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. 373(26):2512-21.
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Clinical Question

Among adolescents with urogenital chlamydia, is azithromycin similar to doxycycline 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 azithromycin versus lower adherence of the twice daily, 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. These findings are in contrast to a recent meta-analysis showing a pooled efficacy for azithromycin 82% and doxycycline 99% in rectal infection.[4]

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.

Guidelines

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. [1]

Design

  • Phase 3, open-label, non-inferiority, randomized control trial
  • N=567
    • Azithromycin: N=284
    • Doxycycline: N=283
  • Setting: 4 Los Angeles County Youth Correctional Facilities, USA, follow-up in 23 facilities due to patient transfer
  • 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

Population

Inclusion Criteria

  • Females (original cohort December 2009)
  • Males (added August 2011)
  • 12-21 years of age
  • Residing in four long-term, sex-segregated youth correctional facilities in Los Angeles
  • Positive nucleic acid amplification test result (APTIMA Combo 2, Gen-Probe)

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

Azithromycin group displayed

  • Sex - Male: 66%
  • Race:
    • White: 38%
    • Black: 42%
    • Other: 20%
  • Median age (range): 14.6-18.9
  • Previous chlamydia infection: 27%
  • HIV or AIDS: 99% not present (1%not collected)
  • Median No. sexual partners in past 12 months: 3(2-6)
  • Male Participant
    • Painful urination: 20%
    • Penile discharge: 5%
    • Pain in scrotum/testicules: 2%
    • Previous history nongonococcal urethritis: 0%
    • Previous epididymitis: 0%
  • Female Participant
    • Painful urination: 6%
    • Abnormal vaginal discharge: 51%
    • Irregular vaginal bleeding: 11%
    • Pelvic pain: 17%
    • History Pelvic Inflammatory Disease: 4%
    • Hormone Contraceptive: 8%

Interventions

  • Azithromycin 1 gram in a single dose
  • Doxycycline 100 mg orally twice daily for 7 days
  • Follow-up visits:
    • Day 28 - if still in facility after enrollment
    • Day 67 - if still in facility after enrollment
  • suspected treatment failures were tested for genotyping to determine concordant strains

Outcomes

Comparisons are azithromycin(n=155 per-protocol) vs. doxycycline(n=155 per-protocol)

Primary Outcomes

Treatment failure
3.2% (95% CI 0.4-7.4)vs. 0%(95% CI 0.0-2.4), (difference 3.2%, 90% CI 0%-5.9%, noninferiority not met), NNH31

Secondary Outcomes

Adherence
1% in the azithromycin group vomited within 1 hour, and a second dose was administered successfully
23% in the doxycycline group received <14 dose treatment course
Zero patients were excluded from Per-Protocol due to insufficient doses

Adverse Events

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

Criticisms

  • Adherence External validity
    • challenged with the staff administering all doses
    • supported given that 23% of doxycycline group not fully-adherent
  • External validity hampered due to using a single geographic location
  • Per-protocol population was 55% of the intention-to-treat population
  • The gender imbalance may skewed the results
  • alpha=0.10 used for power calculation otherwise sample size would have been "unatainable"
  • use of oral and rectal screening may have captured a larger population for evaluation[5][6]

Funding

Funded by National Institute of Allergy and Infectious Diseases

Further Reading