BASHH UK guidelines for the management of syphilis 2024

1Key Updates in the 2024 Guidelines

• TherapeuticsBenzathine penicillin G (BPG) administration with lidocaine is now licensed in the UK and is the recommended first-line option to improve patient tolerability.
• TherapeuticsMacrolides (e.g., azithromycin) are no longer recommended for treatment due to widespread antimicrobial resistance.
• TherapeuticsCeftriaxone is established as the preferred alternative treatment in most cases where penicillin cannot be used.
• DiagnosticsExpanded use of Polymerase Chain Reaction (PCR) testing is recommended for direct detection of Treponema pallidum.
• DiagnosticsSerology testing algorithms have been updated in light of the withdrawal of the Treponema pallidum particle agglutination (TPPA) assay from the UK in 2022.
• ManagementNew guidance is provided for the management of serofast individuals (those who fail to show a fourfold decline in non-treponemal titres despite adequate treatment).
• ManagementManagement of treatment interruptions has changed, extending the acceptable time interval allowed between BPG injections in late syphilis before a course must be restarted.

2Aetiology, Transmission, and Epidemiology of Syphilis

• AetiologySyphilis is a multi-stage infection caused by the spirochete bacterium Treponema pallidum subspecies pallidum.
• TransmissionTransmission occurs via direct contact with an infectious lesion, vertically via transplacental passage during pregnancy, or rarely via needle sharing in injecting drug use.
  • Approximately one-third (range 10% to 60%) of sexual contacts of individuals with infectious syphilis will develop the disease.
  • Blood transfusion transmission is rare due to routine screening and the fact that treponemal survival beyond 24–48 hours at 4°C is highly unlikely.
• Inoculation SitesAnatomical entry sites vary by sexual practice.
  • Typically genital in heterosexual patients.
  • Extra-genital entry (anal, rectal, oral) occurs in 32% to 36% of transmissions among gay, bisexual, and other men who have sex with men GBMSM.
  • Oral sex accounts for an estimated 13.7% of overall transmissions, with some studies reporting 20% to 35% among GBMSM.
• Epidemiology
  • Syphilis predominates among GBMSM aged 25–34 years, with a high prevalence of HIV co-infection.
  • Significant rise in heterosexual cases since 2014, which were previously low and stable.
  • Geographical concentration remains persistently high in specific urban locations, including London, Manchester, and Brighton.

3Classification and Clinical Features

• PrimaryPrimary Syphilis: Characterised by local bacterial multiplication at the site of entry.
  • Incubation period: Typically 21 days (range 9–90 days); shorter incubation is associated with higher infectious doses.
  • Classic Chancre: A single, painless, indurated anogenital papule that ulcerates, presenting with a clean base discharging clear serum (no pus), accompanied by moderate regional lymphadenopathy.
  • Atypical Presentations: * Painful and/or multiple chancres occur in a significant minority. * Extra-genital chancres (most commonly oral) are often multiple, painful, purulent, and destructive.
  • Resolution: Primary lesions resolve spontaneously over 3–8 weeks as bacteria disseminate via blood and lymphatics.
• SecondarySecondary Syphilis: Multi-system dissemination occurring in 25% of untreated patients, typically 3–10 weeks after the chancre (approx. 3 months post-infection).
  • Dermatological: * Widespread, typically non-itchy mucocutaneous rash. * Can be maculopapular (50%–70%), papular (12%), macular (10%), or ulceronodular. * Frequently affects palms and soles (11%–70%) and can cause alopecia.
  • Mucocutaneous: Highly infectious mucous patches (buccal, lingual, genital) and condylomata lata (flat, moist, wart-like lesions in warm areas like the perineum and anus).
  • Systemic: * Generalised lymphadenopathy, splenomegaly, hepatitis, glomerulonephritis (immune-complex mediated). * Rarely bone, joint, gastric, or pulmonary involvement.
  • Neurological: * Acute meningitis (headache, neck stiffness, photophobia, nausea) * Cranial nerve palsies (especially 8th nerve palsy causing hearing loss and tinnitus).
  • Ocular: * Uveitis (most commonly posterior and bilateral), optic neuropathy, interstitial keratitis, and retinal involvement. * HIV co-infection increases the risk and severity of ocular and neurosyphilis.
  • Immunity: Previous infection does not confer immunity; re-infection is possible, though subsequent infections may present with milder or absent clinical symptoms.
• LatentLatent Syphilis: Asymptomatic phase following the spontaneous resolution of secondary symptoms (usually within 3–12 weeks).
  • Early Latent: * Defined as infection acquired within the last 2 years. * Approximately 25% of untreated patients will experience a recurrence of infectious secondary lesions during this stage.
  • Late Latent: * Defined as infection acquired more than 2 years ago (or of unknown duration), ending with the development of tertiary disease.
• TertiaryLate (Tertiary) Syphilis: Occurs in approximately one-third of untreated patients, typically 20–40 years after initial infection.
  • Gummatous Syphilis (15% of untreated): * Granulomatous lesions with central necrosis. * Can occur within 2 years but typically averages 15 years post-infection. * Most commonly affects skin and bones; resolves rapidly with therapy.
  • Cardiovascular Syphilis (10% of untreated): * Typically occurs 15–30 years after infection. * Becomes symptomatic/complicated in 10% of those affected. * Predominantly damage the ascending aorta, leading to dilatation, aortic valve regurgitation, heart failure, coronary ostial stenosis, and saccular aneurysms.
  • Late Neurological Syphilis (7% of untreated): Late-stage neurocognitive and spinal cord degeneration.

4Clinical Diagnosis: History and Examination

• PN WindowsEstablish the correct lookback window for contact tracing based on clinical stage:
  • Primary Syphilis: Include all sexual partners from the last 3 months.
  • Secondary and Early Latent Syphilis: Include all sexual partners from the last 2 years.
  • Late Syphilis: Guided by history, previous treponemal serology, lifetime partners, and potentially children.
• HistoryFully explore any prior syphilis diagnoses and testing history:
  • Document year and place of diagnosis, treatment received (drug, route, duration), and serological results (contact treating clinic if possible).
  • Review previous screening opportunities: antenatal screening, blood donation, and routine sexual health screens.
• DifferentialAssess the potential for non-venereal Treponema pallidum infections (yaws, pinta, bejel) which yield identical serological results.
  • Inquire about childhood skin infections (yaws) and history of residence in endemic countries.
• ObstetricsObtain a full obstetric history where appropriate.
  • Identify adverse pregnancy outcomes (stillbirths, miscarriages) and screen live offspring who may have late congenital disease.
• ExaminationPerform targeted examinations based on suspected stage of disease:
  • Early disease (primary/secondary): Genital, detailed skin (including mouth, scalp, palms, and soles), and neurological examinations.
  • Symptomatic late disease: Targeted exam of the skin, musculoskeletal system, cardiovascular system, and nervous system.

5Laboratory Diagnosis: Direct Detection and Serology

Diagnosis relies on direct detection of T. pallidum from lesions or serological testing, which must differentiate between treponemal and non-treponemal antibodies.

• 2ADark ground microscopy should be performed on possible chancres where appropriate expertise and equipment are available.
  • Less reliable for rectal/non-penile lesions; contraindicated for oral lesions due to commensal treponemes.
  • Can diagnose primary syphilis before a serological response develops.
• 1AMolecular testing (PCR) for T. pallidum is appropriate on lesions where the organism may be expected to be located.
  • Higher sensitivity and specificity than dark ground microscopy.
  • Suitable for oral and other mucosal lesions (distinguishes T. pallidum from commensal treponemes).
  • Can detect primary syphilis before seroconversion; may aid diagnosis in tissue samples or vitreous fluid.
• CautionTreponemal antibody tests cannot differentiate venereal syphilis from endemic treponematoses (yaws, bejel, pinta).
  • Patients from endemic countries with positive treponemal serology should be treated for syphilis as a precaution unless they have a documented history of adequate treatment.
• ClassificationAntibody tests are divided into non-treponemal, treponemal, and IgM-specific assays.
  • Non-treponemal tests (RPR, VDRL): * Detect antibodies to cardiolipin, lecithin, and cholesterol. * RPR (less technically demanding). * Positive ~6 weeks post-infection, peak at 1–2 years, and remain positive at low titres in untreated late disease. * Used to monitor treatment response.
  • Treponemal tests (EIA, CLIA, TPHA, TPLA): * Detect IgG and IgM using recombinant antigens. *Usually remain positive for life. * Note: TPPA was withdrawn from the UK in 2022.
  • T. pallidum-specific IgM (EIA, immunoblot): * Reactivity lasts an average of 6 months (can persist 12–18 months post-treatment). * Suboptimal sensitivity/specificity limits utility. * Not used to stage disease, decide treatment duration, or diagnose re-infection.
• 1BAn EIA/CLIA detecting both IgM and IgG is the screening test of choice.
  • Point-of-care (POC) fingerprick tests: Useful in outreach settings; positive results must be confirmed by laboratory testing. No treponemal POC tests are approved for oral fluid.
  • Self-sampling kits: Capillary blood (dried blood spot or mini-tube) is screened in labs; sample volume is usually insufficient for RPR or confirmatory testing.
• 1BPositive screening tests should be confirmed with a different treponemal test (using different antigen targets) and a second specimen obtained for confirmatory testing.
  • Low-level reactivity in two EIA/CLIAs with a negative RPR may represent non-specific cross-reactivity; repeat in 2 weeks to exclude early syphilis.
  • TPHA/TPLA may be less sensitive than EIA/CLIA, leading to unconfirmed screen-positives; repeat in 2 weeks if early syphilis is suspected to observe marker evolution.
  • Always test a confirmatory specimen on the day treatment is commenced to document the peak baseline RPR titre.
• 1AA quantitative RPR test should be performed when screening tests are positive.
  • An initial RPR titre of >1:16 usually indicates active disease and the need for treatment.
  • An RPR titre of <=1:16 does not exclude active infection, especially in symptomatic patients or those without documented prior treatment.
  • A four-fold rise in RPR titre compared to a previous sample suggests recent infection.
  • Perform a quantitative RPR on the day treatment is started to establish an accurate baseline. Do not use treponemal tests for follow-up.
• 1BNegative serological tests for syphilis should be repeated at 2 weeks after observation of possible chancres that are dark ground microscopy and/or PCR negative.
  • Repeat screening is recommended 3 months after any high-risk contact, as negative results within 3 months cannot exclude early syphilis.
• CautionBe aware of causes of false-negative and false-positive serology.
  • False-negatives: Occur before chancre development and up to 2 weeks after; also seen in immunocompromised individuals.
  • Prozone Phenomenon: High antibody titres in secondary or early latent syphilis can cause false-negative RPR results on undiluted serum. Repeat testing on diluted samples if suspected (more common in people living with HIV).
  • False-positives: More common in older individuals, those with autoimmune disease, and people who inject drugs (PWID). In the absence of symptoms or history, transient or persistent reactivity in a single treponemal test should be considered a false-positive.

6Neurosyphilis and CSF Investigations

T. pallidum can infect the central nervous system at any stage. Diagnosis relies on clinical evaluation and CSF analysis, though indications for lumbar puncture remain debated.

• ClinicalPerform a thorough neurological examination in any patient with positive syphilis serology and neurological symptoms.
  • Symptoms include cognitive dysfunction, motor/sensory deficits, cranial nerve dysfunction, meningitis, or stroke.
  • Include ophthalmic and otological exams if symptoms indicate.
  • Routine neurological exams in asymptomatic patients rarely add value and are not recommended.
• 1ARoutine CSF assessment of patients without symptomatic disease (regardless of HIV status) is not recommended.
• 1CCSF examination is indicated when there is clinical evidence of neurological involvement, except for isolated ophthalmic or otological syphilis where it is rarely useful.
• 2DCSF assessment may be considered in cases of serological failure or serofast status where clinical suspicion exists.
  • Serological failure: <4-fold decrease in non-treponemal titre 6-12 months post-treatment for early syphilis (with no interim reinfection).
  • Serofast: Persistence of stable non-treponemal titre 1-2 years post-treatment.
  • Pragmatic treatment to cover neurosyphilis may be opted for instead of lumbar puncture if results will not change management.
• Pre-LPProcedures required prior to performing a lumbar puncture:
  • Perform fundoscopy to check for signs of raised intracranial pressure.
  • Consider CT or MRI if neurological symptoms or signs are present.
  • Review serum RPR: A negative peripheral blood VDRL has 100% sensitivity in excluding CSF abnormalities in latent syphilis, whereas a serum RPR of >=1:32 is associated with CSF abnormalities.
• CSF AnalysisCSF examination must include total protein, white cell count, and a non-treponemal test (RPR).
  • CSF must not be macroscopically contaminated with blood to ensure accurate interpretation.
  • No single test can definitively diagnose or exclude neurosyphilis.
  • In PLWH, CSF pleocytosis (>5 cells/µl) is common if CD4 <=40 cells/µl or if not on ART. Pleocytosis in patients on ART with viral load <50 copies/ml and CD4 >200 cells/µl is highly likely to indicate neurosyphilis.

7Investigations for Other Systemic Manifestations

Diagnostic and referral pathways for cardiovascular, ophthalmic, otological, and gummatous complications of syphilis.

• 1CPatients with positive syphilis serology and possible neurological, ophthalmic, otological, cardiovascular, or gummatous symptoms or signs require examination and further evaluation by appropriate specialists.
• CardiovascularCardiovascular Syphilis: Diagnosis is made by typical clinical features combined with positive syphilis serology after excluding other causes.
  • Suspected cases must be assessed by a cardiologist.
  • Routine chest X-ray is not recommended in patients without cardiovascular symptoms.
• OphthalmicOphthalmic Syphilis: Diagnosis is based on ophthalmic symptoms/signs and positive serology after excluding other causes.
  • Clinical ophthalmic assessment should be considered in secondary, early latent, tertiary, and late latent syphilis.
  • Perform fundoscopy immediately if any clinical ophthalmic symptoms are noted.
  • Immediate referral to and collaborative management with an ophthalmologist is crucial.
• OtologicalOtosyphilis: Diagnosis is based on audiological symptoms (new hearing loss, tinnitus, vertigo) and positive serology after excluding other causes.
  • Otosyphilis is a potentially reversible cause of hearing loss.
  • Immediate referral to and collaborative management with an audiologist or ENT specialist is required.
• GummatousSyphilitic Gummata: Diagnosis is usually made on clinical grounds (typical nodules/plaques or destructive lesions in individuals with positive syphilis serology).
  • Histological examination of a lesion may suggest the diagnosis.
  • T. pallidum may be identified within nodules by PCR (though PCR is not recommended as a routine test).

8General Management and Treatment Principles

• 1AAll patients with syphilis should receive holistic sexual healthcare, including screening for other STIs/HIV, vaccinations (Hepatitis B, HPV), and PrEP/PEP as appropriate.
• 1DProvide detailed verbal and clear, accurate written information about syphilis, including long-term health implications for patients and partners.
• 1CPatients with early, infectious syphilis must be advised to refrain from sexual contact of any kind until 2 weeks following the completion of treatment and until all lesions have resolved.
• 1BParenteral treatment with an appropriate penicillin preparation is the first-line treatment of choice.
  • Penicillin resistance has never been reported despite decades of use.
  • Parenteral therapy is supervised, ensuring guaranteed bioavailability.
• 1BMacrolide antibiotics are not recommended for treatment.
  • Reason: High rates of antimicrobial resistance worldwide, mediated by point mutations (A2058G or A2059G) in the 23S rRNA gene.
  • Reason: Inability of macrolides to reliably cross the placenta and the blood-brain barrier.
• PharmacokineticsPharmacokinetic requirements for cure:
  • A penicillin level of >0.018 mg/L is considered treponemicidal, with maximal elimination effect attained at 0.36 mg/L.
  • The antimicrobial level must remain treponemicidal for at least 7 days to cover several treponemal division times (30–33 hours) in early syphilis.
  • The sub-treponemicidal interval must not exceed 24–30 hours.
  • Longer treatment durations are required in late syphilis because treponemes divide more slowly or may be in a 'resting' state.
• AllergiesManagement of Penicillin and Other Allergies:
  • In neurosyphilis or pregnancy with significant penicillin allergy, penicillin desensitisation is the preferred option.
  • Patients with soya or peanut allergy should be referred for allergy testing or treated with procaine penicillin or ceftriaxone (due to excipients in certain BPG formulations).

9Recommended Treatment Regimens

• 1BSyphilis in individuals living with HIV should be treated with the same stage-appropriate regimens as HIV-negative individuals.
• 1DIM benzathine penicillin should be diluted with lidocaine to improve patient tolerability.
• 1BTreatment interruptions in neurosyphilis require a complete restart of the course if the interruption exceeds 24 hours.
  • Continuous treponemicidal levels are strictly required within the CNS throughout the course.
• GPPTreatment interruptions in late latent syphilis do not require additional doses if subsequent doses are received within 14 days of the previous dose.
  • A single dose of BPG 2.4 MU produces treponemicidal blood levels for 2-4 weeks.

10Treatment Reactions and Allergy Management

• 1DThe Jarisch-Herxheimer Reaction (JHR) is an acute febrile inflammatory reaction occurring within 2 to 24 hours of initiating anti-treponemal therapy.
  • Triggered by the rapid release of treponemal lipopolysaccharides and cytokines.
  • Can be life-threatening in late syphilis if critical sites are involved (e.g., coronary ostia, larynx, CNS, ocular, or otic structures).
  • Prophylactic Steroid Regimen: Prednisolone 40-60 mg PO OD for 3 days, starting 24 hours before initiating anti-treponemal antibiotics, to prevent or ameliorate JHR.
• 1CObserve all patients on clinic premises for 15 minutes after their first injection to monitor for immediate adverse reactions.
  • Resuscitation facilities and standard protocols for anaphylactic shock must be available in the treatment area.
  • Advise patients to seek urgent medical attention if they experience shortness of breath, itchy wheals, facial swelling, or chest/throat tightness.
• GPPProcaine reaction (Hoignes syndrome / procaine psychosis / procaine mania) is caused by inadvertent intravenous injection of procaine penicillin.
  • Characterised by sudden fear of impending death, hallucinations, or seizures immediately post-injection.
  • Transient duration: typically lasts less than 20 minutes.
  • Management: Calm, verbal reassurance; manage seizures per local emergency protocols.
• 2AConsider skin testing and subsequent penicillin desensitisation for patients reporting a penicillin allergy.
  • Many patients reporting allergy are not truly hypersensitive (due to resolution or mislabelling); a careful history is vital.
  • Skin testing to confirm allergy must precede desensitisation; both carry anaphylaxis risks and must be performed with immediate access to resuscitation.

11Management of Syphilis in Individuals Living with HIV

• 1BTreatment regimens and protocols should be the same as for HIV-negative individuals across all stages of syphilis.
  • Prolonged or additional antibiotic courses do not improve clinical outcomes.
  • Doxycycline is as effective as penicillin for non-tertiary presentations in this cohort.
• 1BStandard serological diagnostic algorithms apply; unusual patterns (false-negatives, delayed seroreactivity) are rare.
  • Active syphilis can cause a transient increase in HIV viral load and a corresponding decrease in CD4+ T-cell counts.
  • Asymptomatic HIV-related CSF pleocytosis and elevated protein can complicate neurosyphilis diagnosis.
  • Indications for CSF examination are identical to HIV-negative patients. Some experts suggest performing a CSF exam if the patient has a high RPR titre (>= 1:32) and/or a low CD4 count (<350 cells/mm3).
• 1BStandard serological follow-up is recommended, ideally timed to coincide with routine HIV care visits.
  • The post-treatment non-treponemal serological response may be delayed at 6 months compared to HIV-negative individuals, but this difference is not significant at 12 months.
  • PLWH on antiretroviral therapy (ART) have reduced serological failure rates.
• 1BRoutine syphilis serological screening for PLWH is recommended at 6-monthly intervals.

12Management of Sexual Partners

Partner notification (PN) strategies, look-back windows, and epidemiological treatment protocols based on the stage of syphilis.

• 1BDiscuss partner notification (PN) with all patients at diagnosis, utilizing a multidisciplinary team approach.
  • Documented attempts to re-interview the patient should be made if PN outcomes are unresolved at the initial interview.
  • Offer both patient and provider referral, and consider electronic contact methods (internet, apps, text).
  • Between 46% and 60% of contactable sexual partners of patients with early syphilis will also be infected.
• 1BOffer epidemiological treatment to asymptomatic contacts within the window period.
  • Asymptomatic contacts of early syphilis should be offered either epidemiological treatment or re-screening 12 weeks after their last exposure.
• GPPPartner notification in latent syphilis:
  • Locate previous serology or documented treatment to aid staging and inform PN.
  • Individuals with late latent syphilis are usually unable to transmit the infection to sexual partners.
  • Screening is recommended for sexual partners of, and children born to, women diagnosed with late latent syphilis of unknown duration (as mother-to-child transmission can occur many years post-infection).

13Follow-Up, Treatment Failure, and Auditable Outcomes

• 1DMinimal recommended follow-up with syphilis serology (RPR) is 3-monthly for 6 months, then at 12 months.
  • Follow up 6-monthly thereafter if indicated (e.g., HIV co-infection) or until the patient is RPR negative or serofast.
  • It may take several months for non-treponemal titres to drop 4-fold, especially following treatment of a re-infection.
  • Specific treponemal tests usually remain positive for life; document clearly to prevent unnecessary re-treatment.
• 2DFollow-up examination of CSF should be performed 6 weeks to 6 months after treatment of neurosyphilis.
  • Used to monitor the decrease in white blood cell count and protein level.
  • Routine CSF measurement can be avoided in patients with a satisfactory reduction of serum RPR titres.
• GPPIdentify treatment failure or re-infection by monitoring RPR titres and clinical signs.
  • A sustained 4-fold or greater increase in the non-treponemal (RPR) test titre suggests re-infection or treatment failure.
  • Treatment failure is defined by: a 4-fold or greater RPR titre increase, recurrence of symptoms, and exclusion of re-infection.
  • Retreating serofast patients (who do not show a 4-fold drop but remain stable) does not improve serological response.

14Service Delivery, Safeguarding, and Equality Impact

• GPPAll cases of syphilis should be managed by Genitourinary Medicine (GUM) physicians.
• GPPDepartmental safeguarding procedures must actively identify and address risks of sexual exploitation and abuse.
  • Particularly critical for vulnerable groups, including patients with sensory, learning, mental health, cognitive, or mobility impairments.