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Syphilis Treatment is usually with

Syphilis is a treatable and curable infection. Penicillin given by injection is the drug of choice; it effectively cures a person with syphilis in the early stage and prevents further organ damage in the late stages. Thereafter routine monitoring of blood every six months for up to two years is needed to ensure adequate treatment.





Parenteral penicillin G (aqueous crystalline, aqueous procaine, or benzathine) is the drug of choice for treating all stages of syphilis. If the patient is allergic to penicillin, tetracycline, doxycycline, azithromycin and erythromycin are the alternatives. However, they do not have the established and well-evaluated high rate of success of penicillin.

Early Syphilis

Primary syphilis
Secondary syphilis
Latent syphilis of less than 1 year’s duration

Recommended Regimens

  1. Benzathine Penicillin G 2.4 million units i/m weekly x single dose [III, B]
  2. Procaine Penicillin G 600,000 units i/m daily x 10 days [III, B]

Penicillin-allergic patients

  1. Doxycycline 100 mg orally bid x 14 days [III, B]
  2. Tetracycline 500 mg orally qid x 14 days [III, B]
  3. Erythromycin 500 mg orally qid x 14 days [III, B]
  4. Azithromycin 500 mg orally od x 10 days [IV, C]
  5. Ceftriaxone 500 mg i/m od x 10 days [IV, C] (limited data only; note low risk of possible cross reaction with penicillin).

For HIV-infected individuals, we recommend the same treatment regimens as those who are HIV negative (see section on infection in HIV infected individuals) [IV, C]

Late Syphilis (excluding neurosyphilis)

Latent syphilis of more than 1 year’s duration, or of unknown duration
Late benign syphilis
Cardiovascular syphilis

Recommended Regimens

  1. Benzathine penicillin G 2.4 million units i/m weekly x 3 doses [III, B] (7.2 million units total)
  2. Procaine penicillin G 600,000 units i/m daily x 17-21 days [III, B]

Penicillin-allergic patients (close follow-up required)

  1. Doxycycline 100 mg orally bid x 28 days [IV, C]
  2. Tetracycline 500 mg orally qid x 28 days [IV, C]
  3. Erythromycin 500 mg orally qid x 28 days [IV, C]

Neurosyphilis, ocular and otologic syphilis

A high sustained blood level of penicillin is required for adequate penetration of the blood- brain barrier in the treatment of neurosyphilis.
Patients with syphilis and the following should have CSF examination:

  • Neurologic, cognitive, auditory or ophthalmic symptoms and signs
  • Evidence of active tertiary syphilis (e.g. aortitis, gumma, iritis)
  • Treatment failure

Some experts recommend CSF examination in HIV infection with late syphilis or syphilis of unknown duration (some experts would treat all HIV positive syphilis with neurosyphilis regimens) but newer evidence suggests that treatment outcomes are not significantly altered.

The CSF findings in neurosyphilis are:

  • Increased mononuclear cell count (>5 cells/mm3)
  • Increased total protein (>0.4 g/I)
  • Positive CSF VDRL (negative in about 20%)
  • Positive CSF LIA

Recommended Regimens

  1. Procaine penicillin G 2.4 million units i/m daily x 10 days with Probenecid 500 mg orally qid x 10 days followed by Benzathine penicillin G 2.4 mega units i/m weekly x 3 doses [III, B]
  2. Crystalline Benzyl penicillin 3 to 4 million units i/v every 4 hours (total 18 to 24 million units a day) x 10 days followed by Benzathine Penicillin G 2.4 million units i/m weekly x 3 doses [III, B]

Penicillin-allergic patients

RAST tests, skin testing and desensitisation should be performed in consultation with an expert.
Penicillin is the drug of choice unless really contraindicated.

  1. Doxycycline 100 mg orally bid x 28 days [IV, C]
  2. Tetracycline 500 mg orally qid x 28 days [IV, C]
  3. Erythromycin base or stearate 500mg orally qid x 28 days (least effective) [IV, C]

Doxycycline is the preferred oral alternative in view of its more favourable dosing intervals.

Oral corticosteroid cover

This is to minimize the effects of the Jarisch-Herxheimer reaction that may occur 4 to 12 hours after the first dose of antibiotic therapy and is indicated in the following situations where the reaction may result in morbidity or even mortality:

  • Laryngeal gumma
  • Cardiovascular syphilis
  • Neurosyphilis

Recommended Regimen

Prednisolone orally 20 mg tid (60mg/day) for 24 hours before treatment and continued for 2 days after starting therapy [IV, C].


Quantitative nontreponemal tests should be repeated for a total period of two years (at 3 months; 6 months; 12 months; 18 months; 24 months).

Following treatment of early syphilis, VDRL/RPR should demonstrate a 4 x (2 dilutions) decrease in titre within 6 months. Failure to do so probably means treatment failure, and is an indication for retreatment with 3 injections of Benzathine penicillin. Some experts recommend CSF examination.

Clinical signs that persist or recur, or a rising VDRL/RPR titre of 4 x or more suggests either reinfection or relapse. In these situations CSF examination is recommended before retreatment. Seroreversion in primary syphilis often occurs within 12 months; it may take a longer time for secondary and early latent syphilis, but usually occurs within 24 months. Following treatment of late syphilis, seroreversion occurs rarely; a stable, low titre, serological scar, is the result in most patients.

All patients treated for neurosyphilis should be followed up for life at 6-month intervals. If CSF pleocytosis was present initially, CSF examinations should be repeated every 6 to 12 months until the cell count returns to normal. Serologic tests for HIV should be performed 3 months after the last risky exposure.


At risk partners are those who have been exposed within the following periods – 3 months plus duration of symptoms for primary syphilis, 6 months plus duration of symptoms for secondary syphilis, and 1 year for early latent syphilis.

Epidemiologic treatment should be given to sexual contacts who were exposed 3 months prior to the diagnosis of primary, secondary or early latent syphilis, if follow-up is uncertain. Sexual partners of late syphilis should be screened and evaluated for syphilis, and treated on the basis of these findings.

Epidemiologic treatment can be given as follows

  1. Benzathine Penicillin G 2.4 million units i/m weekly x single dose [III, B]
  2. Doxycycline 100 mg orally bid x 14 days [III, B]
  3. Azithromycin 1 g orally stat [III, B]

Syphilis in pregnancy

All pregnant women should have serological tests for syphilis at the first antenatal visit. This should be repeated in women who have high-risk behaviour or have spouses who have high-risk behaviour.

Penicillin should be used in dosage schedules appropriate for the stage of syphilis as recommended for the treatment of non-pregnant patients. A Jarisch-Herxheimer reaction may precipitate premature labour or foetal distress; women should be advised to seek obstetric care if abnormal contractions and decreased foetal movements occur.

For penicillin-allergic patients, give erythromycin in dosage schedules appropriate for the stage of syphilis as recommended for the treatment of non-pregnant patients. However, as erythromycin exhibits poor penetration across the placental barrier, the infant should be routinely treated with penicillin at birth. For these patients, retreatment with doxycycline can be considered after delivery when breastfeeding has been stopped.

Ceftriaxone 500 mg i/m od x 10 days and Azithromycin 500 mg orally od x 10 days (limited data only) have been tried.

Tetracyclines are contraindicated in pregnancy. Pregnant woman treated for early syphilis should have monthly RPR/VDRL for the remainder of the current pregnancy.

Children with acquired syphilis

Birth and maternal records should be reviewed to exclude congenital syphilis.

Primary, Secondary and Early Latent Syphilis

Benzathine penicillin G 50,000 units/kg i/m, up to adult dose of 2.4 mega units in single dose.

Late latent syphilis, latent syphilis of unknown duration, late syphilis (not neurosyphilis)

Benzathine penicillin G 50,000 units/kg i/m, up to adult dose of 2.4 mega units, administered as three doses at 1 week intervals (total 150,000 units/kg up to adult dose of 7.2 million units).


Aq. Crystalline Penicillin G 50,000 unit/kg i/v every 4-6 hours (total 200,000 – 300,000 unit/ kg/day) for 10 days.

Congenital Syphilis

Diagnosis and treatment decisions must be based on

  1. Identification of syphilis in the mother.
  2. Adequacy of maternal treatment.
  3. Clinical, laboratory, radiological evidence of syphilis in the infant.
  4. Comparison of the infant’s VDRL/RPR result with the mother’s.

Who should be evaluated?

Infants should be evaluated if they have been born to seropositive mothers who –

  • have untreated syphilis
  • were treated for syphilis < 1 month before delivery
  • were treated for syphilis during pregnancy with a non-penicillin regimen
  • did not have the expected decrease in non-treponemal antibody (RPR or VDRL) titres after treatment for syphilis
  • were treated but had insufficient serologic follow-up during pregnancy to assess disease activity

Evaluation is not required if both these criteria are met –

  • Mother had well-documented history of treatment in pregnancy with a penicillin regime appropriate for the stage of syphilis
  • Mother has sufficient serologic follow-up after treatment to show that she responded to treatment (≥ 4 fold decrease in RPR/VDRL titre in early syphilis; stable or declining titres of ≤ 1:4 in other patients)

Some experts would treat the infant with a single dose of Benzathine Penicillin 50,000 units/ kg i/m; others would not but instead provide close serologic follow-up. If the infant’s RPR/ VDRL is non-reactive, no treatment is needed.

What to evaluate in the infant?

  • Thorough physical examination
  • Infants blood – RPR/VDRL, LIA IgM or EIA IgM on the serum – if available
  • DG or DIF microscopy of suspicious lesions or body fluids
  • Other tests as clinically indicated (e.g. long bone and chest X-rays, FBC)

When to treat infants?

  • Positive syphilis serology with evidence of active disease (physical examination or X-ray)– rhinitis, mucocutaneous signs, hepatosplenomegaly, osteitis, periostitis, osteochondritis, glomerulonephritis, ascites, stigmata
  • A reactive CSF-VDRL
  • An abnormal CSF finding (WBC >5/cmm or protein >50mg/ml) regardless of CSF VDRL titre
  • A detectable LIA IgM in the infant
  • VDRL titre in the infant is fourfold or greater than in the mother
  • VDRL titres in the infant show a serial rise
  • Treatment of the mother was inadequate or unknown (adequate maternal treatment means full dosage of penicillin at least 1 month before delivery)
  • Drugs other than penicillin e.g. erythromycin was used to treat the mother during pregnancy

Recommended Regimens

  1. Crystalline Penicillin G 50,000 units/kg/day i/v daily every 12 hours (total 100,000 to 150,000 units/kg/day) during the first 7 days of life, and every 8 hours thereafter for a total of 10 days [III, B]
  2. Procaine Penicillin G 50,000 units/kg i/m daily single dose x 10 days [III, B]
  3. Benzathine penicillin 50,000 units i/m single dose may be used if the infant’s evaluation is normal and follow-up is certain; however if any part of the evaluation is abnormal, not done or cannot be interpreted, a 10 day course of penicillin is needed [IV, C]


Seroreactive infants and infants whose mothers were reactive at delivery should be followed up every 2-3 months until the test becomes nonreactive or the titre falls fourfold; the RPR/ VDRL should fall by 3 months of age and be nonreactive by 6 months of age if the infant was not infected (passive transfer) or if treatment was adequate. Treatment after the neonatal period may result in a slower decline of titres.

Passively transferred treponemal antibodies may be present in the infant for 15 months, the presence of a reactive treponemal test after 18 months indicates congenital syphilis, and the infant should be (re)evaluated.

Congenital syphilis in older infants and children

  • Review maternal serology and records if congenital syphilis is possible
  • Full evaluation including CSF examination, eye and auditory examination, X-rays etc.

Recommended Regimens

  1. crystalline penicillin G 200,000-300,000 units/kg/day i/v (administered as 50,000 units/kg every 4-6 hours) for 10 days [IV, C]
  2. Procaine Penicillin G 50,000 units/kg i/m daily single dose x 10 days [IV, C]

Treatment of syphilis in a HIV infected person

Serological tests for syphilis are generally reliable in HIV co-infection. Some authorities recommend routine CSF examination and/or treatment for neurosyphilis for all patients, regardless of the stage of syphilis. However, most HIV-infected persons respond appropriately to standard benzathine penicillin for primary and secondary syphilis. CSF abnormalities (e.g. mononuclear pleocytosis and elevated protein levels) are common in HIV-infected persons, even in those without neurologic symptoms, although the clinical and prognostic significance of such CSF abnormalities with primary and secondary syphilis is unknown. Several studies have demonstrated that among persons infected with both HIV and syphilis, clinical and CSF abnormalities consistent with neurosyphilis are associated with a CD4 count of ≤350 cells/ mL and/or an RPR titer of ≥1:32; however, unless neurologic symptoms are present, CSF examination in this setting has not been associated with improved clinical outcomes.

A lumbar puncture is recommended for HIV patients with syphilis if there are any neurological abnormalities, or if titres do not decline after penicillin therapy. All HIV patients should be treated wherever possible with penicillin.
Some experts recommend treatment in the same doses as for HIV-negative patients, while others would treat all HIV-infected patients with the neurosyphilis regimen [IV, C].

We recommend that all HIV-infected patients without evidence of neurosyphilis be given doses of benzathine penicillin that are appropriate for the stage of syphilis as in non HIV patients.
However, it is more important to monitor for treatment failures in these patients.
Such patients should be followed-up clinically and with nontreponemal tests at 3, 6, 9, 12 and 24 months after treatment.


Best to refer to a specialist.
Indications –

  • Clinical signs and symptoms of syphilis persist or recur (clinical relapse)
  • Four-fold or greater rise in VDRL/RPR titre e.g. from R4 to R16 (serological relapse)
  • Initial high VDRL/RPR titre e.g. R32 or greater persists for a year (sero-fast)
  • Failure of VDRL/RPR titre to decrease four-fold after a year for treated early syphilis
  • For pregnant women treated for early syphilis, the failure to show a four-fold decrease in VDRL/RPR titre after 3 months.



Syphilis treatment:

Sexual risk (of HIV/STD/pregnancy), and what you can do before and after exposure.
Timeline HIV STD Pregnancy
Before exposure
Abstain from sex, Be faithful, or Condom use
Circumcision (males only)
Contraception (females only)
HIV PrEP (pre-exposure prophylaxis) - Stop HIV infection before exposure STD vaccine: - Hepatitis vaccine - HPV vaccine
STD / HIV exposure
Unsafe sex / unprotected sex: No condom / Condom broke / Condom slip
0-72 hours HIV PEP (post-exposure prophylaxis) - Stop HIV infection after exposure STD testing * - Screening test - to look for asymptomatic infections - from previous exposures Emergency contraception with the morning-after pill (females only)
2 weeks HIV DNA Test
1 month HIV 4th Generation Test - SD Bioline HIV Ag/Ab Combo - Fingerprick blood sampling. - 20 minutes to results
3 months HIV 3rd Generation Test - OraQuick® HIV-1/2 Antibody - Oral fluid or - Fingerprick blood sampling. - 20 minutes to results STD testing * - Full & comprehensive - diagnostic test - to look for current infections
Watch for HIV Symptoms STD Symptoms
If infected HIV Treatment STD Treatment Abortion
* Males: Do not urinate for at least 4 hours before arriving. * Females: testing is more accurate when you are not menstruating.


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