BASHH Guidelines

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Aetiology

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

Approximately one-third of sexual contacts of infectious syphilis will develop the disease. Transmission is by direct contact with an infectious lesion or by vertical transmission during pregnancy (T. pallidum crosses the placenta).

Site of bacterial entry is typically genital in heterosexual patients, but 32–36% of transmissions among men who have sex with men (MSM) may be at extragenital (anal, rectal, oral) sites through oral-anal or genital-anal contact.

Syphilis predominates among white MSM aged 25–34, many of whom (40%) are HIV-1 co-infected.

Clinical Features

(1) Acquired (adult) disease

 

(i) Primary Syphilis

Incubation is usually 21 days (range 9-90)

Signs

Chancre (develops from a single papule)

Anogenital, single, painless and indurated with clean base, non-purulent

Can be multiple, painful and purulent (usually extra-genital)

Resolve over 3-8 weeks

 

(ii) Secondary syphilis

If primary syphilis is untreated 25% will develop secondary syphilis

Occurs 4-10 weeks after initial chancre

Multi-system

Signs

Rash

  • Widespread mucocutaneous
  • May be itchy
  • Can affect palms and soles

Mucous patches (buccal, lingual and genital)

Condylomata lata (higly infectious, mainly affecting perineum and anus)

Hepatitis

Splenomegaly

Glomerulonephritis

Neurological complications

  • Acute meningitis
  • Cranial nerve palsies
  • Uveitis
  • Optic neuropathy
  • Interstitial keratitis and retinal involvement

 

(iii) Latent disease

Secondary syphilis will resolve spontaneously in 3–12 weeks and the disease enters an asymptomatic latent stage

Approximately 25% of patients will develop a recurrence of secondary disease during the early latent stage

 

(iv) Late (tertiary) disease

Occurs in approximately one third of untreated patients

20-40 years after intial infection

Divided into gummatous, cardiovascular and neurological complications. See Table 1, below

 

(2) Congenital syphilis

 

(i) Early (within two years of birth)

2/3 will be asymptomatic at birth but will develop signs within 5 weeks

Signs

Common:

  • rash
  • haemorrhagic rhinitis
  • generalised lymphadenopathy
  • hepatosplenomegaly
  • skeletal abnormalities

Other signs:

  • condylomata lata
  • vesiculobullous lesions
  • osteochondritis
  • periostitis
  • pseudoparalysis
  • mucous patches
  • perioral fissures
  • non-immune hydrops
  • glomerulonephritis
  • neurological ocular involvement,
  • haemolysis and thrombocytopenia

 

(ii) Late (after two years)

Manifestations:

  • interstitial keratitis;
  • Clutton’s joints;
  • Hutchinson’s incisors;
  • mulberry molars (maldevelopment of cuspsof first molars);
  • high palatal arch;
  • rhagades (peri-oralfissures);
  • sensineural deafness;
  • frontal bossing;
  • short
  • maxilla;
  • protuberance of mandible;
  • saddlenose
  • deformity;
  • sterno-clavicular thickening;
  • paroxysmal
  • cold haemoglobinuria;
  • neurological involvement
  • (intellectual disability, cranial nerve palsies)

Diagnosis

(1) Clinical diagnosis

History

  • Full sexual history
  • Direct questioning for symptoms of syphilis
  • Explore previous syphilis diagnoses and treatment
  • Previous syphilis testing and tests used
  • Potential for previous infection for non-venereal T. pallidum infection (yaws, pinta, bejel)
  • Obstetric history

Examination

Early disease (primary or secondary) to include the following, when indicated:

  • Genital examination
  • Skin examination including eyes, mouth, scalp, palms and soles
  • Neurological examination if neurological symptoms elicited

Symptomatic late disease clinical examination should be undertaken as indicated, with attention to:

  • Skin
  • Musculoskeletal system (congenital)
  • Cardiovascular system (for signs of aortic regurgitation)
  • Nervous system (general paresis: dysarthria, hypotonia, intention tremor, and reflex abnormalities; Tabes dorsalis: pupil abnormalities, impaired reflexes, impaired vibration and joint position sense, sensory ataxia and optic atrophy)

 

(2) Laboratory diagnosis

(i) Demonstration of T. pallidum from lesions or infected lymph nodes

Dark ground microscopy:

  • Should be performed by experienced observer
  • Is less reliable in examining rectal and non-penile genital lesions
  • Not suitable for examining oral lesions due to the presence of commensal treponemes

Polymerase chain reaction (PCR):

  • Can be used on oral or other lesions where commensal treponemes may also be present
  • Available at reference laboratories
  • May be helpful in diagnosis by demonstrating T.pallidum in tissue samples, vitreous fluid and cerebrospinal fluid (CSF)

 

(ii) Serological tests for syphilis

Treponemal antibody tests cannot differentiate syphilis cause by T. pallidum subspecies pallidum from endemic treponematoses (yaws, bejel and pinta)

(a) Primary screening tests

Treponemal EIA/CLIA (preferably that detects both IgG and IgM) or TPPA, which is preferred to TPHA.

Request anti-treponemal IgM test if primary syphilis is suspected.

The clinical utility is limited by suboptimal sensitivity - should not be used to stage disease or decide the duration treatment.

Rapid treponemal tests might be useful is some outreach settings, provided positive results are confirmed by laboratory tests.

 

(b) Confirmatory tests

Positive screening tests should be confirmed with a different treponemal test.

An IgG immunoblot is recommended as a supplementary confirmatory test when the standard confirmatory test does not confirm the positive screening test result. The FTA-abs is not recommended as a standard confirmatory test, although it may have a role in specialist laboratories.

A second specimen should always be tested to confirm positive results, and on the day that treatment is commenced so the peak RPR/VDRL is documented.

 

(c) Tests for assessing serological activity of syphilis

A quantitative RPR/VDRL should be performed when treponemal tests indicate syphilis to help stage the infection indicates the need for treatment in some cases, for example, where the patient has been previously treated and may have been re-infected.

An initial RPR/VDRL titre of 16 usually indicates active disease and the need for treatment, although serology must be interpreted in the light of the treatment history and clinical findings.

An RPR/VDRL titre of 16 or less does not exclude active infection, particularly in a patient with clinical signs suggestive of syphilis or where adequate treatment of syphilis is not documented.

A negative anti-treponemal IgM test does not exclude active infection, particularly in late disease.

 

(d) Tests for monitoring the effect of treatment

A quantitative RPR/VDRL test is recommended for monitoring the serological response to treatment and should be performed on a specimen aken on the day that treatment is started as this provides an accurate baseline for monitoring response to treatment.

 

(iii) Special situations:

Repeat screening is recommended:

  • six and 12 weeks after a single ‘high risk’ exposure 
  • in individuals at ongoing risk due to frequent ‘high risk’ exposures, screening as part of routine sexual health check-ups for all STIs including HIV and others is recommended, usually every three months and informed by sexual history
  • two weeks after presentation in those with dark field or PCR negative ulcerative lesions that could be due to syphilis

 

False-negative syphilis serology

Treponemal screening tests are negative before a chancre develops and may be for up to two weeks afterwards.

A false-negative RPR/VDRL test may occur in secondary or early latent syphilis due to the prozone phenomenon when testing undiluted serum, in such cases negative tests on undiluted sera should b repeated on diluted sera. This may be more likely to occur in HIV-infected individuals

The RPR/VDRL and IgM may be negative in late syphilis

 

False-positive syphilis serology

Occasional false-positive results may occur with any of the serological tests for syphilis.

In general, false-positive reactivity is more likely in autoimmune disease, older age and injecting drug use.

In the absence of symptoms of syphilis, a history of syphilis or a concomitant positive anti-treponemal IgM; transient or persistent reactivity in a single treponemal antigen test should be considered to be a false-positive result.

For further information on evaluation of neurological, cardiovascular or ophthalmic involvement, please refer to full guideline

 

Diagnosis of congenital syphilis

  • Direct demonstration of T. pallidum by dark ground microscopy and/or PCR of exudates from suspicious lesions, or body fluids, e.g. nasal discharge
  • Serological tests should be performed on infant’s blood not cord blood and if the infant’s serum is positive on screening, perform treponemal IgM EIA, quantitative RPR/VDRL and quantitative TPPA tests on the infant and mother in parallel. Serological tests detecting IgG may be positive due to passive transfer of maternal antibodies whether or not the infant is infected
  • The following, if confirmed on testing a second specimen from the infant, indicate a diagnosis of congenital infection
    • A positive IgM EIA test
    • A positive RPR/VDRL test on CSF
    • A fourfold or greater difference of RPR/VDRL titre or TPPA titre above that of the mother
    • A fourfold or greater increase in RPR/VDRL or TPPA titre within 3 months of birth
    • In a child more than 18 months age, positive treponemal tests
  • If a mother acquires syphilis and seroconverts late in pregnancy the baby may be delivered, and possibly infected, prior to a mature antibody response. In addition an unwell baby may receive empirical antibiotics for sepsis which may attenuate the antibody response. This may mean a low RPR titre and negative IgM, even in the presence of congenital infection.
  • Further investigations may be required:
    • Blood: full blood count, liver function, electrolytes
    • CSF: cells, protein, serological tests
    • X-rays of long bones
    • Ophthalmic assessment as indicated
  • RECOMMENDATION: INFANTS WITH POSSIBLE SIGNS OF CONGENITAL SYPHILIS REQUIRE APPROPRIATE EVAULATION AND TESTING IN CONJUNCTION WITH MATERNAL STS AND TREATMENT HISTORY: 1A

 

Management

Recommended regimens

 

(1) Early syphilis (primary, secondary and early latent)

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

Alternative regimens

  • Procaine penicillin G 600,000 units IM daily 10 days: 1C.
  • Doxycycline 100mg PO BD 14 days: 1C.
  • Ceftriaxone 500mg IM daily10 days (if no anaphylaxis to penicillin): 1C.
  • Amoxycillin 500mg PO QDS plus Probenecid 500mg QDS14 days: 1C.
  • Azithromycin 2g PO stator Azithromycin500mg daily10 days: 2B. (See 'Caution re: macrolide therapy for syphilis' section)
  • Erythromycin 500mg PO QDS14 days: 2B.(See 'Caution re: macrolide therapy for syphilis' section)

 

(2) Late latent, cardiovascular and gummatous syphilis

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

Alternative regimens

  • Doxycycline 100mg PO BD for 28 days: 2D.
  • Amoxycillin 2g PO TDS plus probenecid 500mg QDS for 28 days: 2C.

Steroids should be given with all anti-treponemal antibiotics for cardiovascular syphilis; 40–60mg prednisolone OD for three days starting 24hbefore the antibiotics.

 

(3) Neurosyphilis including neurological/ophthalmic involvement in early syphilis

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

Alternative regimens

  • Doxycycline 200mg PO BD for 28 days: 2D.
  • Amoxycillin 2g PO TDS plus probenecid 500mg PO QDS for 28 days: 2D.
  • Ceftriaxone 2g IM or IV for 10–14 days: 2D.

Steroids should be given with all anti-treponemal antibiotics for neurosyphilis; 40–60mg prednisolone OD for three days starting 24h before the antibiotics.

 

(4) Syphilis in Pregnancy

(i) Early syphilis in pregnancy

Trimesters one and two (up to and including 27 weeks):

  • Benzathine penicillin G 2.4 MU IM. Single dose: 1B.

Trimester three (from week 28 to term):

  • Benzathine penicillin G 2.4 MU IM, on days 1 and 8: 1B.

Alternative regimens (all three trimesters)

  • Procaine penicillin G 600,000 unit IM. Daily for 10 days: 1C.
  • Amoxycillin 500mg PO q.d.s. plus probenecid 500mg PO q.d.s for 14 days: 2C.
  • Ceftriaxone 500mg IM daily for 10 days: 2C.
  • Erythromycin 500mg PO q.d.s for 14 days: 2C (see 'Caution re: macrolide therapy for syphilis' section in full guideline, and addendum below)
  • Azithromycin 500mg PO daily for 10 days: 2C (see 'Caution re: macrolide therapy for syphilis' section in full guideline, and addendum below)

***Caution against use of macrolides for early syphilis in pregnancy - UPDATED JUNE 2019***

Click here for the full statement regarding the removal of macrolides as a treatment option for pregnant women with early syphilis. A summary follows:

We are removing macrolides as a treatment option. This is consistent with the Centres for Disease Control and International Union Against Sexually Transmitted Infections – Europe7guidelines. World Health Organisation guidelines, as the UK guideline did until now, continue to offer macrolide treatment as a last option for pregnant women with the caveat the neonates need to be treated at birth. However in our experience, this may result in treatment failure in pregnancy and transmission to the neonate.

For pregnant women who report intolerance or allergy to penicillin or other beta-lactam antibiotics we are making the following recommendations for management which must include consultation with the patient at all stages:

  1. A thorough history of drug allergy is taken and substantiated from primary care practitioners
  2. If a true allergy history is ascertained refer urgently to immunology/allergy services for testing for allergy to penicillin and ceftriaxone (this is consistent with current NICE guidance). A rapid access referral pathway has been established within Manchester (UK); a high prevalence area with a specialist tertiary foetal-maternal medicine unit which could be adopted in other services.
  3. If possible following this treat with penicillin (first line) or ceftriaxone (second line)
  4. In the rare circumstance of true beta-lactam allergy being confirmed:
    1. Refer to the tertiary foetal medicine unit for co-management by obstetric, midwifery, paediatric and tertiary GUM (or infection) specialists. Such services exist for the management of HIV positive pregnant women and are best placed to manage such difficult cases.
    2. Management should be on a case by case and multi-disciplinary basis (including the pregnant woman) where the risk of treatment is balanced against the risk of infection to the neonate and pregnancy loss, still birth or congenital infection and subsequent disability. Factors to consider include the stage of syphilis and any previous treatment history. Such teams also have the ability to monitor mother and baby as needed.
    3. Desensitisation to penicillin and immediate treatment of the mother with penicillin should be considered and discussed within the team including the mother.
    4. The authors of this guideline amendment are available for sub-specialist clinical advice and referral within the UK as needed.  

(ii) Late syphilis in pregnancy

(a) Late latent, cardiovascular and gummatous syphilis (all three trimesters):

  • Benzathine penicillin G 2.4 MU IM weekly on days 1, 8 and 15 (three doses): 1C.

Steroids should be given with all anti-treponemal antibiotics for cardiovascular syphilis; 40–60mg prednisolone OD for three days starting 24h before the antibiotics.

Alternative regimens

  • Procaine penicillin G 600,000 units IM OD for 14 days: 1C.
  • Amoxycillin 2g PO t.d.s. plus probenecid 500mg q.d.s for 28 days: 2C

(b) Neurosyphilis in pregnancy

  • Procaine penicillin G 1.8–2.4 MU IM o.d. plus pro-benecid 500mg PO q.d.s. for 14 days: 1C 2010.
  • Benzylpenicillin 10.8–14.4g daily, given as 1.8–2.4g IV every 4h for 14 days: 1C.

 Alternative regimens

  • Amoxycillin 2g PO t.d.s. plus probenecid 500mg PO q.d.s. for 28 days: 2D.
  • Ceftriaxone 2g IM (with lidocaine as diluent) or IV (with water for injections as diluent, NOT Lidocaine) for 10–14 days (if no anaphylaxis to penicillin): 2D.

Steroids should be given with all anti-treponemal antibiotics for neurosyphilis; 40–60mg prednisolone OD for three days starting 24h before the antibiotics.

  

(5) Congenital syphilis

  • Benzyl penicillin sodium 60–90 mg/kg daily IV (in divided doses given as – 30 mg/kg 12 hourly) in the first seven days of life and 8 hourly thereafter for a further 3 days for a total of 10 days: 1C

 Alternative regimens

  • Procaine penicillin 50,000/kg daily IM 10 days.
  • In children, IV therapy (option one here) is preferable due to the pain associated with IM injections: 1C

 

Additional management points:

Interruptions in treatment for late and congenital syphilis

If drug administration is interrupted for more than one day at any point during the treatment course, it is recommended that the entire course is restarted: 1D.

 

Reactions to treatment

Patients should be warned of possible reactions to treatment

Resuscitation facilities should be available in the treatment area

All patients should be kept on clinic premises for 15 minutes and advised to seek urgent medical attention if allergic symptoms occur

Possible reactions:

(i) Jarisch-Herxheimer reaction: An acute febrile illness with headache, myalgia, chills and rigours which resolves within 24 hours

(ii) Procaine reaction (procaine psychosis, procainemania, Hoigne’s syndrome)

Due to inadvertent intravenous injection of procaine penicillin.

Characterised by fear of impending death and may cause hallucinations or fits immediately after injection and lasts less than 20minutes

(iii) Anaphylactic shock

(iv) Allergy: penicillin desensitisation should be considered for patients reporting a history of penicillin allergy

 

Follow-up and partner notification

All patients should have PN discussed at diagnosis with re-interview if required. The look-back period is as appropriate for their stage of syphilis: 1B.

Epidemiologic treatment should be offered for asymptomatic contacts in the window period: 1B.

Recommended clinical and serological (RPR orVDRL) follow-up is at three, six and 12 months, then if indicated, six monthly until VDRL/RPRnegative or serofast

A sustained four-fold or greater increase in the VDRL or RPR titre suggests re-infection or treatment failure. Treatment failure is characterised by:

  • Four-fold or greater increase in non-treponemal test titre.
  • Recurrence of signs or symptoms.
  • Re-infection excluded

CSF examination and re-treatment are indicated for individuals whose non-treponemal test titres do not decrease four-fold within 12 months of therapy. If CSF examination is normal, re-treatment should be with benzathine penicillin G administered as three doses of 2.4 million units IM each at weekly intervals

In those with HIV infection, initial follow-up is as detailed above. Lifelong annual monitoring with syphilis serology is recommended and in outbreak situations six monthly (coinciding with HIV follow-up visits)

 

Syphilis Birth Plan

This birth plan has been developed to facilitate liaison with obstetric and paediatric colleagues in the care of women diagnosed with syphilis in pregnancy. Click here

Download the full guideline

Download the full guideline here

 

UPDATE JUNE 2019:

Please note, macrolides have been removed as a recommended treatment for early syphilis in pregnancy. This are not reflected in the published guideline attached. Please refer to the Management section above for details

UPDATE JUNE 2017:

Please note, minor changes have been made to the sections on diagnosis of congenital syphilis, and treatment of congenital syphilis. They are not reflected in the published guideline attached. Please refer to the Diagnosis and Management sections above for details