What are the recommended treatment regimens for syphilis at each stage, including options for penicillin-allergic patients?

Syphilis Treatment Recommendations

Primary and Secondary Syphilis

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

• This single-dose regimen has been validated by decades of clinical experience and represents the gold standard for early syphilis treatment 1, 2
• The FDA-approved dosing for primary and secondary syphilis is 2.4 million units IM in a single dose 2
• All patients diagnosed with syphilis should be tested for HIV at the time of diagnosis 1

Penicillin-Allergic Patients (Non-Pregnant)

For non-pregnant adults with penicillin allergy, doxycycline 100 mg orally twice daily for 14 days is the preferred alternative regimen. 1, 3

• Doxycycline is preferred over tetracycline due to better adherence with twice-daily versus four-times-daily dosing 1, 3
• Alternative: tetracycline 500 mg orally four times daily for 14 days 1
• Ceftriaxone 1 gram IM or IV daily for 10-14 days may be considered, though evidence is limited and cross-reactivity with penicillin allergy is possible 1
• Never use a single dose of ceftriaxone—the full 10-14 day course is mandatory 1
• If adherence to oral regimens cannot be assured, penicillin desensitization followed by benzathine penicillin G is strongly recommended 1

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Early Latent Syphilis (≤1 Year Duration)

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

• Early latent syphilis is defined as infection acquired within the preceding year, documented by: seroconversion, fourfold increase in titer, history of symptoms within the past year, or a sex partner with documented early syphilis 1
• For penicillin-allergic non-pregnant adults: doxycycline 100 mg orally twice daily for 14 days 1, 3
• Alternative: tetracycline 500 mg orally four times daily for 14 days 1

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Late Latent Syphilis and Syphilis of Unknown Duration (>1 Year)

Benzathine penicillin G 7.2 million units total, administered as three weekly injections of 2.4 million units IM each, is the standard regimen for late latent syphilis. 1, 2

• CSF examination must be performed before treatment to exclude neurosyphilis in 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 1
• For penicillin-allergic non-pregnant adults: doxycycline 100 mg orally twice daily for 28 days 4, 1, 3
• Alternative: tetracycline 500 mg orally four times daily for 28 days 4, 1
• CSF examination must exclude neurosyphilis before using any non-penicillin regimen for late latent infection 1

Recent High-Quality Evidence

• A 2025 retrospective cohort study of 761 patients found that serological cure rates in high-titer late latent syphilis were similar between one dose of BPG (88%), three doses of BPG (88%), and 28 days of doxycycline (88%) 5
• However, current CDC guidelines still recommend three doses for late latent disease, and this remains the standard of care 1

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Tertiary Syphilis

Benzathine penicillin G 7.2 million units total, administered as three weekly injections of 2.4 million units IM each, is recommended for tertiary syphilis (gummatous and cardiovascular). 4, 1

• CSF examination should be performed before therapy to exclude neurosyphilis 4
• For penicillin-allergic patients: doxycycline 100 mg orally twice daily for 28 days 4
• Patients with symptomatic late syphilis require consultation with an infectious diseases specialist 4

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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 definitive treatment for neurosyphilis. 4, 1, 6

• This regimen achieves adequate CSF penicillin concentrations to eradicate Treponema pallidum from the central nervous system 1
• Some experts add benzathine penicillin G 2.4 million units IM weekly for up to 3 weeks after completion of the IV course, though consensus on this practice is lacking 4, 1

Alternative Outpatient Regimen

• Procaine penicillin 2.4 million units IM once daily PLUS probenecid 500 mg orally four times daily for 10-14 days 4, 1
• Probenecid is mandatory—procaine penicillin without probenecid does not achieve adequate CSF levels and is inadequate for neurosyphilis 1
• This regimen is contraindicated in patients with sulfonamide allergy due to cross-reactivity with probenecid 1

Penicillin-Allergic Patients

All patients with neurosyphilis and penicillin allergy should undergo penicillin desensitization followed by standard penicillin G treatment—this remains the only proven effective therapy. 4, 6

• If desensitization is refused or not feasible, ceftriaxone 2 grams IV daily for 10-14 days may be considered, but evidence is extremely limited and cross-reactivity occurs in approximately 10% of penicillin-allergic patients 1, 6
• No alternative antibiotics have been systematically evaluated or proven effective for neurosyphilis 6

Follow-Up for Neurosyphilis

• Repeat CSF examination every 6 months until the white blood cell count normalizes—CSF WBC is the most sensitive measure of treatment effectiveness 1, 6
• Consider retreatment if CSF WBC has not decreased after 6 months or if CSF abnormalities persist beyond 2 years 1

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Syphilis in Pregnancy

All pregnant patients with syphilis must receive the penicillin regimen appropriate for the disease stage—penicillin is the only therapy with documented efficacy for preventing congenital syphilis and treating fetal infection. 4, 1

• Pregnant patients with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no exceptions. 4, 1, 6
• For primary, secondary, or early latent syphilis: some experts recommend an additional dose of benzathine penicillin 2.4 million units IM one week after the initial dose 1
• Pregnant patients who miss any dose of the three-dose regimen must repeat the entire course of therapy 1
• Tetracycline, doxycycline, erythromycin, azithromycin, and ceftriaxone are inadequate—erythromycin does not reliably cure fetal infection 1

Screening in Pregnancy

• Screen all pregnant women for syphilis at the first prenatal visit, at 28 weeks gestation, and at delivery 1
• Treatment must be administered >4 weeks before delivery to optimize fetal outcomes 1

Jarisch-Herxheimer Reaction in Pregnancy

• Women treated during the second half of pregnancy are at risk for premature labor and/or fetal distress from Jarisch-Herxheimer reaction 1
• Obstetric monitoring for 24 hours after therapy is advised for women >20 weeks gestation 1
• Patients should seek immediate medical attention if they notice contractions or changes in fetal movements after treatment 1

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Syphilis in HIV-Infected Patients

HIV-infected patients receive the same penicillin regimens as HIV-negative patients for all stages of syphilis. 4, 1

• For primary and secondary syphilis: benzathine penicillin G 2.4 million units IM as a single dose 4
• For late latent syphilis with normal CSF: benzathine penicillin G 7.2 million units (three weekly doses of 2.4 million units each) 1
• CSF examination should be considered before therapy for late latent syphilis in HIV-infected patients to exclude neurosyphilis 4, 1

Enhanced Monitoring in HIV

• HIV-infected patients require more intensive post-treatment monitoring: clinical and serologic evaluation at 3,6,9,12, and 24 months 4, 1
• CSF examination and re-treatment should be strongly considered for patients whose nontreponemal test titer does not decrease fourfold within 6-12 months 4
• Most experts would re-treat with benzathine penicillin G 7.2 million units (three weekly doses) if CSF examinations are normal 4

Recent High-Quality Evidence

• A 2025 randomized controlled trial of 249 patients (61% HIV-positive) found that one dose of benzathine penicillin G was noninferior to three doses for early syphilis, with serologic response rates of 76% vs 70% at 6 months 7
• In the HIV-positive subgroup, serologic response was 76% with one dose and 71% with three doses 7
• However, current CDC guidelines still recommend a single dose for early syphilis regardless of HIV status, and this trial supports that recommendation 1, 7

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Follow-Up and Monitoring

Quantitative nontreponemal serologic tests (RPR or VDRL) should be repeated at 6 and 12 months after treatment for primary/secondary syphilis, and at 6,12, and 24 months for latent syphilis. 1, 3

• A fourfold decline in titer is expected within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 1
• Treatment failure is defined as: persistent or recurring signs/symptoms, sustained fourfold increase in nontreponemal titers, or failure of initially high titer (≥1:32) to decline at least fourfold within 6-12 months for early syphilis or 12-24 months for late syphilis 1

Management of Treatment Failure

• Re-evaluate for HIV infection and perform CSF examination 1
• Re-treatment typically involves three weekly injections of benzathine penicillin G 2.4 million units IM, unless CSF examination indicates neurosyphilis 1
• If CSF is normal after treatment failure, most experts retreat with benzathine penicillin G 7.2 million units (three weekly doses) 4

Important Monitoring Pitfalls

• Do not use different testing methods (e.g., switching between VDRL and RPR) when monitoring serologic response, as results cannot be directly compared 1
• Do not rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity 1
• 15-25% of successfully treated patients remain "serofast" with persistent low titers (<1:8) that do not indicate treatment failure 1

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Management of Sexual Partners

Sexual partners exposed within 90 days before the index patient's diagnosis of primary, secondary, or early latent syphilis should receive presumptive treatment with benzathine penicillin G 2.4 million units IM, even if seronegative. 1

• Partners exposed >90 days prior should also receive presumptive treatment when serologic results are unavailable and reliable follow-up cannot be ensured 1
• Time windows for presumptive treatment: 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

Penicillin-Allergic Partners

• First-line alternative: doxycycline 100 mg orally twice daily for 14 days 1
• Second-line alternative: tetracycline 500 mg orally four times daily for 14 days 1
• Third-line alternative (when adherence can be ensured): ceftriaxone 1 g IM or IV daily for 8-10 days 1
• If reliable adherence to oral regimens cannot be assured, penicillin desensitization followed by benzathine penicillin G is strongly recommended 1

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Jarisch-Herxheimer Reaction

The Jarisch-Herxheimer reaction is an acute febrile reaction—often accompanied by headache, myalgia, and other systemic symptoms—that can occur within the first 24 hours after any syphilis therapy. 1, 2

• This reaction occurs most commonly in patients with early-stage syphilis (primary, secondary, or early latent) 1
• No proven preventive measures exist; however, antipyretics may be used for symptom relief 1
• Patients should be counseled about the possibility of this reaction before initiating therapy 1

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Critical Safety Warnings

Administration of Benzathine Penicillin G

Benzathine penicillin G is for DEEP INTRAMUSCULAR INJECTION ONLY—never inject intravenously or admix with other IV solutions. 2

• Inadvertent intravenous administration has been associated with cardiorespiratory arrest and death 2
• Inject into the upper, outer quadrant of the buttock (dorsogluteal) or ventrogluteal site 2
• Do not inject into or near an artery or nerve—injection into or near a nerve may result in permanent neurological damage 2
• Inadvertent intravascular administration has resulted in severe neurovascular damage, including transverse myelitis with permanent paralysis, gangrene requiring amputation, and Nicolau syndrome 2

Severe Allergic Reactions

• Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy 2
• Serious anaphylactic reactions require immediate emergency treatment with epinephrine, oxygen, intravenous steroids, and airway management including intubation 2
• Severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, and AGEP have been reported 2

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Medications to Avoid

• Never use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 1
• Never use oral penicillin preparations for syphilis treatment—they are ineffective 1
• A 2026 genomic analysis found putative doxycycline resistance mutations in 9 of 801 T. pallidum genomes, establishing a baseline for monitoring resistance 8