@article {1391, title = {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.}, journal = {Clin Infect Dis}, year = {2024}, month = {2024 May 13}, abstract = {

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.

}, issn = {1537-6591}, doi = {10.1093/cid/ciae267}, author = {Peterson, Brittany and Arzika, Ahmed M and Amza, Abdou and Maliki, Ramatou and Mankara Karamba, Alio and Moussa, Mariama and Kemago, Mariama and Liu, Zijun and Houpt, Eric and Liu, Jie and Pholwat, Suporn and Doan, Thuy and Porco, Travis and Keenan, Jeremy D and Lietman, Thomas M and O{\textquoteright}Brien, Kieran S} } @article {1361, title = {Gut Microbiome Diversity and Antimicrobial Resistance After a Single Dose of Oral Azithromycin in Children: A Randomized Placebo-Controlled Trial.}, journal = {Am J Trop Med Hyg}, year = {2024}, month = {2024 Jan 16}, abstract = {

Mass antibiotic distribution to preschool children resulted in alterations of the gut microbiome months after distribution. This individually randomized, placebo-controlled trial evaluated changes in the gut microbiome and resistome in children aged 8 days to 59 months after one dose of oral azithromycin in Burkina Faso. A total of 450 children were randomized in a 1:1 ratio to either placebo or azithromycin. Rectal samples were collected at baseline, 2 weeks, and 6 months after randomization and subjected to DNA deep sequencing. Gut microbiome diversity and normalized antimicrobial resistance determinants for different antibiotic classes were evaluated. Azithromycin decreased gut bacterial diversity (Shannon P < 0.0001; inverse Simpson P < 0.001) 2 weeks after treatment relative to placebo. Concurrently, the normalized abundance of macrolide resistance genetic determinants was 243-fold higher (95\% CI: 76-fold to 776-fold, P < 0.0001). These alterations did not persist at 6 months, suggesting that disruptions were transient. Furthermore, we were unable to detect resistance changes in other antibiotic classes, indicating that co-resistance with a single course of azithromycin when treated at the individual level was unlikely.

}, issn = {1476-1645}, doi = {10.4269/ajtmh.23-0651}, author = {Doan, Thuy and Liu, Zijun and Sie, Ali and Dah, Clarisse and Bountogo, Mamadou and Ouattara, Mamadou and Coulibaly, Boubacar and Kiemde, Dramane and Zonou, Guillaume and Nebie, Eric and Brogdon, Jessica and Lebas, Elodie and Hinterwirth, Armin and Zhong, Lina and Chen, Cindi and Zhou, Zhaoxia and Porco, Travis and Arnold, Benjamin F and Oldenburg, Catherine E and Lietman, Thomas M} } @article {1281, title = {Wastewater-Based Surveillance of Antimicrobial Resistance in Niger: An Exploratory Study.}, journal = {Am J Trop Med Hyg}, year = {2023}, month = {2023 Aug 28}, abstract = {

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.

}, issn = {1476-1645}, doi = {10.4269/ajtmh.23-0204}, author = {Ousmane, Sani and Kollo, Issifi A and Jambou, Ronan and Boubacar, Rakia and Arzika, Ahmed M and Maliki, Ramatou and Amza, Abdou and Liu, Zijun and Lebas, Elodie and Colby, Emily and Zhong, Lina and Chen, Cindi and Hinterwirth, Armin and Doan, Thuy and Lietman, Thomas M and O{\textquoteright}Brien, Kieran S} } @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 {911, title = {Age-based targeting of biannual azithromycin distribution for child survival in Niger: an adaptive cluster-randomized trial protocol (AVENIR).}, journal = {BMC Public Health}, volume = {21}, year = {2021}, month = {2021 04 29}, pages = {822}, abstract = {

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 ).

}, keywords = {Anti-Bacterial Agents, Azithromycin, Child, Child, Preschool, Drug Resistance, Bacterial, Humans, Infant, Macrolides, Mass Drug Administration, Niger, Randomized Controlled Trials as Topic}, issn = {1471-2458}, doi = {10.1186/s12889-021-10824-7}, author = {O{\textquoteright}Brien, Kieran S and Arzika, Ahmed M and Amza, Abdou and Maliki, Ramatou and Ousmane, Sani and Kadri, Boubacar and Nassirou, Beido and Mankara, Alio Karamba and Harouna, Abdoul Naser and Colby, Emily and Lebas, Elodie and Liu, Zijun and Le, Victoria and Nguyen, William and Keenan, Jeremy D and Oldenburg, Catherine E and Porco, Travis C and Doan, Thuy and Arnold, Benjamin F and Lietman, Thomas M} } @article {176, title = {Evaluation of Metagenomic Deep Sequencing as a Diagnostic Test for Infectious Keratitis.}, journal = {Ophthalmology}, year = {2020}, month = {2020 Jul 17}, issn = {1549-4713}, doi = {10.1016/j.ophtha.2020.07.030}, author = {Lalitha, Prajna and Prajna, N Venkatesh and Sikha, Misra and Gunasekaran, Rameshkumar and Hinterwirth, Armin and Worden, Lee and Chen, Cindi and Zhong, Lina and Liu, Zijun and Lietman, Thomas M and Seitzman, Gerami D and Doan, Thuy} }