilis should be retested for HIV after 3 months 4

Jarisch-Herxheimer Reaction

• An acute febrile reaction may occur within 24 hours after any syphilis therapy, especially in early syphilis 1, 2, 3
• Symptoms may include fever, headache, myalgia, and other constitutional symptoms 1, 3
• Inform all patients about this possible adverse reaction before treatment 2, 3

Critical Pitfalls to Avoid

• Never use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 1, 2, 9
• Do not use oral penicillin preparations for syphilis treatment as they are ineffective 2
• Do not rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity 2
• Do not switch between different testing methods (e.g., VDRL and RPR) when monitoring serologic response, as results cannot be directly compared 2
• Remember that 15-25% of successfully treated patients remain "serofast" with persistent low titers (<1:8) that do not indicate treatment failure 2
• Administer adequate amounts of fluid with doxycycline or tetracycline to reduce the risk of esophageal irritation and ulceration 7