Trachoma is the world's leading cause of preventable blindness, accounting for an estimated 15% of visual loss worldwide. 1 Although trachoma has disappeared from Western Europe and the United States, it remains endemic in parts of sub-Saharan Africa, Southeast Asia, Australia, and the Middle East. Many investigators feel that worldwide elimination of blinding trachoma may be an attainable goal. The World Health Organization (WHO), in association with nongovernmental organizations and national health services, has implemented a program to eliminate blinding trachoma by the year 2020. 2 The WHO's GET 2020 program (G lobal E limination of T rachoma by 2020) involves four control measures referred to as the SAFE strategy:3
- S urgery for trichiasis/entropion (in-turned eyelids and lashes)
- A ntibiotics to eliminate ocular chlamydia, the causative agent of trachoma
- F acial cleanliness to reduce transmission
- E nvironmental improvements (clean water, fly control, etc.)
Public health workers are relying on the antibiotic component, particularly single-dose oral azithromycin, to reduce the prevalence of ocular Chlamydia infection. Azithromycin is a macrolide antibiotic similar to erythromycin but with better bioavailability and tolerance, a longer half-life, and a broader spectrum of antimicrobial activity. 4 A single oral dose of azithromycin has been shown to be as effective as doxycycline (twice daily for 7 days) in the eradication of chlamydia from individuals with urogenital disease. 5–10 Azithromycin has also been shown to be effective against active trachoma. Individual infections can be successfully treated in the majority of cases with one to three doses of azithromycin, as has been shown in The Gambia, 11 Egypt, 12 and Saudi Arabia. 13 Studies have also shown a marked reduction in both clinically active trachoma and chlamydial infection at the community level in Tanzania, The Gambia, Egypt, and Nepal. 14,15
Determining whom to treat is difficult, as infections are not easily identified by clinical examination alone, and laboratory tests are expensive, time-consuming, and not readily available in trachoma-endemic areas. 16 In addition, successfully treated individuals may be reinfected by other members of the community who have not received treatment. 17 Therefore, antibiotic treatment is now commonly directed toward a large part of, if not an entire, community. Recent studies have supported this mass-treatment approach. 14,15
There is evidence that a single course of mass antibiotic administration can have a dramatic effect on the prevalence of active trachoma in a community. 14,15 However, because a single mass treatment with azithromycin will presumably not eradicate chlamydia in an entire population, a long-term treatment strategy must be designed. 18 This raises various questions: Will a single treatment be effective in reducing chlamydial infection permanently in a community? Can annual treatment eliminate chlamydia locally? Will annual treatment be required indefinitely to maintain a low level of endemicity? Can nonantibiotic interventions prevent infection from returning after mass antibiotic treatment? In this chapter, we will discuss four possible rationales for the antibiotic treatment component of the SAFE strategy.
Four Possible Rationales for Antibiotic Treatment
A single mass antibiotic distribution (Fig 1) may reduce the prevalence of infection below a threshold from which it is unable to return. Studies in Egypt, after three doses of azithromycin, have shown a marked reduction in chlamydia prevalence 1 year after mass treatment. 14 It is unclear whether this reduction will be sustained or whether disease will eventually return to pretreatment levels. Studies in Nepal have shown marked reductions in clinical trachoma and chlamydia by DNA amplification assays after a single azithromycin dose. 15,19 In some villages in Nepal, prevalence has not returned to pretreatment levels even 2 years after a single treatment. 20
Trachoma has been found to return more slowly into these communities than was predicted from mathematical models. 14,15,18 In fact, it is not clear from clinical surveys that trachoma ever returns to its previous level after a single treatment, even in the absence of face washing and fly control programs; no other significant public health measures were attempted in either the Egypt or Nepal studies. 14,15 The fact that we have not observed a return of infection to pretreatment levels does not in itself indicate that treatment has a long-term effect. We need to account for artifactual reasons for decline, including cohort aging, random fluctuation, seasonal effects, and regression to the mean of villages: For instance, in Egypt, only the highest-prevalence villages were chosen for the study so, if these prevalences were elevated at all owing to chance, we would expect a subsequent decrease. Nonetheless, such artifactual reasons may certainly account for small variations but are not enough to explain the observed success of treatment. Other than a lingering effect of antibiotics, another reason for a decline is that trachoma is known to disappear in the absence of trachoma programs. 21–23 A secular trend was clearly present in the Nepalese study. 20
Mass antibiotic treatments will lower trachoma prevalence, but disease may return to pretreatment levels. Periodic retreatments may be able to maintain a low prevalence of infection (Fig 2). 18 In this scenario, for example, prevalence returns to approximately 30% before the next annual treatment. Even though infection is not eradicated, communities will have a lower burden of infection on average. Although antibiotic treatments themselves may not eliminate trachoma, concomitant socioeconomic developments independent of the trachoma program could supply the additional benefit necessary to allow eventually complete eradication. Trachoma has clearly disappeared from many areas in the absence of organized control programs. 21,22 Trachoma was endemic to parts of Western Europe and the United States during the last century but has disappeared, presumably owing to socioeconomic development alone. 23
Mass, periodic antibiotic treatments may be able to eradicate chlamydia at a local level—for example, from communities (Fig 3). 18 In an Egyptian study, one set of azithromycin treatments reduced the prevalence of ocular chlamydia by more than 95%. 14 In a village in Nepal, three annual treatments reduced the prevalence of active trachoma from 39% to 4%. 15,20 Results such as these make local eradication of ocular chlamydia seem feasible with multiple annual azithromycin treatments.
After several mass treatments, the institution of hygienic and environmental improvements might prevent infection from returning to previous levels or might eliminate disease entirely (Fig 4A). As outlined earlier, community-wide antibiotic administration has been associated with marked decreases in trachoma prevalence. It is a fundamental assumption of the facial cleanliness and environmental improvement portions of the WHO SAFE strategy that nonantibiotic measures, such as fly control and face washing, will prevent transmission. However, it is unclear how large an effect these interventions will have on eliminating infection from a community or preventing infection from returning after antibiotic treatment. 24 If these do not have the necessary effect, then infection may return to near-pretreatment levels once antibiotics have been completed (see Fig 4B).
Despite common wisdom, there is little available evidence that any particular nonantibiotic intervention can reduce by a large amount the prevalence of chlamydial infection in a community. 24 Nonetheless, there is compelling anecdotal and circumstantial evidence that facial cleanliness is associated with trachoma elimination. 25–27 However, evidence that a face-washing program has a causative effect on infection is marginal; many studies lack controls or lack masked outcomes. 24 One well-designed interventional facial cleanliness study found that an intense facial cleanliness program had only a modest (and statistically insignificant) effect on clinically active trachoma. 28 This may be because trials such as this have relied on clinical activity as an outcome (although chlamydia infection itself may be a more sensitive indicator), because the full effect of such programs is not realized after only 1 year, or because face washing indeed has only a marginal effect on the prevalence of active trachoma.
There is circumstantial evidence that face flies (Musca sorbens) transmit trachoma. 29,30 Active trachoma tends to be higher in seasons with higher fly density. 31 Fluorescein dye was shown to spread from one child to another via flies. 30 Polymerase chain reaction has revealed evidence of Chlamydia trachomatis DNA on flies, although in fewer than 1% of flies tested in an endemic area. 20 One recent pilot study offers some intriguing results 32 : Active trachoma was reduced more in two villages with an intensive fly control program than in two nearby villages without fly control. This is encouraging, although the outcome was unmasked and it is difficult to compare such small numbers of villages statistically. 33 (If analyzed as a group-randomized trial, n would equal only 2 in each group). A well-designed fly control study involving multiple villages is now taking place in The Gambia to address this important issue. 20 It is not clear how much of a contribution facial cleanliness and environmental programs will need to provide to the antibiotic program to ensure trachoma elimination.
The WHO estimates that 500 million people are at risk for developing trachoma, and a global elimination program has already begun. 34 Pfizer, Inc. (New York, NY) has generously donated more than 2 million doses of azithromycin to Morocco, Nepal, Tanzania, and the Sudan, and has promised millions more to Ghana, Mali, Vietnam, and Niger. 20 Many nongovernmental organizations are devoting a great deal of resources to these trachoma programs as well.
Preliminary results have been encouraging. Initial surveys have shown that a single dose (or a course of three doses) of oral azithromycin distributed to a community is highly effective at reducing the prevalence of ocular chlamydial infection in trachoma-endemic communities. 14 However, this single treatment alone cannot be expected to eradicate infection, so antibiotic treatment must be repeated or supplemented with nonantibiotic measures in a comprehensive treatment plan. 18 Here we have presented several possible rationales for the distribution of antibiotics. Rationale 1, that a single treatment may have a lingering effect on the prevalence of chlamydia in a community, is not at all intuitive and seems optimistic. If nothing else in the community is changed, then we might expect the prevalence of infection to return to pretreatment levels. However, the few results available are encouraging and imply that such a lingering effect should not be ruled out 14,20 —it would be a tremendous boost to the program if this were the case. Rationale 2, that repeat annual mass antibiotic treatment be given until socioeconomic improvements reduce trachoma transmission, is somewhat discouraging. Such prolonged treatment is expensive and may result in increased concerns about side effects and drug resistance. Rationale 3, that chlamydial infection be eradicated locally with several annual mass treatments, may be theoretically possible but is untested. 18 Rationale 4, that antibiotics be used to reduce infection and that nonantibiotic measures be used to prevent infection from returning in a community, is promising: In fact, a large portion of trachoma control personnel prefer this rationale. It remains unclear, however, whether nonantibiotic measures can have the necessary effect. 24
These rationales can be tested in future studies. Such studies will need to evaluate ocular chlamydial infection itself, as the clinical examination can be misleading. 16 With community treatment programs, the unit of analysis should be the community, so an adequate number of villages needs to be evaluated to obtain sufficient statistical power. 33 Secular trends should be identified with appropriate control villages: If infection is disappearing in an area anyway, then the effect attributed to the control program may be exaggerated, and the same success may not be achieved in less fortunate areas. 20,21 The appropriate studies to validate a rationale for mass antibiotic distribution can be performed; in fact, these studies can be incorporated directly into existing trachoma control programs.
We would like to thank the Alta California Eye Research Foundation, Research to Prevent Blindness, Inc., and the National Institute of Allergy and Infectious Diseases (grant K08 AI 01441) for their generous support. We especially thank Ms. Joan Williamson for her assistance.
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