Syphilis

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

A sexual-health assessment for syphilis begins with chronology. Ask when lesions, rash or systemic symptoms began and resolved; map oral, anal and genital exposure; establish pregnancy possibility; and retrieve prior results and treatment records. Those details distinguish a new infectious episode from previously treated infection and determine both the regimen and which partners may need action.

Treponema pallidum often declares itself at an exposed but unexamined site. A primary lesion can be painless and internal, while disseminated early infection can resemble a viral illness, drug rash, hepatitis, alopecia or another ulcerative STI. Absence of the classic chancre-rash sequence should therefore lower neither anatomical curiosity nor the threshold for parallel STI testing.

Serology answers two different questions. A treponemal screen plus a different confirmatory treponemal method supports present or past infection, whereas a quantitative RPR or VDRL supplies the baseline used to follow treatment. Staging still depends on documented earlier negativity, symptoms, partner diagnosis and treatment history; calling every asymptomatic reactive result “early latent” risks undertreatment.

Before choosing a depot course, screen for eye, ear and neurological symptoms and ask about pregnancy. Primary, secondary and early latent disease without those features receives benzathine benzylpenicillin 2.4 million units intramuscularly once. Late latent or unknown-duration disease receives that dose weekly for three doses. Neuro-ocular or otic disease moves to intravenous benzylpenicillin 1.8 to 2.4 g every four hours for 14 days.

Treatment is an episode of care rather than an injection. Explain the Jarisch–Herxheimer reaction, agree an abstinence and partner plan, offer HIV and site-directed chlamydia and gonorrhoea testing, and book the titre checks before the patient leaves. Partner periods are stage-specific: three months for primary disease and up to two years for secondary, relapse or early latent infection; late latent infection instead prompts history-led screening.

Key points

Build the stage from today’s examination, earlier symptoms, contact dates, previous serology and documented treatment; the laboratory result alone cannot date acquisition.
Swab or sample a compatible active lesion for direct detection where available and send a treponemal screen, a second treponemal assay and a quantitative RPR or VDRL before treatment when this causes no unsafe delay.
A chancre may be hidden in the cervix, rectum or mouth, and secondary disease may present through rash, mucous lesions, alopecia, nodes, hepatitis or sensory symptoms; examine every anatomical site suggested by the history.
Treponemal antibodies commonly remain reactive after cure. Use the quantitative non-treponemal titre, measured comparably over time, to judge activity and response.
Give benzathine benzylpenicillin 2.4 million units intramuscularly once for primary, secondary or early latent infection; late latent or unknown-duration infection needs 2.4 million units weekly for three doses.
Neurological, ocular or otic infection needs a CNS-active course: intravenous benzylpenicillin 1.8 to 2.4 g every four hours for 14 days under the specialist pathway, not a single depot injection.
Pregnancy requires parenteral penicillin with maternity coordination; when early syphilis treatment begins in the third trimester, add a second benzathine penicillin dose one week later and preserve the neonatal plan.
Schedule quantitative RPR at 3, 6 and 12 months and, when indicated, every six months until RPR-negative or serofast. Trace three months for primary syphilis and up to two years for secondary, relapse or early latent infection.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Contact with an infectious lesion

Transmission probability comes from direct mucosal or skin contact with a primary or secondary lesion; asking which anatomical sites were exposed identifies both hidden chancres and the samples required.

Pregnancy transmission

Organisms circulating in maternal blood can reach the fetus during any maternal stage, so an asymptomatic pregnancy result still triggers urgent penicillin and coordinated fetal care.

Repeat acquisition

Previous cure leaves no dependable immunity. A new partner diagnosis, new symptoms or a fourfold titre rise therefore demands a fresh exposure history and partner episode.

Non-sexual blood route

Shared injecting equipment or unscreened blood provides a biologically plausible route, although it is uncommon in the current UK setting; history should remain neutral and route-specific.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Inoculation-site disease
After crossing a small epithelial defect, organisms expand locally and provoke vascular inflammation, producing a chancre that may be internal and painless enough to escape notice.
2
Early dissemination
Blood and lymphatic spread can seed skin, mucosa, nodes, liver, eye, ear and nervous system; this explains why the sexual-health history and a whole-body symptom screen must accompany ulcer testing.
3
Clinically silent persistence
Host responses can suppress visible illness without clearing all organisms. The patient then has reactive serology but no examination findings, and chronology becomes central to treatment duration.
4
Late vascular and granulomatous injury
Long-standing infection may damage small vessels or produce destructive inflammatory lesions in neural, cardiovascular and other tissues, sometimes years after the transmissible phase.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Ulcer at an exposed site

Inspect oral, anal and genital sites indicated by the history; a solitary, indurated lesion with relatively little pain increases probability, but pain or multiple lesions do not rule syphilis out.

Disseminated early illness

A widespread eruption, especially with palm or sole involvement, mucous patches, broad moist papules, patchy hair loss, constitutional symptoms and generalised nodes should trigger serology and a full STI assessment.

Serology without symptoms

When examination is normal, earlier negative results, recalled symptoms, partner timing and reliable treatment documentation decide whether infection is early latent, late latent, previously treated or of uncertain duration.

Eye, ear or neurological signalRed flag

Uveitis, altered vision, auditory or vestibular change, meningitic symptoms, cranial neuropathy, stroke in a younger adult or cognitive decline overrides routine staging and needs urgent organ-specific assessment.

Pregnancy exposureRed flag

A reactive test or credible infectious contact in pregnancy requires prompt confirmation, stage-appropriate penicillin and a communicated fetal and neonatal pathway, even when the patient feels well.

Possible repeat infection

New exposure, recurrent lesions or rash, or a sustained fourfold non-treponemal titre increase after earlier response supports reinfection and requires a new partner history rather than assuming old serological scar.

Red flags requiring action

Treat new visual loss, photophobia or ocular inflammation with compatible syphilis serology as a same-day ophthalmic and sexual-health problem.
Escalate sudden hearing loss, new tinnitus or vestibular symptoms because otic disease may leave permanent deficit despite few other syphilis signs.
Ask directly about headache, meningism, cranial-nerve symptoms, cognitive or personality change, sensory ataxia and young stroke before assigning a simple stage.
Link any syphilis diagnosis in pregnancy immediately to maternity care: clinical stage and maternal wellbeing do not reliably express fetal risk.
Do not close an ulcer episode after a single early negative antibody test when lesion appearance, contact history or timing keeps pre-test probability high.
A sustained fourfold RPR or VDRL rise after therapy starts a new assessment for fresh exposure, incomplete therapy, an incorrect original stage or neurological involvement.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Treponemal screen plus a different treponemal assayFirst step
Why
Establish whether the immune pattern supports T. pallidum exposure while reducing the chance of relying on one assay.
Interpretation and limitations
Concordant reactivity supports current or previous infection. Resolve discordance with the laboratory and sexual-health team using exposure, old records and repeat sampling rather than guessing the stage.
02
Quantitative RPR or VDRL
Why
Set the pretreatment activity marker that can be compared with later samples.
Interpretation and limitations
Record the exact titre and assay. A fourfold change is two dilution steps; smaller movement can reflect variation, and a stable low titre may remain after adequate care.
03
Direct testing of an active lesion
Why
Detect the organism during chancre or mucosal disease, including before antibodies become detectable.
Interpretation and limitations
Use PCR or locally available direct methods from the correct lesion site. A positive result establishes infectious disease; a negative result does not cancel repeat serology when timing and phenotype fit.
04
Document search and stage interview
Why
Separate newly acquired infection from old treated infection and assign the course and partner period safely.
Interpretation and limitations
Seek dated negative and positive serology, exact medicines and doses, completion, previous titre response, symptom dates and the contact’s stage; absent proof usually leaves duration uncertain.
05
Site-directed STI and HIV testing
Why
Find coinfection and prevention needs generated by the same exposure network.
Interpretation and limitations
Sample genital, rectal or pharyngeal anatomy according to exposure and offer HIV, hepatitis and other STI testing with repeat testing after applicable windows.
06
Neurological, ophthalmic, audiological and CSF assessment
Why
Identify organ disease that needs the neurosyphilis regimen and its own outcome measures.
Interpretation and limitations
Use urgent specialist examination for eye or ear symptoms and CSF cell count, protein and VDRL when indicated. An insensitive CSF result does not overrule a convincing organ presentation.
07
Pregnancy and fetal pathway assessment
Why
Prevent congenital infection and ensure treatment timing reaches the maternity and neonatal teams.
Interpretation and limitations
Confirm gestation, ultrasound or fetal assessment needs and previous maternal treatment; record stage, regimen and dates in the birth plan.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Herpes simplex ulceration

Multiple tender vesicles or shallow ulcers favour herpes, but overlap is common; take lesion HSV testing and syphilis studies together instead of choosing solely from pain.

Chancroid after relevant travel or contact

A painful friable ulcer with tender suppurating nodes and an epidemiologically plausible exposure raises H. ducreyi, while parallel syphilis and HSV testing protects against coinfection.

Mpox in the exposure network

Firm or umbilicated lesions, systemic prodrome and a compatible contact pattern prompt lesion PCR; syphilis serology should still run in parallel because appearance and risk groups overlap.

Drug or inflammatory rash

A medication timeline, itch or alternative systemic features may support exanthem, but palms-and-soles disease should still prompt syphilis serology before the rash is closed as non-infectious.

Persistent non-infectious ulcer

Aphthosis, Behçet disease and malignancy enter the pathway when infection testing is unrevealing or the lesion persists, recurs or feels mass-like; biopsy or specialty assessment then becomes necessary.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01STAGETurn a positive test into a dated clinical diagnosisFirst stepA lesion, rash, contact notification or screening result raises the possibility of syphilis.

1Take direct lesion testing when possible, two-method treponemal testing and a quantitative RPR or VDRL before therapy if this is safe.
2Reconstruct symptom, exposure and testing dates and verify every previous treatment rather than accepting “treated before” without a usable record.
3Examine exposure-relevant skin and mucosal sites and actively screen for pregnancy, visual, hearing and neurological features.
4Agree the stage and infectious period with sexual health; classify missing acquisition evidence as unknown duration rather than optimistically early.

02EARLYTreat infectious early disease and activate contactsPrimary, secondary or early latent infection is established with no neuro-ocular or otic involvement.

1Administer benzathine benzylpenicillin 2.4 million units intramuscularly once with the correct product and divided-site technique.
2Use doxycycline 100 mg orally twice daily for 14 days only in a suitable non-pregnant adult when the guided allergy pathway permits.
3Prepare the patient for fever, myalgia and headache from a Jarisch–Herxheimer reaction in the first 24 hours and distinguish it from immediate allergy.
4Book RPR at 3, 6 and 12 months and later six-monthly checks when indicated; trace three months for primary disease or up to two years for secondary, relapse or early latent disease, offering applicable early contacts epidemiological treatment or retesting 12 weeks after their last exposure.

03LATEComplete the longer course when acquisition is late or unclearLate latent or unknown-duration infection is present and neurological, ocular and otic assessment does not redirect treatment.

1Give benzathine benzylpenicillin 2.4 million units intramuscularly weekly for three consecutive doses and document each administration date.
2If a dosing interval is substantially exceeded, obtain specialist advice about restarting the series instead of inventing a catch-up schedule.
3AlternativeUse doxycycline 100 mg twice daily for 28 days only when pregnancy is excluded and the specialist alternative is appropriate.
4Use history-led partner screening, examine for neurological, cardiovascular or gummatous disease, and follow same-assay RPR at 3, 6 and 12 months and then six-monthly when indicated until RPR-negative or serofast.

04ORGAN / PREGNANCYProtect function and the fetusEye, ear, neurological features or pregnancy accompanies confirmed or strongly suspected infection.

1Arrange same-day relevant specialty assessment and obtain CSF when indicated without letting the procedure postpone urgent treatment.
2For neurological, ocular or otic disease, use intravenous benzylpenicillin 1.8 to 2.4 g every four hours for 14 days under the specialist protocol.
3In pregnancy use parenteral penicillin; if early-disease treatment starts in the third trimester, give the required second benzathine dose one week later.
4Transfer stage, regimen, exact dates, titres, fetal findings and neonatal assessment requirements through a named multidisciplinary follow-up plan.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

The single-dose depot course for primary, secondary and early latent disease when eye, ear and neurological involvement has been excluded.

Benzathine benzylpenicillin for early syphilis

Give 2.4 million units intramuscularly once, usually divided between two gluteal sites according to product and local administration protocol.

Verify the benzathine formulation and intramuscular route, document allergy assessment and prepare the patient for a possible first-day Jarisch–Herxheimer reaction.

The three-visit depot course used when latency is late or the acquisition date cannot be established safely.

Benzathine benzylpenicillin for late latent syphilis

Give 2.4 million units intramuscularly once weekly for three doses for late latent or unknown-duration infection.

Book all three administration dates, record any interval breach for specialist review and route pregnancy through the penicillin-based maternity pathway.

A guided oral option for selected non-pregnant adults with early or late latent disease who cannot receive penicillin.

Doxycycline penicillin-allergy alternative

Give 100 mg orally twice daily for 14 days in early syphilis or 28 days in late latent disease when current guidance permits.

Exclude pregnancy and neuro-ocular or otic disease; discuss adherence, photosensitivity, oesophageal irritation and interacting cations and retain close titre follow-up.

The CNS-penetrating course used for neurological, ocular or otic involvement under specialist supervision.

Intravenous benzylpenicillin for neurosyphilis

Give 1.8 to 2.4 g intravenously every four hours for 14 days under specialist neuro-ocular syphilis guidance.

Use renal and electrolyte monitoring as clinically indicated and resolve allergy through expert advice because an improvised shorter regimen may not protect the affected organ.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Neural injury

Meningeal, vascular or parenchymal involvement may present with cranial neuropathy, stroke, pain, ataxia or cognitive change; delayed recognition can leave deficit after microbiological treatment.

Loss of sight or hearing

Inflammation affecting ocular structures, optic pathways or the inner ear can progress quickly, which is why organ symptoms trigger urgent examination and CNS-active penicillin.

Congenital infection

Untreated maternal disease can cause pregnancy loss, neonatal illness or later auditory, dental, skeletal and neurological harm; prevention depends on maternal treatment plus completed neonatal assessment.

Cardiovascular late disease

Chronic aortic inflammation can lead to ascending aneurysm, valve regurgitation or coronary ostial compromise and requires specialty assessment beyond routine STI follow-up.

Destructive gumma

A granulomatous lesion in skin, bone or viscera can imitate cancer or another inflammatory mass, making tissue assessment and syphilis history complementary rather than competing explanations.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Keep the pretreatment quantitative RPR or VDRL value, assay and laboratory visible in the follow-up record so later numbers are genuinely comparable.
Check quantitative RPR at 3, 6 and 12 months and, when indicated, every six months until RPR-negative or serofast; interpret a fourfold fall or sustained fourfold rise alongside symptoms and new exposure.
Contact the patient soon enough to detect immediate allergy, explain an expected Jarisch–Herxheimer illness and re-examine any lesion or neuro-sensory feature that persists.
If titre rises fourfold, repeat the sexual history, HIV testing, stage assessment and neurological screen before deciding between reinfection and treatment failure.
Measure vision, hearing and neurological recovery through the relevant specialty because serological improvement alone cannot prove organ recovery.
For primary syphilis trace the preceding three months; for secondary, relapse or early latent infection trace up to two years. Offer applicable early contacts epidemiological treatment or retesting 12 weeks after last exposure.
Use history-led screening for late latent disease rather than applying infectious-stage lookbacks to a non-infectious interval.
In pregnancy keep treatment dates, serial titres, fetal assessment and the neonatal examination plan in a named shared record through delivery.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

A positive screen is the start of staging

The result establishes possible exposure; old results, treatment proof, symptoms and contact dates determine whether this is active, treated, early or of unknown duration.

Count dilutions, not impressions

RPR 1:32 to 1:8 is the two-step, fourfold fall used for response. A change only to 1:16 is too small to carry that meaning on its own.

The inoculation site may be outside the genital examination

Oral and rectal chancres can be missed unless exposure guides examination and lesion sampling.

Eyes and ears set the regimen

Ocular or otic manifestations can occur at any nominal stage and move treatment to the neuro-ocular pathway even if the rest of the examination appears uncomplicated.

Post-treatment fever needs pattern recognition

A self-limited inflammatory reaction in the first 24 hours is managed differently from urticaria, bronchospasm, hypotension or another feature of immediate penicillin hypersensitivity.

Pregnancy care ends after neonatal assessment

Maternal penicillin is essential, but completion also requires fetal surveillance, clear birth communication and assessment of the infant.

11Common pitfallsFrequent interpretation and management errors.

01
Do not label a reactive treponemal test as active early infection without finding prior treatment, titre and timing evidence.
02
Do not reassure after one negative early serology result when an active lesion or recent infectious contact keeps probability high.
03
Do not limit examination and sampling to genitals when oral or anal exposure can locate the lesion elsewhere.
04
Do not give a depot-only early-syphilis regimen to ocular, otic or neurological disease.
05
Do not replace penicillin with doxycycline in pregnancy; use the specialist allergy and desensitisation route.
06
Do not administer treatment without booking titre follow-up and agreeing confidential partner action for the correct stage.

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