Syphilis management for primary and secondary stages

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]

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Parenteral penicillin G has been an effective regimen to achieve clinical resolution and to prevent late sequelae of syphilis.

Management for Primary and Secondary Syphilis

CDC Recommendations: Pharmacotherapy for Adults[2]

Primary Syphilis
Preferred Regimen
▸ Benzathine Penicillin G (Bicillin L-A) 2.4 million units IM x 1 dose
Alternative Regimen
Doxycycline 100 mg po bid x 14 days
Tetracycline 500 mg po qid x 14 days
Ceftriaxone 1 gm IM/IV q24h x 10 -14 days
Azithromycin2 gm po x 1 dose
  • Infants and children aged >/= 1 month
    • Upon diagnosis with syphilis, birth and maternal medical records should be reviewed for assessment of congenital or acquired syphilis.
    • Those with primary and secondary syphilis should also be evaluated for sexual abuse, through consultation with child-protection service.

CDC Recommendations: Pharmacotherapy for Infants and Children

Primary Syphilis
Preferred Regimen
▸ Benzathine Penicillin G (Bicillin L-A) 50,000 units/kg body weight IM, up to the adult dose of 2.4 million units x 1 dose

Other Management Considerations

HIV Infection

  • All persons who have syphilis should be tested for HIV infection.
  • In geographic areas in which the prevalence of HIV is high, persons who have primary syphilis should be retested for HIV after 3 months if the first HIV test result was negative.


  • Invasion of CSF by T. pallidum accompanied by CSF laboratory abnormalities is common among adults who have primary or secondary syphilis.[3] Therefore, in the absence of clinical neurologic findings, no evidence exists to support variation from the recommended treatment regimen for early syphilis.
  • Symptomatic neurosyphilis develops in only a limited number of persons after treatment with the penicillin regimens recommended for primary and secondary syphilis. Therefore, unless clinical signs or symptoms of neurologic or ophthalmic involvement are present or treatment failure is documented, routine CSF analysis is not recommended for persons who have primary or secondary syphilis.

Special Considerations

Penicillin Allergy: Alternative Regimen

  • Data to support the use of alternatives to penicillin in the treatment of early syphilis are limited. However, several therapies may be effective in non-pregnant, penicillin-allergic patients who have primary or secondary syphilis.
  • Doxycycline 100 mg orally twice daily for 14 days[4][5] and tetracycline (500 mg four times daily for 14 days) are regimens that have been used for many years.
  • Compliance is likely to be better with doxycycline than tetracycline, because tetracycline can cause gastrointestinal side effects.
  • Clinical studies, though limited, along with biologic and pharmacologic evidence suggest that ceftriaxone (1 g daily either IM or IV for 10-14 days) is effective for treating early syphilis; the optimal dose and duration of ceftriaxone therapy have not been defined.[6]
  • Azithromycin as a single 2-g oral dose is effective for treating early syphilis.[7][8][9] However, T. pallidum chromosomal mutations associated with azithromycin resistance and treatment failures have been documented in several geographical areas in the United States.[10][11] As such, the use of azithromycin should be used with caution only when treatment with penicillin or doxycycline is not feasible. Azithromycin should not be used in MSM or pregnant women.
  • Close follow-up of persons receiving any alternative therapies is essential.
  • Skin testing for penicillin allergy may be useful in some circumstances in which the reagents and expertise are available to perform the test adequately.


Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin.


  • Treatment failure can occur with any regimen. However, assessing response to treatment frequently is difficult, and definitive criteria for cure or failure have not been established.
  • Clinical and serologic evaluation should be performed 6 months and 12 months after treatment; more frequent evaluation may be prudent if follow-up is uncertain.
  • Patients who have signs or symptoms that persist or recur or who have a sustained fourfold increase in nontreponemal test titer (i.e. compared with the maximum or baseline titer at the time of treatment) probably failed treatment or were reinfected. These patients should be retreated and reevaluated for HIV infection.
  • Because treatment failure usually cannot be reliably distinguished from reinfection with T. pallidum, a CSF analysis also should be performed.
  • Clinical trial data have demonstrated that greater than 15% of patients with early syphilis treated with the recommended therapy will not achieve the two dilution decline in nontreponemal titer used to define response at 1 year after treatment.[14]
  • Persons whose titers do not decline should be reevaluated for HIV infection.
  • Optimal management of such patients is unclear.
  • At a minimum, these patients should receive additional clinical and serologic follow-up.
  • If additional follow-up cannot be ensured, retreatment is recommended.
  • Because treatment failure may be the result of unrecognized CNS infection, CSF examination can be considered in such situations.
  • In rare instances, serologic titers do not decline despite a negative CSF examination and a repeated course of therapy. In these circumstances, the need for additional therapy or repeated CSF examinations is unclear, but is not generally recommended.


  1. Accessed on September 27, 2016
  2. "Sexually Transmitted Diseases Treatment Guidelines, 2010". Retrieved 2012-12-19.
  3. Lukehart SA, Hook EW, Baker-Zander SA, Collier AC, Critchlow CW, Handsfield HH (1988) Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and treatment. Ann Intern Med 109 (11):855-62. PMID: 3056164
  4. Ghanem KG, Erbelding EJ, Cheng WW, Rompalo AM (2006) Doxycycline compared with benzathine penicillin for the treatment of early syphilis. Clin Infect Dis 42 (6):e45-9. DOI:10.1086/500406 PMID: 16477545
  5. Wong T, Singh AE, De P (2008) Primary syphilis: serological treatment response to doxycycline/tetracycline versus benzathine penicillin. Am J Med 121 (10):903-8. DOI:10.1016/j.amjmed.2008.04.042 PMID: 18823862
  6. Hook EW, Roddy RE, Handsfield HH (1988) Ceftriaxone therapy for incubating and early syphilis. J Infect Dis 158 (4):881-4. PMID: 3171231
  7. Riedner G, Rusizoka M, Todd J, Maboko L, Hoelscher M, Mmbando D et al. (2005) Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis. N Engl J Med 353 (12):1236-44. DOI:10.1056/NEJMoa044284 PMID: 16177249
  8. Hook EW, Martin DH, Stephens J, Smith BS, Smith K (2002) A randomized, comparative pilot study of azithromycin versus benzathine penicillin G for treatment of early syphilis. Sex Transm Dis 29 (8):486-90. PMID: 12172535
  9. Hook EW, Behets F, Van Damme K, Ravelomanana N, Leone P, Sena AC et al. (2010) A phase III equivalence trial of azithromycin versus benzathine penicillin for treatment of early syphilis. J Infect Dis 201 (11):1729-35. DOI:10.1086/652239 PMID: 20402591
  10. Lukehart SA, Godornes C, Molini BJ, Sonnett P, Hopkins S, Mulcahy F et al. (2004) Macrolide resistance in Treponema pallidum in the United States and Ireland. N Engl J Med 351 (2):154-8. DOI:10.1056/NEJMoa040216 PMID: 15247355
  11. Mitchell SJ, Engelman J, Kent CK, Lukehart SA, Godornes C, Klausner JD (2006) Azithromycin-resistant syphilis infection: San Francisco, California, 2000-2004. Clin Infect Dis 42 (3):337-45. DOI:10.1086/498899 PMID: 16392078
  12. Ghanem KG, Erbelding EJ, Wiener ZS, Rompalo AM (2007) Serological response to syphilis treatment in HIV-positive and HIV-negative patients attending sexually transmitted diseases clinics. Sex Transm Infect 83 (2):97-101. DOI:10.1136/sti.2006.021402 PMID: 16943224
  13. Seña AC, Wolff M, Behets F, Van Damme K, Martin DH, Leone P; et al. (2013). "Response to therapy following retreatment of serofast early syphilis patients with benzathine penicillin". Clin Infect Dis. 56 (3): 420–2. doi:10.1093/cid/cis918. PMC 3590030. PMID 23118269.
  14. Rolfs RT, Joesoef MR, Hendershot EF, Rompalo AM, Augenbraun MH, Chiu M et al. (1997) A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. The Syphilis and HIV Study Group. N Engl J Med 337 (5):307-14. DOI:10.1056/NEJM199707313370504 PMID: 9235493

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