Syphilis
Syphilis rates are surging, cases have tripled since 2018. The "great imitator" mimics nearly anything. Penicillin G is the ONLY proven treatment. Screen all HIV patients, pregnant women, and MSM. Congenital syphilis is preventable with prenatal screening.
🔍 Overview
Stages of Syphilis
| Stage | Timing | Presentation | Key Features |
|---|---|---|---|
| Primary | 10–90 days post-exposure (avg 21 days) | Painless chancre, single, firm, round ulcer with clean base and raised borders at site of inoculation (genital, anal, oral). | Painless + non-tender lymphadenopathy. Heals spontaneously in 3–6 weeks even without treatment. Highly infectious. Often missed (painless, internal location). |
| Secondary | 4–10 weeks after chancre | Diffuse maculopapular rash including palms and soles (classic). Condylomata lata (moist, flat, gray lesions in intertriginous areas). Mucous patches. Patchy alopecia ("moth-eaten"). | Constitutional symptoms: fever, malaise, weight loss, diffuse lymphadenopathy. Highest spirochete burden = most infectious stage. Resolves in weeks–months even untreated. |
| Latent (early) | < 1 year since infection | Asymptomatic. Positive serology only. | Still infectious (sexual + vertical transmission). Diagnosed by positive serology without symptoms. May relapse to secondary syphilis. |
| Latent (late) | > 1 year since infection (or unknown duration) | Asymptomatic. Positive serology only. | Low infectivity. Not sexually transmitted at this stage. Important for treatment duration (requires 3 weekly IM penicillin doses vs 1). |
| Tertiary | Years–decades after infection | Gummatous (destructive granulomas of skin, bone, organs). Cardiovascular (aortitis, ascending aortic aneurysm). Late neurologic. | Rare in antibiotic era. Aortitis with "tree-bark" calcification of ascending aorta is classic. Gummas are non-infectious. Treat with penicillin. |
| Neurosyphilis CAN OCCUR AT ANY STAGE | Early (meningitis, CN palsies, ocular, otic) or late (tabes dorsalis, general paresis) | Early: headache, meningitis, cranial nerve palsies (CN VII, VIII), uveitis, hearing loss. Late: tabes dorsalis (lightning pains, Argyll Robertson pupils, ataxia), general paresis (dementia, personality change). | Argyll Robertson pupils = accommodate but do not react (to light). "Prostitute's pupils", accommodate but don't react. LP for CSF VDRL. Treat with IV penicillin G × 10–14 days. |
Syphilis is the "great imitator." Secondary syphilis can mimic: pityriasis rosea, drug eruption, psoriasis, viral exanthem, SLE, Rocky Mountain spotted fever. Key clue: rash involving palms and soles in a sexually active patient = syphilis until proven otherwise. Always screen for HIV concurrently.
🧪 Workup
Diagnostic Algorithm
| Test | What It Detects | Key Points |
|---|---|---|
| RPR or VDRL (Non-treponemal) | Antibodies to cardiolipin released by damaged cells | Screening test. Quantitative titer correlates with disease activity. Use to follow treatment response (expect 4-fold decline by 6–12 months). False positives: pregnancy, lupus, antiphospholipid syndrome, endocarditis, hepatitis, aging. |
| FTA-ABS or TP-PA (Treponemal) | Antibodies to T. pallidum antigens | Confirmatory test. Once positive, stays positive for life (even after treatment), cannot be used to follow treatment response. More specific than RPR/VDRL. |
| Reverse screening (increasingly used) | Treponemal test first (EIA/CIA), then RPR | Many labs now use automated treponemal EIA as first step. If EIA positive + RPR negative → get TP-PA to confirm. Can detect early primary syphilis before RPR turns positive. |
| Darkfield microscopy | Direct visualization of spirochetes | Gold standard for primary chancre (before serology turns positive). Rarely available. Operator-dependent. |
| CSF VDRL | Neurosyphilis | Highly specific but insensitive (30–70%). A positive CSF VDRL confirms neurosyphilis. A negative CSF VDRL does NOT rule it out. Also check CSF cell count, protein, and CSF FTA-ABS (sensitive but less specific). |
When to do LP for neurosyphilis: (1) Neurologic or ophthalmologic symptoms at any stage, (2) Treatment failure (titer not declining), (3) HIV + late latent syphilis, (4) Tertiary syphilis. Ocular syphilis (uveitis, optic neuritis) and otosyphilis (hearing loss) are always treated as neurosyphilis with IV penicillin, even if LP is normal.
Screening Recommendations
- All pregnant women, at first prenatal visit, repeat at 28 weeks and delivery in high-risk populations
- All HIV-positive patients, at diagnosis and annually (more often if high-risk behavior)
- MSM, at least annually; every 3–6 months if multiple partners or high-risk behavior
- Anyone diagnosed with another STI (gonorrhea, chlamydia, HIV)
- Incarcerated populations, commercial sex workers
🚨 Management
Treatment by Stage
| Stage | Treatment | PCN Allergy | Follow-Up |
|---|---|---|---|
| Primary, Secondary, Early Latent (<1 year) | Benzathine penicillin G (Bicillin L-A) 2.4 million units IM × 1 dose | Doxycycline 100 mg PO BID × 14 days | RPR at 6 and 12 months. Expect 4-fold decline by 6–12 months. If not declining → retreat or evaluate for neurosyphilis. |
| Late Latent, Unknown Duration, Tertiary (non-neuro) | Benzathine penicillin G 2.4 million units IM weekly × 3 doses | Doxycycline 100 mg PO BID × 28 days | RPR at 6, 12, and 24 months. Slower decline expected. Missing a dose → restart series if >14 days late. |
| Neurosyphilis (including ocular and otic) IV REQUIRED | Aqueous crystalline penicillin G 18–24 million units/day IV (3–4 million q4h) × 10–14 days | Desensitize to penicillin (no reliable alternative for neurosyphilis). Ceftriaxone 2g IV daily × 10–14d is a second-line option. | Repeat LP at 6 months. CSF pleocytosis should normalize. If not improving → retreat. |
Jarisch-Herxheimer reaction: Occurs in 10–35% of patients within 24h of first penicillin dose (most common in secondary syphilis). Fever, rigors, myalgia, headache, tachycardia, transient rash flare. Caused by cytokine release from spirochete lysis. Self-limited. Treat with NSAIDs/antipyretics. Warn patients in advance. In pregnancy, can trigger contractions/fetal distress, monitor closely.
🔄 Updated Practice: Penicillin is the ONLY proven treatment for neurosyphilis and syphilis in pregnancy. For PCN-allergic pregnant patients, desensitize to penicillin (protocol takes ~4 hours in monitored setting). Doxycycline is contraindicated in pregnancy. Azithromycin resistance is emerging, no longer recommended as alternative.
💊 Medications
Key Medications
| Drug (Brand) | Dose / Route | Key Notes |
|---|---|---|
| Benzathine penicillin G (Bicillin L-A) | 2.4 million units IM (gluteal) | Drug of choice for all stages (except neurosyphilis). Long-acting depot provides sustained treponemicidal levels. Do NOT confuse with Bicillin C-R (combination product, wrong formulation). Painful injection, can mix with 1% lidocaine. |
| Aqueous crystalline penicillin G | 3–4 million units IV q4h | For neurosyphilis, ocular syphilis, otic syphilis. Achieves adequate CSF levels (benzathine does NOT). 10–14 days. Requires IV access. |
| Doxycycline | 100 mg PO BID | Alternative for non-pregnant PCN-allergic patients. 14 days (early) or 28 days (late). NOT adequate for neurosyphilis. Contraindicated in pregnancy. |
| Ceftriaxone | 1–2g IV/IM daily | Limited data. May be used for neurosyphilis in PCN allergy if desensitization not possible (cross-reactivity <2%). Not first-line. |
📋 On Rounds
A patient has a positive RPR (1:64) and positive FTA-ABS. What stage and how do you treat?
High RPR titer (1:64) with positive confirmatory FTA-ABS = active syphilis. Determine stage by history and exam: if primary/secondary/early latent (<1 year) → benzathine penicillin G 2.4 MU IM × 1 dose. If late latent or unknown duration → 3 weekly IM doses. If neurologic symptoms → LP and IV penicillin. Follow RPR at 6 and 12 months, expect 4-fold decline. Always test for HIV concurrently.
What are Argyll Robertson pupils and what do they indicate?
Argyll Robertson pupils accommodate (constrict to near focus) but do NOT react to light. They are small, irregular, and bilateral. Classic for neurosyphilis (tabes dorsalis). Mnemonic: "Prostitute's pupils", they accommodate but don't react. The lesion is in the pretectal area of the midbrain disrupting the pupillary light reflex while sparing the accommodation pathway.
What rash involves the palms and soles?
The differential for rash on palms and soles: Secondary syphilis (#1 to rule out in a sexually active adult), Rocky Mountain spotted fever (tick exposure, starts on wrists/ankles, spreads centripetally), hand-foot-mouth disease (coxsackievirus, children), endocarditis (Janeway lesions, painless), reactive arthritis (keratoderma blennorrhagicum), psoriasis (palmoplantar). In a sexually active patient, always rule out syphilis first with RPR.
Why is penicillin the ONLY option for neurosyphilis and syphilis in pregnancy?
Neurosyphilis: Only IV penicillin G achieves reliable treponemicidal CSF concentrations. Benzathine penicillin does not cross the blood-brain barrier adequately. Doxycycline and ceftriaxone have limited CNS data. Pregnancy: Penicillin is the only agent proven to treat the fetus and prevent congenital syphilis. Doxycycline is contraindicated (tooth/bone effects). Azithromycin has emerging resistance and doesn't cross placenta reliably. If PCN-allergic and pregnant → penicillin desensitization is mandatory.
📣 Sample Presentation
One-Liner
"Mr. Jackson is a 32-year-old MSM presenting with diffuse maculopapular rash including palms and soles, oral mucous patches, and low-grade fever × 2 weeks, with RPR 1:128 and positive FTA-ABS, consistent with secondary syphilis."
Key Points to Cover on Rounds
Secondary syphilis, confirmed by high-titer RPR (1:128) + positive FTA-ABS + classic rash. Treated with benzathine penicillin G 2.4 MU IM × 1 dose. Counseled on Jarisch-Herxheimer reaction (fever/myalgias within 24h, self-limited). HIV test sent (negative). Sexual partners within 90 days need testing and empiric treatment. RPR follow-up at 6 and 12 months, expect 4-fold titer decline. Reported to public health department.
⚡ Summary
Summary
Stage It, Because Stage Sets the Treatment
Primary: a painless chancre 10 to 90 days after exposure that heals on its own. Secondary: weeks to months later, with a diffuse rash including palms and soles, condylomata lata, mucous patches and systemic symptoms. Latent: asymptomatic, early (under 1 year) or late. Tertiary: gummas, cardiovascular and neurologic disease years later.
The Great Imitator
Secondary syphilis mimics pityriasis rosea, drug eruption, psoriasis, viral exanthem, lupus and Rocky Mountain spotted fever. The clue is a rash involving the palms and soles in a sexually active patient, which very few other conditions produce. Test for it whenever that rash appears, because the chancre is painless and is routinely missed or never seen.
Understand What the Two Test Types Do
Non-treponemal tests (RPR, VDRL) are quantitative and used to follow response, and they eventually become negative after treatment. Treponemal tests (FTA-ABS, TP-PA, EIA) confirm and stay positive for life, so they can never distinguish current from treated past infection. The reverse sequence algorithm screens with a treponemal test first, then confirms with RPR, then a second treponemal test to settle discordant results.
Know the Two Ways the Serology Fools You
The prozone phenomenon: a very high antibody titer, typically in secondary syphilis or HIV, produces a falsely negative RPR until the sample is diluted, so ask the lab to dilute when the clinical picture is convincing. Biologic false positives on non-treponemal tests occur in pregnancy, autoimmune disease, older age and other infections, which is what the confirmatory treponemal test exists to sort out.
Treat by Stage With Penicillin
Primary, secondary and early latent: benzathine penicillin G 2.4 million units IM once. Late latent, unknown duration and tertiary: 2.4 million units IM weekly for 3 weeks. Neurosyphilis and ocular or otic syphilis: aqueous crystalline penicillin G 18 to 24 million units daily IV for 10 to 14 days. Benzathine penicillin does not reach the CNS, which is why the neurosyphilis regimen is completely different.
Penicillin Is Non-Negotiable in Two Groups
Pregnancy and neurosyphilis have no proven alternative. A penicillin-allergic pregnant patient is desensitized, a roughly 4-hour protocol in a monitored setting, and then treated. Doxycycline is contraindicated in pregnancy and does not treat the fetus; it is an option only for non-pregnant penicillin-allergic patients with early or late latent disease.
Know When to Tap
LP for neurologic or ophthalmologic symptoms at any stage, for treatment failure with a titer that will not fall, for HIV with late latent syphilis, and for tertiary disease. Ocular syphilis is treated as neurosyphilis regardless of the CSF result, and it needs same-day ophthalmology because untreated it blinds.
Warn About Jarisch-Herxheimer and Follow the Titer
Fever, rigors, myalgia, headache and a transient rash flare within 24 h of the first penicillin dose, in 10 to 35% of patients, most often in secondary syphilis. It is cytokine release from dying spirochetes, not an allergy, so treat with antipyretics and do not stop the penicillin. Warn pregnant patients specifically, since it can precipitate contractions and fetal distress. Follow RPR at 6 and 12 months, expecting a fourfold fall, test for HIV and other STIs, and treat the partners.
📄 One Pager
Text version
Syphilis, Quick Reference Card
Print this page (Ctrl/Cmd + P) for a condensed reference card.
SYPHILIS, AT A GLANCE
📋 Stages: Primary (painless chancre) → Secondary (rash palms/soles) → Latent → Tertiary/Neurosyphilis
🧪 Dx: RPR/VDRL (screening + follow titers) + FTA-ABS (confirmation). CSF VDRL for neurosyphilis.
⚡ Tx Early: Benzathine PCN G 2.4 MU IM × 1. Late: × 3 weekly doses. Neuro: IV PCN G × 10–14d.
⚠️ Jarisch-Herxheimer: Fever within 24h of first dose. Self-limited. Warn patient.
🤰 Pregnancy: Penicillin ONLY. Desensitize if allergic. Screen at first prenatal visit.
🔍 Follow: RPR at 6, 12 (and 24 for late). Expect 4-fold decline. If not → retreat or LP.
🧪 Dx: RPR/VDRL (screening + follow titers) + FTA-ABS (confirmation). CSF VDRL for neurosyphilis.
⚡ Tx Early: Benzathine PCN G 2.4 MU IM × 1. Late: × 3 weekly doses. Neuro: IV PCN G × 10–14d.
⚠️ Jarisch-Herxheimer: Fever within 24h of first dose. Self-limited. Warn patient.
🤰 Pregnancy: Penicillin ONLY. Desensitize if allergic. Screen at first prenatal visit.
🔍 Follow: RPR at 6, 12 (and 24 for late). Expect 4-fold decline. If not → retreat or LP.
Related Topics
Cellulitis & Skin InfectionsCLABSI & Line InfectionsDiabetic Foot InfectionFungal InfectionsHantavirus (HPS & HFRS)Herpes Simplex (HSV)