What is the recommended treatment for syphilis?

Syphilis: History, Examination, Transmission, and Treatment

Transmission

Syphilis is transmitted exclusively through direct contact with infectious mucocutaneous lesions during vaginal, anal, or oral sex, or vertically from mother to fetus via the placenta during pregnancy. 1, 2

• Sexual transmission occurs only when syphilitic lesions are present, which are uncommon after the first year of infection 1
• Individuals at highest risk include people with HIV, those engaging in condomless sex with multiple partners, and men who have sex with men (MSM)—who comprised one-third of all males with primary and secondary syphilis in 2023 2
• The causative organism is Treponema pallidum, a gram-negative spirochete bacterium 2

Clinical History and Physical Examination

Primary Syphilis

• Characterized by painless anogenital lesions (chancres) that appear at the site of inoculation 2
• These lesions are highly infectious and typically heal spontaneously within 3-6 weeks even without treatment 2

Secondary Syphilis

• Presents with a diffuse rash (often involving palms and soles), mucocutaneous lesions, and generalized lymphadenopathy 2
• This stage represents disseminated infection and is also highly infectious 1

Latent Syphilis

• Early latent syphilis is defined as infection acquired within the preceding year, based on documented seroconversion, fourfold increase in titer, history of symptoms, or having a sex partner with documented early syphilis 3
• Late latent syphilis refers to infection of more than one year's duration or unknown duration 3
• Patients are seroreactive but demonstrate no clinical evidence of disease 1

Tertiary Syphilis

• Can manifest as cardiovascular syphilis, gummatous disease, or neurosyphilis 3
• Neurosyphilis can occur at any stage and may present with meningitis, uveitis, hearing loss, or stroke 2

Diagnostic Approach

Diagnosis relies on serologic testing combined with clinical history and physical examination findings consistent with active or latent infection. 2

• Use quantitative nontreponemal tests (VDRL or RPR) for initial screening and monitoring treatment response 1, 3
• Critical: Use the same testing method (VDRL or RPR) by the same laboratory for sequential tests, as results are not directly comparable between methods 4
• Treponemal tests (FTA-ABS, TPHA) remain positive for life and should NOT be used to assess treatment response 4
• For neurosyphilis diagnosis, CSF examination showing elevated WBC count (>5 cells/mm³), elevated protein, or reactive VDRL-CSF is diagnostic 1
• CSF examination is recommended for patients with neurological signs/symptoms, tertiary syphilis, or those whose serological titers fail to decline appropriately 3, 5

Treatment Recommendations

Primary and Secondary Syphilis

Benzathine penicillin G 2.4 million units IM as a single dose is the definitive treatment for primary and secondary syphilis. 3, 2

• This regimen has a 98.2% success rate across all stages when used appropriately 6
• For penicillin-allergic non-pregnant adults: Doxycycline 100 mg orally twice daily for 14 days 3, 7
• Pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no alternatives are acceptable 1, 3

Early Latent Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose 3
• For penicillin-allergic non-pregnant adults: Doxycycline 100 mg orally twice daily for 14 days 3, 7

Late Latent Syphilis and Tertiary Syphilis

• Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals 3
• For penicillin-allergic non-pregnant adults: Doxycycline 100 mg orally twice daily for 28 days 3, 7
• If a dose is missed during weekly therapy, an interval of 10-14 days between doses might be acceptable before restarting the sequence 3, 5

Neurosyphilis

Aqueous crystalline penicillin G 18-24 million units per day IV (administered as 3-4 million units IV every 4 hours or by continuous infusion) for 10-14 days is the only proven effective treatment for neurosyphilis. 3, 8

• Alternative regimen: Procaine penicillin 2.4 million units IM once daily plus probenecid 500 mg orally four times daily for 10-14 days 8
• Penicillin-allergic patients must undergo desensitization—there are no acceptable alternatives 3, 8

Special Populations

Pregnancy

• Parenteral penicillin G is the ONLY therapy with documented efficacy for preventing maternal transmission and treating fetal infection 1, 3, 6
• Screen all pregnant women at first prenatal visit, during third trimester (28 weeks), and at delivery 1, 3, 2
• Some experts recommend an additional dose of benzathine penicillin 2.4 million units IM one week after the initial dose for women with primary, secondary, or early latent syphilis 1
• The highest risk of fetal treatment failure (94.7% success rate) occurs with maternal secondary syphilis 6
• Warning: Jarisch-Herxheimer reaction during second half of pregnancy may precipitate premature labor or fetal distress—women should seek immediate medical attention if they notice contractions or decreased fetal movements 1, 3

HIV-Infected Patients

• Use the same treatment regimens as non-HIV-infected patients 3, 8
• Require more frequent monitoring at 3-month intervals instead of 6-month intervals 1, 4
• May have atypical serologic responses but generally respond well to standard treatment 3, 8
• Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis compared to a single dose 3

Follow-Up and Monitoring

Clinical and serologic evaluation should occur at 6 and 12 months after treatment for primary and secondary syphilis, with more frequent evaluation (3-month intervals) if follow-up is uncertain. 4

• A fourfold decline in nontreponemal titer is expected within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 3, 4
• Treatment failure is defined as failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis 3, 4
• A sustained fourfold increase in titer or persistent/recurrent clinical signs indicates treatment failure or reinfection 1, 4

Management of Treatment Failure

• Re-evaluate for HIV infection 1, 4
• Perform CSF examination unless reinfection is certain 1, 4
• Re-treat with three weekly injections of benzathine penicillin G 2.4 million units IM, unless CSF examination indicates neurosyphilis 1, 4

Management of Sexual Partners

Persons exposed within 90 days preceding the diagnosis of primary, secondary, or early latent syphilis should be treated presumptively even if seronegative. 1, 3

• Persons exposed >90 days before diagnosis should be treated presumptively if serologic results are not immediately available and follow-up is uncertain 1, 3
• Partner testing and treatment are critical to prevent reinfection and further community transmission 9

Critical Pitfalls to Avoid

• Never use oral penicillin preparations—they are completely ineffective for syphilis treatment 3
• Never use erythromycin in pregnancy—it does not reliably cure fetal infection 1
• Never use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 3
• Never switch between VDRL and RPR when monitoring treatment response—results cannot be directly compared 1, 4
• Do not delay treatment in pregnancy due to concerns about Jarisch-Herxheimer reaction—the risk of untreated syphilis far exceeds this concern 1

Jarisch-Herxheimer Reaction

• An acute febrile reaction often accompanied by headache and myalgia that occurs within 24 hours after initiating therapy 1, 3
• Most common in patients with early syphilis 1
• Patients should be informed about this expected reaction, but it should never delay necessary treatment 1, 3
• Antipyretics may be recommended, though no proven methods prevent this reaction 1