Clinical Management of Early Syphilis

Katherine M Holman; Edward W HookIII


Expert Rev Anti Infect Ther. 2013;11(8):839-843. 

In This Article

Other Alternative Therapies

Although penicillin remains the only recommended therapy for syphilis, both frequent patient report of allergies, as well as barriers to parenteral administration, such as large volumes of administration, cost and difficulties in storage (refrigeration requirement), have spurred the continued search for alternative therapies. Ceftriaxone and azithromycin are two therapies determined to be effective; although both have limitations.

Cephalosporin antibiotics were shown to be effective early in syphilis treatment history at relatively low concentrations. However, oral cephalosporins, like available oral penicillin formulations, typically required multiple daily doses, and data about efficacy are limited. Ceftriaxone overcame many of these obstacles, namely its long half-life that allows for daily dosing. Also, given the finding that treponemes are often present in the CSF even in early syphilis, ceftriaxone's improved penetration into the CSF allays some fears regarding benzathine penicillin G's performance. Case series and small studies support ceftriaxone's efficacy,[21,22] however, no large studies have been done to determine the most effective dosing regimen and duration. The 2010 CDC STD Treatment Guidelines suggest a dosing regimen of ceftriaxone 1 g intramuscularly/intravenously daily X 10–14 days, but state this is based on small clinical studies.[17] Ceftriaxone does not completely solve the issue of penicillin allergic patients, as a cross-reaction is possible, but does provide a valid alternative.

Given past effectiveness of macrolide antibiotics for syphilis treatment, azithromycin has also been explored as an alternate therapy. Ease of administration and its long half-life suggested that a single dose of azithromycin might be a suitable alternative to penicillin. Early success, along with the support from three large trials,[23–25] led to considerable enthusiasm, particularly for resource limited settings, as well as for use as field treatment in syphilis outbreaks. However, azithromycin treatment failures associated with a 23S rRNA mutation for macrolide resistance were reported from San Francisco, as well as other locations, both in patients treated for early syphilis, as well as case contacts.[26] Treatment failures were also reported from China,[27] Canada[28] and azithromycin has failed to cure experimental syphilis (a strain of Treponema pallidum with proven macrolide resistance, the Street 14 strain) in rabbits. A convenience sample was analyzed for the identified mutation in the 23S rRNA, which was found in 88% of samples from Dublin, 22% in San Francisco, 13% in Seattle and 11% in Baltimore, with data suggesting that later samples had a higher frequency of the mutation.[29] A follow-up analysis of a large trial by Hook et al. did not show any macrolide resistance in Madagascar, where T. pallidum with the 23S rRNA mutation is rare,[30] and no treatment failures were reported in trials in Tanzania and Uganda.[31] Thus, although azithromycin therapy has been highly effective against syphilis, caution is recommended with its use, as is close follow-up of azithromycin-treated patients to monitor for treatment failure.