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.
๐ 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)
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.
๐งช 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
๐จ 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.
๐ 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.
๐ 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.
๐ 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.
๐ฃ 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.
โก Summary
Summary
Primary/Secondary/Early Latent
Benzathine PCN G 2.4 MU IM × 1 dose. RPR follow-up at 6 and 12 months.
Late Latent / Unknown
Benzathine PCN G 2.4 MU IM weekly × 3 doses. RPR at 6, 12, 24 months.
Neurosyphilis
IV penicillin G 18–24 MU/day × 10–14 days. LP follow-up at 6 months. Desensitize if PCN allergy.
Diagnosis
RPR/VDRL (screen + follow titers) + FTA-ABS/TP-PA (confirm). CSF VDRL for neurosyphilis (specific, not sensitive).
Screen
All pregnant women, HIV+, MSM, other STI diagnosis. Always co-test for HIV.
Jarisch-Herxheimer
Fever/rigors within 24h of first PCN dose. Self-limited. Warn patients. NSAIDs for symptoms.
๐ One Pager
Syphilis, Quick Reference Card
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SYPHILIS, AT A GLANCE
๐ Stages: Primary (painless chancre) → Secondary (rash palms/soles) → Latent → Tertiary/Neurosyphilis ๐งช Dx: RPR/VDRL (screening + follow titers) + FTA-ABS (confirmation). CSF VDRL for neurosyphilis. โก Tx Early: Benzathine PCN G 2.4 MU IM × 1. Late: × 3 weekly doses. Neuro: IV PCN G × 10–14d. โ ๏ธ Jarisch-Herxheimer: Fever within 24h of first dose. Self-limited. Warn patient. ๐คฐ Pregnancy: Penicillin ONLY. Desensitize if allergic. Screen at first prenatal visit. ๐ Follow: RPR at 6, 12 (and 24 for late). Expect 4-fold decline. If not → retreat or LP.