What is the recommended treatment for a patient with syphilis infection?

Treatment of Syphilis Infection

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

Treatment by Stage

Primary, Secondary, and Early Latent Syphilis

• Administer benzathine penicillin G 2.4 million units intramuscularly as a single dose 1, 2, 3
• Early latent syphilis is defined as infection acquired within the preceding year, documented by seroconversion, fourfold increase in titer, symptoms within the past year, or having a sex partner with documented early syphilis 1
• This single-dose regimen is equally effective in HIV-infected patients—do not use multiple doses unless treating late-stage disease 1, 4

Late Latent Syphilis and Tertiary Syphilis

• Administer benzathine penicillin G 2.4 million units intramuscularly once weekly for 3 consecutive weeks (total 7.2 million units) 1, 5, 2
• Before treating tertiary syphilis, perform CSF examination to exclude neurosyphilis, as the tertiary regimen is inadequate for CNS involvement 5
• If a dose is missed, an interval of 10-14 days between doses is acceptable before restarting the sequence 1

Neurosyphilis

• Administer aqueous crystalline penicillin G 18-24 million units IV daily (given as 3-4 million units every 4 hours or continuous infusion) for 10-14 days 6, 1, 5
• Alternative: procaine penicillin 2.4 million units IM once daily PLUS probenecid 500 mg orally four times daily for 10-14 days 6, 1
• Procaine penicillin without probenecid does not achieve adequate CSF levels and must not be used 1
• Some specialists recommend following neurosyphilis treatment with 3 weeks of benzathine penicillin 2.4 million units IM weekly, though no consensus exists 6

Penicillin-Allergic Patients

Non-Pregnant Adults

• For early syphilis (primary, secondary, early latent): doxycycline 100 mg orally twice daily for 14 days 1, 2, 7
• For late latent syphilis: doxycycline 100 mg orally twice daily for 28 days 1, 2, 7
• Doxycycline has a slightly lower success rate than penicillin, particularly in late and indeterminate syphilis 8
• Ceftriaxone 1 gram IM/IV daily for 10-14 days is a reasonable alternative based on randomized trial data showing comparable efficacy to benzathine penicillin 1
• Do not use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 1

Pregnant Women

• All pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no exceptions 1, 5, 2
• Penicillin is the only therapy proven to prevent maternal transmission and treat fetal infection 1, 2
• Tetracycline, doxycycline, erythromycin, azithromycin, and ceftriaxone are inadequate—erythromycin does not reliably cure fetal infection 1
• Screen all pregnant women for syphilis at first prenatal visit, during third trimester, and at delivery 1

Neurosyphilis in Penicillin-Allergic Patients

• Penicillin desensitization followed by IV penicillin is the preferred approach 6
• Ceftriaxone 2 grams IV daily for 10-14 days has limited supporting data but may be considered if desensitization is not feasible 6, 1
• Patients with severe penicillin allergy (Stevens-Johnson syndrome) may also be allergic to ceftriaxone as both are beta-lactam antibiotics 1

HIV-Infected Patients

• Use the same treatment regimens as HIV-negative patients for all stages of syphilis 1, 2, 4
• A single dose of benzathine penicillin is sufficient for early syphilis in HIV-infected patients—multiple doses do not improve outcomes 1, 4
• Closer follow-up is mandatory to detect treatment failure or disease progression 6, 1
• All HIV-infected patients with late latent syphilis or syphilis of unknown duration should undergo CSF examination before treatment 6
• Some specialists recommend CSF examination for all HIV-infected patients with syphilis, regardless of stage 6

Follow-Up and Monitoring

Serologic Monitoring

• Repeat quantitative nontreponemal tests (RPR or VDRL) at 3,6,9,12, and 24 months after treatment 6, 1
• Expect a fourfold decline in titer within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 1, 2
• Do not switch between RPR and VDRL when monitoring response, as results cannot be directly compared 1

Treatment Failure Criteria

• Treatment failure is defined as: persistent or recurring clinical signs/symptoms, sustained fourfold increase in nontreponemal titers, or failure of initially high titer to decline fourfold within expected timeframes 1, 5
• If treatment failure occurs, re-evaluate for HIV infection, perform CSF examination, and re-treat with three weekly injections of benzathine penicillin G 2.4 million units IM unless neurosyphilis is diagnosed 1, 5
• 15-25% of successfully treated patients remain "serofast" with persistent low titers (<1:8) that do not indicate treatment failure 1

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 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
• Long-term sex partners of patients with late syphilis should be evaluated clinically and serologically 2

Critical Pitfalls to Avoid

• Do not use oral penicillin preparations—they are completely ineffective for any stage of syphilis 1, 5
• Do not skip CSF examination before treating tertiary syphilis, as this may miss neurosyphilis requiring different treatment 5
• Do not use procaine penicillin without probenecid for neurosyphilis—it does not achieve adequate CSF levels 1
• Do not substitute non-penicillin antibiotics in pregnancy without desensitization 1, 5
• Warn patients about Jarisch-Herxheimer reaction, an acute febrile reaction with headache and myalgia that may occur within 24 hours of treatment, especially in early syphilis 1, 5
• In pregnant women treated during the second half of pregnancy, Jarisch-Herxheimer reaction may precipitate premature labor or fetal distress—advise immediate medical attention if contractions or changes in fetal movements occur 1

Special Considerations

Pediatric Dosing

• For children with acquired primary or secondary syphilis: benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose 1, 2
• 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 1
• Children require CSF examination to exclude neurosyphilis before treatment 1

All Patients

• Test all patients with syphilis for HIV infection 1
• Patients with syphilis should be evaluated for clinical evidence of CNS or ocular involvement regardless of disease stage 6