What is the treatment for syphilis?

Treatment of Syphilis

Benzathine penicillin G is the definitive treatment for all stages of syphilis, with dosing determined by disease stage: a single 2.4 million unit IM injection for early syphilis (primary, secondary, and early latent) or three weekly 2.4 million unit IM injections for late latent syphilis and tertiary syphilis. 1, 2, 3

Primary and Secondary Syphilis Treatment

• Administer benzathine penicillin G 2.4 million units IM as a single dose for all patients with primary or secondary syphilis 1, 2, 4
• This regimen has over 40 years of proven clinical effectiveness in achieving cure, healing lesions, preventing sexual transmission, and preventing late sequelae 2
• The same single-dose regimen applies regardless of HIV status 2, 5
• A randomized trial in HIV-infected patients demonstrated that single-dose therapy achieved 93% treatment success (per-protocol analysis), with no significant benefit from three-dose regimens 5

Early Latent Syphilis Treatment

• Give benzathine penicillin G 2.4 million units IM as a single dose for early latent syphilis 1, 2
• Early latent syphilis is defined as syphilis acquired within the preceding year, documented by seroconversion, fourfold increase in titer, history of symptoms of primary or secondary syphilis within the past year, or having a sex partner with documented early syphilis 6, 2
• All other cases that do not meet these criteria should be treated as late latent syphilis 2

Late Latent Syphilis and Tertiary Syphilis Treatment

• Administer benzathine penicillin G 7.2 million units total as three doses of 2.4 million units IM each at 1-week intervals for late latent syphilis, latent syphilis of unknown duration, or tertiary syphilis 1, 2, 4
• If a dose is missed during weekly therapy, an interval of 10-14 days between doses might be acceptable before restarting the sequence 1
• For HIV-infected patients with late latent syphilis and normal CSF examination, use the same three-dose regimen 1

Neurosyphilis Treatment

• Treat with aqueous crystalline penicillin G 18-24 million units per day IV (administered as 3-4 million units IV every 4 hours) for 10-14 days for neurosyphilis 1, 4
• CSF examination is recommended 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 2

Alternative Regimens for Penicillin Allergy

Non-Pregnant Adults

• For primary, secondary, or early latent syphilis: doxycycline 100 mg orally twice daily for 14 days 1, 2, 4, 7
• For late latent syphilis: doxycycline 100 mg orally twice daily for 28 days 2, 4, 7
• Doxycycline is preferred over tetracycline due to better compliance with twice-daily versus four-times-daily dosing 2

Critical Caveat: Pregnant Women and Neurosyphilis

• Pregnant women and patients with neurosyphilis who are penicillin-allergic MUST undergo desensitization followed by penicillin treatment 6, 1, 4
• Penicillin is the only therapy with documented efficacy for preventing maternal transmission and congenital syphilis 1
• Never substitute with inadequate alternatives in pregnancy 1

Azithromycin Should NOT Be Used

• Azithromycin should NOT be used in the United States due to widespread macrolide resistance and documented treatment failures 1
• Emergence of macrolide-resistant T. pallidum has essentially precluded the empirical use of azithromycin 8

Ceftriaxone as Alternative

• 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
• However, data on ceftriaxone remain limited, and single-dose ceftriaxone therapy is not effective 6

Pediatric Dosing

• For early latent syphilis in children: benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose 6
• For late latent syphilis in children: benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units, for three total doses at 1-week intervals (total 150,000 units/kg up to adult total dose of 7.2 million units) 6
• Children diagnosed with syphilis should have a CSF examination to exclude neurosyphilis 6

Follow-Up and Monitoring

• Perform quantitative nontreponemal serologic tests (RPR or VDRL) at 3,6,12, and 24 months after treatment 1, 4
• A fourfold decline in titer is expected within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 1, 4
• Treatment failure is defined as failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis, or persistent/recurring signs and symptoms 2, 4
• If treatment failure is suspected, re-evaluate for HIV infection and perform CSF examination 1

Critical Pitfall: Do Not Switch Testing Methods

• 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 rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity 1

Special Populations

HIV-Infected Patients

• HIV-infected patients receive the same penicillin regimens as HIV-negative patients 2, 5
• Require closer follow-up every 3 months to detect potential treatment failure or disease progression 1, 2
• Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis in HIV-infected patients compared to a single dose 1, 5

Pregnant Women

• Screen all pregnant women for syphilis at first prenatal visit, during third trimester, and at delivery 1
• Treat with parenteral penicillin G appropriate for their stage of syphilis 4
• Up to 40% of fetuses with in-utero exposure to syphilis are stillborn or die from their infection during infancy 3
• Jarisch-Herxheimer reaction during 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

Management of Sex Partners

• 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

Jarisch-Herxheimer Reaction

• An acute febrile reaction with headache, myalgia, and other symptoms may occur within 24 hours after any syphilis therapy, especially in early syphilis 1, 4
• Patients should be informed about this possible adverse reaction before treatment 1

Critical Pitfalls to Avoid

• Do not use oral penicillin preparations for syphilis treatment as they are ineffective 1
• Administer adequate amounts of fluid along with capsule and tablet forms of drugs to wash down the drugs and reduce the risk of esophageal irritation and ulceration 7
• All patients with syphilis should be tested for HIV 4, 3