Harran Mkocha

Azithromycin in control of trachoma

The new Global Initiative by the World Health Organization has an ambitious goal of eliminating blinding trachoma by 2020, twenty years into the next millennium. GET 2020 consists of a four-pronged strategy to reduce active trachoma through community-based antibiotic distribution and health education on face washing and environmental sanitation, and to reduce vision loss from trichiasis through provision of appropriate surgical services. The SAFE strategy – Surgery, Antibiotics, Face-washing, Environmental change – is currently being implemented or planned for five pilot countries where the antibiotic component will be based on the drug azithromycin under a donation programme by Pfizer, Inc. Azithromycin represents a breakthrough for the community-based, antibiotic treatment of ocular Chlamydia trachomatis infection. Trachoma is a community disease, which clusters in neighbourhoods and within families, children having the highest rates of disease.1 Treatment of a few cases in such a setting guarantees re-infection from familial or neighbourhood sources, unless the treatment is more widespread. Moreover, re-infection from extra-ocular sites can occur if only topical treatment is used,2 and re-infection from other people can occur if treatment of members of the community is not carried out at the same time. Previously, topical agents, such as tetracycline, have been the agents of choice. This was done due to the absence of systemic side effects in children (seen with oral tetracycline) and the high cost and lack of availability of oral erythromycin in many of these remote communities. However, topical tetracycline must be used every day for four to six weeks to be effective. It also stings, is messy to use, and results in blurred vision because of its oily base. Compliance (regular use of the prescribed medicine) with topical agents is typically quite poor.

Strategies for control of trachoma: observational study with quantitative PCR

BACKGROUND Antibiotics are an important part of WHOs strategy to eliminate trachoma as a blinding disease by 2020. At present, who needs to be treated is unclear. We aimed to establish the burden of ocular Chlamydia trachomatis in three trachoma-endemic communities in Tanzania and The Gambia with real-time quantitative PCR. METHODS Conjunctival swabs were obtained at examination from 3146 individuals. Swabs were first tested by the qualitative Amplicor PCR, which is known to be highly sensitive. In positive samples, the number of copies of omp1 (a single-copy C trachomatis gene) was measured by quantitative PCR. FINDINGS Children had the highest ocular loads of C trachomatis, although the amount of pooling in young age groups was less striking at the site with the lowest trachoma frequency. Individuals with intense inflammatory trachoma had higher loads than did those with other conjunctival signs. At the site with the highest prevalence of trachoma, 48 of 93 (52%) individuals with conjunctival scarring but no sign of active disease were positive for ocular chlamydiae. INTERPRETATION Children younger than 10 years old, and those with intense inflammatory trachoma, probably represent the major source of ocular C trachomatis infection in endemic communities. Success of antibiotic distribution programmes could depend on these groups receiving effective treatment.

Infection with Chlamydia trachomatis after mass treatment of a trachoma hyperendemic community in Tanzania: a longitudinal study.

Summary Background Data from studies done in communities where trachoma is mesoendemic suggest that ocular infection with Chlamydia trachomatis can be eliminated after one mass treatment with antibiotics. However, there are no comparable long-term data from trachoma hyperendemic communities. Our aim, therefore, was two-fold: first, to ascertain the disease pattern of trachoma and ocular infection with C trachomatis in a trachoma hyperendemic community after mass treatment; and, second, to ascertain the risk factors for incident infection. Methods We did a longitudinal study of a trachoma hyperendemic community (n=1017) in Tanzania. We did surveys, including ocular swabs, at baseline, 2, 6, 12, and 18 months to identify the presence, and quantity, of C trachomatis after single mass treatment of all individuals aged 6 months or older with azithromycin 20 mg per kg; pregnant women without clinical disease received topical tetracycline. Findings Mass treatment (coverage 86%) significantly reduced the prevalence of infection from 57% (495 of 871) to 12% (85 of 705) at 2 months. Infection remained fairly constant to 12 months, with evidence of increasing numbers and load of infection by 18 months post-treatment. Incident infection at 6 months was 3·5-times more likely if another member of the household had more than 19 organisms per swab at 2 months. Travel outside the village, and visitors to the household, did not increase the risk of infection within households up to 12 months. Interpretation In this trachoma hyperendemic community, infection levels after high antibiotic coverage persisted at a low level to 18 months, with evidence for re-emergence after 1 year. Fairly light loads of infection were associated with household transmission. Yearly mass treatment over a few years could be sufficient to eliminate infection.

Progression of active trachoma to scarring in a cohort of Tanzanian children

Risk factors for the incidence of scarring are needed to inform trachoma control programs in countries hyperendemic for this blinding disease. A cohort of pre-school children with constant, severe trachoma, and an age, sex, and neighborhood matched cohort of children without constant severe trachoma were followed for seven years to determine the incidence of scarring. The incidence of scarring in the children with constant severe trachoma was 29.2% versus 9.6% in the comparison group. In a model adjusting for multiple factors, significant predictors of scarring were increasing age, female, and constant severe trachoma (OR = 4.85, 95% CL = 2.05, 11.40). Infection with C. trachomatis at follow up was also associated with scarring in both groups of children. It is likely that these children have a different host response to infection, and represent a subgroup at high risk for the blinding complications of trachoma. Reducing exposure to infection in the community through antibiotics and changes in hygiene practices is still the most promising control strategy.

Diagnosis of Chlamydia trachomatis eye infection in Tanzania by polymerase chain reaction/enzyme immunoassay

Detection of Chlamydia trachomatis eye infection is largely unsatisfactory by standard laboratory methods. A polymerase chain reaction/enzyme immunoassay (PCR-EIA) that had previously been successful for diagnosis of genital C trachomatis infection was compared with direct antibody immunofluorescence (DFA) for detection of the organism in conjunctival scrapes. 234 Tanzanian children aged 1-7 years living in a village that had had no previous trachoma control programme were classified clinically as having no sign of trachoma (0) n = 97, follicular trachoma (TF) n = 100, or intense inflammatory trachoma with or without TF (TI +/- TF) n = 37. PCR-EIA detected C trachomatis in 24%, 54%, and 95% of subjects, respectively, compared with elementary body (EB) detection by DFA of 1%, 28%, and 60%, respectively. Overall prevalence of chlamydial eye infection was 22% by DFA compared with 48% by PCR-EIA. Of subjects with chlamydial DNA at pretreatment, 103 (92%) had no detectable chlamydial DNA at the end of 4 weeks of ocular tetracycline. The findings show that PCR-EIA is likely to affect trachoma diagnosis and epidemiology because of the increased sensitivity for detection of C trachomatis in all clinical groups; the less stringent requirements for specimen collection and transport make this method suitable for field use. Moreover, the semi-quantitative aspect of PCR-EIA may be useful for monitoring a decrease in chlamydial DNA after treatment.

Evaluation of barriers to surgical compliance in the treatment of trichiasis

Purpose: Eyelid repair surgery can preventthe effects of trichiasis leading to visual loss.Cost, transportation difficulties, and familialresponsibilities have been identified as majorbarriers to surgical compliance. We evaluated whetheroffering trichiasis surgery in the village waseffective in increasing the rate of surgicalacceptance and in decreasing perceived barriers tosurgery. Methods: In 1989, 205 women withtrichiasis were identified in Central Tanzania andwere offered free surgery along with free transport. As of 1991, only 18% of these women had undergone thesurgery. We followed-up these women 7 years laterafter village level surgery was introduced.Results: Since 1991, an additional 12% ofthe women had undergone eyelid surgery. 44% wereconducted in the village. Surgical cases since 1991reported shorter travel times to the place of surgery,similar post-surgical problems, and fewer days in thehospital. While providing benefits to the patient,increased village eye services did not increase therate of surgical acceptance. The women who declinedsurgery did not know surgery in the village wasavailable and the perceived cost and transportationdifficulties continued to be barriers. 50% of thenon-acceptors stated that there was nothing that wouldenable them to accept surgical intervention despitethe fact that 3/4 of them reported eye symptoms thatinterfered with their daily activities.Conclusions: The cost efficacy of villagelevel eye services needs to be evaluated and theawareness of these services increased.

CT694 and pgp3 as Serological Tools for Monitoring Trachoma Programs

Background Defining endpoints for trachoma programs can be a challenge as clinical signs of infection may persist in the absence of detectable bacteria. Antibody-based tests may provide an alternative testing strategy for surveillance during terminal phases of the program. Antibody-based assays, in particular ELISAs, have been shown to be useful to document C. trachomatis genital infections, but have not been explored extensively for ocular C. trachomatis infections. Methodology/Principal Findings An antibody-based multiplex assay was used to test two C. trachomatis antigens, pgp3 and CT694, for detection of trachoma antibodies in bloodspots from Tanzanian children (n = 160) collected after multiple rounds of mass azithromycin treatment. Using samples from C. trachomatis-positive (by PCR) children from Tanzania (n = 11) and control sera from a non-endemic group of U.S. children (n = 122), IgG responses to both pgp3 and CT694 were determined to be 91% sensitive and 98% specific. Antibody responses of Tanzanian children were analyzed with regard to clinical trachoma, PCR positivity, and age. In general, children with more intense ocular pathology (TF/TI = 2 or most severe) had a higher median antibody response to pgp3 (p = 0.0041) and CT694 (p = 0.0282) than those with normal exams (TF/TI = 0). However, 44% of children with no ocular pathology tested positive for antibody, suggesting prior infection. The median titer of antibody responses for children less than three years of age was significantly lower than those of older children. (p<0.0001 for both antigens). Conclusions/Significance The antibody-based multiplex assay is a sensitive and specific additional tool for evaluating trachoma transmission. The assay can also be expanded to include antigens representing different diseases, allowing for a robust assay for monitoring across NTD programs.

Mass Distribution of Azithromycin for Trachoma Control Is Associated With Increased Risk of Azithromycin-Resistant Streptococcus pneumoniae Carriage in Young Children 6 Months After Treatment

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

Number of Years of Annual Mass Treatment With Azithromycin Needed to Control Trachoma in Hyper-endemic Communities in Tanzania

Background. The World Health Organization recommends mass treatment as part of a trachoma control strategy. However, scant empirical data from hyperendemic communities exist on the number of rounds of treatment needed to reach a goal of <5% prevalence in children. We determined the prevalence of trachoma and infection with Chlamydia trachomatis in communities after 3–7 years of annual mass treatment in Tanzania. Methods. Seventy-one communities with trachoma and annual azithromycin coverage data were enrolled. A cross-sectional survey of ≥100 randomly selected children aged <5 years in each community was performed. Children were examined for clinical trachoma, and swab samples were taken for determination of ocular C. trachomatis infection. Results. After 3 years of mass treatment, the prevalence of trachoma decreased in a linear fashion with number of years of mass treatment, whereas decreased prevalences of C. trachomatis infection were related to the extent of the previous year’s azithromycin coverage. Our model suggests that, for communities with baseline trachoma prevalence of 50% and annual treatment coverage of 75%, >7 years of annual mass treatment will be needed to reach a prevalence of trachoma of <5%. Conclusions  Country programs in trachoma-endemic regions must realistically expect that several years of annual mass treatment may be necessary to eliminate trachoma.

Intensive insecticide spraying for fly control after mass antibiotic treatment for trachoma in a hyperendemic setting: a randomised trial

BACKGROUND There are no data on the cumulative effect of fly control and antibiotic distribution on trachoma in hyperendemic communities. We sought to determine whether insecticide spray intervention after mass antibiotic treatment could reduce trachoma and ocular infection with Chlamydia trachomatis in hyperendemic neighbourhoods in Tanzania. METHODS We did a single-blind, randomised clinical trial in 16 neighbourhoods (balozi) in Kongwa, Tanzania. All children aged 1-7 years were enrolled, with 119 children in the eight balozi of the intervention group and 183 in the eight control balozi. Children were examined at baseline, 6 months, and 1 year for clinical trachoma and ocular C trachomatis infection. One dose of azithromycin was offered to all residents of both intervention and control balozi after the baseline survey. Households (and surrounding areas) in the intervention group were then sprayed with insecticide throughout the ensuing year and monitored for reductions in fly counts. This study is registered at ClinicalTrials.gov, number NCT00347763. FINDINGS The intervention balozi had significantly lower fly counts than controls at all monitored weeks (p<0.05), apart from weeks 7-9. The trachoma rate did not differ significantly in the intervention and control balozi at 6 months post-treatment (20%vs 33%, p=0.07), nor did it at 1 year (43%vs 44%, p=0.90). Infection with C trachomatis did not differ between groups at 6 months post-treatment (9%vs 7%, p=0.45). INTERPRETATION Intensive insecticide spraying reduced flies in the environment, but our results suggest that fly reduction after mass antibiotic treatment has no added benefit on reduction of trachoma.