What is the recommended treatment regimen for syphilis?

Syphilis Treatment Guidelines

For primary and secondary syphilis, administer benzathine penicillin G 2.4 million units intramuscularly as a single dose. This remains the gold standard treatment with over 50 years of proven efficacy in achieving clinical resolution and preventing late sequelae 1, 2, 3.

Treatment by Stage

Early Syphilis (Primary, Secondary, and Early Latent)

• Benzathine penicillin G 2.4 million units IM as a single dose is the recommended regimen for adults 4, 1.
• Early latent syphilis is defined as infection acquired within the preceding year, documented by seroconversion, fourfold titer increase, symptoms within the past year, or having a sex partner with documented early syphilis 1.
• For children with acquired early syphilis, administer benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) as a single dose 4, 1.
• Children require CSF examination before treatment to exclude neurosyphilis 1.

Late Latent Syphilis or Syphilis of Unknown Duration

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals 1, 3.
• If a dose is missed, an interval of 10-14 days between doses may be acceptable before restarting the sequence 1.
• For children, administer benzathine penicillin G 50,000 units/kg IM (up to 2.4 million units) for three total doses at weekly intervals (total 150,000 units/kg up to 7.2 million units) 1.

Neurosyphilis

• Aqueous crystalline penicillin G 18-24 million units per day IV (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days 1, 2, 3.
• CSF examination is indicated for patients with neurologic or ophthalmic signs/symptoms, evidence of active tertiary syphilis, treatment failure, HIV infection with late latent syphilis, or serum nontreponemal titer ≥1:32 1.

Penicillin Allergy Alternatives

Non-Pregnant Adults

• Doxycycline 100 mg orally twice daily for 14 days for primary, secondary, or early latent syphilis 1, 2, 3, 5.
• Doxycycline 100 mg orally twice daily for 28 days for late latent syphilis 1, 5.
• Tetracycline 500 mg orally four times daily is an alternative (14 days for early syphilis, 28 days for late latent), though compliance is better with doxycycline due to less frequent dosing 1, 2.
• Ceftriaxone 1 gram IV/IM daily for 10 days is a reasonable alternative based on randomized trial data showing comparable efficacy to benzathine penicillin 1.

Pregnant Women

• All pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment 1, 2, 3.
• Penicillin is the only therapy with documented efficacy for preventing maternal transmission and congenital syphilis 1.
• Alternative antibiotics are not adequately studied in pregnancy and should never be substituted 1, 2.

Special Populations

HIV-Infected Patients

• Use the same penicillin regimens as HIV-negative patients 1, 2.
• A 2017 randomized clinical trial demonstrated that single-dose benzathine penicillin G achieved 93% treatment success in HIV-infected patients with early syphilis, with no significant benefit from three doses 6.
• Closer follow-up is mandatory (every 3 months rather than every 6 months) to detect potential treatment failure 1, 2.

Pregnancy

• Screen all pregnant women for syphilis at first prenatal visit, during third trimester, and at delivery 1, 3.
• Use the same stage-appropriate penicillin regimens as non-pregnant patients 3.
• Jarisch-Herxheimer reaction during the second half of pregnancy may precipitate premature labor or fetal distress 1.
• Women should seek immediate medical attention if they notice changes in fetal movements or contractions after treatment 1.

Partner Management

• Treat sex partners presumptively with benzathine penicillin G 2.4 million units IM if exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis, even if seronegative 4, 3.
• Persons exposed >90 days before diagnosis should be treated presumptively if serologic results are not immediately available and follow-up is uncertain 4.
• Time periods for identifying at-risk partners: 3 months plus duration of symptoms for primary syphilis, 6 months plus duration of symptoms for secondary syphilis, and 1 year for early latent syphilis 4.

Follow-Up Protocol

• Perform quantitative nontreponemal serologic tests (RPR or VDRL) at 6 and 12 months after treatment for primary/secondary syphilis 1, 3.
• For latent syphilis, repeat tests at 6,12, and 24 months 1.
• Expect a fourfold decline in titer within 6 months for early syphilis and within 12-24 months for late syphilis 1, 3.
• HIV-infected patients should be monitored every 3 months 2.
• Treatment failure is defined as persistent or recurring signs/symptoms, sustained fourfold increase in nontreponemal titers, or failure of initially high titer to decline at least fourfold within the expected timeframe 1, 2.

Additional Management Considerations

• Test all patients with syphilis for HIV infection at the time of diagnosis 4, 1, 3.
• In high HIV prevalence areas, retest patients with primary syphilis for HIV after 3 months if initially negative 4.
• Patients with neurologic signs (meningitis) or ophthalmic disease (uveitis) require CSF analysis and slit-lamp examination 4.
• Unless clinical signs of neurologic or ophthalmic involvement are present, CSF analysis is not recommended for routine evaluation of primary or secondary syphilis 4.

Common Pitfalls and Caveats

• Jarisch-Herxheimer reaction (fever, headache, myalgia) may occur within 24 hours after treatment, especially in early syphilis 1, 2, 3.
• Do not use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 1.
• Do not use oral penicillin preparations for syphilis treatment as they are ineffective 1.
• Do not rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity 1.
• Do not switch between different testing methods (VDRL and RPR) when monitoring serologic response, as results cannot be directly compared 1.
• Serologic test titers may decline more slowly in patients who previously had syphilis 4, 2.
• Benzathine penicillin G shortages have been reported; doxycycline can serve as a temporary alternative while locating BPG supplies 7.