More Antibiotic Resistance—Now Syphilis

Abstract & Commentary

Synopsis: Treponema pallidum strains resistant to azithromycin are prevalent in San Francisco, Seattle, Baltimore, and Dublin.

Source: Lukehart SA, et al. Macrolide Resistance in Treponema pallidum in the United States and Ireland. N Engl J Med. 2004;351:154-158.

Azithromycin therapy failed in a patient in San Francisco with a primary syphilitic chancre which subsequently resolved after administration of a single dose of benzathine penicillin. Sequencing of the 23S rRNA genes of Treponema pallidum from 2 San Francisco patients who had failed azithromycin therapy revealed the presence of a mutation (AG in a position cognate to A2058 in E. coli) identical to that previously associated with macrolide resistance in a single isolate (T. pallidum, Street 14 strain). This mutation was subsequently identified in 4 isolates in Dublin, Ireland, and 2 in Seattle.

Screening of convenience samples identified the AG mutation in 15 of 17 (88%) samples from Dublin, 12 of 55 (22%) from San Francisco, 3 of 23 (13%) from Seattle, and 2 of 19 (11%) from Baltimore. While the mutation was present in only 4% of samples from 1999 through 2002 in San Francisco, this prevalence increased to 37% in 2003. Therapeutic studies in a rabbit model of infection confirmed the relevance of the mutation to treatment failure with macrolide therapy.

Comment by Stan Derensinski, MD, FACP

Previous studies demonstrated the effectiveness of azithromycin in the treatment of syphilis. Because of the convenience of a single oral dose (2 grams), its use has been increasingly utilized. Prior to this study, initiated by the identification of a series of cases in San Francisco,1 only one macrolide resistant T. pallidum, called Street 14, had been identified.2 The emergence of azithromycin resistance is undoubtedly related to the widespread use of this antibiotic , primarily for respiratory tract infection.

Lukehart and colleagues point out that there have, to date, been no failures among 100 patients with early syphilis treated with azithromycin in a randomized trial. This trial excludes HIV-infected patients, and is being performed at 4 sites (Madagascar; Birmingham, Alabama; Chapel Hill, North Carolina; and Indianapolis, Indiana) that did not include those utilized in this study.

No documented resistance of T. pallidum to penicillin has been identified, and penicillin remains the antibiotic of choice for the treatment of syphilis at all stages.3 Despite the lack of resistance, I have the impression that we are seeing more non-HIV infected patients with latent syphilis who remain seropositive at high titers despite receipt of recommended doses of penicillin. Whether this is the result of resistance or of host factors (or both) can only be conjectured.


1. CDC. Brief Report: Azithromycin Treatment Failures in Syphilis Infections-San Francisco, California, 2002-2003. MMWR (Morb Mortal Wkly Rep). 2004;53:197-198.

2. Stapleton JT, et al. Potential For Development of Antibiotic Resistance in Pathogenic Treponemes. Rev Infect Dis. 1985;7(Suppl 2):S314-S317.

3. CDC. Sexually Transmitted Diseases Treatment Guidelines. 2002. MMWR. 2002;51(NO. RR-6).

Stan Deresinski, MD, FACP, Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, and Editor for Infectious Disease Alert.