Syphilis 2024: Updated Guideline

Syphilis is caused by infection with the spirochete bacterium Treponema pallidum.

It is transmitted by direct contact with an infectious lesion or by mother-to-child transmission during pregnancy.

Syphilis cases have risen in almost all parts of the UK and remain persistently high in some geographical locations, including London, Manchester and Brighton.

Syphilis predominates among GBMSM aged 25–34 years, many of whom are living with HIV.

Since 2014, the overall rise in infectious syphilis cases has included an increase in heterosexual cases.

Site of bacterial entry is typically genital in heterosexual patients, but 32%–36% of transmissions among GBMSM may be at extra-genital (anal, rectal and oral) sites.

Syphilis is a multi-stage, multi-system disease, which is broadly defined as congenital or acquired syphilis.

Acquired (adult) disease

Early (infectious) disease

Following contact T. pallidum invades through the mucosal surface or abraded skin and divides at the point of entry to produce the chancre of primary disease.

The incubation period is typically 21 days (range 9–90 days)

Primary syphilis is characterised by a single papule and moderate regional lymphadenopathy. The papule subsequently ulcerates to produce a chancre, which is classically anogenital, single, painless and indurated with a clean base discharging clear serum but not pus.

Chancres may also be multiple, painful, purulent, destructive and extra-genital (most frequently oral)

Early after infection the bacteria disseminate widely via blood and lymphatic systems and are subject to local immune clearance

Ulcers resolve over 3–8 weeks

Untreated, 25% of patients will develop signs of secondary syphilis approximately 3–10 weeks after the appearance of the initial chancre.

Secondary syphilis affects multiple systems and typically develops 3 months after infection.

It often presents with a widespread mucocutaneous rash and generalised lymphadenopathy.

It can affect the palms and soles and hair follicles resulting in alopecia.

Two further important mucocutaneous signs are mucous patches (buccal, lingual and genital) and highly infectious condylomata lata affecting mostly the perineum and anus.

Patients can develop neurological complications during secondary syphilis. These are typically acute meningitis and cranial nerve palsies including eighth nerve palsy with resultant hearing loss and possible tinnitus.

Eye involvement may result in uveitis, optic neuropathy, interstitial keratitis and retinal involvement.

Secondary syphilis may also result in hepatitis, glomerulonephritis, splenomegaly and,more rarely, pulmonary, bone and gastric involvement.

Coinfection with HIV may increase the likelihood and severity of ocular and neurosyphilis

Secondary syphilis will resolve spontaneously in 3–12 weeks and the disease enters a latent (asymptomatic) stage.

The latent stage is defined as early within 2 years and late thereafter.

Late (tertiary) disease

Late disease occurs in approximately one-third of untreated patients around 20–40 years after initial infection.

It is divided into gummatous (15% of patients),cardiovascular (10%) and late neurological disease (7%).

The clinical manifestations of late syphilis are highly variable and are rarely seen due to the use of treponemicidal antibiotics for other indications.

History

A full and accurate history is important to identify potential complications of symptomatic infection (both early and late) and to distinguish between late latent, previously treated and non-venereal T. pallidum infection (yaws, pinta and bejel), which may have identical serological results.

Directly question for symptoms of syphilis.

Fully explore previous syphilis diagnoses, testing results and treatment received.

Potential for previous infection with non-venereal T. pallidum infection e.g. Previously resident in an endemic area/country.

Full obstetric history (where appropriate) See separate guidelines for management of syphilis in pregnancy.

Examination

Early disease (primary or secondary) to include the following, when relevant symptoms are present:

• Genital examination
• Skin examination including mouth, scalp, palms and soles
• Neurological examination

Symptomatic late disease (including suspected late congenital disease); clinical examination may be undertaken when relevant symptoms are present and may include:

• Skin
• Musculoskeletal system
• Cardiovascular system
• Nervous system.

Laboratory diagnosis 

Demonstration of T. pallidum using direct detection methods

Where appropriate expertise and equipment are available, dark ground microscopy should be performed on possible chancres: 2A.

Molecular testing for T. pallidum is appropriate on lesions where the organism may be expected to be located: 1A.

Serological tests for syphilis

An EIA/CLIA detecting both IgM and IgG is the screening test of choice: 1B.

Positive screening tests should be confirmed with a different treponemal test and a second specimen for confirmatory testing obtained: 1B.

A quantitative RPR test should be performed when screening tests are positive: 1A. Including an RPR on the day that treatment is commenced so the peak RPR titre is documented.

A four-fold rise in the RPR titre in comparison to an earlier sample, is suggestive of recent syphilis infection.

Negative serological tests for syphilis should be repeated at 2 weeks after observation of possible chancres that are dark ground microscopy and/or PCR negative: 1B.

Recommended regimens

Potentially incubating syphilis/ epidemiological treatment

1. Benzathine penicillin G 2.4 MU IM single dose: 1C.
2. Doxycycline 100 mg orally (PO) BD for 14 days: 1C.

Early syphilis (primary, secondary and early latent)

1. Benzathine penicillin G 2.4 MU IM single dose: 1B.

Alternative regimens:

1. Procaine penicillin G 600,000 units IM OD for 10 days 1C.
2. Doxycycline 100 mg PO BD for 14 days: 1C.
3. Ceftriaxone 500 mg–1 g IM or IV OD for 10 days (if no anaphylaxis to penicillin): 1C.
4. Amoxycillin 500 mg PO QDS PLUS probenecid 500 mg QDS for 14 days: 1C.

Late latent syphilis

1. Benzathine penicillin 2.4 MU IM weekly for 3 weeks (three doses) 1C.

Alternative regimens:

1. Doxycycline 100 mg PO BD for 28 days 2D.
2. Amoxycillin 2 g PO three times daily (TDS) PLUS probenecid 500 mg QDS for 28 days 2C.
3. Ceftriaxone 2 g IM or IV for 10–14 days: 2D.

Neurosyphilis:

T. pallidum can infect the central nervous system (CNS), and this can occur at any stage of syphilis and result in neurosyphilis.

Every patient with a positive serological test for syphilis and symptoms suggestive of neurological involvement (such as cognitive dysfunction, motor or sensory deficits, cranial nerve dysfunction or symptoms/signs of meningitis or stroke) should have a thorough neurological examination. If symptoms indicate, this may include ophthalmic and otological examination.

For full investigation and management of neurosyphilis, see full guidelines.

Neurosyphilis including neurological involvement in early syphilis

1. Procaine penicillin 1.8–2.4 MU IM OD PLUS probenecid 500 mg PO QDS for 14 days : 1C.
2. Benzylpenicillin 10.8–14.4 g OD, given as 1.8–2.4 g IV every 4 h for 14 days 1C.

Alternative regimens:

1. Ceftriaxone 2 g IM or IV for 10–14 days9 2D.
2. Doxycycline 200 mg PO BD for 28 days 2D.
3. Amoxycillin 2 g PO TDS PLUS probenecid 500 mg PO QDS for 28 days 2D. Steroids should be given with all anti-treponemal antibiotics for neurosyphilis; 40–60 mg prednisolone OD for 3 days starting 24 h before the antibiotics.

Cardiovascular and Gummatous syphilis: See full guidelines

Guidelines for the management of syphilis in pregnancy and children: See separate guidelines

Management of sexual partners: See full guidelines