Azithromycin vs. Doxycycline for Chlamydia

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Geisler WM, et al. "Azithromycin versus doxycycline for urogenital Chlamydia trachomatis infection". The New England Journal of Medicine. 2015. :.

Clinical Question

Among adolescents with urogenital chlamydia, is azithromycin similar to doxycycline treatment for the treatment of chlamydia infection

Bottom Line

Among adolescents being treated for urogenital chlamydia infection, azithromycin treatment was 97% effective compared to 100% effectiveness of doxycycline. Azithromycin was not deemed to be noninferior to doxycycline. Treatment response for both groups was high and small difference in treatment response might be offset by the comparative ease of administration of single dose of doxycycline versus lower adherence of 7 days course of doxycycline.

Major Points

Urogenital chlamydia infection is the most frequently reported sexually transmitted infection in the United States and worldwide.[1] With a growing prevalence, efforts to prevent and control chlamydia infections have been high and the efficacy of the current treatment guidelines have been at the foundation of the chlamydia control programs.

The Centers for Disease Control and Prevention (CDC) recommends oral administration of azithromycin 1 gram in a single dose or doxycycline 100 mg twice daily for 7 days for the treatment of C. trachomatis infections. These guidelines are based off of a meta-analysis of 12 randomized clinical trials, where the goal of was to evaluate the efficacy and tolerance of azithromycin versus doxycycline for genital chlamydial infections. The efficacy of azithromycin against chlamydia was 97% and that of doxycycline was 98%, however the trials had limitations. Some of the limitations included the use of nucleic acid amplification tests that were not as sensitive as currently recommended testing, adherence rates of doxycycline, and re-exposure to chlamydia infected partners.[2]

In order to assess the current treatment guidelines for C. trachomatis infections, a phase 3, open-label, randomized trial was conducted to see whether azithromycin is non-inferior to doxycycline in the treatment of urogenital chlamydia.[3] The primary outcome was treatment failure at first follow-up: defined as a positive test for chlamydia and concordant C. trachomatis strains at baseline and follow-up. In the context of a closed population receiving directly observed treatment, the efficacy of azithromycin was 97% and the efficacy of doxycycline was 100%. The noninferiority of azithromycin was not established.

This study took place in a youth correctional facility where the prevalence of chlamydia infection was high and the participants were directly observed. A sexual history was obtained on each participant and an outer membrane protein A (OmpA) genotyping on C. trachomatis strains was done to more accurately classify treatment outcomes. This study corrected those limitations by improved accuracy in the detection and treatment failure of the antibiotics with the use of nucleic acid amplification testing and OmpA genotyping. The trial also minimized the possibility of infected partners and enhanced treatment adherence by taking place in the youth correctional facility.


The CDC recommends patients with C. trachomatis (and their sexual partners) may be treated with Azithromycin 1 g orally in a single dose OR Doxycycline 100 mg orally twice a day for 7 days. [4]


  • Phase 3, open-label, non-inferiority, randomized control trial
  • Participants were randomly assigned in a 1:1 fashion by utilization of block randomization to receive one of two treatment regimens
  • N=567 total participants
    • Azithromycin: N=284
    • Doxycycline: N= 283
  • Setting: 23 Los Angeles County Youth Correctional Facilities
  • Enrollment: December 2009-August 2011
  • Follow-up: Day 28 and day 67 if still active participant
  • Analysis: Per-protocol analysis
  • Primary Outcome: Treatment failure at first follow-up: defined as a positive test for chlamydia and concordant C. trachomatis strains at baseline and follow-up


Inclusion Criteria

  • Males and females 12 to 21 years of age who were residing in four long-term, sex-segregated youth correctional facilities in Los Angeles
  • Positive nucleic acid amplification test result

Exclusion Criteria

  • Pregnancy
  • Breastfeeding
  • Gonorrhea coinfection
  • Allergy to tetracyclines or macrolides
  • Previous photosensitivity from doxycycline
  • An inability to swallow pills
  • Receipt of an antibiotic with antichlamydial activity within 21 days before screening or between screening and enrollment
  • Concomitant infection requiring treatment with an antibiotic agent that had antichlamydial activity
  • Pelvic inflammatory disease
  • Epididymitis

Baseline Characteristics

From the azithromycin group (both groups similar)

  • Sex:
    • Male: 66%
    • Female: 34%
  • Race:
    • White:38%
    • Black: 42%
    • Other: 20%
  • Median age (range): 14.6-18.9
  • Previous chlamydia infection: 27%
  • HIV or AIDS: 99% not present


  • Randomized to Doxycycline 100 mg orally twice daily for 7 days vs. Azithromycin 1 gram in a single dose
  • Oral intake of all doses of study drug was directly observed by youth correctional facility staff
  • Participants who had a positive chlamydia test result at enrollment and who were still in a youth correctional facility at day 28 attended a first follow-up on that day and interviewed regarding symptoms, sexual behaviors, antibiotics taken, and furloughs from the correctional facility; and provided with a first-catch urine specimen for the test of cure by nucleic acid amplification testing
  • Participants who tested positive for chlamydia at the first follow-up were initially classified as having possible treatment failure and their participation was complete
  • Participants who tested negative for chlamydia at the first follow-up and who were still in a youth correctional facility on day 67 attended a second follow-up on that day for repeat nucleic acid amplification testing, and for an interview in which the same information was collected as at the day 28 follow-up
  • Participants who tested positive for chlamydia at the first or second follow-up had OmpA genotyping performed on their urine specimens to assess for concordant strains
  • Participants with suspected treatment failure had genotyping performed on urine specimens from both the enrollment visit and the follow-up visit


Comparisons are azithromycin vs. doxycycline

Primary Outcomes

Treatment failure
3.2% vs. 0% (difference 3.2%, 90% CI 0%-5.9%, noninferiority not met)
Noninferiority criterion for azithromycin was upper bound of 90% CI < 5% for difference in treatment failure rates

Secondary Outcomes

1% in the azithromycin group vomited within 1 hour, and a second dose was administered successfully
23% in the doxycycline group received less than 14 dose treatment course

Adverse Events

Adverse events
23% vs. 27% (no p-value reported)


  • Extensive list of exclusion criteria does not allow for broad spectrum evaluation and accurate representation of the population that would be receiving treatment the effectiveness
  • Adherence for all regimens was 100% in this study as the medications were administered by the correctional facility staff. In real-life clinical practice, effectiveness could be limited by potential non-adherence.


Funded by National Institute of Allergy and Infectious Diseases

Further Reading

  1. Template:Http://
  2. Lau CY & Qureshi AK Azithromycin versus doxycycline for genital chlamydial infections: a meta-analysis of randomized clinical trials. Sex Transm Dis 2002. 29:497-502.
  3. Geisler WM et al. Azithromycin versus Doxycycline for Urogenital Chlamydia trachomatis Infection. N. Engl. J. Med. 2015. 373:2512-21.
  4. Template:Http://