What is the recommended treatment regimen and dosage for syphilis in adults?

Syphilis Treatment and Dosage

Primary and Secondary Syphilis

For primary and secondary syphilis in adults, administer benzathine penicillin G 2.4 million units intramuscularly as a single dose. 1, 2, 3

• This single-dose regimen has over 40 years of proven effectiveness in healing lesions, preventing sexual transmission, and preventing late sequelae 3
• The same regimen applies regardless of HIV status 3
• All patients with syphilis should be tested for HIV infection 1

Pediatric Dosing for Primary/Secondary Syphilis

• Children with acquired syphilis: benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) as a single dose 1, 2
• Children require CSF examination to exclude neurosyphilis before treatment 1

Early Latent Syphilis

Treat early latent syphilis with benzathine penicillin G 2.4 million units IM as a single dose. 1, 2, 4, 3

• 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 2, 4, 3
• Pediatric dose: benzathine penicillin G 50,000 units/kg IM (up to 2.4 million units) as a single dose 2, 4

Late Latent Syphilis and Syphilis of Unknown Duration

For late latent syphilis or latent syphilis of unknown duration, administer benzathine penicillin G 7.2 million units total as three doses of 2.4 million units IM at weekly intervals. 1, 2, 4, 3

• All other cases not meeting early latent criteria should be treated as late latent syphilis 3
• Pediatric dose: benzathine penicillin G 50,000 units/kg IM (up to 2.4 million units) administered as three doses at 1-week intervals (total 150,000 units/kg up to 7.2 million units) 2, 4

Pre-Treatment CSF Examination Indications

Perform lumbar puncture before treating late latent syphilis if any of the following are present: 2, 4, 3

• Neurologic or ophthalmic signs or symptoms
• Evidence of active tertiary syphilis (aortitis, gumma, iritis)
• Treatment failure
• HIV infection with late latent syphilis or syphilis of unknown duration
• Serum nontreponemal titer ≥1:32 (unless duration of infection is known to be <1 year)

Neurosyphilis

For neurosyphilis, administer 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. 2, 5

• Many experts recommend additional therapy with benzathine penicillin G 2.4 million units IM weekly for 3 doses after completion of IV therapy 5
• If CSF shows abnormalities consistent with neurosyphilis, treat as neurosyphilis regardless of stage 4

Penicillin Allergy Alternatives (Non-Pregnant Patients Only)

For penicillin-allergic non-pregnant adults with primary, secondary, or early latent syphilis, use doxycycline 100 mg orally twice daily for 14 days. 1, 2, 3, 6

For penicillin-allergic non-pregnant adults with late latent syphilis, use doxycycline 100 mg orally twice daily for 28 days. 1, 2, 3, 6

• Doxycycline is preferred over tetracycline due to better compliance with twice-daily versus four-times-daily dosing 3
• CSF examination must exclude neurosyphilis before using alternative regimens 4
• Tetracycline 500 mg orally four times daily is an alternative (14 days for early latent, 28 days for late latent) 1

Critical Caveat: Pregnancy

Pregnant patients who are penicillin-allergic MUST undergo desensitization followed by penicillin treatment—there are no acceptable alternatives. 1, 2, 4

• Only penicillin prevents congenital syphilis 2
• Never substitute with inadequate alternatives in pregnancy 2

Azithromycin Warning

Azithromycin should NOT be used in the United States due to widespread macrolide resistance and documented treatment failures. 2

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 quantitative nontreponemal tests at 6,12, and 24 months. 1, 2, 4, 3

Treatment Failure Criteria

Re-treat and evaluate for HIV if any of the following occur: 1, 3

• 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
• Perform CSF examination when treatment failure is suspected 1, 2

Important Monitoring Notes

• Do not use different testing methods (e.g., switching between VDRL and RPR) when monitoring serologic response, as results cannot be directly compared 2
• Do not rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity 2
• HIV-infected patients require closer follow-up every 3 months 3

Management of Sex Partners

Treat sex partners presumptively if exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis, even if seronegative. 2

Treat partners exposed >90 days before diagnosis presumptively if serologic test results are not immediately available and follow-up is uncertain. 2

• 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

Special Considerations

Jarisch-Herxheimer Reaction

• An acute febrile reaction may occur within 24 hours after any syphilis therapy, especially in early syphilis 2
• May include headache, myalgia, fever, and other symptoms 2
• In pregnant women during second half of pregnancy, may precipitate premature labor or fetal distress 2
• Women should seek immediate medical attention if they notice changes in fetal movements or contractions after treatment 2

Missed Doses in Weekly Therapy

• If a dose is missed during weekly therapy for late syphilis, an interval of 10-14 days between doses might be acceptable before restarting the sequence 2, 7
• Missed doses are NOT acceptable for pregnant women 7

Critical Pitfall to Avoid

Do not use oral penicillin preparations for syphilis treatment—they are ineffective. 2