A Cross-Sectional Study of the Availability of Azithromycin in Local Pharmacies and Associated Antibiotic Resistance in Communities in Kilosa District, Tanzania.

Mass drug administration (MDA) for trachoma control using azithromycin has generated concern for the development of resistant organisms. However, the contribution from azithromycin available in local pharmacies has not been studied. In Kilosa district, Tanzania, MDA stopped over 4 years ago, and this study sought to determine the availability of azithromycin in local pharmacies and correlate it with azithromycin resistance in children born after MDA. A cross-sectional survey was conducted in 644 randomly selected hamlets in Kilosa district, in which the presence of a pharmacy and the availability of azithromycin and erythromycin were determined. In 30 randomly selected hamlets, a random sample of 60 children less than 5 years were tested for azithromycin-resistant Streptococcus pneumoniae (Spn) and Escherichia coli (Ec), from nasopharyngeal and rectal swabs, based on disk diffusion criteria. Only 26.6% of hamlets had a pharmacy. Azithromycin and erythromycin were available in 30.8% and 89.1% of pharmacies closest to the hamlets, respectively. In the 30 communities tested for resistance, the overall prevalence of azithromycin-resistant Spn isolates was 14%. Six of seven (87%) hamlets where azithromycin was available had resistant Spn, compared with 14 of 23 (61%) hamlets without availability. Similarly, six of seven (87%) hamlets where azithromycin was available had resistant Ec isolates compared with 21 of 23 (70%) hamlets without availability. However, the differences were not statistically significant (P = 0.46 and 0.49, respectively). The availability of azithromycin in pharmacies in the district was limited, and a strong correlation with azithromycin-resistant Spn or Ec was not observed

Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa.

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 (±SD) azithromycin and placebo coverage over the four twice-yearly distributions was 90.4±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 .)

Mass Oral Azithromycin for Childhood Mortality: Timing of Death After Distribution in the MORDOR Trial.

In a large community-randomized trial, biannual azithromycin distributions significantly reduced postneonatal childhood mortality in sub-Saharan African sites. Here, we present a prespecified secondary analysis showing that much of the protective effect was in the first 3 months postdistribution. Distributing more frequently than biannually could be considered if logistically feasible. Clinical Trials Registration. NCT02047981

Causes of death after biannual azithromycin treatment: A community-level randomized clinical trial.

The MORDOR study, a masked, community-level randomized clinical trial conducted in Niger, Malawi and Tanzania (2015 to 2017), showed that biannual administration of single-dose azithromycin to preschool children reduced all-cause mortality. We sought to evaluate its impact on causes of death in children aged 1-59 months in Tanzania. A random sampling of 614 communities was conducted in Kilosa District, Tanzania, with simple random assignment of communities to receive either azithromycin or placebo. In these communities, a census was carried out every 6 months and children aged 1-59 months received biannual (every 6 months), single-dose azithromycin (~20mg/kg) or placebo depending on community assignment, over a 2-year period. Mortality was determined at the time of the biannual census. For child deaths, a verbal autopsy was performed to ascertain the cause using a standardized diagnostic classification. A total of 190- (0.58 /100 person-years) and 200 deaths (0.59/100 person-years) were reported in the azithromycin and placebo arms, respectively. Malaria, pneumonia and diarrhea, accounted for 71% and 68% of deaths in the respective arms. Overall, the mortality was not different by treatment arm, nor were the distribution of causes of death after adjusting for community clustering. The cause-specific mortality for diarrhea/pneumonia was no different over time. In children aged 1-5 months, 32 deaths occurred in the placebo arm and 25 deaths occurred in the azithromycin arm; 20 (62.5%) deaths in the placebo- and 10 (40%) in the azithromycin arm were attributed to diarrhea or pneumonia. Neither differences in the number of deaths nor the diarrhea/pneumonia attribution was statistically significant after adjusting for community clustering. In conclusion, azithromycin was not associated with a significant decline in deaths by specific causes compared to placebo. The non-significant lower rates of diarrhea or pneumonia in children &lt;6 months who received azithromycin merit further investigation in high-mortality settings. Trial registration: NCT02048007

Impact of Biannual Azithromycin on Anemia in Preschool Children in Kilosa District, Tanzania: A Cluster-Randomized Clinical Trial.

A cluster-randomized clinical trial showed that biannual single-dose azithromycin reduced mortality in preschool children; we sought to determine the effect on anemia. A simple random sample of 30 communities from Kilosa district, Tanzania, were themselves randomized to receive either 6-monthly treatment of children aged 1-59 months with single-dose azithromycin or placebo. From each community, 40 preschool children were randomly selected at baseline, 12 months, and 24 months. At surveys, the children underwent hemoglobin testing; WHO definitions for anemia were applied. After adjusting for community clustering, the prevalence of anemia was not significantly different by treatment assignment at baseline, 12 months, and 24 months. In each of the cross-sectional surveys, anemia prevalence was associated with younger age; the odds of being anemic was highest in those aged &lt; 12 months. There was also a general decrease in the prevalence of anemia during the study. Although azithromycin was not shown to affect anemia, significantly, the study highlights burden of anemia in rural, African communities

Impact of Biannual Azithromycin on Anemia in Preschool Children in Kilosa District, Tanzania: A Cluster-Randomized Clinical Trial.

A cluster-randomized clinical trial showed that biannual single-dose azithromycin reduced mortality in preschool children; we sought to determine the effect on anemia. A simple random sample of 30 communities from Kilosa district, Tanzania, were themselves randomized to receive either 6-monthly treatment of children aged 1-59 months with single-dose azithromycin or placebo. From each community, 40 preschool children were randomly selected at baseline, 12 months, and 24 months. At surveys, the children underwent hemoglobin testing; WHO definitions for anemia were applied. After adjusting for community clustering, the prevalence of anemia was not significantly different by treatment assignment at baseline, 12 months, and 24 months. In each of the cross-sectional surveys, anemia prevalence was associated with younger age; the odds of being anemic was highest in those aged &lt; 12 months. There was also a general decrease in the prevalence of anemia during the study. Although azithromycin was not shown to affect anemia, significantly, the study highlights burden of anemia in rural, African communities

Causes of death after biannual azithromycin treatment: A community-level randomized clinical trial.

The MORDOR study, a masked, community-level randomized clinical trial conducted in Niger, Malawi and Tanzania (2015 to 2017), showed that biannual administration of single-dose azithromycin to preschool children reduced all-cause mortality. We sought to evaluate its impact on causes of death in children aged 1-59 months in Tanzania. A random sampling of 614 communities was conducted in Kilosa District, Tanzania, with simple random assignment of communities to receive either azithromycin or placebo. In these communities, a census was carried out every 6 months and children aged 1-59 months received biannual (every 6 months), single-dose azithromycin (~20mg/kg) or placebo depending on community assignment, over a 2-year period. Mortality was determined at the time of the biannual census. For child deaths, a verbal autopsy was performed to ascertain the cause using a standardized diagnostic classification. A total of 190- (0.58 /100 person-years) and 200 deaths (0.59/100 person-years) were reported in the azithromycin and placebo arms, respectively. Malaria, pneumonia and diarrhea, accounted for 71% and 68% of deaths in the respective arms. Overall, the mortality was not different by treatment arm, nor were the distribution of causes of death after adjusting for community clustering. The cause-specific mortality for diarrhea/pneumonia was no different over time. In children aged 1-5 months, 32 deaths occurred in the placebo arm and 25 deaths occurred in the azithromycin arm; 20 (62.5%) deaths in the placebo- and 10 (40%) in the azithromycin arm were attributed to diarrhea or pneumonia. Neither differences in the number of deaths nor the diarrhea/pneumonia attribution was statistically significant after adjusting for community clustering. In conclusion, azithromycin was not associated with a significant decline in deaths by specific causes compared to placebo. The non-significant lower rates of diarrhea or pneumonia in children &lt;6 months who received azithromycin merit further investigation in high-mortality settings. Trial registration: NCT02048007

Antibiotic Resistance in Young Children in Kilosa District, Tanzania 4 Years after Mass Distribution of Azithromycin for Trachoma Control.

Mass administration of azithromycin (MDA) is integral to trachoma control. Recent studies suggest that MDA may increase drug-resistant pathogens, yet findings from prior studies suggest little long-term impact on resistance. This disparity may be linked to differences in pre-MDA community-level resistance patterns. We describe carriage prevalence and antibiotic resistance patterns for Streptococcus pneumoniae (Spn) (nasopharyngeal swab collection), Staphylococcus aureus (SA) (nasopharyngeal swabs), and Escherichia coli (EC) (rectal swabs) in 1,047 children ages 1-59 months in a district with MDA cessation 4 years ago. Antibiotic susceptibility was evaluated by disk diffusion and Etest. The carriage rates for Spn, SA, and EC were 43.5% (455/1,047), 13.2% (138/1,047), and 61.7% (646/1,047), respectively. Resistance to AZM was observed in 14.3%, 29.0%, and 16.6% of the Spn, SA, and EC isolates, respectively. Spn resistance was variable (0-67%) by hamlet. Future analyses will assess the influence of pre-MDA antibiotic resistance patterns on those observed following MDA

Can We Use Antibodies to Chlamydia trachomatis as a Surveillance Tool for National Trachoma Control Programs? Results from a District Survey.

BACKGROUND:Trachoma is targeted for elimination by 2020. World Health Organization advises districts to undertake surveillance when follicular trachoma (TF) <5% in children 1-9 years and mass antibiotic administration has ceased. There is a question if other tools could be used for surveillance as well. We report data from a test for antibodies to C. trachomatis antigen pgp3 as a possible tool. METHODOLOGY:We randomly sampled 30 hamlets in Kilosa district, Tanzania, and randomly selected 50 children ages 1-9 per hamlet. The tarsal conjunctivae were graded for trachoma (TF), tested for C. trachomatis infection (Aptima Combo2 assay: Hologic, San Diego, CA), and a dried blood spot processed for antibodies to C. trachomatis pgp3 using a multiplex bead assay on a Luminex 100 platform. PRINCIPAL FINDINGS:The prevalence of trachoma (TF) was 0.4%, well below the <5% indicator for re-starting a program. Infection was also low, 1.1%. Of the 30 hamlets, 22 had neither infection nor TF. Antibody positivity overall was low, 7.5% and increased with age from 5.2% in 1-3 year olds, to 9.3% in 7-9 year olds (p = 0.015). In 16 of the 30 hamlets, no children ages 1-3 years had antibodies to pgp3. CONCLUSIONS:The antibody status of the 1-3 year olds indicates low cumulative exposure to infection during the surveillance period. Four years post MDA, there is no evidence for re-emergence of follicular trachoma

Biannual Treatment of Preschool Children with Single Dose Azithromycin to Reduce Mortality: Impact on Azithromycin Resistance in the MORDOR Trial in Tanzania.

The Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance study showed that administration of biannual, single-dose azithromycin to preschool children reduces mortality. We sought to evaluate its impact on azithromycin resistance. Thirty randomly selected communities in Kilosa district, Tanzania, were randomized to receive 6-monthly single-dose azithromycin (∼20 mg/kg) versus placebo treatment of children aged 1-59 months. From each community, 40 children (aged 1-59 months) were randomly selected at baseline, 12 and 24 months. Isolation and resistance testing of Streptococcus pneumoniae and Escherichia coli were evaluated using nasopharyngeal and rectal swabs, respectively. The carriage prevalence and the proportion of azithromycin-resistant isolates were determined using disk diffusion. At baseline, the characteristics of the randomly selected children were similar by treatment arms. Both at baseline and in annual cross-sectional surveys, rates of S. pneumoniae and E. coli isolation between treatment arms were similar. The proportions of azithromycin-resistant S. pneumoniae isolates in the children in communities treated with azithromycin versus placebo at baseline, 12 months, and 24 months were 26.5% (18.1%; P = 0.26), 26.8% (16.5%; P = 0.29), and 13.4% (17.0%; P = 0.57), respectively. The proportions of azithromycin-resistant E. coli isolates at baseline, 12 months, and 24 months in the azithromycin (versus placebo) arms were 14.9% (18.9%; P = 0.16), 21.5% (16.6%; P = 0.10), and 14.9% (14.7%; P = 0.95), respectively. Over the 24 months, the mean treatment coverage for the azithromycin and placebo was 76.9% and 74.8%, respectively (P = 0.49). Biannual administration of single-dose azithromycin to children did not appear to result in excess azithromycin resistance in S. pneumoniae and E. coli isolates over 24 months of follow-up