We hypothesized that mass distribution of a broad-spectrum antibiotic agent to preschool children would reduce mortality in areas of sub-Saharan Africa that are currently far from meeting the Sustainable Development Goals of the United Nations. In this cluster-randomized trial, we assigned communities in Malawi, Niger, and Tanzania to four twice-yearly mass distributions of either oral azithromycin (approximately 20 mg per kilogram of body weight) or placebo. Children 1 to 59 months of age were identified in twice-yearly censuses and were offered participation in the trial. Vital status was determined at subsequent censuses. The primary outcome was aggregate all-cause mortality; country-specific rates were assessed in prespecified subgroup analyses. A total of 1533 communities underwent randomization, 190,238 children were identified in the census at baseline, and 323,302 person-years were monitored. The mean (±SD) azithromycin and placebo coverage over the four twice-yearly distributions was 90.4±10.4%. The overall annual mortality rate was 14.6 deaths per 1000 person-years in communities that received azithromycin (9.1 in Malawi, 22.5 in Niger, and 5.4 in Tanzania) and 16.5 deaths per 1000 person-years in communities that received placebo (9.6 in Malawi, 27.5 in Niger, and 5.5 in Tanzania). Mortality was 13.5% lower overall (95% confidence interval [CI], 6.7 to 19.8) in communities that received azithromycin than in communities that received placebo (P<0.001); the rate was 5.7% lower in Malawi (95% CI, −9.7 to 18.9), 18.1% lower in Niger (95% CI, 10.0 to 25.5), and 3.4% lower in Tanzania (95% CI, −21.2 to 23.0). Children in the age group of 1 to 5 months had the greatest effect from azithromycin (24.9% lower mortality than that with placebo; 95% CI, 10.6 to 37.0). Serious adverse events occurring within a week after administration of the trial drug or placebo were uncommon, and the rate did not differ significantly between the groups. Evaluation of selection for antibiotic resistance is ongoing. Among postneonatal, preschool children in sub-Saharan Africa, childhood mortality was lower in communities randomly assigned to mass distribution of azithromycin than in those assigned to placebo, with the largest effect seen in Niger. Any implementation of a policy of mass distribution would need to strongly consider the potential effect of such a strategy on antibiotic resistance. (Funded by the Bill and Melinda Gates Foundation; MORDOR ClinicalTrials.gov number, NCT02047981.)

ObjectiveTo compare topical natamycin vs voriconazole in the treatment of filamentous fungal keratitis.MethodsThis phase 3, double-masked, multicenter trial was designed to randomize 368 patients to voriconazole (1%) or natamycin (5%), applied topically every hour while awake until reepithelialization, then 4 times daily for at least 3 weeks. Eligibility included smear-positive filamentous fungal ulcer and visual acuity of 20/40 to 20/400.Main Outcome MeasuresThe primary outcome was best spectacle-corrected visual acuity at 3 months; secondary outcomes included corneal perforation and/or therapeutic penetrating keratoplasty.ResultsA total of 940 patients were screened and 323 were enrolled. Causative organisms included Fusarium (128 patients [40%]), Aspergillus (54 patients [17%]), and other filamentous fungi (141 patients [43%]). Natamycin-treated cases had significantly better 3-month best spectacle-corrected visual acuity than voriconazole-treated cases (regression coefficient = −0.18 logMAR; 95% CI, −0.30 to −0.05; P = .006). Natamycin-treated cases were less likely to have perforation or require therapeutic penetrating keratoplasty (odds ratio = 0.42; 95% CI, 0.22 to 0.80; P = .009). Fusarium cases fared better with natamycin than with voriconazole (regression coefficient = −0.41 logMAR; 95% CI, −0.61 to −0.20; P < .001; odds ratio for perforation = 0.06; 95% CI, 0.01 to 0.28; P < .001), while non- Fusarium cases fared similarly (regression coefficient = −0.02 logMAR; 95% CI, −0.17 to 0.13; P = .81; odds ratio for perforation = 1.08; 95% CI, 0.48 to 2.43; P = .86).ConclusionsNatamycin treatment was associated with significantly better clinical and microbiological outcomes than voriconazole treatment for smear-positive filamentous fungal keratitis, with much of the difference attributable to improved results in Fusarium cases.Application to Clinical PracticeVoriconazole should not be used as monotherapy in filamentous keratitis.Trial Registrationclinicaltrials.gov Identifier: NCT00996736

Research from JAMA — Effect of Mass Distribution of Azithromycin for Trachoma Control on Overall Mortality in Ethiopian Children — A Randomized Trial

Research from JAMA Ophthalmology — Antimicrobial Susceptibility of Fusarium, Aspergillus, and Other Filamentous Fungi Isolated From Keratitis

At present, trachoma remains the most important infectious cause of blindness in the world.¹ Repeated infection with the ocular strains of Chlamydia trachomatis can bring about scarring of the conjunctiva, resulting in a cascade of entropion, inward-turned eyelashes, and eventually blindness due to corneal opacity.² To reduce infection, the World Health Organization (WHO) has recommended community-wide antibiotic distributions as part of its strategy to eliminate blinding trachoma as a public health concern by the year 2020.³ Previous studies have shown that in the short term, mass antibiotic distribution can dramatically decrease the prevalence of ocular strains of chlamydia in villages.^4-7

Antibiotics are a major tool in the WHO's trachoma control program. Even a single mass distribution reduces the prevalence of the ocular chlamydia that causes trachoma. Unfortunately, infection returns after a single treatment, at least in severely affected areas. Here, we test whether additional scheduled treatments further reduce infection, and whether infection returns after distributions are discontinued. Sixteen communities in Ethiopia were randomly selected. Ocular chlamydial infection in 1- to 5-year-old children was monitored over four biannual azithromycin distributions and for 24 months after the last treatment. The average prevalence of infection in 1- to 5-year-old children was reduced from 63.5% pre-treatment to 11.5% six months after the first distribution (P<0.0001). It further decreased to 2.6% six months after the fourth and final treatment (P = 0.0004). In the next 18 months, infection returned to 25.2%, a significant increase from six months after the last treatment (P = 0.008), but still far lower than baseline (P<0.0001). Although the prevalence of infection in any particular village fluctuated, the mean prevalence of the 16 villages steadily decreased with each treatment and steadily returned after treatments were discontinued. In some of the most severely affected communities ever studied, we demonstrate that repeated mass oral azithromycin distributions progressively reduce ocular chlamydial infection in a community, as long as these distributions are given frequently enough and at a high enough coverage. However, infection returns into the communities after the last treatment. Sustainable changes or complete local elimination of infection will be necessary. ClinicalTrials.gov NCT00221364 Trachoma is one of the leading causes of blindness in the developing world. The World Health Organization has a multi-pronged approach to controlling the ocular chlamydial infection that causes the disease, including distributing antibiotics to entire communities. Even a single community treatment dramatically reduces the prevalence of the infection. Unfortunately, infection returns back into communities after treatment, at least in severely affected areas such as rural Ethiopia. Here, we assess whether additional scheduled treatments in 16 communities in the Gurage area of Ethiopia further reduce infection, and whether the disease returns after distributions are stopped. In communities with the highest levels of trachoma ever studied, we find that repeated mass oral azithromycin distributions gradually reduce the prevalence of trachoma infection in a community, as long as these treatments are given frequently enough and to enough people in the community. Unfortunately, infection returns into the communities after the last treatment. Sustainable changes or complete local elimination of infection will be necessary to stop the return of ocular chlamydial in communities with very high prevalence of the disease.