Syphilis Workup and Treatment
Diagnostic Workup
All patients with suspected syphilis require serologic testing with both nontreponemal tests (RPR or VDRL) and confirmatory treponemal tests (FTA-ABS or MHA-TP). 1, 2
Initial Diagnostic Steps
- Darkfield examination or direct fluorescent antibody testing of lesion exudate provides definitive diagnosis in early syphilis with visible lesions. 2
- Nontreponemal tests (RPR/VDRL) are quantitative and used for both diagnosis and monitoring treatment response. 1, 2
- Treponemal tests confirm the diagnosis but remain positive for life and cannot be used to monitor treatment response. 1, 2
- A fourfold change in nontreponemal titer (e.g., from 1:16 to 1:4) is clinically significant. 2
Critical Additional Testing
- All patients diagnosed with syphilis must be tested for HIV infection. 1, 2
- CSF examination is mandatory before treating tertiary syphilis to exclude neurosyphilis, which requires entirely different treatment. 3
- CSF examination is also indicated for patients with neurological signs/symptoms, treatment failure (titers not declining appropriately), or HIV infection with late syphilis. 1, 3
Pregnancy-Specific Screening
- Screen all pregnant women at first prenatal visit, during third trimester (28 weeks), and at delivery. 4, 1
- Any woman delivering a stillborn infant after 20 weeks gestation must be tested for syphilis. 4
- In high-prevalence areas, perform RPR screening and immediate treatment when pregnancy is diagnosed. 4
Treatment by Stage
Primary and Secondary Syphilis
Benzathine penicillin G 2.4 million units IM as a single dose is the definitive treatment. 1, 2, 5
- This single injection provides treponemicidal levels for the necessary 7-10 days. 6
- For penicillin-allergic non-pregnant adults: doxycycline 100 mg orally twice daily for 14 days. 1, 2
- Ceftriaxone 1 gram IV/IM daily for 10 days is a reasonable alternative based on randomized trial data showing comparable efficacy. 1
- Never use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures. 1
Early Latent Syphilis
Benzathine penicillin G 2.4 million units IM as a single dose. 1
- Early latent is defined as syphilis acquired within the preceding year based on documented seroconversion, fourfold titer increase, history of symptoms, or sex partner with documented early syphilis. 1
- For penicillin-allergic non-pregnant adults: doxycycline 100 mg orally twice daily for 14 days. 1
Late Latent Syphilis and Latent Syphilis of Unknown Duration
Benzathine penicillin G 7.2 million units total: three doses of 2.4 million units IM given at weekly intervals. 1, 3, 2
- For penicillin-allergic non-pregnant adults: doxycycline 100 mg orally twice daily for 28 days. 1
- If a dose is missed, an interval of 10-14 days between doses may be acceptable before restarting the sequence. 1
- Only 44% of patients become seronegative within 5 years; 56% maintain persistently positive titers despite adequate treatment. 7
Tertiary Syphilis
Benzathine penicillin G 7.2 million units total: three doses of 2.4 million units IM given at weekly intervals. 1, 3
- CRITICAL: Perform CSF examination first to exclude neurosyphilis—if present, the entire treatment regimen changes to IV aqueous penicillin. 3
- The tertiary syphilis regimen is inadequate for CNS involvement. 3
- Some specialists treat all cardiovascular syphilis cases with neurosyphilis regimens due to concern for CNS involvement. 3
- Penicillin desensitization is strongly preferred over alternative antibiotics for tertiary disease. 3
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, 3, 2
- This is the only regimen proven effective for CNS syphilis. 1, 3
- Benzathine penicillin does not reliably achieve adequate CSF levels. 8
Special Populations
Pregnancy
Pregnant women must receive penicillin—it is the only therapy proven to prevent maternal transmission and treat fetal infection. 4, 1, 3
- Use the penicillin regimen appropriate for the stage of syphilis. 4, 1
- Pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no alternatives are acceptable. 4, 1, 3
- Erythromycin does not reliably cure fetal infection. 4
- Tetracycline and doxycycline are contraindicated in pregnancy. 4
- Some experts recommend a second dose of benzathine penicillin 2.4 million units IM one week after the initial dose for primary, secondary, or early latent syphilis in pregnancy. 4
Jarisch-Herxheimer Reaction Warning:
- Women treated during the second half of pregnancy risk premature labor or fetal distress from this acute febrile reaction. 4, 1
- Advise patients to seek immediate obstetric attention if they notice contractions or decreased fetal movements after treatment. 4, 1
- Stillbirth is a rare complication, but concern should not delay necessary treatment. 4
HIV-Infected Patients
Use the same treatment regimens as HIV-negative patients for all stages of syphilis. 1, 3
- Penicillin regimens must be used—skin testing to confirm allergy followed by desensitization if needed. 4
- Closer follow-up is mandatory to detect treatment failure or disease progression. 1, 3
- Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis in HIV patients compared to single dose. 1
- HIV-infected patients may have atypical serologic responses but generally respond well to standard treatment. 1
- For late latent syphilis with HIV and normal CSF, use benzathine penicillin G 7.2 million units (three weekly doses). 1
Follow-Up and Monitoring
Repeat quantitative nontreponemal tests (RPR or VDRL) at 3,6,12, and 24 months after treatment. 1, 2
Expected Serologic Response
- Primary/secondary syphilis: Expect fourfold decline in titer within 6 months. 1, 2
- Late syphilis: Expect fourfold decline in titer within 12-24 months. 1, 3
- Treatment failure is defined as failure of titers to decline fourfold within these timeframes, sustained fourfold increase in titers, or persistent/recurring clinical signs. 1, 3, 2
Management of Treatment Failure
- Re-evaluate for HIV infection. 1, 3
- Perform CSF examination. 1, 3
- Retreat with three weekly injections of benzathine penicillin G 2.4 million units unless neurosyphilis is diagnosed. 3
- If nontreponemal titers fail to decline fourfold between 12-24 months, repeat CSF examination and treat accordingly. 4
Pregnancy Follow-Up
- Repeat serologic titers in third trimester and at delivery. 4
- Check titers monthly in women at high risk for reinfection or in high-prevalence areas. 4
- Most women deliver before serologic response can be definitively assessed. 4
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
- Persons exposed >90 days before diagnosis should be treated presumptively if serologic results are not immediately available and follow-up is uncertain. 1
Critical Pitfalls to Avoid
- Never use oral penicillin preparations—they are completely ineffective for syphilis treatment. 1, 3
- Never switch between different nontreponemal test methods (RPR vs VDRL) when monitoring response—results cannot be directly compared. 1, 3
- Never skip CSF examination before treating tertiary syphilis—missing neurosyphilis leads to treatment failure. 3
- Never rely on treponemal test titers to assess treatment response—they correlate poorly with disease activity. 1
- Never substitute non-penicillin antibiotics in pregnancy—only penicillin prevents congenital syphilis. 4, 1
- Do not use bacteriostatic antibiotics (chloramphenicol, erythromycins, sulfonamides, tetracyclines) concurrently with penicillin—they may antagonize its bactericidal effect. 9, 10
Jarisch-Herxheimer Reaction
An acute febrile reaction may occur within 24 hours after any syphilis therapy, especially in early syphilis. 1, 3