What is the appropriate management for a patient with latent syphilis (positive serology, no clinical signs), including first‑line penicillin regimen, alternatives for penicillin allergy, pregnancy considerations, HIV‑related issues, and serologic follow‑up?

Latent Syphilis Management

For latent syphilis, benzathine penicillin G is the definitive first-line treatment: 2.4 million units IM as a single dose for early latent disease (acquired within the past year), or 7.2 million units total administered as three weekly injections of 2.4 million units IM for late latent or unknown-duration syphilis. 1

Defining the Stage of Latent Syphilis

Before initiating therapy, you must determine whether the infection is early latent (≤1 year) or late latent (>1 year or unknown duration), because this dictates treatment duration. 1

Early latent syphilis is documented by any of the following: 1

• Seroconversion within the past 12 months
• Fourfold increase in nontreponemal titer within the past year
• History of primary or secondary syphilis symptoms within the past year
• Sexual partner with confirmed early syphilis

Late latent syphilis applies when infection duration exceeds one year or cannot be established. 1

First-Line Penicillin Regimens

Early Latent Syphilis (≤1 year)

Benzathine penicillin G 2.4 million units IM as a single dose achieves 85–90% cure rates and is the CDC-recommended standard. 1, 2

Late Latent or Unknown-Duration Syphilis

Benzathine penicillin G 7.2 million units total, administered as three weekly injections of 2.4 million units IM (one dose per week for three consecutive weeks). 1, 2 This extended regimen is necessary because late latent infection requires prolonged treponemicidal coverage. 1

Critical timing note: If a patient misses a weekly dose, an interval of 10–14 days before the next injection may be acceptable before restarting the entire sequence—but pregnant women must repeat the full three-dose course if any dose is missed. 1

Pre-Treatment Cerebrospinal Fluid Examination

Before treating late latent syphilis with any regimen, perform lumbar puncture to exclude neurosyphilis if any of the following are present: 1, 2

• Neurologic signs or symptoms (cognitive dysfunction, motor/sensory deficits, cranial nerve palsies, meningismus)
• Ocular manifestations (uveitis, neuroretinitis, optic neuritis)
• Auditory symptoms
• Evidence of active tertiary syphilis (aortitis, gummas, iritis)
• Treatment failure (persistent symptoms or rising titers after prior therapy)
• HIV infection with late latent syphilis or unknown duration
• Nontreponemal titer ≥1:32 in the setting of late latent disease

Do not skip CSF examination in these scenarios—undiagnosed neurosyphilis will not respond to standard benzathine penicillin regimens and requires IV aqueous crystalline penicillin G. 1

Alternatives for Penicillin-Allergic Patients (Non-Pregnant)

Early Latent Syphilis

Doxycycline 100 mg orally twice daily for 14 days is the preferred alternative when penicillin cannot be used. 1, 2 Tetracycline 500 mg orally four times daily for 14 days is also acceptable, but doxycycline is favored because of better adherence and fewer gastrointestinal side effects. 1

Late Latent or Unknown-Duration Syphilis

Doxycycline 100 mg orally twice daily for 28 days is the sole acceptable oral alternative. 1, 2 Tetracycline 500 mg orally four times daily for 28 days is also an option. 1

Mandatory pre-treatment step: Before using any non-penicillin regimen for late latent syphilis, CSF examination must exclude neurosyphilis—oral antibiotics do not achieve treponemicidal levels in cerebrospinal fluid. 1, 2

Ceftriaxone 1 gram IM or IV daily for 10–14 days may be considered for early latent syphilis in penicillin-allergic patients, but evidence is limited (one randomized trial) and cross-reactivity with penicillin allergy is possible. 1 Ceftriaxone is not recommended for late latent syphilis due to insufficient data. 1

Never use azithromycin—widespread macrolide resistance and documented treatment failures make it unacceptable in the United States. 1

Pregnancy Considerations

All pregnant patients with syphilis must receive the penicillin regimen appropriate for their disease stage—no exceptions. 1, 2 Penicillin is the only therapy with documented efficacy for preventing congenital syphilis and treating fetal infection. 1, 2

Penicillin Allergy in Pregnancy

Pregnant women with a documented penicillin allergy must undergo penicillin desensitization followed by penicillin therapy. 1, 2 Skin testing should precede desensitization to confirm true allergy status. 1, 2

Do not substitute doxycycline, tetracycline, erythromycin, azithromycin, or ceftriaxone—these agents do not reliably prevent congenital infection and may cause maternal or fetal toxicity. 1, 2 Tetracyclines cause maternal hepatotoxicity and fetal bone/tooth staining; erythromycin does not cross the placenta adequately to cure fetal infection. 1, 2

Timing and Enhanced Regimens

Complete the full penicillin course at least 4 weeks before expected delivery to optimize prevention of congenital syphilis. 1, 2

For pregnant women with primary, secondary, or early latent syphilis, some experts recommend an additional dose of benzathine penicillin G 2.4 million units IM one week after the initial dose, particularly in the third trimester or when treating secondary syphilis. 1, 2

Jarisch-Herxheimer Reaction Precautions

Advise pregnant patients to seek immediate obstetric care if they develop fever, uterine contractions, or decreased fetal movements within 24 hours after penicillin administration. 1, 2 This reaction occurs in up to 44% of pregnant women treated for syphilis and can precipitate preterm labor or fetal distress, especially when ultrasound shows fetal hepatomegaly or hydrops. 1, 2

For pregnancies beyond 20 weeks gestation, consider fetal and uterine-contraction monitoring for 24 hours after the first dose. 2 Do not delay treatment because of fear of this reaction—untreated syphilis poses far greater fetal risk. 2

Screening Requirements

Screen all pregnant women for syphilis at the first prenatal visit, at 28–32 weeks gestation, and again at delivery. 1, 2 In high-risk populations, perform monthly titer checks until delivery. 2 No newborn may be discharged without documented evidence that the mother was screened for syphilis at least once during pregnancy. 1, 2

HIV-Related Issues

HIV-infected patients receive the same penicillin regimens as HIV-negative patients for all stages of syphilis. 1, 2 Evidence shows no benefit to enhanced regimens (multiple benzathine penicillin doses, amoxicillin plus probenecid) in HIV-infected individuals with early syphilis. 1, 2

Pre-Treatment CSF Examination in HIV

For late latent syphilis in HIV-infected patients, consider CSF examination before therapy to exclude neurosyphilis, particularly when CD4 count is ≤350 cells/µL or nontreponemal titer is ≥1:32. 1, 2

Penicillin Allergy in HIV

Penicillin desensitization is strongly preferred for HIV-infected patients with a penicillin allergy, followed by standard penicillin therapy. 2 If desensitization is not feasible, doxycycline may be used (14 days for early latent, 28 days for late latent after CSF examination), but efficacy data in HIV-infected patients are extremely limited and close monitoring is mandatory. 1, 2

Enhanced Monitoring in HIV

HIV-infected patients require more intensive follow-up: clinical and serologic evaluations at 3,6,9,12, and 24 months after treatment. 1, 2 They have higher rates of treatment failure and atypical serologic responses (unusually high, low, or fluctuating titers), but these do not alter the recommended treatment regimens. 1, 2

Serologic Follow-Up

Monitoring Schedule

For early latent syphilis: Perform quantitative nontreponemal serologic tests (RPR or VDRL) at 6 and 12 months after treatment. 1, 2

For late latent syphilis: Repeat quantitative nontreponemal tests at 6,12,18, and 24 months. 1, 2

Use the same laboratory and the same test method (RPR vs. VDRL) for all follow-up testing—RPR titers are often slightly higher than VDRL titers and cannot be directly compared. 1, 2

Defining Treatment Success

A fourfold decline in nontreponemal titers (equivalent to a two-dilution drop, e.g., from 1:32 to 1:8) indicates successful treatment. 1, 2

Expected timeframe for fourfold decline: 1, 2

• Early latent syphilis: 6–12 months
• Late latent syphilis: 12–24 months

Treatment Failure Criteria

Re-treat and perform CSF examination if any of the following occur: 1, 2

• Persistent or recurring clinical signs or symptoms of syphilis
• Sustained fourfold increase in nontreponemal titers compared with post-treatment nadir
• Failure of an initially high titer (≥1:32) to decline fourfold within 6–12 months for early syphilis or 12–24 months for late syphilis

When treatment failure is identified and CSF is normal, retreat with benzathine penicillin G 7.2 million units (three weekly doses of 2.4 million units IM). 1, 2 If CSF indicates neurosyphilis, treat with IV aqueous crystalline penicillin G 18–24 million units per day for 10–14 days. 1, 2

Serofast State

Approximately 15–25% of successfully treated patients remain "serofast" with persistent low titers (<1:8) that do not indicate treatment failure or active infection. 1, 3 These patients do not require retreatment in the absence of clinical findings or rising titers. 1, 3

Management of Sexual Partners

Presumptively treat sexual partners exposed within 90 days before the index patient's diagnosis of primary, secondary, or early latent syphilis with a single dose of benzathine penicillin G 2.4 million units IM, even if serologic testing is negative. 1, 2 Partners exposed more than 90 days prior should also receive presumptive treatment when serologic results are unavailable and reliable follow-up cannot be ensured. 1, 2

Common Pitfalls to Avoid

• Do not use oral penicillin preparations for any stage of syphilis—they are ineffective. 1
• Do not rely solely on treponemal test antibody titers (FTA-ABS, TP-PA) to assess treatment response—they correlate poorly with disease activity and remain positive for life. 1
• Do not switch between RPR and VDRL assays when monitoring serologic response—results cannot be directly compared. 1, 2
• Do not omit CSF examination in high-risk scenarios (neurologic symptoms, HIV with late latent disease, treatment failure)—undiagnosed neurosyphilis will progress despite standard therapy. 1, 2
• Do not use non-penicillin antibiotics in pregnancy—penicillin desensitization is mandatory. 1, 2
• Do not shorten the 28-day doxycycline course for late latent syphilis—the full duration is essential. 1

Additional Recommendations

Test all patients diagnosed with syphilis for HIV if their status is unknown. 1, 2 Syphilis and HIV co-infection is common, and HIV status influences monitoring intensity. 1, 2

Counsel all patients about the Jarisch-Herxheimer reaction—an acute febrile reaction with headache, myalgia, and other systemic symptoms that may occur within 24 hours of treatment, especially in early syphilis. 1, 2 Antipyretics may be used for symptom relief, but no proven preventive measures exist. 1