Primary and Secondary Syphilis


Parenteral penicillin G has been used effectively for achieving clinical resolution (i.e., the healing of lesions and prevention of sexual transmission) and for preventing late sequelae. However, no comparative trials have been conducted to guide selection of an optimal penicillin regimen. Substantially fewer data are available for nonpenicillin regimens.

Recommended Regimen for Primary and Secondary Syphilis* Among Adults

Benzathine penicillin G 2.4 million units IM in a single dose

* Recommendations for treating syphilis among persons with HIV infection and pregnant women are discussed elsewhere in this report (see Syphilis Among Persons with HIV Infection; Syphilis During Pregnancy).

Available data demonstrate that use of additional doses of benzathine penicillin G, amoxicillin, or other antibiotics do not enhance efficacy of this recommended regimen when used to treat primary and secondary syphilis, regardless of HIV status (591593).

Recommended Regimen for Syphilis Among Infants and Children

Benzathine penicillin G 50,000 units/kg body weight IM, up to the adult dose of 2.4 million units in a single dose

Infants and children aged ≥1 month who receive a syphilis diagnosis should have birth and maternal medical records reviewed to assess whether they have congenital or acquired syphilis (see Congenital Syphilis). Infants and children aged ≥1 month with primary and secondary syphilis should be managed by a pediatric infectious disease specialist and evaluated for sexual abuse (e.g., through consultation with child protective services) (see Sexual Assault or Abuse of Children).

Other Management Considerations

All persons who have primary and secondary syphilis should be tested for HIV at the time of diagnosis and treatment. Those persons whose HIV test results are negative should be offered HIV PrEP. In geographic areas in which HIV prevalence is high, persons who have primary or secondary syphilis should be offered PrEP and retested for HIV in 3 months if the initial HIV test result was negative.

Persons who have syphilis and symptoms or signs indicating neurologic disease (e.g., cranial nerve dysfunction, meningitis, stroke, or altered mental state) should have an evaluation that includes CSF analysis. Persons with syphilis who have symptoms or signs of ocular syphilis (e.g., uveitis, iritis, neuroretinitis, or optic neuritis) should have a thorough cranial nerve examination and ocular slit-lamp and ophthalmologic examinations. CSF evaluation is not always needed for persons with ocular syphilis if no evidence of cranial nerves 2, 3, 4, 5, and 6 dysfunction or other evidence of neurologic disease exists. If symptoms and signs of otic syphilis are present then an otologic examination is needed; CSF evaluation in persons with otic syphilis does not aid in the clinical management and therefore is not recommended (see Cerebrospinal Fluid Evaluation). Treatment should be guided by the results of these evaluations. Invasion of CSF by T. pallidum accompanied by CSF laboratory abnormalities is common among adults who have primary or secondary syphilis but has unknown medical significance (585). In the absence of clinical neurologic findings, no evidence supports variation from the recommended treatment regimen for primary or secondary syphilis. Symptomatic neurosyphilis after treatment with the penicillin regimens recommended for primary and secondary syphilis is rare. Therefore, unless clinical signs or symptoms of neurologic or ophthalmic involvement are present, routine CSF analysis is not recommended for persons who have primary or secondary syphilis.


Clinical and serologic evaluation should be performed at 6 and 12 months after treatment; more frequent evaluation might be prudent if opportunity for follow-up is uncertain or if repeat infection is a clinical concern. Serologic response (i.e., titer) should be compared with the titer at the time of treatment. However, assessing serologic response to treatment can be difficult, and definitive criteria for cure or failure by serologic criteria have not been well established. In addition, nontreponemal test titers might decrease more slowly for persons previously treated for syphilis (594,595).

Persons who have signs or symptoms that persist or recur and those with at least a fourfold increase in nontreponemal test titer persisting for >2 weeks likely were reinfected or experienced treatment failure. Among persons who have neurologic findings or persons with no neurologic findings without any reported sexual exposure during the previous 3–6 months indicating that treatment failure might be possible, a CSF examination is recommended with treatment guided by CSF findings. These persons should also be reevaluated for HIV infection.

Among persons with no neurologic findings after a thorough neurologic examination and who are sexually active, reinfection is likely and repeat treatment for early syphilis is recommended. These persons should also be reevaluated for HIV infection.

Failure of nontreponemal test titers to decrease fourfold within 12 months after therapy for primary or secondary syphilis (inadequate serologic response) might be indicative of treatment failure. However, clinical trial data have demonstrated that 10%–20% of persons with primary and secondary syphilis treated with the recommended therapy will not achieve the fourfold decrease in nontreponemal titer within 12 months after treatment (591,596,597). Serologic response to treatment appears to be associated with multiple factors, including the person’s syphilis stage (earlier stages are more likely to decrease fourfold and become nonreactive), initial nontreponemal antibody titers (titers <1:8 are less likely to decline fourfold than higher titers), and age (titers among older patients might be less likely to decrease fourfold than those of younger patients) (596598). Optimal management of persons who have an inadequate serologic response after syphilis treatment is unclear. At a minimum, these persons should receive additional neurologic examinations, clinical and serologic follow-up annually, and reevaluation for HIV infection. If neurologic symptoms or signs are identified, a CSF evaluation is recommended, with findings guiding management. If additional follow-up cannot be ensured, retreatment is recommended. Because treatment failure might be the result of unrecognized CNS infection, CSF examination can be considered in situations in which follow-up is uncertain.

For retreatment, weekly injections of benzathine penicillin G 2.4 million units intramuscularly (IM) for 3 weeks is recommended, unless CSF examination indicates that neurosyphilis is present (see Neurosyphilis, Ocular Syphilis, and Otosyphilis). Serologic titers might not decrease, despite a negative CSF examination and a repeated 3-week therapy course (599). In these circumstances, the benefit of additional therapy or repeated CSF examinations is unclear, and it is not typically recommended. Serologic and clinical monitoring at least annually should continue to monitor for any sustained increases in nontreponemal titer.

Management of Sex Partners

See Syphilis, Management of Sex Partners.

Special Considerations

Penicillin Allergy

Data to support use of alternatives to penicillin in treating primary and secondary syphilis are limited. However, multiple therapies might be effective for nonpregnant persons with penicillin allergy who have primary or secondary syphilis. Doxycycline (100 mg orally 2 times/day for 14 days) (600,601) and tetracycline (500 mg orally 4 times/day for 14 days) have been used for years and can be effective. Compliance is likely to be better with doxycycline than tetracycline because tetracycline can cause more gastrointestinal side effects and requires more frequent dosing. Limited clinical studies, along with biologic and pharmacologic evidence, indicate that ceftriaxone (1 g daily either IM or IV for 10 days) is effective for treating primary and secondary syphilis; however, the optimal dose and duration of ceftriaxone therapy have not been defined (602,603). Azithromycin as a single 2-g oral dose has been effective for treating primary and secondary syphilis among certain populations (602,604,605). However, because of T. pallidum chromosomal mutations associated with azithromycin and other macrolide resistance and documented treatment failures in multiple U.S. geographic areas, azithromycin should not be used as treatment for syphilis (606608). Thorough clinical and serologic follow-up of persons receiving any alternative therapy is essential.

Persons with a penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with benzathine penicillin G. Skin testing for penicillin allergy might be useful in circumstances in which the reagents and expertise are available for performing the test adequately (see Management of Persons Who Have a History of Penicillin Allergy).


Pregnant women with primary or secondary syphilis who are allergic to penicillin should be desensitized and treated with penicillin G. Skin testing or oral graded penicillin dose challenge might be helpful in identifying women at risk for acute allergic reactions (see Management of Persons Who Have a History of Penicillin Allergy; Syphilis During Pregnancy).

HIV Infection

Persons with HIV infection who have primary or secondary syphilis should be treated similarly to those without HIV (see Syphilis Among Persons with HIV Infection).