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Background: Early childhood enteric infection with Shigella/EIEC, enteroaggregative E. coli (EAEC), Campylobacter, and Giardia has been associated with reduced child growth, yet a recent randomized trial of antimicrobial therapy to reduce these infections did not improve growth outcomes. To interrogate this discrepancy, we measured the enteric infections from this study. Methods: We leveraged the Early Life Interventions for Childhood Growth and Development in Tanzania (ELICIT) trial, a randomized double-blind placebo-controlled trial of antimicrobial therapy with azithromycin and nitazoxanide provided quarterly to infants from 6 to 15 months of age. We tested 5,479 stool samples at time points across the study for 34 enteropathogens using quantitative PCR. Results: There was substantial carriage of enteropathogens in stool. Azithromycin administration led to reductions in Campylobacter jejuni/coli, enteroaggregative E. coli, and Shigella/EIEC (absolute risk difference ranged from -0.06 to 0.24) 2 weeks after treatment however there was no effect after 3 months. There was no difference in Giardia after nitazoxanide administration (ARR 0.03 at the 12 month administration). When examining the effect of azithromycin versus placebo on the subset of children infected with specific pathogens at the time of treatment, a small increase in weight-for-age Z score was seen only in those infected with Campylobacter jejuni/coli (0.10 Z score, 95% CI -0.01–0.20; length-for-age Z score 0.07, 95% CI -0.06–0.20). Conclusion: The antimicrobial intervention of quarterly azithromycin plus or minus nitazoxanide led to only transient decreases in enteric infections with Shigella/EIEC, enteroaggregative E. coli (EAEC), Campylobacter, and Giardia. There was a trend towards improved growth in children infected with Campylobacter that received quarterly azithromycin. [ABSTRACT FROM AUTHOR]

Background: Mass drug administration (MDA) of azithromycin (AZI) has been shown to reduce under-5 mortality in some but not all sub-Saharan African settings. A large-scale cluster-randomized trial conducted in Malawi, Niger, and Tanzania suggested that the effect differs by country, may be stronger in infants, and may be concentrated within the first 3 months after treatment. Another study found no effect when azithromycin was given concomitantly with seasonal malaria chemoprevention (SMC). Given the observed heterogeneity and possible effect modification by other co-interventions, further trials are needed to determine the efficacy in additional settings and to determine the most effective treatment regimen. Methods: LAKANA stands for Large-scale Assessment of the Key health-promoting Activities of two New mass drug administration regimens with Azithromycin. The LAKANA trial is designed to address the mortality and health impacts of 4 or 2 annual rounds of azithromycin MDA delivered to 1–11-month-old (29–364 days) infants, in a high-mortality and malaria holoendemic Malian setting where there is a national SMC program. Participating villages (clusters) are randomly allocated in a ratio of 3:2:4 to three groups: placebo (control):4-dose AZI:2-dose AZI. The primary outcome measured is mortality. Antimicrobial resistance (AMR) will be monitored closely before, during, and after the intervention and both among those receiving and those not receiving MDA with the study drugs. Other outcomes, from a subset of villages, comprise efficacy outcomes related to morbidity, growth and nutritional status, outcomes related to the mechanism of azithromycin activity through measures of malaria parasitemia and inflammation, safety outcomes (AMR, adverse and serious adverse events), and outcomes related to the implementation of the intervention documenting feasibility, acceptability, and economic aspects. The enrolment commenced in October 2020 and is planned to be completed by the end of 2022. The expected date of study completion is December 2024. Discussion: If LAKANA provides evidence in support of a positive mortality benefit resulting from azithromycin MDA, it will significantly contribute to the options for successfully promoting child survival in Mali, and elsewhere in sub-Saharan Africa. Trial registration: ClinicalTrials.gov NCT04424511. Registered on 11 June 2020. [ABSTRACT FROM AUTHOR]

The MORDOR trial in Niger, Malawi, and Tanzania found that biannual mass distribution of azithromycin to children younger than 5 years led to a 13.5% reduction in all-cause mortality (NCT02048007). To help elucidate the mechanism for mortality reduction, we report IgG responses to 11 malaria, bacterial, and protozoan pathogens using a multiplex bead assay in pre-specified substudy of 30 communities in the rural Niger placebo-controlled trial over a three-year period (n = 5642 blood specimens, n = 3814 children ages 1–59 months). Mass azithromycin reduces Campylobacter spp. force of infection by 29% (hazard ratio = 0.71, 95% CI: 0.56, 0.89; P = 0.004) but serological measures show no significant differences between groups for other pathogens against a backdrop of high transmission. Results align with a recent microbiome study in the communities. Given significant sequelae of Campylobacter infection among preschool aged children, our results support an important mechanism through which biannual mass distribution of azithromycin likely reduces mortality in Niger. In a randomized placebo-controlled trial in rural Niger, biannual azithromycin distribution to children 1-59 months reduced all-cause mortality. Based on serology, Arzika et al. here report a reduction of Campylobacter infection, supporting one mechanism for the intervention's impact on mortality. [ABSTRACT FROM AUTHOR]

We evaluated the gut resistome of children from communities treated with 10 twice-yearly azithromycin distributions. Although the macrolide resistance remained higher in the azithromycin arm, the selection of non-macrolide resistance observed at earlier time points did not persist. Longitudinal resistance monitoring should be a critical component of mass distribution programs. Clinical trials registration NCT02047981 [ABSTRACT FROM AUTHOR]

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 <6 months who received azithromycin merit further investigation in high-mortality settings. Trial registration:NCT02048007. [ABSTRACT FROM AUTHOR]

Background The mechanisms underlying the finding of reduced child mortality in communities with biannual treatment with azithromycin remain unclear. We determined if there was a difference in morbidity in a cohort of children aged 1–36 months, residing in communities randomized to biannual treatment of preschool-aged children with azithromycin or placebo. Methods Thirty villages in Kilosa, Tanzania, were randomly assigned to receive biannual treatment of all children aged 1–59 months with either azithromycin (20/mg/kg single dose) or placebo. Children who were aged 1–36 months and participated in the baseline survey were enrolled in this cohort study and followed prospectively for 2 years. Children were monitored every 6 months for signs and symptoms of diarrheal disease, acute respiratory illness, and anemia. Mixed-effects models that include age, time, treatment arm, and the interaction of treatment arm and time as independent predictors were used to evaluate differences between children by treatment assignment over time. Results There was no difference in rates of diarrhea, fever, or anemia by treatment arm at baseline and at all phases of follow-up. The decline over time in reported cough was statistically significant in the children residing in the azithromycin communities, but not in the placebo communities. Once adjusting for clustering and age, the difference in decline between the 2 treatment arms was not significant (P =.09). Conclusions A beneficial effect of azithromycin treatment on morbidity outcomes was not evident at biannual surveys. Clinical Trials Registration NCT02048007. [ABSTRACT FROM AUTHOR]

Background: Trachoma, caused by Chlamydia trachomatis, remains the leading infectious cause of blindness worldwide. Persistence and progression of the resulting clinical disease appears to be an immunologically mediated process. Azithromycin, which is distributed at the community level for trachoma control, has immunomodulatory properties. We investigated the impact of one round of oral azithromycin on conjunctival immune responses, C. trachomatis infection and clinical signs three- and six- months post treatment relative to three pre-treatment time-points. Methodology: A cohort of children aged 6 to 10 years were recruited from a trachoma endemic region of northern Tanzania and were visited five times in a 12-month period. They were examined for clinical signs of trachoma and conjunctival swabs were collected for laboratory analysis. C. trachomatis infection was detected and the expression of 46 host genes was quantified using quantitative PCR. All community members were offered azithromycin treatment immediately after the six-month timepoint according to international guidelines. Findings: The prevalence of C. trachomatis infection and inflammatory disease signs were significantly reduced three- and six- months post-mass drug administration (MDA). C. trachomatis infection was strongly associated with clinical signs at all five time-points. A profound anti-inflammatory effect on conjunctival gene expression was observed 3 months post-MDA, however, gene expression had largely returned to pre-treatment levels of variation by 6 months. This effect was less marked, but still observed, after adjusting for C. trachomatis infection and when the analysis was restricted to individuals who were free from both infection and clinical disease at all five time-points. Interestingly, a modest effect was also observed in individuals who did not receive treatment. Conclusion: Conjunctival inflammation is the major clinical risk factor for progressive scarring trachoma, therefore, the reduction in inflammation associated with azithromycin treatment may be beneficial in limiting the development of potentially blinding disease sequelae. Future work should seek to determine whether this effect is mediated directly through inhibition of pro-inflammatory intracellular signalling molecules, through reductions in concurrent, sub-clinical infections, and/or through reduction of infection exposure. Author summary: Trachoma, caused by conjunctival infection with Chlamydia trachomatis, remains the leading infectious cause of blindness. Repeated infection during childhood can trigger prolonged inflammation, which is the main risk factor for conjunctival scarring. Azithromycin is distributed globally for trachoma control, however it is also widely reported to have immunomodulatory properties. This report investigated the impact of one round of oral azithromycin for trachoma control on conjunctival immune responses, clinical signs and C. trachomatis infection in Tanzanian children. A large anti-inflammatory effect of azithromycin on conjunctival gene expression was observed 3 months post-treatment, however, gene expression patterns had mostly resumed to pre-treatment levels by 6 months. The effect was evident after adjusting for C. trachomatis infection and when analysis was restricted to uninfected individuals, however it was also observed to a lesser extent in individuals that did not receive treatment. These findings suggest that azithromycin may have a direct immunomodulatory effect on conjunctival gene expression but that it may also reduce inflammation by reducing exposure to C. trachomatis and other infections. This anti-inflammatory effect could have therapeutic potential in limiting the development of disease sequelae, that goes beyond its effect on the clearance of ocular C. trachomatis infection. [ABSTRACT FROM AUTHOR]

Objective: Prevention of Trachoma, the leading cause of infectious blindness, requires community treatment assistants (CTAs) to perform mass drug administration (MDA) of azithromycin. Previous research has shown that female CTAs have higher MDA coverage, but no studies have focused on the content of conversation. We hypothesize that female CTAs had more patient-centered communication and higher MDA coverage.Methods: In 2011, CTAs from 23 distribution sites undergoing MDA as part of the Partnership for Rapid Elimination of Trachoma were selected. CTA - villager interactions were audio recorded. Audio was analyzed using an adaptation of the Roter Interaction Analysis System. The outcome of interest was the proportion of adults receiving MDA in 2011 who returned in 2012.Results: 58 CTAs and 3122 interactions were included. Sites with female CTAs had significantly higher patient-centeredness ratio (0.548 vs 0.400) when compared to sites with male CTAs. Sites with more patient-centered interactions had higher proportion of patients return (p = 0.009).Conclusion: Female CTAs had higher proportion of patient-centered communication. Patient centered communication was associated with higher rates of return for MDA.Practice Implications: Greater patient-centered connection with health care providers affects participation in public health efforts, even when those providers are lay health workers. [ABSTRACT FROM AUTHOR]

Objective To examine the effects of gender and demographics of community treatment assistants (CTAs) on their performance of assigned tasks and quantity of speech during mass drug administration of azithromycin for trachoma in rural Tanzania. Design Surveys of CTAs and audio recordings of interactions between CTAs and villagers during drug distribution. Setting Mass drug administration program in rural Kongwa district. Participants Fifty-seven randomly selected CTAs, and 3122 residents of villages receiving azithromycin as part of the Kongwa Trachoma Project. Interventions None. Main Outcome Measures Speech quantity graded by Roter interaction analysis system, presence of culturally appropriate greeting and education on facial hygiene for trachoma prevention from coded analysis of audio-recorded interactions. Results At sites with all female CTAs, each CTA spent more time and spoke more in each interaction in comparison with CTAs at sites with only male CTAs and CTAs at ‘mixed gender’ sites (sites with both male and female CTAs). At ‘mixed gender’ sites, males spoke significantly more than females. Female CTAs mentioned trachoma prevention with facial cleanliness more than twice as often as male CTAs; however, both genders mentioned hygiene in <10% of interactions. Both genders had culturally appropriate greetings in <25% of interactions. Conclusions Gender dynamics affect the amount of time that CTAs spend with villagers during drug distribution, and the relative amount of speech when both genders work together. Both genders are not meeting expectations for trachoma prevention education and greeting villagers, and novel training methods are necessary. [ABSTRACT FROM PUBLISHER]

Background: Antibiotic dispensing without prescription is a major determinant of the emergence of Antimicrobial Resistance (AMR) which has impact on population health and cost of healthcare delivery. This study used simulated clients describing UTI like symptoms to explore compliance with regulation, variations in dispensing practices and drug recommendation, and quality of seller-client interaction on the basis of the gender of the client and the type of drug outlets in three regions in Tanzania., Method: A total of 672 Accredited Drug Dispensing Outlets (ADDOs) and community pharmacies were visited by mystery clients (MCs). The study was conducted in three regions of Tanzania namely Kilimanjaro (180, 26.79%), Mbeya (169, 25.15%) and Mwanza (323, 48.07%) in March-May 2020. During data collection, information was captured using epicollect5 software before being analyzed using Stata version 13., Results: Overall, 89.43% (CI: 86.87-91.55%) of drug sellers recommended antibiotics to clients who described UTI like symptoms but held no prescription and 58.93% were willing to sell less than the minimum recommended course. Female clients were more likely than male to be asked if they were taking other medications (27.2% vs 9.8%), or had seen a doctor (27.8% vs 14.7%), and more likely to be advised to consult a doctor (21.6% vs 9.0%); pharmacies addressed these issues more often than ADDOs (17.7% vs 13.2, 23.9% vs 16.6%, 17.7 vs 10.9% respectively). Sellers recommended 32 different drugs to treat the same set of symptoms, only 7 appear in the Tanzanian Standard Treatment Guidelines as recommended for UTI and 30% were 2nd and 3rd line drugs. ADDO sellers recommended 31 drug types (including 2nd and 3rd line) but had permission to stock only 3 (1st line) drugs. The most commonly suggested antibiotics were Azithromycin (35.4%) and ciprofloxacin (20.5%). Azithromycin was suggested more often in pharmacies (40.8%) than in ADDOs (34.4%) and more often to male clients (36.0%) than female (33.1%)., Conclusion: These findings support the need for urgent action to ensure existing regulations are adhered to and to promote the continuing professional development of drug sellers at all outlet levels to ensure compliance with regulation, high quality service and better antibiotic stewardship., (© 2022. The Author(s).)

Background: Trachoma, caused by ocular infection with Chlamydia trachomatis , is a neglected tropical disease that can lead to blinding pathology. Current trachoma control programmes have successfully used mass drug administration (MDA) with azithromycin to clear C. trachomatis infection and reduce transmission, alongside promoting facial cleanliness for better personal hygiene and environmental improvement. In areas of low-trachoma endemicity, the relationship between C. trachomatis infection and trachomatous disease weakens, and non-chlamydial bacteria have been associated with disease signs., Methods: We enrolled a cohort of children aged 6-10 years from three adjacent trachoma endemic villages in Kilimanjaro and Arusha regions, Northern Tanzania. Children were divided into four clinical groups based on the presence or absence of ocular C. trachomatis infection and clinical signs of trachomatous papillary inflammation (TP). To determine the impact of treatment on the ocular microbiome in these clinical groups, we performed V4-16S rRNA sequencing of conjunctival DNA from children 3-9 months pre-MDA ( n = 269) and 3 months post-MDA ( n = 79)., Results: Chlamydia trachomatis PCR-negative, no TP children had the highest pre-MDA ocular microbiome alpha diversity, which was reduced in C. trachomatis infected children and further decreased in those with TP. Pre-MDA, Haemophilus and Staphylococcus were associated with C. trachomatis infection with and without concurrent TP, while Helicobacter was increased in those with TP in the absence of current C. trachomatis infection. Post-MDA, none of the studied children had ocular C. trachomatis infection or TP. MDA increased ocular microbiome diversity in all clinical groups, the change was of greater magnitude in children with pre-MDA TP. MDA effectively reduced the prevalence of disease causing pathogenic non-chlamydial bacteria, and promoted restoration of a normal, healthy conjunctival microbiome., Conclusion: We identified Helicobacter as a non-chlamydial bacterium associated with the clinical signs of TP. Further investigation to determine its relevance in other low-endemicity communities is required. MDA was shown to be effective at clearing C. trachomatis infection and other non-chlamydial ocular pathogens, without any detrimental longitudinal effects on the ocular microbiome. These findings suggest that azithromycin MDA may be valuable in trachoma control even in populations where the relationship between clinical signs of trachoma and the prevalence of current ocular C. trachomatis infection has become dissociated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pickering, Ramadhani, Massae, Mafuru, Malisa, Mbuya, Makupa, Mtuy, Derrick, Houghton, Bailey, Mabey, Burton and Holland.)

Background: The World Health Organization recommends at least 3 annual antibiotic mass drug administrations (MDA) where the prevalence of trachoma is >10% in children ages 1–9 years, with coverage at least at 80%. However, the additional value of higher coverage targeted at children with multiple rounds is unknown. Trial Design: 2×2 factorial community randomized, double blind, trial. Trial methods: 32 communities with prevalence of trachoma ≥20% were randomized to: annual MDA aiming for coverage of children between 80%–90% (usual target) versus aiming for coverage>90% (enhanced target); and to: MDA for three years versus a rule of cessation of MDA early if the estimated prevalence of ocular C. trachomatis infection was less than 5%. The primary outcome was the community prevalence of infection with C. trachomatis at 36 months. Results: Over the trial's course, no community met the MDA cessation rule, so all communities had the full 3 rounds of MDA. At 36 months, there was no significant difference in the prevalence of infection, 4.0 versus 5.4 (mean adjusted difference = 1.4%, 95% CI = −1.0% to 3.8%), nor in the prevalence of trachoma, 6.1 versus 9.0 (mean adjusted difference = 2.6%, 95% CI = −0.3% to 5.3%) comparing the usual target to the enhanced target group. There was no difference if analyzed using coverage as a continuous variable. Conclusion: In communities that had pre-treatment prevalence of follicular trachoma of 20% or greater, there is no evidence that MDA can be stopped before 3 annual rounds, even with high coverage. Increasing coverage in children above 90% does not appear to confer additional benefit. Author Summary: The World Health Organization recommends at least 3 annual antibiotic mass drug administrations (MDA) where the prevalence of trachoma is >10% in children ages 1–9 years, with coverage at least at 80%. However, the additional value of higher coverage targeted at children with multiple rounds is unknown. We randomized 32 communities in Kongwa, Tanzania, with starting prevalence estimated at >20% to four arms: annual MDA aiming for coverage of children between 80%–90% (usual target) versus aiming for coverage>90% (enhanced target); and to: MDA for three years versus a rule of cessation of MDA early if the estimated prevalence of ocular C. trachomatis infection was less than 5%. After three rounds of MDA, infection with C. trachomatis and trachoma had declined significantly from baseline but no communities had treatment stopped. There was no difference in infection or in trachoma at three years comparing the usual coverage communities to the enhanced coverage communities. We conclude that in communities that had pre-treatment prevalence of follicular trachoma of 20% or greater, there is no evidence that MDA can be stopped before 3 annual rounds, even with high coverage. Increasing coverage in children above 90% does not appear to confer additional benefit. [ABSTRACT FROM AUTHOR]

Background: Trachoma, caused by ocular Chlamydia trachomatis infection, is the leading infectious cause of blindess, but its prevalence is now falling in many countries. As the prevalence falls, an increasing proportion of individuals with clinical signs of follicular trachoma (TF) is not infected with C. trachomatis. A recent study in Tanzania suggested that other bacteria may play a role in the persistence of these clinical signs. Methodology/Principal Findings: We examined associations between clinical signs of TF and ocular colonization with four pathogens commonly found in the nasopharnyx, three years after the initiation of mass azithromycin distribution. Children aged 0 to 5 years were randomly selected from 16 Gambian communitites. Both eyes of each child were examined and graded for trachoma according to the World Health Organization (WHO) simplified system. Two swabs were taken from the right eye: one swab was processed for polymerase chain reaction (PCR) using the Amplicor test for detection of C. trachomatis DNA and the second swab was processed by routine bacteriology to assay for the presence of viable Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus and Moraxella catarrhalis. Prevalence of TF was 6.2% (96/1538) while prevalence of ocular C. trachomatis infection was 1.0% (16/1538). After adjustment, increased odds of TF were observed in the presence of C. trachomatis (OR = 10.4, 95%CI 1.32–81.2, p = 0.03), S. pneumoniae (OR = 2.14, 95%CI 1.03–4.44, p = 0.04) and H. influenzae (OR = 4.72, 95% CI 1.53–14.5, p = 0.01). Conclusions/Significance: Clinical signs of TF can persist in communities even when ocular C. trachomatis infection has been controlled through mass azithromycin distribution. In these settings, TF may be associated with ocular colonization with bacteria commonly carried in the nasopharnyx. This may affect the interpretation of impact surveys and the determinations of thresholds for discontinuing mass drug administration. Author Summary: Trachoma, the world's leading infectious cause of blindness, is caused by ocular infection with the bacterium Chlamydia trachomatis. In low-prevalence settings and following mass treatment campaigns, clinically active follicular trachoma (TF) can be found in the absence of C. trachomatis infection. We carried out this study to investigate associations between ocular carriage of non-chlamydial pathogens and a clinical diagnosis of TF following a mass treatment campaign in The Gambia. We found that children who carried Streptococcus pneumoniae or Haemophilus influenza in their eyes were more likely to have been diagnosed with TF than children who did not carry these pathogens. In The Gambia, non-chlamydial pathogens may be inducing or exacerbating TF in the absence of C. trachomatis infection. [ABSTRACT FROM AUTHOR]

In disease control or elimination programs, diagnostics are essential for assessing the impact of interventions, refining treatment strategies, and minimizing the waste of scarce resources. Although high-performance tests are desirable, increased accuracy is frequently accompanied by a requirement for more elaborate infrastructure, which is often not feasible in the developing world. These challenges are pertinent to mapping, impact monitoring, and surveillance in trachoma elimination programs. To help inform rational design of diagnostics for trachoma elimination, we outline a nonparametric multilevel latent Markov modeling approach and apply it to 2 longitudinal cohort studies of trachoma-endemic communities in Tanzania (2000–2002) and The Gambia (2001–2002) to provide simultaneous inferences about the true population prevalence of Chlamydia trachomatis infection and disease and the sensitivity, specificity, and predictive values of 3 diagnostic tests for C. trachomatis infection. Estimates were obtained by using data collected before and after mass azithromycin administration. Such estimates are particularly important for trachoma because of the absence of a true “gold standard” diagnostic test for C. trachomatis. Estimated transition probabilities provide useful insights into key epidemiologic questions about the persistence of disease and the clearance of infection as well as the required frequency of surveillance in the postelimination setting. [ABSTRACT FROM PUBLISHER]

Background: Trachoma is the leading infectious cause of blindness in the world, and for endemic communities, mass treatment with azithromycin reduces the pool of infection. High coverage is essential, especially in children as they are the infectious reservoir. However, infection remains post-mass treatment. We sought to determine risk factors for infection in children post-mass treatment. Methodology: All children under 9 years in 4 villages in Tanzania were followed from baseline pre-mass treatment to six months post treatment. 1,991 children under nine years were enrolled in the longitudinal study and data on individual and household characteristics was collected at baseline. Clinical trachoma was determined by an ocular exam and infection detected by PCR of an eyelid swab. Azithromycin was offered and infection was reassessed at 6 months. A multilevel logistic regression model was used, accounting for household clustering of children for analysis. Principal Findings: Baseline infection was 23.7% and at 6 months was 10.4%, despite 95% coverage. Infection at baseline was positively associated with infection at 6 months (OR = 3.31, 95%CI 2.40-4.56) and treatment had a protective effect (OR = 0.45, 95%CI 0.25-0.80). The age group 2-4 years had an increased risk of infection at 6 months. The household characteristics predictive of infection at 6 months were increasing number of children infected in the household at baseline and increasing number of untreated children in the household. Conclusions: While one round of mass treatment with high coverage did decrease infection by over 50%, it appears that it is not sufficient to eliminate infection. Findings that young children (ages 2-4 years) and households with increasing numbers of infected and untreated children have a positive association with infection at 6 months suggest that such households could be targeted for more intensive follow up. [ABSTRACT FROM AUTHOR]

Objectives: Trachoma is the principal cause of infectious blindness. As part of its strategy to eliminate trachoma, the World Health Organization recommends annual mass antibiotic treatment for at least 3 years with an 80% population coverage target. However, to date, ideal population coverage and mass treatment duration have not been determined and further evaluation of treatment recommendations in areas of varying endemicity is warranted. The studies presented here evaluate the impact of coverage level and frequency of mass treatment with single dose azithromycin on trachoma and ocular C. trachomatis infection. Methods: The Partnership for the Rapid Elimination of Trachoma supervises 2 randomized, community-based clinical trials in Tanzania and The Gambia. Although each trial is a stand-alone effort, protocols, data collection, and analytic approaches have been harmonized to permit generalizations. Communities in each site were randomized using a 2X2 factorial design to standard (80%--90.0%) versus high (over 90.0%) treatment coverage; communities were further randomized to annual treatment for 3 years versus a ''graduation'' rule where evidence indicates an absence of follicular trachoma or infection and annual treatment is halted. Results: Average prevalence of follicular trachoma in children age less than 5 years was 32.2% in Tanzania and 5.96% in The Gambia. Randomization appeared to be effective, as prevalence was not statistically different between the arms within each country. Conclusions: There are challenges in harmonizing 2, large trials in Africa. Study outcomes will provide critical data to national trachoma control programs on treatment methodology and resource allocation toward elimination of the disease. [ABSTRACT FROM AUTHOR]

Background: Mass treatment to trachoma endemic communities is a critical part of the World Health Organization SAFE strategy. However, non-participation may not be at random, affecting coverage surveys and effectiveness if infection is differential. Methodology/Principal Findings: As part of the Partnership for Rapid Elimination of Trachoma (PRET), 32 communities in Tanzania, and 48 in The Gambia had a detailed census taken followed by mass treatment with azithromycin. The target coverage in each community was >80% of children ages <10 years. Community treatment assistants observed treatment and recorded compliance, thus coverage at the community, household, and individual level could be determined. Within each community, we determined the actual proportions of households where all, some, or none of the children were treated. Assuming the coverage in children <10 years of the community was as observed and non-participation was at random, we did 500 simulations to derive expected proportions of households where all, some, or none of the children were treated. Clustering of household treatment was detected comparing greater-than-expected proportions of households where none or all of children were treated, and the intraclass correlation (ICC) was calculated. Tanzanian and Gambian mass treatment coverages for children <10 years of age ranged from 82–100% and 62–99%, respectively. Clustering of households where all children were treated or no children were treated was greater than expected. Compared to model simulations, all Tanzanian communities and 44 of 48 (91.7%) Gambian communities had significantly higher proportions of households where all children were treated. Furthermore, 30 of 32 (93.8%) Tanzanian communities and 34 of 48 (70.8%) Gambian communities had a significantly elevated proportion of households compared to the expected proportion where no children were treated. The ICC for Tanzania was 0.77 (95% CI 0.74–0.81) and for The Gambia was 0.55 (95% CI 0.51–0.59). Conclusions/Significance: In programs aiming for high coverage, complete compliance or non-compliance with mass treatment clusters within households. Non-compliance cannot be assumed to be at random. Author Summary: Trachoma, an infectious disease, continues to cause blindness. A great deal of the trachoma burden is concentrated in developing countries. The World Health Organization recommends mass treatment for entire communities in trachoma-endemic regions. In 32 Tanzanian and 48 Gambian communities with trachoma, mass treatment was directly observed following a census. Community coverage was mostly greater than 80%. Larger-than-expected proportions of households where all children were treated and where none of the children were treated were found in each country. Household clustering of treatment was higher in Tanzania compared to The Gambia. However, children who were not treated were not more likely to be infected compared to children who were treated. We found that treatment and non-treatment within communities does not occur at random but rather clusters within households. These findings impact the design of future coverage surveys and suggest that further research evaluate factors that are associated with familial non-compliance. [ABSTRACT FROM AUTHOR]

Background: Repeated mass azithromycin distributions are effective in controlling the ocular strains of chlamydia that cause trachoma. However, it is unclear when treatments can be discontinued. Investigators have proposed graduating communities when the prevalence of infection identified in children decreases below a threshold. While this can be tested empirically, results will not be available for years. Here we use a mathematical model to predict results with different graduation strategies in three African countries. Methods: A stochastic model of trachoma transmission was constructed, using the parameters with the maximum likelihood of obtaining results observed from studies in Tanzania (with 16% infection in children pre-treatment), The Gambia (9%), and Ethiopia (64%). The expected prevalence of infection at 3 years was obtained, given different thresholds for graduation and varying the characteristics of the diagnostic test. Results: The model projects that three annual treatments at 80% coverage would reduce the mean prevalence of infection to 0.03% in Tanzanian, 2.4% in Gambian, and 12.9% in the Ethiopian communities. If communities graduate when the prevalence of infection falls below 5%, then the mean prevalence at 3 years with the new strategy would be 0.3%, 3.9%, and 14.4%, respectively. Graduations reduced antibiotic usage by 63% in Tanzania, 56% in The Gambia, and 11% in Ethiopia. Conclusion: Models suggest that graduating communities from a program when the infection is reduced to 5% is a reasonable strategy and could reduce the amount of antibiotic distributed in some areas by more than 2-fold. [ABSTRACT FROM AUTHOR]

Background: Children with a heavy load of C. trachomatis infection may continue to be infected following a single dose of 20 mg/kg of azithromycin. We compared the C. trachomatis infection rates at six weeks post-treatment of children randomized to 30 mg/kg single dose of azithromycin versus 20 mg/kg single dose of azithromycin. Methods: Ninety-nine children with severe trachoma (defined as either trachoma intense or follicular trachoma with ten or more follicles) were enrolled and randomly assigned. Baseline data on age, sex, and trachoma status was obtained, and swabs for determination of C. trachomatis were taken. Dosing was weight-based and observed. Children were followed up at six weeks for trachoma and infection. The laboratory was masked to treatment assignment. Results: Both groups experienced reductions in infection and in severe trachoma. Twelve percent of the 20 mg/kg group were PCR positive at 6 weeks, compared with 69% at baseline, an 82% reduction (p-value < .001). In the 30 mg/kg group, 15% were infected, compared with 62% at baseline, a 76% reduction (p < .001). The rate of infection comparing treatment groups was not significantly different at 6 weeks (p = 0.71). Analyses on children who were infected at baseline showed those remaining positive at six weeks were 18%, and 14% in the standard and high dose groups, respectively. Conclusion: Increasing the single dose of azithromycin to 30 mg/kg in children with severe trachoma did not result in significantly less infection at six weeks post-treatment compared to 20 mg/kg. [ABSTRACT FROM AUTHOR]

Summary Background There are no data on the cumulative effect of fly control and antibiotic distribution on trachoma in hyperendemic communities. We sought to determine whether insecticide spray intervention after mass antibiotic treatment could reduce trachoma and ocular infection with Chlamydia trachomatis in hyperendemic neighbourhoods in Tanzania. Methods We did a single-blind, randomised clinical trial in 16 neighbourhoods (balozi) in Kongwa, Tanzania. All children aged 1-7 years were enrolled, with 119 children in the eight balozi of the intervention group and 183 in the eight control balozi. Children were examined at baseline, 6 months, and 1 year for clinical trachoma and ocular C trachomatis infection. One dose of azithromycin was offered to all residents of both intervention and control balozi after the baseline survey. Households (and surrounding areas) in the intervention group were then sprayed with insecticide throughout the ensuing year and monitored for reductions in fly counts. This study is registered at ClinicalTrials.gov, number NCT00347763. Findings The intervention balozi had significantly lower fly counts than controls at all monitored weeks (p<0·05), apart from weeks 7-9. The trachoma rate did not differ significantly in the intervention and control balozi at 6 months post-treatment (20% vs 33%, p=0·07), nor did it at 1 year (43% vs 44%, p=0·90). Infection with C trachomatis did not differ between groups at 6 months post-treatment (9% vs 7%, p=0·45). Interpretation Intensive insecticide spraying reduced flies in the environment, but our results suggest that fly reduction after mass antibiotic treatment has no added benefit on reduction of trachoma. [ABSTRACT FROM AUTHOR]

Summary: Trachoma causes blindness; the prevention strategy includes mass antibiotic treatment. In a community in Northern Tanzania offered mass treatment with azithromycin for the control of trachoma, we used focus group discussions, individual interviews, questionnaires and direct observation to quantify, explore and contextualize reasons for acceptance or refusal of the drug. In the village studied, 76% of the population eligible to receive azithromycin were treated. Uptake was significantly higher among women (79% treated) than men (72%). Factors affecting acceptability included: local prevention norms (such as the belief that injections, rather than oral medicine, should be used for prevention); perceptions of drugs in general and azithromycin in particular; perceptions of the distribution team''s expertise; witnessing adverse effects in others; and the timing, quality and quantity of information about azithromycin and its availability. Familiarity with trachoma as a blinding disease was significantly associated with uptake. Individuals who refused treatment seemed to be less altruistic than other respondents. Neither socio-economic status nor use of traditional healers was related to uptake. Pre-distribution community assessment and community education, advance notice of the distribution, standardized distribution guidelines and improved distributor training are recommended to maximize acceptance of azithromycin in future campaigns. [Copyright &y& Elsevier]

Relationships between socioeconomic status, risk of trachoma, perceptions of the effects of azithromycin, and the household willingness to pay for future mass treatment with azithromycin were tested. Surveys of 394 households in six villages located in central United Republic of Tanzania regarding their willingness to pay for future azithromycin treatment were conducted. 38 percent of responding households stated that they would not be willing to pay anything for future azithromycin treatment, although they would be willing to participate in the treatment.

Background: The MORDOR study, a cluster randomized clinical trial, showed that single-dose azithromycin (20 mg/kg) administered biannually for 2 years to preschool children reduced mortality; a study was conducted to determine its effect on clinical symptomatic episodes of malaria as a potential mechanism for mortality benefit. Methods: A randomized control trial (RCT) was conducted, whereby 30 randomly selected communities in Kilosa District, Tanzania were randomized to receive 6-monthly treatment of children ages 1–59 months with single-dose azithromycin (20 mg/kg) vs. placebo. A prospective cohort study was nested within the RCT: children, aged 1 to 35 months at baseline, were randomly selected in each community and evaluated at 6-monthly intervals for 2 years. At each visit, the children were assessed for recent or ongoing fever and anti-malarial treatment; a rapid diagnostic test (RDT) for malaria was performed. The two major outcomes of interest were prevalence of RDT positivity and clinical malaria. The latter was defined as RDT-positivity with fever at time of evaluation and/or reported fever in the 3 days prior to evaluation. Methods that account for correlations at community level and within individuals over time were used to evaluate associations. Results: At baseline, the prevalence rates in the children in the azithromycin and placebo arms were 17.6% vs. 15.5% for RDT positivity (p = 0.76) and 6.1% vs. 4.3% (p = 0.56) for clinical malaria. There was a decline in both RDT-positivity and clinical malaria over time in both arms. The difference by treatment assignment was not significant for clinical malaria; it was significant for RDT-positivity with greater odds of decline in the placebo arm (p = 0.01). Conclusions: Lack of evidence for a significant difference in the prevalence of clinical malaria in children at any visit following treatment suggests that the effect of single-dose azithromycin on malaria is at best transient and limited in scope. Chance overrepresentation of non-seasonal transmission in the communities in the azithromycin arm may account for higher rates of RDT-positivity and less decline over time. Trial registration Clinicaltrials.gov NCT02047981 [ABSTRACT FROM AUTHOR]

This article presents information on the treatment for trachoma with azithromycin. Nearly 1000 residents of an area in Tanzania where trachoma is endemic were given a single dose of azithromycin, with a resultant decrease in prevalence of trachoma from 9.5% at baseline, to 2.1% at month 2 of the study, and to 0.1% at month 24. Residents with active trachoma at months 6, 12, and 24 were treated with tetracycline eye ointment. This study demonstrates that 1 round of extraordinarily high-coverage (97.8% in this study) mass administration of azithromycin can interrupt the transmission of trachoma. The elimination of trachoma from many more developed countries is considered to have resulted from reduced crowding, the availability of clean water, and improved individual hygiene.

Background: Trachoma, caused by repeated ocular infection with Chlamydia trachomatis, is an important cause of blindness. Current recommended dosing intervals for mass azithromycin treatment for trachoma are based on a mathematical model. Methods: We collected conjunctival swabs for quantitative polymerase-chain-reaction assay of C. trachomatis before and 2, 6, 12, 18, and 24 months after mass treatment with azithromycin in a Tanzanian community in which trachoma was endemic. For ethical reasons, at 6, 12, and 18 months, we gave tetracycline eye ointment to residents who had clinically active trachoma. Results: At baseline, 956 of 978 residents (97.8 percent) received either one oral dose of azithromycin or (if azithromycin was contraindicated) a course of tetracycline eye ointment. The prevalence of infection fell from 9.5 percent before mass treatment to 2.1 percent at 2 months and 0.1 percent at 24 months. The quantitative burden of ocular C. trachomatis infection in the community was 13.9 percent of the pretreatment level at 2 months and 0.8 percent at 24 months. At each time point after baseline, over 90 percent of the total community burden of C. trachomatis infection was found among subjects who had been positive the previous time they were tested. Conclusions: The prevalence and intensity of infection fell dramatically and remained low for two years after treatment. One round of very-high-coverage mass treatment with azithromycin, perhaps aided by subsequent periodic use of tetracycline eye ointment for persons with active disease, can interrupt the transmission of ocular C. trachomatis infection. N Engl J Med 2004;351:1962-71. [ABSTRACT FROM AUTHOR]

Background: Mass drug treatment with azithromycin (MDA) is part of the WHO-endorsed 'SAFE' strategy for trachoma control in endemic communities. MDA has been associated with reduced trachoma prevalence and short-term reductions in other bacterial infections, but can also lead to increased circulation of macrolide-resistant bacteria., Methods: We prospectively monitored macrolide resistance in fecal E. coli collected from young children participating in the PRET+ Study in rural Tanzania. MDA was administered in four villages with >10% trachoma prevalence. Four nearby communities with lower trachoma prevalence served as controls. Rectal swabs were collected during cross-sectional surveys performed at baseline, 1, 3 and 6 months after MDA. Fecal E. coli isolates were screened for macrolide susceptibility using disc diffusion and minimum inhibitory concentration methods. Cross-sectional and longitudinal differences in resistance prevalence by MDA exposure were compared using t-tests and logistic regression., Results: There was no difference in the proportion of individuals carrying azithromycin-resistant E. coli at baseline (0.21 vs. 0.16, P > 0.05). Azithromycin resistance carriage prevalence remained stable over follow-up in non-MDA villages but increased sharply in MDA villages (0.61 at 1 month, 0.42 at 3 months and 0.31 at 6 months). MDA exposure was highly associated with azithromycin resistance carriage at 1 month post-MDA (OR 15.27, P < 0.001) and subsequent surveys. Younger age and recent diarrhoea were also associated with increased odds of resistance (P < 0.01)., Conclusions: MDA resulted in significantly increased prevalence of macrolide resistance in E. coli. Although MDA is effective for trachoma elimination, it has costs; it is essential to monitor antimicrobial resistance following MDA., (© The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Purpose: We detected spatial clustering of households with Chlamydia trachomatis infection (CI) and active trachoma (AT) in villages undergoing mass treatment with azithromycin (MDA) over time., Methods: We obtained global positioning system (GPS) coordinates for all households in four villages in Kongwa District, Tanzania. Every 6 months for a period of 42 months, our team examined all children under 10 for AT, and tested for CI with ocular swabbing and Amplicor. Villages underwent four rounds of annual MDA. We classified households as having ≥1 child with CI (or AT) or having 0 children with CI (or AT). We calculated the difference in the K function between households with and without CI or AT to detect clustering at each time point., Results: Between 918 and 991 households were included over the 42 months of this analysis. At baseline, 306 households (32.59%) had ≥1 child with CI, which declined to 73 households (7.50%) at 42 months. We observed borderline clustering of households with CI at 12 months after one round of MDA and statistically significant clustering with growing cluster sizes between 18 and 24 months after two rounds of MDA. Clusters diminished in size at 30 months after 3 rounds of MDA. Active trachoma did not cluster at any time point., Conclusions: This study demonstrates that CI clusters after multiple rounds of MDA. Clusters of infection may increase in size if the annual antibiotic pressure is removed. The absence of growth after the three rounds suggests the start of control of transmission., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Single-dose mass drug administration of azithromycin (AZT) is underway to eliminate trachoma worldwide. Studies in Ethiopia showed a reduction in all-cause childhood deaths after administration. To examine the effect of single-dose AZ MDA on prevalent malaria infections in a large prospective cohort of children and parents in Dodoma Province, Tanzania, we quantified the temporal prevalence of malaria parasitemia by real-time PCR for 6 months after single-dose AZT. In the first month after treatment but not in subsequent months, Plasmodium falciparum infections were reduced by 73% (95% CI 43%-89%) in treatment versus control villages and differences remained significant (p = 0.00497) in multivariate models with village-level random effects. Genetic sequencing of P. falciparum ribosomal L4 protein showed no mutations associated with AZT resistance. AZT mass drug administration caused a transient, 1-month antimalarial effect without selecting for P. falciparum ribosomal L4 resistance mutations in a region with a 10-year history of treating trachoma with this drug.

Mass oral azithromycin distributions have dramatically reduced the prevalence of the ocular strains of chlamydia that cause trachoma. Assessing efficacy of the antibiotic in an individual is important in planning trachoma elimination. However, the efficacy is difficult to estimate, because post-treatment laboratory testing may be complicated by nonviable organisms or reinfection. Here, we monitored ocular chlamydial infection twice a year in pre-school children in 32 communities as part of a cluster-randomized clinical trial in Tanzania (prevalence in children was lowered from 22.0% to 4.7% after 3-year of annual treatment). We used a mathematical transmission model to estimate the prevalence of infection immediately after treatment, and found the effective field efficacy of antibiotic in an individual to be 67.6% (95% CI: 56.5-75.1%) in this setting. Sensitivity analyses suggested that these results were not dependent on specific assumptions about the duration of infection. We found no evidence of decreased efficacy during the course of the trial. We estimated an 89% chance of elimination after 10 years of annual treatment with 95% coverage., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Emerging evidence suggests that the mass distribution of azithromycin for trachoma control (MDA) may increase circulation of macrolide resistance in bacteria associated with severe pediatric infections in treated communities., Methods: We examined the effect of MDA on nasopharyngeal carriage of antibiotic-resistant Streptococcus pneumoniae among 1015 young children living in rural Tanzania. MDA with a single dose of oral azithromycin was provided in 4 of 8 communities where trachoma prevalence was ≥10%. Isolates were tested for susceptibility to azithromycin (AZM) and commonly used antibiotics by disk diffusion and Etest. We calculated the proportion of antibiotic-resistant S. pneumoniae carriage at baseline and again 1, 3, and 6 months after treatment, and at comparable intervals in the untreated villages., Results: The proportion of AZM-resistant isolates was similar between groups at baseline (MDA: 35.8% vs non-MDA: 35.4%), however, this proportion was greater in the MDA group in all subsequent surveys. At 6 months, the percentage of AZM-resistant isolates was significantly higher in the MDA group (81.9% vs 46.9%, P < .001). The odds of AZM-resistant carriage was 5-fold greater in the MDA group (odds ratio, 4.95 [95% confidence interval, 3.23-7.61]). The proportion of isolates clinically resistant to AZM (minimum inhibitory concentration ≥16 µg/mL) was also significantly greater in the MDA group at 6 months (35.3% vs 12.4%, P < .006)., Conclusions: Mass distribution of a single dose of oral azithromycin for trachoma was associated with increased circulation of macrolide-resistant S. pneumoniae carriage among young children in the 6 months following treatment. It is crucial that changes in antibiotic resistance patterns and their clinical significance in the treatment of severe pediatric infections be assessed in future MDA trials.