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

Syphilis Treatment

First-Line Treatment: Benzathine Penicillin G

Benzathine penicillin G is the preferred treatment for all stages of syphilis, with dosing determined by disease stage. 1, 2

Primary and Secondary Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose is the recommended treatment 1, 2, 3
• This single injection is highly effective, with serum becoming negative within 1 year for primary syphilis and within 2 years for secondary syphilis 4
• Children with acquired syphilis require benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) as a single dose 1, 2

Early Latent Syphilis

• Same regimen as primary/secondary: benzathine penicillin G 2.4 million units IM as a single dose 1, 2
• Early latent syphilis is defined as infection acquired within the preceding year, documented by seroconversion, fourfold titer increase, recent symptoms, or partner with documented early syphilis 1

Late Latent Syphilis and Tertiary Syphilis

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals 5, 1, 2, 6
• If a weekly dose is missed, an interval of 10-14 days between doses is acceptable before restarting the sequence 1
• All patients with tertiary syphilis must undergo CSF examination before treatment to exclude neurosyphilis 1, 6

Neurosyphilis

• Aqueous crystalline penicillin G 18-24 million units IV daily (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days 5, 1
• Alternative regimen: Procaine penicillin 2.4 million units IM daily PLUS probenecid 500 mg orally four times daily for 10-14 days 5, 1
• Some experts recommend following neurosyphilis treatment with benzathine penicillin 2.4 million units IM to provide comparable total duration of therapy 5
• CSF examination is mandatory for patients with neurologic/ophthalmic symptoms, tertiary syphilis, treatment failure, HIV with late latent syphilis, or nontreponemal titer ≥1:32 1

Alternative Treatments for Penicillin-Allergic Patients

Non-Pregnant Adults

• For primary, secondary, or early latent syphilis: 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
• Tetracycline 500 mg orally four times daily is an alternative (14 days for early syphilis, 28 days for late syphilis), though compliance is typically better with doxycycline 1, 6
• 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
• Do NOT use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 1

Pregnant Women

• Pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no exceptions 1, 2, 6
• Penicillin is the only therapy with documented efficacy for preventing maternal transmission to the fetus and treating fetal infection 1, 2
• Some experts recommend a second dose of benzathine penicillin 2.4 million units IM one week after the initial dose for pregnant women with primary, secondary, or early latent syphilis 1
• Tetracycline, doxycycline, erythromycin, azithromycin, and ceftriaxone are inadequate—erythromycin does not reliably cure fetal infection 1

Critical Caveat for Ceftriaxone

• Patients with severe penicillin allergy (such as Stevens-Johnson syndrome) may also be allergic to ceftriaxone, as both are beta-lactam antibiotics 1
• Evidence for ceftriaxone in late latent syphilis and tertiary syphilis is extremely limited 1
• For neurosyphilis, if ceftriaxone must be used, the dose is 2 grams daily IV (not IM) for 10-14 days, with very limited supporting data 1

Special Populations

HIV-Infected Patients

• Treatment regimens are the same as for non-HIV-infected patients 1, 2
• HIV-infected patients require more frequent monitoring at 3-month intervals due to higher risk of treatment failure 6
• Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis in HIV-infected patients compared to a single dose 1
• All patients with syphilis should be tested for HIV 5, 1

Pediatric Patients

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

Follow-Up and Monitoring

Serologic Testing Schedule

• Quantitative nontreponemal serologic tests (RPR or VDRL) should be repeated at 6 and 12 months after treatment for primary/secondary syphilis 1, 2
• For latent syphilis, repeat at 6,12, and 24 months 1, 2
• A fourfold decline in titer is expected within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 1, 2, 3

Treatment Failure Criteria

• Treatment failure is defined as failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis 1, 2
• Other indicators: persistent or recurring signs/symptoms, or sustained fourfold increase in nontreponemal titers 1, 6
• If treatment failure is suspected, re-evaluate for HIV infection and perform CSF examination to exclude neurosyphilis 1, 6
• Re-treatment typically involves three weekly injections of benzathine penicillin G 2.4 million units IM, unless CSF examination indicates neurosyphilis requiring IV penicillin 1, 6

Neurosyphilis Follow-Up

• If CSF pleocytosis was present initially, repeat CSF examination every 6 months until cell count is normal 5
• If cell count has not decreased after 6 months, or if CSF is not entirely normal after 2 years, re-treatment should be considered 5

Important Testing Caveats

• 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
• Treponemal tests (FTA-ABS, TP-PA) remain positive for life and should not be used to monitor treatment response 6
• 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

• Persons exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis should be treated presumptively, 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
• Persons exposed >90 days before diagnosis should be treated presumptively if serologic test results are not immediately available and follow-up is uncertain 1
• Long-term sex partners of patients with late syphilis should be evaluated clinically and serologically 2

Important Clinical Considerations

Jarisch-Herxheimer Reaction

• The Jarisch-Herxheimer reaction is an acute febrile reaction that may occur within 24 hours after any syphilis therapy, especially in early syphilis 1, 6
• Symptoms include fever, headache, myalgia, and other constitutional symptoms 1, 8
• Patients should be informed about this possible adverse reaction before treatment 1
• In pregnant women treated during the second half of pregnancy, this reaction may precipitate premature labor or fetal distress 1
• Women should seek immediate medical attention if they notice contractions or changes in fetal movements after treatment 1

Pregnancy Screening

• Screen all pregnant women for syphilis at first prenatal visit, during third trimester, and at delivery 1, 3
• Up to 40% of fetuses with in-utero exposure to syphilis are stillborn or die from their infection during infancy 3

Prevention Strategies

• Screening of sexually active people aged 15 to 44 years at least once and at least annually for those at increased risk 3
• Counseling about condom use 3
• Offering doxycycline postexposure prophylaxis (200 mg doxycycline taken within 72 hours after sex) to men who have sex with men and transgender women with a history of sexually transmitted infection in the past year 3

Common Pitfalls to Avoid

• Do not use oral penicillin preparations for syphilis treatment as they are ineffective 1
• Do not use procaine penicillin without probenecid for neurosyphilis, as it does not achieve adequate CSF levels 1
• Patients being treated for gonococcal infection should have a serologic test for syphilis before receiving penicillin 9
• All cases of penicillin-treated syphilis should receive adequate follow-up including clinical and serological examinations 9