What antibiotics are recommended for the treatment of syphilis?

Antibiotics for Syphilis Treatment

First-Line Treatment: Benzathine Penicillin G

Parenteral penicillin G is the preferred drug for treatment of all stages of syphilis, with benzathine penicillin G being the specific formulation of choice for most presentations. 1, 2

Primary and Secondary Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose is the recommended treatment. 1, 3, 2, 4
• This regimen achieves 90-100% treatment success rates in early syphilis. 5
• The single-dose approach is both simple and highly effective for early-stage disease. 6

Early Latent Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose (same as primary/secondary syphilis). 1, 2
• Early latent syphilis is defined as infection acquired within the preceding year, documented by seroconversion, fourfold titer increase, history of symptoms, or exposure to a partner with documented early syphilis. 1

Late Latent Syphilis and Latent Syphilis of Unknown Duration

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals. 7, 1, 2
• This extended regimen is necessary to prevent progression of late complications. 7

Tertiary Syphilis

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals. 1, 2

Neurosyphilis

• Aqueous crystalline penicillin G 18-24 million units per day IV (administered as 3-4 million units every 4 hours) for 10-14 days. 3
• CSF examination is recommended for patients with neurological signs/symptoms, tertiary syphilis, or those whose serological titers fail to decline appropriately. 1

Alternative Treatment for Penicillin-Allergic Patients

Non-Pregnant Adults with Early Syphilis

• Doxycycline 100 mg orally twice daily for 14 days is the recommended alternative. 1, 3, 2, 8
• This regimen has been used for many years with acceptable efficacy, though less rigorously studied than penicillin. 7, 9
• Compliance is better with doxycycline than tetracycline due to fewer gastrointestinal side effects. 7

Non-Pregnant Adults with Late Latent Syphilis

• Doxycycline 100 mg orally twice daily for 28 days (4 weeks). 1, 3, 2, 8

Ceftriaxone as an 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
• The optimal dose and duration have not been definitively established, but regimens providing 8-10 days of treponemicidal levels are recommended. 7

Critical Pitfalls and Special Populations

Pregnant Women

• Pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no exceptions. 1, 2
• Penicillin is the only therapy with documented efficacy for preventing maternal transmission and congenital syphilis. 1, 2
• Doxycycline and other alternatives are contraindicated in pregnancy. 7
• Screen all pregnant women at first prenatal visit, during third trimester, and at delivery. 1

Neurosyphilis and Ocular/Otic Syphilis

• Penicillin desensitization is mandatory for penicillin-allergic patients with neurosyphilis—there are no acceptable alternatives. 1, 3
• Aqueous crystalline penicillin G remains the only proven effective therapy. 7

HIV-Infected Patients

• Use the same treatment regimens as non-HIV-infected patients. 1, 2
• Available data suggest no clinical benefit to multiple doses of benzathine penicillin for early syphilis in HIV-infected patients compared to a single dose. 7, 1
• However, closer follow-up is mandatory (at 3-month intervals instead of 6-month intervals) to detect potential treatment failure. 7, 1

Important Warnings

Azithromycin

• Do NOT use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures. 1

Oral Penicillin

• Do not use oral penicillin preparations—they are ineffective for syphilis treatment. 1

Jarisch-Herxheimer Reaction

• An acute febrile reaction may occur within 24 hours after any syphilis therapy, especially in early syphilis. 1, 3
• Patients should be informed about possible headache, myalgia, and fever. 1
• In pregnant women during the second half of pregnancy, this reaction may precipitate premature labor or fetal distress. 1

Follow-Up and Treatment Response

Serologic Monitoring

• Repeat quantitative nontreponemal tests (RPR or VDRL) at 3,6,12, 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
• Do not switch between different testing methods (VDRL vs RPR) when monitoring response—results cannot be directly compared. 1

Treatment Failure

• Treatment failure is defined as failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis. 7, 3, 2
• Re-treat with weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks. 2
• Perform CSF examination to exclude neurosyphilis. 7, 1
• Re-evaluate for HIV infection. 7, 1

Management of Sexual Partners

• Persons exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis should be treated presumptively, even if seronegative. 1, 2
• Persons exposed >90 days before diagnosis should be treated presumptively if serologic results are not immediately available and follow-up is uncertain. 1, 2