Syphilis Organism-Specific Therapy 

Updated: Aug 18, 2015
  • Author: Bruce M Lo, MD, MBA, CPE, RDMS, FACEP, FAAEM, FACHE; Chief Editor: Thomas E Herchline, MD  more...
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Therapeutic Regimens

Syphilis is a disease that is caused by Treponema pallidum. The treatment recommendations for syphilis are categorized by stage, such as primary (ulcer or chancre), secondary (skin rash, mucocutaneous lesions, and lymphadenopathy), tertiary (cardiac or gummatous lesions), or neurologic (cranial nerve dysfunction, meningitis, stroke, acute or chronic altered mental status, loss of vibration sense, auditory or ophthalmic abnormalities). [1, 2]

Latent syphilis (ie, without symptoms) is detected by serological testing and is divided into early latent syphilis (acquired within the preceding year) and late latent syphilis or latent syphilis of unknown origin. [1]

Penicillin is the treatment of choice for all stages of syphilis, with the type of penicillin and dosing based on clinical staging of the disease. [1] However, it is important to be sure to order the appropriate formulation of penicillin. Alternatives to penicillin may be used, but should be used with caution. [1]

Primary and secondary syphilis

Benzathine penicillin G 2.4 million units IM for 1 dose [1]

Retreatment: benzathine penicillin G 2.4 million units IM once weekly for 3 weeks

Pediatric dosing: Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units for 1 dose [1]

Early latent syphilis (seropositive without symptoms, <1 year since infection)

Benzathine penicillin G 2.4 million units IM for 1 dose [1]

Pediatric dosing: Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units for 1 dose [1]

Late latent syphilis or latent syphilis of unknown duration

Benzathine penicillin G 2.4 million units IM once weekly for 3 weeks [1]

Pediatric dosing: Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units, once weekly for 3 weeks [1]

Tertiary syphilis

Benzathine penicillin G 2.4 million units IM once weekly for 3 weeks [1]

Neurosyphilis

First-line therapy [1]

Aqueous crystalline penicillin G 18-24 million units divided into 3-4 million units IV q4h or continuous infusion for 10-14 days

Second-line therapy

Procaine penicillin 2.4 million units IM daily plus probenecid 500 mg PO QID for 10-14 days

Penicillin-allergic patients

Primary, secondary, or early latent syphilis [1]

Doxycycline 100 mg PO q12h for 14d or

Tetracycline 500 mg PO QID for 14d or

Azithromycin 2000 mg PO single dose (see below) or

Ceftriaxone 250 mg IM/IV qd for 10-14 days

Late latent syphilis

Doxycycline 100 mg PO q12h for 28d or

Tetracycline 500 mg PO QID for 28d

Pregnancy, tertiary syphilis, or neurosyphilis

Desensitize and treat with appropriate penicillin regimen

Management recommendations for sex partners

Persons who were exposed within the 90 days preced­ing the diagnosis of primary, secondary, or early latent syphilis in a sex partner might be infected even if seronegative; therefore, such persons should be treated presumptively. [1]

Persons who were exposed > 90 days before the diagnosis of primary, secondary, or early latent syphilis in a sex partner should be treated presumptively if serologic test results are not available immediately and the opportunity for follow-up is uncertain.

Patients with syphilis of unknown duration who have high nontreponemal serologic test titers (i.e. > 1:32) can be assumed to have early syphilis.

Long-term sex partners of patients who have latent syphilis should be evaluated clinically and serologically for syphilis and treated on the basis of the evaluation findings.

Sex partners of infected patients should be considered at risk and provided treatment if they have had sexual contact with the patient within 3 months plus the duration of symp­toms for patients diagnosed with primary syphilis, within 6 months plus the duration of symptoms for patients with secondary syphilis, and within 1 year for patients with early latent syphilis.

All patients diagnosed with syphilis should be screened for the human immunodeficiency virus (HIV).

Pregnant women and HIV-infected patients should be treated with the penicillin regimen appropriate for their stage of infection.

Pregnant women who have a history of penicillin allergy should be desensitized and treated with penicillin.

Follow-up testing

Patients should have follow-up testing at 6 and 12 months for early syphilis (primary, secondary, and early latent). Patients should have follow-up testing at 6, 12, and 24 months for late latent or latent syphilis of unknown duration. [1]

Patients with neurosyphilis should have repeat CSF testing every 6 months until cell count is normal. [1]

Other considerations

HIV-positive patients should be treated the same as HIV-negative patients in all stages of syphilis. [1]

All patients with syphilis should be tested for HIV infection if their HIV status is unknown. If the geographic area has a high prevalence for HIV, the patient should be retested for acute HIV infection if the initial HIV test was negative.

Doxycycline is the preferred second-line agent if penicillin cannot be given. Ceftriaxone may also be given, but it has not been studied as thoroughly. [1]

Azithromycin has been shown to be as effective as penicillin in early syphilis. [3] However, resistance to azithromycin has been reported, and it should only be used when penicillin or doxycycline are not feasible. [1, 4] Azithromycin should not be used in men who have sex with men. [1]

Jarisch-Herxheimer reaction may occur within the first 24 hours after the initiation of any therapy for syphilis. It is an acute febrile reaction frequently accompanied by headache, myalgia, fever, and other symptoms. This can be treated symptomatically with antipyretics. [1]