Pulsed Azithromycin Matches Doxycycline for Meibomian Dysfunction, With Fewer AEs

A short course of azithromycin matched a standard doxycycline regimen for relief of severe meibomian gland dysfunction (MGD) and caused fewer adverse events (AEs), a randomized trial showed.

After 6 weeks of follow-up, weekly azithromycin for 3 weeks achieved a similar reduction in total MGD score (P=0.01 for equivalence) and the Ocular Surface Disease Index (OSDI; P=0.02) as compared with 6 weeks of doxycycline. Assessment at 8 weeks showed the between-group differences in both outcomes had increased (P<0.001).

The azithromycin regimen was associated with almost a fourfold reduction in gastrointestinal AEs, reported Chulaluck Tangmonkongvoragul, MD, of Chiang Mai University in Thailand, and co-authors in JAMA Ophthalmology.

"The evidence of equivalence of both treatments in reducing MGD score at the sixth week was robust, but not at the eighth week," the authors wrote. "Although MGD was associated with the presence of dry eye symptoms, in our study, at both time points, the reduction in OSDI score was not considered clinically relevant."

"The reduced dosing of azithromycin supports its use as an alternative to doxycycline for at least 6 weeks," they added. "However, longer-term follow-up in each group would be needed to determine if these outcomes persist for this chronic condition."

Prior randomized controlled trials of antibiotics for MGD have been limited by high attrition rates, selective reporting, and small sample sizes, noted B. Michele Melia, ScM, of the Jaeb Center for Health Research in Tampa, Florida, in an accompanying editorial. The current study addressed the major deficiencies of earlier studies, with one exception.

"The test of the equivalence hypothesis is not justified due to the absence of prior high-quality RCTs [randomized clinical trials] supporting use of antibiotics for MGD," Melia wrote. "Absent such evidence, there is a risk of declaring equivalence of the two antibiotics, when the efficacy of one or both antibiotics may not be significantly better than a placebo. When testing an equivalence hypothesis, the efficacy of the standard active treatment must be definitively established."

"For those in clinical practice who are using oral doxycycline to treat MGD with dosing as in this trial, this trial provides strong evidence that switching to azithromycin provides similar efficacy with lower risk of gastrointestinal adverse effects," she added. "However, it must also be recognized there is a possibility that one or both treatments are no better than conservative management or no better than no treatment at all."

MGD arises from terminal duct obstruction or changes in glandular secretion, leading to production of bacterial lipolytic enzymes, tear-film instability, and ocular surface inflammation. The condition has an estimated global prevalence of 36%, surpassing 50% in East Asia.

Initial therapy consists of eyelid warming and massage, artificial tears, topical antibiotics, and topical anti-inflammatories. For moderate or severe MGD, a 6-week course of doxycycline is common, but compliance with the extended regimen and frequent gastrointestinal AEs make the treatment problematic, Tangmonkongvoragul and team noted.

Several different azithromycin regimens have been evaluated in MGD, most involving shorter-duration treatment, which makes it a potentially attractive alternative to doxycycline.

"Dosing azithromycin 1 g per week for 3 weeks [pulsed dosing] for MGD should provide effective drug tissue levels for more than 1 month with a treatment regimen that could result in better patient compliance than therapies requiring daily dosing," the authors wrote.

Tangmonkongvoragul and colleagues evaluated pulsed dosing of azithromycin in a randomized trial involving patients with MGD that had not responded to initial therapies. Patients were allocated to azithromycin for 3 weeks or standard daily doxycycline (BID) for 6 weeks. The primary objective was therapeutic equivalence, as assessed by the MGD score and OSDI at 6 and 8 weeks. Gastrointestinal AEs were a key secondary objective.

Data analysis included 137 patients and 137 eyes. Baseline variables were balanced, including MGD total score and OSDI, requiring no adjustments for statistical analyses.

Baseline mean MGD score was 12.94-12.95 in the two groups. At 6 weeks, the mean score had decreased to 7.63 in the azithromycin group and 7.98 in the doxycycline arm. At 8 weeks, these scores were 6.14 and 6.03, respectively.

Baseline OSDI score averaged 18-19 in the two groups, decreasing to 14.31 at 6 weeks with azithromycin and 14.41 with doxycycline. At 8 weeks, the mean scores were 11.14 and 11.63, respectively.

Gastrointestinal AEs (nausea, vomiting, dyspepsia, abdominal cramping, and decreased appetite) occurred in 4.4% of the azithromycin arm versus 15.9% of the doxycycline arm (P=0.03). Two patients in the doxycycline arm requested discontinuation versus none in the azithromycin group.

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