@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 {901, title = {Impact of Sample Collection Order on the Diagnostic Performance of Metagenomic Deep Sequencing for Infectious Keratitis.}, journal = {Cornea}, volume = {41}, year = {2022}, month = {2022 Jan 01}, pages = {39-44}, abstract = {

PURPOSE: The purpose of this article was to evaluate the impact of sample collection order on the diagnostic yield of metagenomic deep sequencing (MDS) for determining the causative pathogen in infectious keratitis.

METHODS: We performed a cross-sectional diagnostic test evaluation among subjects with infectious keratitis at Aravind Eye Hospital in Madurai, India. All subjects underwent corneal scrapings of the affected eye to obtain potassium hydroxide smear, Gram stain, bacterial culture, and fungal culture, in this order. The order of MDS specimen collection relative to smear and culture samples was randomized and served as the primary predictor. Outcomes included the normalized copy number of pathogenic RNA detected by MDS, the proportion of MDS samples that were diagnostic, and the agreement of MDS results with cultures.

RESULTS: MDS samples from 46 subjects with corneal ulcers were evaluated. MDS was positive in 33 subjects (76\%) and had 74\% overall agreement with culture results. There was no association between order of MDS sample collection and normalized copy number of genetic material detected (P = 0.62) or the likelihood of MDS positivity (P = 0.46). However, the likelihood of agreement between MDS and cultures decreased when MDS corneal swabs were collected after other diagnostic corneal scrapings (P = 0.05).

CONCLUSIONS: The overall yield of MDS for detecting the cause of infectious keratitis was not affected by sample collection order. However, diagnostic agreement between MDS and cultures decreased when MDS samples were collected after other specimens. Additional investigation is warranted to determine whether this represents increased sensitivity of MDS compared with cultures or higher susceptibility to contaminants.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Bacteria, Cornea, Cross-Sectional Studies, DNA, Bacterial, DNA, Fungal, Eye Infections, Bacterial, Eye Infections, Fungal, Female, Fungi, High-Throughput Nucleotide Sequencing, Humans, Keratitis, Male, Metagenome, Middle Aged, Specimen Handling, Young Adult}, issn = {1536-4798}, doi = {10.1097/ICO.0000000000002766}, author = {Redd, Travis K and Lalitha, Prajna and Prajna, N Venkatesh and Sikha, Misra and Gunasekaran, Rameshkumar and Hinterwirth, Armin and Chen, Cindi and Zhong, Lina and Liu, Zijun and Lietman, Thomas M and Keenan, Jeremy D and Doan, Thuy and Seitzman, Gerami D} } @article {161, title = {Gut Bacterial Diversity and Growth among Preschool Children in Burkina Faso.}, journal = {Am J Trop Med Hyg}, volume = {103}, year = {2020}, month = {2020 12}, pages = {2568-2573}, abstract = {

There is a lack of empirical, prospective human data on the gut microbiome and its relationship with growth, especially in low- and middle-income countries. We prospectively assessed the association between gut microbial diversity and short-term growth in a cohort of preschool children in Burkina Faso to better characterize whether there is any evidence that changes in gut microbial diversity may affect growth. Data were obtained from a randomized controlled trial evaluating the effect of antibiotic administration on gut microbial diversity in preschool children. We followed up the enrolled children for 35 days, with anthropometric measurements at baseline and day 35 and microbial diversity measured at baseline and day 9 (analytic sample, = 155). We estimated linear mixed-effects regression models with household random intercepts to assess the association of Simpson{\textquoteright}s and Shannon{\textquoteright}s alpha diversity with measures of change in anthropometry (e.g., ponderal growth since baseline) and absolute anthropometric measurements (e.g., day 35 weight). We did not find evidence that alpha gut microbial diversity was associated with growth or absolute anthropometric measurements after adjusting for confounding variables. Effect estimates were close to the null ( >= 0.15 for all fully adjusted comparisons), with the association between Simpson{\textquoteright}s alpha diversity and day 35 height (cm) farthest from the null (coefficient = -0.03, 95\% CI: -0.07, 0.01). The change in gut microbial diversity also was not associated with the change in anthropometry in crude or adjusted models. Future research is needed to explore whether gut diversity has an impact on growth over a longer time period, in both healthy and malnourished children.

}, keywords = {Anti-Bacterial Agents, Bacteria, Burkina Faso, Child Development, Child, Preschool, Female, Gastrointestinal Microbiome, Humans, Infant, Male, Nutritional Status, Prospective Studies}, issn = {1476-1645}, doi = {10.4269/ajtmh.20-0059}, author = {Digitale, Jean and Sie, Ali and Coulibaly, Boubacar and Ouermi, Lucienne and Dah, Clarisse and Tapsoba, Charlemagne and B{\"a}rnighausen, Till and Lebas, Elodie and Arzika, Ahmed M and Glymour, Medellena Maria and Keenan, Jeremy D and Doan, Thuy and Oldenburg, Catherine E} } @article {71, title = {Macrolide and Nonmacrolide Resistance with Mass Azithromycin Distribution.}, journal = {N Engl J Med}, volume = {383}, year = {2020}, month = {2020 11 12}, pages = {1941-1950}, abstract = {

BACKGROUND: Mass distribution of azithromycin to preschool children twice yearly for 2 years has been shown to reduce childhood mortality in sub-Saharan Africa but at the cost of amplifying macrolide resistance. The effects on the gut resistome, a reservoir of antimicrobial resistance genes in the body, of twice-yearly administration of azithromycin for a longer period are unclear.

METHODS: We investigated the gut resistome of children after they received twice-yearly distributions of azithromycin for 4 years. In the Niger site of the MORDOR trial, we enrolled 30 villages in a concurrent trial in which they were randomly assigned to receive mass distribution of either azithromycin or placebo, offered to all children 1 to 59 months of age every 6 months for 4 years. Rectal swabs were collected at baseline, 36 months, and 48 months for analysis of the participants{\textquoteright} gut resistome. The primary outcome was the ratio of macrolide-resistance determinants in the azithromycin group to those in the placebo group at 48 months.

RESULTS: Over the entire 48-month period, the mean ({\textpm}SD) coverage was 86.6{\textpm}12\% in the villages that received placebo and 83.2{\textpm}16.4\% in the villages that received azithromycin. A total of 3232 samples were collected during the entire trial period; of the samples obtained at the 48-month monitoring visit, 546 samples from 15 villages that received placebo and 504 from 14 villages that received azithromycin were analyzed. Determinants of macrolide resistance were higher in the azithromycin group than in the placebo group: 7.4 times as high (95\% confidence interval [CI], 4.0 to 16.7) at 36 months and 7.5 times as high (95\% CI, 3.8 to 23.1) at 48 months. Continued mass azithromycin distributions also selected for determinants of nonmacrolide resistance, including resistance to beta-lactam antibiotics, an antibiotic class prescribed frequently in this region of Africa.

CONCLUSIONS: Among villages assigned to receive mass distributions of azithromycin or placebo twice yearly for 4 years, antibiotic resistance was more common in the villages that received azithromycin than in those that received placebo. This trial showed that mass azithromycin distributions may propagate antibiotic resistance. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT02047981.).

}, keywords = {Anti-Bacterial Agents, Azithromycin, Child Mortality, Child, Preschool, Drug Resistance, Bacterial, Female, Gastrointestinal Microbiome, Humans, Infant, Macrolides, Male, Mass Drug Administration, Metagenome, Niger, Sequence Analysis, DNA}, issn = {1533-4406}, doi = {10.1056/NEJMoa2002606}, author = {Doan, Thuy and Worden, Lee and Hinterwirth, Armin and Arzika, Ahmed M and Maliki, Ramatou and Abdou, Amza and Zhong, Lina and Chen, Cindi and Cook, Catherine and Lebas, Elodie and O{\textquoteright}Brien, Kieran S and Oldenburg, Catherine E and Chow, Eric D and Porco, Travis C and Lipsitch, Marc and Keenan, Jeremy D and Lietman, Thomas M} } @article {41, title = {Effect of Corticosteroid-Sparing Treatment With Mycophenolate Mofetil vs Methotrexate on Inflammation in Patients With Uveitis: A Randomized Clinical Trial.}, journal = {JAMA}, volume = {322}, year = {2019}, month = {2019 09 10}, pages = {936-945}, abstract = {

Importance: Methotrexate and mycophenolate mofetil are commonly used immunomodulatory therapies for achieving corticosteroid-sparing control of noninfectious uveitis, but there is uncertainty about which drug is more effective.

Objective: To compare the effect of methotrexate and mycophenolate for achieving corticosteroid-sparing control of noninfectious intermediate uveitis, posterior uveitis, and panuveitis.

Design, Setting, and Participants: The First-line Antimetabolites as Steroid-sparing Treatment (FAST) uveitis trial screened 265 adults with noninfectious uveitis requiring corticosteroid-sparing immunosuppressive therapy from 9 referral eye centers in India, the United States, Australia, Saudi Arabia, and Mexico between August 22, 2013, and August 16, 2017. Follow-up ended on August 20, 2018.

Interventions: Patients were randomized to receive oral methotrexate, 25 mg weekly (n = 107), or oral mycophenolate mofetil, 3 g daily (n = 109).

Main Outcomes and Measures: The primary outcome was treatment success at 6 months, which was defined as having control of inflammation in both eyes, no more than 7.5 mg prednisone daily and less than or equal to 2 drops of prednisolone acetate 1\%, and no treatment failure due to safety or intolerability. Patients underwent follow-up to 12 months while receiving the same treatment or switched to the other antimetabolite, depending on their 6-month outcome.

Results: Among 216 patients who were randomized (median age, 38 years; 135 (62.5\%) women), 194 (89.8\%) completed follow-up through 6 months. Treatment success occurred in 64 (66.7\%) patients in the methotrexate group vs 56 (57.1\%) in the mycophenolate group (difference, 9.5\% [95\% CI, -5.3\% to 21.8\%]; odds ratio [OR], 1.50 [95\% CI, 0.81 to 2.81]; P = .20). Among patients with posterior uveitis or panuveitis, treatment success was achieved in 58 (74.4\%) in the methotrexate group vs 42 (55.3\%) in the mycophenolate group (difference, 19.1\% [95\% CI, 3.6\% to 30.6\%]; OR, 2.35 [95\% CI, 1.16 to 4.90]; P = .02); whereas among patients with intermediate uveitis treatment success occurred in 6 (33.3\%) in the methotrexate group vs 14 (63.6\%) in the mycophenolate group (difference, -30.3\% [95\% CI, -51.6\% to 1.1\%]; OR, 0.29 [95\% CI, 0.08 to 1.05]; P = .07; P for interaction = .004). Elevated liver enzymes were the most common nonserious laboratory adverse event, occurring in 14 patients (13.0\%) in the methotrexate group and 8 patients (7.4\%) in the mycophenolate group.

Conclusions and Relevance: Among adults with noninfectious uveitis, the use of mycophenolate mofetil compared with methotrexate as first-line corticosteroid-sparing treatment did not result in superior control of inflammation. Further research is needed to determine if either drug is more effective based on the anatomical subtype of uveitis.

Trial Registration: ClinicalTrials.gov Identifier: NCT01829295.

}, keywords = {Adult, Anti-Inflammatory Agents, Drug Therapy, Combination, Enzyme Inhibitors, Female, Humans, Immunosuppressive Agents, Liver Function Tests, Male, Methotrexate, Middle Aged, Mycophenolic Acid, Prednisolone, Uveitis}, issn = {1538-3598}, doi = {10.1001/jama.2019.12618}, author = {Rathinam, S R and Gonzales, John A and Thundikandy, Radhika and Kanakath, Anuradha and Murugan, S Bala and Vedhanayaki, R and Lim, Lyndell L and Suhler, Eric B and Al-Dhibi, Hassan A and Doan, Thuy and Keenan, Jeremy D and Rao, Maya M and Ebert, Caleb D and Nguyen, Hieu H and Kim, Eric and Porco, Travis C and Acharya, Nisha R} } @article {151, title = {High-throughput sequencing of pooled samples to determine community-level microbiome diversity.}, journal = {Ann Epidemiol}, volume = {39}, year = {2019}, month = {2019 11}, pages = {63-68}, abstract = {

PURPOSE: Community-level interventions in cluster randomized controlled trials may alter the gut microbiome of individuals. The current method of estimating community diversities uses microbiome data obtained from multiple individual{\textquoteright}s specimens. Here we propose randomly pooling a number of microbiome samples from the same community into one sample before sequencing to estimate community-level microbiome diversity.

METHODS: We design and analyze an experiment to compare community microbiome diversity (gamma-diversity) estimates derived from 16S rRNA gene sequencing of 1) individually sequenced specimens vs. 2) pooled specimens collected from a community. Pool sizes of 10, 20, and 40 are considered. We then compare the gamma-estimates using Pearson{\textquoteright}s correlation as well as using Bland and Altman agreement analysis for three established diversity indices including richness, Simpson{\textquoteright}s and Shannon{\textquoteright}s.

RESULTS: The gamma-diversity estimates are highly correlated, with most being statistically significant. All correlations between all three diversity estimates are significant in the 10-pooled data. Pools comprising 40 specimens are closest to the line of agreement, but all pooled samples and individual samples fall within the 95\% limits of agreement.

CONCLUSIONS: Pooling microbiome samples before DNA amplification and metagenomics sequencing to estimate community-level diversity is a viable measure to consider in population-level association research studies.

}, keywords = {Administration, Oral, Anti-Bacterial Agents, Azithromycin, Bacteria, Biodiversity, Child, Preschool, Female, Gastrointestinal Microbiome, Gastrointestinal Tract, High-Throughput Nucleotide Sequencing, Humans, Infant, Infant, Newborn, Male, Metagenomics, Microbiota, Niger, Placebos, RNA, Ribosomal, 16S, Sequence Analysis, DNA}, issn = {1873-2585}, doi = {10.1016/j.annepidem.2019.09.002}, author = {Ray, Kathryn J and Cotter, Sun Y and Arzika, Ahmed M and Kim, Jessica and Boubacar, Nameywa and Zhou, Zhaoxia and Zhong, Lina and Porco, Travis C and Keenan, Jeremy D and Lietman, Thomas M and Doan, Thuy} } @article {121, title = {Longer-Term Assessment of Azithromycin for Reducing Childhood Mortality in Africa.}, journal = {N Engl J Med}, volume = {380}, year = {2019}, month = {2019 Jun 06}, pages = {2207-2214}, abstract = {

BACKGROUND: The MORDOR I trial (Macrolides Oraux pour R{\'e}duire les D{\'e}c{\`e}s avec un Oeil sur la R{\'e}sistance) showed that in Niger, mass administration of azithromycin twice a year for 2 years resulted in 18\% lower postneonatal childhood mortality than administration of placebo. Whether this benefit could increase with each administration or wane owing to antibiotic resistance was unknown.

METHODS: In the Niger component of the MORDOR I trial, we randomly assigned 594 communities to four twice-yearly distributions of either azithromycin or placebo to children 1 to 59 months of age. In MORDOR II, all these communities received two additional open-label azithromycin distributions. All-cause mortality was assessed twice yearly by census workers who were unaware of participants{\textquoteright} original assignments.

RESULTS: In the MORDOR II trial, the mean ({\textpm}SD) azithromycin coverage was 91.3{\textpm}7.2\% in the communities that received twice-yearly azithromycin for the first time (i.e., had received placebo for 2 years in MORDOR I) and 92.0{\textpm}6.6\% in communities that received azithromycin for the third year (i.e., had received azithromycin for 2 years in MORDOR I). In MORDOR II, mortality was 24.0 per 1000 person-years (95\% confidence interval [CI], 22.1 to 26.3) in communities that had originally received placebo in the first year and 23.3 per 1000 person-years (95\% CI, 21.4 to 25.5) in those that had originally received azithromycin in the first year, with no significant difference between groups (P = 0.55). In communities that had originally received placebo, mortality decreased by 13.3\% (95\% CI, 5.8 to 20.2) when the communities received azithromycin (P = 0.007). In communities that had originally received azithromycin and continued receiving it for an additional year, the difference in mortality between the third year and the first 2 years was not significant (-3.6\%; 95\% CI, -12.3 to 4.5; P = 0.50).

CONCLUSIONS: We found no evidence that the effect of mass administration of azithromycin on childhood mortality in Niger waned in the third year of treatment. Childhood mortality decreased when communities that had originally received placebo received azithromycin. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT02047981.).

}, keywords = {Anti-Bacterial Agents, Azithromycin, Child Mortality, Child, Preschool, Drug Administration Schedule, Female, Humans, Infant, Infant Mortality, Male, Mass Drug Administration, Niger}, issn = {1533-4406}, doi = {10.1056/NEJMoa1817213}, author = {Keenan, Jeremy D and Arzika, Ahmed M and Maliki, Ramatou and Boubacar, Nameywa and Elh Adamou, Sanoussi and Moussa Ali, Maria and Cook, Catherine and Lebas, Elodie and Lin, Ying and Ray, Kathryn J and O{\textquoteright}Brien, Kieran S and Doan, Thuy and Oldenburg, Catherine E and Callahan, E Kelly and Emerson, Paul M and Porco, Travis C 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} } @article {276, title = {Gut Microbial Diversity in Antibiotic-Naive Children After Systemic Antibiotic Exposure: A Randomized Controlled Trial.}, journal = {Clin Infect Dis}, volume = {64}, year = {2017}, month = {2017 05 01}, pages = {1147-1153}, abstract = {

Background: Antibiotic exposure can alter the gut microbiome. We evaluate the effects of azithromycin on the gut microbiome diversity of children from an antibiotic-naive community in Niger.

Methods: A population-based sample of 80 children aged 1-60 months in the Dosso region of Niger was randomized to receive a single dose of either oral azithromycin or placebo. Fecal samples were collected immediately before treatment and 5 days after treatment for 16S rRNA gene sequencing. The prespecified outcome was α-diversity (inverse Simpson{\textquoteright}s α-diversity index), with secondary outcomes of β and γ Simpson{\textquoteright}s and Shannon{\textquoteright}s diversities.

Results: At 5 days after treatment, 40 children aged 1-60 months were analyzed in the azithromycin-treated group and 40 children in the placebo-treated group. Diversity of the gut microbiome was significantly lower in the treated group (inverse Simpson{\textquoteright}s α-diversity, 5.03; 95\% confidence interval [CI], 4.08-6.14) than in the placebo group (6.91; 95\% CI, 5.82-8.21; P = .03). Similarly, the Shannon{\textquoteright}s α-diversity was lower in the treated group (10.60; 95\% CI, 8.82-12.36) than the placebo group (15.42; 95\% CI, 13.24-17.80; P = .004). Simpson{\textquoteright}s community-level (γ) diversity decreased with azithromycin exposure from 17.72 (95\% CI, 13.80-20.21) to 10.10 (95\% CI, 7.80-11.40; P = .00008), although β-diversity was not significantly reduced (2.56, 95\% CI, 1.88-3.12; to 2.01, 95\% CI, 1.46-2.51; P = .26).

Conclusions: Oral administration of azithromycin definitively decreases the diversity of the gut microbiome of children in an antibiotic-naive community.

Clinical Trials Registration: NCT02048007.

}, keywords = {Administration, Oral, Anti-Bacterial Agents, Azithromycin, Bacteria, Biodiversity, Child, Preschool, Cluster Analysis, DNA, Ribosomal, Female, Gastrointestinal Microbiome, Gastrointestinal Tract, Humans, Infant, Male, Niger, Phylogeny, Placebos, RNA, Ribosomal, 16S, Sequence Analysis, DNA}, issn = {1537-6591}, doi = {10.1093/cid/cix141}, author = {Doan, Thuy and Arzika, Ahmed M and Ray, Kathryn J and Cotter, Sun Y and Kim, Jessica and Maliki, Ramatou and Zhong, Lina and Zhou, Zhaoxia and Porco, Travis C and Vanderschelden, Benjamin and Keenan, Jeremy D and Lietman, Thomas M} }