What is the first‑line treatment for uncomplicated syphilis, including dosing, pregnancy considerations, alternative regimens, partner management, and follow‑up?

First-Line Treatment for Uncomplicated Syphilis

Benzathine penicillin G 2.4 million units intramuscularly as a single dose is the definitive first-line treatment for primary, secondary, and early latent syphilis, achieving 90-100% treatment success. 1, 2

Treatment Regimens by Stage

Primary and Secondary Syphilis

• Benzathine penicillin G 2.4 million units IM as a single injection is the standard treatment for adults with primary or secondary syphilis 1, 3
• This single-dose regimen is supported by more than four decades of clinical experience with excellent efficacy 1
• All patients diagnosed with syphilis should be tested for HIV at the time of diagnosis 1

Early Latent Syphilis (≤1 year duration)

• Benzathine penicillin G 2.4 million units IM as a single dose is recommended 1
• 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

Late Latent Syphilis or Syphilis of Unknown Duration (>1 year)

• Benzathine penicillin G 7.2 million units total, administered as three weekly injections of 2.4 million units IM is the standard regimen 1, 3
• CSF examination should be performed before treatment in 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 1
• If a dose is missed during weekly therapy, an interval of 10-14 days between doses might be acceptable, but pregnant patients who miss any dose must repeat the entire course 1

Alternative Regimens for Penicillin-Allergic Patients

Non-Pregnant Adults with Early Syphilis (Primary, Secondary, or Early Latent)

• Doxycycline 100 mg orally twice daily for 14 days is the preferred alternative 1, 4
• Tetracycline 500 mg orally four times daily for 14 days is an acceptable alternative, but doxycycline is preferred due to better compliance with twice-daily versus four-times-daily dosing 1, 4
• Close clinical and serological follow-up is essential for all patients treated with alternative regimens 4

Non-Pregnant Adults with Late Latent Syphilis

• Doxycycline 100 mg orally twice daily for 28 days is the recommended alternative 1, 4
• Tetracycline 500 mg orally four times daily for 28 days is also acceptable 1
• A CSF examination must exclude neurosyphilis before using any non-penicillin regimen for late latent infection 1

Ceftriaxone as a Second-Line Alternative

• Ceftriaxone 1 gram IM or IV daily for 10-14 days may be considered when doxycycline cannot be used 1, 5
• Critical caveat: Patients with severe penicillin allergy (such as Stevens-Johnson syndrome) may also be allergic to ceftriaxone, as both are beta-lactam antibiotics 1
• The optimal dose and duration have not been definitively established, and evidence for late latent and tertiary syphilis is extremely limited 1

Avoid Azithromycin

• Azithromycin should NOT be used in the United States due to widespread macrolide resistance and documented treatment failures 1, 6

Pregnancy Considerations

Mandatory Penicillin Treatment

• All pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no exceptions 1, 4, 5
• Penicillin is the only therapy with documented efficacy for preventing maternal transmission to the fetus and treating fetal infection 7, 1
• Tetracycline, doxycycline, erythromycin, azithromycin, and ceftriaxone are inadequate—erythromycin does not reliably cure fetal infection 1

Screening Requirements

• All pregnant women should be screened for syphilis at the first prenatal visit, during the third trimester (at 28 weeks), and at delivery 1, 3
• Any woman who delivers a stillborn infant after 20 weeks' gestation should be tested for syphilis 7

Jarisch-Herxheimer Reaction Risk

• Women treated during the second half of pregnancy are at risk for premature labor and/or fetal distress from Jarisch-Herxheimer reaction 1
• Women should seek immediate medical attention if they notice contractions or changes in fetal movements after treatment 1

Enhanced Treatment Considerations

• 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 7, 1

Partner Management

Presumptive Treatment Criteria

• Persons exposed within 90 days preceding the diagnosis of primary, secondary, or early latent syphilis should be treated presumptively even if seronegative 1
• Persons exposed >90 days before diagnosis should be treated presumptively if serologic test results are not immediately available and follow-up is uncertain 1

Time Windows for At-Risk Partners

• Primary syphilis: 3 months plus duration of symptoms 1
• Secondary syphilis: 6 months plus duration of symptoms 1
• Early latent syphilis: 1 year 1
• Long-term partners of patients with late syphilis should undergo clinical and serologic evaluation 1

Follow-Up Protocol

Primary and Secondary Syphilis

• Perform quantitative nontreponemal serologic tests (RPR or VDRL) at 6 and 12 months after treatment 1
• A fourfold decline in titer is expected within 6 months for primary/secondary syphilis 1

Late Latent Syphilis

• Repeat quantitative nontreponemal tests at 6,12, and 24 months 1, 4
• A fourfold decline in titer is expected within 12-24 months for late syphilis 1

Treatment Failure Indicators

• Re-treat and evaluate for HIV if any of the following occur: 1
  • Persistent or recurring signs/symptoms
  • Sustained fourfold increase in nontreponemal titers
  • 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
• Unless reinfection is likely, lumbar puncture should be performed to evaluate for neurosyphilis in cases of treatment failure 1
• Re-treatment typically involves three weekly injections of benzathine penicillin G 2.4 million units IM, unless CSF examination indicates neurosyphilis 1

Serofast State

• Remember that 15-25% of successfully treated patients remain "serofast" with persistent low titers (<1:8) that do not indicate treatment failure 1

HIV-Infected Patients

Treatment Regimens

• HIV-infected patients have the same treatment regimens as non-HIV-infected patients 1
• Penicillin regimens should be used for all stages of syphilis in HIV-infected patients 1
• Patients with penicillin allergy should undergo skin testing and desensitization, then be treated with penicillin 1

Enhanced Monitoring

• HIV-infected patients may have atypical serologic responses but generally respond well to standard treatment 1
• Closer follow-up is mandatory to detect potential treatment failure or disease progression 1
• For patients treated with alternative regimens, monitoring should occur at 3-month intervals instead of 6-month intervals 4, 5
• HIV-infected patients who have either late latent syphilis or syphilis of unknown duration should have a CSF examination before treatment 7

Follow-Up for HIV-Infected Patients with Late Latent Syphilis

• Patients should be evaluated clinically and serologically at 6,12,18, and 24 months after therapy 7
• If at any time clinical symptoms develop or nontreponemal titers rise fourfold, a repeat CSF examination should be performed and treatment administered accordingly 7

Neurosyphilis Treatment

First-Line Therapy

• 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

Alternative Penicillin-Based Regimen (Outpatient)

• Procaine penicillin 2.4 million units IM once daily plus probenecid 500 mg orally four times daily for 10-14 days is acceptable when adherence can be assured 1
• Critical caveat: Procaine penicillin without probenecid is inadequate because it fails to achieve therapeutic CSF penicillin levels 1
• Patients with known sulfonamide allergy should not receive the procaine-penicillin + probenecid regimen, as they are highly likely to be allergic to probenecid 1

Supplemental Therapy

• Some clinicians add three weekly intramuscular doses of benzathine penicillin G 2.4 million units after the IV course to provide additional coverage, although consensus on this practice has not been reached 1

Ceftriaxone for Neurosyphilis

• If ceftriaxone must be used for neurosyphilis, the dose is 2 grams daily IV (not IM) for 10-14 days, with very limited supporting data 1

Common Pitfalls to Avoid

• 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 use different testing methods (e.g., switching between VDRL and RPR) when monitoring serologic response, as results cannot be directly compared 1
• Do not substitute inadequate alternatives in pregnancy—only penicillin prevents congenital syphilis 1
• Do not use azithromycin in the United States due to widespread resistance 1