Childhood ocular rosacea is believed to be the consequence of chronic meibomian gland dysfunction. Secondary staphylococcal infection of the lid margin is often present and is probably responsible for the corneoconjunctival inflammation by means of an immunological specific T cell response. This combined mechanism explains the efficacy of both topical anti-inflammatory drugs (steroids or cyclosporine) and systemic antibiotics such as macrolides or tetracyclines.
Azithromycin is a new treatment option for cutaneous rosacea and seems to be as effective as tetracyclines
], and its efficacy in treating ocular rosacea has been demonstrated when administered orally
Azithromycin eye drops are now available for the treatment of bacterial conjunctivitis, and in this indication, azithromycin 1.5% eye drops given twice daily for 3 days is as effective as tobramycin 0.3% eye drops four times a day for 7 days
Our study showed that topical azithromycin 1.5% is a very effective treatment of ocular rosacea in children. Its efficacy on conjunctival and corneal inflammation is remarkable. However, because of the delayed action on corneal inflammation, prior clinical experience has shown that very severe cases with vision threat should be concomitantly treated with topical steroids and/or cyclosporine. Oral erythromycin is usually prescribed in childhood ocular rosacea
]. In this study, in one patient who had been unsuccessfully treated with oral erythromycin, replacement by azithromycin resulted in a complete control of inflammation. Our previous treatment strategy was to use oral erythromycin as a first-line treatment in combination with lid hygiene. However, our early experience with topical azithromycin showed us that this local treatment was superior to systemic erythromycin. This is why we decided to use, since then, topical azithromycin as a first-line therapy. Topical azithromycin has several advantages over oral antibiotics. Azithromycin has a very long half-life, with significant tissular accumulation and concentrations. In a rabbit model, after administration of 1% azithromycin ophthalmic solution, significant concentrations are detected in the tears, conjunctiva, cornea, and lids for as long as 6 days in the lids
]. Concentrations in the tears, conjunctiva, and cornea remained above minimal inhibitory concentrations for respectively 7, 17, and more than 24 days after instillation of Azyter® (Thea Laboratories, Clermont-Ferrand, France) twice a day (bid) for 3 days
]. This is why we chose a discontinuous treatment regimen which was very simple for the patients; one treatment corresponds to one box of eye drops, and so the initial scheme of three treatments per month tapered to two and then one per month was convenient, easy to understand, and well accepted by the children and their parents. The initial dosing (3 days three times monthly) was chosen because of the 7-day persistence of azithromycin in the tears. The tapering scheme was chosen empirically. Oral erythromycin has to be taken twice daily for a continuous period of several weeks. In the 16 patients studied, topical azithromycin did not induce systemic side effects, whereas oral erythromycin frequently induces gastrointestinal troubles. Oral metronidazole has also been proposed as a treatment for ocular rosacea, but while it seems to be an effective treatment, the fact that short-course therapy is required in order to avoid peripheral neuropathy may result in more frequent relapses
Few publications reported the efficacy of topical antibiotics in this disease. In a retrospective study by Viswalingam et al., topical chloramphenicol eyedrops four times daily for 1 month and chloramphenicol ointment at night for 4 months were successfully prescribed in mild to moderate cases
]. Azithromycin ophthalmic solution 1% has been evaluated in posterior blepharitis in adults in two small studies
]. In one study, meibum quality and lid margin redness improved more in patients treated with lid hygiene and azithromycin for 2 weeks than in controls treated with only lid hygiene. In the second study, symptoms, meibum quality, and lid margin redness improved after treatment with lid hygiene and azithromycin for 4 weeks. While we did not specifically analyze the posterior lid margin in our study, the effect of topical azithromycin on anterior blepharitis was noticeable, and no chalazia were noted.
Topical steroids are frequently prescribed in children with ocular rosacea and phlyctenular blepharokeratoconjunctivitis, but relapses occur after the end of the treatment in up to 40% of cases
]. Treatment duration is a key element for avoiding recurrences. In our study, treatment was stopped after 4 to 10 months, and no recurrence was observed during a median follow-up of 11 months (8 to 14 months). Long-term treatments are usually required to control the inflammation. A complete disappearance of the phlyctenules and corneal infiltrates is necessary before stopping the treatment, which was attained in 3 to 6 months in the majority of children included in this study with topical azithromycin. This minimal treatment duration is comparable with topical cyclosporine
] or topical chloramphenicol
]. Such duration is not acceptable with topical steroids because of the risk of ocular complications. In our series, topical steroids were withdrawn in all patients when topical azithromycin was prescribed, and none of the patients required additional steroid therapy thereafter.
In a previous study, we showed that topical 2% cyclosporine is a very potent treatment of phlyctenular blepharokeratoconjunctivitis
]. The efficacy of topical azithromycin was sufficient in most cases, but as clinical experience indicates that topical cyclosporine may have greater efficacy, patients with very severe corneal inflammation were prescribed topical cyclosporine as first-line treatment.
A biphasic effect was observed in this study. The effect on ocular redness was very fast, within a month, whereas phlyctenules and corneal infiltrates took several months to heal. This may point to different mechanisms. Ocular redness might be related to bacterial toxin production. Phlyctenules and corneal infiltrates are thought to be caused by a type IV cell-mediated delayed hypersensitivity reaction against parietal staphylococcal antigens
]. In addition to its antibiotic effect, azithromycin also has anti-inflammatory effects. Indeed, it has been shown to reduce the production of the pro-inflammatory cytokines IL-12 and IL-6 by macrophages in vitro
]; to suppress matrix metalloproteases 2 and 9, nuclear transcription factor NFkB, and Toll-like receptor 2 in corneal epithelial cells in vitro
]; and to inhibit macrophage and dendritic cell migration after corneal burn in a mouse model
The safety profile of topical 1.5% azithromycin seems good in children suffering from ocular rosacea. Discontinuous treatment with topical 1.5% azithromycin was well tolerated. Local intolerance was seen in a small number of cases and was usually mild, except in two patients who stopped the treatment after 5 and 10 months, respectively. Comparable side effects have been reported in the literature
The main limitation of our study is the small number of patients, but rosacea in children is infrequent, and the largest series published to date included 44 children
]. The retrospective nature of this study is also an important limitation. A multicenter prospective controlled study should be the next step for evaluating azithromycin eyedrops in childhood ocular rosacea.