Search tips
Search criteria

Results 1-25 (29)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
1.  The Association between Latrine Use and Trachoma: A Secondary Cohort Analysis from a Randomized Clinical Trial 
Latrine use has been promoted as a component of an integrated strategy for trachoma control. As part of a randomized trial in Ethiopia, 12 communities received a mass azithromycin distribution followed by a latrine promotion intervention. A random sample of children ages 0–9 years in each community was monitored longitudinally for ocular chlamydia. After latrine construction ended, those communities with a higher proportion of households using latrines were more likely to experience a reduction in the prevalence of ocular chlamydia. Specifically, for each 10% increase in latrine use, there was a 2.0% decrease (95% confidence interval = 0.2–3.9% decrease) in the community prevalence of ocular chlamydia over the subsequent year (P = 0.04).
PMCID: PMC3795102  PMID: 24002488
2.  Does Mass Azithromycin Distribution Impact Child Growth and Nutrition in Niger? A Cluster-Randomized Trial 
Antibiotic use on animals demonstrates improved growth regardless of whether or not there is clinical evidence of infectious disease. Antibiotics used for trachoma control may play an unintended benefit of improving child growth.
In this sub-study of a larger randomized controlled trial, we assess anthropometry of pre-school children in a community-randomized trial of mass oral azithromycin distributions for trachoma in Niger. We measured height, weight, and mid-upper arm circumference (MUAC) in 12 communities randomized to receive annual mass azithromycin treatment of everyone versus 12 communities randomized to receive biannual mass azithromycin treatments for children, 3 years after the initial mass treatment. We collected measurements in 1,034 children aged 6–60 months of age.
Principal Findings
We found no difference in the prevalence of wasting among children in the 12 annually treated communities that received three mass azithromycin distributions compared to the 12 biannually treated communities that received six mass azithromycin distributions (odds ratio = 0.88, 95% confidence interval = 0.53 to 1.49).
We were unable to demonstrate a statistically significant difference in stunting, underweight, and low MUAC of pre-school children in communities randomized to annual mass azithromycin treatment or biannual mass azithromycin treatment. The role of antibiotics on child growth and nutrition remains unclear, but larger studies and longitudinal trials may help determine any association.
Author Summary
Recent studies suggest that antibiotic use could have an effect on growth in humans. Azithromycin is an antibiotic used for trachoma control, and hence, may have an unintended benefit of improving child growth. Niger is a trachoma-endemic country where mass antibiotic distributions for trachoma take place and where malnutrition is widespread among children. In addition, azithromycin may have an effect on common childhood diseases associated with malnutrition, such as diarrhea, pneumonia, and malaria. In a community-randomized trachoma trial in Matameye, Niger, we assessed child growth by measuring height, weight, and mid-upper arm circumference of pre-school children who have received 3 years of annual or biannual mass azithromycin treatment. While these measures were better in the biannually treated communities, the difference was not statistically significant. Thus, further research will help determine the impact of antibiotics on child growth and nutrition.
PMCID: PMC4161345  PMID: 25210836
3.  A Cluster-Randomized Controlled Trial Evaluating the Effects of Mass Azithromycin Treatment on Growth and Nutrition in Niger 
Antimicrobials are used primarily to treat infectious disease, but they have other effects. Here, we assess anthropometry measurements in children 6–60 months in 24 communities randomized to one or two mass azithromycin distributions over a 1-year period in Niger. We compared the prevalence of wasting, low mid-upper arm circumference, stunting, and underweight in communities in the two treatment arms. We were unable to prove that there was a difference in the prevalence of wasting in the 12 communities that received one mass azithromycin distribution versus the 12 communities that received two mass azithromycin distributions (odds ratio = 0.75, 95% confidence interval = 0.46–1.23). Likewise, we were unable to detect a difference in the two treatment arms for low mid-upper arm circumference, stunting, and underweight. There may not be an association between antibiotic use and improved growth in humans, or this trial was not powerful enough to detect an association if it exists.
PMCID: PMC3541724  PMID: 23208876
4.  Reliability of Trachoma Clinical Grading—Assessing Grading of Marginal Cases 
Clinical examination of trachoma is used to justify intervention in trachoma-endemic regions. Currently, field graders are certified by determining their concordance with experienced graders using the kappa statistic. Unfortunately, trachoma grading can be highly variable and there are cases where even expert graders disagree (borderline/marginal cases). Prior work has shown that inclusion of borderline cases tends to reduce apparent agreement, as measured by kappa. Here, we confirm those results and assess performance of trainees on these borderline cases by calculating their reliability error, a measure derived from the decomposition of the Brier score.
Methods and Findings
We trained 18 field graders using 200 conjunctival photographs from a community-randomized trial in Niger and assessed inter-grader agreement using kappa as well as reliability error. Three experienced graders scored each case for the presence or absence of trachomatous inflammation - follicular (TF) and trachomatous inflammation - intense (TI). A consensus grade for each case was defined as the one given by a majority of experienced graders. We classified cases into a unanimous subset if all 3 experienced graders gave the same grade. For both TF and TI grades, the mean kappa for trainees was higher on the unanimous subset; inclusion of borderline cases reduced apparent agreement by 15.7% for TF and 12.4% for TI. When we assessed the breakdown of the reliability error, we found that our trainees tended to over-call TF grades and under-call TI grades, especially in borderline cases.
The kappa statistic is widely used for certifying trachoma field graders. Exclusion of borderline cases, which even experienced graders disagree on, increases apparent agreement with the kappa statistic. Graders may agree less when exposed to the full spectrum of disease. Reliability error allows for the assessment of these borderline cases and can be used to refine an individual trainee's grading.
Author Summary
Trachoma is the leading infectious cause of blindness and the World Health Organization plans to eliminate it as a public health concern worldwide by the year 2020. This effort in large part involves mass oral antibiotic distributions to communities. A simplified trachoma grading scale is used to assess presence of active infection. Field workers must be properly trained and certified to perform these eye exams because their findings inform when to start and stop community-wide antibiotic treatments. Certification involves measuring agreement in trachoma grades between a trainee and an experienced grader on a test-set of trachoma photographs. Often, these test-sets have hard-to-grade cases of trachoma removed. We found that removing these borderline cases inflates agreement. Including these borderline cases in the test-set allows a more realistic estimate of agreement, but it is still difficult to assess a trainee's grades for cases which even experts disagree on. We found that reliability error, a measure derived from the decomposition of the Brier score (the mean squared error of a set of forecasts), can be used to assess a trainee's evaluation of these borderline cases.
PMCID: PMC4006735  PMID: 24784355
5.  Comparison of an rRNA‐based and DNA‐based nucleic acid amplification test for the detection of Chlamydia trachomatis in trachoma 
The World Health Organisation (WHO) hopes to achieve global elimination of trachoma, still the leading cause of preventable blindness worldwide, in part through mass antibiotic treatment. DNA‐based nucleic acid amplification tests (NAATs) are currently used to evaluate the success of treatment programmes by measuring the prevalence of C trachomatis infection. Some believe that newer ribosomal RNA (rRNA)‐based tests may be much more sensitive since bacterial rRNA is present in amounts up to 10 000 times that of genomic DNA. Others believe that rRNA‐based tests are instead less sensitive but more specific, due to the presence of dead or subviable organisms that the test may not detect. This study compares an rRNA‐based test to a DNA‐based test for the detection of ocular C trachomatis infection in children living in trachoma‐endemic villages.
An rRNA‐based amplification test and DNA‐based polymerase chain reaction (PCR) were performed on swab specimens taken from the right upper tarsal conjunctiva of 56 children aged 0–10 years living in two villages in Amhara, Ethiopia.
The rRNA‐based test detected ocular C trachomatis infection in 35 (63%) subjects compared with 22 (39%) detected by PCR (McNemar's test, p = 0.0002). The rRNA‐based test gave positive results for all subjects that were positive by PCR, and also detected infection in 13 (23%) additional subjects.
The rRNA‐based test appears to have significantly greater sensitivity than PCR for the detection of ocular chlamydial infection in children in trachoma‐endemic villages. Using the rRNA‐based test, we may be able to detect infection that was previously missed with PCR. Past studies using DNA‐based tests to assess prevalence of infectious trachoma following antibiotic treatment may have underestimated the true prevalence of infection.
PMCID: PMC1857674  PMID: 17050583
6.  Elimination and Eradication of Neglected Tropical Diseases with Mass Drug Administrations: A Survey of Experts 
Lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminths, and trachoma are the five most prevalent neglected tropical diseases in the world, and each is frequently treated with mass drug administrations. We performed a survey of neglected tropical diseases experts to elicit their opinions on the role of mass drug administrations for the elimination of these infections.
Methodology/Principal Findings
We sent an online survey to corresponding authors who had published an article about a neglected tropical disease from 2007 to 2011. Of 825 unique authors who were invited to complete the survey, 365 (44.2%) responded, including 234 (28.4%) who answered questions regarding one of the five most prevalent neglected tropical diseases. Respondents had varying opinions about the goals of programmatic activities for their chosen neglected tropical disease, with elimination or eradication identified as the most important goal by 87% of lymphatic filariasis respondents, 66% of onchocerciasis respondents, 55% of trachoma respondents, 24% of schistosomiasis respondents, and 21% of soil-transmitted helminth respondents. Mass drug administrations, other non-medication health measures, and education were generally thought to be more important for elimination than vector control, development of a new tool, or the presence of a secular trend. Drug resistance was thought to be a major limitation of mass drug administrations for all five neglected tropical diseases. Over half of respondents for lymphatic filariasis and trachoma thought that repeated mass drug administrations could eliminate infection within ten years of the initiation of mass treatments.
Respondents for lymphatic filariasis, onchocerciasis, and trachoma were more enthusiastic about the prospects of elimination and eradication than were respondents for schistosomiasis or soil-transmitted helminths. Mass drug administrations were generally believed to be among the most important factors for the success of elimination efforts for each of the five neglected tropical diseases, highlighting the opportunity for integrating drug distributions.
Author Summary
Mass drug administrations are used for each of the five most common neglected tropical diseases: lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminths, and trachoma. Three of these infections—lymphatic filariasis, onchocerciasis, and trachoma—are officially targeted for elimination, and mass drug administrations play a key role in the elimination plans for each. While progress has been demonstrated for each of these diseases, it is unclear whether researchers of these diseases think that elimination is feasible, or whether mass drug administrations should play an important role given the potential for drug resistance. We performed a survey of neglected tropical diseases experts to assess their opinions on the likelihood of elimination and the role of mass drug administrations for the five most common neglected tropical diseases. Most experts in lymphatic filariasis, onchocerciasis, and trachoma thought elimination was the appropriate goal of treatment programs, whereas most experts in schistosomiasis and soil-transmitted helminths thought that treatment programs were intended to control, but not eliminate, infection. Drug resistance was thought to be a major limitation for each of the infections. Although there were differences between the five infections, mass drug administrations, non-medication health measures, and education were generally thought to be the most important pieces of a control program.
PMCID: PMC3855072  PMID: 24340111
7.  Topical Fluoroquinolone Use as a Risk Factor for In Vitro Fluoroquinolone Resistance in Ocular Cultures 
Archives of ophthalmology  2011;129(4):10.1001/archophthalmol.2011.45.
To determine whether recent use of topical fluoroquinolones is a risk factor for in vitro fluoroquinolone resistance in Staphylococcus aureus ocular isolates.
Disk diffusion susceptibility testing for ciprofloxacin, moxifloxacin, and gatifloxacin was performed for all ocular isolates of S aureus at the Francis I. Proctor Foundation microbiology laboratory from January 1, 2005, to December 31, 2008. The medical records of patients with positive S aureus cultures were reviewed to determine topical or systemic fluoroquinolone use within the 3 months prior to culture. The Fisher exact test was used to compare the proportion of patients who used topical fluoroquinolones in the past 3 months among fluoroquinolone-sensitive and -resistant cases. Logistic regression was used to determine risk factors for fluoroquino-lone resistance.
Of 200 S aureus cultures, 41 were resistant to ciprofloxacin, moxifloxacin, and gatifloxacin (20.5%). Fluoroquinolone-resistant S aureus isolates were from older patients (mean [SD] age, 65.5 [25.0] years) compared with fluoroquinolone-susceptible isolates (mean [SD] patientage, 52.1 [22.1] years) (P=.003). Use of fluoroquinolones within the 3 months before testing was more frequent in resistant isolates (29%) than in susceptible isolates (11%) (P=.005), as was recent hospitalization (22% of resistant isolates, 0% of susceptible isolates) (P<.001). In the multivariate regression analysis, topical fluoroquinolone use within 3 months was a significant predictor of fluoroquinolone resistance (P=.046), along with age, systemic immunosuppression, and topical fluoroquinolone use between 3 and 6 months before testing.
Recent topical fluoroquinolone use is significantly associated with fluoroquinolone resistance in S aureus isolates from ocular cultures.
PMCID: PMC3830547  PMID: 21482865
9.  Chlamydial infection during trachoma monitoring: are the most difficult-to-reach children more likely to be infected? 
During mass antibiotic distributions for trachoma, certain individuals are difficult to locate, and go untreated. These untreated individuals may serve as a source of community re-infection. The importance of this difficult-to-locate, untreated population is unclear. We sought to determine whether individuals who are difficult to locate were more likely to be infected with ocular chlamydia than those who were easier to locate.
We monitored 12 Ethiopian communities 1 year after a third annual mass azithromycin treatment for trachoma. Conjunctival swabbing for chlamydial RNA was performed in a random sample of children from each community. If insufficient numbers of children were enrolled on the first monitoring day, we returned on subsequent days.
Of the 12 communities, 10 required more than 1 monitoring day. On average, 16.1% (95% CI 7.9–30.0) of children were enrolled after the initial day. Evidence of chlamydia was found in 7.1% (95% CI 2.7–17.4) of 0–9 year-old children. No ocular swabs collected after the initial day were positive for chlamydial RNA. Children examined after the initial monitoring day were significantly less likely to have ocular chlamydial infection than children seen on the initial day; Mantel-Haenszel common OR = 0 (95% CI 0 – 0.77).
In a setting of repeated annual mass azithromycin treatments, after approximately 80% of individuals have been located in a community, extra efforts to find absent individuals may not yield significantly more cases of ocular chlamydia.
PMCID: PMC3292692  PMID: 22122734
sampling bias; chlamydia; RNA; neglected diseases
10.  Ribosomal RNA Evidence of Ocular Chlamydia trachomatis Infection Following 3 Annual Mass Azithromycin Distributions in Communities With Highly Prevalent Trachoma 
Twelve trachoma-hyperendemic communities were treated with 3 annual mass azithromycin distributions. Children aged 0–9 years were monitored 1 year following the third treatment. An RNA-based test detected ocular chlamydial infection in more children than did a DNA-based test (6.9% vs 4.2%), and in a larger number of communities (8 vs 7).
PMCID: PMC3245728  PMID: 22095569
11.  The Easiest Children to Reach Are Most Likely to Be Infected with Ocular Chlamydia trachomatis in Trachoma Endemic Areas of Niger 
Control programs for trachoma use mass antibiotic distributions to treat ocular Chlamydia trachomatis in an effort to eliminate this disease worldwide. To determine whether children infected with ocular Chlamydia are more likely to present later for examination than those who are uninfected, we compare the order of presentation for examination of children 0–5 years, and the presence of ocular Chlamydia by PCR in 4 villages in Niger where trachoma is endemic.
We conducted a cluster-randomized, controlled trial where 48 randomly selected villages in Niger are divided into 4 study arms of different mass treatment strategies. In a substudy of the main trial, we randomly selected 1 village from each of the 4 study arms (4 total villages) and we evaluated the odds of ocular Chlamydia versus the rank order of presentation for examination and laboratory assessment before treatment was offered.
We found the odds of harboring ocular Chlamydia dropped by more than 70% from the first child examined to the last child examined (OR 0.27, 95% CI 0.13–0.59, P = 0.001) in the 4 randomly selected villages. We found the odds of active trachoma dropped by 80% from the first child examined to the last child examined (OR 0.20, 95% CI 0.10–0.4, P<0.0001) in the 48 villages in the main trial.
This study demonstrates that even if the WHO recommended 80% treatment coverage is not reached in certain settings, children 0–5 years with the greatest probability of ocular Chlamydia have higher odds of receiving attention because they are the first to present. These results suggest there may be diminishing returns when using scarce resources to track down the last few children in a mass treatment program.
Trial Registration NCT00792922
Author Summary
Trachoma is the most common cause of blindness from an infection in the world. The bacterium that causes trachoma is called Chlamydia trachomatis and it can be treated with the antibiotic azithromycin. Experts recommend trying to reach at least 80% of children for treatment in a community but it is unknown if this is necessary. We began a clinical trial in Niger in 48 villages in the summer of 2010 with mass drug administration (MDA) of azithromycin. We found that the odds of an eye infection were the highest in the first children to come for an examination. This means the extra time and money needed to reach all of the children in a village may provide diminishing returns because the easiest children to reach have the highest odds of infection. Perhaps it would be better to try to reach more villages for MDA instead of spending a lot of time and money trying to reach every single child in every single village.
PMCID: PMC3542188  PMID: 23326612
12.  Practice patterns and opinions in the treatment of acanthamoeba keratitis 
Cornea  2011;30(12):1363-1368.
Management of acanthamoeba keratitis remains challenging for ophthalmologists. We conducted a survey of members of the Cornea Society to elicit expert opinions on the diagnosis and treatment of acanthamoeba keratitis.
An online survey was sent to all subscribers of the Cornea Society kera-net listserv. Descriptive statistics were performed.
Eighty-two participants completed the online survey. Of the 82 respondents, 76.8% included the combination of clinical examination and culture in their diagnostic strategy, and 43.9% used confocal microscopy. Most respondents (97.6%) had used combination therapy with multiple agents to treat acanthamoeba keratitis at some point in the past, whereas a smaller proportion (47.6%) had ever used monotherapy. Respondents most commonly chose PHMB as the ideal choice for monotherapy (51.4%), and dual therapy with a biguanide and diamidine as the ideal choice for combination therapy (37.5%). The majority of respondents (62.2%) reported using topical corticosteroids at least some of the time for acanthamoeba keratitis. Keratoplasty was an option considered by most respondents (75.6%), although most (85.5%) would only perform surgery after medical treatment failure.
There was a wide range of current practice patterns for the diagnosis and treatment of acanthamoeba keratitis. The lack of sufficiently-powered comparative effectiveness studies and clinical trials makes evidenced-based decision making for this disease difficult.
PMCID: PMC3219806  PMID: 21993459
monotherapy; combination therapy; corticosteroids; keratoplasty; Bayesian
14.  Latrine Promotion for Trachoma: Assessment of Mortality from a Cluster-Randomized Trial in Ethiopia 
Trachoma control strategies, including latrine construction and antibiotic distribution, are directed at reducing ocular chlamydia, but may have additional benefits. In a cluster-randomized clinical trial, 24 subkebeles (administrative geographic units) in Ethiopia were offered a single mass azithromycin treatment, and half were randomized to receive an intensive latrine promotion. At a follow-up census 26 months after the baseline treatment, 320 persons had died. The mortality rate of children 1–5 years of age was 3.87 (95% confidence interval [CI] = 2.19–6.82) per 1,000 person-years in the latrine promotion arm, and 2.72 (95% CI = 1.37–5.42) per 1,000 person-years in the control arm. In a multi-level mixed effects logistic regression model controlling for age, there was no difference in mortality in persons randomized into the latrine or control arms (odds ratio = 1.18, 95% CI = 0.89–1.58). Latrine promotion provided no additional effect on mortality in the context of an azithromycin distribution program (, #NCT00322972).
PMCID: PMC3163877  PMID: 21896815
15.  Adverse Events after Mass Azithromycin Treatments for Trachoma in Ethiopia 
During a cluster-randomized clinical trial for trachoma in Ethiopia, two rounds of adverse event surveillance were performed in a random sample of communities after community-wide mass azithromycin treatment. The prevalence of any reported adverse event ranged from 4.9% to 7.0% in children 1–9 years of age and from 17.0% to 18.7% in persons ≥ 10 years of age. Adverse events appeared to cluster by household and perhaps by village. Mass azithromycin distributions were well tolerated in this setting.
PMCID: PMC3144828  PMID: 21813850
16.  Diagnostic Characteristics of Tests for Ocular Chlamydia after Mass Azithromycin Distributions 
After three mass azithromycin distributions for trachoma, a grade of follicular trachomatous inflammation was a sensitive indicator of ocular chlamydial infection but was limited by a poor positive predictive value. A test for chlamydial RNA was considerably more sensitive than a DNA-based test.
Although trachoma control programs frequently use the World Health Organization (WHO) simplified grading system for trachoma to monitor the clinical response after repeated mass azithromycin treatments, the programmatic relevance of this evaluation after multiple rounds of antibiotic treatments is unclear.
Three rounds of annual mass azithromycin were distributed to 12 villages in Ethiopia. Twelve months after the third treatment, children were assessed for follicular trachomatous inflammation (TF) and intense trachomatous inflammation (TI) using the WHO simplified grading system and for ocular chlamydial infection using DNA-based and RNA-based tests. Test characteristics for predicting chlamydial infection were computed assuming a chlamydial RNA-based gold standard. As a secondary analysis, test characteristics were also assessed using a latent class analysis.
The prevalence of RNA evidence of ocular chlamydia was 7.1% (95% confidence interval [CI], 2.7–17.4). A DNA-based test and TF had sensitivities of 61.0% (95% CI, 47.1–73.3) and 65.9% (95% CI, 41.6–83.9), specificities of 100% (95% CI, 99.3–100) and 67.5% (95% CI, 61.0–73.5), and positive predictive values of 100% (95% CI, 86.3–100) and 13.4% (95% CI, 5.5–29.3) compared with an RNA-based gold standard. The latent class analysis confirmed that the RNA-based test was a reasonable choice for a gold standard, with a sensitivity of 100% (95% CI, 67.1–100) and specificity of 99.6% (95% CI, 98.1–100).
Basing treatment decisions after mass azithromycin distributions on the WHO simplified grading system will maximize the treatment of infected persons compared with a DNA-based test but will also result in more uninfected persons being treated. The RNA-based test was considerably more sensitive, and almost equivalently specific, compared with a DNA-based test. ( number, NCT00322972.)
PMCID: PMC3292361  PMID: 22159017
17.  Efficacy of latrine promotion on emergence of infection with ocular Chlamydia trachomatis after mass antibiotic treatment: a cluster-randomized trial 
International health  2011;3(2):75-84.
The World Health Organization (WHO) recommends environmental improvements such as latrine construction in the integrated trachoma control strategy, SAFE. We report a cluster-randomized trial assessing the effect of intensive latrine promotion on emergence of infection with ocular Chlamydia trachomatis after mass treatment with antibiotics.
Twenty-four communities in Goncha Seso Enesie woreda, Amhara Regional State, Ethiopia, were enumerated, and a random selection of 60 children aged 0– 9 years in each was monitored for clinical signs of trachoma and ocular chlamydial infection at baseline, 12 and 24 months. All community members were offered treatment with a single dose of oral azithromycin or topical tetracycline. After treatment, 12 subkebeles were randomized to receive intensive latrine promotion. Mean cluster ocular infection in the latrine and the non-latrine arms were reduced from 45.5% (95% CI 34.1–56.8%) and 43.0% (95% CI 31.1–54.8%) respectively at baseline to 14.6% (95% CI 7.4–21.8%) and 14.8% (95% CI 8.9–20.8%) respectively at 24 months (P=0.93). Clinical signs fell from 72.0% (95% CI 58.2–85.5%) and 61.3% (95% CI 44.0–78.5%) at baseline to 45.8% (36.0–55.6%) and 48.5% (34.0–62.9%) respectively at 24 months (P=0.69). At 24 months, estimated household latrine coverage and use were 80.8% and 61.7% respectively where there had been intensive latrine promotion and 30.0% and 25.0% respectively in the single treatment only arm. We were unable to detect a difference in the prevalence of ocular chlamydial infection in children due to latrine construction.
PMCID: PMC3139980  PMID: 21785663
azithromycin; chlamydia; elimination; Ethiopia; latrines; trachoma
18.  Community Risk Factors for Ocular Chlamydia Infection in Niger: Pre-Treatment Results from a Cluster-Randomized Trachoma Trial 
Trachoma control programs utilize mass azithromycin distributions to treat ocular Chlamydia trachomatis as part of an effort to eliminate this disease world-wide. But it remains unclear what the community-level risk factors are for infection.
This cluster-randomized, controlled trial entered 48 randomly selected communities in a 2×2 factorial design evaluating the effect of different treatment frequencies and treatment coverage levels. A pretreatment census and examination established the prevalence of risk factors for clinical trachoma and ocular chlamydia infection including years of education of household head, distance to primary water source, presence of household latrine, and facial cleanliness (ocular discharge, nasal discharge, and presence of facial flies). Univariate and multivariate associations were tested using linear regression and Bayes model averaging.
There were a total of 24,536 participants (4,484 children aged 0–5 years) in 6,235 households in the study. Before treatment in May to July 2010, the community-level prevalence of active trachoma (TF or TI utilizing the World Health Organization [WHO] grading system) was 26.0% (95% CI: 21.9% to 30.0%) and the mean community-level prevalence of chlamydia infection by Amplicor PCR was 20.7% (95% CI: 16.5% to 24.9%) in children aged 0–5 years. Univariate analysis showed that nasal discharge (0.29, 95% CI: 0.04 to 0.54; P = 0.03), presence of flies on the face (0.40, 95% CI: 0.17 to 0.64; P = 0.001), and years of formal education completed by the head of household (0.07, 95% CI: 0.07 to 0.13; P = 0.03) were independent risk factors for chlamydia infection. In multivariate analysis, facial flies (0.26, 95% CI: 0.02 to 0.49; P = 0.03) and years of formal education completed by the head of household (0.06, 95% CI: 0.008 to 0.11; P = 0.02) were associated risk factors for ocular chlamydial infection.
We have found that the presence of facial flies and years of education of the head of the household are risk factors for chlamydia infection when the analysis is done at the community level.
Trial Registration NCT00792922
Author Summary
Trachoma is one of the most important neglected tropical diseases because it is the leading cause of blindness from an infection in the world. There are about 1.3 million persons blind from the disease and many more at risk of blindness in the future. It is caused by the common bacterium Chlamydia trachomatis and can be treated with mass drug administrations (MDA) of azithromycin. We have begun a clinical trial in Niger, a country with limited resources in Africa, to determine the best treatment strategy. Our study from May to July 2010, which began before MDA's were given, showed that 26% of children aged 0–5 years were infected with the disease. In these children, we found that discharge from the nose, presence of flies on the face, and the number of years of education completed by the head of the household were risk factors for infection in 48 different communities. We hope to use this information about risk factors of infection to help guide future studies for trachoma and also to help with the WHO goal of eliminating the disease worldwide by the year 2020.
PMCID: PMC3335874  PMID: 22545165
19.  Childhood Mortality in a Cohort Treated With Mass Azithromycin for Trachoma 
During a mass azithromycin campaign for trachoma, all-cause and infectious mortality rates were lower in treated children compared to untreated children. Treated children had a lower mortality rate even when compared only to members of the same household.
Background. Mass azithromycin distributions are used to clear ocular strains of chlamydia that cause trachoma, but treatments may also affect respiratory infections, diarrhea, and malaria. Here, we monitor a large cohort in which almost 90% of individuals received azithromycin. We assess whether receiving treatment is associated with reduced all-cause and infectious childhood mortality.
Methods. As part of a clinical trial for trachoma, a census was conducted in 24 communities in rural Ethiopia. All individuals ≥1 year of age were eligible for single-dose oral azithromycin, although antibiotic coverage was not universal. A follow-up census was performed 26 months after treatment to estimate all-cause mortality among children 1–5 years of age, and verbal autopsies were performed to identify infectious mortality.
Results. The cohort included 35,052 individuals ≥1 year of age and 5507 children 1–5 years of age, of whom 4914 received a dose of azithromycin. All-cause mortality was significantly lower among those 1–5-year-old children who received azithromycin (odds ratio [OR] = 0.35 [95% confidence interval {CI}, 0.17–0.74]), as was infectious mortality (OR = 0.20 [95% CI, 0.07–0.58]). When individuals were compared only with members of the same household, azithromycin treatment was still associated with reduced all-cause mortality in children 1–5 years of age (OR = 0.40 [95% CI, 0.16–0.96]), although this relationship was not statistically significant for infectious mortality (OR = 0.35 [95% CI, 0.10–1.28]).
Conclusions. This study demonstrated an association between mass oral azithromycin treatment and reduced all-cause and infectious childhood mortality. This relationship could not be attributed to bias at the level of the household. Mass azithromycin distributions may have benefits unrelated to trachoma.
PMCID: PMC3106233  PMID: 21427395
20.  How Reliable Are Tests for Trachoma?—A Latent Class Approach 
Latent class analysis allows the estimation of test sensitivities and specificities in the absence of a gold standard. PCR outperformed clinical examination and intense trachomatous inflammation (TI) appeared much more specific than follicular trachomatous inflammation (TF).
Tests for ocular Chlamydia trachomatis have not been well characterized, because there is no gold standard test. Latent class analysis (LCA) was performed to estimate the sensitivity and specificity of laboratory and clinical tests for trachoma in the absence of a gold standard.
Individual data from pretreatment, hyperendemic areas in Ethiopia were used. A clustered LCA was performed for three diagnostic tests: PCR and WHO simplified criteria grades of follicular trachoma (TF) and intense trachomatous inflammation (TI).
Data from 2111 subjects in 40 villages were available. TF was estimated to be 87.3% (95% CI, 83.3–90.1) sensitive and 36.6% (95% CI, 23.6–40.3) specific; TI was estimated to be 53.6% (95% CI, 46.1–88.0) sensitive and 88.3% (95% CI, 83.3–92.0) specific, and PCR was estimated to be 87.5% (95% CI, 79.9–97.2) sensitive and 100% (95% CI 69.3–100) specific.
LCA allows for an estimate of test characteristics without prior assumption of their performance. TF and TI were found to act in a complementary manner: TF is a sensitive test and TI is a specific test. PCR is highly specific but lacks sensitivity. The performance of these tests may be due to the time course of ocular chlamydial infection, and for this reason, results may differ in areas of low prevalence or recent mass treatment ( number, NCT00221364).
PMCID: PMC3176003  PMID: 21685340
21.  Reliability of Measurements Performed by Community-Drawn Anthropometrists from Rural Ethiopia 
PLoS ONE  2012;7(1):e30345.
Undernutrition is an important risk factor for childhood mortality, and remains a major problem facing many developing countries. Millennium Development Goal 1 calls for a reduction in underweight children, implemented through a variety of interventions. To adequately judge the impact of these interventions, it is important to know the reproducibility of the main indicators for undernutrition. In this study, we trained individuals from rural communities in Ethiopia in anthropometry techniques and measured intra- and inter-observer reliability.
Methods and Findings
We trained 6 individuals without prior anthropometry experience to perform weight, height, and middle upper arm circumference (MUAC) measurements. Two anthropometry teams were dispatched to 18 communities in rural Ethiopia and measurements performed on all consenting pre-school children. Anthropometry teams performed a second independent measurement on a convenience sample of children in order to assess intra-anthropometrist reliability. Both teams measured the same children in 2 villages to assess inter-anthropometrist reliability. We calculated several metrics of measurement reproducibility, including the technical error of measurement (TEM) and relative TEM. In total, anthropometry teams performed measurements on 606 pre-school children, 84 of which had repeat measurements performed by the same team, and 89 of which had measurements performed by both teams. Intra-anthropometrist TEM (and relative TEM) were 0.35 cm (0.35%) for height, 0.05 kg (0.39%) for weight, and 0.18 cm (1.27%) for MUAC. Corresponding values for inter-anthropometrist reliability were 0.67 cm (0.75%) for height, 0.09 kg (0.79%) for weight, and 0.22 kg (1.53%) for MUAC. Inter-anthropometrist measurement error was greater for smaller children than for larger children.
Measurements of height and weight were more reproducible than measurements of MUAC and measurements of larger children were more reliable than those for smaller children. Community-drawn anthropometrists can provide reliable measurements that could be used to assess the impact of interventions for childhood undernutrition.
PMCID: PMC3265464  PMID: 22291939
22.  The Fitness Cost of Antibiotic Resistance in Streptococcus pneumoniae: Insight from the Field 
PLoS ONE  2012;7(1):e29407.
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.
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.
PMCID: PMC3260144  PMID: 22272234
23.  Risk Factors for Ocular Chlamydia after Three Mass Azithromycin Distributions 
An important component of the World Health Organization's comprehensive trachoma elimination strategy is the provision of repeated annual mass azithromycin distributions, which are directed at reducing the burden of ocular chlamydia. Knowledge of characteristics associated with infection after mass antibiotic treatments could allow trachoma programs to focus resources to those most likely to be infected with ocular chlamydia.
Methodology/Principal Findings
We monitored 12 communities in rural Ethiopia that had received 3 annual mass azithromycin treatments as part of a cluster-randomized trial for trachoma. One year after the third treatment, a random sample of children from each village received conjunctival examination for follicular trachomatous inflammation (TF) and intense trachomatous inflammation (TI), conjunctival swabbing for chlamydial RNA and DNA, and a household survey. The primary outcome for this study was RNA evidence of ocular chlamydia, which we detected in 41 of 573 swabbed children (7.2%, 95%CI 2.7–17.8). In multivariate mixed effects logistic regression models, ocular chlamydial RNA was significantly associated with ocular discharge (OR 2.82, 95%CI 1.07–7.42), missing the most recent mass azithromycin treatment (OR 2.49, 95%CI 1.02–6.05), having a sibling with ocular chlamydia (OR 4.44, 95%CI 1.60–12.29), and above-median community population (OR 7.81, 95%CI 1.56–39.09). Ocular chlamydial infection was also independently associated with TF (OR 3.42, 95%CI 1.56–7.49) and TI (OR 5.39, 95%CI 2.43–11.98).
In areas with highly prevalent trachoma treated with multiple rounds of mass azithromycin, trachoma programs could consider continuing mass azithromycin treatments in households that have missed prior mass antibiotic treatments, in households with clinically active trachoma, and in larger communities.
Author Summary
Trachoma, which is the leading infectious cause of blindness worldwide, is caused by repeated ocular infection with Chlamydia trachomatis. Treatment for trachoma includes mass azithromycin treatments to the entire community. The World Health Organization recommends at least 3 rounds of annual mass antibiotic distributions in areas with trachoma, with further mass treatments based on the prevalence of trachoma. However, there are other options for communities that have received several rounds of treatment. For example, programs could continue antibiotic treatments only in those households most likely to have infected individuals. In this study, we performed trachoma monitoring on children from 12 Ethiopian communities one year after a third mass azithromycin treatment, and conducted a household survey at the same time. We found that children were more likely to be infected with ocular chlamydia if they had ocular inflammatory signs or ocular discharge, or if they had missed the preceding antibiotic treatment, had an infected sibling, or came from a larger community. These risk factors suggest that after mass azithromycin treatments, trachoma programs could consider continuing antibiotic distributions to households that have missed prior antibiotic distributions, in households with children who have the clinical signs of trachoma, and in larger communities.
PMCID: PMC3236733  PMID: 22180804
24.  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.
PMCID: PMC2829914  PMID: 20207878
25.  Antibiotic Selection Pressure and Macrolide Resistance in Nasopharyngeal Streptococcus pneumoniae: A Cluster-Randomized Clinical Trial 
PLoS Medicine  2010;7(12):e1000377.
Jeremy Keenan and colleagues report that during a cluster-randomized clinical trial in Ethiopia, nasopharyngeal pneumococcal resistance to macrolides was significantly higher in communities randomized to receive azithromycin compared with untreated control communities.
It is widely thought that widespread antibiotic use selects for community antibiotic resistance, though this has been difficult to prove in the setting of a community-randomized clinical trial. In this study, we used a randomized clinical trial design to assess whether macrolide resistance was higher in communities treated with mass azithromycin for trachoma, compared to untreated control communities.
Methods and Findings
In a cluster-randomized trial for trachoma control in Ethiopia, 12 communities were randomized to receive mass azithromycin treatment of children aged 1–10 years at months 0, 3, 6, and 9. Twelve control communities were randomized to receive no antibiotic treatments until the conclusion of the study. Nasopharyngeal swabs were collected from randomly selected children in the treated group at baseline and month 12, and in the control group at month 12. Antibiotic susceptibility testing was performed on Streptococcus pneumoniae isolated from the swabs using Etest strips. In the treated group, the mean prevalence of azithromycin resistance among all monitored children increased from 3.6% (95% confidence interval [CI] 0.8%–8.9%) at baseline, to 46.9% (37.5%–57.5%) at month 12 (p = 0.003). In control communities, azithromycin resistance was 9.2% (95% CI 6.7%–13.3%) at month 12, significantly lower than the treated group (p<0.0001). Penicillin resistance was identified in 0.8% (95% CI 0%–4.2%) of isolates in the control group at 1 year, and in no isolates in the children-treated group at baseline or 1 year.
This cluster-randomized clinical trial demonstrated that compared to untreated control communities, nasopharyngeal pneumococcal resistance to macrolides was significantly higher in communities randomized to intensive azithromycin treatment. Mass azithromycin distributions were given more frequently than currently recommended by the World Health Organization's trachoma program. Azithromycin use in this setting did not select for resistance to penicillins, which remain the drug of choice for pneumococcal infections.
Trial registration NCT00322972
Please see later in the article for the Editors' Summary
Editors' Summary
In 1928, Alexander Fleming discovered penicillin, the first antibiotic (a drug that kills bacteria). By the early 1940s, scientists were able to make large quantities of penicillin and, in the following decades, several other classes of powerful antibiotics were discovered. For example, erythromycin—the first macrolide antibiotic—was developed in the early 1950s. For a time, it looked like bacteria and the diseases that they cause had been defeated. But bacteria rapidly become resistant to antibiotics. Under the “selective pressure” of an antibiotic, bacteria that have acquired a random change in their DNA that allows them to survive in the antibiotic's presence outgrow nonresistant bacteria. What's more, bacteria can transfer antibiotic resistance genes between themselves. Nowadays, antibiotic resistance is a major public health concern. Almost every type of disease-causing bacteria has developed resistance to one or more antibiotic in clinical use and multi-drug resistant bacteria are causing outbreaks of potentially fatal diseases in hospitals and in the community.
Why Was This Study Done?
Although epidemiological studies (investigations of the causes, distribution, and control of disease in population) show a correlation between antibiotic use and antibiotic resistance in populations, such studies cannot prove that antibiotic use actually causes antibiotic resistance. It could be that the people who use more antibiotics share other characteristics that increase their chance of developing antibiotic resistance (so-called “confounding”). A causal link between antibiotic use and the development of antibiotic resistance can only be established by doing a randomized controlled trial. In such trials, groups of individuals are chosen at random to avoid confounding, given different treatments, and outcomes in the different groups compared. Here, the researchers undertake a randomized clinical trial to assess whether macrolide resistance is higher in communities treated with azithromycin for trachoma than in untreated communities. Azithromycin—an erythromycin derivative—is used to treat common bacterial infections such as middle ear infections caused by Streptococcus pneumoniae. Trachoma—the world's leading infectious cause of blindness—is caused by Chlamydia trachomatis. The World Health Organization's trachoma elimination strategy includes annual azithromycin treatment of at-risk communities.
What Did the Researchers Do and Find?
In this cluster-randomized trial (a study that randomly assigns groups of people rather than individuals to different treatments), 12 Ethiopian communities received mass azithromycin treatment of children aged 1–10 years old at 0, 3, 6, and 9 months, and 12 control communities received the antibiotic only at 12 months. The researchers took nasopharyngeal (nose and throat) swabs from randomly selected treated children at 0 and 12 months and from randomly selected control children at 12 months. They isolated S. pneumoniae from the swabs and tested the isolates for antibiotic susceptibility. 70%–80% of the children tested had S. pneumoniae in their nose or throat. In the treated group, 3.6% of monitored children were carrying azithromycin-resistant S. pneumoniae at 0 months, whereas 46.9% were doing so at 12 months—a statistically significant increase. Only 9.2% of the monitored children in the untreated group were carrying azithromycin-resistant S. pneumoniae at 12 months, a significantly lower prevalence than in the treated group. Importantly, there was no resistance to penicillin in any S. pneumoniae isolates obtained from the treated children at 0 or 12 months; one penicillin-resistant isolate was obtained from the control children.
What Do These Findings Mean?
These findings indicate that macrolide resistance is higher in nasopharyngeal S. pneumoniae in communities receiving intensive azithromycin treatment than in untreated communities. Thus, they support the idea that frequent antibiotic use selects for antibiotic resistance in populations. Although the study was undertaken in Ethiopian communities with high rates of nasopharyngeal S. pneumoniae carriage, this finding is likely to be generalizable to other settings. Importantly, these findings have no bearing on current trachoma control activities, which use less frequent antibiotic treatments and are less likely to select for azithromycin resistance. The lack of any increase in penicillin resistance, which is usually the first-line therapy for S. pneumoniae infections, is also reassuring. However, although these findings suggest that the benefits of mass azithromycin treatment for trachoma outweigh any potential adverse affects, they nonetheless highlight the importance of continued monitoring for the secondary effects of mass antibiotic distributions.
Additional Information
Please access these Web sites via the online version of this summary at
The Bugs and Drugs website provides information about antibiotic resistance and links to other resources
The US National Institute of Allergy and Infectious Diseases provides information on antimicrobial drug resistance and on diseases caused by S. pneumoniae (pneumococcal diseases)
The US Centers for Disease Control and Prevention also have information on antibiotic resistance (in English and Spanish)
The World Health Organization has information about the global threat of antimicrobial resistance and about trachoma (in several languages)
More information about the trial described in this paper is available on
PMCID: PMC3001893  PMID: 21179434

Results 1-25 (29)