Prospects for the Control of Neglected Tropical Diseases by Mass Drug Administration

Henk L. Smits


Expert Rev Anti Infect Ther. 2009;7(1):37-56. 

In This Article


Etiology of Trachoma

Trachoma is a chronic follicular keratoconjunctivitis caused by repeated eye infection with the intracellular bacterium C. trachomatis of, in particular, the tarsal conjunctiva underlying the upper eyelid.[158,159] In endemic communities, the pathogen is spread from eye to eye by flies (Musca sorbens) contaminated fingers and human secretions. These repeated infections produce scarring and lead to the inwards turning of the eyelashes (trichiasis), which causes, in addition to constant discomfort, damage of the corneal surface, corneal opacification and may, eventually, result in blindness. The prevalence of active trachoma is often higher than 20% and may approach 100% in some areas of intense transmission.[160] In endemic areas, trachomatous trichiasis may be observed in 10% of people aged 40 years and over and bilateral trachomatous trichiasis may be responsible for 10–40% of all blindness.[161]

MDA for Trachoma

The infection may be treated by topical application of antibiotics. However, compliance in self-administration of eye ointments is low because they are difficult to apply, sting and temporarily blur vision. Therefore, the use of eye ointments is not recommended for the control of trachoma. Ocular chlamydial infection may also be treated with a single oral dose of AZM,[162,163,164] and when the drug is administered to an entire community it is possible to reduce the prevalence of infection to a low level, provided that the administration of the drug is accompanied with a set of specific measures.[14,162,165,166,167] The recommended strategy for the prevention of blinding trachoma relies on the annual administration of one oral dose of AZM (20 mg/kg bodyweight to a maximum of 1 g) in combination with trichiasis surgery (to prevent eyelashes from damaging the cornea), improved hygiene and sanitation (to reduce the risk of infection and the number of flies, and to contain the spread of the infection) and health education.[168,169] This strategy is called SAFE, 'S' stands for corrective eyelid surgery, 'A' for antibiotics for treatment of individuals with signs of active disease and MDA to at-risk communities, 'F' for facial cleanliness hygiene promotion and 'E' for environmental improvements, such as provision of sanitation and water. These measures are primarily intended to minimize discomfort (by surgery) and to control the infection by disrupting transmission and prevention of new infections. A review of the literature has demonstrated that surgery for trichiasis does not prevent blindness, even if AZM is administered at the time of surgery, and while antibiotic treatment has only a modest effect on the development of active trachoma, neither does face washing or fly control by spraying or provision of latrines.[170,171,172,173] Health education might be effective,[174] and seems to be essential to increase participation and to take away prejudices and fears for surgery. However, by controlling the pathogen and prevention of its transmission and spread the number of new cases is strongly reduced. The control of trachoma by SAFE is recommended for all eligible individuals in areas where the prevalence of the clinical sign 'trachomatous inflammation follicular' is at least 10%, and in areas where the prevalence is lower than 10% for those communities with a prevalence of at least 10%.[175,176] The SAFE policy was first started less than a decade ago and has been very successful. For instance, by implementing the SAFE strategy between 1997 and 1999, Morocco has virtually eliminated the disease. In 1992, approximately 5.4% of the population of this country showed signs of trachoma with almost all cases concentrated in five arid and rural provinces. SAFE was applied in a staged approach with annual treatment of everyone in areas with more than 20% of children under 10 years of age showing signs of active trachoma. In areas where infection rates were lower, treatment was focused on affected children and their families, and in areas where the level of infection was less than 10%, cases were treated individually. This strategy has resulted in a 99% reduction of active trachoma in children in a period of less than 6 years. In 2010, it is expected that trachoma will be controlled in several other countries, including the Gambia, Ghana, Mauritania and Vietnam, and other countries will probably follow in subsequent years. The trachoma situation probably is worst in Ethiopia in which almost the entire rural population, approximately 65 million people, is at risk.[31]

Evaluation of the SAFE strategy has demonstrated that, in general, the coverage of drug administration is acceptable but that the quality and quantity of surgery is inadequate.[177] Furthermore, the scarcity of good-quality water supplies often hampers improvement of personal hygiene. Although the elimination of the infection from a village as demonstrated in Nepal and Tanzania[168,169] is possible, the infection, unfortunately, tends to return over time.[165,166,176,178,179] Mathematical modeling has indicated that, in a country-wide approach, depending on the prevalence of infection, elimination from a large proportion of communities is feasible in a period of 5 years provided that treatment coverage is at least 90% and the treatment is administered biannually.[180] However, the model also indicated that in hyperendemic areas and with the WHO recommended coverage of 80%, elimination would take at least 12 years. Beside coverage, several factors may influence the effectiveness of the SAFE strategy. It has been found that MDA strongly reduces the number of face flies that are infected,[181] and this might be an essential factor in the interruption of transmission and elimination of the infection. Individuals who did not receive the drug during MDA have a reduced chance of becoming infected, indicating that a single dose already reduces transmission.[182] However, a single dose of AZM may not be sufficient to clear the infection from sites other than the eye, and it was demonstrated that children with a chlamydial-positive nasal discharge at the time of drug administration had an increased risk for ocular reinfection with the same pathogen.[183] Such extraocular sites could be important sources of chlamydial eye infections through direct transfer by fingers or via clothes, bed sheets or towels. Furthermore, waning immunity may make communities more susceptible to reinfection after successful MDA.[184]

Clinically active trachoma has disappeared almost completely from some villages in Western Nepal, and it has been argued that the elimination of the infection is only in part the result of the antibiotic treatment programs that had been in place.[185] It was noted that, in these villages, no specific attempts were made to improve hygiene and sanitation, such as building of pit toilets or building water supplies as measures for fly control and to improve facial cleanliness. Other secular effects, such as increases in economic prosperity or, perhaps, education, may have helped to eliminate the disease. A reduction in the prevalence of active trachoma has also been noted in a village in The Gambia long after a modest antibiotic administration program was completed and in a district in Malawi in the absence of organized distribution of antibiotics.[186,187] Most probably, general improvements in the standard of living had contributed to the observed reduction of trachoma. Recent economic development and improved living conditions may also have contributed to some extent to the success of the SAFE program in Morocco. The prevalence of active trachoma was reduced significantly by MDA in communities in rural Ethiopia.[188] However, it is increasingly recognized that in areas with extreme poverty, trachoma remains a substantial health problem after MDA and that major educational and environmental improvements are crucial to control the infection in particular in such areas.[189] After MDA, children with ocular discharge and the presence of flies are risk factors for active trachoma and, hence, children remain an important target group in communities that already have received MDA. To increase the effect of the SAFE strategy, biannual MDA may be considered in high-risk areas; after 2 years of biannual MDA, ocular chlamydial infection was observed in only one out of eight rural communities in Ethiopia compared with six out of eight after annual treatment.[190]

Drug Resistance

In spite of the enormous number of people that have received treatment, no evidence of emerging drug resistance has been presented; a single study performed in Tanzania did not reveal any evidence of reduced AZM or tetracycline susceptibility.[191] Drug resistance in Chlamydiae is very rare, and resistance to macrolides particularly seems to be difficult to induce in vitro .[192] Macrolide drug resistance in organisms with single copies of the rRNA genes in their genome, such as Chlamydia , usually arises by mutations in 23S rRNA at the antibiotic contact site but other mechanisms, such as mutations in the ribosomal binding proteins, may be involved as well. Mutations in the 23S rRNA have been demonstrated to occur in some rare Chlamydia pneumoniae isolates and these were associated with high-level resistance.[193,194]

Given the profound impact of blindness on physical and social well-being as well as on the economic prospects of individuals, their relatives and communities in which they live and the considerable improvement that relatively small but apparently crucial changes may have on the prevalence of trachoma, urgent efforts should be taken to realize such changes in the communtities that are the most affected.