Azithromycin Distribution Research Articles

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.

Childhood Mortality in a Cohort Treated With Mass Azithromycin for Trachoma

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. 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. 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]). 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.

Antibiotic Selection Pressure and Macrolide Resistance in Nasopharyngeal Streptococcus pneumoniae: A Cluster-Randomized Clinical Trial

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. 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. www.ClinicalTrials.gov NCT00322972. Please see later in the article for the Editors' Summary.

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.

Estimation of effects of community intervention with Antibiotics, Facial cleanliness, and Environmental improvement (A,F,E) in five districts of Ethiopia hyperendemic for trachoma

AimsThe WHO recommends the SAFE (surgery, antibiotics, facial cleanliness and environmental improvement) strategy for trachoma control. We aimed to investigate the association between active trachoma and community intervention with antibiotics,...

Complete Local Elimination of Infectious Trachoma from Severely Affected Communities after Six Biannual Mass Azithromycin Distributions

To determine whether infectious trachoma can be completely eliminated from severely affected villages. Cross-sectional survey of 2 villages previously enrolled and monitored over 42 months as part of a larger, group-randomized clinical trial. A total of 758 individuals residing in 2 villages with high baseline trachoma prevalence, of a total population of 768 (98.7%). 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. Clinical activity by World Health Organization simplified grading scale for trachoma and laboratory evidence of chlamydial RNA. 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. Biannual mass distribution of azithromycin can locally eliminate ocular chlamydial infection from severely affected communities.

Effect of Mass Distribution of Azithromycin for Trachoma Control on Overall Mortality in Ethiopian Children

Mass oral azithromycin distribution to affected communities is a cornerstone of the World Health Organization's trachoma elimination program. Antibiotics are provided to target the ocular strains of chlamydia that cause trachoma, but may also be efficacious against respiratory disease, diarrhea, and malaria--frequent causes of childhood mortality in trachoma-endemic areas. To compare mortality rates of participants aged 1 to 9 years in treated communities with those in untreated communities. We conducted a cluster-randomized clinical trial of mass azithromycin administration for trachoma control. Forty-eight communities (known as subkebeles) were randomized into 1 of 3 treatment schedules (annual treatment of all residents [15,902 participants], biannual treatment of all residents [17,288 participants], or quarterly treatment of children only [14,716 participants]) or into 1 group for which treatment was delayed by 1 year (control, 18,498 participants). Twelve subkebeles were randomized to each of the 4 schedules with all children in each of the 3 communities being eligible for treatment. The trial was conducted in a field setting in rural Ethiopia, May 2006 to May 2007. A single dose of oral azithromycin (adults, 1 g; children, 20 mg/kg) was administered for treatment of ocular Chlamydia trachomatis infection. Antibiotic coverage levels for children aged 1 to 9 years exceeded 80% at all visits. The main outcome measure was the community-specific mortality risk for children aged 1 to 9 years over the course of 1 year. Mortality was measured by enumerative census at baseline and again after 1 year. Comparison of the risk of mortality was a prespecified outcome for the clinical trial. The odds ratio for childhood mortality in the intervention communities was 0.51 (95% confidence interval, 0.29-0.90; P = .02; clustered logistic regression) compared with the control group. In the treated communities, the estimated overall mortality rate during this period for children aged 1 to 9 years in the untreated group was 8.3 per 1000 person-years (95% confidence interval, 5.3-13.1), while among the treated communities, the estimated overall mortality rate was 4.1 per 1000 person-years (95% confidence interval, 3.0-5.7) for children aged 1 to 9 years. In a trachoma-endemic area, mass distribution of oral azithromycin was associated with reduced mortality in children. clinicaltrials.gov Identifier: NCT00322972.

When Can Antibiotic Treatments for Trachoma Be Discontinued? Graduating Communities in Three African Countries

BackgroundRepeated 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.MethodsA 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.ResultsThe 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.ConclusionModels 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.

Assessment of herd protection against trachoma due to repeated mass antibiotic distributions: a cluster‐randomised trial

. House J. I., Ayele B., Porco T. C., Zhou Z., Hong K. C., Gebre T., Ray K. J., Keenan J. D., Stoller N. E. &amp; Whitcher J. P. ( 2009 ) , 373 , 1111 – 1118 . Background Trachoma‐control programmes distribute oral azithromycin to treat the ocular strains of chlamydia that cause the disease and to control infection. Theoretically, elimination of infection is feasible if untreated individuals receive an indirect protective effect from living in repeatedly treated communities, which is similar to herd protection in vaccine programmes. We assessed indirect protection against trachoma with mass azithromycin distributions. Methods In a cluster randomized trial, 24 subkebeles (government‐defined units) in Amhara, Ethiopia, were randomized, with use of a simple random sample, to distribution four times per year of single‐dose oral azithromycin to children aged 1–10 years (12 subkebeles, 4764 children), or to delayed treatment until after the study (control; 12 subkebeles, 6014 children). We compared the prevalence of ocular chlamydial infection in untreated individuals 11 years and older between baseline and 12 months in the treated subkebeles, and at 12 months between the treated and control subkebeles. Healthcare and laboratory personnel were blinded to study group. Analysis was intention to treat. The study is registered with clinicaltrials.gov, number NCT00322972. Findings At 12 months, 637 children aged 1–10 years and 561 adults and children aged 11 years and older were analysed in the children‐treated group, and 618 and 550, respectively, in the control group. The mean prevalence of infection in children decreased from 48.4% (95% CI 42.9–53.9) to 3.6% (0.8–6.4) after four mass treatments. At 12 months, the mean prevalence of infection in the untreated age group (≥11 years) was 47% (95% CI 33–57) less than baseline (P= 0.002), and 35% (95% CI 1–57) less than that in untreated communities (P= 0.04). Interpretation Frequent treatment of children, who are a core group for transmission of trachoma, could eventually eliminate infection from the entire community. Herd protection is offered by repeated mass antibiotic treatments, providing a strategy for elimination of a bacterial disease when an effective vaccine is unavailable.

Assessment of herd protection against trachoma due to repeated mass antibiotic distributions: a cluster-randomised trial

Trachoma-control programmes distribute oral azithromycin to treat the ocular strains of chlamydia that cause the disease and to control infection. Theoretically, elimination of infection is feasible if untreated individuals receive an indirect protective effect from living in repeatedly treated communities, which is similar to herd protection in vaccine programmes. We assessed indirect protection against trachoma with mass azithromycin distributions. In a cluster randomised trial, 24 subkebeles (government-defined units) in Amhara, Ethiopia, were randomised, with use of a simple random sample, to distribution four times per year of single-dose oral azithromycin to children aged 1-10 years (12 subkebeles, 4764 children), or to delayed treatment until after the study (control; 12 subkebeles, 6014 children). We compared the prevalence of ocular chlamydial infection in untreated individuals 11 years and older between baseline and 12 months in the treated subkebeles, and at 12 months between the treated and control subkebeles. Health-care and laboratory personnel were blinded to study group. Analysis was intention to treat. The study is registered with clinicaltrials.gov, number NCT00322972. At 12 months, 637 children aged 1-10 years and 561 adults and children aged 11 years and older were analysed in the children-treated group, and 618 and 550, respectively, in the control group. The mean prevalence of infection in children decreased from 48.4% (95% CI 42.9-53.9) to 3.6% (0.8-6.4) after four mass treatments. At 12 months, the mean prevalence of infection in the untreated age group (>/=11 years) was 47% (95% CI 33-57) less than baseline (p=0.002), and 35% (95% CI 1-57) less than that in untreated communities (p=0.04). Frequent treatment of children, who are a core group for transmission of trachoma, could eventually eliminate infection from the entire community. Herd protection is offered by repeated mass antibiotic treatments, providing a strategy for elimination of a bacterial disease when an effective vaccine is unavailable. National Institutes of Health.

Reduction and Return of Infectious Trachoma in Severely Affected Communities in Ethiopia

BackgroundAntibiotics 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.MethodsSixteen 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.FindingsThe 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.ConclusionIn 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 RegistrationClinicalTrials.gov NCT00221364

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.

Longitudinal evaluation of three azithromycin distribution strategies for treatment of trachoma in a sub-Saharan African country, Mali

Objectives Trachoma, caused by repeated ocular infections with Chlamydia trachomatis is an important cause of blindness. Mass azithromycin distribution is part of current recommended strategies for controlling trachoma. In order to ascertain an efficient strategy model at an acceptable cost, an intervention study was conducted in Mali between May 2000 and February 2002. Methods Three azithromycin administration strategies were evaluated: mass community-based treatment of all residents (strategy I), treatment of all children under 11 years of age and of women between 15 and 50 (strategy II), and treatment targeted to inhabitants of households where at least one child had clinically active trachoma diagnosed (strategy III). In a particular Malian area in which trachoma was known to be mesoendemic, three villages were selected for each of the three strategies. According to the strategy allocation, adults were eventually given a single dose of 1 g azithromycin, and children a unique dose of 20 mg/kg. Moreover, cleanliness and washing of children's faces were assessed, and additional questions were addressed about education, environmental and socio-economic conditions for each household at baseline. Ophthalmic examination was performed at baseline and 1, 6 and 12 months after inclusion. The outcome variable was clinically active trachoma frequency 12 months after intervention among children under 11 years of age. A descriptive analysis was performed, and then logistic regression models were built to test the efficiency of the three strategies. Results Among children under 11 years of age, the active trachoma prevalence fell dramatically in each strategy, from 23.7% to 6.4% in strategy I, from 20.8% to 6.8% in strategy II, and from 20.2% to 8.5% in strategy III. After adjustment on age (adjusted odds ratio [AOR] = 0.81; 95% confidence interval [95% CI]: 0.75–0.87) and on active trachoma occurrence at baseline (AOR = 3.81; [95% CI]: 2.70–5.39), the multiple logistic regression model showed that both strategies I and II gave similar results, while strategy III appeared significantly less effective (AOR = 1.56; [95% CI]: 1.00–2.43). Conclusion In mesoendemic trachoma areas, targeted treatment to all children under 11 years of age and women between 15 and 50 (strategy II) was as effective as indiscriminate mass distribution (strategy I) and more effective than treatment targeted to inhabitants of households where at least one child had active trachoma diagnosed (strategy III). Strategy II could therefore reduce the prevalence and intensity of trachoma infection at a lower cost than mass community-based treatment of all residents (strategy I).

Effect of a Single Mass Antibiotic Distribution on the Prevalence of Infectious Trachoma

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. 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. 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. A single dose of oral azithromycin was offered to all residents of the 8 selected villages who were aged 1 year or older. 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. 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). 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.

Impact of azithromycin administration for trachoma control on the carriage of antibiotic-resistant Streptococcus pneumoniae.

Community distribution of azithromycin has an important role to play in trachoma control. Previous studies have suggested that this may increase the prevalence of macrolide-resistant Streptococcus pneumoniae. S. pneumoniae was isolated from children under 7 years of age in Rombo District, northern Tanzania, before and 2 and 6 months after community-wide administration of azithromycin. Overall carriage rates were 11, 12, and 7%, respectively. Only one macrolide-resistant isolate carrying the mef gene was obtained 6 months after azithromycin administration. This contrasted with cotrimoxazole and penicillin resistance, both of which were common (cotrimoxazole resistance, 42, 43, and 47%, and penicillin resistance, 21, 17, and 16% at baseline, 2 months, and 6 months, respectively). There was a significant association between cotrimoxazole and penicillin resistance (P < 0.0001, Fisher's exact). These data suggest that in communities where macrolide resistance is rare, azithromycin distribution for trachoma control is unlikely to increase the prevalence of resistant organisms.

Pattern of antibiotic use in a trachomaendemic region of Nepal: implications for mass azithromycin distribution

Purpose To investigate antibiotic utilization in a rural district of western Nepal that is currently receiving azithromycin as part of a trachoma program and is being monitored by the Centers for Disease Control and Prevention (CDC) for drug resistance. Methods Antibiotic purchase receipts were collected for 3 months from all medicine halls, pharmacies, and government sub-health posts in a sub-district of Western Nepal. Supplementary surveys of antibiotic sales were performed in different seasons. Results Macrolides account for 3.9% of total antibiotic use, far less than quinolones, penicillins, tetracyclines, and sulfonamides. Conclusions If trachoma programs in Western Nepal generate transient macrolide resistance in pneumococcus and other bacteria, the epidemiological impact may not be great, as macrolides are not commonly used in the area.