Assessment of spillover of antimicrobial resistance to untreated children 7 to 12 years old after mass drug administration of azithromycin for child survival in Niger: a secondary analysis of the MORDOR cluster-randomized trial.

BACKGROUND: The risk of antibiotic resistance is complicated by the potential for spillover effects from one treated population to another. Azithromycin mass drug administration programs report higher rates of antibiotic resistance among treatment arms in targeted groups. This study aims to understand the risk of spillover of antibiotic resistance to non-target groups in these programs. METHODS: Data was used from a cluster-randomized trial comparing the effect of biannual azithromycin and placebo distribution to children 1-59 months on child mortality. Nasopharyngeal samples from untreated children 7-12 years old were tested for genetic determinants of macrolide resistance (primary outcome) and resistance to other antibiotic classes (secondary outcomes). Linear regression was used to compare the community-level mean difference in prevalence by arm at the 24-month timepoint adjusting for baseline prevalence. RESULTS: 1,103 children 7-12 years old in 30 communities were included in the analysis (15 azithromycin, 15 placebo). Adjusted mean differences in prevalence of resistance determinants for macrolides, beta-lactams and tetracyclines were 3.4% (95% CI -4.1% to 10.8%, P-value 0.37), -1.2% (95% CI -7.9% to 5.5%, P-value 0.72), and -3.3% (95% CI -9.5% to 2.8%, P-value 0.61), respectively. CONCLUSIONS: We were unable to demonstrate a statistically significant increase in macrolide resistance determinants in untreated groups in an azithromycin mass drug administration program. While the result might be consistent with a small spillover effect, this study was not powered to detect such a small difference. Larger studies are warranted to better understand the potential for spillover effects within these programs.

Difference of central foveal thickness measurement in patients with macular edema using optical coherence tomography in different display modes.

Purpose: To assess the differences in the measurement of central foveal thickness (CFT) in patients with macular edema (ME) between two display modes (1:1 pixel and 1:1 micron) on optical coherence tomography (OCT). Design: This is a retrospective, cross-sectional study. Methods: Group A consisted of participants with well-horizontal OCT B-scan images and group B consisted of participants with tilted OCT B-scan. We manually measured the CFT under the two display modes, and the values were compared statistically using the paired t-test. Spearman's test was used to assess the correlations between the OCT image tilting angle (OCT ITA) and the differences in CFT measurement. The area under the curve (AUC) was calculated to define the OCT ITA cutoff for a defined CFT difference. Results: In group A, the mean CFT in the 1:1 pixel display mode was 420.21 ± 130.61 µm, similar to the mean CFT of 415.27 ± 129.85 µm in the 1:1 micron display mode. In group B, the median CFT in the 1:1 pixel display mode is 409.00 µm (IQR: 171.75 µm) and 368.00 µm (IQR: 149.00 µm) in the 1:1 micron display mode. There were significant differences between the two display modes with the median (IQR) absolute difference and median (IQR) relative difference of 38.00 µm (75.00 µm) and 10.19% (21.91%) (all p = 0.01). The differences in CFT measurement between the two display modes were correlated with the OCT ITA (absolute differences, r = 0.88, p < 0.01; relative differences, r = 0.87, p < 0.01). The AUC for a predefined CFT difference was 0.878 (10 µm), 0.933 (20 µm), 0.938 (30 µm), 0.961 (40 µm), 0.962 (50 µm), and 0.970 (60 µm). Conclusion: In patients with DM, when the OCT B-scan images were well-horizontal, manual CFT measurements under the two display modes were similar, but when the B-scan images were tilted, the CFT measurements were different under the two display modes, and the differences were correlated to the OCT ITA.

Gender differences in the surgical management of trachomatous trichiasis: an exploratory analysis of global trachoma survey data, 2015-2019.

BACKGROUND: Trachomatous trichiasis (TT) is a painful, potentially blinding eye condition that can be managed through epilation or surgery. Women are affected by TT approximately twice as often as men and are believed to face gendered barriers to receiving surgical care to prevent vision loss. METHODS: We used data from 817 cross-sectional surveys conducted during 2015-2019 in 20 African countries to estimate the prevalence difference (PD) between female and male eyes for four outcomes potentially indicating gender-related differences in TT management: (1) received surgery and developed postoperative TT (PTT), (2) never offered surgery, (3) offered surgery but declined it, and (4) offered epilation but never offered surgery. RESULTS: The prevalence was modestly elevated among female eyes compared with male eyes for having PTT (PD:1.8 [95% confidence limits (CL): 0.6, 3.0]) and having declined surgery for the eye (PD: 6.2 [95% CL: 1.8, 10.7]). The proportion offered epilation was similar by gender (PD:0.5 [95% CL: -0.4, 1.3]), while never having been offered surgery was somewhat more prevalent among male eyes (PD: -2.1 [95% CL: -3.5, -0.7]). CONCLUSIONS: Our results suggest potential gender differences in TT management. More research is needed to determine the causes and implications of the observed differences.

Comparison of door-to-door and fixed-point delivery of azithromycin distribution for child survival in Niger: A cluster-randomized trial.

Recent evidence indicates mass azithromycin distribution reduces under-5 mortality. This intervention is being considered for child survival programs in high mortality sub-Saharan African settings. The delivery approach used in prior studies required a full-time census and distribution team, which is not feasible for most programs. To determine the optimal programmatic approach to delivery, this study aimed to compare treatment coverage, costs, and acceptability of different delivery approaches with existing community health workers (CHWs). This cluster-randomized trial included rural and peri-urban communities in Dosso, Niger (clinicaltrials.gov, NCT04774991). A random sample of 80 eligible communities was randomized 1:1 to biannual door-to-door or fixed-point delivery of oral azithromycin to children 1-59 months old over 1 year. Data analysts alone were masked given the nature of the intervention. The primary outcome was community-level treatment coverage defined as the number of children treated recorded by CHWs divided by the number of eligible children determined using a post-distribution census. Costs were monitored through routine administrative data collection and micro-costing. The census included survey questions on intervention acceptability among caregivers, community leaders, and CHWs. After randomization, 1 community was excluded due to inaccuracies in available administrative data, resulting in 39 communities receiving door-to-door delivery. At the second distribution, community-level mean treatment coverage was 105% (SD 44%) in the door-to-door arm and 92% (SD 20%) in the fixed-point arm (Mean difference 13%, 95% CI -2% to 28%, P-value = 0.08). The total cost per dose delivered was $1.91 in the door-to-door arm and $2.51 in the fixed-point arm. Indicators of acceptability were similar across stakeholder groups in both arms, with most respondents in each group indicating a preference for door-to-door. Overall, door-to-door delivery is the preferred approach to azithromycin distribution in this setting and might reach more children at a lower cost per dose delivered than fixed-point. Trial Registration: clinicaltrials.gov NCT04774991.

Comprehensive Profile of Pathogens and Antimicrobial Resistance in Conjunctivitis Cases from Niger.

Infectious conjunctivitis outbreaks remain a public health burden. This study focuses on the pathogen and antimicrobial resistance (AMR) profiles identified in Niger. Sixty-two patients with acute infectious conjunctivitis who presented to health posts were enrolled from December 2021 to May 2022. Nasal and conjunctival swabs were obtained from each patient. Unbiased RNA deep sequencing (RNA-seq) was used to identify associated pathogens. A pathogen was identified in 39 patients (63%; 95% CI, 50-74). Of those, an RNA virus was detected in 23 patients (59%; 95% CI, 43-73). RNA viruses were diverse and included human coronaviruses (HCoVs): SARS-CoV-2, HCoV-229E, HCoV-HKU1, and HCoV-OC43. A DNA virus was identified in 11 patients (28%; 95% CI, 17-44). Of those, four patients had a coinfection with an RNA virus and two patients had a coinfection with both an RNA virus and a bacterium. DNA viruses were predominantly human herpesvirus (cytomegalovirus, Epstein-Barr virus, human herpesvirus 8) and human adenovirus species B, C, and F. Eighteen patients (46%; 95% CI, 32-61) had a bacteria-associated infection that included Haemophilus influenza, Haemophilus aegyptius, Staphylococcus aureus, Streptococcus pneumoniae, and Moraxella spp. Antimicrobial resistance determinants were detected in either the conjunctiva or nasal samples of 20 patients (32%; 95% CI, 22-45) and were found to be more diverse in the nose (Shannon alpha diversity, 1.12 [95% CI, 1.05-1.26] versus 1.02 [95% CI, 1.00-1.05], P = 0.01). These results suggest the potential utility of leveraging RNA-seq to surveil pathogens and AMR for ocular infections.

Micropulse diode laser therapy in refractory glaucoma.

Purpose: Description of safety and efficacy of micropulse Transscleral cyclophotocoagulation as a treatment option for refractory glaucoma. Methods: This is a prospective study including 39 eyes of 31 patients followed for refractory glaucoma, who benefited from transscleral cyclophotocoagulation using a microplused laser. The main indication for the procedure was increased ocular pressure refractory to quadritherapy in various types of glaucoma. The patients were treated using iridex Cyclo G6 laser with a Micropulse P3 infrared probe with a wavelength of 810 â€‹nm. The parameters for the procedure were a duration of 90 â€‹s per hemisphere with a power of 2000 mW and an energy of 180 â€‹J. Both the upper and lower hemispheres were treated in the same procedure, sparing the 3 o'clock and 9 o'clock meridians, and all the patients benefited from a single treatment session. The following parameters were evaluated: ocular pain and overall tolerance; visual acuity; and the evolution of IOP postoperatively up to 9 months. Results: The glaucoma subtypes treated are as follows: primary open-angle glaucoma (n â€‹= â€‹05), chronic angle-closure glaucoma (n â€‹= â€‹13), neovascular glaucoma (n â€‹= â€‹07), aphakic glaucoma (n â€‹= â€‹06), malignant glaucoma (n â€‹= â€‹04), post-traumatic angle recession (n â€‹= â€‹02), and inflammatory glaucoma (n â€‹= â€‹02). The mean pre-operative intraocular pressure was 42.3 â€‹± â€‹5.2 â€‹mmHg and the mean post-operative intraocular pressure at 9 months was 16.9 â€‹± â€‹1.9 â€‹mmHg. The reduction in IOP was 49.9%. The average number of intraocular pressure-lowering medications used prior to surgery was four, and the average number of medications used at the 9-month post-operative visit was 2.0 â€‹± â€‹1.2 (70.3% of patients were on dual therapy). The overall success rate was 60.5%. Conclusions: Micropulse transscleral cyclophotocoagulation appears to be a safe and efficient treatment for refractory glaucoma. Its indications should therefore be broadened and proposed early in various situations.

Comparison of Population-Based Census versus Birth History for the Estimation of Under-5 Mortality in Niger.

The WHO guidelines on mass distribution of azithromycin for child survival recommend monitoring of mortality to evaluate effectiveness. Trials that contributed evidence to these guidelines used a population-based census to monitor vital status, requiring census workers to visit each household biannually (twice yearly). Birth history is an alternative to the census approach that may be more feasible because it decreases the time and labor needed for mortality monitoring. This study aimed to compare the population-based census (reference standard) and birth history (index test) approaches to estimating mortality among children 1 to 59 months old using data from the Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) trial. Sixteen communities that received 5 years of biannual census in the MORDOR trial were selected randomly also to receive birth history surveys. The census approach recorded more participants and households than birth history, with correlations more than 0.94 for each. The correlation between number of deaths in each community was 0.84 (95% CI, 0.59-0.94). A comparison of the mortality incidence rate estimated from the census against the under-5 mortality rate estimated from the birth history resulted in a correlation of 0.60 (95% CI, 0.15-0.84). Of the 47% of children who were linked individually to compare vital status from each method, the death status of children had a sensitivity of 80% (95% CI, 73-89) and a specificity of 98% (95% CI, 98-99), comparing birth history to census. Overall birth histories were found to be a reasonable alternative to biannual census for tracking vital status.

Wastewater-Based Surveillance of Antimicrobial Resistance in Niger: An Exploratory Study.

Wastewater-based surveillance is increasingly recognized as an important approach to monitoring population-level antimicrobial resistance (AMR). In this exploratory study, we examined the use of metagenomics to evaluate AMR using untreated wastewater samples routinely collected by the Niger national polio surveillance program. Forty-eight stored samples from two seasons each year over 4 years (2016-2019) in three regions were selected for inclusion in this study and processed using unbiased DNA deep sequencing. Normalized number of reads of genetic determinants for different antibiotic classes were compared over time, by season, and by location. Correlations in resistance were examined among classes. Changes in reads per million per year were demonstrated for several classes, including decreases over time in resistance determinants for phenicols (-3.3, 95% CI: -8.7 to -0.1, P = 0.029) and increases over time for aminocoumarins (3.8, 95% CI: 0.0 to 11.4, P = 0.043), fluoroquinolones (6.8, 95% CI: 0.0 to 20.5, P = 0.048), and beta-lactams (0.85, 95% CI: 0.1 to 1.7, P = 0.006). Sulfonamide resistance was higher in the post-rainy season compared with the dry season (5.2-fold change, 95% CI: 3.4 to 7.9, P < 0.001). No differences were detected when comparing other classes by season or by site for any antibiotic class. Positive correlations were identified in genetic determinants of resistance among several antibiotic classes. These results demonstrate the potential utility of leveraging existing wastewater sample collection in this setting for AMR surveillance.

Using model-based geostatistics for assessing the elimination of trachoma.

BACKGROUND: Trachoma is the commonest infectious cause of blindness worldwide. Efforts are being made to eliminate trachoma as a public health problem globally. However, as prevalence decreases, it becomes more challenging to precisely predict prevalence. We demonstrate how model-based geostatistics (MBG) can be used as a reliable, efficient, and widely applicable tool to assess the elimination status of trachoma. METHODS: We analysed trachoma surveillance data from Brazil, Malawi, and Niger. We developed geostatistical Binomial models to predict trachomatous inflammation-follicular (TF) and trachomatous trichiasis (TT) prevalence. We proposed a general framework to incorporate age and gender in the geostatistical models, whilst accounting for residual spatial and non-spatial variation in prevalence through the use of random effects. We also used predictive probabilities generated by the geostatistical models to quantify the likelihood of having achieved the elimination target in each evaluation unit (EU). RESULTS: TF and TT prevalence varied considerably by country, with Brazil showing the lowest prevalence and Niger the highest. Brazil and Malawi are highly likely to have met the elimination criteria for TF in each EU, but, for some EUs, there was high uncertainty in relation to the elimination of TT according to the model alone. In Niger, the predicted prevalence varied significantly across EUs, with the probability of having achieved the elimination target ranging from values close to 0% to 100%, for both TF and TT. CONCLUSIONS: We demonstrated the wide applicability of MBG for trachoma programmes, using data from different epidemiological settings. Unlike the standard trachoma prevalence survey approach, MBG provides a more statistically rigorous way of quantifying uncertainty around the achievement of elimination prevalence targets, through the use of spatial correlation. In addition to the analysis of existing survey data, MBG also provides an approach to identify areas in which more sampling effort is needed to improve EU classification. We advocate MBG as the new standard method for analysing trachoma survey outputs.

Monitoring transmission intensity of trachoma with serology.

Trachoma, caused by ocular Chlamydia trachomatis infection, is targeted for global elimination as a public health problem by 2030. To provide evidence for use of antibodies to monitor C. trachomatis transmission, we collated IgG responses to Pgp3 antigen, PCR positivity, and clinical observations from 19,811 children aged 1-9 years in 14 populations. We demonstrate that age-seroprevalence curves consistently shift along a gradient of transmission intensity: rising steeply in populations with high levels of infection and active trachoma and becoming flat in populations near elimination. Seroprevalence (range: 0-54%) and seroconversion rates (range: 0-15 per 100 person-years) correlate with PCR prevalence (r: 0.87, 95% CI: 0.57, 0.97). A seroprevalence threshold of 13.5% (seroconversion rate 2.75 per 100 person-years) identifies clusters with any PCR-identified infection at high sensitivity ( >90%) and moderate specificity (69-75%). Antibody responses in young children provide a robust, generalizable approach to monitor population progress toward and beyond trachoma elimination.

Exploring water, sanitation, and hygiene coverage targets for reaching and sustaining trachoma elimination: G-computation analysis.

BACKGROUND: Trachoma is the leading infectious cause of blindness. To reduce transmission, water, sanitation, and hygiene (WaSH) improvements are promoted through a comprehensive public health strategy. Evidence supporting the role of WaSH in trachoma elimination is mixed and it remains unknown what WaSH coverages are needed to effectively reduce transmission. METHODS/FINDINGS: We used g-computation to estimate the impact on the prevalence of trachomatous inflammation-follicular among children aged 1-9 years (TF1-9) when hypothetical WaSH interventions raised the minimum coverages from 5% to 100% for "nearby" face-washing water (<30 minutes roundtrip collection time) and adult latrine use in an evaluation unit (EU). For each scenario, we estimated the generalized prevalence difference as the TF1-9 prevalence under the intervention scenarios minus the observed prevalence. Data from 574 cross-sectional surveys conducted in 16 African and Eastern Mediterranean countries were included. Surveys were conducted from 2015-2019 with support from the Global Trachoma Mapping Project and Tropical Data. When modeling interventions among EUs that had not yet met the TF1-9 elimination target, increasing nearby face-washing water and latrine use coverages above 30% was generally associated with consistent decreases in TF1-9. For nearby face-washing water, we estimated a ≥25% decrease in TF1-9 at 65% coverage, with a plateau upon reaching 85% coverage. For latrine use, the estimated decrease in TF1-9 accelerated from 80% coverage upward, with a ≥25% decrease in TF1-9 by 85% coverage. Among EUs that had previously met the elimination target, results were inconclusive. CONCLUSIONS: Our results support Sustainable Development Goal 6 and provide insight into potential WaSH-related coverage targets for trachoma elimination. Targets can be tested in future trials to improve evidence-based WaSH guidance for trachoma.

Monitoring transmission intensity of trachoma with serology.

Trachoma, caused by ocular Chlamydia trachomatis infection, is targeted for global elimination as a public health problem by 2030. To provide evidence for use of antibodies to monitor C. trachomatis transmission, we collated IgG responses to Pgp3 antigen, PCR positivity, and clinical observations from 19,811 children aged 1- 9 years in 14 populations. We demonstrate that age-seroprevalence curves consistently shift along a gradient of transmission intensity: rising steeply in populations with high levels of infection and active trachoma and becoming flat in populations near elimination. Seroprevalence (range: 0-54%) and seroconversion rates (range: 0-15 per 100 person-years) correlate with PCR prevalence (r: 0.87, 95% CI: 0.57, 0.97). A seroprevalence threshold of 13.5% (seroconversion rate 2.75 per 100 person-years) identifies clusters with any PCR-identified infection at high sensitivity (>90%) and moderate specificity (69-75%). Antibody responses in young children provide a robust, generalizable approach to monitor population progress toward and beyond trachoma elimination.

Measurement of Foveal Retinal Thickness in Myopic Patients Using Different Display Modes on Optical Coherence Tomography: A Retrospective, Cross-Sectional Study.

INTRODUCTION: The aim of this work is to investigate the differences in the measurement of foveal retinal thickness in myopic patients between two display modes (1:1 pixel and 1:1 micron) on optical coherence tomography (OCT). METHODS: Horizontal OCT line scan through the central fovea was used for manual measurement of foveal retinal thickness under the two display modes, and the values were compared using Wilcoxon signed-rank test. Correlations between the OCT image tilting angle (OCT ITA) and differences in OCT measurement were analyzed by Spearman's test. RESULTS: 127 participants with a median age of 28 years, a median spherical equivalent (SE) of - 8.5 D, and a median axial length (AL) of 27.04 mm. There were significant differences between the two display modes, with a median absolute difference (median relative difference) of 13.33 µm (2.75%) for the central foveal thickness (CFT), 5.33 µm (1.28%) for the Henle fiber and outer nuclear layer thickness (HFL + ONL), 3 µm (6.47%) for the external limiting membrane to ellipsoid zone distance (ELM-EZ), and 4 µm (8.77%) for the ellipsoid zone to retinal pigment epithelium distance (EZ-RPE) (all p < 0.05). The differences in foveal retinal thickness between the two display modes were significantly correlated with the OCT ITA (r = 0.732 for CFT, 0.561 for HFL + ONL, 0.642 for ELM-EZ, and 0.471 for EZ-RPE, all p < 0.05). CONCLUSIONS: Disparities between the two display modes were found in the manual measurement of foveal retinal thickness and correlated to the OCT ITA.

Azithromycin distribution and childhood mortality in compliance-related subgroups in Niger: complier average causal effect and spillovers in a cluster-randomized, placebo-controlled trial.

BACKGROUND: Biannual azithromycin distribution to children 1-59 months old reduced all-cause mortality by 18% [incidence rate ratio (IRR) 0.82, 95% confidence interval (CI): 0.74, 0.90] in an intention-to-treat analysis of a randomized controlled trial in Niger. Estimation of the effect in compliance-related subgroups can support decision making around implementation of this intervention in programmatic settings. METHODS: The cluster-randomized, placebo-controlled design of the original trial enabled unbiased estimation of the effect of azithromycin on mortality rates in two subgroups: (i) treated children (complier average causal effect analysis); and (ii) untreated children (spillover effect analysis), using negative binomial regression. RESULTS: In Niger, 594 eligible communities were randomized to biannual azithromycin or placebo distribution and were followed from December 2014 to August 2017, with a mean treatment coverage of 90% [standard deviation (SD) 10%] in both arms. Subgroup analyses included 2581 deaths among treated children and 245 deaths among untreated children. Among treated children, the incidence rate ratio comparing mortality in azithromycin communities to placebo communities was 0.80 (95% CI: 0.72, 0.88), with mortality rates (deaths per 1000 person-years at risk) of 16.6 in azithromycin communities and 20.9 in placebo communities. Among untreated children, the incidence rate ratio was 0.91 (95% CI: 0.69, 1.21), with rates of 33.6 in azithromycin communities and 34.4 in placebo communities. CONCLUSIONS: As expected, this analysis suggested similar efficacy among treated children compared with the intention-to-treat analysis. Though the results were consistent with a small spillover benefit to untreated children, this trial was underpowered to detect spillovers.

Stopping azithromycin mass drug administration for trachoma: A systematic review.

The World Health Organization (WHO) recommends continuing azithromycin mass drug administration (MDA) for trachoma until endemic regions drop below 5% prevalence of active trachoma in children aged 1-9 years. Azithromycin targets the ocular strains of Chlamydia trachomatis that cause trachoma. Regions with low prevalence of active trachoma may have little if any ocular chlamydia, and, thus, may not benefit from azithromycin treatment. Understanding what happens to active trachoma and ocular chlamydia prevalence after stopping azithromycin MDA may improve future treatment decisions. We systematically reviewed published evidence for community prevalence of both active trachoma and ocular chlamydia after cessation of azithromycin distribution. We searched electronic databases for all peer-reviewed studies published before May 2020 that included at least 2 post-MDA surveillance surveys of ocular chlamydia and/or the active trachoma marker, trachomatous inflammation-follicular (TF) prevalence. We assessed trends in the prevalence of both indicators over time after stopping azithromycin MDA. Of 140 identified studies, 21 met inclusion criteria and were used for qualitative synthesis. Post-MDA, we found a gradual increase in ocular chlamydia infection prevalence over time, while TF prevalence generally gradually declined. Ocular chlamydia infection may be a better measurement tool compared to TF for detecting trachoma recrudescence in communities after stopping azithromycin MDA. These findings may guide future trachoma treatment and surveillance efforts.

Age-based targeting of biannual azithromycin distribution for child survival in Niger: an adaptive cluster-randomized trial protocol (AVENIR).

BACKGROUND: Biannual distribution of azithromycin to children 1-59 months old reduced mortality by 14% in a cluster-randomized trial. The World Health Organization has proposed targeting this intervention to the subgroup of children 1-11 months old to reduce selection for antimicrobial resistance. Here, we describe a trial designed to determine the impact of age-based targeting of biannual azithromycin on mortality and antimicrobial resistance. METHODS: AVENIR is a cluster-randomized, placebo-controlled, double-masked, response-adaptive large simple trial in Niger. During the 2.5-year study period, 3350 communities are targeted for enrollment. In the first year, communities in the Dosso region will be randomized 1:1:1 to 1) azithromycin 1-11: biannual azithromycin to children 1-11 months old with placebo to children 12-59 months old, 2) azithromycin 1-59: biannual azithromycin to children 1-59 months old, or 3) placebo: biannual placebo to children 1-59 months old. Regions enrolled after the first year will be randomized with an updated allocation based on the probability of mortality in children 1-59 months in each arm during the preceding study period. A biannual door-to-door census will be conducted to enumerate the population, distribute azithromycin and placebo, and monitor vital status. Primary mortality outcomes are defined as all-cause mortality rate (deaths per 1000 person-years) after 2.5 years from the first enrollment in 1) children 1-59 months old comparing the azithromycin 1-59 and placebo arms, 2) children 1-11 months old comparing the azithromycin 1-11 and placebo arm, and 3) children 12-59 months in the azithromycin 1-11 and azithromycin 1-59 arms. In the Dosso region, 50 communities from each arm will be followed to monitor antimicrobial resistance. Primary resistance outcomes will be assessed after 2 years of distributions and include 1) prevalence of genetic determinants of macrolide resistance in nasopharyngeal samples from children 1-59 months old, and 2) load of genetic determinants of macrolide resistance in rectal samples from children 1-59 months old. DISCUSSION: As high-mortality settings consider this intervention, the results of this trial will provide evidence to support programmatic and policy decision-making on age-based strategies for azithromycin distribution to promote child survival. TRIAL REGISTRATION: This trial was registered on January 13, 2020 (clinicaltrials.gov: NCT04224987 ).

Azithromycin Reduction to Reach Elimination of Trachoma (ARRET): study protocol for a cluster randomized trial of stopping mass azithromycin distribution for trachoma.

BACKGROUND: The World Health Organization (WHO) recommends annual mass azithromycin distribution until districts drop below 5% prevalence of trachomatous inflammation-follicular (TF). Districts with very low TF prevalence may have little or no transmission of the ocular strains of Chlamydia trachomatis that cause trachoma, and additional rounds of mass azithromycin distribution may not be useful. Here, we describe the protocol for a randomized controlled trial designed to evaluate whether mass azithromycin distribution can be stopped prior to the current WHO guidelines. METHODS: The Azithromycin Reduction to Reach Elimination of Trachoma (ARRET) study is a 1:1 community randomized non-inferiority trial designed to evaluate whether mass azithromycin distribution can be stopped in districts with baseline prevalence of TF under 20%. Communities in Maradi, Niger are randomized after baseline assessment either to continued annual mass azithromycin distribution or stopping annual azithromycin distribution over a 3-year period. We will compare the prevalence of ocular C. trachomatis (primary outcome), TF and other clinical signs of trachoma, and serologic markers of trachoma after 3 years. We hypothesize that stopping annual azithromycin distribution will be non-inferior to continued annual azithromycin distributions for all markers of trachoma prevalence and transmission. DISCUSSION: The results of this trial are anticipated to provide potentially guideline-changing evidence for when mass azithromycin distributions can be stopped in low TF prevalence areas. TRIAL REGISTRATION NUMBER: This study is registered at clinicaltrials.gov ( NCT04185402 ). Registered December 4, 2019; prospectively registered pre-results.

Can we eradicate trachoma? A survey of stakeholders.

BACKGROUND/AIMS: Although tremendous progress towards the 2020 goal of global elimination of trachoma as a public health problem has been made, it will not be achieved. Future targets are now being considered. One option is changing the goal to eradication. We surveyed trachoma experts to assess beliefs related to trachoma eradication and determine perceived obstacles to achieving it. METHODS: We conducted a survey at the beginning of a trachoma eradication session at the 2019 Coalition for Operational Research on Neglected Tropical Diseases meeting in National Harbor, Maryland, USA. We asked respondents what the most important goal of azithromycin mass drug administration was for trachoma (control, elimination of infection or eradication) and if and when they believed trachoma eradication would occur. We then asked what the biggest obstacles were to global eradication. RESULTS: Fifty-six surveys were returned (95%). Most (91%) participants reported that the most important goal of azithromycin mass drug administration was control or elimination of infection, and 24% of participants reported that global eradication was not possible. Of the 76% who reported a year by which they believed trachoma could be eradicated, most fell between 2040 and 2050. Commonly cited barriers to global eradication included lack of surveillance tools to confirm eradication or monitor for infection recrudescence (32%) and lack of resources (23%). CONCLUSIONS: Development of alternative indicators for trachoma surveillance and continued investment in trachoma programmes, particularly focused support in the most heavily affected populations, might increase enthusiasm for the feasibility of eradication.

Effectiveness and safety of azithromycin 1.5% eye drops for mass treatment of active trachoma in a highly endemic district in Cameroon.

OBJECTIVE: To evaluate the effectiveness and safety of azithromycin 1.5% eye drops under field conditions to reduce active trachoma in a highly endemic district in Cameroon. This is a follow-up of an initial report published in 2010. METHODS AND ANALYSIS: Three annual campaigns were performed in 2008, 2009 and 2010 to treat the population (~1 20 000 individuals) of the Kolofata Health District with topical azithromycin 1.5% (one drop in each eye, morning and evening for three consecutive days). The effectiveness of this intervention against active trachoma was assessed in children aged 1-9 years in cross-sectional studies prior to each mass treatment using a systematic sampling procedure (in 2008, 2009 and 2010) and then 1 year (2011) and 3 years (2013) after the last intervention among the villages with previously high active trachoma prevalence or never tested. RESULTS: The prevalence of trachomatous inflammation-follicular (TF) dropped from 24.0% (95% CI 20.7 to 27.5) before treatment to 2.8% (95% CI 2.2 to 3.7) 1 year after completion of the 3 year campaign. Trachomatous inflammation-intense was present in only 4 (0.2%) children 1 year after the third round of treatment. Three years after the last campaign, the surveillance survey among the most prevalent villages and villages never tested before showed a prevalence of 5.2% (95% CI 3.6 to 7.2) of active trachoma. Tolerance was excellent, with no report of treatment interruption, serious ocular or systemic adverse events. CONCLUSION: Annual mass treatment with azithromycin eye drops was shown to be effective in reducing TF to a level ≤5% one year after a 3-round annual mass treatment in an endemic region at the district level.

Comparison of anthropometric indicators to predict mortality in a population-based prospective study of children under 5 years in Niger.

OBJECTIVE: In the present study, we aimed to compare anthropometric indicators as predictors of mortality in a community-based setting. DESIGN: We conducted a population-based longitudinal study nested in a cluster-randomized trial. We assessed weight, height and mid-upper arm circumference (MUAC) on children 12 months after the trial began and used the trial's annual census and monitoring visits to assess mortality over 2 years. SETTING: Niger. PARTICIPANTS: Children aged 6-60 months during the study. RESULTS: Of 1023 children included in the study at baseline, height-for-age Z-score, weight-for-age Z-score, weight-for-height Z-score and MUAC classified 777 (76·0 %), 630 (61·6 %), 131 (12·9 %) and eighty (7·8 %) children as moderately to severely malnourished, respectively. Over the 2-year study period, fifty-eight children (5·7 %) died. MUAC had the greatest AUC (0·68, 95 % CI 0·61, 0·75) and had the strongest association with mortality in this sample (hazard ratio = 2·21, 95 % CI 1·26, 3·89, P = 0·006). CONCLUSIONS: MUAC appears to be a better predictor of mortality than other anthropometric indicators in this community-based, high-malnutrition setting in Niger.