Randomised controlled trial of single-dose azithromycin in treatment of trachoma

doi:10.1016/0140-6736(93)91591-9

The Lancet

Volume 342, Issue 8869, 21 August 1993, Pages 453-456

https://doi.org/10.1016/0140-6736(93)91591-9 Get rights and content

Abstract

Blindness due to trachoma is a serious public health issue world wide. The currently recommended treatment of active trachoma with repeated doses of tetracycline eye ointment has many disadvantages. The new azalide antibiotic azithromycin is effective as a single oral dose in the chemotherapy of genital Chlamydia trachomatis infections, and we have assessed its efficacy for trachoma treatment. We carried out a randomised single-blind comparison of azithromycin (a single oral dose of 20 mg/kg) with conventional treatment (6 weeks of topical tetracycline plus erythromycin for severe cases) in two villages with endemic trachoma in The Gambia. The patients were followed up for 26 weeks from the start of treatment by an observer unaware of treatment allocation. By 6 months' follow-up, trachoma had resolved in 76 (78%) of 97 subjects who received azithromycin compared with 70 (72%) of 97 who were treated conventionally (95% Cl for difference - 6% to 18%). Compliance with both treatments was good, but that for conventional treatment could probably not be achieved outside the research setting. There were no significant differences in treatment effect, baseline characteristics, or re-emergent disease between the treatment groups. Azithromycin was well tolerated. As a systemic treatment effective in a single dose it has important potential for trachoma control.

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Cited by (191)

Safety of integrated mass drug administration of azithromycin, albendazole and ivermectin versus standard treatment regimens: a cluster-randomised trial in Ethiopia
2023, eClinicalMedicine
Neglected Tropical Disease (NTD) programs require separate and distinct drug regimens for treatment. This has required countries to undertake multiple independent mass drug administration (MDA) programmes, each targeting one or more diseases. The possibility of safely combining different drug regimens together in one MDA may offer several advantages to national programs. We conducted a study to assess the safety of combining ivermectin, albendazole and azithromycin in one integrated MDA.
We conducted an open-label, non-inferiority cluster-randomised trial comparing the frequency of adverse events in communities receiving co-administered ivermectin, albendazole and azithromycin to that in communities given albendazole and ivermectin MDA followed by azithromycin MDA after a two-week interval. The study took place in 58 gares (small administrative units) across two kebeles (sub-districts) in Kofele woreda (district) in the Oromia region of Ethiopia. We randomly assigned 29 gares to the combined treatment arm and 29 gares to the control arm. The study team revisited all individuals within 48 h and actively collected data on the occurrence of adverse events using a dedicated questionnaire and a pre-specified list of adverse events. The study team followed the same process in the control arm for the azithromycin distribution and again after the ivermectin plus albendazole distribution. Following this initial active surveillance, passive surveillance was undertaken for one week after the first visit. The primary outcome was the frequency of adverse events occurring following MDA. The study team determined that the safety of the combined MDA would be non-inferior to that of separate MDAs if the upper limit of the two-sided CI for the difference in rates was equal to or lower than 5%. The trial was registered with ClinicalTrials.gov, NCT03570814.
The study took place from December 2021 to January 2022. The combined MDA arm consisted of 7292 individuals who were eligible to participate, of whom 7068 received all three medications. The separate MDA arm consisted of 6219 eligible individuals of whom 6211 received ivermectin and albendazole and 4611 received azithromycin two weeks later. Overall, adverse events were reported by 197 (1.2%) of individuals. The most commonly reported adverse events included headache, gastrointestinal disturbance and dizziness. There were no serious adverse events in either arm. The cluster-level mean frequency of reported adverse events varied markedly between clusters, ranging from 0.1 to 10.4%. The cluster-level mean frequency of adverse events was 1.4% in the combined MDA arm and 1.2% following ivermectin and albendazole MDA (absolute difference 0.2%, 95% confidence interval [CI] −0.6% to +1.1%). This met the pre-defined 1.5% non-inferiority margin. For the combined MDA comparison to the stand-alone azithromycin MDA the absolute difference was −0.4% (1.4 versus 1.8%, 95% CI −0.8 to +1.5) which also met the pre-specified non-inferiority margin.
This study is the largest of its kind to date and demonstrates that the safety of combined MDA of azithromycin, ivermectin and albendazole is non-inferior to the safety of ivermectin-plus-albendazole MDA then azithromycin MDA conducted separately although we may not have been powered to detect very small differences between arms. Co-administration of these three medicines is safe and feasible in this setting and allows national programs to develop new strategies for integrated MDA programs.
Ivermectin (Mectizan) was donated by the Mectizan Donation Program, albendazole was donated by GlaxoSmithKline, and azithromycin (Zithromax®) was donated by Pfizer via the International Trachoma Initiative (ITI). The trial was funded by ITI using operational research funds from the Bill and Melinda Gates Foundation.
Prevalence of nasopharyngeal Streptococcus pneumoniae carriage and resistance to macrolides in the setting of azithromycin mass drug administration: analysis from a cluster-randomised controlled trial in Malawi, 2015–17
2022, The Lancet Microbe
Azithromycin mass drug administration (MDA) could reduce child mortality. However, macrolide resistance, which has generally been reported to develop after whole-community MDA for trachoma control, is a concern, and it has less commonly been studied in the context of treating children to reduce mortality. Here, we report on macrolide resistance after biannual azithromycin MDA at the Malawi site of the MORDOR study.
In the MORDOR cluster-randomised trial in Malawi, 30 communities in Mangochi District were randomly selected. Communities were randomly assigned to receive azithromycin or placebo by simple randomisation without stratification. Children aged 1–59 months were administered azithromycin 20 mg/kg or placebo as an oral suspension biannually for a total of four treatments in 2015–17. 1200 children (40 children per community) were randomly selected for nasopharyngeal swabs at baseline, 12 months (6 months after the second treatment visit), and 24 months (6 months after the fourth treatment visit). Samples were processed to culture Streptococcus pneumoniae. The primary outcome was the proportion of S pneumoniae isolates exhibiting macrolide resistance at 12 months and 24 months, assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02048007.
At baseline, 3467 (76%) of 4541 eligible children in the azithromycin group and 3107 (72%) of 4308 eligible children in the placebo group were treated. 564 nasopharyngeal swabs were taken from the azithromycin group and 563 from the placebo group, with similar numbers of swabs taken at 12 months and 24 months. In both groups at baseline, carriage of S pneumoniae was greater than 85% and the proportion of strains resistant to macrolides was 28%. At the 12-month follow-up, macrolide resistance was higher in the azithromycin group (36·9%, 95% CI 32·5–41·2) than in the placebo group (21·6%, 17·7–25·4; OR 2·26, 95% CI 1·46–3·49; p=0·0002). At 24 months, macrolide resistance remained higher in the azithromycin group (43·9%, 39·2–48·5) compared with placebo (32·8%, 28·5–37·1; OR 1·66, 1·15–2·40; p=0·0069).
These findings support previous evidence from trachoma MDA programmes and suggest that monitoring of macrolide resistance should remain a key component of azithromycin interventions for reducing child mortality.
Bill & Melinda Gates Foundation.
Trachoma: Time to Talk Eradication
2020, Ophthalmology
Eye Infections in the Tropics
2017, Infectious Diseases, 2-Volume Set
Chlamydia (Trachoma and Sexually Transmitted Infections)
2016, International Encyclopedia of Public Health
Chlamydia trachomatis is the most common bacterial sexually transmitted infection, and the most common infectious cause of blindness. Oculogenital strains (serovars D–K) cause a number of common clinical syndromes of the urogenital tract, as well as conjunctivitis in newborns and sexually active adults. In poor rural populations, trachoma strains (serovars A, B, and C) are responsible for trachoma, the commonest infectious cause of blindness. Serovars L1, L2, and L3 cause lymphogranuloma venereum, a more invasive sexually transmitted disease. Successful control of these conditions will require both medical interventions and behavioral change through health education.
Safety of Integrated Mass Drug Administration of Azithromycin, Albendazole and Ivermectin Versus Standard Treatment Regimens: A Cluster Randomised Trial in Ethiopia
2023, SSRN

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ArticlesRandomised controlled trial of single-dose azithromycin in treatment of trachoma

Abstract

Lancet

A guide to trachoma control

The epidemiology of trachoma predicts more blindness in the future

Scand J Infect Dis

Strategies for the prevention of blindness in national programmes: a primary health care approach

Sociomedical aspects of trachoma

Acta Ophthalmol

Treatment of trachoma in the West Bank

Eye

The impact of medical services on trachoma in a Gambian village: antibiotics alone are not the answer

Ann Trop Paediatr

In vitro activity of azithromycin, erythromycin, ciprofloxacin and norfloxacin against Neisseria gonorrhoeae, Haemophilus ducreyi, and Chlamydia trachomatis

J Antimicrob Chemother

Articles
Randomised controlled trial of single-dose azithromycin in treatment of trachoma