@article {106, title = {Reduction of Coronavirus Burden With Mass Azithromycin Distribution.}, journal = {Clin Infect Dis}, volume = {71}, year = {2020}, month = {2020 11 19}, pages = {2282-2284}, abstract = {

We evaluated the potential antiviral effects of azithromycin on the nasopharyngeal virome of Nigerien children who had received multiple rounds of mass drug administration. We found that the respiratory burden of non-severe acute respiratory syndrome coronaviruses was decreased with azithromycin distributions. Clinical Trials Registration. NCT02047981.

}, keywords = {Administration, Oral, Antiviral Agents, Azithromycin, Child, Preschool, Coronavirus, Coronavirus Infections, Humans, Infant, Infant, Newborn, Mass Drug Administration, Nasopharynx, Nigeria, Viral Load}, issn = {1537-6591}, doi = {10.1093/cid/ciaa606}, author = {Doan, Thuy and Hinterwirth, Armin and Arzika, Ahmed M and Worden, Lee and Chen, Cindi and Zhong, Lina and Oldenburg, Catherine E and Keenan, Jeremy D and Lietman, Thomas M} } @article {76, title = {A double masked randomised 4-week, placebo-controlled study in the USA, Thailand and Taiwan to compare the efficacy of oral valganciclovir and topical 2\% ganciclovir in the treatment of cytomegalovirus anterior uveitis: study protocol.}, journal = {BMJ Open}, volume = {9}, year = {2019}, month = {2019 12 19}, pages = {e033175}, abstract = {

INTRODUCTION: Cytomegalovirus (CMV) anterior uveitis is a recognised cause of anterior uveitis in immunocompetent patients and is preventable cause of vision loss. Ocular sequelae include corneal endothelial damage which can cause corneal oedema and failure, as well as glaucoma. Recurrences of inflammation are common and therefore patients are often exposed to long-term therapy. Oral therapy is available in the form of valganciclovir, although with the caveat of systemic side effects such as bone marrow suppression and renal failure necessitating regular interval laboratory monitoring. Recent reports have demonstrated that topical 2\% ganciclovir solution may offer promising treatment outcomes in patients with CMV anterior uveitis with superior safety, cost-effectiveness and convenience profiles. An investigation into the relative equipoise of these therapies is warranted for these reasons.

METHODS AND ANALYSIS: The Systemic and Topical Control of Cytomegalovirus Anterior uveitis: Treatment Outcomes (STACCATO) trial is designed as a multicentre, block randomised by site, double-masked, placebo-controlled trial comparing the efficacy of oral valganciclovir, 2\% topical ganciclovir and placebo in treating PCR-proven CMV anterior uveitis. Participant clinical evaluation will occur at three study time points by a masked study ophthalmologist over a 28-day period to assess resolution of ocular inflammation (secondary outcome). A control group will provide additional information about the possible impact that the infected host{\textquoteright}s immune response may play in controlling local viral replication. The primary analysis is an analysis of covariance (three arms) correcting for baseline to compare quantitative CMV viral load in the anterior chamber (AC) aqueous fluid before and 7 days after treatment.

ETHICS AND DISSEMINATION: The University of California San Francisco Committee on Human Research and the Khon Kaen University Institutional Review Board have given ethical approval. The results of this trial will be presented at local and international meetings and submitted for peer-reviewed journals for publication.

TRIAL REGISTRATION NUMBER: NCT03576898.

}, keywords = {Administration, Oral, Administration, Topical, Antiviral Agents, Cytomegalovirus Infections, Double-Blind Method, Ganciclovir, Humans, Multicenter Studies as Topic, Randomized Controlled Trials as Topic, Taiwan, Thailand, United States, Uveitis, Anterior, Valganciclovir, Viral Load}, issn = {2044-6055}, doi = {10.1136/bmjopen-2019-033175}, author = {Takhar, Jaskirat S and Joye, Ashlin S and Somkijrungroj, Thanapong and Laovirojjanakul, Wipada and Lin, Chang-Ping and Lietman, Thomas M and Porco, Travis C and Keenan, Jeremy D and Gebreegziabher, Elisabeth A and Seitzman, Gerami D and Rose-Nussbaumer, Jennifer and Thuy A Doan and Acharya, Nisha R and Gonzales, John A} } @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 {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 {116, title = {Time Trade-off Utility Values in Noninfectious~Uveitis.}, journal = {Am J Ophthalmol}, volume = {208}, year = {2019}, month = {2019 12}, pages = {47-55}, abstract = {

PURPOSE: To investigate time trade-off (TTO) utility values in patients with noninfectious uveitis and determine whether patient demographics and clinical characteristics are associated with utility scores.

DESIGN: Time trade-off utility analysis.

METHODS: Setting: A tertiary care uveitis center in San Francisco, California, USA.

PATIENT POPULATION: One hundred and four consecutive adults with noninfectious uveitis, enrolled between November 2016 and February 2017.

MAIN OUTCOME MEASURES: TTO utility values, as collected by an interviewer-guided survey. Information regarding general health, ocular symptoms, and religion was also collected and medical record review was conducted to record anatomic location of uveitis, disease activity, visual acuity, and treatments. Multivariable regression analysis with backward selection was used to identify variables associated with TTO values.

RESULTS: Median TTO score was 0.975 (interquartile range [IQR]: 0.8-1.0), corresponding to trading a median 1.28 years of remaining life for healthy eyes (IQR: 0-6.29). Regression analysis revealed that worse eye visual acuity, \>6\ months of oral corticosteroid use, and current antidepressant use were associated with lower TTO scores (P\ = .008, P\ = .006, P\ = .008, respectively), controlling for age and sex. In particular, patients who had been taking oral corticosteroids for more than 6\ months, regardless of dose, were 10.5 times more likely to trade 20\% or more years of remaining life (TTO <=0.8) than patients not taking oral corticosteroids (95\% confidence interval: 2.3, 48.1; P\ = .002).

CONCLUSIONS: Patients with noninfectious uveitis had measurable, though modest, reductions in quality of life, as assessed by TTO, and these decreases were significantly associated with visual acuity in the worse eye and long-term oral corticosteroid use.

}, keywords = {Administration, Oral, Adult, Antidepressive Agents, Cross-Sectional Studies, Female, Glucocorticoids, Health Status, Health Surveys, Humans, Male, Middle Aged, Quality of Life, Sickness Impact Profile, Surveys and Questionnaires, Tertiary Care Centers, Uveitis, Visual Acuity}, issn = {1879-1891}, doi = {10.1016/j.ajo.2019.06.005}, author = {Niemeyer, Katherine M and Gonzales, John A and Doan, Thuy and Browne, Erica N and Rao, Maya M and Acharya, Nisha R} } @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} }