Doxycycline Trumps Azithromycin for Asymptomatic Rectal Chlamydia in Men Who Have Sex With Men

Judy Stone, MD

June 29, 2021

A 1-week course of doxycycline is more effective than single-dose azithromycin to treat rectal chlamydia in men who have sex with men (MSM), according to newly published results in the New England Journal of Medicine.

Chlamydia is the most commonly reported bacterial sexually transmitted infection in the United States, with 4 million cases reported in 2018, and 127 million globally. Most infections are asymptomatic.

Rates of rectal chlamydia among MSM screened for infection range from 3% to 10.5%.

The most recent Centers for Disease Control and Prevention (CDC) chlamydia guidelines recommend either a single dose of azithromycin (1 gm) or doxycycline 100 mg twice daily for 7 days. These 2015 guidelines were based on a meta-analysis of urogenital chlamydia infections, which showed comparable efficacy of 97% or 98%, respectively.

Dr Jane S. Hocking

Study coauthor Jane S. Hocking, PhD, head of the Sexual Health Unit at the University of Melbourne's School of Population and Global Health in Australia, told Medscape Medical News that "observational studies had suggested that azithromycin was about 20% less effective than doxycycline," prompting this clinical trial.

The study, conducted at five sexual health clinics in Australia, was a double-blind, randomized, controlled trial of doxycycline (100 mg twice daily for 7 days) or azithromycin (1 gm single dose).

Because 85% of infected men are asymptomatic, the study's primary outcome was a negative nucleic acid amplification test at 4 weeks, confirming a microbiologic cure.

Using a modified intention-to-treat population, the study showed a microbiologic cure in 281 of 290 men (96.9%) in the doxycycline group and 227 of 297 (76.4%) in the azithromycin group (P < .001).

Adverse events were more common in the azithromycin group. Nausea, diarrhea, and vomiting occurred in 134 (45.1%) men in that group vs 98 men (33.8%) in those receiving doxycycline (P = .006).

A similar study was reported in Clinical Infectious Diseases in February 2021 by Dombrowski et al. It was also randomized, double-blinded, and placebo-controlled but was smaller and conducted in Seattle and Boston. A 20% difference was found, with 80/88 (91%) in the doxycycline group and 63/89 (71%) in the azithromycin group having a microbiologic cure at 4 weeks of follow-up.

Dr Jeanne Marrazzo

Jeanne Marrazzo, MD, director of the division of infectious diseases at the University of Alabama at Birmingham, told Medscape Medical News that the researchers focused solely on asymptomatic proctitis because "other symptoms might indicate need for broader presumptive antibiotics" for coinfections. Similarly, symptomatic proctitis "could indicate LGV [lymphogranuloma venereum] chlamydia, which…automatically mandates that 3-weeks of doxycycline be used." Marrazzo concluded, "The fact that this was a blinded study obviously strengthens the conclusions/findings, which is great. It's very reassuring that results overall are so consistent with the CID paper." Marrazzo was not involved in either the New England Journal of Medicine investigation or CID study.

Dr Ina Park

Ina Park, MD, associate professor in the Department of Family and Community Medicine at the University of California San Francisco School of Medicine and author of Strange Bedfellows: Adventures in the Science, History, and Surprising Secrets of STDs, was not involved in either study but has a long history of working with adolescents in clinics for sexually transmitted diseases. Based on that experience, she told Medscape Medical News that while doxycycline now clearly appears to be the drug of choice, "if compliance is an issue and rectal chlamydia is not likely, then I think azithromycin is still something we need to consider, particularly for younger patients, and folks for whom compliance is going to be an issue." She added, "with adolescent patients, there are issues of parents possibly discovering the antibiotic and asking lots of questions. So, it's very nice for folks to be able to get therapy, sort of a one and done approach in the clinic."

The 2020 CDC Guidelines for Gonococcal Infections says, "CDC recommends a single 500 mg intramuscular dose of ceftriaxone for uncomplicated gonorrhea. Treatment for coinfection with Chlamydia trachomatis with oral doxycycline (100 mg twice daily for 7 days) should be administered when chlamydial infection has not been excluded."

Hocking concluded — and Marrazzo and Park concur — that this study "provides conclusive evidence that doxycycline should be the first-line treatment for rectal chlamydia, but probably for just any chlamydia infection," with specific exceptions.

The University of Melbourne researchers also noted that the doxycycline course requires more compliant patients, as adherence isn't assured. The issue of compliance and need for directly observed therapy, allergy to doxycycline, and pregnancy (where doxycycline is contraindicated) will remain the primary indications for continued use of azithromycin.

N Engl J Med. Published online June 24, 2021. DOI: 10.1056/NEJMoa2031631. Abstract

Hocking, Marrazzo, and Park reported no relevant financial relationships.

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