Doxycycline Barely Beats Azithromycin for Chlamydia

Tara Haelle

December 24, 2015

Azithromycin is less effective than doxycycline in treating chlamydia when treatment compliance is high, according to a randomized trial published in the December 24 issue of the New England Journal of Medicine. With an efficacy of 97%, azithromycin failed to meet the standard of noninferiority compared with doxycycline, with an efficacy of 100%.

"It is unclear why all the treatment failures in our study occurred in azithromycin-treated participants," write William M. Geisler, MD, MPH, from the University of Alabama at Birmingham Department of Medicine, and colleagues. They propose that resistance to the drug is an unlikely possibility, but that some patients did not have sufficient levels of azithromycin to eradicate chlamydia. "Even with sufficient levels, it is possible that some organisms are not eradicated in acute infection," as a previous in vitro study suggested, they write.

Yet the use of a "unique adolescent population in correctional facilities" calls the current study's generalizability into question, write Thomas C. Quinn, MD, and Charlotte A. Gaydos, DrPH, both from the Johns Hopkins University School of Medicine in Baltimore, Maryland, in an accompanying editorial.

The researchers compared the effectiveness of a single, 1-g dose of azithromycin vs 100 mg of doxycycline twice daily for 7 days to treat chlamydia in 567 adolescents aged 12 to 21 years in youth correctional facilities in Los Angeles, California. Because this was a noninferiority study, the researchers used a per protocol analysis instead of an intent-to-treat analysis, resulting in 155 participants in each treatment group.

At a 28-day follow-up, no treatment failures had occurred in the doxycycline group, and treatment failed in 3.2% of participants receiving azithromycin (95% confidence interval, 0.4% - 7.4%). The researchers used genotyping to differentiate treatment failures from new infections, defining noninferiority based on the percentage point difference in treatment failures between the two groups, with 5 percentage points set as the cutoff for the upper boundary within a 90% confidence interval. The treatment difference of 3.2% had an upper boundary of 5.9 percentage points in the 90% confidence interval, thereby missing the threshold for noninferiority. The authors note that two fewer failures in the azithromycin group would have achieved noninferiority.

Two participants in the azithromycin group (1%) vomited the medication within an hour after taking it but successfully kept down a second dose. Only 77% of the participants in the doxycycline group received all 14 doses because of setting logistics. All others received at least 11 doses, and at most 16 doses, with 12% receiving 13 doses. The most common adverse event reported was gastrointestinal symptoms in both groups. Adverse events were similar in both groups, reported by 23% of those receiving azithromycin and 27% of those receiving doxycycline.

"Because doxycycline is not given under direct observation in practice outside institutional settings, the generalizability of our findings is unknown," the authors note. "When chlamydia treatment is provided in real-world clinical practice, the possibility that the efficacy of doxycycline could be offset by limited adherence should be taken into consideration."

Although two previous studies suggest anywhere from 3% to 28% of individuals miss at least one dose of doxycycline when taking it for chlamydia, another study suggested adherence is over-reported.

"The ease of administration of single-dose azithromycin addressed the problem of nonadherence to doxycycline treatment," write Dr Quinn and Dr Gaydos in their editorial, referring to the study that established azithromycin as a viable alternative treatment to doxycycline. Despite the current study's finding that azithromycin failed to be noninferior to doxycycline, "there are several caveats to consider," they write. "Because directly observed administration of doxycycline is not always possible, the higher efficacy of doxycycline could be offset by limited adherence to a multiple-dose regimen," they add, as the study authors suggest as well.

The editorialists also reiterate the authors' note that just a handful fewer treatment failures would have changed the evaluation of azithromycin's noninferiority, and they suggest a reasonable alternative margin for noninferiority assessment.

"Thus, with the above caveats in mind, it does not seem reasonable to recommend doxycycline over azithromycin as the preferred regimen for chlamydia treatment," Dr Quinn and Dr Gaydos write. "We believe that the current [Centers for Disease Control and Prevention] recommendation that either drug be used in the treatment of persons with chlamydia infection seems appropriate and remains valid."

The research was funded by the National Institute of Allergy and Infectious Diseases. Dr Geisler reports receiving grant support from ActivBiotics Pharma. The other authors and the editorialists have disclosed no relevant financial relationships.

N Engl J Med. 2015;373:2512-2521, 2573-2575. Article abstract, Editorial extract/

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