Concordance of ompA types in children re-infected with ocular Chlamydia trachomatis following mass azithromycin treatment for trachoma.

BACKGROUND: The chlamydial major outer membrane protein, encoded by the ompA gene, is a primary target for chlamydial vaccine research. However, human studies of ompA-specific immunity are limited, and prior studies have been limited in differentiating re-infection from persistent infection. The purpose of this study was to assess whether children living in trachoma-endemic communities with re-infections of ocular chlamydia were more likely to be infected with a different or similar genovar. METHODOLOGY AND FINDINGS: The study included 21 communities from a trachoma-hyperendemic area of Ethiopia that had been treated with a mass azithromycin distribution for trachoma. Conjunctival swabbing was offered to all children younger than 5 years of age at baseline (i.e., pre-treatment), and then at follow-up visits 2 and 6 months later. Swabs were subjected to polymerase chain reaction (PCR) to detect C. trachomatis. A random sample of 359 PCR-positive swabs, stratified by study visit and study community, was chosen for ompA sequencing. In addition, ompA sequencing was performed on all swabs of 24 children who experienced chlamydial re-infection (i.e., positive chlamydial test before treatment, negative test 2 months following mass distribution of azithromycin, and again a positive test 6 months post-treatment). ompA sequencing was successful for 351 of 359 swabs of the random sample and 44 of 48 swabs of the re-infection sample. In the random sample, ompA types clustered within households more than would be expected by chance. Among the 21 re-infected children with complete ompA data, 14 had the same ompA type before and after treatment. CONCLUSION: The high frequency of ompA concordance suggests incomplete genovar-specific protective immunity and the need for multiple antigens as vaccine targets.

A Longitudinal Analysis of Chlamydial Infection and Trachomatous Inflammation Following Mass Azithromycin Distribution.

BACKGROUND: Mass azithromycin distributions are effective for clearing ocular strains of Chlamydia trachomatis, yet infection frequently returns in areas with hyperendemic trachoma. A better understanding of the factors associated with chlamydial reinfection could be helpful to plan trachoma elimination strategies. METHODS: This was a prospective cohort study conducted in a trachoma-hyperendemic region of Ethiopia in 2003. As part of a larger cluster-randomized trial, 21 villages were treated with a single mass azithromycin distribution and all children 5 years and younger were monitored for ocular chlamydia and clinically active trachoma at baseline and at 2 and 6 months following the treatment. RESULTS: In 20 villages with available data, azithromycin treatment coverage was 88.7% (95% confidence interval [CI] 85.7-91.8%). In total, 1005 children tested negative for ocular chlamydia at the 2-month visit, of whom 41 became infected by 6 months (1.0 incident chlamydia infections per 100 person-months, 95%CI 0.7-1.4). The presence of intense trachomatous inflammation (TI) at baseline was associated with incident infection at 6 months (incidence rate ratio 1.91, 95%CI 1.03-3.55). Ocular chlamydia infections clustered more within households than communities: (intraclass correlation coefficient 0.01 for communities and 0.29 for households six months posttreatment). Younger children were more likely to have persistent clinically active trachoma (P = 0.03). CONCLUSIONS: More intensive antibiotic distributions may be warranted for younger children, for children with TI, and for households containing children with ocular chlamydia infections.

Diversity of Chlamydia trachomatis in Trachoma-Hyperendemic Communities Treated With Azithromycin.

Prior studies have theorized that low chlamydial genetic diversity following mass azithromycin treatments for trachoma may create a population bottleneck that prevents the return of infection, but little empirical evidence exists to support this hypothesis. In this study, a single mass azithromycin distribution was administered to 21 communities in the Gurage Zone of Ethiopia in 2003. All children aged 1-5 years had conjunctival swabs performed before treatment and 2 and 6 months after treatment. All swabs positive for Chlamydia trachomatis at 2 months underwent typing of the gene encoding the major outer membrane protein (ompA) of C. trachomatis, as did the same number of swabs per community from the pretreatment and 6-month visits. Diversity of ompA types, expressed as the reciprocal of Simpson's index, was calculated for each community. In total, 15 ompA types belonging to the A and B genovars were identified. The mean diversity was 2.11 (95% confidence interval: 1.79, 2.43) before treatment and 2.16 (95% confidence interval: 1.76, 2.55) 2 months after treatment (P = 0.78, paired t test). Diversity of ompA was not associated with the prevalence of ocular chlamydia (P = 0.76) and did not predict subsequent changes in the prevalence of ocular chlamydia (P = 0.32). This study found no evidence to support the theory that ompA diversity is associated with transmission of ocular chlamydia.

The fitness cost of antibiotic resistance in Streptococcus pneumoniae: insight from the field.

BACKGROUND: Laboratory studies have suggested that antibiotic resistance may result in decreased fitness in the bacteria that harbor it. Observational studies have supported this, but due to ethical and practical considerations, it is rare to have experimental control over antibiotic prescription rates. METHODS AND FINDINGS: We analyze data from a 54-month longitudinal trial that monitored pneumococcal drug resistance during and after biannual mass distribution of azithromycin for the elimination of the blinding eye disease, trachoma. Prescription of azithromycin and antibiotics that can create cross-resistance to it is rare in this part of the world. As a result, we were able to follow trends in resistance with minimal influence from unmeasured antibiotic use. Using these data, we fit a probabilistic disease transmission model that included two resistant strains, corresponding to the two dominant modes of resistance to macrolide antibiotics. We estimated the relative fitness of these two strains to be 0.86 (95% CI 0.80 to 0.90), and 0.88 (95% CI 0.82 to 0.93), relative to antibiotic-sensitive strains. We then used these estimates to predict that, within 5 years of the last antibiotic treatment, there would be a 95% chance of elimination of macrolide resistance by intra-species competition alone. CONCLUSIONS: Although it is quite possible that the fitness cost of macrolide resistance is sufficient to ensure its eventual elimination in the absence of antibiotic selection, this process takes time, and prevention is likely the best policy in the fight against resistance.

The decline of pneumococcal resistance after cessation of mass antibiotic distributions for trachoma.

After 6 biannual mass distributions of oral azithromycin for trachoma in Ethiopian communities, 76.8% (95% confidence interval [CI], 66.3%-85.1%) of nasopharyngeal Streptococcus pneumoniae isolates from children aged 1-5 years were resistant to macrolides. Twelve and 24 months after the last azithromycin treatment, resistance decreased to 30.6% (95% CI, 18.8%-40.4%; P <.001 ) and 20.8% (95% CI, 12.7%-30.7%; P < .001), respectively. Macrolide resistance decreases after antibiotic pressure is removed.

Clinical activity and polymerase chain reaction evidence of chlamydial infection after repeated mass antibiotic treatments for trachoma.

It is unclear how the prevalence of clinically active trachoma correlates with the prevalence of ocular chlamydial infection at the community level. In 24 villages from a cluster-randomized clinical trial of mass azithromycin distributions in Ethiopia, the correlation between the prevalence of clinical activity (on examination) and chlamydial infection (by polymerase chain reaction) was moderately strong before mass antibiotic treatments (Pearson's correlation coefficient r = 0.75, 95% confidence interval [CI] = 0.52-0.87), but decreased at each time point during four biannual treatments (at 24 months, r = 0.15, 95% CI = -0.14-0.41). One year after the final treatment, the correlation coefficient had increased, but not to the pre-treatment level (r = 0.55, 95% CI = 0.30-0.73). In a region with hyperendemic trachoma, conjunctival examination was a useful indicator of the prevalence of chlamydial infection before treatments, less useful during mass treatments, but regained utility by one year after treatments had stopped.

Travel and implications for the elimination of trachoma in ethiopia.

PURPOSE: Trachoma is the leading infectious cause of blindness. The World Health Organization has set a goal of reducing the trachoma disease burden to a level where it is no longer a public health concern by the year 2020. Some investigators feel that local elimination of ocular chlamydia infection is possible, but little has been done to study the likelihood of reintroduction of infection from neighboring areas. Mass administration of azithromycin has been shown to dramatically reduce the prevalence of infection in many villages in central Ethiopia. However, after treatment is discontinued, infection returns. Reintroduction of infection could occur from the few remaining infected cases in a treated community or from outside the community. People traveling between villages might be responsible thus complicating the elimination of trachoma. METHODS: We conducted a survey to assess the travel pattern of the Gurage zone residents in Ethiopia. Seven hundred and seventeen households with at least one child aged 1-5 years in 48 villages were surveyed to collect the details of travel in 1 month prior to the survey. RESULTS: Seventy-eight percent of the surveyed households had at least one traveler, with the majority being women. Pre-school children, the main reservoir of clinically active infection, rarely traveled. Most travel was to the market or to school, and most for less than 1 day. CONCLUSIONS: Travel routinely takes place in these villages. Trachoma control programs in this area might consider treating areas with the same markets and schools in the same period to increase the efficacy of mass treatment.

Complete local elimination of infectious trachoma from severely affected communities after six biannual mass azithromycin distributions.

OBJECTIVE: To determine whether infectious trachoma can be completely eliminated from severely affected villages. DESIGN: Cross-sectional survey of 2 villages previously enrolled and monitored over 42 months as part of a larger, group-randomized clinical trial. PARTICIPANTS: A total of 758 individuals residing in 2 villages with high baseline trachoma prevalence, of a total population of 768 (98.7%). METHODS: All members of the 2 villages were offered 6 biannual mass treatments with oral azithromycin. At 42 months, each current village member was examined. The right upper tarsal conjunctiva was everted and swabbed. Samples were processed for evidence of Chlamydia trachomatis RNA. MAIN OUTCOME MEASURES: Clinical activity by World Health Organization simplified grading scale for trachoma and laboratory evidence of chlamydial RNA. RESULTS: Average antibiotic coverage over the study period was 90% and 94% in the 2 villages. Clinical trachoma activity in children aged 1 to 5 years decreased from 78% and 83% in the 2 villages before treatment to 17% and 24% at 42 months. Polymerase chain reaction (PCR) evidence of infection in the same age group decreased from 48% to 0% in both villages at 42 months. When all age groups were examined, there were zero cases with evidence of chlamydial RNA among 758 total villagers tested. CONCLUSIONS: Biannual mass distribution of azithromycin can locally eliminate ocular chlamydial infection from severely affected communities.

Importance of coverage and endemicity on the return of infectious trachoma after a single mass antibiotic distribution.

BACKGROUND: As part of the SAFE strategy, mass antibiotic treatments are useful in controlling the ocular strains of chlamydia that cause trachoma. The World Health Organization recommends treating at least 80% of individuals per community. However, the role of antibiotic coverage for trachoma control has been poorly characterized. METHODOLOGY/PRINCIPAL FINDINGS: In a collection of cluster-randomized clinical trials, mass oral azithromycin was administered to 40 villages in Ethiopia. The village prevalence of ocular chlamydia was determined before treatment, and at two and six months post-treatment. The mean prevalence of ocular chlamydia was 48.9% (95% CI 42.8 to 55.0%) before mass treatments, decreased to 5.4% (95% CI 3.9 to 7.0%) at two months after treatments (p<0.0001), and returned to 7.9% (95% CI 5.4 to 10.4%) by six months after treatment (p = 0.03). Antibiotic coverage ranged from 73.9% to 100%, with a mean of 90.6%. In multivariate regression models, chlamydial prevalence two months after treatment was associated with baseline infection (p<0.0001) and antibiotic coverage (p = 0.007). However, by six months after treatment, chlamydial prevalence was associated only with baseline infection (p<0.0001), but not coverage (p = 0.31). CONCLUSIONS/SIGNIFICANCE: In post-hoc analyses of a large clinical trial, the amount of endemic chlamydial infection was a strong predictor of chlamydial infection after mass antibiotic treatments. Antibiotic coverage was an important short-term predictor of chlamydial infection, but no longer predicted infection by six months after mass antibiotic treatments. A wider range of antibiotic coverage than found in this study might allow an assessment of a more subtle association.

Reduction and return of infectious trachoma in severely affected communities in Ethiopia.

BACKGROUND: Antibiotics are a major tool in the WHO's trachoma control program. Even a single mass distribution reduces the prevalence of the ocular chlamydia that causes trachoma. Unfortunately, infection returns after a single treatment, at least in severely affected areas. Here, we test whether additional scheduled treatments further reduce infection, and whether infection returns after distributions are discontinued. METHODS: Sixteen communities in Ethiopia were randomly selected. Ocular chlamydial infection in 1- to 5-year-old children was monitored over four biannual azithromycin distributions and for 24 months after the last treatment. FINDINGS: The average prevalence of infection in 1- to 5-year-old children was reduced from 63.5% pre-treatment to 11.5% six months after the first distribution (P<0.0001). It further decreased to 2.6% six months after the fourth and final treatment (P = 0.0004). In the next 18 months, infection returned to 25.2%, a significant increase from six months after the last treatment (P = 0.008), but still far lower than baseline (P<0.0001). Although the prevalence of infection in any particular village fluctuated, the mean prevalence of the 16 villages steadily decreased with each treatment and steadily returned after treatments were discontinued. CONCLUSION: In some of the most severely affected communities ever studied, we demonstrate that repeated mass oral azithromycin distributions progressively reduce ocular chlamydial infection in a community, as long as these distributions are given frequently enough and at a high enough coverage. However, infection returns into the communities after the last treatment. Sustainable changes or complete local elimination of infection will be necessary. TRIAL REGISTRATION: ClinicalTrials.gov NCT00221364.

Comparison of annual and biannual mass antibiotic administration for elimination of infectious trachoma.

CONTEXT: Treatment recommendations assume that repeated mass antibiotic distributions can control, but not eradicate or even locally eliminate, the ocular strains of chlamydia that cause trachoma. Elimination may be an important end point because of concern that infection will return to communities that have lost immunity to chlamydia after antibiotics are discontinued. OBJECTIVE: To determine whether biannual treatment can eliminate ocular chlamydial infection from preschool children and to compare results with the World Health Organization-recommended annual treatment. DESIGN, SETTING, AND PARTICIPANTS: A cluster-randomized clinical trial of biannual vs annual mass azithromycin administrations to all residents of 16 rural villages in the Gurage Zone, Ethiopia, from March 2003 to April 2005. INTERVENTIONS: At scheduled treatments, all individuals aged 1 year or older were offered a single dose of oral azithromycin either annually or biannually. MAIN OUTCOME MEASURE: Village prevalence of ocular chlamydial infection and presence of elimination at 24 months in preschool children determined by polymerase chain reaction, correcting for baseline prevalence. Antibiotic treatments were performed after sample collections. RESULTS: Overall, 14,897 of 16,403 eligible individuals (90.8%) received their scheduled treatment. In the villages in which residents were treated annually, the prevalence of infection in preschool children was reduced from a mean of 42.6% (range, 14.7%-56.4%) to 6.8% (range, 0.0%-22.0%) at 24 months. In the villages in which residents were treated biannually, infection was reduced from 31.6% pretreatment (range, 6.1%-48.6%) to 0.9% (range, 0.0%-4.8%) at 24 months. Biannual treatment was associated with a lower prevalence at 24 months (P = .03, adjusting for baseline prevalence). At 24 months, no infection could be identified in 6 of 8 of those treated biannually and in 1 of 8 of those treated annually (P = .049, adjusting for baseline prevalence). CONCLUSION: Local elimination of ocular chlamydial infection appears feasible even in the most severely affected areas, although it may require biannual mass antibiotic distributions at a high coverage level. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00221364.

Complete elimination is a difficult goal for trachoma programs in severely affected communities.

The World Health Organization has distributed millions of doses of azithromycin to control the ocular chlamydial infection that causes trachoma. Theoretically, a loftier goal of elimination is feasible. Here, we demonstrate that, although local elimination of infection in the most severely affected communities is difficult, it is possible with biannual antibiotic distributions.

A rationale for continuing mass antibiotic distributions for trachoma.

BACKGROUND: The World Health Organization recommends periodic mass antibiotic distributions to reduce the ocular strains of chlamydia that cause trachoma, the world's leading cause of infectious blindness. Their stated goal is to control infection, not to completely eliminate it. A single mass distribution can dramatically reduce the prevalence of infection. However, if infection is not eliminated in every individual in the community, it may gradually return back into the community, so often repeated treatments are necessary. Since public health groups are reluctant to distribute antibiotics indefinitely, we are still in need of a proven long-term rationale. Here we use mathematical models to demonstrate that repeated antibiotic distributions can eliminate infection in a reasonable time period. METHODS: We fit parameters of a stochastic epidemiological transmission model to data collected before and 6 months after a mass antibiotic distribution in a region of Ethiopia that is one of the most severely affected areas in the world. We validate the model by comparing our predicted results to Ethiopian data which was collected biannually for two years past the initial mass antibiotic distribution. We use the model to simulate the effect of different treatment programs in terms of local elimination of infection. RESULTS: Simulations show that the average prevalence of infection across all villages progressively decreases after each treatment, as long as the frequency and coverage of antibiotics are high enough. Infection can be eliminated in more villages with each round of treatment. However, in the communities where infection is not eliminated, it returns to the same average level, forming the same stationary distribution. This phenomenon is also seen in subsequent epidemiological data from Ethiopia. Simulations suggest that a biannual treatment plan implemented for 5 years will lead to elimination in 95% of all villages. CONCLUSION: Local elimination from a community is theoretically possible, even in the most severely infected communities. However, elimination from larger areas may require repeated biannual treatments and prevention of re-introduction from outside to treated areas.

Chlamydia on children and flies after mass antibiotic treatment for trachoma.

There are various approaches to control trachoma. These include the elimination of the ocular strains of Chlamydia trachomatis that cause the disease and to decrease the spread of infection by other measures such as fly control. Here, we examined how these two are related (i.e., how treating children with antibiotics affects carriage of Chlamydia by flies). Flies were collected in villages that had received mass oral azithromycin distribution and were compared with flies in untreated villages. Polymerase chain reaction (PCR) was performed to detect chlamydial DNA on the flies. Conjunctival swabs were also taken to assay for chlamydial prevalence in the children. Chlamydia was found on 23% of the flies in the untreated villages but only 0.3% in treated villages. Prevalence of trachoma in children proved to be an excellent predictor of the prevalence on flies (correlation coefficient, 0.89). Thus, treating children with antibiotics may drastically reduce the role of flies as a vector.

Effect of a single mass antibiotic distribution on the prevalence of infectious trachoma.

CONTEXT: The World Health Organization recommends mass antibiotic distributions in its strategy to eliminate blinding trachoma as a public health concern. Some hypothesize that a single distribution is sufficient to control the ocular strains of chlamydia that cause trachoma. Others believe infection will inevitably return and periodic treatments or other measures are essential. OBJECTIVE: To determine whether ocular chlamydial infection returns to the community up to 24 months after a single mass antibiotic distribution in a hyperendemic region of Ethiopia. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal cohort study conducted March 2003 to March 2005 in the Gurage Zone of Ethiopia. Eight randomly selected villages were assessed for ocular chlamydial infection. Fifteen untreated villages were randomly chosen at 12 months to allow assessment of a secular trend. INTERVENTION: A single dose of oral azithromycin was offered to all residents of the 8 selected villages who were aged 1 year or older. MAIN OUTCOME MEASURE: Prevalence of ocular chlamydial infection in all children aged 1 to 5 years from each intervention village prior to treatment and 2, 6, 12, 18, and 24 months after mass antibiotic treatment, and also in untreated villages enrolled at 12 months. RESULTS: Five hundred fifteen children were examined for ocular chlamydial infection at baseline. For the follow-up examinations, the mean participation rate was 83%. The mean prevalence of infection in children aged 1 to 5 years decreased from 43.5% (95% confidence interval [CI], 35.0%-52.0%) to 5.1% (95% CI, 1.1%-9.2%) after treatment. On average, infection returned gradually over 24 months to 11.3% (95% CI, 4.5%-18.1%; P = .001). In 7 of 8 villages, infection was higher at 24 months than at 2 months. In the remaining village, no infection could be identified at any point after treatment. Villages enrolled at 12 months had significantly fewer infections than those enrolled 12 months earlier, suggesting a secular trend (P<.001). CONCLUSIONS: Ocular chlamydial infection was not eliminated in children aged 1 to 5 years after a single mass azithromycin distribution; it slowly returned over 24 months, although not to baseline levels. Repeated treatments or other effective measures will be necessary for elimination.