Background:
There are few proven alternatives to benzathine penicillin for treatment of persons with early syphilis and no study of syphilis treatment has ever been conducted under the auspices of U.S. FDA Investigational New Drug (IND) oversight. Penicillin allergy not uncommonly hampers syphilis therapy, as does the requirement to administer therapy parentally. Preliminary data suggest that single doses of azithromycin 2.0g may be effective for treatment of early syphilis.

Objective:
To conduct a Phase III randomized, controlled equivalency trial evaluating azithromycin vs. benzathine penicillin G for treatment of early syphilis.

Method:
Between 2000 and 2008 we conducted a multinational, multicenter randomized controlled trial of azithromycin 2.0g vs. 2.4Mu of benzathine penicillin G for treatment of early (primary, secondary, and early latent) syphilis at 5 North American (2 in North Carolina and one each in Alabama, Louisiana, and Indiana) and 3 Madagascar sites). All participants were HIV seronegative and had strictly defined primary, secondary or early latent syphilis. For each participant serological response to therapy was evaluated using the RPR test at 1, 3 and 6 months using data generated at one time in a single laboratory using both intent to treat and per protocol analyses.

Result:
593 participants were enrolled, 21% from the U.S. and 79% from Madagascar with 26%, 45%, and 28% of participants having primary, secondary and early latent syphilis, respectively. Sixty-one percent of participants were male, 39% were female. Study results including response to therapy through six months of follow-up will be presented in detail.

Conclusion:
Results should help to determine if azithromycin, as an orally active medication unrelated to penicillin, is as effective as benzathine penicillin for syphilis treatment.

Implications:
Should azithromycin be as effective as benzathine penicillin for syphilis treatment, it would open up multiple new possibilities for improved syphilis control.