What is the recommended treatment for syphilis?

Syphilis Testing and Treatment

Diagnostic Testing

Syphilis diagnosis relies on serologic testing combined with clinical presentation, using both nontreponemal tests (VDRL, RPR) and treponemal tests (FTA-ABS, MHA-TP) to confirm infection. 1

• Darkfield examination and direct fluorescent antibody tests of lesion exudate provide definitive diagnosis for early syphilis when lesions are present 1
• Nontreponemal tests (VDRL, RPR) are used for initial screening and monitoring treatment response - a fourfold change in titer is clinically significant 1
• Treponemal tests confirm the diagnosis but correlate poorly with disease activity and should not be used to assess treatment response 2
• All patients diagnosed with syphilis must be tested for HIV 1
• CSF examination is indicated for patients with neurological signs/symptoms, tertiary syphilis, or those whose serological titers fail to decline appropriately 2

Common pitfall: Do not switch between different nontreponemal testing methods (VDRL vs RPR) when monitoring treatment response, as results cannot be directly compared 2

First-Line Treatment by Stage

Parenteral penicillin G is the only proven effective treatment for all stages of syphilis, with dosing determined by disease stage. 3, 2

Primary and Secondary Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose 3, 2, 1
• This regimen is recommended by the CDC for all patients with early-stage symptomatic disease 3
• Children with acquired primary/secondary syphilis: Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose 3

Early Latent Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose (same as primary/secondary) 3, 2
• Early latent is defined as syphilis acquired within the preceding year based on documented seroconversion, fourfold titer increase, symptom history, or partner with documented early syphilis 2

Late Latent Syphilis or Latent Syphilis of Unknown Duration

• Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM at 1-week intervals 3, 2, 1
• If a dose is missed, an interval of 10-14 days between doses may be acceptable before restarting the sequence 2

Tertiary Syphilis

• Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM at 1-week intervals 3, 2

Neurosyphilis

• Aqueous crystalline penicillin G 18-24 million units daily, administered as 3-4 million units IV every 4 hours for 10-14 days 1
• Aqueous crystalline penicillin G is the only recommended regimen for neurosyphilis 2

Critical warning: Oral penicillin preparations are completely ineffective for syphilis treatment and must never be used 2

Alternative Treatment for Penicillin-Allergic Patients

For non-pregnant adults with penicillin allergy:

• Primary and secondary syphilis: Doxycycline 100 mg orally twice daily for 14 days 3, 2, 1
• Late latent syphilis or latent syphilis of unknown duration: Doxycycline 100 mg orally twice daily for 28 days 3, 2

Absolute contraindication to alternatives: Pregnant women and patients with neurosyphilis cannot use doxycycline or other alternatives - they must undergo penicillin desensitization and receive penicillin therapy 3, 2

Special Populations

Pregnant Women

• Only penicillin G is proven effective for preventing maternal transmission to the fetus 3, 2
• Pregnant women with penicillin allergy must undergo desensitization and be treated with penicillin 3, 2
• Screen pregnant patients 3 times: at first prenatal visit, during third trimester, and at delivery 4
• Up to 40% of fetuses with in-utero syphilis exposure are stillborn or die during infancy if untreated 4

HIV-Infected Patients

• Treatment regimens are identical to those for non-HIV-infected patients 3, 2
• HIV-infected individuals may have more apparent clinical lesions, atypical chancres, and accelerated disease progression 2, 1
• May have atypical serologic responses but generally respond well to standard treatment 2

Follow-Up and Monitoring

Quantitative nontreponemal serologic tests must be repeated at 6,12, and 24 months after treatment 3, 2, 1

• Expected response: 4-fold decline in titer within 6 months for primary/secondary syphilis 3, 1
• Expected response: 4-fold decline in titer within 12-24 months for late syphilis 3
• Treatment failure is defined as failure of nontreponemal test titers to decline 4-fold within 6 months after therapy for primary or secondary syphilis 3, 2, 1

CSF examination is indicated if:

• Titers increase 4-fold 3
• An initially high titer fails to decline at least 4-fold within 12-24 months 3
• Neurological signs or symptoms develop 3

Management of treatment failure:

• Re-treat with weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks 3
• Re-evaluate for HIV infection 2
• Perform CSF examination 2

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 3, 2

• Persons exposed >90 days before diagnosis should be treated presumptively if serologic results are not immediately available and follow-up is uncertain 2
• Long-term sex partners of patients with late syphilis should be evaluated clinically and serologically 3

Important Clinical Considerations

Jarisch-Herxheimer Reaction:

• An acute febrile reaction may occur within 24 hours after any syphilis therapy, especially in early syphilis 2
• Symptoms include headache, myalgia, fever, and other constitutional symptoms 2
• Patients must be informed about this possible adverse reaction before treatment 2

Benzathine Penicillin G Shortage:

• Recent supply shortages have complicated first-line treatment availability 5
• When BPG is unavailable, doxycycline serves as an alternative for non-pregnant patients with early syphilis, though it requires extended searching for BPG supplies 5