What is the recommended treatment and dosing for syphilis?

Syphilis Treatment and Dosing

Treatment by Stage

For early syphilis (primary, secondary, or early latent), administer benzathine penicillin G 2.4 million units IM as a single dose, and for late latent syphilis or syphilis of unknown duration, administer benzathine penicillin G 7.2 million units total as three doses of 2.4 million units IM at weekly intervals. 1, 2

Primary and Secondary Syphilis

• Benzathine penicillin G 2.4 million units IM as a single injection is the first-line treatment 1, 2, 3
• Recent high-quality evidence confirms that one dose is noninferior to three doses for early syphilis, with 76% serologic response at 6 months regardless of HIV status 4
• Early latent syphilis (diagnosed within the preceding year based on documented seroconversion, fourfold titer increase, recent symptoms, or partner with documented early syphilis) receives the same single-dose regimen 1, 2

Late Latent and Tertiary Syphilis

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at 1-week intervals 1, 2
• If a dose is missed, an interval of 10-14 days between doses may be acceptable before restarting the sequence, though 7-9 days is more optimal based on pharmacologic considerations 2, 5
• This flexibility does NOT apply to pregnant women—missed doses are unacceptable in pregnancy 5

Neurosyphilis

• Aqueous crystalline penicillin G 18-24 million units per day IV for 10-14 days is required 1, 2
• CSF examination should be performed before treatment if any of the following are present: neurologic or ophthalmic signs/symptoms, evidence of active tertiary syphilis, treatment failure, HIV infection with late latent syphilis or unknown duration, or serum nontreponemal titer ≥1:32 (unless duration <1 year) 1

Penicillin Allergy Alternatives

Non-Pregnant Patients

• CSF examination must exclude neurosyphilis before using alternative regimens 1, 2
• For early syphilis (primary, secondary, or early latent): Doxycycline 100 mg orally twice daily for 14 days 1, 2, 6
• For late latent syphilis or unknown duration: Doxycycline 100 mg orally twice daily for 28 days 1, 2, 6
• Tetracycline 500 mg orally four times daily is an alternative with the same duration as doxycycline 1

Pregnant Patients

• Pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment—there are no acceptable alternatives 7, 2, 8
• Penicillin is the only therapy with documented efficacy for preventing maternal transmission and treating fetal infection 7, 2
• Erythromycin, tetracycline, and doxycycline should not be used as they do not reliably cure the fetus or are contraindicated in pregnancy 7

Critical pitfall: Azithromycin should NOT be used in the United States due to widespread macrolide resistance and documented treatment failures 2

Pediatric Dosing

• After the newborn period, children diagnosed with syphilis require CSF examination to exclude neurosyphilis 1
• For early latent syphilis: Benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) as a single dose 1
• For late latent syphilis or unknown duration: Benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) administered as three doses at 1-week intervals (total 150,000 units/kg up to 7.2 million units) 1

Follow-Up Protocol

Early Syphilis (Primary, Secondary, Early Latent)

• Repeat quantitative nontreponemal serologic tests at 6 and 12 months after treatment 2, 8
• Expect a fourfold decline in titer within 6 months 2
• For HIV-infected patients, perform clinical and serologic evaluation at 3,6,9,12, and 24 months 8

Late Latent Syphilis

• Repeat quantitative nontreponemal serologic tests at 6,12, and 24 months 1, 2
• Expect a fourfold decline in titer within 12-24 months 2

Treatment Failure Criteria

• Re-treat if titers increase fourfold, an initially high titer (≥1:32) fails to decline at least fourfold within 12-24 months, or signs/symptoms of syphilis develop 1, 2
• Evaluate for neurosyphilis with CSF examination and re-evaluate HIV status 2

Important monitoring pitfall: Do not switch between different nontreponemal tests (VDRL vs RPR) when monitoring serologic response, as results cannot be directly compared 2

Special Populations

HIV-Infected Patients

• Use the same treatment regimens as non-HIV-infected patients 2
• Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis in HIV-infected patients compared to a single dose 2
• Closer follow-up is mandatory to detect potential treatment failure or disease progression 2

Pregnancy

• Screen all pregnant women for syphilis at first prenatal visit, during third trimester (at 28 weeks), and at delivery 7, 8
• Use the same stage-appropriate penicillin regimens as non-pregnant patients 7, 8
• Some specialists recommend an additional dose of benzathine penicillin 2.4 million units IM one week after the initial dose for women with primary, secondary, or early latent syphilis in the second half of pregnancy 7
• Women treated in the second half of pregnancy are at risk for premature labor and/or fetal distress from Jarisch-Herxheimer reaction; advise them to seek obstetric attention if they notice contractions or decreased fetal movements 7, 2

Partner Management

• Persons exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis should receive presumptive treatment with benzathine penicillin G 2.4 million units IM even if seronegative 2, 8
• Persons exposed >90 days before diagnosis should be treated presumptively if serologic test results are not immediately available and follow-up is uncertain 2

Additional Considerations

HIV Testing

• All patients with syphilis must be tested for HIV infection at the time of diagnosis 7, 2, 8

Jarisch-Herxheimer Reaction

• An acute febrile reaction may occur within 24 hours after any syphilis therapy, especially in early syphilis 2
• Patients should be informed about this possible adverse reaction, which may include headache, myalgia, fever, and other symptoms 2
• This concern should not delay necessary treatment 7

Administration Considerations

• Administer adequate fluids with oral medications to reduce risk of esophageal irritation and ulceration 6
• If gastric irritation occurs with doxycycline, give with food or milk; absorption is not markedly affected 6