What is the treatment for congenital syphilis?

Treatment of Congenital Syphilis

All neonates with proven or highly probable congenital syphilis should be treated with aqueous crystalline penicillin G 100,000-150,000 units/kg/day IV (divided every 12 hours for the first 7 days of life, then every 8 hours thereafter) for 10-14 days. 1

Treatment Regimens by Clinical Scenario

Neonates with Proven or Highly Probable Congenital Syphilis

First-line treatment options:

• Aqueous crystalline penicillin G 100,000-150,000 units/kg/day IV (50,000 units/kg every 12 hours during first 7 days of life, then every 8 hours) for 10-14 days 1

• Procaine penicillin G 50,000 units/kg IM daily for 10 days (alternative regimen) 1

Critical caveat: Aqueous crystalline penicillin G achieves superior CSF concentrations (mean 0.465 mcg/mL) compared to procaine penicillin G (mean 0.077 mcg/mL), with 100% of aqueous penicillin specimens achieving treponemicidal levels versus only 82% with procaine penicillin 2. For infants with neurosyphilis or severe disease, aqueous crystalline penicillin G is strongly preferred 2.

If more than 1 day of therapy is missed, restart the entire 10-14 day course. 1

Infants with Normal Evaluation but Inadequate Maternal Treatment

For infants with normal physical examination, normal CSF, and serum titers ≤4-fold maternal titer, whose mothers received erythromycin during pregnancy, were treated <1 month before delivery, or did not achieve adequate serologic response:

• Benzathine penicillin G 50,000 units/kg IM as a single dose 1

Infants with Normal Evaluation and Adequate Maternal Treatment

For infants with normal examination, titers ≤4-fold maternal titer, whose mothers were adequately treated >4 weeks before delivery with appropriate serologic response:

• Benzathine penicillin G 50,000 units/kg IM single dose 1
• Alternative: Close follow-up without treatment if maternal titers decreased fourfold after early syphilis treatment or remained stable/low for late syphilis 1

Infants with Adequate Maternal Treatment Before Pregnancy

For infants whose mothers were treated before pregnancy with stable low titers (VDRL <1:2; RPR <1:4) throughout pregnancy:

• No treatment required, but benzathine penicillin G 50,000 units/kg IM single dose may be considered if follow-up is uncertain 1

Treatment of Older Infants and Children (>1 Month of Age)

Any child with suspected congenital syphilis or neurologic involvement:

• Aqueous crystalline penicillin G 200,000-300,000 units/kg/day IV or IM (administered as 50,000 units/kg every 4-6 hours) for 10-14 days 1

Some specialists recommend adding: Benzathine penicillin G 50,000 units/kg IM as a single dose following the 10-day IV course 1

For children with no clinical manifestations, normal CSF examination, and negative CSF VDRL:

• Up to 3 weekly doses of benzathine penicillin G 50,000 units/kg IM can be considered 1

Required Pre-Treatment Evaluation

All infants requiring treatment should have:

• CSF analysis for VDRL, cell count, and protein 1
• Complete blood count, differential, and platelet count 1
• Long-bone radiographs 1
• Ophthalmologic examination (especially if clinically evident disease) 1
• Additional tests as indicated: chest radiograph, liver function tests, abdominal ultrasound, auditory brain stem response 1

Follow-Up Protocol

For all seroreactive infants or infants whose mothers were seroreactive at delivery:

• Examine and test nontreponemal titers every 2-3 months until nonreactive or decreased fourfold 1
• Expected response: Nontreponemal titers should decline by 3 months and become nonreactive by 6 months of age 1
• Treatment failure indicators: Stable or increasing titers after 6-12 months require re-evaluation with CSF examination and full 10-day parenteral penicillin course 1

For infants with abnormal initial CSF:

• Repeat lumbar puncture every 6 months until normal 1
• If CSF cell count remains abnormal after 2 years or lacks downward trend, re-treat 1
• If CSF VDRL remains reactive at 6 months, re-treat 1

Treponemal tests should NOT be used to evaluate treatment response as they remain positive despite effective therapy 1. A reactive treponemal test after 18 months is diagnostic of congenital syphilis, but if nontreponemal test is nonreactive, no further treatment is needed 1.

Special Considerations

Penicillin Allergy

Children requiring treatment with penicillin allergy history must undergo desensitization and receive penicillin. 1 There are no proven alternatives to penicillin for congenital syphilis 1. If non-penicillin agents are used (e.g., ceftriaxone), close serologic and CSF follow-up are mandatory 1.

HIV Co-infection

Infants with congenital syphilis whose mothers have HIV should be tested for HIV 1. However, current data do not indicate different evaluation, therapy, or follow-up requirements for HIV-exposed infants with congenital syphilis 1.

Common Pitfalls to Avoid

• Never use doxycycline in neonates or children <8 years - it is contraindicated and only approved for adults with syphilis 3, 4
• Do not use erythromycin - infants born to mothers treated with erythromycin during pregnancy require full treatment as if untreated 1
• Restart the entire course if any day is missed - partial treatment is inadequate 1
• Do not rely on procaine penicillin for severe disease or neurosyphilis - 33% of CSF specimens obtained 18-24 hours after procaine penicillin dosing had subtherapeutic levels 2