Azithromycin resistance in Treponema pallidum.

Benzathine penicillin remains the treatment of choice for syphilis and, 65 years after it was first used, there has been no report of penicillin resistant Treponema pallidum. However, it needs to be given by intramuscular injection, which is painful and could potentially lead to the transmission of bloodborne infections, including HIV, when strict sterile precautions are not observed. The risk of anaphylactic shock following the administration of intramuscularly penicillin is extremely small but, in some parts of the world, it deters physicians from treating syphilis with penicillin. An effective single dose oral treatment for syphilis would be a significant advance in the management and control of syphilis. The macrolide antibiotic azithromycin has excellent tissue penetration and a long half life. In vitro and animal studies published in 1990 showed that it is effective against T. pallidum,1,2 and non randomized trials of multiple and single dose treatment regimens in the 1990s showed that it was effective, and cost-effective in the treatment of syphilis in humans.3–6 One of these trials, conducted in Uganda, suggested that azithromycin was superior to benzathine penicillin in the treatment of those with high nontreponemal antibody titres.5 Small randomized controlled trials conducted in the United States comparing single dose azithromycin with benzathine penicillin for the treatment of incubating and early syphilis suggested that both were equally effective,7,8 and this was confirmed by a larger trial comparing a single dose of azithromycin 2G with benzathine penicillin in early and latent syphilis in Tanzania.9 In the early years of this century, the convenience and acceptability of single dose azithromycin led to it being used for patient-delivered partner therapy, and as targeted chemoprophylaxis for syphilis contacts in San Francisco, Los Angeles, and Vancouver, and as an alternative to penicillin for the treatment of primary and secondary syphilis in San Francisco.10,11 However, soon after it was introduced, cases of azithromycin treatment failure were reported among men who have sex with men (MSM) in San Francisco.12,13 Three patients with syphilitic ulcers failed to respond clinically, and 2 of them remained dark field positive after treatment. Five seronegative contacts seroconverted in spite of receiving a 1G prophylactic dose of azithromycin, and 4 of these presented with signs of primary or secondary syphilis. Sequencing of the 23S rRNA gene from 2 of these patients identified A to G mutations at the A2058 position,14 the same mutation as had been found in a strain of T. pallidum isolated in the 1980s from a patient who had failed treatment with erythromycin. This strain was resistant to both erythromycin and azithromycin in a rabbit model.14,15 The A2058G mutation was found to be present in 12 of 55 strains from MSM in San Francisco (22%), 2 of 19 from Baltimore (11%), 3/23 from Seattle (13%), and 15/17 from Dublin (88%). 14 The proportion of strains harboring the A2058G mutation appears to have increased in recent years in San Francisco, Seattle, and British Columbia.13,16–18 In this issue of the journal, Van Damme et al describe the results of testing 141 strains from subjects with primary and secondary syphilis in Madagascar for the A2058G mutation.18 It was not found in any of them. This is the first study that has looked for resistance mutations in T. pallidum in Africa. The results are reassuring, and in keeping with the results of clinical trials in Tanzania and Uganda that have shown azithromycin to be at least as effective as standard treatment with benzathine penicillin. It suggests that sexual networks in sub-Saharan Africa do not overlap with the sexual networks (predominantly involving MSM) in which syphilis is transmitted in North America. The lack of macrolide resistance in African strains of T. pallidum probably also reflects the lack of selection pressure, due to the limited use of macrolides in sub-Saharan Africa. The risk of harboring a resistant strain in Seattle was found to be twice as high among those who had been treated with macrolides for an unrelated condition.19 Moreover, macrolide resistant strains were shown not to be clonal in that study, suggesting that resistance mutations have arisen in multiple strains as a result of antibiotic selection pressure. Macrolide resistance is also rare in African isolates of Streptococcus pneumoniae and Chlamydia trachomatis.20,21 Resistant strains of S. pneumoniae have been found in a small proportion of nasopharyngeal isolates shortly after azithromycin mass treatment of com-