Syphilis Treatment
Benzathine penicillin G is the definitive treatment for all stages of syphilis, with dosing determined by disease stage: a single 2.4 million unit IM injection for early syphilis (primary, secondary, or early latent ≤1 year), or three weekly 2.4 million unit IM injections (total 7.2 million units) for late latent, latent of unknown duration, or tertiary syphilis. 1, 2
Treatment by Stage
Primary, Secondary, and Early Latent Syphilis (≤1 Year)
Administer benzathine penicillin G 2.4 million units IM as a single dose for adults with primary syphilis (painless chancre), secondary syphilis (diffuse rash, mucocutaneous lesions, lymphadenopathy), or early latent syphilis acquired within the preceding year. 3, 1, 2
Early latent syphilis is defined by documented seroconversion within the past year, fourfold increase in titer, history of primary/secondary symptoms within 12 months, or a sex partner with documented early syphilis. 1
This single-dose regimen achieves 90–100% treatment success based on decades of clinical experience. 1, 4
For pediatric patients with acquired syphilis (after CSF examination to exclude neurosyphilis), give benzathine penicillin G 50,000 units/kg IM up to the adult dose of 2.4 million units as a single injection. 1
Late Latent Syphilis, Latent of Unknown Duration, and Tertiary Syphilis
Administer benzathine penicillin G 2.4 million units IM once weekly for three consecutive weeks (total 7.2 million units) for late latent syphilis (>1 year duration), latent syphilis of unknown duration, or tertiary syphilis (gummatous or cardiovascular disease). 3, 1, 5
Before treating tertiary syphilis, perform a CSF examination to exclude neurosyphilis, particularly in patients with cardiovascular or gummatous disease, because the tertiary regimen is inadequate for CNS involvement. 5
For pediatric patients with late latent syphilis, give benzathine penicillin G 50,000 units/kg IM (up to 2.4 million units) weekly for three doses (total 150,000 units/kg up to 7.2 million units). 1
Neurosyphilis
Administer aqueous crystalline penicillin G 18–24 million units per day IV (given as 3–4 million units every 4 hours or continuous infusion) for 10–14 days for any patient with clinical evidence of neurologic involvement (cognitive dysfunction, motor/sensory deficits, cranial nerve palsies, meningitis), ophthalmic manifestations (uveitis, neuroretinitis, optic neuritis), or auditory symptoms. 3, 1, 5
CSF examination is mandatory before initiating therapy for patients with neurologic or ophthalmic signs/symptoms, evidence of active tertiary syphilis, treatment failure, HIV infection with late latent syphilis, or nontreponemal titer ≥1:32. 3, 1
An alternative outpatient regimen (only if compliance can be ensured) is procaine penicillin 2.4 million units IM once daily PLUS probenecid 500 mg orally four times daily for 10–14 days; probenecid is mandatory because procaine penicillin alone does not achieve adequate CSF levels. 3, 1
Some specialists add benzathine penicillin G 2.4 million units IM weekly for up to 3 weeks after completing the IV course to match the total duration used for late latent syphilis, though consensus on this practice is lacking. 3, 1
If CSF pleocytosis was present at baseline, repeat CSF examination every 6 months until the white cell count normalizes; the CSF WBC count is the most sensitive marker of treatment response. 1
Retreatment is indicated if the CSF cell count has not decreased after 6 months or if CSF abnormalities persist beyond 2 years. 1
Penicillin-Allergic Patients (Non-Pregnant)
Early Syphilis (Primary, Secondary, or Early Latent)
Prescribe doxycycline 100 mg orally twice daily for 14 days as the first-line alternative for penicillin-allergic non-pregnant adults with early syphilis. 3, 1
Tetracycline 500 mg orally four times daily for 14 days is an acceptable alternative, but doxycycline is preferred because of better adherence and fewer gastrointestinal side effects. 3, 1
Ceftriaxone 1 gram IM or IV daily for 10–14 days may be considered based on randomized trial data showing comparable efficacy to benzathine penicillin, but cross-reactivity with penicillin allergy is possible and optimal dosing is not definitively established. 1
Late Latent Syphilis or Latent of Unknown Duration
Prescribe doxycycline 100 mg orally twice daily for 28 days as the only acceptable oral alternative for penicillin-allergic non-pregnant adults with late latent syphilis. 3, 1
Tetracycline 500 mg orally four times daily for 28 days is also acceptable. 3, 1
Perform a CSF examination to exclude neurosyphilis before using any non-penicillin regimen for late latent infection, because oral regimens are inadequate for CNS disease. 1
Close serologic and clinical follow-up is mandatory due to limited long-term efficacy data compared with penicillin. 3
Neurosyphilis in Penicillin-Allergic Patients
Penicillin desensitization followed by standard penicillin therapy is the preferred approach for penicillin-allergic patients with neurosyphilis. 1
Ceftriaxone 2 grams IV daily for 10–14 days may be considered when desensitization is not feasible, but evidence is extremely limited (very low-quality data from small case series). 1
Special Populations
Pregnancy
All pregnant patients with syphilis must receive the penicillin regimen appropriate for their disease stage, administered >4 weeks before delivery to optimize fetal outcomes. 1
Pregnant patients with penicillin allergy must undergo desensitization and receive penicillin therapy—no exceptions—because penicillin is the only therapy with documented efficacy for preventing maternal transmission to the fetus and treating fetal infection. 3, 1, 5
Doxycycline, tetracycline, erythromycin, azithromycin, and ceftriaxone are absolutely contraindicated in pregnancy because they do not reliably cure fetal infection or prevent congenital syphilis. 1
For primary, secondary, or early latent syphilis in pregnancy, some experts recommend an additional dose of benzathine penicillin 2.4 million units IM one week after the initial dose. 1
Women treated during the second half of pregnancy are at risk for Jarisch-Herxheimer reaction (acute febrile reaction with headache, myalgia occurring within 24 hours of treatment) that may precipitate premature labor or fetal distress; they should seek immediate medical attention if they notice contractions or changes in fetal movements. 1
Screen all pregnant women for syphilis at the first prenatal visit, during the third trimester (28 weeks), and at delivery. 1, 2
HIV-Infected Patients
HIV-infected patients receive the same penicillin regimens as HIV-negative patients for all stages of syphilis. 3, 1
More intensive post-treatment monitoring is required: perform clinical and serologic evaluation at 3,6,9,12, and 24 months (compared to 6,12, and 24 months for HIV-negative patients). 3, 1
For late latent syphilis in HIV-infected patients, consider CSF examination before therapy to exclude neurosyphilis. 3, 1
HIV-infected patients may have atypical serologic responses (higher or lower titers, delayed seroreactivity) but generally respond well to standard treatment. 3, 1
Penicillin-allergic HIV-infected patients should undergo skin testing and desensitization before receiving penicillin. 3, 1
Follow-Up and Monitoring
Early Syphilis (Primary, Secondary, or Early Latent)
Perform quantitative nontreponemal serologic tests (RPR or VDRL) at 6 and 12 months after treatment. 1
Expect a fourfold decline in titer within 6 months for primary and secondary syphilis. 1
Treatment failure is defined as persistent or recurring clinical signs/symptoms, sustained fourfold increase in nontreponemal titers, or failure of initially high titer (≥1:32) to decline fourfold within 6 months. 1
Late Latent Syphilis
Perform quantitative nontreponemal serologic tests at 6,12, and 24 months after treatment. 1, 5
Expect a fourfold decline in titer within 12–24 months. 1, 5
Treatment failure is defined as failure of initially high titer to decline fourfold within 12–24 months. 1
Management of Treatment Failure
If treatment failure occurs, re-evaluate for HIV infection, perform CSF examination, and retreat with benzathine penicillin G 7.2 million units (three weekly doses of 2.4 million units each) unless neurosyphilis is diagnosed. 1
If CSF examination indicates neurosyphilis, treat with the neurosyphilis regimen (aqueous crystalline penicillin G 18–24 million units IV daily for 10–14 days). 1
Serofast State
A significant proportion of successfully treated patients remain "serofast" with persistent low titers (<1:8) that do not indicate treatment failure; 15–25% of patients maintain low-level seropositivity despite adequate treatment. 1, 4
Treponemal test antibody titers (e.g., FTA-ABS, TP-PA) correlate poorly with disease activity and should not be used to assess treatment response. 1
Management of Sexual Partners
Treat sexual partners presumptively with benzathine penicillin G 2.4 million units IM if exposed within 90 days before the index patient's diagnosis of primary, secondary, or early latent syphilis, even if the partner's serology is negative. 1
Partners exposed >90 days before diagnosis should also receive presumptive treatment when serologic results are unavailable and reliable follow-up cannot be ensured. 1
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
Long-term partners of patients with late syphilis should undergo clinical and serologic evaluation. 1
For penicillin-allergic non-pregnant partners, use doxycycline 100 mg orally twice daily for 14 days as first-line alternative. 1
Critical Pitfalls to Avoid
Never use oral penicillin preparations for syphilis treatment—they are completely ineffective for any stage of syphilis. 1, 5
Never use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures. 1
Never substitute non-penicillin antibiotics in pregnancy—penicillin desensitization is mandatory. 1, 5
Never skip the CSF examination before treating tertiary syphilis—this may miss neurosyphilis that requires different treatment. 5
Never use procaine penicillin without probenecid for neurosyphilis—CSF levels will be inadequate. 1
Never use different serologic test methods (RPR vs. VDRL) when monitoring treatment response—results cannot be directly compared. 1, 5
Never assume a single dose of ceftriaxone is effective—a complete 10–14 day course is required. 1
Never retreat a patient for syphilis based solely on new lesions appearing shortly after treatment—true treatment failure is defined serologically at 6–12 months, not by clinical appearance of lesions in the weeks following therapy. 1
Additional Considerations
All patients with syphilis should be tested for HIV infection at the time of diagnosis. 1, 2
Jarisch-Herxheimer reaction (acute febrile reaction with headache, myalgia, and other systemic symptoms) may occur within 24 hours after any syphilis therapy, especially in early syphilis; patients should be counseled about this possibility before treatment, and antipyretics may be used for symptom relief. 1, 5
Syphilis is a reportable disease in every state and should be reported by stage according to individual state requirements. 6