Letters to the Editor
To the Editor:
Syphilis remains a global problem, with an estimated 11 million people infected each year in the world.1 Effective antibiotic treatment is a key component of syphilis control programs.2 There is still a debate on whether to include azithromycin at all as an alternate single-dose therapy for the treatment of early syphilis.3 However, a systematic review by Bai and colleagues4 was recently published in Cochrane Database Systematic Review, concluding no statistically significant difference between azithromycin and penicillin G benzathine in relative effectiveness for treatment of early syphilis. Although this conclusion would seem to be rational on the basis of meta-analysis of the 3 available randomized controlled trials, I would like to bring to the readers’ attention the important considerations that were not warned in the article.
First, the authors did not consider the evolution of azithromycin treatment failures or resistance over time and its relationship to the inclusion criteria of this systematic review. On the basis of clinical effectiveness in the treatment of syphilis from nonrandomized studies and randomized controlled trial in 1990s, azithromycin was used for targeted syphilis chemoprophylaxis in 2000 in Vancouver and Los Angeles.5 However, azithromycin treatment failures began to be noted in San Francisco in 20026 and result from an A→G mutation at position 2058 of the 23S rRNA gene of Treponema pallidum. On the basis of detection of this mutation, azithromycin resistance has also been identified in clinical samples from elsewhere in the United States and other countries,7 and the number of resistant specimens has increased with time. Because the trial in the United States8 was carried out before the emergence of azithromycin-resistant T. pallidum, inclusion of this study into the review should be with caution.
Second, the authors did not mention the geographic bias of the available clinical trials to limit the generalization to other areas. Actually, most study subjects of clinical trials were recruited from 2 African countries—Tanzania (328 study subjects)9 and Madagascar (accounting for 82% of the total study participants enrolled in the studies).10,11 In this case, the conclusion from the systematic review may be only appropriate to these 2 countries or can be probably generalized to other African countries, which was supported by a recent study in which no evidence of resistance to azithromycin was found in specimens from Madagascar.11 However, ongoing monitoring for the resistance using the molecular sequencing techniques in these countries is needed.
Because the systematic review of quality randomized clinical trials has been considered the “gold standard” for judging whether one treatment is better than or equal to the other,12 careful preparation of the review and appropriate interpretation of the results would be more important than the review itself. Otherwise, it will be much less likely to inform us and so much more likely to mislead us. Although further studies that validate the efficacy of azithromycin are usually recommended, it would be unethical to design any randomized controlled trial that compares penicillin to azithromycin by deliberately assigning the patients with active syphilis into a potentially ineffective arm of azithromycin in areas where the evidence on high efficacy of penicillin and high resistance of azithromycin from observational studies is so overwhelmingly strong.
Xiang-Sheng Chen, MD, PhD
National Center for STD Control
and Chinese Academy of Medical Sciences
Institute of Dermatology
1. World Health Organization. Prevalence and Incidence of Selected Sexually Transmitted Infections, Chlamydia trachomatis, Neisseria gonorrhoeae, syphilis and Trichomonas vaginalis: Methods and Results Used by WHO to Generate 2005 Estimates. Geneva: World Health Organization; 2011.
2. Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines 2010. MMWR Recomm Rep 2010; 59: 1–116.
3. Ghanem KG, Workowski KA. Management of adult syphilis. Clin Infect Dis 2011; 53 (suppl 3): S110–S128.
4. Bai ZG, Wang B, Yang K, et al.. Azithromycin versus penicillin G benzathine for early syphilis. Cochrane Database Syst Rev 2012; 6: CD007270.
5. Katz KA, Klausner JD. Azithromycin resistance in Treponema pallidum
. Curr Opin Infect Dis 2008; 21: 83–91.
6. CDC. Azithromycin treatment failures in syphilis infections—San Francisco, California, 2002–2003. MMWR Morb Mortal Wkly Rep 2004; 53: 197–198.
7. Lukehart SA, Godornes C, Molini BJ, et al.. Macrolide resistance in Treponema pallidum
in the United States and Ireland. N Engl J Med 2004; 351: 154–158.
8. Hook EW 3rd, Martin DH, Stephens J, et al.. A randomized, comparative pilot study of azithromycin versus benzathine penicillin G for treatment of early syphilis. Sex Transm Dis 2002; 29: 486–490.
9. Klausner JD, Kohn RP, Kent CK. Azithromycin versus penicillin for early syphilis. N Engl J Med 2006; 354: 203–205.
10. Hook EW 3rd, Behets F, Van Damme K, et al.. A phase III equivalence trial of azithromycin versus benzathine penicillin for treatment of early syphilis. J Infect Dis 2010; 201: 1729–1735.
11. Van Damme K, Behets F, Ravelomanana N, et al.. Evaluation of azithromycin resistance in Treponema pallidum
specimens from Madagascar. Sex Transm Dis 2009; 36: 775–776.
12. Sackett DL, Rosenberg WM, Gray JA, et al.. Evidence based medicine: What it is and what it isn’t. BMJ 1996; 312: 71–72.