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

Penicillin G Treatment for Syphilis

Benzathine penicillin G remains the only FDA-approved and guideline-recommended first-line treatment for all stages of syphilis, with specific dosing determined by disease stage. 1, 2

Primary, Secondary, and Early Latent Syphilis

Administer benzathine penicillin G 2.4 million units intramuscularly as a single dose. 3, 1, 4

• 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
• This single-dose regimen is supported by over 40 years of clinical experience and maintains therapeutic penicillin concentrations above 18 ng/mL for 18-25 days, well exceeding the necessary 7-10 day treatment duration 3, 5
• HIV-infected patients should receive the same single-dose regimen for early syphilis, as multiple doses have not demonstrated improved outcomes 1, 6

Late Latent Syphilis and Tertiary Syphilis

Administer benzathine penicillin G 7.2 million units total as three doses of 2.4 million units intramuscularly at weekly intervals. 3, 1, 4

• This applies to late latent syphilis (infection >1 year duration), latent syphilis of unknown duration, and tertiary syphilis (gumma and cardiovascular syphilis) 3, 1
• If a dose is missed, an interval of 10-14 days between doses may be acceptable before restarting the sequence 1

Neurosyphilis

Administer aqueous crystalline penicillin G 18-24 million units per day intravenously (as 3-4 million units every 4 hours or continuous infusion) for 10-14 days. 3, 1, 7

• This regimen requires hospitalization or outpatient parenteral antibiotic therapy 8
• An alternative regimen is procaine penicillin 2.4 million units intramuscularly once daily PLUS probenecid 500 mg orally four times daily, both for 10-14 days 3, 1
• Critical pitfall: Procaine penicillin without probenecid does not achieve adequate CSF levels and is inadequate for neurosyphilis 1
• Many experts recommend additional therapy with benzathine penicillin G 2.4 million units intramuscularly weekly for 3 doses after completion of IV therapy 7

Indications for CSF Examination

Perform lumbar puncture before treatment in patients with: 1

• Neurologic or ophthalmic signs/symptoms
• Evidence of active tertiary syphilis
• Treatment failure (lack of fourfold titer decline)
• HIV infection with late latent syphilis or syphilis of unknown duration
• Serum nontreponemal titer ≥1:32

Penicillin-Allergic Patients (Non-Pregnant)

For primary, secondary, or early latent syphilis: doxycycline 100 mg orally twice daily for 14 days. 3, 1, 2

For late latent syphilis: doxycycline 100 mg orally twice daily for 28 days. 3, 1, 2

• Tetracycline 500 mg orally four times daily is an alternative (14 days for early syphilis, 28 days for late latent) 1
• 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, 2
• Azithromycin should NOT be used in the United States due to widespread macrolide resistance and documented treatment failures 1, 2

Pregnancy Considerations

All pregnant women with syphilis must be treated with penicillin—no exceptions. 1, 8, 2

• Penicillin is the only therapy with documented efficacy for preventing maternal transmission to the fetus and treating fetal infection 1, 2
• Pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment 1, 8, 2
• Some experts recommend a second dose of benzathine penicillin 2.4 million units intramuscularly 1 week after the initial dose for women with primary, secondary, or early latent syphilis 1
• Women treated during the second half of pregnancy are at risk for premature labor and/or fetal distress from Jarisch-Herxheimer reaction; they should seek immediate medical attention if they notice contractions or changes in fetal movements 1
• Screen all pregnant women for syphilis at first prenatal visit, during third trimester, and at delivery 1

Follow-Up and Monitoring

Perform quantitative nontreponemal serologic tests (RPR or VDRL) at 6 and 12 months after treatment for primary/secondary syphilis. 1

For latent syphilis, repeat tests at 6,12, and 24 months. 1

• A fourfold decline in titer is expected within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 1, 2
• Critical pitfall: Use the same nontreponemal test method (RPR or VDRL) throughout follow-up, as results cannot be directly compared between different methods 1
• HIV-infected patients require more frequent monitoring at 3,6,9,12, and 24 months 8

Treatment Failure Criteria

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 to decline at least fourfold within 6-12 months for early syphilis or 12-24 months for late syphilis

When treatment failure is suspected, perform lumbar puncture to evaluate for neurosyphilis unless reinfection is likely. 1

• Re-treatment typically involves three weekly injections of benzathine penicillin G 2.4 million units intramuscularly, unless CSF examination indicates neurosyphilis 1

Management of Sex Partners

Treat sex partners presumptively with benzathine penicillin G 2.4 million units intramuscularly if exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis, even if seronegative. 1, 8

• Time periods for 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 1

Important Clinical Considerations

• All patients with syphilis must be tested for HIV infection at the time of diagnosis 1, 8
• The Jarisch-Herxheimer reaction is an acute febrile reaction that may occur within 24 hours after any syphilis therapy, especially in early syphilis, and may include headache, myalgia, and fever 1
• Do not use oral penicillin preparations for syphilis treatment as they are ineffective 1
• Enhanced penicillin therapy (standard benzathine penicillin combined with high-dose oral amoxicillin and probenecid) did not improve clinical outcomes in early-stage syphilis and is not recommended 2