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Sexually Transmitted Disease 2010 Guideline.pdf  |  STD_RX_2010.htm   

Sexually Transmitted Diseases Treatment Guidelines 2002  MMWR May 10, 2002/Vol. 51/No.RR-6

Syphilis                                 RX  |  DX  


Treatment of Primary & Secondary Syphilis for Adults:  

For Penicillin Allergy Patients - Rx of Early Syphilis:
Primary, Secondary, and Early Latent Disease of Less Than 1 Year's Duration

Management of Sex Partners of Syphilis patients.

Sexual transmission of T. pallidum is thought to occur only when mucocutaneous syphilitic lesions are present. Although such manifestations are uncommon after the first year of infection, persons exposed sexually to a patient who has syphilis in any stage should be evaluated clinically and serologically and treated with a recommended regimen, according to the following recommendations:

Sexual 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, 6 months plus duration of symptoms for those with secondary syphilis, and 1 year for patients with early latent syphilis.

Latent Syphilis                                   2010 Guideline

Latent syphilis is defined as syphilis characterized by seroreactivity without other evidence of disease.
Patients who have latent syphilis and who acquired syphilis during the preceding year are classified as having early latent syphilis.
Patients' conditions can be diagnosed as early latent syphilis if, during the year preceding the evaluation, they had 1) a documented seroconversion or fourfold or greater increase in titer of a nontreponemal test; 2) unequivocal symptoms of primary or secondary syphilis; or 3) a sex partner documented to have primary, secondary, or early latent syphilis. In addition, for persons whose only possible exposure occurred during the previous 12 months, reactive nontreponemal and treponemal tests are indicative of early latent syphilis. In the absence of these conditions, an asymptomatic person should be considered to have late latent syphilis or syphilis of unknown duration. Nontreponemal serologic titers usually are higher during early latent syphilis than late latent syphilis. However, early latent syphilis cannot be reliably distinguished from late latent syphilis solely on the basis of nontreponemal titers. All patients with latent syphilis should have careful examination of all accessible mucosal surfaces (i.e., the oral cavity, perianal area, perineum and vagina in women, and underneath the foreskin in uncircumcised men) to evaluate for internal mucosal lesions. All patients who have syphilis should be tested for HIV infection.

Treatment of Latent Syphilis  

Because latent syphilis is not transmitted sexually, the objective of treating patients with this stage of disease is to prevent complications. Although clinical experience supports the effectiveness of penicillin in achieving this goal, limited evidence is available to guide choice of specific regimens.

The following regimens are recommended for penicillin nonallergic patients who have normal CSF examinations (if performed).

Recommended Regimens for Adults*

Rx of Early Latent Syphilis

Rx of Late Latent Syphilis or Latent Syphilis of Unknown Duration

* Recommendations for treating syphilis in HIV-infected persons and pregnant women are discussed later in this report (see Syphilis among HIV-Infected Persons and Syphilis in Pregnancy).

Available data demonstrate no enhanced efficacy of additional doses of penicillin G, amoxicillin, or other antibiotics in early syphilis, regardless of HIV status.

Penicillin Allergy Patients

The effectiveness of alternatives to penicillin in the treatment of latent syphilis has not been well documented. Nonpregnant patients allergic to penicillin who have clearly defined early latent syphilis should respond to therapies recommended as alternatives to penicillin for the treatment of primary and secondary syphilis (see Primary and Secondary Syphilis, Treatment).

The only acceptable alternatives for the treatment of late latent syphilis or latent syphilis of unknown duration are doxycycline (100 mg orally twice daily) or tetracycline (500 mg orally four times daily), both for 28 days. These therapies should be used only in conjunction with close serologic and clinical follow-up. Based on biologic plausibility and pharmacologic properties, ceftriaxone might be effective for treating late latent syphilis or syphilis of unknown duration. However, the optimal dose and duration of ceftriaxone therapy have not been defined, and treatment decisions should be discussed in consultation with a specialist. Some patients who are allergic to penicillin also might be allergic to ceftriaxone; in these circumstances, use of an alternative agent might be required. The efficacy of these alternative regimens in HIV-infected persons has not been well studied.

Treatment of Late Latent Syphilis or Latent Syphilis of Unknown Duration, or Tertiary syphilis:

Treatment Regimens  for Neurosyphilis:

After treatment, the quantitative RPR titer should decline fourfold by the third month, eightfold by the sixth month; all patients with primary syphilis should be nonreactive at 12 months, and those with secondary syphilis in 24 months.

Patients with a first attack of latent syphilis of 1 to 4 years' duration and treated with the recommended schedules will have a nonreactive RPR test result within 5 years after treatment.


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Syphilis is a systemic disease caused by Treponema pallidum:

Diagnostic Considerations and Use of Serologic Tests
Darkfield examinations and direct fluorescent antibody tests of lesion exudate or tissue are the definitive methods for diagnosing early syphilis.
A presumptive diagnosis is possible with the use of two types of serologic tests for syphilis:

The use of only one type of test is insufficient for diagnosis because false-positive nontreponemal test results occasionally occur secondary to various medical conditions. Nontreponemal test antibody titers usually correlate with disease activity, and results should be reported quantitatively. A fourfold change in titer, equivalent to a change of two dilutions (e.g., from 1:16 to 1:4 or from 1:8 to 1:32), usually is considered necessary to demonstrate a clinically significant difference between two nontreponemal test results that were obtained by using the same serologic test. It is expected that the nontreponemal test will eventually become nonreactive after treatment; however, in some patients, nontreponemal antibodies can persist at a low titer for a long period, sometimes for the remainder of their lives. This response is referred to as the serofast reaction. Most patients who have reactive treponemal tests will have reactive tests for the remainder of their lives, regardless of treatment or disease activity. However, 15%-25% of patients treated during the primary stage might revert to being serologically nonreactive after 2-3 years. Treponemal test antibody titers correlate poorly with disease activity and should not be used to assess treatment response.

The diagnosis of neurosyphilis can be made based on various combinations of reactive serologic test results, abnormalities of cerebrospinal fluid (CSF) cell count or protein, or a reactive VDRL-CSF with or without clinical manifestations. The CSF leukocyte count usually is elevated (greater than 5 WBCs/mm3) when neurosyphilis is present, and it also is a sensitive measure of the effectiveness of therapy. The VDRL-CSF is the standard serologic test for CSF; when reactive in the absence of substantial contamination of CSF with blood, it is considered diagnostic of neurosyphilis. However, the VDRL-CSF may be nonreactive when neurosyphilis is present. Some experts recommend performing an FTA-ABS test on CSF. The CSF FTA-ABS is less specific (i.e., yields more false-positive results) for neurosyphilis than the VDRL-CSF. However, the test is believed to be highly sensitive, and some experts believe that a negative CSF FTA-ABS test excludes neurosyphilis.

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The Jarisch-Herxheimer reaction is an acute febrile reaction -- often accompanied by headache, myalgia, and other symptoms -- that might occur within the first 24 hours after any therapy for syphilis; patients should be advised of this possible adverse reaction. The Jarisch-Herxheimer reaction often occurs among patients who have early syphilis. Antipyretics may be recommended, but no proven methods prevent this reaction. The Jarisch-Herxheimer reaction may induce early labor or cause fetal distress among pregnant women. This concern should not prevent or delay therapy (see Syphilis During Pregnancy).

Management of 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.

Persons who were exposed greater than 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.  

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

The time periods before treatment used for identifying at-risk sex partners are
a) 3 months plus duration of symptoms for primary syphilis,
b) 6 months plus duration of symptoms for secondary syphilis, and
c) 1 year for early latent syphilis.

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Primary and Secondary Syphilis
Patients who have syphilis and who also have symptoms or signs suggesting neurologic disease (e.g., meningitis) or ophthalmic disease (e.g., uveitis) should be evaluated fully for neurosyphilis and syphilitic eye disease; this evaluation should include CSF analysis and ocular slit-lamp examination. Such patients should be treated appropriately according to the results of this evaluation.

Invasion of CSF by T. pallidum accompanied by CSF abnormalities is common among adults who have primary or secondary syphilis. However, neurosyphilis develops in only a few patients after treatment with the regimens described in this report. Therefore, unless clinical signs or symptoms of neurologic or ophthalmic involvement are present, lumbar puncture is not recommended for routine evaluation of patients who have primary or secondary syphilis.

Serologic test titers may decline more slowly for patients who previously had syphilis. Patients should be reexamined clinically and serologically at both 6 months and 12 months; 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., in comparison with either the baseline titer or a subsequent result) probably failed treatment or were reinfected. These patients should be re-treated after reevaluation for HIV infection.   Unless reinfection with T. pallidum is certain, a lumbar puncture also should be performed.

Failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis identifies persons at risk for treatment failure. Such persons should be reevaluated for HIV infection. Optimal management of such patients is unclear. At a minimum, these patients should have additional clinical and serologic follow-up. HIV-infected patients should be evaluated more frequently (i.e., at 3-month intervals instead of 6-month intervals).

If additional follow-up cannot be ensured, re-treatment is recommended. Some experts recommend CSF examination in such situations.

When patients are re-treated, most experts recommend re-treatment with three weekly injections of benzathine penicillin G 2.4 million units IM, unless CSF examination indicates that neurosyphilis is present.

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Latent Syphilis
Latent syphilis is defined as those periods after infection with T. pallidum when patients are seroreactive, but demonstrate no other evidence of disease.

Other Management Considerations
All patients who have latent syphilis should be evaluated clinically for evidence of tertiary disease (e.g., aortitis, neurosyphilis, gumma, and iritis). Patients who have syphilis and who demonstrate any of the following criteria should have a prompt CSF examination:

If dictated by circumstances and patient preferences, a CSF examination may be performed for patients who do not meet these criteria. If a CSF examination is performed and the results indicate abnormalities consistent with neurosyphilis, the patient should be treated for neurosyphilis (see Neurosyphilis).

Quantitative nontreponemal serologic tests should be repeated at 6, 12, and 24 months. Limited data are available to guide evaluation of the treatment response for patients who have latent syphilis. Patients should be evaluated for neurosyphilis and re-treated appropriately if a) titers increase fourfold, b) an initially high titer (greater than or equal to 1:32) fails to decline at least fourfold (i.e., two dilutions) within 12-24 months, or c) signs or symptoms attributable to syphilis develop in the patient.

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Tertiary Syphilis
Tertiary syphilis refers to gumma and cardiovascular syphilis, but not to neurosyphilis. Nonallergic patients without evidence of neurosyphilis should be treated with the following regimen.

If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal. Follow-up CSF examinations also can be used to evaluate changes in the VDRL-CSF or CSF protein after therapy; however, changes in these two parameters are slower, and persistent abnormalities are of less importance. If the cell count has not decreased after 6 months, or if the CSF is not entirely normal after 2 years, re-treatment should be considered.

Syphilis During Pregnancy
All women should be screened serologically for syphilis during the early stages of pregnancy.
Seropositive pregnant women should be considered infected unless an adequate treatment history is documented clearly in the medical records and sequential serologic antibody titers have declined.

Penicillin is effective for preventing maternal transmission to the fetus and for treating fetal-established infection.
Treatment during pregnancy should be the penicillin regimen appropriate for the stage of syphilis.
Some experts recommend additional therapy in some settings. A second dose of benzathine penicillin 2.4 million units IM may be administered 1 week after the initial dose for women who have primary, secondary, or early latent syphilis. Ultrasonographic signs of fetal syphilis (i.e., hepatomegaly and hydrops) indicate a greater risk for fetal treatment failure; such cases should be managed in consultation with obstetric specialists.

There are no proven alternatives to penicillin for treatment of syphilis during pregnancy. Pregnant women who have a  history of penicillin allergy should be desensitized and treated with penicillin. Skin testing may be helpful (see Management of Patients Who Have a History of Penicillin Allergy).

Tetracycline and doxycycline usually are not used during pregnancy.
Erythromycin should not be used, because it does not reliably cure an infected fetus. Data are insufficient to recommend azithromycin or ceftriaxone.

Women treated for syphilis during the second half of pregnancy are at risk for premature labor and/or fetal distress if the treatment precipitates the Jarisch-Herxheimer reaction. These women should be advised to seek obstetric attention after treatment if they notice any contractions or decrease in fetal movements. Stillbirth is a rare complication of treatment, but concern for this complication should not delay necessary treatment. All patients who have syphilis should be offered testing for HIV infection.

Coordinated prenatal care and treatment follow-up are important, and syphilis case management may help facilitate prenatal enrollment. Serologic titers should be repeated in the third trimester and at delivery. Serologic titers may be checked monthly in women at high risk for reinfection or in geographic areas in which the prevalence of syphilis is high. The clinical and antibody response should be appropriate for the stage of disease. Most women will deliver before their serologic response to treatment can be assessed definitively.

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