What are the recommended treatment regimens for syphilis in adults for each stage (primary, secondary, early latent, late latent, neurosyphilis) and in special situations such as pregnancy, HIV infection, and penicillin allergy?

Syphilis Treatment Guidelines

Primary and Secondary Syphilis

Benzathine penicillin G 2.4 million units IM as a single dose is the definitive treatment for primary and secondary syphilis in adults, achieving 90-100% cure rates. 1

• For children with acquired syphilis, administer benzathine penicillin G 50,000 units/kg IM (maximum 2.4 million units) as a single dose after CSF examination to exclude neurosyphilis 1
• All patients diagnosed with syphilis must be tested for HIV infection 1, 2
• Patients should be warned about Jarisch-Herxheimer reaction—an acute febrile reaction with headache and myalgia occurring within 24 hours of treatment 1

Penicillin-Allergic Patients (Non-Pregnant)

• Doxycycline 100 mg orally twice daily for 14 days is the preferred alternative 1
• Tetracycline 500 mg orally four times daily for 14 days is acceptable but adherence is typically worse 1
• Pregnant women with penicillin allergy must undergo desensitization followed by penicillin treatment—no exceptions 1, 3

Early Latent Syphilis (≤1 Year Duration)

Benzathine penicillin G 2.4 million units IM as a single dose is recommended for early latent syphilis. 1

• Early latent syphilis is defined by documented seroconversion within the past year, unequivocal symptoms of primary/secondary syphilis within the past year, or a sex partner with documented early syphilis 4, 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, administered as three doses of 2.4 million units IM at weekly intervals, is the standard regimen. 1

• CSF examination is indicated 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 nontreponemal titer ≥1:32 4, 1
• For penicillin-allergic non-pregnant adults: doxycycline 100 mg orally twice daily for 28 days, but only after CSF examination excludes neurosyphilis 1, 3
• If a dose is missed during weekly therapy, an interval of 10-14 days between doses may be acceptable before restarting; however, pregnant women must repeat the entire course if any dose is missed 1, 5

Neurosyphilis

Aqueous crystalline penicillin G 18-24 million units per day IV (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days is the first-line treatment. 1, 3

• Alternative outpatient regimen: procaine penicillin 2.4 million units IM once daily plus probenecid 500 mg orally four times daily for 10-14 days 1
• Procaine penicillin without probenecid is inadequate because it fails to achieve therapeutic CSF levels 1
• Some experts add benzathine penicillin G 2.4 million units IM weekly for up to 3 weeks after completing the IV course 1, 3
• Ocular syphilis (uveitis, neuroretinitis, optic neuritis) must be managed as neurosyphilis regardless of other clinical features 1, 3

Follow-Up for Neurosyphilis

• If CSF pleocytosis was present initially, repeat CSF examination every 6 months until cell count normalizes 1, 3
• Consider retreatment if CSF white blood cell count has not decreased after 6 months or if CSF remains abnormal after 2 years 4, 1

Tertiary Syphilis

Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals, is recommended for tertiary syphilis. 1

• CSF examination must be performed before initiating therapy for symptomatic tertiary syphilis (aortitis, gummas, iritis) 1, 3
• Some experts recommend treating all cardiovascular syphilis cases with the neurosyphilis regimen (IV aqueous crystalline penicillin G) 3
• Consultation with an infectious disease specialist is advised 3

Syphilis in Pregnancy

Pregnant women must receive the penicillin regimen appropriate for their stage of syphilis; treatment must occur more than 4 weeks before delivery for optimal outcomes. 1, 3

• All pregnant women with penicillin allergy must undergo desensitization and receive penicillin—penicillin is the only therapy with documented efficacy for preventing congenital syphilis 4, 1, 3
• Some experts recommend an additional dose of benzathine penicillin G 2.4 million units IM one week after the initial dose for pregnant women with primary, secondary, or early latent syphilis 4, 1, 3
• Erythromycin does not reliably cure fetal infection; tetracyclines cause maternal hepatotoxicity and fetal bone/tooth staining; azithromycin and ceftriaxone are inadequate alternatives 4, 3

Jarisch-Herxheimer Reaction in Pregnancy

• Treatment during the second half of pregnancy may precipitate preterm labor or fetal distress from Jarisch-Herxheimer reaction 4, 1
• Women should seek immediate obstetric attention if they notice contractions or decreased fetal movement after treatment 4, 1
• Consider fetal and contraction monitoring for 24 hours after treatment for early syphilis in women >20 weeks gestation 4

Screening Requirements

• Screen all pregnant women at first prenatal visit, during third trimester (28 weeks), and at delivery 4, 1, 2
• No infant should leave the hospital without documented maternal syphilis serology status 4, 1

Syphilis in HIV-Infected Patients

HIV-infected patients should receive the same penicillin regimens as HIV-negative patients for all stages of syphilis. 1, 3

• More intensive monitoring is mandatory: clinical and serologic evaluation at 3,6,9,12, and 24 months after treatment 4, 1, 3
• For late latent syphilis in HIV-infected patients, consider CSF examination before treatment to exclude neurosyphilis 4, 1, 3
• If nontreponemal titers do not decline fourfold within 3 months for primary/secondary syphilis, perform CSF examination and consider retreatment 1, 3
• When CSF is normal after treatment failure, most experts retreat with benzathine penicillin G 7.2 million units (three weekly doses) 4, 1
• Penicillin-allergic HIV-infected patients should undergo skin testing and desensitization, then receive penicillin 4

Follow-Up and Treatment Response Monitoring

Primary and Secondary Syphilis

• Perform quantitative nontreponemal serologic tests (RPR or VDRL) at 6 and 12 months after treatment 1, 3
• Treatment success is defined as a fourfold (two-dilution) decline in nontreponemal titers within 6 months 1, 3

Latent Syphilis

• Repeat quantitative nontreponemal tests at 6,12,18, and 24 months 1, 3
• Expect fourfold decline within 12-24 months for late syphilis 1, 3

Treatment Failure Indicators

• Persistent or recurring signs/symptoms of syphilis 1, 3
• Sustained fourfold increase in nontreponemal titers 1, 3
• Failure of initially high titer (≥1:32) to decline fourfold within 6-12 months for early syphilis or 12-24 months for late syphilis 1, 3

Management of Treatment Failure

• Perform HIV testing if not previously done 1
• Conduct CSF examination to rule out neurosyphilis 1, 3
• Re-treat with benzathine penicillin G 7.2 million units (three weekly doses) if CSF is normal 1, 3
• If CSF indicates neurosyphilis, treat according to neurosyphilis recommendations 4

Management of Sexual Partners

Presumptively treat sexual partners exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis, even if seronegative. 1, 3

• 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, 3
• Partners exposed >90 days before diagnosis should be treated presumptively if serologic results are not immediately available and follow-up is uncertain 1, 3
• Long-term partners of patients with late syphilis should undergo clinical and serologic evaluation 3

Alternative Regimens: Critical Limitations

Ceftriaxone

• Ceftriaxone 1 gram IM/IV daily for 10-14 days may be considered for early syphilis based on randomized trial data showing comparable efficacy to benzathine penicillin 1, 5
• For neurosyphilis, ceftriaxone 2 grams daily IV for 10-14 days has very limited supporting data 1
• Patients with severe penicillin allergy (Stevens-Johnson syndrome) may also be allergic to ceftriaxone as both are beta-lactam antibiotics 1
• Evidence for ceftriaxone in late latent and tertiary syphilis is extremely limited 1

Azithromycin

• Azithromycin should NOT be used in the United States due to widespread macrolide resistance and documented treatment failures 1, 3

Erythromycin

• Erythromycin 500 mg orally four times daily for 14 days is less effective and should be used only when strict compliance and reliable follow-up can be guaranteed 1

Important Clinical Pitfalls to Avoid

• Do not use oral penicillin preparations—they are ineffective for syphilis treatment 1
• Do not switch between different nontreponemal testing methods (RPR vs VDRL) when monitoring serologic response, as results cannot be directly compared 1, 3
• Do not rely solely on treponemal test antibody titers to assess treatment response—they correlate poorly with disease activity 1
• Do not assume new genital lesions after recent treatment represent treatment failure without appropriate serologic confirmation at the required time interval 1
• Remember that 15-25% of successfully treated patients remain "serofast" with persistent low titers (<1:8) that do not indicate treatment failure 1
• Sequential RPR tests should use the same method and ideally the same laboratory, as RPR titers are often slightly higher than VDRL titers 3