@article {1381, title = {Prolonged mass azithromycin distributions and macrolide resistance determinants among preschool children in Niger: A sub-study of a cluster-randomized trial (MORDOR).}, journal = {PLoS Med}, volume = {21}, year = {2024}, month = {2024 May}, pages = {e1004386}, abstract = {

BACKGROUND: Randomized controlled trials found that twice-yearly mass azithromycin administration (MDA) reduces childhood mortality, presumably by reducing infection burden. World Health Organization (WHO) issued conditional guidelines for mass azithromycin administration in high-mortality settings in sub-Saharan Africa given concerns for antibiotic resistance. While prolonged twice-yearly MDA has been shown to increase antibiotic resistance in small randomized controlled trials, the objective of this study was to determine if macrolide and non-macrolide resistance in the gut increases with the duration of azithromycin MDA in a larger setting.

METHODS AND FINDINGS: The Macrolide Oraux pour R{\'e}duire les D{\'e}c{\`e}s avec un Oeil sur la R{\'e}sistance (MORDOR) study was conducted in Niger from December 2014 to June 2020. It was a cluster-randomized trial of azithromycin (A) versus placebo (P) aimed at evaluating childhood mortality. This is a sub-study in the MORDOR trial to track changes in antibiotic resistance after prolonged azithromycin MDA. A total of 594 communities were eligible. Children 1 to 59 months in 163 randomly chosen communities were eligible to receive treatment and included in resistance monitoring. Participants, staff, and investigators were masked to treatment allocation. At the conclusion of MORDOR Phase I, by design, all communities received an additional year of twice-yearly azithromycin treatments (Phase II). Thus, at the conclusion of Phase II, the treatment history (1 letter per 6-month period) for the participating communities was either (PP-PP-AA) or (AA-AA-AA). In Phase III, participating communities were then re-randomized to receive either another 3 rounds of azithromycin or placebo, thus resulting in 4 treatment histories: Group 1 (AA-AA-AA-AA-A, N = 51), Group 2 (PP-PP-AA-AA-A, N = 40), Group 3 (AA-AA-AA-PP-P, N = 27), and Group 4 (PP-PP-AA-PP-P, N = 32). Rectal swabs from each child (N = 5,340) were obtained 6 months after the last treatment. Each child contributed 1 rectal swab and these were pooled at the community level, processed for DNA-seq, and analyzed for genetic resistance determinants. The primary prespecified outcome was macrolide resistance determinants in the gut. Secondary outcomes were resistance to beta-lactams and other antibiotic classes. Communities recently randomized to azithromycin (groups 1 and 2) had significantly more macrolide resistance determinants than those recently randomized to placebo (groups 3 and 4) (fold change 2.18, 95\% CI 1.5 to 3.51, Punadj \< 0.001). However, there was no significant increase in macrolide resistance in communities treated 4.5 years (group 1) compared to just the most recent 2.5 years (group 2) (fold change 0.80, 95\% CI 0.50 to 1.00, Padj = 0.010), or between communities that had been treated for 3 years in the past (group 3) versus just 1 year in the past (group 4) (fold change 1.00, 95\% CI 0.78 to 2.35, Padj = 0.52). We also found no significant differences for beta-lactams or other antibiotic classes. The main limitations of our study were the absence of phenotypic characterization of resistance, no complete placebo arm, and no monitoring outside of Niger limiting generalizability.

CONCLUSIONS: In this study, we observed that mass azithromycin distribution for childhood mortality among preschool children in Niger increased macrolide resistance determinants in the gut but that resistance may plateau after 2 to 3 years of treatment. Co-selection to other classes needs to be monitored.

TRIAL REGISTRATION: NCT02047981 https://classic.clinicaltrials.gov/ct2/show/NCT02047981.

}, keywords = {Anti-Bacterial Agents, Azithromycin, Child Mortality, Child, Preschool, Drug Resistance, Bacterial, Female, Humans, Infant, Macrolides, Male, Mass Drug Administration, Niger}, issn = {1549-1676}, doi = {10.1371/journal.pmed.1004386}, author = {Arzika, Ahmed M and Abdou, Amza and Maliki, Ramatou and Beido, Nassirou and Kadri, Boubacar and Harouna, Abdoul N and Galo, Abdoul N and Alio, Mankara K and Lebas, Elodie and Oldenburg, Catherine E and O{\textquoteright}Brien, Kieran S and Chen, Cindi and Zhong, Lina and Zhou, Zhaoxia and Yan, Daisy and Hinterwirth, Armin and Keenan, Jeremy D and Porco, Travis C and Lietman, Thomas M and Doan, Thuy} } @article {136, title = {Macrolide Resistance in MORDOR I - A Cluster-Randomized Trial in Niger.}, journal = {N Engl J Med}, volume = {380}, year = {2019}, month = {2019 Jun 06}, pages = {2271-2273}, keywords = {Administration, Oral, Anti-Bacterial Agents, Azithromycin, Child, Preschool, Drug Resistance, Bacterial, Humans, Infant, Macrolides, Niger, Pneumococcal Infections, Streptococcus pneumoniae}, issn = {1533-4406}, doi = {10.1056/NEJMc1901535}, author = {Doan, Thuy and Arzika, Ahmed M and Hinterwirth, Armin and Maliki, Ramatou and Zhong, Lina and Cummings, Susie and Sarkar, Samarpita and Chen, Cindi and Porco, Travis C and Keenan, Jeremy D and Lietman, Thomas M} } @article {56, title = {Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa.}, journal = {N Engl J Med}, volume = {378}, year = {2018}, month = {2018 Apr 26}, pages = {1583-1592}, abstract = {

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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 ({\textpm}SD) azithromycin and placebo coverage over the four twice-yearly distributions was 90.4{\textpm}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.

CONCLUSIONS: 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 .).

}, keywords = {Administration, Oral, Anti-Bacterial Agents, Azithromycin, Child Mortality, Child, Preschool, Communicable Disease Control, Communicable Diseases, Drug Resistance, Bacterial, Female, Humans, Infant, Infant Mortality, Malawi, Male, Mass Drug Administration, Niger, Public Health, Tanzania}, issn = {1533-4406}, doi = {10.1056/NEJMoa1715474}, author = {Keenan, Jeremy D and Bailey, Robin L and West, Sheila K and Arzika, Ahmed M and Hart, John and Weaver, Jerusha and Kalua, Khumbo and Mrango, Zakayo and Ray, Kathryn J and Cook, Catherine and Lebas, Elodie and O{\textquoteright}Brien, Kieran S and Emerson, Paul M and Porco, Travis C and Lietman, Thomas M} }