What is the recommended treatment for latent syphilis compared to primary and secondary syphilis?

Treatment of Latent Syphilis vs Primary and Secondary Syphilis

For primary, secondary, and early latent syphilis, a single intramuscular injection of benzathine penicillin G 2.4 million units is recommended, whereas late latent syphilis or latent syphilis of unknown duration requires three weekly injections of benzathine penicillin G 2.4 million units (total 7.2 million units). 1, 2

Treatment Regimens by Stage

Primary and Secondary Syphilis

• Single dose: Benzathine penicillin G 2.4 million units IM as a one-time injection 1, 2
• This single-dose regimen is highly effective, with 76% of patients achieving serologic response (seroreversion or ≥2 dilution decrease in RPR titer) at 6 months 3
• Recent high-quality evidence confirms that one dose is noninferior to three doses for early syphilis, including in HIV-infected patients 3

Early Latent Syphilis

• Single dose: Benzathine penicillin G 2.4 million units IM 1, 2
• Early latent syphilis is defined as infection acquired within the preceding year, documented by: seroconversion, fourfold increase in titer, history of primary/secondary symptoms within the past year, or having a sex partner with documented early syphilis 1
• Treatment is identical to primary and secondary syphilis because the infection is still within the first year 4, 1

Late Latent Syphilis or Latent Syphilis of Unknown Duration

• Three-dose regimen: Benzathine penicillin G 7.2 million units total, administered as 2.4 million units IM weekly for three consecutive weeks 4, 1, 2
• This extended regimen is necessary because the infection has been present for more than one year or the duration is uncertain 4, 1
• If a patient misses a dose during weekly therapy, an interval of 10-14 days between doses might be acceptable before restarting the sequence, though this is NOT acceptable for pregnant patients who must repeat the full course 4

Key Differences in Management

Pre-Treatment Evaluation

• Late latent syphilis requires more extensive evaluation: CSF examination is indicated if patients have neurologic or ophthalmic signs/symptoms, evidence of active tertiary syphilis, treatment failure, HIV infection with late latent syphilis, or nontreponemal titer ≥1:32 4, 1
• Primary and secondary syphilis typically do not require routine CSF examination unless neurosyphilis is clinically suspected 4

Follow-Up Monitoring

• Primary/secondary syphilis: Quantitative nontreponemal tests at 6 and 12 months, expecting fourfold decline in titer within 6 months 1, 2
• Latent syphilis: Quantitative nontreponemal tests at 6,12, and 24 months, with slower expected decline (fourfold decline within 12-24 months) 4, 1
• HIV-infected patients require more frequent monitoring at 3,6,9,12, and 24 months 5

Penicillin Allergy Alternatives

For Non-Pregnant Patients

• Primary, secondary, or early latent syphilis: Doxycycline 100 mg orally twice daily for 14 days 1, 2, 6
• Late latent syphilis: Doxycycline 100 mg orally twice daily for 28 days (double the duration) 4, 1, 6
• Tetracycline 500 mg orally four times daily is an alternative (14 days for early, 28 days for late latent) 4, 1
• Critical caveat: These alternatives have less documented efficacy than penicillin and require close serologic and clinical follow-up 4

For Pregnant Patients

• No exceptions: All pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment 1, 5, 2
• Penicillin is the only therapy with documented efficacy for preventing maternal transmission and treating fetal infection 1, 2
• Doxycycline, tetracycline, erythromycin, azithromycin, and ceftriaxone are inadequate in pregnancy—erythromycin does not reliably cure fetal infection 1

Special Considerations

HIV-Infected Patients

• Use the same penicillin regimens as non-HIV-infected patients (single dose for early, three doses for late latent) 1, 2
• Recent evidence shows no benefit to multiple doses for early syphilis in HIV-infected patients compared to single dose 1
• However, closer follow-up is mandatory to detect potential treatment failure 1

Ceftriaxone as Alternative

• Ceftriaxone 1 gram IM/IV daily for 10-14 days may be considered based on randomized trial data showing comparable efficacy to benzathine penicillin 1
• Major limitations: Optimal dose and duration not definitively established; evidence for late latent and tertiary syphilis is extremely limited 1
• Patients with severe penicillin allergy may also be allergic to ceftriaxone (both are beta-lactams) 1

Common Pitfalls to Avoid

• Do not use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 1
• Do not use oral penicillin preparations for syphilis treatment—they are ineffective 1
• Do not switch testing methods (e.g., between VDRL and RPR) when monitoring serologic response, as results cannot be directly compared 1
• Do not rely solely on treponemal test titers to assess treatment response—they correlate poorly with disease activity 1
• Remember that 15-25% of successfully treated patients remain "serofast" with persistent low titers (<1:8) that do not indicate treatment failure 1

Partner Management

• Persons exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis should receive presumptive treatment with benzathine penicillin G 2.4 million units IM, even if seronegative 1, 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

Jarisch-Herxheimer Reaction

• This acute febrile reaction may occur within 24 hours after any syphilis therapy, especially in early syphilis 1, 2
• Patients should be informed about possible symptoms including headache, myalgia, and fever 1, 2
• Pregnant women treated during the second half of pregnancy are at risk for premature labor and/or fetal distress and should seek immediate medical attention if they notice contractions or changes in fetal movements 1