What is the recommended treatment regimen for syphilis?

Syphilis Treatment

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 preventing late sequelae and achieving clinical resolution. 1, 2, 3

Treatment by Stage

Early Syphilis (Primary, Secondary, and Early Latent)

Adults:

• Benzathine penicillin G 2.4 million units IM as a single dose 4, 1, 2
• Early latent syphilis is defined as infection acquired within the preceding year, documented by seroconversion, fourfold increase in titer, history of symptoms within the past year, or having a sex partner with documented early syphilis 1

Children (after newborn period):

• Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units, as a single dose 4, 1
• Children require CSF examination to exclude neurosyphilis before treatment and evaluation for possible sexual abuse 4, 1

Late Latent Syphilis or Syphilis of Unknown Duration

Adults:

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals 1, 2

Children:

• Benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) for three total doses at 1-week 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

For non-pregnant adults with early syphilis:

• Doxycycline 100 mg orally twice daily for 14 days is the preferred alternative 1, 2, 3, 5
• Tetracycline 500 mg orally four times daily for 14 days is an alternative, though compliance is better with doxycycline due to less frequent dosing 1, 3
• Ceftriaxone 1 gram IV/IM daily for 8-10 days may be considered, though optimal dosing is not well established 1, 3

For non-pregnant adults with late latent syphilis:

• Doxycycline 100 mg orally twice daily for 28 days 1, 5
• Tetracycline 500 mg orally four times daily for 28 days 1

Critical caveat: Azithromycin should NOT be used in the United States due to widespread macrolide resistance and documented treatment failures 1, 3

Special Populations

Pregnant Women

• All pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no exceptions 1, 2
• Penicillin is the only therapy with documented efficacy for preventing maternal transmission and congenital syphilis 1, 2
• Screen all pregnant women for syphilis at first prenatal visit, during third trimester, and at delivery 1, 2
• Jarisch-Herxheimer reaction during second half of pregnancy may precipitate premature labor or fetal distress; women should seek immediate medical attention if they notice changes in fetal movements or contractions after treatment 1

HIV-Infected Patients

• Use the same stage-appropriate penicillin regimens as HIV-negative patients 1, 3
• A 2017 randomized trial showed no benefit to three doses of benzathine penicillin versus a single dose for early syphilis in HIV-infected patients (93% vs 100% success rates, respectively) 6
• However, a 2024 study found that single-dose benzathine penicillin G plus 7-day doxycycline achieved higher serologic response rates than benzathine penicillin alone in HIV-infected patients (79.5% vs 70.3% at 12 months) 7
• Closer follow-up is mandatory: monitor every 3 months rather than every 6 months to detect potential treatment failure 1, 3

Follow-Up Protocol

For primary/secondary syphilis:

• Perform quantitative nontreponemal serologic tests (RPR or VDRL) at 6 and 12 months after treatment 1, 2
• Expect a fourfold decline in titer within 6 months 1

For latent syphilis:

• Repeat quantitative nontreponemal tests at 6,12, and 24 months 1
• Expect fourfold decline within 12-24 months 1

Treatment failure is defined as:

• Persistent or recurring signs/symptoms 1, 3
• Sustained fourfold increase in nontreponemal test titers 1, 3
• Failure of initially high titer to decline at least fourfold within 6-12 months for early syphilis or 12-24 months for late syphilis 1

If treatment failure occurs: Re-evaluate for HIV infection and perform CSF examination 1

Management of Sex Partners

• Treat presumptively with benzathine penicillin G 2.4 million units IM for persons exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis, even if seronegative 4, 2
• 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 4, 1
• 6 months plus duration of symptoms for secondary syphilis 4, 1
• 1 year for early latent syphilis 4, 1

Essential Testing and Monitoring

• All patients with syphilis should be tested for HIV infection 4, 1, 2
• In high HIV prevalence areas, retest HIV-negative patients with primary syphilis after 3 months 4
• Do not use different testing methods (e.g., switching between VDRL and RPR) when monitoring serologic response, as results cannot be directly compared 1

Critical Pitfalls to Avoid

• Never use oral penicillin preparations for syphilis treatment—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
• Jarisch-Herxheimer reaction (acute febrile reaction with headache, myalgia, fever) may occur within 24 hours after treatment, especially in early syphilis—inform patients about this expected reaction 1, 2, 3
• If a dose is missed during weekly therapy for late latent syphilis, an interval of 10-14 days between doses might be acceptable before restarting the sequence 1
• Be aware of ongoing benzathine penicillin G shortages that may necessitate use of alternative regimens like doxycycline 8