• Cure of syphilis defined as a negative RPR titer or greater than or equal to a 4-fold (2 dilution) decrease in RPR titer at 6 months following treatment and resolution of all signs and symptoms of syphilis. [ Time Frame: Month 6. ] [ Designated as safety issue: No ]
  

• Cure rates at 9, 12 and 24 months post treatment and the rate of relapse or reinfection defined as cure followed by recurrent clinical manifestations or a 2-dilution increase in RPR titer over previous lowest result. [ Time Frame: Months 9, 12, and 24. ] [ Designated as safety issue: No ]
  

Syphilis is a disease with a worldwide distribution. It causes genital ulceration, thereby amplifying risk for HIV acquisition and transmission and it may cause congenital infection, spontaneous abortion, and stillbirth if untreated in pregnant women. About one third of all cases, if untreated, result in late sequelae which include neurosyphilis, gumma formation and cardiovascular involvement. This study will be a multi-center, randomized, open-label trial to evaluate the efficacy of azithromycin in treating primary, secondary and early latent syphilis in HIV (Human Immunodeficiency Virus) uninfected volunteers. Up through version 6.0 of this protocol volunteers were only followed for 12 months. The protocol was amended starting with version 7.0 to include follow-up visits at month 18 and 24 in order to capture possible "late failures." Each subject will be randomized into a treatment group. If the subject does not have a self-reported history of penicillin allergy, the subject will be randomized to receive either a single 2.0 gram dose of azithromycin administered orally, or 2.4 million units of benzathine penicillin G administered intramuscularly once. Eligible patients who report a history of penicillin allergy will be randomized (using a separate randomization schedule) to receive either a single dose of azithromycin or doxycycline, 100 milligrams, taken orally, twice a day for 14 days. Block randomization will be used within each clinical center with subjects allocated in equal numbers to either standard therapy or azithromycin. Participants found to be ineligible for study participation after they have been randomized and treated, will be treated again with benzathine penicillin G (or doxycycline if they are allergic to penicillin) and will continue follow-up for safety evaluation. The treatment assignments will not be blinded. The primary outcome for this trial is the cure of syphilis, at the 6 month post treatment visit. Irrespective of the outcome at 6 months, all participants will be encouraged to complete additional follow-up visits at 9, 12, 18 and 24 months. A subject cured at the 6 month visit who subsequently relapses or becomes reinfected and does not meet these criteria for a cure at a later outcome visit will still be considered cured and a success for the primary outcome. Secondary outcomes will consist of the cure rates at 9, 12 and 24 months post treatment and the rate of relapse or reinfection defined as cure followed by recurrent clinical manifestations or a 2-dilution increase in RPR (reactive serologic test for syphilis) titer over previous lowest result. Participants not cured at 6 months will be given standard therapy, either penicillin or doxycycline depending on their allergy status. Secondary analyses will attempt to control for loss to follow-up and reinfection. Secondary analyses will also provide useful descriptive information on disease course and subject retention. Analyses will be conducted separately for the cohorts allergic and not allergic to penicillin. No attempt will be made to recruit a sufficient sample size among penicillin allergic subjects to attain the desired power for the primary outcome. Therefore these results will be seen as preliminary to a possible future trial and as confirmatory to the primary comparison. The study endpoint will be determined at 6 months, all participants, including those in the substudy; will have follow-up visits for two full years. At the end of the 6 month evaluation period, all participants will have been classified in one of the following groups: cure; clinical response/serological nonresponse; or failure.