Ijsa-08-279 729.740

UK National Guidelines on the Management of Syphilis 2008 M Kingston BMBS MRCP*, P French MBChB FRCP†, B Goh FRCP‡, P Goold MBBS MRCP§, S Higgins FRCP**, A Sukthankar FRCP*, C Stott RGN BSc*, A Turner MBChB FRCPath††, C Tyler RGN MSc‡ and *Manchester Centre for Sexual Health, The Hathersage Centre, 280, Upper Brook Street, Manchester M13 OFH; †Department of GenitourinaryMedicine, Mortimer Market Centre, Off Capper Street, London WC1E 6JB; ‡Department of Genitourinary Medicine, Ambrose King Centre, TheRoyal London Hospital, Turner Street, London E1 1BB; §Department of Genitourinary Medicine, Whittall Street Clinic, Whittall Street, B4 6DH;**Department of Genitourinary Medicine, Outpatients Department, North Manchester General Hospital, Pennine Acute Hospitals NHS Trust,Crumpsall, Manchester M13 9WL; ††Department of Clinical Virology, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL; ‡‡RoyalInfirmary of Edinburgh, 51 Little France Cr, Old Dalkeith Road, Edinburgh EH16 4SA, UK (the Syphilis Guidelines Revision Group 2008) The main objective is to reduce the number of sexually trans- † New guideline format: A single guideline covering screen- mitted infections (STIs) and the complications that can arise ing and investigations for syphilis, clinical features, man- in people either presenting with signs and symptoms of an agement and follow-up for all stages of infections: early, STI, or undergoing investigation for possible infection.
late, congenital, in pregnancy and in HIV-positive Specifically this guideline offers recommendations on the diagnostic tests, treatment regimens and health promotion † When evaluating possible neurological involvement a principles needed for the effective management of syphilis; lumbar puncture is indicated in those with neurological covering the management of the initial presentation, as well symptoms/signs or those who have failed therapy and as how to prevent transmission and future infection.
consideration should be given to neurological imaging It is aimed primarily at people aged 16 years or older, first. A section on interpretation of the cerebrospinal fluid although there is a section referring to the management of congenital syphilis, presenting to health-care professionals, † When managing syphilis infection in pregnancy, referral to working in departments offering level 3 care in STI manage- fetal medicine consultant for evaluation of fetal involvement ment (see national strategy)1 within the United Kingdom.
and monitoring for fetal distress during treatment is rec- However, the principles of the recommendations should be adopted across all levels (levels 1 and 2 may need to develop, where appropriate, local care pathways).
The recommendation of this guideline may not be appro- W Benzathine penicillin G single dose first-line therapy priate for use in all clinical situations. Decisions to follow W Azithromycin single dose as a second-line alternative these recommendations must be based on the professional judgement of the clinician and consideration of individual patient circumstances and available resources.
W Benzathine penicillin G three weekly doses first-line therapy (except for neurosyphilis: procaine penicillin G with concomitant oral probenecid remains first-linetherapy for this) The document was reviewed by the Clinical Effectiveness Group of British Association for Sexual Health and HIV W First and second trimesters: give benzathine penicillin (BASHH), and their comments incorporated. The draft guide- G, single dose. However, when maternal treatment is line was placed on the BASHH website and any comments initiated in the third trimester, a second dose of received after three months were reviewed by the authors and benzathine penicillin G to be given one week after the W Ceftriaxone 500 mg i.m. Â 10 days added to alternatives Correspondence to: Dr Margaret Kingston, Manchester W Late: As in non-pregnant patients (avoid tetracyclines) Centre for Sexual Health, The Hathersage Centre, 280 Upper W Guidance for screening and treatment for babies born to DOI: 10.1258/ijsa.2008.008279. International Journal of STD & AIDS 2008; 19: 729 – 740 – HIV-positive patients: Treat as appropriate for stage of macular–papular often affecting the palms and soles), condy- infection, that is, HIV-positive patients are treated with lomata lata, mucocutaneous lesions, generalized lymphadeno- the same regimens as HIV-negative patients pathy and less commonly: patchy alopecia, anterior uveitis, † Management of sexual partners: Recognition that partner meningitis, cranial nerve palsies, hepatitis, splenomegaly, notification may be difficult in context of current syphilis periosteitis and glomerulonephritis.10–15 The rash is classically outbreaks and achieving 60% partner notification rates is non-itchy but may be itchy, particularly in dark-skinned not always possible and screening in high-risk venues may † Latent syphilis is T. pallidum infection diagnosed on serologi- † Auditable outcomes: Measuring rapid plasma reagin test cal testing with no symptoms or signs. Within the first two (RPR)/Venereal Diseases Research Laboratory (VDRL) at years of infection this is early latent syphilis and beyond commencement of therapy introduced as an auditable † Symptomatic late syphilis can be categorized into neurosy- philis, cardiovascular syphilis and gummatous syphilis, – Reference to sources of procaine penicillin G and these may coexist. Tertiary syphilis is a term often – Use of lidocaine as diluent for Benzathine penicillin G used synonymously with late symptomatic syphilis butgenerally excludes meningovascular syphilis. A large pros-pective cohort study of untreated patients with T. pallidum infection in the pre-antibiotic era demonstrated that sympto-matic late syphilis may develop in approximately one third The objective of this guideline is to facilitate the appropriate of individuals.17 The clinical features of symptomatic late investigation and management of individuals with all stages syphilis are summarized in table one.
of syphilis. This guideline has been developed by a group (see membership of the guideline revision group for details) W Early; includes a rash, condylomata lata, vesiculobullous who have reviewed the previous published guidelines for the lesions, snuffles, haemorrhagic rhinitis, osteochondritis, management of early and late syphilis2,3 together with more periostitis, pseudoparalysis, mucous patches, perioral recent clinical data in order to produce this updated, unified fissures, hepatosplenomegaly, generalized lymphade- guideline. Recommendations made are graded as stated in the BASHH guideline specifications4 as level of evidence (Ia-V) neurological or ocular involvement, haemolysis and and grade of recommendations (A –C).
W Late; including stigmata: Interstitial keratitis, Clutton’s joints, Hutchinson’s incisors, mulberry molars, high palatal arch, rhagades, deafness, frontal bossing, short Syphilis is caused by infection with the spirochete bacterium Treponema pallidum subsp pallidum. This is transmitted from one person to another either by direct contact with an infectious lesion (usually occurring during sexual contact), during preg- nancy from mother to child or via infected blood products.
Syphilis is classified as acquired or congenital. Acquired syphi- lis is divided into early ( primary, secondary and early latent † Details of previous treatment (place of treatment, diagnosis ,2 years of infection) and late (late latent .2 years of infection, made, treatment given, RPR/VDRL titre at discharge) tertiary including gummatous, cardiovascular and neurologi- † Obstetric history, potential complications of syphilis e.g.
cal) syphilis. Congenital syphilis is divided into early (diag- nosed in the first two years of life) and late ( presenting after † Blood donation and antenatal screening history † Other treponemal infections; yaws, pinta and a history of living in countries where these conditions are endemic † In early infection examination of the genitals, skin, mucosal surfaces and lymph nodes for signs of primary and second- Primary syphilis is characterized by an ulcer (the chancre) † In late and congenital syphilis a thorough clinical examin- and regional lymphadenopathy. The chancre is classically ation should be undertaken for the clinical manifestations in the anogenital region, is single, painless and indurated of syphilis. This should include a full systems review includ- with a clean base discharging clear serum. However, ing skin and mucosal surfaces, lymph nodes, cardiovascular chancres may be multiple, painful, purulent, destructive, extragenital (most frequently oral) and may cause the syphi-litic balanitis of Follman.8 There may also be mixed aetiol-ogy.9 Any anogenital ulcer should be considered to be due to syphilis unless proven otherwise.
involvement within the first two years of infection. There is often a rash (typically generalized macular, papular or W Should be performed by experienced observers.
W If the initial test is negative repeat daily for three days.
confirmatory test does not confirm the positive treponemal W Less reliable in examining rectal and non-penile genital screening test result (European Syphilis Guideline IUSTI/ lesions and not suitable for examining oral lesions due WHO, 2007, in final preparation). The FTA-abs is not rec- ommended as a standard confirmatory test (European † Polymerase chain reaction (PCR)21–23 (IIb, B) Syphilis Guideline IUSTI/WHO, 2007, in final preparation).
W May be used on oral or other lesions where contamination Always repeat positive tests on a second specimen to with commensal treponemes is likely.
W Available at the Sexually Transmitted Bacteria Reference A quantitative VDRL/RPR should be performed on a speci- men taken on the day that treatment is started (IV, C) as this provides an accurate baseline for monitoring response to Manchester Royal Infirmary and for Scotland at the W Three months after exposure in the case of a single ‘high W Due to limited availability and the time taken to obtain a risk’ exposure (unprotected oral, anal or vaginal intercourse result this is not a replacement for dark field microscopy with homosexual male multiple partners, anonymous partner in saunas and other venues, commercial sex W In certain circumstances PCR may be helpful in diagnosis worker, partner linked with a country where the preva- by demonstrating T. pallidum in tissue samples, vitreous lence of syphilis is known to be high).
W Six weeks and at three months (including a specific IgM test) after presentation in those with dark field negativeulcerative lesions that could be due to syphilis or contactsof suspected or proven syphilis. (IV, C) † The VDRL/RPR and EIA-IgM27 are often negative in late † These should be routinely performed in genitourinary medi- syphilis but this does not exclude the need for treatment.
† Other treponemal infections such as Yaws or Pinta may give † Specific (treponemal) tests: treponemal enzyme immunoassay identical results although the RPR/VDRL is usually of low (EIA) to detect immunoglobulin G (IgG), IgG and immunoglo- titre (,1:8). Because it is not possible to exclude latent syphi- bulin M (IgM) or IgM, T. pallidum chemiluminescent assay,28–30 lis in this situation, many clinicians manage patients who T. pallidum haemagglutination assay (TPHA), T. pallidum par- may have these infections as though they have syphilis.
ticle agglutination assay (TPPA), fluorescent treponemal The rationale of this approach should be discussed with antibody absorbed test (FTA-abs), T. pallidum recombinant † Rapid tests for syphilis are available41 but their main role is W Request EIA for antitreponemal IgM if primary syphilis is likely to be in field conditions in developing countries and suspected (European Syphilis Guideline IUSTI/WHO, towards the end of the second week of infection whileIgG is detectable usually in the fourth or fifth week.
Evaluation of neurological, cardiovascular or W All the specific tests are almost invariably positive in sec- ondary and early latent syphilis (a delayed serologicalresponse may occur in secondary infection but this is † Chest X-ray (CXR) in late latent syphilis or if there are any rare, even in the presence of HIV).34– 36 signs of aortic disease. In pregnant women with late latent † Cardiolipin (non-treponemal) tests: VDRL carbon antigen syphilis, a CXR is not routinely recommended unless cardio- vascular signs or symptoms deem it is necessary.
W A quantitative VDRL/RPR should be performed when † Neurological imaging should be considered in those with treponemal tests indicate syphilis (European Syphilis neurological symptoms or signs. Patients should have a Guideline IUSTI/WHO, 2007, in final preparation) as thorough neurological examination to rule out focal neurol- this helps stage the disease and indicates the need for ogy or papilloedema that may indicate raised intracranial pressure and a computed tomography of the head requested W A false-negative cardiolipin (reagin) test may occur in if these signs are present prior to lumbar puncture.
secondary or early latent syphilis due to the prozone † There is continued debate around the necessity of CSF exam- phenomenon when testing undiluted serum.37 This may ination in asymptomatic patients. A study of risks and be more likely to occur in HIV-infected individuals.38 benefits of lumbar puncture in this group has suggested W A VDRL/RPR titre of .16 and/or a positive IgM test indi- that it is not indicated42 and a wide range of penicillin cate active disease and the need for treatment,39 although doses appear efficacious in preventing clinical progression serology must be interpreted in the light of the treatment of asymptomatic neurosyphilis.43 In a retrospective study of patients with latent syphilis, a negative VDRL in the peri- † Recommended for screening: Treponemal EIA (preferably a pheral blood was found to have 100% sensitivity in excluding test that detects both IgG and IgM) or TPPA or VDRL/RPR CSF abnormalities compatible with the diagnosis of neurosy- and TPHA and confirm a positive screening test with a philis44 whereas a serum RPR ! 1:32 has been demonstrated different treponemal test (European Syphilis Guideline to predict CSF abnormalities.45 Indications for CSF examin- IUSTI/WHO, 2007, in final preparation).32,33 An immuno- ation in late syphilis infection include: W Neurological or ophthalmic signs or symptoms immunoassay)40 is recommended when the standard Clinical features of symptomatic late syphilis W In order for these tests to be interpreted accurately, it is vital that the CSF should not be macroscopically contami- W Positive syphilis tests on CSF should be interpreted in con- junction with biochemical examination of the CSF as well W The majority of individuals who have symptomatic neuro- found in up to 30% of primary andsecondary syphilis142 yet this does not syphilis have a raised white cell count (.5 cells/mm3).
W Positive CSF VDRL and CSF TPPA tests should be W The overall sensitivity of the CSF VDRL/RPR is around 50% with a range of 10% for asymptomatic cases to 90% dependent on site of vascular insult.
Occasional prodrome; headache, for symptomatic cases;47 a negative CSF VDRL/RPR does not exclude neurosyphilis and a positive CSF VDRL/RPR (in the absence of substantial contamination Cortical neuronal loss; gradual decline in of CSF with blood) is diagnostic of neurosyphilis.48 memory and cognitive functions,emotional lability, personality change, W A negative treponemal test on CSF excludes neurosyphilis and a positive test is highly sensitive for neurosyphilis but lacks specificity49 because reactivity may be caused by transudation of immunoglobulins from the serum into the CSF or by leakage through a damaged blood brain nerve roots; lightening pains, areflexia,paraesthesia, sensory ataxia, barrier resulting from conditions other than syphilis.
Neurosyphilis is unlikely when the CSF TPHA titre is ,320 or the TPPA titre ,640. The TPHA index (CSF albumin]) allows for impaired barrier function and is more sensitive than the CSF VDRL while maintaining high specificity.50,51 A TPHA index .70 and a CSF TPHA titre .320 are the most reliable in supporting a diagnosis of neurosyphilis50 but unfortunately determi- nation of the TPHA index is not widely available.
all tests become negative (usually by six months). Also This diagnosis is made by the presence of the typical clinical repeat the IgM at three months in case the infant’s features of cardiovascular syphilis (Table 1) combined with positive syphilis serology. Patients with suspected cardiovascu- W If the infant’s serum is negative on screening, and there lar syphilis need assessment by a cardiologist.
are no signs of congenital infection, no further testing isnecessary.
† A positive IgM EIA test52,53 and/or a sustained four-fold or Diagnosis of syphilitic gummata is usually made on clinical greater difference of VDRL/RPR titre or TPPA titre above grounds; typical nodules/plaques or destructive lesions in that of the mother (confirmed on testing a second specimen individuals with positive syphilis serology. Histological exam- from the infant) indicates a diagnosis of congenital infection.
ination of a lesion may suggest this diagnosis and T.pallidum may be identified within the nodules by PCR.
W Blood: full blood count, liver function, electrolytesW CSF: cells, protein, serological tests Direct demonstration of T. pallidum by dark groundmicroscopy and/or PCR of exudates from suspiciouslesions, or body fluids, e.g. nasal discharge.52,53 Serological tests should be performed on infant’s blood, notcord blood and if the infant’s serum is positive on screening, † HIV-infected patients with early syphilis are more likely to perform treponemal IgM EIA, quantitative VDRL/RPR and have multiple, large and deep genital ulcers54 and the quantitative TPPA tests on the infant and mother in parallel.
risk of neurological complications may be higher in † Serological tests detecting IgG may be positive due to HIV-positive patients with early syphilis.44,55,56 However, passive transfer of maternal antibodies whether or not the the clinical features in HIV-positive and negative individuals with early syphilis are often similar.54,57 W If the IgM test is negative, the other tests are reactive with † In a minority of cases, serology may be unreliable: there is a titres less than four-fold higher than those of the mother tendency for the RPR/VDRL titre to be lower in primary and there are no signs of congenital syphilis, then repeat reactive tests at three, six and 12 months of age or until syphilis,57 although lower or false-negative titres have been reported.35,36,58 When clinical findings are suggestive of common in early syphilis, CSF abnormalities are uncom- syphilis but serological tests are non-reactive, alternative mon after recommended treatment of early syphilis. The tests (e.g. biopsy of a lesion, dark ground microscopy) may remains low indicating that treatment is effective andsuggests that host immune responses in early syphilisplay an essential part. A single dose of 2.4 MU benzathinepenicillin G in asymptomatic neurosyphilis showed a 21% CSF relapse rate which was twice that of other penicillin † All patients should be offered screening for other STIs † Cardiovascular lesions may progress despite adequate treatment for syphilis. Steroid therapy is recommended in † Patients should be given a detailed explanation of syphilis, cardiovascular syphilis to prevent potential consequences including the long term implications for the health of them- of Jarisch –Herxheimer reaction. All patients with suspec- selves and their partners/families. This should be reinforced ted cardiovascular syphilis should be reviewed by a by giving them clear and accurate written information.
† There is very little evidence to inform advice about the time † Gummata affecting vital organs should be managed in sexual abstinence is required for following treatment, collaboration with the appropriate specialist.
however patients should be advised to refrain from sexual † For neurosyphilis 2.4 g (2.4 MU) i.m. o.d. for 10–14 days of contact of any kind until the lesions of early syphilis (if procaine penicillin ( plus probenecid 500 mg PO q.d.s. for they were present) are fully healed or until after the results the same duration) is the favoured dose in the Centers for of the first follow-up serology are known.
Disease Control and Prevention (CDC) 2006 guidelines48 as † A treponemicidal level of antimicrobial should be achieved it has been shown to produce treponemicidal levels in the in serum, and in the case of neurosyphilis, in the CSF. A CSF,89 although this may be an inconsistent finding.92 It is penicillin level of .0.018 mg/L is considered treponemici- likely that lower doses of procaine penicillin are as effica- dal,59 but a higher concentration might be preferable for cious,91 so a range of possible doses is given to reflect this more rapid elimination of treponemes. The maximal elimin- and the available formulations of this drug. No treatment ation effect is attained at a level of 0.36 mg/L.60 Duration of regimens for syphilis have been demonstrated to be more treponemicidal levels of antimicrobial should be at least effective in preventing neurosyphilis in HIV-infected seven days to cover a number of division times (30 –33 patients than the syphilis regimens recommended for hours) of treponemes in early syphilis with a subtreponemi- HIV-negative patients (although some treatment failures cidal interval of not more than 24–30 hours.59 Longer dur- ation of treatment is given in late syphilis on the basis of † Both benzathine and procaine penicillins G are unlicensed in Treponemes may persist despite apparently successful treat- W The prescriber should be aware that the product is unli- ment indicating that some treponemes may be ‘resting’ or censed and ensures that they are aware of the uses and dividing very slowly.61–66 Clinical data are lacking on the actions of the product and is assured of its quality and optimal dose and duration of treatment and the long term efficacy of antimicrobials other than penicillin. The rec- W The use of the unlicensed medicine is justified by the clini- ommendations are based mainly on laboratory consider- ations, biological plausibility, expert opinion, case studies W Legal responsibility for prescribing falls to the doctor who † Parenteral rather than oral treatment has been the treatment W The unlicensed status of the medicine should be explained of choice because therapy is supervised and bioavailability is to the patient and Trust policy relating to informed patient † Non-penicillin antibiotics that have been evaluated W Records are made in the patient’s medical notes of the unlicensed medicine and the indication for use.
Erythromycin is least effective and does not penetrate the W Incidents of untoward patient reactions are recorded and CSF or placental barrier well.67,68 Doxycycline has super- reported to the Committee on the Safety of Medicines ceded the older tetracyclines; although 100 mg once or (CSM) via the yellow card scheme and to the Trust’s criti- twice daily for 14 days is effective,48,69 failure of once daily doxycyline has been reported.70 One study of a single doseof 2 g of azithromycin has shown efficacy in early syphilis Management in pregnancy: general considerations equivalent to that of benzathine penicillin71 however thereare concerns regarding azithromycin treatment failure72 † All pregnant women should be screened for syphilis at the which appears to be linked to intrinsic macrolide resistance in some strains of T. pallidum.73 In small studies, a † Syphilis may be transmitted transplacentally at any stage of number of ceftriaxone regimens have been shown to be pregnancy94– 97 and may result in polyhydramnios, miscar- riage, pre-term labour, stillbirth, hydrops and congenital † The host immune response is important as 60% of untreated individuals go through life without developing late compli- † Maternal early stage syphilis98–101 and high titre RPR/ cations.17 Although both benzathine penicillin G and stan- VDRL102,103 are risk factors for congenital syphilis, although dard regimens of procaine penicillin G do not achieve transmission rates of 10% in late latent disease have been treponemicidal levels in CSF82 – 87 and CSF involvement is reported.104 Treatment in the last trimester is also associated with poorer outcomes.59,98,99,105–107 Maternal co-infection with † For infants born to mothers treated with a penicillin-based HIV may increase the transmission risk of syphilis.108–111 regimen more than four weeks prior to delivery with no evi- † A single dose of Benzathine penicillin G 2.4 MU is effective in dence of re-infection or relapse, monitoring as detailed above most cases,102,112,113 although failures have been reported in is indicated. The CDC guidelines recommend a stat dose of case reports and small series; mainly in those at increased risk Benzathine penicillin G 50,000 units/kg in this situation,48 of transmission (higher RPR/VDRL titre, early stage maternal and treatment may be indicated particularly if follow-up is disease and last trimester treatment).99,103 Physiological uncertain or if treatment was in the last trimester of preg- changes in pregnancy alter drug pharmacokinetics and may nancy following the regimens detailed below.
result in reduced penicillin concentrations.114 For this reason, † For infants born to mothers treated for syphilis prior to preg- when maternal treatment is initiated in the third trimester a nancy with serofast titres, monitoring of the infants as detailed second dose of benzathine penicillin is recommended to be in the section ‘Diagnosis of congenital syphilis’ is indicated.
given one week after the first, with careful assessment of the † Babies born to mothers treated antenatally for syphilis neonate and consideration of treatment at birth.
should be managed jointly with paediatricians.
† Re-treatment in those with a previous diagnosis of syphilis † Older siblings should be screened for congenital syphilis.
should be considered when there is uncertainty of efficacious † Congenital syphilis diagnosed in an older child or in adult- past treatment, a four-fold drop in RPR/VDRL titre has not hood should be managed as for late syphilis but the been achieved, or if the RPR/VDRL titre is serofast at greater parents, all siblings and any sexual partner(s) should be † Non-penicillin alternatives include ceftriaxone, for which there is limited data,115 and erythromycin or azithromycin. There areno studies evaluating azithromycin in pregnancy and treatment failure has been reported with erythromycin116,117 and azithro- Incubating syphilis/epidemiological treatment mycin118 with placental penetration uncertain;119,120 for thesereasons treatment of the baby at birth with penicillin is rec- (1) Benzathine penicillin G 2.4 MU i.m. single dose (III, B) ommended following maternal treatment with macrolides.
(2) Doxycycline 100 mg PO b.d.  14 days (III, B) † Desensitization to penicillin in those reporting allergies † Management should be in close liaison with obstetric, mid- Early syphilis ( primary, secondary and early latent) wifery and paediatric colleagues. Referral to fetal medicinefor ultrasound to evaluate fetal involvement including (1) Benzathine penicillin G 2.4 MU i.m. single dose55,71 (1b, A) non-immune hydrops or hepatospenomegaly and fetal (2) Procaine penicillin G 600 000 units i.m. daily  10 monitoring for fetal distress in the early stages of therapy is recommended after 26 weeks gestation. Although thereis a paucity of evidence in this area some physicians These may be required for those with penicillin allergy or refus- Herxheimer reaction in order to avoid precipitating early labour. A large epidemiological study123 reported anincrease in the risk of orofacial cleft defects in children (1) Doxycycline 100 mg PO b.d.  14 days (III, B) born to women who had received oral steroid treatment in (2) Azithromycin 2 g PO stat71 (1b, B) or Azithromycin 500 mg the first trimester of pregnancy. Clinicians should discuss the balance of possible risk to perceived benefits with (3) Erythromycin 500 mg PO q.d.s.  14 days127 (III, B) women before making a decision on use of adjunctive (4) Ceftriaxone 500 mg i.m. daily  10 days (if no anaphylaxis steroid treatment. Appropriate follow-up of babies is (5) Amoxycillin 500 mg PO q.d.s. plus Probenecid 500 mg Late latent, cardiovascular and gummatous syphilis MANAGEMENT OF INFANTS BORN TOMOTHERS WITH SYPHILIS (1) Benzathine penicillin 2.4 MU i.m. weekly for two weeks † All infants to have serial serological tests for syphilis as (2) Procaine penicillin 600,000 units i.m. o.d. for 17 days130 (III, B) detailed in the section ‘Diagnosis of congenital syphilis’and have a thorough physical examination for signs of con- genital syphilis; where these signs are suspected furtherinvestigations are indicated as detailed in the section above.
(1) Doxycycline 100 mg PO b.d. for 28 days131 (IV, C) † For infants with suspected congenital syphilis and those (2) Amoxycillin 2 g PO t.d.s. plus probenecid 500 mg q.d.s. for born to mothers treated less than four weeks prior to deliv- ery or those treated with non-penicillin regimens, or thosewho were not treated, who were inadequately treated or Neurosyphilis including neurological/ophthalmic who have no documentation of being treated, treat for congenital syphilis using the regimen detailed below.
Further investigations are indicated as detailed in the (1) Procaine penicillin 1.8 –2.4 MU i.m. o.d. plus probenecid 500 mg PO q.d.s. for 17 days48,89 (III, C) (2) Benzylpenicillin 18–24 MU daily, given as 3 –4 MU i.m.
immediate adverse reactions. In addition patients should be advised to seek urgent medical attention if they experienceshortness of breath, itchy wheals on their skin, facial swelling or tightness in their chest or throat.
(1) Doxycycline 200 mg PO b.d. for 28 days131 (IV, C) † Jarisch–Herxheimer Reaction: An acute febrile illness with (2) Amoxycillin 2 g PO t.d.s. plus probenecid 500 mg PO q.d.s.
headache, myalgia, chills and rigours and resolving within 24 hours. This is common in early syphilis but is usually (3) Ceftriaxone 2 g i.m. (with lidocaine as diluent) or i.v. (with not important unless there is neurological or ophthalmic water for injections as diluent, NOT Lidocaine) for 10 – involvement or in pregnancy when it may cause fetal dis- 14 days49,75 –77,81,134– 136 (IV, C) (if no anaphylaxis to tress and premature labour. It is uncommon in late syphilis but can potentially be life threatening if there is involvementof strategic sites (e.g. coronary ostia, larynx and nervoussystem). Prednisolone can reduce the febrile episode136 but (1) Benzathine penicillin G 2.4 MU i.m. single dose in the first Nevertheless, severe clinical deterioration in early syphilis and second trimesters (II, B). When maternal treatment is with optic neuritis and uveitis has been reported following initiated in the third trimester, a second dose of benzathine treatment and, as a steroid is also used in the management penicillin G 2.4 MU i.m. should be given after one week of these conditions unrelated to syphilis, biological plausi- bility would suggest that it may help. If cardiovascular or (2) Procaine penicillin G 600,000 unit i.m. daily  10 days (III, B) neurological involvement including optic neuritis, inpatientmanagement is advisable. Management should include anti-pyretics and reassurance. Steroids are recommended when there is neurological or cardiovascular involvement and (1) Amoxycillin 500 mg PO q.d.s. plus probenecid 500 mg PO some physicians recommend this treatment in pregnancy when additional fetal monitoring is required.
(2) Ceftriaxone 500 mg i.m. daily  10 days (III, B) W Prednisolone 40 – 60 mg daily for three days, starting anti- (3) Erythromycin 500 mg PO q.d.s.  14 days or Azithromycin treponemal treatment 24 hours after commencing predni- 500 mg PO daily  10 days plus evaluation and treatment of neonates at birth with penicillin (III, B) † Procaine reaction, (procaine psychosis, procaine mania, Hoignes syndrome): This is due to inadvertent intravenous injection of procaine penicillin. It is characterized by fear ofimpending death and may cause hallucinations or fits Manage as in non-pregnant patients but without the use of 20 minutes. Calm and verbal reassurance is required andrestraint may be necessary. If fits occur give diazepam † Anaphylactic shock: Facilities for treatment of anaphylaxis Treatment as appropriate for the stage of infection; that is, should be available as penicillin is amongst the commonest HIV-positive individuals to be given the same treatment regi- mens as HIV-negative individuals. Some experts believe that W Epinephrine (adrenaline) 0.5 mg i.m. (as 0.5 mL of 1:1000 HIV patients with syphilis should be treated as for neurosyphi- solution) followed, if necessary, by i.m./i.v. antihistamine lis to prevent the development of neurological involvement, but e.g. chlorpheniramine 10 mg and i.m./i.v. hydrocortisone hard evidence for this policy is lacking.
† Allergy: Penicillin desensitization may be considered for patients reporting penicillin allergy.121,122 Many people reporting penicillin allergy will not display hypersensitivity (1) Benzyl penicillin sodium 100,000 –150,000 units/kg daily on re-exposure to penicillin either because the hypersensi- i.v. (in divided doses given as 50,000 units/kg 12 hourly tivity has faded or they were never allergic to penicillin.
in the first 7 days of life and 8 hourly thereafter ) Â 10 A careful history may help to identify the latter group.
Skin testing to confirm allergy should precede desensitiza- (2) Procaine penicillin 50,000 units/kg daily i.m. Â 10 days (III, B) tion. Skin testing and desensitization do carry risks of ana-phylaxis and should be carried out with immediate access In children, intravenous therapy (option one here) may be pre- to resuscitation equipment and expertise.
ferable due to the pain associated with intramuscular injections(Table 2).
† All patients with a diagnosis of syphilis should have partner Patients should be warned of possible reactions to treatment.
notification discussed at the time of treatment by a trained Facilities for resuscitation should be available in the treatment area. All patients should be kept on clinic premises for 15 † For patients with primary syphilis, sexual partners within minutes after receiving their first injection to observe for the past three months should be notified as the incubation period is up to 90 days. Partner notification may have to † All patients should be offered patient and provider referral extend to two years for patients in secondary syphilis, with as a method of contacting any sexual partners. The method clinical relapse or in early latent syphilis. Of contactable agreed upon with the patient should be clearly documented.
sexual partners of patients and pregnant women withearly syphilis 46 –60% also have the infection.137,138 Manysexual contacts are met in anonymous sex venues e.g.
saunas, internet or cruising grounds,139 – 141 which makes The follow-up is in case of re-infection and relapse.
partner notification difficult. Links within high-risk venuesto provide screening and advice may prove useful.140 † For early syphilis, minimum clinical and serological (VDRL or † Epidemiological treatment for asymptomatic contacts of RPR) follow-up should be at months 1, 2, 3, 6 and 12, then six early syphilis should be considered unless partners are monthly until VDRL/RPR negative or serofast.
able to attend regularly for exclusion of syphilis.
† For late syphilis minimum serological follow-up is three † In latent syphilis strenuous attempts should be made to locate any previous serology or documented treatment which would † A sustained two bottle dilution (i.e. four-fold) or greater aid disease staging. This should then inform partner notifica- increase in the VDRL or RPR titre suggests re-infection or tion activities. Individuals with late latent syphilis are usually treatment failure. Treatment failure is characterized by unable to transmit the infection to sexual partners. Although W Four-fold or greater increase in non-treponemal test titre vertical transmission may occur at any time within 10 years of initial infection, this becomes unusual more than two years after the onset of early syphilis. It is reasonable for † CSF examination and re-treatment is indicated and should sexual partners and children born to women diagnosed with also be considered for persons whose non-treponemal test late latent syphilis of unknown duration to undergo screening titres do not decrease four-fold within 6–12 months of therapy. The majority of specialists would re-treat patients (1) Benzathine penicillin 2.4 MU i.m. single dose (2) Doxycycline 100 mg PO b.d. Â 14 days(3) Azithromycin 1 g PO stat (1) Benzathine penicillin 2.4 MU i.m. single dose (1) Doxycycline 100 mg PO b.d. Â 14 days 2.Procaine penicillin G 600 000 units i.m.
(2) Azithromycin 2 g PO stat or Azithromycin (3) Erythromycin 500 mg PO q.d.s.  14 days(4) Ceftriaxone 500 mg i.m. daily  10 days(5) Amoxycillin 500 mg PO q.d.s. plus (1) Benzathine penicillin 2.4 MU i.m. weekly for (1) Doxycycline 100 mg PO b.d. for 28 days (2) Amoxycillin 2 g PO t.d.s. plus probenecid (2) Procaine penicillin 600,000 units i.m. OD for (1) Procaine penicillin 1.8 – 2.4 MU i.m. OD plus (1) Doxycycline 200 mg PO b.d. for 28 days (2) Amoxycillin 2 g PO t.d.s. plus probenecid (2) Benzylpenicillin 18 – 24 MU daily, given as 3 – 4 MU i.v. every 4 hours for 17 days (3) Ceftriaxone 2 g i.m. OD for 10 – 14 days Treatment of early syphilis in (1) Benzathine penicillin 2.4 MU i.m. single dose (1) Amoxycillin 500 mg PO q.d.s. plus maternal treatment is initiated in the third (2) Ceftriaxone 500 mg i.m. daily  10 days (3) Erythromycin 500 mg PO q.d.s.  14 days penicillin 2.4 MU i.m. should be given after (2) Procaine penicillin G 600,000 unit i.m.
Manage as in non-pregnant patient but without Treatment as appropriate for the stage of 150,000 units/kg daily i.v. (in divided doses given as 50,000 units/kg 12 hourly in the first 7 days of life and 8 hourly thereafter ) Â 10 (2) Procaine penicillin 50,000 units/kg daily with benzathine penicillin G administered as three doses of 2 UK National Guidelines on the Management of Early Syphilis. Clinical 2.4 million units i.m. each at weekly intervals, if CSF exam- Effectiveness Group, BASHH. See http://www.bashh.org/guidelines(last accessed 20 August 2008) 3 UK National Guidelines for the Management of Late Syphilis. Clinical Specific treponemal tests may remain positive for life follow- Effectiveness Group, BASHH. See http://www.bashh.org/guidelines ing effective treatment; clear documentation is necessary to 4 Specifications for the Development of UK Guidelines on the Management of † Reinfection or relapse should be retreated preferably with Sexually Transmitted Infections and Closely Related Conditions 2005. ClinicalEffectiveness Group, BASHH. See http://www.bashh.org/documents/25/ supervised treatment schedules to ensure compliance, and sexual partners should be screened and treated.
5 Stokes JH, Beerman H, Ingraham NR. Modern Clinical Syphilology. 3rd edn.
† If the patient remains asymptomatic and the VDRL/RPR is negative or serofast at one year, the patient may be discharged.
6 Mindel A, Tovey SJ, Timmins DJ, Williams P. Primary and secondary † In those with concomitant HIV infection, initial follow-up as syphilis, 20 years’ experience. 2. Clinical features. Genitourin Med 1989;65:1–3 7 Hira SK, Patel JS, Bhat SG, Chilikima K, Mooney N. Clinical manifestations of above and then lifelong monitoring with syphilis serology at secondary syphilis. Int J Dermatol 1987;26:103 –7 least annually and in outbreak situations three monthly 8 Lejman K, Starzycki Z. Syphilitic balanitis of Follman developing after the (coinciding with HIV follow-up visits).
appearance of the primary chancre. Br J Vener Dis 1975;51:138 –40 9 Orle KA, Gates CA, Martin DH, et al. Simultaneous PCR detection of Haemphilus ducreyi, Treponema pallidum and Herpes simplex type 1 and 2 from genital ulcers. J Clin Micro 1996;34:49 –54 10 Feher J, Somogyi T, Timmer M, Jozsa L. Early syphilitic hepatitis. Lancet † Performing VDRL/RPR titre at commencement of therapy 11 Campisi D, Whitcomb C. Liver disease in early syphilis. Arch Intern Med 12 Bhorade MS, Carag HB, Lee HJ, Potter EV, Dunea G. Nephropathy of W A two dilution (four-fold) or greater titre decrease in the secondary syphilis: A clinical and pathological spectrum. JAMA VDRL/RPR within three to six months after treatment W For neurosyphilis, the CSF cell count should have decreased 13 Wetherill JH, Webb HE, Catterall RD. Syphilis presenting as an acute by six months and the CSF should be entirely normal by neurological illness. BMJ 1965;1:1157– 8 14 Willcox RR, Goodwin PG. Nerve deafness in early syphilis. Br J Vener Dis two years except for persistent positive specific tests.
W Ninety-five percent of patients with early syphilis should 15 Zwink FB, Dunlop EM. Clinically silent anterior uveitis in secondary syphilis. Trans Ophthalmol Soc UK 1976;96:148– 50 † At least 60% of contactable partners should attend for 16 Chapel TA. The signs and symptoms of secondary syphilis. Sex Transm Dis /or treatment (although while this standard 17 Gjestland T. The Oslo study of untreated syphilis: an epidemiologic may be achievable in some settings it may not be in all).
investigation of the natural course of syphilitic infection based on a restudy ofthe Boeck-Bruusgaard material. Arch Derm Venereol 1955;35(Suppl.):1 18 Hutchinson J. Syphilis. 1st ed. London: Cassell and Co, 188719 Fiumara, Lessell S. The stigmata of late congenital syphilis: an analysis of 100 patients. Sex Transm Dis 1983;10:126 –9 Members of the guidelines revision group conducted literature 20 Wheeler HL, Agarwal S, Goh BT. Dark ground microscopy of treponemal serological tests in the diagnosis of early syphilis. Sex Transm Infect reviews that included searching Medline for the years 1970– 2007 and the Cochrane library using the keywords ‘syphilis’ 21 Palmer HM, Higgins SP, Herring AJ, Kingston MA. Use of PCR in the and ‘syphilis and HIV’ plus additional MeSH headings ‘neuro- diagnosis of early syphilis in the United Kingdom. Sex Transm Infect syphilis’, ‘cardiovascular syphilis’, ‘latent syphilis’ and ‘syphilis and treatment.’ A search on EMBASE from 1996–present was 22 Koek AG, Bruisten SM, Dierdorp M, vanDam AP, Templeton K. Specific and sensitive diagnosis of syphilis using a real-time PCR for Treponema pallidum.
also conducted. Only English language papers were used.
Clin Microbiol Infect Dis 2006;12:1233–6 Previous guidelines were sought, and the 2006 CDC guidelines 23 Leslie DE, Azzato F, Karapanagiotidis T, Leydon J, Fyfe J. Development of a reviewed. The previous 2001 guidelines were used as a basis.
real-time PCR assay to detect Treponema pallidum in clinical specimens and anassessment of its performance compared with syphilis serology results. J ClinMicrobiol 2007;45:93 –6 and erratum in J Clin Microbiol 2008;46:1895 24 Zoechling N, Schluepen EM, Soyer HP, et al. Molecular detection of Treponema pallidum in secondary and tertiary syphilis. Br J Dermatol1997;136:683 –6 This guideline was commissioned and edited by the CEG of the 25 Inagaki H, Kawai T, Miyata M, et al. Gastric syphilis: polymerise chain BASHH, without external funding being sought or obtained.
reaction detection of treponemal DNA in pseudolymphomatous lesions.
Human Pathol 1996;27:761 –5 26 Muller M, Ewart I, Hansmann F, et al. Detection of Treponema pallidum in the vitreous by PCR. Br J Ophthalmol 2007;91:592 –5 27 Michelow IC, Wendel GD, Norgard MV, et al. Central nervous system infection in congenital syphilis. New Engl J Med 2002;346:1792 –8 We are grateful to Dr D Lewis, Dr K Chan, Dr D McKee, Mrs J 28 Marangoni A, Sambri V, Accardo S, et al. Evaluation of LIAISON treponema Law and Miss H Hodgson for their expert input and opinion on screen, a novel recombinant antigen-based chemiluminescence immunoassay a number of aspects of this guideline.
for laboratory diagnosis of syphilis. Clin Diagn Lab Immunol 2005;12:1231– 4 29 Yoshioka N, Deguchi M, Kagita M, et al. Evaluation of a chemiluminescent microparticle immunoassay for determination of Treponema pallidumantibodies. Clin Lab 2007;53:597 –603 30 Knight CS, Crum MA, Hardy RW. Evaluation of the LIAISON chemiluminescence immunoassay for diagnosis of syphilis. Clin Vaccine 1 The National Strategy for Sexual Health and HIV, Department of Health, 27 July 2001. See http://www.dh.gov.uk/en/consultations/ 31 Schmidt BL, Edjlalipour M, Luger A. Comparative evaluation of nine closedconsultations/DH_40846 (last accessed 20 August 2008) different enzyme-linked immunosorbent assays for determination of antibodies against Treponema pallidum in patients with primary syphilis.
infected with human immunodeficiency virus? Genitourin Med 32 Egglestone SI, Turner AJL. Serological diagnosis of syphilis. Commun Dis 59 Idsøe O, Guthe T, Willcox RR. Penicillin in the treatment of syphilis. The experience of three decades. Bull WHO 1972;47:1–68 33 Lewis DA, Young H. Testing guidelines for individual sexually transmitted 60 Eagle H, Fleischman R, Musselman AD. The effective concentration of infections – syphilis. In: Ross J, Ison C, eds. UK National Screening and Testing penicillin in vitro and in vivo for streptococci, pneumococci and Treponema Guidelines for Sexually Transmitted Infections. Sex Transm Infect 2006;82(Suppl.
61 Collart P, Borel L-J, Durel P. Significance of spiral organisms found, after 34 Anderson J, Mindel A, Tovey SJ, Williams P. Primary and secondary syphilis, treatment, in late human and experimental syphilis. Br J Vener Dis 20 years experience. 3. Diagnosis, treatment and follow-up. Genitourin Med 62 Yobs AR, Clark JW Jr, Mothershed SE, Bullard JC, Artley CW. Further 35 Hicks CB, Benson PM, Lupton GP, Tramont EC. Seronegative secondary observations on the persistence of Treponema pallidum after treatment in syphilis in a patient infected with human immunodeficiency virus (HIV) rabbits and humans. Br J Vener Dis 1968;44:116 –30 with Kaposi’s sarcoma. Ann Intern Med 1987;107:492– 5 63 Smith JL, Israel CW, McCrary JA, Harner RE. Recovery of Treponema pallidum 36 Halperin LS. Neuroretinitis due to seronegative syphilis associated with from acqueous humor removed at cataract surgery in man by passive transfer human immunodeficiency virus. J Clin Neuroophthalmol 1992;12:171 –2 to rabbit testis. Am J Ophthalmol 1968;65:242 –7 37 Geisler WM. The prozone phenomenon in syphilis testing. South Med J 64 Hardy JB, Hardy PH, Oppenheimer EH, Ryan SJ, Sheff RN. Failure of penicillin in a newborn with congenital syphilis. JAMA 1970;212:1345 –9 38 Smith G, Holman RP. The prozone phenomenon with syphilis and HIV-1 65 Yogeswari L, Chako CW. Persistence of T. pallidum and its Significance in co-infection. South Med J 2004;97:379 –82 Penicillin-treated Late Syphilis with Persistence Seroreactivity, 1972. WHO/VDT/ 39 Luger AFH. Serological diagnosis of syphilis: current methods. In: Young H, McMillan A, eds. Immunological Diagnosis of Sexually Transmitted Diseases.
66 Tramont EC. Persistence of Treponema pallidum following penicillin G therapy. Report of two cases. JAMA 1976;236:2206 –7 40 Hagendorn HJ, Kraminer-Hagendorn A, De Bosschere K, Hulstaert F, Pottel 67 Kiefer L, Rubin A, McCoy JB, Foltz EL. Placental transfer of erythromycin.
H, Zrein M. Evaluation of INNOL-LIA syphilis assay as a confirmatory test for syphilis. J Clin Microbiol 2002;40:973 –8 68 Philipson A, Sabath LD, Charles D. Transplacental passage of erythromycin 41 Siedner M, Zapitz V, Ishida M, de la Roca R, Klausner JD. Performance of and clindamycin. N Engl J Med 1973;288:1219 –21 rapid syphilis tests in venous and fingerstick whole blood specimens. Sex 69 Harshan V, Jayakumar W. Doxycycline in early syphilis: a long term follow-up. Ind J Dermatol 1982;27:119 –24 42 Wiesel J, Rose DN, Silver AL, et al. Lumbar puncture in asymptomatic late 70 Zenilman JM, Rand S, Barditch P, Pompalo AM. Asymptomatic syphilis. An analysis of benefits and risks. Arch Int Med 1985;145:465 –8 neurosyphilis after doxycycline therapy for early latent syphilis. Sex Transm 43 Hahn RD, Cutler JC, Curtis AC, et al. Penicillin treatment of asymptomatic central nervous system syphilis I. Probability of progression to symptomatic 71 Riedner G, Ruzizoka M, Todd J, et al. Single dose Azithromycin versus neurosyphilis. Arch Dermatol 1956;74:355 –66 penicillin G Benzathine for the treatment of early syphilis. N Engl J Med 44 Wohrl S, Geusau A. Neurosyphilis is unlikely in patients with late latent syphilis and a negative blood VDRL Test. Acta Derm Venereol 2006;86:335 –9 72 CDC. Brief report: Azithromycin treatment failures in syphilis infections – 45 Marra CM, Maxwell CL, Smith, et al. Cerebrospinal fluid abnormalities in San Fransisco, California, 2002 –2003. MMWR 2004;53:197 –8 patients with syphilis: association with clinical and laboratory features.
73 Lukehart SA, Godornes C, Molini BJ, et al. Macrolide resistance in Treponema pallidum in the United States and Ireland. N Engl J Med 46 Izzat NN, Bartruff JK, Glicksman JM, et al. Validity of the VDRL test on cerebrospinal fluid contaminated by blood. Br J Vener Dis 1971;47:162 –4 74 Steele RW. Ceftriaxone therapy for meningitis and serious infections. Am J 47 Larsen SA, Hambie EA, Wobig GH, Kennedy EJ. Cerebrospinal serologic test for syphilis: treponemal and non-treponemal tests. In: Morisett R, Kurstak E, 75 Marra CM, Slatter V, Tartaglione TA, et al. Evaluation of aqueous eds. Advances in Sexually Transmitted Diseases. Utrecht, The Netherlands: penicillin G and ceftriaxone for experimental neurosyphilis. J Infect Dis 48 Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines, 2006. MMWR 2006;55 (No. RR-11):22 –35 76 Hook EW III, Baker-Zander SA, Moskovitz BL, Lukehart SA, Handfield HH.
49 Castro R, Prieto ES, Aguas MJ, et al. Evaluation of the treponema particle Ceftriaxone therapy for asymptomatic neurosyphilis: case report and western agglutination technique (TPPA) in the diagnosis of neurosyphilis. J Clin Lab blot analysis of serum and CSF IgG response to therapy. Sex Transm Dis 50 Luger A, Schmidt BL, Kaulich M. Significance of laboratory findings for the 77 Hook EW 3rd, Roddy RE, Handsfield HH. Ceftriaxone therapy for diagnosis of neurosyphilis. Int J STD AIDS 2000;11:224 –34 incubating and early syphilis. J Infect Dis 1988;158:881– 4 51 Tomberlin MG, Holtom PD, Owens JL, et al. Evaluation of neurosyphilis in 78 Kaksambas A, Adoniou C, Katsarou A, Kerkidou A, Stratigos J. Comparative human immunodeficiency virus-infected individuals. Clin Infect Dis study of ceftriaxone and benzathine penicillin G in the treatment of primary and secondary syphilis. Chemiotherapia 1987;6:549 –50 52 Hollier LM, Harstad TW, Sanchez PJ, Twickler DM, Wendel GD.
79 Moorthy T, Lee C, Lim K, Tan T. Ceftriaxone for the treatment of primary Fetal syphilis: clinical and laboratory characteristics. Obstet Gynecol syphilis in man: a preliminary study. Sex Transm Dis 1987;14:116 –9 80 Dowell M, Ross P, Musher D, Cate T, Baughn R. Response of latent syphilis 53 Rawstron SA, Mehta S, Bromberg K. Evaluation of a Treponema or neurosyphilis to ceftriaxone therapy in persons infected with human pallidum-specific IgM EIA and Treponema pallidum Western blot antibody immunodeficiency virus. Am J Med 1992;93:481 –8 detection in the diagnosis of maternal and congenital syphilis. Sex Transm Dis 81 Augenbraun M, Workowski K. Ceftriaxone therapy for syphilis: report from the emerging infections network. Clin Infect Dis 1999;29:1337–8 54 Rompalo AM, Lawlor J, Seaman PPAC, Quinn TC, Zenilman JM, Hook EW.
82 Mohr JA, Griffiths W, Jackson R, Saadah H, Bird P, Riddle J. Neurosyphilis Modification of syphilitic genital ulcer manifestations by co-existent HIV and penicillin levels in CSF. JAMA 1976;236:2208 –9 infection. Sex Transm Dis 2001;28:448– 54 83 Ducas J, Robsob HG. CSF penicillin levels during therapy for latent syphilis.
55 Rolfs RT, Joesoef MR, Hendershot EF, et al. For the Syphilis and HIV Study Group. A randomised trial of enhanced therapy for early syphilis in patients 84 Polnikorn N, Witoonpanich R, Vorachit M, Vejjajiva S, Vejjajiva A. Penicillin with and without human immunodeficiency virus infection. N Engl J Med concentrations in CSF aafter different treatment regimens for syphilis. Br J 56 Bordon J, Martinez-Vazquez C, Alvarez M, et al. Neurosyphilis in 85 Goldmeier D, Waterworth PM. Penetration of penicillin into the HIV-infected patients. Eur J Clin Microbiol Infect Dis 1995;14:864– 9 cerebrospinal fluid of patients with latent syphilis. Pharmatherapeutica 57 Rompalo AM, Joesoef MR, O’Donnell JA, et al. Clinical manifestations of early syphilis by HIV status and gender: results from the syphilis and HIV 86 Lowhagen G-B, Brorson J-E, Kaijser B. Penicillin concentrations in cerebrospinal fluid and serum after intramuscular, intravenous and 58 Terry PM, Page ML, Goldmeier D. Are serological tests of value in oral administration to syphilitic patients. Acta Derm Venereol (Stockh) diagnosing and mentoring response to treatment of syphilis in patients 87 Goh BT, Smith GW, Samarasinghe L, Singh V, Lim KS. Penicillin 116 Fenton LJ, Light IJ. Congenital syphilis after maternal treatment with concentrations in serum and cerebrospinal fluid after intramuscular injection erythromycin. Obstet Gynecol 1976;47:492 –4 of aqueous procaine penicillin 0.6 MU with and without oral probenecid.
117 South MA, Short DH, Knox JM. Failure of erythromycin estolate therapy in 88 Smith CA, Kamp M, Olansky S, Price EV. Benzathine penicillin G in the 118 Zhou P, Qian Y, Xu J, Gu Z, Liao K. Occurrence of congenital syphilis after treatment of syphilis. Bull WHO 1956;15:1087 –96 maternal treatment with azithromycin during pregnancy. Sex Transm Dis 89 Dunlop EM, Al-Egaily SS, Houang ET. Production of treponemicidal concentrations of penicillin in cerebrospinal fluids. BMJ 119 Kiefer L, Rubin A, McCoy JB, et al. The placental transfer of erythromycin.
90 Van der Valk PGM, Kraai EJ, Van Voorst Vader PC, et al. Penicillin 120 Philipson A, Sabath LD, Charles D. Transplacental passage of erythromycin concentrations in cerebrospinal fluid (CSF) during repository treatment and clindamycin. N Engl J Med 1973;288:1219 –21 regimen for syphilis. Genitourin Med 1988;64:223 –5 121 Chisholm C, Katz V, McDonald T, et al. Penicillin desensitisation in the 91 Rolfs R, Joesoef MR, Hendershot EF, et al. A randomised controlled trial of treatment of syphilis during pregnancy. Am J Perinatol 1997;14:553– 4 enhanced therapy for early syphilis in patients with and without human 122 Wendel GD, Stark BJ, Jamison RB, et al. Penicillin allergy and immune deficiency virus infection. N Engl J Med 1997;337:307 –14 desensitisation in serious infections during pregnancy. N Engl J Med 92 Walter T, Lebouche B, Miailhes P, et al. Symptomatic relapse of neurologic 123 Carmichael SL, Shaw GM, Ma C, et al. Maternal corticosteroid use and syphilis after benzathine penicillin G therapy for primary or secondary orofacial clefts. Am J Obstet Gynecol 2007;197:e1 –7 syphilis in HIV-infected patients. Clin Infect Dis 2006;43:787 –90 124 Weiner AL, Wilybach CA, Ludlow CE. Ambulatory penicillin therapy of 93 Screening for Infectious Diseases in Pregnancy: Standards to Support the UK syphilis in a public health clinic –report on four hundred and two patients Antenatal Screening Programme. Department of Health, 2003 http://www.dh.
treated in 1949 and 1950. Ohio State Med J 1951;47:720 –3 gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicy 125 Pedrup A. Penicillin treatment of early syphilis. Acta Derm Venereo (Stockh) AndGuidance/DH_40509 (last accessed 20 August 2008) 94 Tsui AO, Wasserheit JN, Haaga JG, eds. Reproductive health in developing 126 Crowe G, Theodore C, Forster GE, Goh BT. Acceptability and compliance countries, expanding dimensions, building solutions. Washington DC: National with daily injections of procaine penicillin in the outpatient treatment of syphilis/treponemal infection. Sex Transm Dis 1997;24:127 –30 95 Harter CA, Benirschke K. Fetal syphilis in the first trimester. Am J Obstet 127 Fernando WL. Erythromycin in early syphilis. Br J Vener Dis 1969;45:200 –1 128 Onada Y. Clinical evaluation of amoxycillin in the treatment of syphilis.
96 Nathan L, Bohman Van R, Sanchez PJ, et al. In utero infection with Treponema pallidum in early pregnancy. Prenatal Diagn 1997;17:119 –23 129 Goldman JN. Clinical experience with ampicillin and probenecid in the 97 Bernischke K. Syphilis: the placenta and the fetus. Am J Dis Child management of treponeme-associated uveitis. Trans Acad Ophthalmol 98 Alexander JM, Sheffield JS, Sanchez PJ, Mayfield J, Wendel GD. Efficacy of 130 Hellerstrom S, Skog E. Outcome of penicillin therapy for syphilis. Acta Derm treatment for syphilis in pregnancy. Obstet Gynecol 1999;93:5–8 99 Sheffield JS, Sanchez PJ, Morris G, et al. Congenital syphilis after maternal 131 Whiteside-Yim CW, Flynn NM, Fitzgerald FT. Penetration of oral treatment for syphilis during pregnancy. Am J Obstet Gynecol doxycycline into the cerebrospinal fluid for patients with latent or neurosyphilis. Antimicrob Agents Chemother 1985;28:347 –8 100 Zenker PN, Rolfs RT. Treatment of syphilis, 1989. Revi Infect Dis 132 Morrison RE, Harrison SM, Tramout EC. Oral amoxycillin, an alternative treatment for neurosyphilis. Genitourin Med 1985;61:359 –62 101 Fiumara NJ, Fleming WL, Downing JG, Good F. The incidence of prenatal 133 Dowell ME, Ross PG, Musher DM, Cate TR, Baughn RE. Response of latent syphilis at the Boston City Hospital. N Engl J Med 1951;245:634 –40 syphilis or neurosyphilis to ceftriaxone therapy in persons infected with 102 Watson-Jones D, Changalucha J, Gumodoka B. Syphilis in pregnancy in human immunodeficiency virus. Am J Med 1992;93:481 –8 Tanzania I et al. Impact of syphilis on maternal outcome in pregnancy. J Infect 134 Patel IH, Kaplan SA. Pharmokinetic profile of ceftriaxone in man. Am J Med 103 Donders GG, Desmyter J, Hooft P, Dewet GH. Apparent failure of one 135 Shann S, Wilson J. Treatment of neurosyphilis with ceftriaxone. Sex Transm injection of benzathine penicillin G for syphilis during pregnancy in human immunodeficiency virus-seronegative African women. Sex Transm Dis 136 Gudjonsson H, Skog E. The effect of prednisolone on the Jarisch –Herxheimer reaction. Acta Derm Venereol 1968;48:15 – 8 104 Fiumara NJ. Syphilis in newborn children. Clin Obstet Gynecol 1975;18:183 –9 137 Schober PC, Gabriel G, White P, Felton WF, Thin RN. How infectious is 105 McFarlin BL, Bottoms SF, Dock BS, Isada NB. Epidemic syphilis: maternal syphilis? Br J Vener Dis 1983;59:217 –9 factors associated with congenital infection. Am J Obstet Gynecol 138 Phaosovasdi S, Snidvongs W, Tasanapradit P, et al. Treatment of sexual contacts of syphilitic pregnant women. J Med Assoc Thai 1989;72:132– 7 106 Mascola L, Pelosi R, Alexander CE. Inadeqaute treatment of syphilis in 139 Health Protection Agency North West Regional Epidemiology Service.
pregnancy. Am J Obstet Gynecol 1984;150:945 –7 Enhanced Surveillance of Syphilis in North West England. 2005 Report for the 107 Ricci J, Fojaco RM, O’Sullivan MJ. Congenital syphilis: the Universtiy of North West Region, Health Protection Agency, 2005 140 Kingston MA, Higgins SP. Audit of the management of early syphilis at Miami, Jackson Memorial Medical Centre Experience. 1986– 1988. Obstet North Manchester General Hospital. Int J STD AIDS 2004;15:352 –4 141 Simms I, Fenton K, Ashton M, et al. The re-emergence of syphilis in 108 Rawstron SA, Bromberg K. Failure of recommended maternal therapy to the United Kingdom: the new epidemic phases. Sex Transm Dis prevent congenital syphilis. Sex Transm Dis 1991;18:102 –6 109 Hook EW III, Marra CM. Acquired syphilis in adults. N Engl J Med 142 Lukehart SA, Hook EW, Baker-Zander SA, et al. Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and 110 McFarlin B, Bottoms S, Dock B, et al. Epidemic syphilis: maternal factors treatment. Ann Intern Med 1988;109:855– 62 associated with congenital infection. Am J Obstet Gynecol 1994;170:535 –40 111 Rolfs RT. Treatment of syphilis, 1993. Clin Infect Dis 1995;20(Suppl. 1):S23 –38112 Alexander JM, Sheffield JS, Sanchez JP, et al. Efficacy of treatment of syphilis in pregnancy. Obstet Gynecol 1999;93:5–8 113 Watson-Jones D, Gumodoka B, Weiss H, et al. Syphilis in pregnancy in Tanzania.II .The effectiveness of antenatal screening and single doseBenzathine penicillin treatment for the prevention of adverse pregnancy outcomes. J Infect Dis 2002;186:948 –57 114 Nathan L, Bawdon RE, Sidawi JE, Stettler RW, McIntire DM, Wendel GD Jr.
† Acquiring Procaine Penicillin G and Benzathine Penicillin G: Penicillin levels following the administration of benzathine penicillin G in Refer to the BASHH website for guidance (2006) on obtain- pregnancy. Obstet Gynecol 1993;82:338 –42 ing supplies of Procaine Penicillin G and Benzathine 115 Zhou P, Gu Z, Xu J, Wang X, Liao K. A study evaluating ceftriaxone as a treatment agent for primary and secondary syphilis in pregnancy. Sex Transm Penicillin G: http://www.bashh.org/guidelines/penicillin_ † Administering Benzathine penicillin intramuscularly can be The solution should be administered by deep intramuscular very painful for patients, this may be substantially improved by using lidocaine as the diluent: (Protocol from Manchester Solutions in Lidocaine MUST NOT be administered Centre for Sexual Health courtesy of Matron Helen Inadvertant intravenous administration of Lidocaine can cause the patient to suffer bradycardia (which may lead to cardiac arrest), fitting This protocol is to be used for the reconstitution of Benzathine and/or sedation. Use the ‘aspiration technique’ of injection to mini- penicillin for the treatment of syphilis.
Dose: 2.4 Mega units i.m. weekly for up to 3 weeksPresentation: Powder for solution for injectionContraindications:Allergy to penicillin or lignocaine Lidocaine as a diluent for administration of benzathine penicil- lin G. Pediatr Infect Dis J 1998;17:890–3 Precautions: Cross allergy to other beta-lactams such as cephalosporins should be taken into account.
Administration: To reduce the pain experienced by patients receiving this injection, 1% lidocaine (lignocaine) can be used as an alternative diluent to water for injections (unlicensedindication).
Clinical Effectiveness Group, British Association for Sexual Health and HIV: Keith Radcliffe (Chair), Imtyaz Ahmed- Hydrochloride BP solution. Split the resultant solution into Jushuf, David Daniels, Mark FitzGerald, Neil Lazaro, Gill

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