By Richard R. Watkins, MD, MS, FACP
Dr. Watkins is with the Division of Infectious Diseases, Akron General Medical Center, Akron, OH; Associate Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH.
Dr. Watkins reports that he has received research support from Actavis.
SYNOPSIS: Although a well-conducted randomized clinical trial did not show that azithromycin was non-inferior to doxycycline for the treatment of chlamydia, both treatments resulted in a high rate of cure (97% and 100%, respectively).
SOURCE: Geisler WM, et al. Azithromycin versus doxycycline for urogenital Chlamydia trachomatis infection. N Engl J Med 2015;373:2512-2521.
Chlamydia continues to be the most prevalent bacterial sexually transmitted infection worldwide. Currently the CDC recommends treatment with either a single 1-g dose of oral azithromycin or doxycycline 100 mg twice a day by mouth for 7 days. Because of limitations to previous studies comparing the two regimens, Geisler and colleagues sought to clarify whether azithromycin is non-inferior to doxycycline for the treatment of Chlamydia infection.
The study was conducted in youth correctional facilities in Los Angles and enrolled males and females between 12 and 21 years of age. A physical exam and nucleic acid amplification testing (NAAT) to screen for chlamydia is routinely performed on individuals within 96 hours of intake to the facility. All those who had a positive screen were offered enrollment in the study. Exclusion criteria included pregnancy, breast feeding, gonorrhea co-infection, allergies to tetracyclines or macrolides, photosensitivity, concomitant infection, receipt of an antibiotic within 21 days with antichlamydial activity, pelvic inflammatory disease, or epididymitis. Enrollees were randomly assigned on a 1:1 ratio to receive azithromycin or doxycycline therapy as per the CDC recommendations. On day 28, an interview and test of cure were performed using NAAT. Participants who tested negative at day 28 and were still in a correctional facility at day 67 had a second interview and test of cure done. The primary outcome was treatment failure at the 28-day follow-up. The study was designed to test the null hypothesis that the absolute rate of azithromycin treatment failure would be at least 5 percentage points higher than the absolute rate of doxycycline treatment failure against the hypothesis that there would be no difference between the two groups.
Out of 567 enrollees, 284 were randomized to receive azithromycin and 283 were randomized to receive doxycycline. After early discontinuation, mainly due to discharge from the correctional facility, 155 participants in each group completed the first follow-up. No treatment failures occurred in the doxycycline group (0%; 95% confidence interval [CI], 0.0-2.4) and five occurred in the azithromycin group (3.2%, 95% CI, 0.4-7.4). All of the treatment failures were asymptomatic. Since the upper boundary of the CI exceeded 5 percentage points, the null hypothesis was not rejected, and the non-inferiority of azithromycin to doxycycline was not shown. Adverse reactions occurred in 23% and 27% of participants in the azithromycin and doxycycline groups, respectively, with gastrointestinal symptoms the most commonly reported.
COMMENTARY
One of the most interesting aspects of this study is that it was conducted in youth correctional facilities. This allowed the investigators a degree of control that is often not present in other settings. For example, the possibility of chlamydia re-exposure was far less than would have been possible with a more conventional trial. Also, the setting facilitated the adherence of the participants to therapy. Adherence would have been particularly important for the doxycycline group. As the authors mentioned in their discussion, previous studies have shown that non-adherence to doxycycline therapy contributes to treatment failure in the magnitude of 20% for those who took fewer than 10 doses. Despite a higher treatment failure rate for azithromycin compared to doxycycline, overall it was still low (3%). In 2012, a total of 1,422,976 chlamydial infections were reported to CDC in 50 states and the District of Columbia.1 The public health implications of not successfully treating three out of every 100 individuals with chlamydia would be significant. However, this study should not be interpreted in a broad context since it was conducted in a highly controlled and regimented setting. Indeed, in the “real world,” many patients are unable to complete 7 days of doxycycline, and it is far simpler for them to take a single dose of azithromycin with a strong recommendation to have a test of cure 4 weeks later.
Why is azithromycin seemingly less effective than doxycycline? One theory is that azithromycin drug levels might not be sufficient in some patients to eradicate chlamydia. Testing this hypothesis could involve giving higher doses of azithromycin (e.g., 2 g orally), although this approach would be limited by increased gastrointestinal symptoms. Another possible explanation is that azithromycin might be less efficient in eradicating chlamydia from acutely infected human epithelial cells compared to doxycycline. Further studies on azithromycin and other agents, particularly ones under development, in acute chlamydia infection are needed.
REFERENCE
- Centers for Disease Control and Prevention web site. Available at www.cdc.gov. Accessed Jan. 1, 2016.
Although a well-conducted randomized clinical trial did not show that azithromycin was non-inferior to doxycycline for the treatment of chlamydia, both treatments resulted in a high rate of cure (97% and 100%, respectively).
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