Topical azithromycin and oral doxycycline therapy of meibomian gland dysfunction: a comparative clinical and spectroscopic pilot study

Abstract

Purpose: Meibomian gland dysfunction (MGD) is a common clinical problem that is often associated with evaporative dry eye disease. Alterations of the lipids of the meibomian glands have been identified in several studies of MGD. This prospective, observational, open-label clinical trial documents the improvement in both clinical signs and symptoms of disease as well as spectroscopic characteristics of the meibomian gland lipids after therapy with topical azithromycin ophthalmic solution and oral doxycycline treatment.

Methods: Subjects with symptomatic MGD were recruited. Signs of MGD were evaluated with a slit lamp. Symptoms of MGD were measured by the response of subjects to a questionnaire. Meibum lipid-lipid interaction strength, conformation, and phase transition parameters, and meibum protein content were measured using Fourier transform infrared spectroscopy and principal component analysis. Terpenoids, short-chain CH3 moieties, lipid oxidation, wax, cholesterylesters and glycerides were measured with a proton nuclear magnetic resonance (H-NMR) spectrometer.

Results: Topical therapy with azithromycin and oral therapy with doxycycline relieved signs and symptoms and restored the lipid properties of the meibomian gland secretion toward normal. Compared with 4 weeks of azithromycin treatment reported in our previous study, oral doxycycline treatment was slightly less effective in improving foreign body sensation and the signs of plugging and secretion. In subjects with clinical evidence of MGD, changes in ordering of the lipids and phase transition temperature were brought closer to normal with azithromycin treatment than doxycycline treatment. Treatment with doxycycline but not azithromycin restored the Fourier transform infrared spectroscopy-principal component analysis scores and relative area of the H-NMR resonance at 1.26 ppm. Both doxycycline and azithromycin treatment restored the levels of the relative areas of the H-NMR resonance at 5.2 and 7.9 ppm to normal levels. The levels of meibum protein and meibum lipid oxidation were not influenced by azithromycin or doxycycline treatment.

Conclusions: The mechanism of action of doxycycline may be different from that of azithromycin in therapy of MGD. It is notable that when carotenoids in meibum are low, as in MGD, the tear film is unstable and patients have the signs and symptoms of dry eyes. When carotenoids are restored with azithromycin and doxycycline treatment, tear film stability is restored and patients no longer have the signs and symptoms of dry eyes.

Figure 1

A) Patients with MGD reported global improvement in symptoms in response to 8 weeks of oral doxycycline therapy. FBS: foreign body sensation, NS: not statistically significant (p > 0.05). Filled bars: Subjects with MGD prior to treatment. Open bars: Patients after 8 weeks of doxycycline treatment. B) Signs of MGD were improved in patients with MGD in response to 8 weeks of oral doxycycline therapy. Symptoms were assessed from a questionnaire. C) Improvement in symptoms after 8 weeks of doxycycline therapy, open bars, compared with published improvement in symptoms after 4 weeks topical azithromycin therapy (filled bars). D) Improvement in signs after 8 weeks of doxycycline therapy, open bars, compared with published improvement in signs after 4 weeks topical azithromycin therapy (filled bars). * Statistically significant difference, p < 0.05.

Figure 2

Tear breakup time increased significantly after 8 weeks of oral doxycycline treatment (open bars) compared to patients with MGD prior to treatment (filled bars).

Figure 3

Data from the FTIR spectra of human meibum. Open bars: data are from a published azithromycin study. Filled bars: data from a larger study. A) Hydrocarbon order of Mn and Md at 33.4°C was not statistically different in patients after 8 weeks of oral doxycycline therapy (gray bars) and 1 month after treatment was stopped. More order indicates stiffer lipids with stronger lipid-lipid interactions. B) The phase transition temperatures of Md and Mn were not statistically different in patients after 8 weeks of oral doxycycline therapy (gray bars) and 1 month after treatment was stopped.

Figure 4

Data from the FTIR spectra of human meibum. Gray bars: azythromycin study. Filled bars: data is from a larger published study. * statistically significant difference p < 0.05. Principal Component analysis was used to analyze the CH and OH stretching region from 3612 to 2490 cm⁻¹ and the fingerprint region from 1814 to 676 cm⁻¹. Based on a training set of 77 infrared spectra from Md and Mn, scores were assigned to the spectra. A score higher than 59 indicates that the infrared spectra is similar to the spectra of Md. A score lower than 59 indicates that the infrared spectra are similar to the spectra of Mn.

Figure 5

Data from the FTIR spectra of human meibum. Gray bars: azythromycin study. Filled bars: data is from a larger published study. * Statistically significant difference, p < 0.05. MGD: meibomian gland dysfunction.

Figure 6

Data from ¹H-NMR spectra of human meibum. Gray bars: azythromycin study. Filled bars: data are from a larger published study (labled MGD and Normal).^, Open bars: doxycycline study(labled DCN). A) The resonance at 5.2 ppm has been tentatively assigned to terpenoids.^, B) The resonance at 5.4 is assigned to unconjugated =CH protons. C) The resonance at 1.26 ppm has been tentatively assigned to short chain CH₃ moieties.^, *Statistically significant difference, p < 0.05.