Syphilis: Treatment and follow-up

This guide is about management of primary, secondary, latent and tertiary syphilis. Some information about neurosyphilis and congenital syphilis is included, however their treatment is outside the scope of this document. Individuals with these conditions should be managed by or in consultation with an infectious disease specialist or an experienced colleague.

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Management and treatment

T. pallidum is highly sensitive to penicillin and the bacteria are rendered non-infectious on average within 24 hours of treatment with long-acting (LA) benzathine penicillin G. Long-acting benzathine penicillin is required to adequately treat infectious syphilis and achieve detectable serum levels of penicillin for two (2) to four (4) weeks in non-pregnant adults. A longer course of treatment is required to cure infections of longer duration (late latent and/or tertiary syphilis).

Short acting penicillin agents are not adequate to cure syphilisFootnote 1. Although treatment regimens containing daily IM procaine penicillin for 10 to 14 days are as effective as those containing benzathine penicillin G-LA, benzathine penicillin G-LA is preferred because less frequent dosing (weekly) usually results in better adherence.

People who are treated with alternative treatments (e.g. doxycycline, ceftriaxone) may take longer to become non-infectious. These individuals should be advised to abstain from condomless sexual contact until treatment has been completed and ideally for seven (7) days after completion of treatment. The efficacy data supporting the use of these agents are limited and as such, they should only be used in exceptional circumstances and when close client follow-up is assured.

There are limited data to definitively guide management decisions in people with HIV with early syphilis. Based on the serologic response to treatment, available data suggest that these individuals should receive the same treatment as people without HIV and that they will respond appropriately to single dose benzathine penicillin G-LA. Some experts recommend three (3) weekly doses (total of 7.2 million units) of benzathine penicillin G-LA in HIV-positive individuals.

Note: To avoid unnecessary retreatment, obtain and document prior history of treatment for syphilis and prior serologic results.

Treatment

The following treatment options are recommended in the absence of contraindication. Consult product monographs for contraindications and side effects.

Recommended treatment of syphilis in non-pregnant adults
Stage Preferred treatment Alternative treatment for people with penicillin allergies
Primary,
secondary and
early latent syphilis
Benzathine penicillin G-LA 2.4 million units IM as a single dose [A-II]Footnote 2,Footnote 3,Footnote 4,Footnote 5,Footnote 6,Footnote 7.
  • Doxycycline 100 mg PO BID for 14 days [B-II]Footnote 8,Footnote 9
  • In exceptional circumstances and when close follow-up is assured:
    • Ceftriaxone 1 g IV or IM daily for 10 days [B-II]Footnote 10
Latent, late latent, cardiovascular syphilis and gumma Benzathine penicillin G-LA 2.4 million units IM weekly for three (3) doses [AII]Footnote 11,Footnote 12
  • Consider penicillin desensitization
    • Doxycycline 100 mg PO BID for 28 days [B-II]Footnote 13
  • In exceptional circumstances and when close follow-up is assured:
    • Ceftriaxone 1 g IV or IM daily for 10 days[C-III]Footnote 14
All adults: Neurosyphilis
  • Refer to a neurologist or infectious disease specialist

Pregnant and lactating females

A single dose of benzathine penicillin G-LA is effective in most cases of early syphilisFootnote 2. Some experts recommend that primary, secondary and early latent cases be treated with two (2) doses of benzathine penicillin G-LA 2.4 million units one (1) week apart, particularly in the third trimesterFootnote 15. This is because of:

The effectiveness of additional doses to prevent fetal syphilis is not known. Retreatment during pregnancy is not necessary unless there is clinical or serologic evidence of new infection (four-fold rise in a NTT titre), serologic evidence of inadequate treatment response or history of recent sexual contact with a person with infectious syphilisFootnote 2,Footnote 17,Footnote 18.

Manage people diagnosed with infectious syphilis during pregnancy in consultation with an obstetric/maternal-fetal specialist.

Recommended treatment for infectious syphilis in pregnancy
Preferred treatment Alternative treatment for people with penicillin allergies
Benzathine penicillin G-LA 2.4 million units IM as a single dose [B-II]
or
Benzathine penicillin-LA G 2.4 million units IM as a single dose weekly for two (2) doses [C-III]
  • Strongly consider penicillin desensitization followed by treatment with penicillin [A-lll]
  • There is no satisfactory alternative to penicillin for the treatment of syphilis in pregnancy. Insufficient data exist to recommend ceftriaxone in pregnancy

Congenital syphilis

All babies born to mothers diagnosed with syphilis should ideally be assessed at delivery by an infectious disease specialist. If a specialist is not available, consult an experienced colleague knowledgeable in the treatment of congenital syphilis.

Infants should be treated at birth if:

For treatment recommendations in congenital syphilis or in babies born to mother with reactive syphilis serology, refer to the Canadian Paediatric Society article Congenital syphilis: no longer just of historic interest.

Special considerations

Inform your clients of a possible Jarisch-Herxheimer reaction to treatment with penicillinFootnote 19,Footnote 20. This reaction includes acute febrile illness with headache, myalgia, chills and rigors. It may occur as early as two (2) hours after treatment and generally resolves within 24 hours. This reaction is more common in secondary syphilis (70% to 90%) but can occur at any stage of infection. It is not usually clinically significant unless there is neurologic or ophthalmic involvement, or in pregnancy because it may cause fetal distress and premature labour.

Persistent and recurrent infection

There are no universally accepted criteria for defining re-infection, however a rising NTT after treatment may indicate treatment failure or re-infection. If treatment failure is suspected (e.g. RPR ≥1:32 dilutions), further investigation (including CSF examination) may be needed.

A persistent, low CSF-VDRL titre after a course of treatment may require retreatment, but if CSF pleocytosis and elevated protein levels have resolved and serum RPR titre has not risen, additional treatment is unneccessaryFootnote 21.

The risk of treatment failure in congenital syphilis increases with sonographic signs of fetal syphilis. Fetal ultrasonographic abnormalities and treatment failure in pregnancies of less than 20 weeks gestation are rare. Treatment failures have been reported with an increase in time from infection to treatment, infection acquired in the third trimester or high RPR titres (≥1:32 dilutions). If the ultrasound is normal, treat on an outpatient basis and advise the person to seek medical attention promptly if they experience fever, decreased fetal movement or regular contractions within 24 hours of treatment.

Discuss treatment options for people with treatment failure with a colleague experienced in this area.

Counselling

Advise people who are treated with single dose benzathine penicillin G -LA to abstain from condomless sexual contact for seven (7) days post treatment to provide a margin of safety.

Note: People who are treated with doxycycline or ceftriaxone may take longer to become non-infectious. Advise them to abstain from condomless sexual contact until treatment has been completed and ideally for seven (7) days after completion of treatment.

Follow-up

Post treatment serology

Treatment response is evaluated based on the clinical picture and NTT titre changes. Monitor NTTs at intervals until they revert to negative or are at a stable low titre (e.g. ≤1:4 dilutions). The rate of titre decline may vary following treatment and is dependent on syphilis stage and treatment providedFootnote 22. Repeat testing is not required if the baseline or follow-up NTT becomes non-reactive but may be considered in HIV-infected individuals or in recent exposures to syphilis (e.g. early primary syphilis). 

To ensure that NTT titre is not rising, some experts recommend follow-up testing start one (1) month after treatment for those with primary, secondary, early latent syphilis and for those co-infected with HIV. 

Recommended serological test follow-up after treatment
Stage Frequency of post treatment serology test
Primary, secondary and early latent
  • 3, 6 and 12 months
Late latent and tertiary syphilis (except neurosyphilis)
  • 12 and 24 months
Neurosyphilis
  • 6, 12 and 24 months
Co-infected with HIV
  • 3, 6, 12 and 24 months and yearly thereafter regardless of stage

Base post treatment serology testing in previously treated pregnant people on the stage and time of previous treatment. Additional testing may be warranted if the stage of diagnosis is uncertain or there are concerns about re-infection.

People treated during pregnancy
Stage Frequency of post treatment serology test
Primary, secondary and early latent syphilis
  • Monthly until delivery if at high risk of re-infection
  • 1, 3, 6 and 12-months post treatment
Late latent syphilis
  • At time of delivery and 12 and 24 months

For recommendations on serology testing in congenital syphilis or in babies born to mothers with reactive syphilis serology, refer to the Canadian Paediatric Society article Congenital syphilis: no longer just of historic interest.

Note: Always collect and disclose relevant health information according to provincial/territorial requirements. This is especially important when a child is born to a mother who was diagnosed with syphilis during pregnancy and the child is placed under the care of child protection services. In these cases, medical information about the mother's diagnosis may be critical to the ongoing protection and monitoring of the infant's health.

Adequate serologic response in infectious syphilis

Serologic decline in NTT following treatment is variable and definitive criteria for cure or treatment failure have not been well established. Serologic response to treatment depends on several factors:

Most people with reactive TT will have reactive tests for the remainder of their lives, regardless of treatment or disease activity. However, 15% to 25% of those treated during the primary stage will revert to being serologically non-reactive after two (2) to three (3) yearsFootnote 25.

 
Stage Adequate serologic response

Primary syphilis

  • 4-fold drop at 6 months
  • 8-fold drop at 12 months
Secondary syphilis
  • 8-fold drop at 6 months
  • 16-fold drop at 12 months
Early latent syphilis
  • 4-fold drop at 12 months

Post treatment CSF examination

People with neurosyphilis and abnormal CSF examinations should have close follow-up after treatment completion, including repeat lumbar puncture (usually repeated every six (6) months), until CSF parameters normalize.

CSF pleocytosis is usually the first measure of improvement and should occur over approximately six (6) monthsFootnote 26. Elevated protein levels, if present, will usually begin to decline during the first six (6) months but may take up to two (2) years to normalize. CSF protein may decline more slowly in people who are neurologically abnormal compared with those who are neurologically normalFootnote 27.

The CSF-VDRL titre should decline (four-fold within a year) if it is initially high, but it may take years to revert to negativeFootnote 26. A persistent, low CSF-VDRL titre after a course of treatment may warrant retreatment, but if CSF pleocytosis and elevated protein levels have resolved and serum RPR titre has not risen, additional treatment is unlikely to be beneficialFootnote 21.

All CSF lab parameters normalize more slowly in people co-infected with HIVFootnote 27. Consider the possibility of treatment failure if there is clinical progression, an increase in RPR by ≥2 dilutions or CSF pleocytosis fails to resolve. Treatment options for people with treatment failure should be discussed with a colleague experienced in this area.

Reporting and partner notification

National/provincial/territorial notification

Infectious syphilis (primary, secondary and early latent syphilis) is reportable in all provinces and territories and notifiable to the Public Health Agency of Canada. Non-infectious syphilis (late latent, cardiovascular and neurosyphilis) may be reportable at the provincial/territorial level.

Partner notification

Case finding and partner notification are critical to the control of syphilis. Notify, clinically evaluate/assess and test all sexual or perinatal contacts within the following time periods. Treat sexual or perinatal contacts if their serology is reactive. Trace-back period refers to the time period prior to symptom onset or date of specimen collection (if asymptomatic).

People diagnosed with syphilis and partners should abstain from condomless intercourse until treatment of the index case and (if indicated) all current partners is complete and ideally for seven (7) days after completion of treatment.

Stage Trace back period

Primary syphilis

  • 3 months

Secondary syphilis

  • 6 months

Early latent syphilis

  • 1 year

Late latent/tertiary

  • Assess other long-term partners and children as appropriate. The decision to test these contacts depends on estimated duration of infection in the index case. If the stage in the index case is undetermined, consult a colleague experienced in syphilis management

Extend the length of time for partner notification to include additional time up to the date of treatment as follows:

Strongly consider epidemiological treatment for sexual contacts of primary, secondary and early latent syphilis cases from the previous 90 days, especially if they may be lost to follow-up, unable to test or follow up of the contact is not feasibleFootnote 28.  Epidemiological treatment of infectious syphilis may be appropriate if the person is likely to be within the incubation period.

Epidemiological treatment recommendation

Benzathine penicillin G-LA 2.4 million units IM as a single dose [B-II]

References

Footnote 1

Peter G, Dudley MN. Clinical pharmacology of benzathine penicillin G. Pediatr Infect Dis J. 1985;4(5):586-591.

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Footnote 2

Clement ME, Okeke NL, Hicks CB. Treatment of syphilis: A systematic review. JAMA. 2014;312(18):1905-1917.

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Footnote 3

Ganesan A, Mesner O, Okulicz JF, et al. A single dose of benzathine penicillin G is as effective as multiple doses of benzathine penicillin G for the treatment of HIV-infected persons with early syphilis. Clin Infect Dis. 2015;60(4):653-660. doi: 10.1093/cid/ciu888 [doi].

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Footnote 4

Cousins D, Taylor M, Lee V. The outcome of treatment of early syphilis with different benzathine penicillin regimens in HIV-infected and-uninfected patients. Int J STD AIDS. 2012;23(9):632-634.

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Footnote 5

Knaute DF, Graf N, Lautenschlager S, Weber R, Bosshard PP. Serological response to treatment of syphilis according to disease stage and HIV status. Clinical infectious diseases. 2012;55(12):1615-1622.

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Footnote 6

Tittes J, Aichelburg MC, Antoniewicz L, Geusau A. Enhanced therapy for primary and secondary syphilis: A longitudinal retrospective analysis of cure rates and associated factors. Int J STD AIDS. 2013;24(9):703-711.

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Footnote 7

Niragira O, Ha S, Pogany L, Singh A. Update on STIs: Benzathine penicillin G for the management of early syphilis among HIV co-infected persons: A systematic review. Canada Communicable Disease Report. 2016;42(2):30.

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Footnote 8

Harshan V, Jayakumar W. Doxycycline in early syphilis: A long term follow up. Indian J Dermatol. 1982;27(4):119-124.

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Footnote 9

Ghanem KG, Erbelding EJ, Cheng WW, Rompalo AM. Doxycycline compared with benzathine penicillin for the treatment of early syphilis. Clinical Infectious Diseases. 2006;42(6):e45-e49.

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Footnote 10

Moorthy TT, Lee CT, Lim KB, Tan T. Ceftriaxone for treatment of primary syphilis in men: A preliminary study. Sex Transm Dis. 1987;14(2):116-118.

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Footnote 11

Rolfs RT. Treatment of syphilis, 1993. Clin Infect Dis. 1995;20 Suppl 1:S23-38.

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Footnote 12

Augenbraun MH, Rolfs R. Treatment of syphilis, 1998: Nonpregnant adults. Clin Infect Dis. 1999;28 Suppl 1:S21-8. doi: 10.1086/514724 [doi].

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Footnote 13

Onoda Y. Therapeutic effect of oral doxycycline on syphilis. Br J Vener Dis. 1979;55(2):110-115.

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Footnote 14

Augenbraun M, Workowski K. Ceftriaxone therapy for syphilis: Report from the emerging infections network. Clinical infectious diseases. 1999;29(5):1337-1338.

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Footnote 15

Donders GG, Desmyter J, Hooft P, Dewet HG. Apparent failure of one injection of benzathine penicillin G for syphilis during pregnancy in human immunodeficiency virus-seronegative african women. Sex Transm Dis. 1997;24(2):94-101.

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Footnote 16

Dabis R, Radcliffe K. Is it useful to perform a chest X-ray in asymptomatic patients with late latent syphilis? Int J STD AIDS. 2011;22(2):105-106.

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Footnote 17

Walker G. Antibiotics for syphilis diagnosed during pregnancy. Cochrane Database of Systematic Reviews. 2001(3):1-22.

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Footnote 18

Wendel Jr GD, Sheffield JS, Hollier LM, Hill JB, Ramsey PS, Sánchez PJ. Treatment of syphilis in pregnancy and prevention of congenital syphilis. Clinical Infectious Diseases. 2002;35(Supplement_2):S200-S209.

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Footnote 19

De Santis M, De Luca C, Mappa I, et al. Syphilis infection during pregnancy: Fetal risks and clinical management. Infect Dis Obstet Gynecol. 2012;2012.

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Footnote 20

See S, Scott EK, Levin MW. Penicillin-induced jarisch-herxheimer reaction. Ann Pharmacother. 2005;39(12):2128-2130. doi: aph.1G308 [pii].

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Footnote 21

Jordan KG. Modern neurosyphilis--a critical analysis. West J Med. 1988;149(1):47-57.

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Footnote 22

Lukehart SA. Serologic testing after therapy for syphilis: Is there a test for cure? Ann Intern Med. 1991;114(12):1057-1058.

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Footnote 23

Ghanem KG, Erbelding EJ, Wiener ZS, Rompalo AM. Serological response to syphilis treatment in HIV-positive and HIV-negative patients attending sexually transmitted diseases clinics. Sex Transm Infect. 2007;83(2):97-101. doi: sti.2006.021402 [pii].

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Footnote 24

Sena AC, Wolff M, Martin DH, et al. Predictors of serological cure and serofast state after treatment in HIV-negative persons with early syphilis. Clinical infectious diseases. 2011;53(11):1092-1099.

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Footnote 25

Romanowski B, Sutherland R, Fick GH, Mooney D, Love EJ. Serologic response to treatment of infectious syphilis. Ann Intern Med. 1991;114(12):1005-1009.

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Footnote 26

Dattner B, Thomas EW, De Mello L. Criteria for the management of neurosyphilis. Am J Med. 1951;10(4):463-467.

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Footnote 27

Marra CM, Longstreth Jr W, Maxwell CL, Lukehart SA. Resolution of serum and cerebrospinal fluid abnormalities after treatment of neurosyphilis: Influence of concomitant human immunodeficiency virus infection. Sex Transm Dis. 1996;23(3):184-189.

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Footnote 28

Hook EW, Stephens J, Ennis DM. Azithromycin compared with penicillin G benzathine for treatment of incubating syphilis. Ann Intern Med. 1999;131(6):434-437.

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