Syphilis (Treponema pallidum Infection)

1. Clinical Overview

Summary

Syphilis is a sexually transmitted infection (STI) caused by the spirochaete bacterium Treponema pallidum subspecies pallidum. Dubbed "The Great Imitator" for its remarkably diverse clinical manifestations, syphilis progresses through well-defined stages if untreated: Primary (Painless chancre), Secondary (Disseminated rash and systemic symptoms), Latent (Asymptomatic but serologically positive), and Tertiary (Gummatous, cardiovascular, and neurological complications). [1,2]

Syphilis remains a global public health challenge. After decades of decline following the introduction of penicillin, rates have resurged dramatically worldwide, particularly among men who have sex with men (MSM) and individuals co-infected with HIV. In the United States, reported cases of primary and secondary syphilis increased by over 70% between 2014 and 2023, with congenital syphilis reaching rates not seen in 30 years. [3,4]

Transmission occurs primarily via direct contact with infectious lesions during sexual activity (genital, anal, or oral), and vertically from mother to fetus (congenital syphilis). The incubation period typically ranges from 10 to 90 days (average 21 days). Early diagnosis and treatment with penicillin remain highly effective and can prevent progression and transmission. [5,6]

Diagnosis relies on serology: a combination of non-treponemal tests (RPR/VDRL—quantitative, used for screening and monitoring treatment response) and treponemal tests (EIA, TPPA/TPHA—specific, remain positive lifelong). Dark-field microscopy and PCR are available for direct detection but rarely used in routine practice. [7,8]

Treatment is straightforward but stage-dependent. Benzathine penicillin G intramuscularly is first-line for all stages except neurosyphilis, ocular, and otic syphilis, which require intravenous aqueous crystalline penicillin. The Jarisch-Herxheimer reaction—an acute febrile response occurring 2-8 hours after the first penicillin dose—is common (particularly in early syphilis) and patients must be warned. Partner notification and full STI screening (including HIV) are mandatory. [9,10]

Clinical Pearls

"The Great Imitator": Syphilis can mimic almost any disease, particularly in its secondary and tertiary stages. Maintain a high index of suspicion in unexplained rashes, neurological syndromes, or aortic pathology—especially in sexually active individuals.

Painless Chancre (Primary): The classic primary lesion is a painless, indurated ulcer with clean base and raised edges. It heals spontaneously within 3-6 weeks, but infection persists and progresses without treatment.

Palms and Soles Rash (Secondary): Secondary syphilis classically involves palms and soles—an essential exam clue. Most viral exanthems spare these sites; syphilis and Rocky Mountain spotted fever do not.

Argyll Robertson Pupil = Neurosyphilis: The classic "Prostitute's Pupil"—accommodates but does not react to light. Highly specific for neurosyphilis (tabes dorsalis).

HIV and Syphilis Co-infection: Syphilis facilitates HIV acquisition and transmission through genital ulceration and immune activation. Always test for HIV in patients with syphilis, and vice versa. [11]

Rising Incidence Alert: Global resurgence in syphilis, particularly in MSM, heterosexual adults, and pregnant women. Congenital syphilis is a re-emerging threat due to inadequate antenatal screening and treatment. [12]

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2. Epidemiology

Global and Regional Incidence

Syphilis is a re-emerging global health threat. The World Health Organization (WHO) estimates approximately 7 million new cases of syphilis annually worldwide among adults aged 15-49 years. [13]

• Global Burden: In 2020, the estimated global prevalence was 0.5% in women and 0.5% in men aged 15-49 years, with substantial regional variation.
• United Kingdom: Approximately 8,000-9,000 cases annually, with a disproportionate burden in MSM and in urban centers (London, Manchester, Brighton). Infectious syphilis (primary, secondary, early latent) cases increased by 15% from 2019 to 2022. [14]
• United States: Over 200,000 cases of syphilis (all stages) reported in 2023—a dramatic increase from historical lows in the early 2000s. Primary and secondary syphilis rates nearly tripled from 2014 to 2023. [15]
• Congenital Syphilis: A major concern—global rates estimated at 473 cases per 100,000 live births in 2020. In the United States, congenital syphilis cases increased from 335 in 2014 to over 3,700 in 2023, driven by rising maternal syphilis and gaps in antenatal care. [16,17]

Transmission Routes

Risk Factors

• Unprotected sexual contact (including oral and anal sex).
• Multiple or anonymous sexual partners.
• Men who have sex with men (MSM): Account for > 50% of primary and secondary syphilis cases in many high-income countries. [18]
• HIV co-infection: Bidirectional relationship—syphilis increases HIV acquisition/transmission, and HIV-infected individuals have higher rates of syphilis.
• Sex workers and their clients.
• Substance use (methamphetamine, alcohol) associated with high-risk sexual behavior.
• Incarceration history.
• Pregnancy: Lack of antenatal screening/treatment drives congenital syphilis.
• Previous history of STI.

Populations at High Risk

• MSM, particularly those with HIV.
• Pregnant women in high-prevalence settings or with inadequate antenatal care.
• People living with HIV.
• Commercial sex workers and clients.
• Adolescents and young adults with high-risk sexual behavior.

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3. Pathophysiology

Causative Organism

• Treponema pallidum subspecies pallidum: A thin, tightly coiled spirochaete (5-15 μm long, 0.1-0.2 μm diameter).
• Obligate human pathogen: Cannot survive outside the human host for extended periods; susceptible to drying, heat, and disinfectants.
• Non-cultivable in vitro: Cannot be grown on artificial media (unlike most bacteria), complicating microbiological diagnosis. Direct visualization via dark-field microscopy or molecular detection (PCR) are alternatives to serology.
• Transmission: Requires direct contact with infectious lesions (chancre, mucous patches, condylomata lata) or transplacental passage.

Molecular Pathogenesis

T. pallidum enters the host through microabrasions in skin or mucous membranes. Key virulence factors include:

1. Outer Membrane Proteins (OMPs): Sparse and antigenically variable, allowing immune evasion. The organism's low immunogenicity delays antibody response—the "window period" in early infection.
2. Adhesins: Facilitate attachment to host cells and extracellular matrix.
3. Hyaluronidase and other enzymes: Promote tissue invasion and dissemination.
4. Immune Evasion: T. pallidum downregulates immune recognition and induces chronic inflammation without effective clearance.

Systemic Dissemination: Within hours to days of inoculation, spirochaetes enter lymphatics and bloodstream, disseminating throughout the body—even during the primary stage. This explains the systemic nature of syphilis and the potential for CNS and ocular involvement at any stage. [19]

Natural History (Stages of Syphilis)

If untreated, syphilis progresses through distinct clinical stages. However, neurosyphilis and ocular syphilis can occur at ANY stage.

1. Incubation Period: 10-90 days (average 21 days). Spirochaetes multiply at inoculation site and disseminate systemically.

2. Primary Syphilis: Develops at the site of inoculation.

   • Chancre: Single (occasionally multiple), painless, indurated ulcer with clean base and raised edges.
   • Lymphadenopathy: Regional, bilateral, non-tender lymph nodes (if genital chancre—inguinal nodes).
   • Duration: Chancre heals spontaneously in 3-6 weeks, even without treatment. Spirochaetes persist.

3. Secondary Syphilis: Appears 4-10 weeks after chancre (may overlap).

   • Disseminated infection: Haematogenous spread leads to multi-system involvement.
   • Clinical features: Rash (classically involving palms and soles), mucous patches, condylomata lata, generalized lymphadenopathy, constitutional symptoms (fever, malaise, weight loss), patchy alopecia ("moth-eaten"), hepatitis, nephritis, uveitis, meningitis.
   • Duration: Resolves spontaneously within weeks to months. Infection enters latent stage.

4. Latent Syphilis: Asymptomatic but serologically positive. Subdivided into:

   • Early Latent: less than 2 years since infection. Infectious relapses (secondary manifestations) can occur. Sexual transmission still possible.
   • Late Latent: > 2 years since infection. Generally non-infectious (except for vertical transmission in pregnancy).

5. Tertiary Syphilis: Develops years to decades after initial infection in ~30% of untreated cases. Now rare in the antibiotic era. Three main subtypes:

   • Gummatous Syphilis: Chronic granulomatous lesions (gummas) in skin, bones, liver, other organs. Destructive but responsive to antibiotics.
   • Cardiovascular Syphilis: Aortitis affecting the ascending aorta (classically described as "tree-bark" intimal surface), leading to aortic aneurysm, aortic regurgitation, and coronary ostial stenosis.
   • Neurosyphilis: CNS involvement (see below).

6. Neurosyphilis: Can occur at ANY stage (early or late). Clinical syndromes include:

   • Asymptomatic Neurosyphilis: CSF abnormalities (pleocytosis, elevated protein, positive VDRL) without clinical signs.
   • Meningeal/Meningovascular Neurosyphilis: Meningitis, cranial neuropathies, stroke (endarteritis obliterans).
   • Parenchymatous Neurosyphilis (Late):
     • General Paresis (Dementia Paralytica): Progressive dementia, personality change, psychiatric symptoms, seizures.
     • Tabes Dorsalis: Posterior column and dorsal root degeneration—sensory ataxia, lightning pains, Charcot joints, Argyll Robertson pupils, bladder dysfunction.
   • Ocular Syphilis: Uveitis (anterior, posterior, panuveitis), optic neuritis, retinitis, chorioretinitis. Can cause irreversible vision loss. Treat as neurosyphilis.
   • Otic Syphilis: Hearing loss (sensorineural), tinnitus, vertigo. Treat as neurosyphilis. [20,21]

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4. Clinical Presentation

Primary Syphilis

Timeline: 10-90 days (average 21 days) post-exposure.

Differential Diagnosis: Genital herpes (painful vesicles/ulcers), chancroid (painful, purulent ulcer), lymphogranuloma venereum (LGV), Behçet disease, trauma, malignancy.

Secondary Syphilis

Timeline: 4-10 weeks after chancre (may overlap with primary stage or appear months later).

Duration: Secondary manifestations resolve spontaneously within weeks to months. Patients enter latent stage.

Differential Diagnosis: Viral exanthems (measles, EBV, HIV seroconversion), drug eruption, pityriasis rosea, psoriasis, lichen planus, scabies.

Latent Syphilis

Definition: Positive syphilis serology (treponemal and non-treponemal tests) in the absence of clinical signs or symptoms.

Diagnosis: Based on history (prior lesions, exposure), serial serology (rising titers), or incidental finding on routine screening.

Tertiary Syphilis

Timeline: Develops years to decades (5-40+ years) after initial infection in ~30% of untreated cases. Now rare in the antibiotic era, but still seen in under-resourced settings and cases of missed diagnosis.

Gummatous Syphilis (Late Benign Syphilis)

Cardiovascular Syphilis

Pathology: Obliterative endarteritis of vasa vasorum of the ascending aorta → ischaemia and inflammation of the aortic wall → medial necrosis and fibrosis.

Neurosyphilis

Critical Concept: Neurosyphilis can occur at ANY STAGE of syphilis (early or late). Maintain high index of suspicion in anyone with neurological or ophthalmological symptoms and positive syphilis serology. [22]

Argyll Robertson Pupil: Pathognomonic for neurosyphilis (tabes dorsalis). Small, irregular pupils that accommodate (constrict for near vision) but do NOT react to light. Mnemonic: "Prostitute's pupil"—accommodates but does not react.

Diagnosis of Neurosyphilis: Requires lumbar puncture in patients with:

• Neurological signs/symptoms (including cognitive, motor, sensory, cranial nerve deficits).
• Ocular or otic symptoms.
• Tertiary syphilis.
• Treatment failure (persistently elevated or rising RPR/VDRL despite appropriate treatment).
• HIV co-infection with late latent syphilis or syphilis of unknown duration (consider LP).

CSF Findings in Neurosyphilis:

• CSF-VDRL: Specific (98-99%) but insensitive (~30-70%). Positive CSF-VDRL = neurosyphilis.
• CSF-FTA-Abs or CSF-TPPA: Sensitive but less specific. Negative test essentially rules out neurosyphilis.
• CSF Pleocytosis: > 5 white cells/mm³ (typically lymphocytic).
• CSF Protein: Elevated (> 0.45 g/L).
• CSF Glucose: Usually normal (unlike bacterial meningitis).

Congenital Syphilis

Transmission: Transplacental, typically after 16 weeks' gestation. Risk highest with primary and secondary maternal syphilis (up to 80-100% transmission), lower in late latent (~10-30%).

Outcomes:

• Stillbirth (40% of untreated maternal syphilis).
• Neonatal Death (perinatal mortality).
• Early Congenital Syphilis (less than 2 years).
• Late Congenital Syphilis (> 2 years).

Early Congenital Syphilis (less than 2 years)

Late Congenital Syphilis (> 2 years)

Diagnosis: Positive serology in neonate + clinical/radiological/laboratory evidence. IgM-specific tests (if available) distinguish neonatal infection from passive maternal IgG transfer.

Screening in Pregnancy: Universal antenatal screening at first visit (ideally less than 12 weeks). Repeat at 28 weeks and delivery in high-risk populations. Essential for prevention. [23]

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5. Investigations

Serology (Mainstay of Diagnosis)

Syphilis serology relies on two types of tests used in combination:

Non-Treponemal Tests (Non-Specific)

Principle: Detect antibodies to cardiolipin (released from damaged cells). Reflect disease activity.

Treponemal Tests (Specific)

Principle: Detect antibodies against T. pallidum antigens. Remain positive for life, even after successful treatment.

Interpretation of Syphilis Serology

Traditional Algorithm vs Reverse Algorithm

• Traditional Algorithm: Screen with RPR/VDRL (non-treponemal) → if positive, confirm with treponemal test (TPPA, FTA-Abs).
• Reverse Algorithm: Screen with EIA/CIA (treponemal) → if positive, reflex to RPR/VDRL and confirmatory treponemal test (TPPA). Increasingly used in high-throughput laboratories due to automation. [24]

Direct Detection Methods

CSF Examination (for Suspected Neurosyphilis)

Indications for Lumbar Puncture:

• Neurological or psychiatric symptoms/signs.
• Ocular symptoms (visual changes, eye pain, uveitis).
• Otic symptoms (hearing loss, tinnitus, vertigo).
• Tertiary syphilis.
• Treatment failure (persistently elevated or rising RPR/VDRL despite treatment).
• HIV co-infection with late latent or syphilis of unknown duration (consider LP).

CSF Findings:

Interpretation:

• Positive CSF-VDRL = Neurosyphilis (very specific).
• Negative CSF-VDRL + normal CSF = Neurosyphilis unlikely (high NPV of CSF-TPPA/FTA-Abs).
• Negative CSF-VDRL + CSF pleocytosis/elevated protein = Possible neurosyphilis. Treat if clinical suspicion high.

Other Investigations

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6. Management

Management Algorithm

       CONFIRMED SYPHILIS (Positive Serology)
                     ↓
       STAGE DISEASE (Clinical History + Examination + Serology)
       (Primary, Secondary, Early Latent, Late Latent, Tertiary, Neurosyphilis?)
                     ↓
       NEUROLOGICAL / OCULAR / OTIC SYMPTOMS?
    ┌────────────────┴────────────────┐
   YES                               NO
    ↓                                 ↓
 LUMBAR PUNCTURE              DETERMINE STAGE
 + NEUROSYPHILIS Rx           AND TREAT
       ↓
       TREATMENT BY STAGE
    ┌──────────────────────────────────────────────────────────┐
    │  PRIMARY / SECONDARY / EARLY LATENT (less than 2 years)           │
    │  - Benzathine Penicillin G 2.4 MU IM (SINGLE DOSE)      │
    │                                                          │
    │  Penicillin Allergy (Non-Pregnant):                     │
    │  - Doxycycline 100mg BD PO for 14 days                  │
    │  - OR Ceftriaxone 1-2g IM/IV daily for 10-14 days       │
    │                                                          │
    │  Penicillin Allergy (Pregnant):                         │
    │  - DESENSITISATION + Benzathine Penicillin              │
    └──────────────────────────────────────────────────────────┘
    ┌──────────────────────────────────────────────────────────┐
    │  LATE LATENT (> 2 years) / LATENT UNKNOWN DURATION       │
    │  / TERTIARY (Non-Neuro)                                 │
    │  - Benzathine Penicillin G 2.4 MU IM WEEKLY x 3 DOSES   │
    │                                                          │
    │  Penicillin Allergy (Non-Pregnant):                     │
    │  - Doxycycline 100mg BD PO for 28 days                  │
    │                                                          │
    │  Penicillin Allergy (Pregnant):                         │
    │  - DESENSITISATION + Benzathine Penicillin              │
    └──────────────────────────────────────────────────────────┘
    ┌──────────────────────────────────────────────────────────┐
    │  NEUROSYPHILIS / OCULAR / OTIC SYPHILIS                 │
    │  - Benzylpenicillin (Aqueous Crystalline Penicillin G)   │
    │    18-24 MU/day IV continuous infusion OR                │
    │    3-4 MU IV every 4 hours for 14 days                   │
    │                                                          │
    │  Alternative (if compliance assured):                    │
    │  - Procaine Penicillin 2.4 MU IM daily                   │
    │    + Probenecid 500mg PO QID for 14 days                 │
    │                                                          │
    │  Penicillin Allergy:                                     │
    │  - DESENSITISATION preferred                             │
    │  - OR Ceftriaxone 2g IV/IM daily for 14 days             │
    └──────────────────────────────────────────────────────────┘
                     ↓
       WARN PATIENT: JARISCH-HERXHEIMER REACTION
       - Fever, Rigors, Headache, Myalgia, Tachycardia,
         Hypotension starting 2-8 hours after first dose.
       - Due to cytokine release from dying spirochaetes.
       - Self-limiting (resolves within 24 hours).
       - Supportive: Paracetamol, Fluids. Monitor if severe.
       - Risk highest in early syphilis (primary, secondary).
       - In pregnancy: Risk of preterm labour. Inform obstetrician.
                     ↓
       PARTNER NOTIFICATION + CONTACT TRACING
       (GUM Clinic - Health Advisor)
       - Sexual partners in past 3 months (primary), 6 months
         (secondary), 12 months (early latent).
       - Test and treat epidemiologically (presumptive treatment).
                     ↓
       FOLLOW-UP SEROLOGY
       - Repeat RPR/VDRL at 3, 6, 12, 24 months.
       - Expect **4-fold decrease in titre** by 6-12 months
         (e.g., 1:32 → 1:8) = Adequate response.
       - If titre fails to decline, rises, or symptoms persist
         → Re-treat / Consider neurosyphilis (LP) / HIV test.
                     ↓
       FULL STI SCREEN (including HIV, Hepatitis B/C)

Treatment by Stage

Primary, Secondary, and Early Latent Syphilis (less than 2 years)

First-Line:

• Benzathine Penicillin G 2.4 million units (MU) IM single dose (1.2 MU in each buttock). [25]

Alternatives (Penicillin Allergy, Non-Pregnant):

• Doxycycline 100mg PO twice daily for 14 days.
• Ceftriaxone 1-2g IM or IV once daily for 10-14 days (some cross-reactivity risk with penicillin allergy).
• Azithromycin 2g PO single dose (increasing resistance; not recommended first-line in many regions). [26]

Pregnancy: Penicillin is the ONLY reliably effective treatment for preventing congenital syphilis. If penicillin-allergic, desensitisation is mandatory. No alternative antibiotic (including ceftriaxone, doxycycline, azithromycin) is adequate. [27]

Late Latent (> 2 years), Latent of Unknown Duration, Tertiary Syphilis (Non-Neurological)

First-Line:

• Benzathine Penicillin G 2.4 MU IM once weekly for 3 consecutive weeks (total 3 doses). [28]

Alternatives (Penicillin Allergy, Non-Pregnant):

• Doxycycline 100mg PO twice daily for 28 days.

Pregnancy: Desensitisation + Benzathine Penicillin. No alternative.

Neurosyphilis, Ocular Syphilis, Otic Syphilis

First-Line:

• Aqueous Crystalline Penicillin G (Benzylpenicillin) 18-24 MU/day IV as continuous infusion OR 3-4 MU IV every 4 hours for 14 days. [29]

Alternative (if compliance and daily IM administration assured):

• Procaine Penicillin 2.4 MU IM once daily PLUS Probenecid 500mg PO four times daily for 14 days. (Probenecid blocks renal excretion of penicillin, increasing CSF levels).

Penicillin Allergy:

• Desensitisation is strongly preferred. Penicillin is most effective for neurosyphilis.
• Alternative: Ceftriaxone 2g IV or IM once daily for 14 days. (Some data support efficacy, but less robust than penicillin. Cross-reactivity risk with penicillin allergy ~1-3%).

Note: Some guidelines recommend additional weekly Benzathine Penicillin G 2.4 MU IM for 3 doses after completing IV therapy to provide total 3 weeks of treatment (similar to late latent).

Congenital Syphilis

Treatment:

• Aqueous Crystalline Penicillin G 50,000 units/kg/dose IV every 12 hours (first week of life) or every 8 hours (> 7 days) for 10 days.
• Alternative: Procaine Penicillin 50,000 units/kg IM once daily for 10 days.
• Benzathine Penicillin G 50,000 units/kg IM single dose (only if definite congenital syphilis excluded but mother inadequately treated).

Jarisch-Herxheimer Reaction (JHR)

Definition: Acute systemic inflammatory response occurring 2-8 hours after first antibiotic dose for syphilis (particularly with penicillin).

Pathophysiology: Massive cytokine release (TNF-α, IL-6, IL-8) following rapid lysis of spirochaetes. [30]

Incidence:

• Primary syphilis: ~50-60%.
• Secondary syphilis: ~75-90%.
• Early latent: ~30-40%.
• Late latent/tertiary: less than 10%.

Clinical Features:

• Fever, rigors, chills.
• Headache, myalgia, arthralgia.
• Tachycardia, tachypnoea.
• Hypotension (mild to moderate; severe hypotension rare).
• Exacerbation of skin lesions (secondary syphilis rash may become more prominent).
• Uterine contractions (pregnant women—risk of preterm labour).

Timing: Starts 2-8 hours post-treatment. Peaks at 6-8 hours. Resolves within 24 hours (self-limiting).

Management:

• Warn patients in advance. Reassure that it is expected and self-limiting.
• Supportive care: Paracetamol (acetaminophen) for fever/pain, oral/IV fluids for hydration.
• Monitor patients with high-risk features: pregnancy, cardiovascular syphilis (aortitis, AR), neurosyphilis (risk of stroke/meningitis exacerbation).
• Corticosteroids (prednisolone) may attenuate reaction but are not routinely recommended (limited evidence; theoretical concern of impairing immune response).
• Do NOT delay or withhold treatment due to fear of JHR. Benefits of treating syphilis far outweigh risks.

Pregnancy Considerations: JHR can trigger preterm labour. Inform obstetrician. Consider inpatient monitoring for treatment in third trimester.

Partner Notification and Contact Tracing

Essential component of syphilis management. Coordinated by GUM/Sexual Health clinic Health Advisors.

Contact Period (trace and test sexual partners within):

• Primary syphilis: 3 months before symptom onset.
• Secondary syphilis: 6 months before symptom onset.
• Early latent syphilis: 12 months before diagnosis.
• Late latent, tertiary: All current sexual partners. Long-term partners may need screening.

Epidemiological (Presumptive) Treatment: Sexual contacts of confirmed cases should be treated presumptively (before serology results, if recent exposure) to prevent onward transmission and progression in contacts.

Follow-Up and Monitoring

Serology:

• Repeat quantitative RPR/VDRL at 3, 6, 12, and 24 months post-treatment.
• Adequate response: 4-fold decline in titer within 6-12 months (e.g., 1:32 → 1:8, or 1:16 → 1:4). [31]
• Serological cure: RPR/VDRL becomes non-reactive (may take years, especially in late syphilis).
• Serofast: Persistent low-level non-treponemal antibody (e.g., 1:2, 1:4) despite adequate treatment and clinical cure. Occurs in ~15% of treated patients. No further treatment required if stable.

Treatment Failure (consider if):

• RPR/VDRL fails to decline 4-fold by 12 months.
• RPR/VDRL titer rises after initial decline (4-fold increase = possible reinfection or treatment failure).
• Persistent or recurrent symptoms.

Management of Treatment Failure:

• Re-examine clinically.
• Re-test for HIV (if negative initially).
• Lumbar puncture to rule out neurosyphilis.
• Re-treat: Benzathine Penicillin G 2.4 MU IM weekly x 3 doses (if not already given). If neurosyphilis confirmed, treat as neurosyphilis.
• Consider re-infection: Re-evaluate sexual history and partners.

Neurosyphilis Follow-Up:

• Repeat LP at 6 months post-treatment. Expect normalization of CSF pleocytosis (WCC should decline within 6 months; protein may take longer).
• If CSF not improving (persistent pleocytosis), consider re-treatment.

Special Populations

HIV Co-Infection

• Diagnosis: Same serological tests. HIV-infected individuals may have atypical serology (higher titers, delayed seroreversion, or false negatives—rare).
• Treatment: Same regimens as HIV-negative patients. Some experts recommend:
  • Enhanced follow-up (more frequent serology).
  • Lower threshold for LP (to rule out neurosyphilis in late latent or unknown duration).
  • Consideration of three-dose regimen (weekly Benzathine Penicillin x 3) for early syphilis in HIV+ patients (controversial; not universally recommended).
• Neurosyphilis: Same treatment. Monitor closely.
• CD4 count: No adjustment to treatment based on CD4 count.
• ART: Continue antiretroviral therapy. No drug interactions with penicillin.

Pregnancy

• Universal screening: Test at first antenatal visit, repeat at 28 weeks and delivery in high-risk populations.
• Treatment: Penicillin ONLY. Desensitisation if allergic. No alternative is adequate for fetal treatment.
• JHR risk: Can trigger preterm labour. Consider inpatient monitoring in third trimester.
• Ultrasound: Serial fetal monitoring for signs of congenital syphilis (hepatomegaly, ascites, hydrops).
• Neonatal evaluation: All infants born to seropositive mothers require full evaluation (serology, clinical exam, CSF if indicated, long bone X-rays if symptomatic).

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7. Complications and Prognosis

Complications (Untreated Syphilis)

Prognosis

With Treatment:

• Early Syphilis (Primary, Secondary, Early Latent): Excellent prognosis. Single dose of Benzathine Penicillin G achieves cure in > 95% of cases. Complete resolution of lesions. Prevents progression. [32]
• Late Latent/Tertiary (Non-Neurological): Good response to antibiotics. Gummas heal. Cardiovascular and neurological damage may be arrested but not reversed (structural damage irreversible).
• Neurosyphilis: Antibiotics halt progression. Cognitive and neurological deficits may stabilize or improve partially, but complete recovery uncommon if advanced disease. Early treatment critical.
• Congenital Syphilis: Treatment in neonatal period effective. Long-term outcomes depend on severity of infection and timing of treatment. Stigmata (dental, skeletal) irreversible.

Without Treatment:

• Spontaneous Resolution: Secondary manifestations resolve spontaneously, entering latent phase. However, infection persists.
• Progression: ~30% develop tertiary syphilis over years to decades.
• Mortality: Cardiovascular syphilis (aortic rupture), neurosyphilis (complications of dementia/stroke), and congenital syphilis (stillbirth/neonatal death) contribute to mortality.

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8. Prevention

Primary Prevention

• Condom use: Reduces but does not eliminate risk (lesions may be in non-covered areas).
• Reduction in number of sexual partners.
• Regular STI screening: MSM, HIV-positive individuals, sex workers, high-risk populations.
• Pre-Exposure Prophylaxis (PrEP) for HIV: Encourages regular STI screening (syphilis often detected incidentally).
• Sexual health education: Awareness of symptoms, importance of testing.

Secondary Prevention (Screening)

• Antenatal Screening: Universal screening of all pregnant women at booking (first trimester). Repeat at 28 weeks and delivery in high-risk populations (MSM partners, IVDU, areas with high prevalence). Prevents congenital syphilis. [33]
• MSM: Screen at least annually; every 3-6 months if high-risk (multiple partners, PrEP use, previous STI).
• HIV-Positive Individuals: Screen at HIV diagnosis, then annually (or more frequently if high-risk).
• Sex Workers: Frequent screening (every 3 months).
• Blood and Organ Donation: Universal screening.
• Incarcerated Populations: Offer screening.

Partner Notification

Critical for prevention. Identify, test, and treat sexual contacts. Prevents reinfection and onward transmission.

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9. Evidence and Guidelines

Key Guidelines

Landmark Studies and Evidence

1. Penicillin for Syphilis: Introduced in 1943. Revolutionized syphilis treatment. Remains gold standard. No resistance documented. [38]
2. Benzathine Penicillin G vs Doxycycline: Meta-analyses confirm superior efficacy of penicillin. Doxycycline acceptable alternative for non-pregnant, penicillin-allergic patients. [39]
3. Neurosyphilis Treatment: IV Benzylpenicillin superior to IM Benzathine Penicillin G for CNS penetration. CSF penicillin levels adequate with IV regimen. [40]
4. Jarisch-Herxheimer Reaction: Described in 1895 (Jarisch) and 1902 (Herxheimer). Cytokine-mediated. Self-limiting. Corticosteroids do not clearly prevent or ameliorate JHR. [41]
5. Congenital Syphilis Prevention: Antenatal screening and treatment reduce congenital syphilis by > 95%. WHO target: eliminate mother-to-child transmission (defined as less than 50 cases per 100,000 live births). [42]

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10. Patient and Layperson Explanation

What is Syphilis?

Syphilis is a sexually transmitted infection (STI) caused by bacteria called Treponema pallidum. It spreads through sexual contact (vaginal, anal, or oral sex) or from a pregnant woman to her baby. If left untreated, it progresses through stages and can cause serious problems with the heart, brain, and other organs years later.

How is it Spread?

• Sexual Contact: The most common way. Bacteria enter through small breaks in the skin or mucous membranes during sex. Infected sores or rashes are highly contagious.
• Mother to Baby: During pregnancy, syphilis can pass to the baby and cause serious illness or death (congenital syphilis). This is preventable with testing and treatment during pregnancy.
• Not Spread By: Toilet seats, doorknobs, swimming pools, sharing utensils, or casual contact like hugging.

What are the Symptoms?

Syphilis has different stages:

1. Stage 1 (Primary Syphilis): A painless sore (chancre) appears on the genitals, anus, or mouth about 3 weeks after infection. The sore heals on its own in a few weeks, but the infection remains.

2. Stage 2 (Secondary Syphilis): Weeks to months later, a rash appears—often on the palms of the hands and soles of the feet (unusual for most rashes). You may also have flu-like symptoms (fever, tiredness, swollen glands, sore throat, hair loss in patches). These symptoms also go away without treatment, but the infection continues.

3. Hidden Stage (Latent Syphilis): No symptoms. The infection is "asleep" but still in your body. You can have this for years without knowing.

4. Late Stage (Tertiary Syphilis): Years later (if never treated), syphilis can damage the heart, brain, nerves, eyes, and other organs. This can cause serious problems like strokes, dementia, blindness, and heart failure.

Good News: Syphilis can be cured with antibiotics at any stage, but damage from late-stage syphilis may be permanent.

How is it Diagnosed?

A blood test checks for syphilis. Sometimes two types of tests are done to confirm the diagnosis. If you have symptoms affecting your brain or eyes, a spinal tap (lumbar puncture) may be needed.

How is it Treated?

• Antibiotics: The treatment is a Penicillin injection (usually one or three injections, depending on how long you've had the infection). Penicillin cures syphilis very effectively.
• Allergic to Penicillin?: Other antibiotics (doxycycline) can be used, except in pregnancy—penicillin is essential to protect the baby. If you're allergic, a process called "desensitization" can make penicillin safe for you.
• Jarisch-Herxheimer Reaction: After the first injection, you may feel flu-like symptoms (fever, chills, headache, muscle aches) for 12-24 hours. This is normal and means the treatment is working. It goes away on its own. Take paracetamol (acetaminophen) if needed.

What About My Partner(s)?

Tell your sexual partners. They need to be tested and may need treatment, even if they have no symptoms. This prevents reinfection and stops the spread. Sexual health clinics have trained staff (health advisors) who can help with this confidentially.

Follow-Up

You'll need repeat blood tests at 3, 6, and 12 months to make sure the treatment worked. The blood test numbers should go down.

Can I Get Syphilis Again?

Yes. Being cured does not make you immune. You can get syphilis again if exposed. Use condoms and get regular testing if you're at risk.

Pregnancy and Syphilis

If you're pregnant or planning pregnancy:

• Get tested early in pregnancy.
• If you have syphilis, treatment with penicillin protects your baby. Without treatment, syphilis can cause miscarriage, stillbirth, or serious illness in the baby.

Prevention

• Use condoms during sex (reduces but doesn't eliminate risk).
• Get tested regularly if you have multiple partners or new partners.
• Avoid sex if you or your partner has sores, rashes, or symptoms.
• Get tested in pregnancy.

Key Takeaways

• Syphilis is curable with antibiotics.
• Early treatment prevents serious complications.
• Tell your partners so they can get tested and treated.
• Syphilis doesn't go away on its own—even if symptoms disappear, the infection remains and can cause serious problems later.
• Get tested regularly if you're sexually active.

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11. Examination Focus (for Medical Trainees)

Common Exam Questions (MRCP, MRCS, PLAB, USMLE)

Question 1: Classic Lesion of Primary Syphilis

Q: Describe the characteristic features of a chancre in primary syphilis.

A: A chancre is a single (occasionally multiple), painless, indurated ulcer with a clean base and raised, well-defined edges. It appears at the site of inoculation (genitals, anus, mouth) approximately 3 weeks (range 10-90 days) after exposure. Associated with bilateral, non-tender regional lymphadenopathy. Heals spontaneously in 3-6 weeks without treatment, but infection persists and progresses to secondary stage.

Differential Diagnosis: Genital herpes (painful vesicles/ulcers, shorter incubation 2-7 days), chancroid (painful purulent ulcer, tender lymph nodes), LGV, Behçet disease.

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Question 2: Rash Distribution in Secondary Syphilis

Q: A 28-year-old man presents with a widespread rash. On examination, you note involvement of the palms and soles. What is the most likely diagnosis, and what other features would you look for?

A: Secondary syphilis. The rash is classically maculopapular, symmetrical, non-pruritic, and "copper-colored". Involvement of palms and soles is a key diagnostic clue (most viral exanthems spare these sites).

Other features to look for:

• Condylomata lata: Flat, moist, wart-like lesions in anogenital/axillary areas.
• Mucous patches: Painless grey-white erosions on oral or genital mucosa.
• Generalized lymphadenopathy: Non-tender, rubbery.
• Constitutional symptoms: Fever, malaise, sore throat, headache.
• Patchy alopecia: "Moth-eaten" hair loss.

Investigations: Serology—positive RPR/VDRL and TPPA/EIA. Full STI screen (including HIV).

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Question 3: Argyll Robertson Pupil

Q: What is the Argyll Robertson pupil, and what is it pathognomonic for?

A: The Argyll Robertson pupil is small, irregular, and exhibits light-near dissociation: it accommodates (constricts for near vision) but does NOT react to light.

Pathognomonic for: Neurosyphilis (specifically tabes dorsalis).

Mnemonic: "Prostitute's pupil"—Accommodates but does not React (A.R.).

Associated Features of Tabes Dorsalis: Sensory ataxia, loss of proprioception/vibration sense, lightning pains, Charcot joints, bladder dysfunction.

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Question 4: Treatment of Primary Syphilis

Q: What is the first-line treatment for primary syphilis?

A: Benzathine Penicillin G 2.4 million units intramuscularly as a SINGLE dose (1.2 MU in each buttock).

Alternative (Penicillin Allergy, Non-Pregnant): Doxycycline 100mg orally twice daily for 14 days.

Pregnancy: Penicillin ONLY (doxycycline contraindicated). If penicillin-allergic, desensitisation is mandatory.

Follow-Up: Repeat quantitative RPR/VDRL at 3, 6, 12 months. Expect 4-fold decline in titer by 6-12 months.

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Question 5: Jarisch-Herxheimer Reaction

Q: A 32-year-old woman with secondary syphilis receives her first dose of Benzathine Penicillin G. Six hours later, she develops fever (39°C), rigors, headache, and myalgia. What is the most likely diagnosis, and how should this be managed?

A: Jarisch-Herxheimer reaction (JHR).

Pathophysiology: Acute cytokine release (TNF-α, IL-6, IL-8) following rapid lysis of spirochaetes.

Clinical Features: Fever, rigors, headache, myalgia, tachycardia, hypotension. Onset 2-8 hours after first antibiotic dose. Self-limiting—resolves within 24 hours.

Management:

• Reassure patient (expected reaction).
• Supportive care: Paracetamol for fever/pain, oral/IV fluids.
• Monitor: Vital signs (especially in pregnancy, cardiovascular, or neurosyphilis).
• Do NOT stop treatment.

Incidence: High in early syphilis (50-90%). Lower in late syphilis (less than 10%).

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Question 6: Neurosyphilis Diagnosis

Q: A 45-year-old HIV-positive man has positive syphilis serology (RPR 1:64, TPPA positive). He reports headaches and blurred vision. What is the next step in management?

A: Lumbar puncture to evaluate for neurosyphilis (or ocular syphilis, which is treated as neurosyphilis).

Indications for LP:

• Neurological symptoms/signs.
• Ocular symptoms (blurred vision, floaters, eye pain, uveitis).
• Otic symptoms (hearing loss, tinnitus, vertigo).
• Tertiary syphilis.
• Treatment failure.
• HIV+ with late latent or unknown duration syphilis (consider LP).

CSF Findings in Neurosyphilis:

• CSF-VDRL: Specific (98-99%) but insensitive (30-70%). Positive = neurosyphilis.
• CSF-TPPA/FTA-Abs: Sensitive. Negative = rules out neurosyphilis.
• CSF Pleocytosis: > 5 WCC/mm³ (lymphocytic).
• CSF Protein: Elevated (> 0.45 g/L).

Treatment: IV Benzylpenicillin (Aqueous Crystalline Penicillin G) 18-24 MU/day for 14 days.

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Viva Scenarios

Scenario 1: You are the on-call medical registrar. A 26-year-old man presents to A&E with a painless genital ulcer. How would you approach this case?

Model Answer:

• History: Sexual history (recent contacts, partners, condom use), duration of ulcer, pain (absence suggests syphilis), associated symptoms (rash, fever, lymphadenopathy), previous STIs, HIV status.
• Examination: Inspect ulcer (size, edges, base, induration, discharge), palpate regional lymph nodes (bilateral, non-tender = syphilis), full skin examination (rash?), oral mucosa.
• Differential Diagnosis: Primary syphilis (painless, indurated chancre), genital herpes (painful vesicles/ulcers), chancroid (painful, purulent ulcer), LGV, Behçet, trauma.
• Investigations: Syphilis serology (RPR/VDRL + TPPA/EIA). Full STI screen (NAAT for gonorrhoea/chlamydia, HIV, Hepatitis B/C). Consider dark-field microscopy or PCR of ulcer exudate if available.
• Management: If high suspicion for syphilis, consider epidemiological (presumptive) treatment while awaiting serology (especially if partner contact uncertain or high-risk behavior). Benzathine Penicillin G 2.4 MU IM single dose for primary syphilis. Partner notification. Warn about Jarisch-Herxheimer reaction. Follow-up serology at 3, 6, 12 months. Avoid sex until treated and lesion healed.

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Scenario 2: A 34-year-old pregnant woman at 12 weeks' gestation has positive syphilis serology (RPR 1:16, TPPA positive). She reports a rash 2 months ago that resolved. How do you manage this case?

Model Answer:

• Diagnosis: Secondary or early latent syphilis (recent rash suggests secondary; now in latent phase).
• Urgency: High priority. Risk of congenital syphilis if untreated (up to 80% transmission in early maternal infection).
• Treatment: Benzathine Penicillin G 2.4 MU IM single dose (early syphilis less than 2 years).
  • "If penicillin-allergic: Desensitisation is MANDATORY. No alternative antibiotic is adequate for fetal treatment."
• Warn about JHR: Can trigger preterm labour. Consider inpatient monitoring if third trimester. Inform obstetrician.
• Partner Notification: Identify and test/treat sexual partners (past 6 months for secondary syphilis).
• Fetal Monitoring: Serial ultrasound for signs of congenital syphilis (hepatomegaly, ascites, hydrops).
• Follow-Up Serology: RPR/VDRL at 28 weeks and delivery (expect 4-fold decline by delivery).
• Neonatal Evaluation: At birth—serology, clinical exam, CSF if indicated, long bone X-rays if symptomatic. Neonatal treatment if congenital syphilis confirmed or maternal treatment inadequate (less than 4 weeks before delivery).

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Scenario 3: A 50-year-old man with known HIV presents with progressive cognitive decline over 6 months. His partner reports personality change and memory problems. On examination, he has hyperreflexia and tremor. RPR is positive (1:32), TPPA positive. What is the most likely diagnosis, and how do you confirm it?

Model Answer:

• Most Likely Diagnosis: Neurosyphilis—General Paresis (Dementia Paralytica).
• Confirmation: Lumbar puncture.
  • "CSF Findings: Elevated protein, lymphocytic pleocytosis, positive CSF-VDRL (specific for neurosyphilis), positive CSF-TPPA/FTA-Abs."
  • "MRI Brain: May show cortical atrophy, non-specific white matter changes."
• Treatment: IV Benzylpenicillin (Aqueous Crystalline Penicillin G) 18-24 MU/day for 14 days.
• Prognosis: Antibiotics arrest progression. Cognitive deficits may partially improve but are often irreversible. Early treatment critical.
• HIV Management: Continue ART. No adjustment needed. Enhanced follow-up.

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12. References

Primary Sources

1. Peeling RW, Mabey D, Chen XS, Garcia PJ. Syphilis. Lancet. 2023;402(10398):336-346. doi:10.1016/S0140-6736(22)02348-0. PMID: 37481272.

2. Hook EW 3rd. Syphilis. Lancet. 2017;389(10078):1550-1557. doi:10.1016/S0140-6736(16)32411-4. PMID: 27993382.

3. Tsuboi M, Evans J, Davies EP, et al. Prevalence of syphilis among men who have sex with men: a global systematic review and meta-analysis from 2000-20. Lancet Glob Health. 2021;9(8):e1110-e1118. doi:10.1016/S2214-109X(21)00221-7. PMID: 34265277.

4. Bowen VB, Su J, Torrone E, Kidd S, Weinstock H. Increase in Incidence of Congenital Syphilis - United States, 2012-2014. MMWR Morb Mortal Wkly Rep. 2015;64(44):1241-1245. doi:10.15585/mmwr.mm6444a3. PMID: 26562062.

5. Workowski KA, Bachmann LH, Chan PA, et al. Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep. 2021;70(4):1-187. doi:10.15585/mmwr.rr7004a1. PMID: 34292926.

6. Kingston M, French P, Higgins S, et al. UK national guidelines on the management of syphilis 2015. Int J STD AIDS. 2016;27(6):421-446. doi:10.1177/0956462415624059. PMID: 26721608.

7. Peeling RW, Ye H. Diagnostic tools for preventing and managing maternal and congenital syphilis: an overview. Bull World Health Organ. 2004;82(6):439-446. PMID: 15356936.

8. Larsen SA, Steiner BM, Rudolph AH. Laboratory diagnosis and interpretation of tests for syphilis. Clin Microbiol Rev. 1995;8(1):1-21. doi:10.1128/CMR.8.1.1. PMID: 7704889.

9. Tuddenham S, Ghanem KG. Management of Adult Syphilis: Key Questions to Inform the 2021 Centers for Disease Control and Prevention Sexually Transmitted Infections Treatment Guidelines. Clin Infect Dis. 2022;74(Suppl_2):S127-S133. doi:10.1093/cid/ciac060. PMID: 35416969.

10. Belum GR, Belum VR, Chaitanya Arudra SK, Reddy BS. The Jarisch-Herxheimer reaction: revisited. Travel Med Infect Dis. 2013;11(4):231-237. doi:10.1016/j.tmaid.2013.04.001. PMID: 23632012.

11. Fleming DT, Wasserheit JN. From epidemiological synergy to public health policy and practice: the contribution of other sexually transmitted diseases to sexual transmission of HIV infection. Sex Transm Infect. 1999;75(1):3-17. doi:10.1136/sti.75.1.3. PMID: 10448335.

12. Gilmour LS, Walls T. Congenital Syphilis: a Review of Global Epidemiology. Clin Microbiol Rev. 2023;36(2):e0012622. doi:10.1128/cmr.00126-22. PMID: 36920205.

13. Rowley J, Vander Hoorn S, Korenromp E, et al. Chlamydia, gonorrhoea, trichomoniasis and syphilis: global prevalence and incidence estimates, 2016. Bull World Health Organ. 2019;97(8):548-562P. doi:10.2471/BLT.18.228486. PMID: 31384073.

14. Public Health England. Sexually transmitted infections and screening for chlamydia in England, 2019. Health Protection Report. 2020;14(20).

15. Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2022. Atlanta: U.S. Department of Health and Human Services; 2023.

16. Fang J, Partridge E, Bautista GM, Sankaran D. Congenital Syphilis Epidemiology, Prevention, and Management in the United States: A 2022 Update. Cureus. 2022;14(12):e33009. doi:10.7759/cureus.33009. PMID: 36712768.

17. Cooper JM, Sánchez PJ. Congenital syphilis. Semin Perinatol. 2018;42(3):176-184. doi:10.1053/j.semperi.2018.02.005. PMID: 29627075.

18. Peterman TA, Su J, Bernstein KT, Weinstock H. Syphilis in the United States: on the rise? Expert Rev Anti Infect Ther. 2015;13(2):161-168. doi:10.1586/14787210.2015.990384. PMID: 25487961.

19. Radolf JD, Deka RK, Anand A, et al. Treponema pallidum, the syphilis spirochete: making a living as a stealth pathogen. Nat Rev Microbiol. 2016;14(12):744-759. doi:10.1038/nrmicro.2016.141. PMID: 27721440.

20. Hamill MM, Ghanem KG, Tuddenham S. State-of-the-Art Review: Neurosyphilis. Clin Infect Dis. 2024;78(5):e57-e68. doi:10.1093/cid/ciad437. PMID: 37593890.

21. Tsan GL, Claiborne RT. Ocular syphilis. Clin Exp Optom. 2021;104(7):756-759. doi:10.1080/08164622.2021.1906848. PMID: 33831337.

22. Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features. J Infect Dis. 2004;189(3):369-376. doi:10.1086/381227. PMID: 14745693.

23. Eppes CS, Stafford I, Rac M. Syphilis in pregnancy: an ongoing public health threat. Am J Obstet Gynecol. 2022;227(6):822-838. doi:10.1016/j.ajog.2022.07.041. PMID: 35932881.

24. Park IU, Tran A, Pereira L, Fakile Y. Sensitivity and Specificity of Treponemal-Specific Tests for the Diagnosis of Syphilis. Clin Infect Dis. 2020;71(Suppl 1):S13-S20. doi:10.1093/cid/ciaa349. PMID: 32725229.

25. Alexander JM, Sheffield JS, Sanchez PJ, Mayfield J, Wendel GD Jr. Efficacy of treatment for syphilis in pregnancy. Obstet Gynecol. 1999;93(1):5-8. PMID: 9916946.

26. Bai ZG, Yang K, Liu Y, et al. Azithromycin vs. benzathine penicillin G for early syphilis: a meta-analysis of randomized clinical trials. Int J STD AIDS. 2012;23(5):e11-e18. doi:10.1258/ijsa.2009.009449. PMID: 22648877.

27. Tsai S, Sun MY, Kuller JA, Rhee EHJ, Dotters-Katz S. Syphilis in Pregnancy. Obstet Gynecol Surv. 2019;74(9):557-564. doi:10.1097/OGX.0000000000000713. PMID: 31830301.

28. Domantay-Apostol GP, Handog EB, Gabriel MT. Syphilis: the international challenge of the great imitator. Dermatol Clin. 2008;26(2):191-202. doi:10.1016/j.det.2007.12.001. PMID: 18346551.

29. Marra CM, Maxwell CL, Tantalo LC, et al. Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: does HIV status matter? Clin Infect Dis. 2004;38(7):1001-1006. doi:10.1086/382532. PMID: 15034833.

30. Dionne JA, Zhu C, Mejia-Galvis J, et al. Jarisch-Herxheimer Reaction After Benzathine Penicillin G Treatment in Adults With Early Syphilis: Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2025;8(2):e2459490. doi:10.1001/jamanetworkopen.2024.59490. PMID: 39946129.

31. Romanowski B, Sutherland R, Fick GH, Mooney D, Love EJ. Serologic response to treatment of infectious syphilis. Ann Intern Med. 1991;114(12):1005-1009. doi:10.7326/0003-4819-114-12-1005. PMID: 2029095.

32. Ghanem KG, Workowski KA, Langenberg A, et al. The "Syphilis 2021" study: design and rationale of a large randomized clinical trial of the efficacy of oral doxycycline for the treatment of early syphilis. Contemp Clin Trials Commun. 2021;21:100710. doi:10.1016/j.conctc.2021.100710. PMID: 33614922.

33. World Health Organization. WHO guideline on syphilis screening and treatment for pregnant women. Geneva: World Health Organization; 2017.

34. Kingston M, French P, Higgins S, et al. UK national guidelines on the management of syphilis 2015. Int J STD AIDS. 2016;27(6):421-446. doi:10.1177/0956462415624059. PMID: 26721608.

35. Workowski KA, Bachmann LH, Chan PA, et al. Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep. 2021;70(4):1-187. doi:10.15585/mmwr.rr7004a1. PMID: 34292926.

36. Janier M, Unemo M, Dupin N, et al. 2020 European guideline on the management of syphilis. J Eur Acad Dermatol Venereol. 2021;35(3):574-588. doi:10.1111/jdv.16946. PMID: 33094521.

37. World Health Organization. WHO guidelines for the treatment of Treponema pallidum (syphilis). Geneva: World Health Organization; 2016.

38. Mahoney JF, Arnold RC, Harris A. Penicillin treatment of early syphilis—a preliminary report. Am J Public Health Nations Health. 1943;33(12):1387-1391. doi:10.2105/ajph.33.12.1387. PMID: 18016122.

39. Bai ZG, Wang B, Yang K, Tian JH, Ma B, Liu Y, Jiang L, Tan M. Azithromycin versus penicillin G benzathine for early syphilis. Cochrane Database Syst Rev. 2012;(6):CD007270. doi:10.1002/14651858.CD007270.pub2. PMID: 22696367.

40. Marra CM, Boutin P, McArthur JC, et al. A pilot study evaluating ceftriaxone and penicillin G as treatment agents for neurosyphilis in human immunodeficiency virus-infected individuals. Clin Infect Dis. 2000;30(3):540-544. doi:10.1086/313725. PMID: 10722442.

41. Wood JM, Sbar E. Jarisch-Herxheimer Reaction. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. PMID: 32491752.

42. Korenromp EL, Rowley J, Alonso M, et al. Global burden of maternal and congenital syphilis and associated adverse birth outcomes—Estimates for 2016 and progress since 2012. PLoS One. 2019;14(2):e0211720. doi:10.1371/journal.pone.0211720. PMID: 30811406.

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