Antibiotics for trachoma

  • Review
  • Intervention

Authors


Abstract

Background

Trachoma is the world's leading cause of preventable blindness. In 1997 the World Health Organization launched an initiative on trachoma control based on the 'SAFE' strategy (surgery, antibiotics, facial cleanliness and environmental improvement).

Objectives

To assess the evidence supporting the antibiotic arm of the SAFE strategy by assessing the effects of antibiotics on both active trachoma (primary objective) and on Chlamydia trachomatis infection of the conjunctiva (secondary objective).

Search strategy

We searched the Cochrane Central Register of Controlled Trials - CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library Issue 1, 2005), MEDLINE (1966 to February 2005), and EMBASE (1980 to February 2005). We used the Science Citation Index to look for articles that cited the included studies. We searched the reference lists of identified articles and we contacted authors and experts for details of further relevant studies.

Selection criteria

We included only randomised trials that satisfied either of two criteria: (a) trials in which topical or oral administration of an antibiotic was compared to placebo or no treatment in people with trachoma, (b) trials in which a topical antibiotic was compared with an oral antibiotic in people with trachoma. A subdivision of particular interest was of trials in which topical tetracycline/chlortetracycline was compared with oral azithromycin, as these are the two World Health Organization recommended treatments.

Data collection and analysis

Two authors independently assessed trial quality and extracted data. We contacted investigators for missing data.

Main results

We found 15 studies that randomised a total of 8678 participants. For both outcomes (active trachoma and laboratory evidence of infection) the results of the chi squared tests suggested that there was significant statistical heterogeneity among the trials. There was also marked clinical heterogeneity. No summary statistics were calculated and we therefore present a narrative summary of the results. For the comparisons of oral or topical antibiotic against placebo/no treatment, the data are consistent with there being no effect of antibiotics but are suggestive of a lowering of the point prevalence of relative risk of both active disease and laboratory evidence of infection at three and 12 months after treatment. For the comparison of oral against topical antibiotics the results suggest that oral treatment is neither more nor less effective than topical treatment.

Authors' conclusions

There is some evidence that antibiotics reduce active trachoma but results are not consistent and cannot be pooled.

Plain language summary

Antibiotics for the treatment of trachoma

Trachoma is the most common cause of preventable vision loss and is common in children living in poor communities. Repeated bouts of conjunctivitis (inflammation of the membranes of the eyes) caused by chlamydia infection eventually lead to scarring and inturning of the eyelid. The lashes rub on the cornea causing opacification and blindness. Antibiotics can be used to treat the chlamydia infection and may be given in an ointment or as a tablet. The review found some evidence that antibiotics reduce trachoma. Ointment is neither better nor worse than tablets.

Background

Trachoma is the world's leading cause of preventable blindness and is second only to cataract as an overall cause of blindness (Thylefors 1995). Active trachoma affects an estimated 150 million people, the majority of them children. About 5.5 million people are blind or at risk of blindness as a consequence of trachoma. It is a disease of poverty and is associated with poor water supplies and sanitation.

There are two phases of trachoma. In the first phase, infancy and childhood, there are repeated attacks of conjunctivitis caused by the organism Chlamydia trachomatis. The conjunctivitis is characterised as active trachoma by the presence of follicles on the under surface of the upper eyelid and by vascular changes. Active trachoma is associated with discharge from the eyes and nose that is particularly noticeable on the faces of children, but the active stage may also be asymptomatic in children and adults. The clinical signs of active trachoma are caused by infection with Chlamydia trachomatis. The symptoms may persist for months after the infection is cleared.

The Chlamydia trachomatis organism is transmitted from child to child through close personal contact. Fingers and household cloths are amongst the carriers. Flies are often found clustered on the moist discharges from the eyes and nose, and their role in spreading the infection has been questioned (Brechner 1956). It has been suggested that fly control by various environmental interventions can reduce trachoma transmission. Insecticide spraying, placement of latrines and animal corralling are possible means of control. As the dirty faces of children are a source of the organism Chlamydia trachomatis, various face-washing strategies have also been suggested to reduce the prevalence of active disease.

Repeated conjunctival infections over a number of years lead to scarring and shortening of the upper eyelid, with the lashes rubbing the cornea, causing pain and blindness through corneal opacification. The blinding phase affects women more commonly than men and starts in early adult life. The treatment at this stage is surgery to reposition the eyelid margin.

Active trachoma has been treated with antibiotics since the 1950s and a variety of regimens have been used. The antibiotic can be applied directly to the conjunctiva (topically) or taken orally (systemic antibiotics). Antibiotics applied topically are usually in the form of an ointment and a variable amount is squeezed onto the inner surface of the lower eyelid. This route gives a high concentration of the antibiotic to the conjunctiva but low doses to the nasopharynx, which is also a reservoir for the organism. Ointments may cause stinging eyes and temporary blurred vision and they are difficult to apply to small children. The World Health Organization (WHO) recommended topical treatment is 1% tetracycline ointment twice daily for six weeks, or on five consecutive days each month for six months. Compliance with this treatment is poor due to the side effects of the ointment and the length of the treatment programme.

Oral treatment gives a higher dose of antibiotic to sites of infection outside of the eye, but systemic antibiotics can have various adverse effects in the person taking them, and other pathological bacteria may develop resistance to the antibiotics. The full course of oral treatment has a higher compliance rate than a directly supervised course of topical antibiotic.

The WHO recommended oral antibiotic is azithromycin, as a single dose of one gram in adults and 20 milligrams/kilogram of body weight (mg/kg) in children. Azithromycin has low plasma levels but high intracellular concentrations and a long half-life and has been shown to be an effective treatment of genital chlamydial infections. The recommended antibiotic for use in pregnancy is erythromycin at a dose of 250 mg four times a day for four weeks.

Efforts in trachoma control have used various antibiotic treatment regimens and have also been aimed at different subgroups within the trachoma endemic area for example diseased cases only (detected actively or passively), active cases and family contacts, and high-risk groups including school children. It has been suggested that trachoma control cannot be achieved by antibiotic treatment given only to subgroups in a trachoma endemic community (Bailey 1993a; Kamiya 1956; Sutter 1983). This led to the concept of community based interventions, in which all residents of a community should receive treatment irrespective of disease status.

The desired primary endpoint of any intervention against active disease is reduction of blindness but this can only be demonstrated 20 to 30 years after the start of the intervention. The usual surrogate outcome measure in intervention trials is clinically active disease. In some trials a secondary endpoint is laboratory evidence of Chlamydia trachomatis.

International interest in trachoma was given a boost in 1997 when the WHO launched a new initiative on trachoma control based on the 'SAFE' strategy. The components giving their name to the acronym are surgery, antibiotics, facial cleanliness and environmental improvement. Cochrane systematic reviews on face washing (Ejere 2004) and environmental sanitary interventions (Rabiu 2005) have already been completed.

Objectives

The aim of this review is to assess the evidence in relation to the antibiotic arm of the SAFE strategy by assessing the effects of antibiotics on both active trachoma (primary objective) and on Chlamydia trachomatis infection (secondary objective). In particular we aimed to investigate the strength of evidence that antibiotics are more effective than placebo in reducing disease and to compare the effects of oral azithromycin with topical tetracycline.

Methods

Criteria for considering studies for this review

Types of studies

This review includes only randomised controlled trials of antibiotic treatment for active trachoma. Clinical and public health trials are included in this review. In clinical trials the unit of randomisation is the individual with active trachoma and outcomes reported at an individual level. In public health trials the unit of randomisation is a community, in which some individuals have active trachoma and outcomes may be reported at an individual or at a community level.

Types of participants

Participants in the trials were people who are usually resident in a trachoma endemic area.

Types of interventions

We included trials in which the interventions were:

(1) topical or oral administration of an antibiotic at any dose or frequency compared to placebo or no treatment;
(2) topical administration of an antibiotic at any dose or frequency compared to oral administration of an antibiotic at any dose or frequency.

Studies were excluded if the antibiotic was combined with an environmental or educational intervention unless this component was used uniformly across the trial and only the antibiotic treatment varied in the different groups.

Types of outcome measures

Primary outcomes

The primary outcome for this review is active trachoma. Five trachoma grading scales have been identified (Dawson 1975b; Dawson 1981b; MacCallan 1936 ;Thylefors 1987; WHO 1962). All the scales, except for MacCallan, quantify the number of follicles and the degree of vascular engorgement of the under surface of the upper eyelid as seen with a low magnification (usually x2.5). The Dawson scales subdivided the follicular and papillary activity as F 0-3 and P 0-3. The Thylefors scale is a simplified version defining active trachoma by the grades TF (mild-moderate) and TI (intense) and this can be directly calculated from the F and P scales. The MacCallan scale is not directly comparable with the later scales as scarring is included as an indicator of active disease. The subsequent scales are comparable and the only minor inconsistency between the scales is that F1 is defined as five or fewer follicles in zones two and three, whereas Not TF is fewer than five follicles in zones two and three.

In this review the absence of active trachoma is defined as:

  • Not TF and Not TI - Thylefors

  • P0 or P1 or P2; F0 or F1 - WHO and Dawson scales

Active trachoma is defined as any other trachoma grade in any of the four scales.

Secondary outcomes

The secondary outcome was a positive test for Chlamydia trachomatis infection. A variety of tests to demonstrate presence of the pathogen has been used. Staining of conjunctival cells to show inclusion bodies was the first method of identifying infection. This was followed by culture of the organism, which was time consuming and lacking in sensitivity. The demonstration of antigen by various antibody staining methods followed, and finally identification of chlamydial DNA by various amplification methods. The tests in order of increasing sensitivity are:

(1) culture by Chlamydia trachomatis isolation in eggs or tissue culture;
(2) staining of conjunctival smears with giemsa, iodine or immunofluorescent;
(3) direct fluorescent antibody cytology;
(4) indirect enzyme immunoassay;
(5) DNA hydridisation;
(6) DNA amplification on conjunctival swab specimen with the ligase chain reaction;
(7) polymerase chain reaction, plasmid and chromosome based.

Adverse side effects were recorded if reported.

Outcomes were measured at three, 12 and 24 months after the start of treatment. Three months is the time at which the maximum effect on active trachoma is expected, given that clinical signs take several months to resolve after the clearance of infection. Twelve months was selected to represent the period during which recurrence or relapse of infection would be most likely to occur, and 24 months was selected to reflect the expected long-term result of one course of treatment. A course of treatment may be a single or multiple doses of an oral antibiotic, or interrupted applications of a topical antibiotic applied over several months.

In order to take into account the fact that studies may not have collected outcomes at those exact times the following ranges were defined for each:

  • 3 months: outcomes measured before six months

  • 12 months: outcomes measured between six months and 18 months

  • 24 months: outcomes measured after 18 months.

If more than one outcome was available then the nearest to three, 12 or 24 months was selected.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials - CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register), MEDLINE and EMBASE. There were no date or language restrictions.

See: Appendices for details of search strategies for each database.

Searching other resources

We used the Science Citation Index to search for articles that cited the included studies. We also contacted experts in the field either directly or through the membership of the WHO workshops, requesting information on unpublished trials.

Data collection and analysis

Selection of trials

One author assessed the titles resulting from the initial searches and selected all titles that made reference to treatment for trachoma. When the review was updated, two authors screened the search results. The searches found references to genital Chlamydia trachomatis infections and to laboratory tests on Chlamydia trachomatis. Titles that clearly referred to either of these groups were excluded at the first viewing. The full copies of all possibly relevant papers were obtained and assessed independently by both authors according to the 'Criteria for considering studies for this review'. Trials meeting these criteria were assessed for quality.

Quality assessment

Trial quality was assessed according to methods set out in section six of the Cochrane Reviewers' Handbook and the Cochrane Eyes and Vision Group Review Development Guidelines. Trials were scored A - Adequate, B - unclear or C - inadequate on allocation concealment. Trials scoring C were excluded. This included trials in which the allocation was entirely transparent before allocation such as alternation, case record numbers, dates of birth or days of the week.

The validity of included trials was assessed on performance, detection and attrition bias. Performance bias related to whether the recipients of care were unaware of their assigned treatment and whether persons providing care were unaware of the assigned therapy. Detection bias related to whether the persons responsible for the outcome assessments were unaware of the assigned therapy. Attrition bias related to whether the follow-up rates were similar for the groups and if there was an intention-to-treat analysis. Each modality was graded as yes, no or unable to determine. The final validity rating was A - low risk of bias if there was a yes response to all questions, B - moderate risk of bias if there was a no response to one question and C - high risk of bias if there was a no response to two or more questions.

Authors of papers were contacted if results were not reported in a usable form or for cluster-randomised trials when individual patient data were required.

Data collection

Both authors independently extracted data. Discrepancies were resolved before entry into Review Manager (RevMan) 4.2.

Data synthesis

Trials randomised by cluster required additional attention in the analysis. It has been shown that there is a tendency for people within a cluster to be more similar to each other than they are to those in different clusters (Bland 1997). The effect of cluster-randomisation is to increase the size of standard errors and hence widen the confidence intervals compared with a study of the same size using individual participant randomisation (Donner 1982). The result is that there is generally less information per person in a cluster-randomised trial than in an individually randomised trial. Viewed another way, the effective sample size is generally less than the number of individuals. To obtain the effective sample size, the number of individuals must be reduced by a factor that depends on the intraclass correlation coefficient (r) (Kerry 1998). The intraclass coefficient lies between zero and one and measures the mutual similarity of people within a cluster. At one extreme, if r equals zero, there is no clustering and the effective sample size is the same as the number of individuals. At the other extreme, if r equals one then the effective sample size is the same as the number of clusters (Hauck 1991).

The intraclass correlation coefficient was calculated for any cluster-randomised studies for which individual level data were available. A range of values for r was obtained. Sensitivity analyses could be performed varying r over its range.

Outcomes from community-based trials in which non-affected and affected cases were treated were pooled with outcomes from individual-based trials, in which only affected cases were treated. A sensitivity analysis could be performed to determine the effect of using only data from cases active at baseline.

The clinical need to change or discontinue antibiotic therapy is likely to be rare. This reduces the potential problems associated with performing the analysis on an intention-to-treat basis. More serious problems may arise from losses to follow-up and non-compliance. Some of the trials have been done in largely transient populations in which losses to follow-up rapidly accumulate as people move on. Such losses were assumed to be independent of the outcome measures, therefore studies were not excluded on this basis.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

The original electronic searches identified 566 reports of studies, of which 51 reported antibiotic treatment trials for trachoma. A total of 15 studies (8678 participants) met the inclusion criteria. Ten trials compared antibiotic to placebo or no treatment (Attiah 1973; Darougar 1980b; Dawson 1969i; Dawson 1969ii; Foster 1966; Hoshiwara 1973; Peach 1986; Shukla 1966; Tabbara 1988; Woolridge 1967). One trial (Tabbara 1988) was later excluded as it was not possible to identify patient outcomes as both eyes of the same patient were in some instances used in the randomisation and the results were reported as eyes not patients. The citations Dawson 1969i and Dawson 1969ii refer to two arms of the same trial, which were conducted in different schools; as the results are reported separately in the paper they have been treated as separate studies. Some of the above studies reported the comparison of topical against oral antibiotics. A further six trials compared topical tetracycline to oral azithromycin (Bowman 2000; Dawson 1997; Schachter 1999i; Schachter 1999ii; Schachter 1999iii; Tabbara 1996). The three Schachter 1999 citations used the same protocol but applied in different countries and reported in the same article. Schachter 1999i refers to results from Egypt, Schachter 1999ii from The Gambia and Schachter 1999iii from Tanzania. One further trial was excluded as an oral antibiotic, erythromycin, was used in conjunction with topical tetracycline in severe cases of trachoma, the comparison being oral azithromycin (Bailey 1993b).
The electronic searches were updated in 2005 and 206 new reports of studies were identified from the electronic searches. Hard copies of two reports were obtained for further scrutiny. One study was excluded as the trial did not take place in a trachoma endemic region (Isenberg 2002). The other is awaiting classification (Humet 1989).

The characteristics of the included studies and reasons for exclusion of studies are detailed in the 'Characteristics of included studies' and 'Characteristics of excluded studies' tables.

Antibiotic versus control

Types of participants
All participants had active trachoma in at least one eye as diagnosed by the clinical criteria of the time. They were all under the age of 22 years but no average age could be determined. The groups described are children aged six to 12 years in country unknown, pre-school children in Iran, boarding school residents aged 12 to 21 years in USA, boarding school residents aged eight to 20 years in USA, boarding school residents aged seven to 13 years in USA, school children aged five to 13 years in India, children under 21 years in northern Australia, children aged seven to 14 years in Saudi Arabia and primary school children in Taiwan.

Types of intervention
There were various treatment strategies given over periods of three weeks to twelve months. In Attiah 1973 one of two antibiotic ointments was applied daily every school day for eleven weeks. In Darougar 1980b ointment was applied twice daily on seven consecutive days every month for a year or an oral treatment was given once a month for a year. In Foster 1966 topical treatment was applied three times a day on five consecutive days every week for six weeks or oral treatment was given for five consecutive days every week for three weeks. In Shukla 1966 there were four treatment arms, topical plus oral twice a day for five consecutive days every month for five months, or oral treatment weekly for five months, or oral treatment twice weekly for five months, or topical treatment twice daily for five consecutive days every month for five months. Thus in three of the trials there were separate oral and topical treatment arms using the same control group (Darougar 1980b; Foster 1966; Shukla 1966) and these trials are used in a later comparison of oral versus topical treatment. The results were analysed by firstly pooling all the topical treatments and secondly pooling all the oral treatments and comparing each in turn to the control. To determine the overall effect of any antibiotic regime, irrespective of type, the various treatments within a trial were pooled and compared with control.

Types of outcome measures
All trials used active trachoma as the main outcome measure. The trachoma grading scales used after 1962 do not have scarring as a feature of active trachoma and so the underlying principles in the grades are equivalent in all of the studies and only use the presence of follicles and papillae for the diagnosis.

The secondary outcome measure was presence of Chlamydia trachomatis. The laboratory tests used were culture in McCoy cells, one to five identifiable inclusions/100 to 1000 cells, elementary bodies < = 200 or > = 200 on conjunctival smears and finally, TRIC positive immunofluorescence.

Follow-up
All studies reported outcomes at three months. Four trials reported outcomes at 12 months. No trials reported outcomes at 24 months.

Oral antibiotics versus topical antibiotics

This is dealt with in two sections. The first compares oral azithromycin with topical tetracycline, as these are the current WHO recommended treatments. The second section compares any oral treatment with any topical treatment.

Oral azithromycin versus topical tetracyline

Types of participants
Two of the trials (Dawson 1997; Tabbara 1996) included only children with active trachoma resident or at school in the study villages. The children were aged two to 10 and six to 14 years respectively and the settings Egypt and Saudi Arabia. The third paper (Schachter 1999i; Schachter 1999ii; Schachter 1999iii) included all residents of the study villages, irrespective of age or trachoma status. The fourth paper (Bowman 2000) included children aged six months to 10 years. The settings were Egypt, Saudi Arabia, The Gambia and Tanzania.

Types of intervention
Azithromycin 20 milligrams/kilogram body weight was given as a single dose, once weekly for three weeks or once every 28 days up to six doses. The comparisons were topical tetracycline, topical oxytetracycline or topical oxytetracycline/polymyxin with oral placebo.

Types of outcome measures
The primary outcome was active trachoma and the definition was consistent across the studies. Secondary outcomes were elementary bodies on conjunctival smear and ligase chain reaction (LCR) positivity.

Follow-up
All reported outcomes at three and 12 months. No trials detailed outcomes at 24 months.

Other oral treatments versus other topical treatments

All trials that fell in this category have already been described above (Darougar 1980b; Foster 1966; Shukla 1966). No further identified trials fulfilled the entry criteria.

Risk of bias in included studies

Allocation concealment was unclear in all studies except in two papers (Bowman 2000; Schachter 1999i; Schachter 1999ii; Schachter 1999iii) in which it was adequate. Five trials were graded B for validity and eight trials were graded C.

Some study designs were unusual. In one study (Attiah 1973) follow-up occurred immediately after treatment termination at 11 weeks from baseline. In another (Darougar 1980b) family members were treated but not analysed.

Cluster-randomisation was used in one set of studies (Schachter 1999i; Schachter 1999ii; Schachter 1999iii) in which one pair of villages was randomised in two of three countries and four pairs were randomised in the third country.

Intention-to-treat analysis was not given in six studies (Darougar 1980b; Foster 1966; Hoshiwara 1973; Schachter 1999i; Schachter 1999ii; Schachter 1999iii) and was unclear in other papers (Dawson 1969i; Dawson 1969ii; Woolridge 1967). Study authors were contacted where possible and individual patient data was made available for two of the three arms of one trial (Schachter 1999i; Schachter 1999ii).

Effects of interventions

The results of the chi squared test suggested that there was significant statistical heterogeneity among the trials. There was also marked clinical heterogeneity. No summary statistics were calculated and we therefore present a narrative summary of the results of the trials.

(1) Antibiotic versus control

(a) Active trachoma at three months (Analysis 1.1)

(i) any antibiotic
There was a total of nine trials comparing any antibiotic treatment to no treatment or placebo. The point estimates of relative risk were:
< 1 in six trials (P < 0.05);
< 1 in two trials (not significant (n.s.));
> 1 in one trial (n.s.).

(ii) oral antibiotics
There were six trials in this subcategory. The point estimates were:
< 1 in three trials (P < 0.05);
< 1 in two trials (n.s.);
> 1 in one trial (n.s.).

(ii) topical antibiotics
There were six trials in this subcategory. The point estimates were:
< 1 in four trials (P < 0.05);
< 1 in one trial (n.s.);
> 1 in one trial (n.s.).

The data are consistent with there being no effect of antibiotics but are suggestive of a lowering of risk.

(b) Active trachoma at 12 months (Analysis 1.2)

(i) any antibiotic
There was a total of four trials comparing antibiotic treatment to no treatment or placebo. The point estimates of relative risk were:
< 1 in three trials (P < 0.05);
> 1 in one trial (n.s.).

(ii) oral antibiotics
There were three trials in this subcategory. The point estimates were:
< 1 in one trial (P < 0.05);
< 1 in one trial (n.s.);
> 1 in one trial (n.s.).

(iii) topical antibiotics
There were four trials in this subcategory. The point estimates were:
< 1 in two trials (P < 0.05);
< 1 in two trials (n.s.).

The data are consistent with there being no effect of antibiotics but is suggestive of a lowering of risk.

(c) Chlamydia trachomatis infection at three months (Analysis 1.3)
At three months none of the four trials found a significant difference between the pooled antibiotic and control groups but the point estimate in all four trials suggested a reduced risk in the antibiotic group.

(d) Chlamydia trachomatis infection at 12 months (Analysis 1.4)
At 12 months only one trial reported an outcome and this found a significantly reduced risk in the antibiotic group compared to the control group.

(2) Oral antibiotics versus topical antibiotics

(a) Active trachoma at three months (Analysis 2.1)

There were six trials in this category. The point estimates of relative risk for oral azithromycin versus topical tetracycline were:
< 1 in two trials (P < 0.05);
< 1 in two trials (n.s.);
> 1 in two trials (n.s.).

For other oral antibiotics versus topical treatment the point estimates in the three trials were:
< 1 in one trial (P < 0.05);
< 1 in one trial (n.s.);
> 1 in one trial (n.s.).

These results suggest that oral treatment is neither more nor less effective than topical treatments.

(b) Active trachoma at 12 months (Analysis 2.2)

(i) for azithromycin versus topical tetracycline the point estimates in relative risk in four trials were:
< 1 in two trials (P < 0.05);
< 1 in one trial (n.s.);
> 1 in one trial (n.s).

(ii) for other oral antibiotics versus topical antibiotics the point estimates in relative risk in four trials were:
< 1 in three trials (n.s.);
> 1 in two trials (n.s.).

These results suggest that oral treatment is neither more nor less effective than topical treatments.

(c) Chlamydia trachomatis infection at three months (Analysis 2.3)
For azithromycin versus topical tetracycline at three months, three of the four trials found a significant reduction in relative risk and the other showed a non-significant reduction.

(d) Chlamydia trachomatis infection at 12 months (Analysis 2.4)
At 12 months, two of the four trials still found a significant reduction, one found some reduction and one showed an increase. Only one other small trial reported outcomes for other antibiotics.

These results suggest that azithromycin is significantly better than topical tetracycline at reducing laboratory evidence of infection. The heterogeneity of these four studies showed a P value of 0.036.

Intraclass correlation coefficients for cluster randomised trials
One report of three cluster randomised trials was identified (Schachter 1999i; Schachter 1999ii; Schachter 1999iii), in which azithromycin was compared with topical tetracycline. The authors were contacted and were able to provide individual patient data on two of the three countries involved (Schachter 1999i; Schachter 1999ii), that is 10 of the 12 clusters. For participants who had active trachoma at baseline the intraclass correlation coefficients (ICC) for trachoma status at three months are 0.076 (95% confidence interval (CI) 0.019 to 0.18) in the azithromycin clusters, and 0.29 (95% CI 0.19 to 0.41) in the tetracycline clusters. At 12 months the ICCs for trachoma status are -0.014 (95% CI -0.021 to 0.060) in the azithromycin clusters and -0.008 (95% CI 0.019 to 0.085) in the tetracycline clusters.

The ICCs at 12 months were negative, with tight confidence intervals that include zero, suggesting that the participants in the cluster can nearly be treated as individuals. At three months however the ICC in the tetracycline clusters is 0.29, suggesting that a reduction should be made in the weight given to each individual. The ICC in the azithromycin clusters is nearer to zero at 0.076 (95% CI 0.019 to 0.18). No method exists at present to incorporate the ICC into the overall analysis within RevMan Analyses, the statistical package within Review Manager 4.2 (RevMan 2004).

A sensitivity analysis was performed substituting the data from Schachter 1999i, Schachter 1999ii and Schachter 1999iii with individual patient data, where available, and using an intention-to-treat analysis. There was no reduction in the heterogeneity of the trials and a summary statistic was not calculated.

Discussion

Antibiotics versus placebo/no treatment
The results of the trials that compare an oral antibiotic to placebo/no treatment and the trials that compare a topical antibiotic to placebo/no treatment show high degrees of heterogeneity. A synthesis of the results to give a summary statistic was therefore not performed. For the outcome of active trachoma, the trials did not show a significant effect of antibiotics but suggested a lowering of risk. This was similarly the case for the outcome of laboratory evidence of trachoma.

The trials were undertaken in widely different countries; some were in children attending boarding schools and others in a village setting. Several unusual study designs were used, for example family-based treatment, whereas in others only the trial participants received treatment. The trials were all of moderate or poor quality and many had no intention to treat analysis. Antibiotic treatments included topical and oral regimen, some of which extended over many months. No trials reported on harm caused by treatment.

Oral versus topical antibiotics
The results of the six trials that compared oral azithromycin with topical tetracycline also show highly significant degrees of heterogeneity for both outcome measures and a summary statistic was not calculated.

Three of the trials were small and low powered. The fourth trial compared mass treatment in which people were treated irrespective of disease status and were randomly allocated by village (cluster-randomisation). Cluster-randomisation was addressed by calculating the intraclass correlation coefficient. Individual patient data was available on 10 of the 12 clusters and a measure of the similarity of individuals in those clusters showed that for the 12 month results little similarity existed between individuals in a cluster and so it would be reasonable to accept the data as presented in the trial results. The three-month outcomes suggest that there is similarity between individuals, particularly in the tetracycline clusters, and that the number of individuals should be proportionately reduced by 27 per cent. The individual patient data also gave access to an intention-to-treat analysis on individuals who had active trachoma at baseline. Using this subgroup instead of the whole group data there continued to be marked heterogeneity for active disease at three months.

It would not have been possible to determine by subgroup analysis who should be treated, whether the whole community, all children under 10 years of age, all women and children or families of all children with active trachoma. This is, however, an important factor in planning treatment strategies. Azithromycin in the trials was given as a single, double or triple dose but it would not have been possible to determine whether there was any difference in effect. There is a major cost difference between topical tetracycline and oral azithromycin but it was not possible to determine which is the more cost effective strategy per extra case cures. Some populations in which trachoma is endemic are subject to migration and that may account in part for the low follow-up rates in the community trials, it may also have implications in determining the most effective treatment in those populations where new infected cases migrate into the community.

No trials reported on either the development of antibiotic resistance or the occurrence of harmful or adverse effects of treatment.

Authors' conclusions

Implications for practice

No conclusions can be drawn on the effectiveness of antibiotic treatment for active trachoma but there is a suggestion of a reduction in the point prevalence of the relative risk for those treated with either oral or topical antibiotics. No conclusions can be drawn on the relative merits of oral azithromycin and topical tetracycline.

Implications for research

The WHO Global Elimination of Trachoma programme has endorsed the donation of azithromycin for the treatment of trachoma in selected countries. This would be an ideal setting for trials using standardised doses of antibiotics to help to determine whether antibiotics are an effective treatment and in view of the uncertainty demonstrated by this review such trials may be mandatory. To determine dosages of azithromycin at various levels of endemicity and also to determine which subgroups will need to be treated would follow later. Cost effectiveness per extra case cured should be part of the outcome measure. The adverse effects of azithromycin and emergence of resistance are also areas that should be addressed.

Acknowledgements

Thanks to the Systematic Review Training Unit at the Institute of Child Health and Neal Alexander for statistical input. Thanks to Hugh Taylor and David Mabey for peer review comments. The Cochrane Eyes and Vision Group developed and executed the electronic searches.

Data and analyses

Download statistical data

Comparison 1. ANTIBIOTIC VERSUS CONTROL
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Active trachoma at three months9 Risk Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Any antibiotic92078Risk Ratio (M-H, Random, 95% CI)0.79 [0.70, 0.89]
1.2 Oral antibiotic6603Risk Ratio (M-H, Random, 95% CI)0.81 [0.67, 0.97]
1.3 Topical antibiotic61593Risk Ratio (M-H, Random, 95% CI)0.82 [0.73, 0.93]
2 Active trachoma at 12 months4 Risk Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Any antibiotic41041Risk Ratio (M-H, Random, 95% CI)0.77 [0.57, 1.04]
2.2 Oral antibiotic3435Risk Ratio (M-H, Random, 95% CI)0.78 [0.48, 1.26]
2.3 Topical antibiotic4724Risk Ratio (M-H, Random, 95% CI)0.83 [0.72, 0.97]
3 Chlamydia trachomatis infection at three months4 Risk Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Any antibiotic4297Risk Ratio (M-H, Random, 95% CI)0.81 [0.63, 1.04]
3.2 Oral antibiotic4259Risk Ratio (M-H, Random, 95% CI)0.83 [0.65, 1.07]
3.3 Topical antibiotic185Risk Ratio (M-H, Random, 95% CI)0.18 [0.02, 1.37]
4 Chlamydia trachomatis infection at 12 months1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
4.1 Any antibiotic1129Risk Ratio (M-H, Random, 95% CI)0.25 [0.08, 0.78]
4.2 Oral antibiotic191Risk Ratio (M-H, Random, 95% CI)0.36 [0.10, 1.23]
4.3 Topical antibiotic185Risk Ratio (M-H, Random, 95% CI)0.14 [0.02, 1.04]
Analysis 1.1.

Comparison 1 ANTIBIOTIC VERSUS CONTROL, Outcome 1 Active trachoma at three months.

Analysis 1.2.

Comparison 1 ANTIBIOTIC VERSUS CONTROL, Outcome 2 Active trachoma at 12 months.

Analysis 1.3.

Comparison 1 ANTIBIOTIC VERSUS CONTROL, Outcome 3 Chlamydia trachomatis infection at three months.

Analysis 1.4.

Comparison 1 ANTIBIOTIC VERSUS CONTROL, Outcome 4 Chlamydia trachomatis infection at 12 months.

Comparison 2. ORAL VERSUS TOPICAL ANTIBIOTIC
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Active trachoma at three months9 Risk Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Oral Azithromycin versus topical Tetracycline66540Risk Ratio (M-H, Random, 95% CI)0.83 [0.60, 1.15]
1.2 Other oral versus topical3425Risk Ratio (M-H, Random, 95% CI)0.91 [0.74, 1.11]
2 Active trachoma at 12 months7 Risk Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Oral Azithromycin versus topical Tetracycline45573Risk Ratio (M-H, Random, 95% CI)0.82 [0.59, 1.15]
2.2 Other oral versus topical3445Risk Ratio (M-H, Random, 95% CI)1.01 [0.77, 1.32]
3 Chlamydia trachomatis infection at three months5 Risk Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Oral Azithromycin versus topical Tetracycline45933Risk Ratio (M-H, Random, 95% CI)0.48 [0.31, 0.74]
3.2 Other oral versus topical182Risk Ratio (M-H, Random, 95% CI)6.05 [0.78, 46.95]
4 Chlamydia trachomatis infection at 12 months5 Risk Ratio (M-H, Random, 95% CI)Subtotals only
4.1 Oral Azithromycin versus topical Tetracycline45414Risk Ratio (M-H, Random, 95% CI)0.65 [0.44, 0.98]
4.2 Other oral versus topical182Risk Ratio (M-H, Random, 95% CI)2.59 [0.28, 23.88]
Analysis 2.1.

Comparison 2 ORAL VERSUS TOPICAL ANTIBIOTIC, Outcome 1 Active trachoma at three months.

Analysis 2.2.

Comparison 2 ORAL VERSUS TOPICAL ANTIBIOTIC, Outcome 2 Active trachoma at 12 months.

Analysis 2.3.

Comparison 2 ORAL VERSUS TOPICAL ANTIBIOTIC, Outcome 3 Chlamydia trachomatis infection at three months.

Analysis 2.4.

Comparison 2 ORAL VERSUS TOPICAL ANTIBIOTIC, Outcome 4 Chlamydia trachomatis infection at 12 months.

Appendices

Appendix 1. CENTRAL search strategy used for Issue 1, 2005

#1 TRACHOMA
#2 CHLAMYDIA TRACHOMATIS
#3 (trachoma or tracoma:ti)
#4 (trachoma or tracoma:ab)
#5 (#1 or #2 or #3 or #4)
#6 ANTI-BACTERIAL AGENTS
#7 AZITHROMYCIN
#8 TETRACYCLINE
#9 CHLORTETRACYCLINE
#10 MACROLIDES
#11 (antibiotic* or azithromycin* or tetracyclin* or chlortetracylin* or macrolid*:ti)
#12 (antibiotic* or azithromycin* or tetracyclin* or chlortetracylin* or macrolid*:ab)
#13 (#6 or #7 or #8 or #9 or #10 or #11 or #12)
#14 (#5 and #13)

Appendix 2. MEDLINE search strategy used on WebSPIRS up to February 2005

#1 explode "Trachoma-" / all SUBHEADINGS
#2 explode "Chlamydia-trachomatis" / all SUBHEADINGS
#3 ( (trac?oma*) in AB )or( (trac?oma*) in TI )
#4 #1 or #2 or #3
#5 explode "Anti-Bacterial-Agents" / all SUBHEADINGS
#6 explode "Azithromycin-" / all SUBHEADINGS
#7 explode "Tetracycline-" / all SUBHEADINGS
#8 explode "Chlortetracycline-" / all SUBHEADINGS
#9 explode "Macrolides-" / all SUBHEADINGS
#10 ( (antibiotic* or azithromycin* or tetracyclin* or chlortetracylin* or macrolid*) in AB )or( (antibiotic* or azithromycin* or tetracyclin* or chlortetracylin* or macrolid*) in TI )
#11 #5 or #6 or #7 or #8 or #9 or #10
#12 #4 and #11

To identify randomised controlled trials, this search was combined with the Cochrane Highly Sensitive Search Strategy phases one and two as contained in the Cochrane Reviewers' Handbook (Alderson 2004).

Appendix 3. EMBASE search strategy used on OVID up to February 2005

#1 exp TRACHOMA/
#2 exp Chlamydia Trachomatis/
#3 (trachom$ or tracom$).mp.
#4 #1 or #2 or #3
#5 exp Antibiotic Agent/
#6 exp Azithromycin/
#7 exp TETRACYCLINE/
#8 exp CHLORTETRACYCLINE/
#9 exp MACROLIDE/
#10 (antibiotic$ or azithromycin$ or tetracyclin$ or chlortetracycline$ or macrolid$).mp.
#11 #5 or #6 or #7 or #8 or #9 or #10
#12 #4 and #11

To identify randomised controlled trials, this search was combined with the following search:

#1 CLINICAL TRIAL/
#2 RANDOMIZED CONTROLLED TRIAL/
#3 CONTROLLED STUDY/
#4 exp RANDOMIZATION/
#5 DOUBLE BLIND PROCEDURE/
#6 SINGLE BLIND PROCEDURE/
#7 CROSSOVER PROCEDURE/
#8 exp FOLLOW UP/
#9 exp PROSPECTIVE STUDY/
#10 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9).mp.
#11 exp ANIMAL/
#12 NONHUMAN/
#13 #11 or #12
#14 HUMAN/
#15 #13 not #14
#16 #10 not #15
#17 exp PLACEBO/
#18 ((clinical or random$ or control$ or prospectiv$ or volunteer$) adj3 (trial$ or method$ or stud$)).mp.
#19 (placebo$ or crossover$ or cross-over$ or latin square$ or latin-square$).mp.
#20 #17 or #18 or #19
#21 #20 not #15
#22 #16 or #21

What's new

Last assessed as up-to-date: 14 February 2005.

DateEventDescription
18 October 2008AmendedConverted to new review format.

History

Protocol first published: Issue 3, 1999
Review first published: Issue 1, 2002

DateEventDescription
1 February 2005New citation required and conclusions have changedSubstantive amendment

Contributions of authors

DM screened the search results, graded selected trials, extracted some data and wrote the review. DM is the guarantor for the review.
NF graded selected trials, extracted the data and contributed to writing the review.
CP screened the search results and worked on the update of the review.
The Cochrane Eyes and Vision Group editorial team developed the search strategies and undertook the electronic searches.

Declarations of interest

The Edna McConnell Clark Foundation supported DM and NF for one half day a week over a 10 month period to undertake the review.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • The Edna McConnell Clark Foundation, USA.

  • Christian Blind Mission, Germany.

  • Sightsavers International, UK.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Attiah 1973

Methods

Type of trial: clinical.

Allocation: stratified random.
Unit of randomisation: individual.

Masking:
participant - no,
provider - yes,
outcome - yes.

Exclusions after randomisation: no.
Losses to follow-up: 0.
Attrition bias: no.
ITT analysis: yes.

Unusual study design: follow-up right after treatment termination, over two weeks.

Validity rating: B.

Participants

Country: not reported.

Number randomised: 228.
Age (ave.): 6 to 12 years.
Sex: not reported.

Clinical grading: WHO.
Lab tests: none.

Inclusion criteria: active trachoma or 'undetermined case'.
Exclusion criteria: none.

Interventions

TREATMENT 1: tetracycline derivative GS2989.
Administration: topical.
Dose: 0.25%.
duration: once every school day for 11 weeks.

TREATMENT 2: terramycin.
Administration: topical.
Dose: not reported.
Duration: once every school day for 11 weeks.

COMPARISON: no treatment.
Administration: not applicable.
Dose: not applicable.
Duration: not applicable.

OutcomesPrimary: active trachoma.
Secondary: -
Adverse effects: n.a.
NotesTreatment irregular, although intended for every school day.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Bowman 2000

Methods

Allocation: randomisation by block.
Unit of randomisation: individual.

Masking:
participant - no,
provider - no,
outcome - yes.

Exclusions after randomisation: no.
Losses to follow up: numbers recorded.
ITT: possible as all participants accounted for.

Validity rating: B.

Participants

Country: The Gambia.

Number randomised: 314.
Age: 6 months to 10 years.
Sex: Boys 50%.

Clinical grading: simplified WHO scale 1987.
No lab tests.

Interventions

TREATMENT: single-dose azithromycin 20 mg/kg.

COMPARISON: topical tetracycline applied once by a nurse in front of the care-giver and then twice daily by care-giver for 6 weeks.

OutcomesPrimary: active trachoma.
No secondary outcome.
NotesTrial aim to compare treatments under operational and not best possible conditions.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Darougar 1980b

Methods

Type of trial: clinical.

Allocation: randomisation schedule, stratification by age, sex, trachoma intensity, diseased children in family.
Unit of randomisation: individual.

Masking:
participant - no,
provider - no,
outcome: unclear.

Exclusions after randomisation: yes, poor compliers.
Losses to follow-up: not given by group.
Attrition bias: unclear.
ITT analysis: no.

Unusual study design: family-based treatment (family members treated but not analysed).

Validity rating: C

Participants

Country: Iran.

Number randomised: 147.
Age (ave.): pre-school (5.5 years).
Sex: 38% male.
Clinical grading: Darougar 1980, 1981.
Lab tests: culture (Darougar 1970).
Inclusion criteria: active trachoma, residence in study village.
Exclusion criteria: none

Interventions

TREATMENT 1: oxytetracycline.
Administration: topical.
Dose: 1%.
Duration: twice daily for 7 consecutive days every month for 12 months.

TREATMENT 2: doxycycline.
Administration: oral.
Dose: 5 mg/kg.
Duration: one dose per month for 12 months.

COMPARISON: vitamin pills
Administration: oral.
Dose: not reported.
Duration: 1 dose per month for 12 months.

OutcomesPrimary: active trachoma.
Secondary: culture (McCoy cells).
Adverse effects: n.a.
NotesSome data only in graphical form; data of whole conjunctiva and of upper conjunctiva given.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Dawson 1969i

Methods

Type of trial: clinical.

Allocation: random.
Unit of randomisation: individual.

Masking:
participant - yes,
provider - yes,
outcome - yes.

Exclusions after randomisation: no
Losses to follow-up: -
Attrition bias: no.
ITT analysis: not clear.

Unusual study design: two similar studies with few participants each.

Validity rating: B.

Participants

Country: USA.

Number randomised: 36.
Age (ave.): 12 to 21 years.
Sex: not reported.

Clinical grading: Dawson 1966.
Lab tests: IFAT on conjunctival smears.

Inclusion criteria: active disease, boarding at Stewart School.
Exclusion criteria: none

Interventions

TREATMENT: trisulfapyrimidines.
Administration: oral.
Dose: 3.5 g/day.
Duration: 3 daily during 3 consecutive weeks.

COMPARISON: lactose-placebo.
Administration: oral.
Dose: not reported.
Duration: 3 daily for 3 consecutive weeks.

OutcomesPrimary: active trachoma.
Secondary: positive IFAT (1 - 5 identifiable inclusions per 100 - 1,000 cells).
NotesParticipants from Indian reservations.
Numbers need to be read from figures, some not very clear.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Dawson 1969ii

Methods

Type of trial: clinical.

Allocation: random.
Unit of randomisation: individual.

Masking:
participant: yes,
provider: yes,
outcome: yes.

Exclusions after randomisation: no
Losses to follow-up: -
Attrition bias: no.
ITT analysis: not clear.

Unusual study design: two similar studies with few participants each.

Validity rating: B.

Participants

Country: USA.

Number randomised: 29.
Age (ave.): 12 to 21 years.
Sex: not reported.

Clinical grading: Dawson 1966.
Lab tests: IFAT on conjunctival smears.

Inclusion criteria: active disease, boarding at Sherman Institute.
Exclusion criteria: none

Interventions

TREATMENT: trisulfapyrimidines.
Administration: oral.
Dose: 3.5 g/day.
Duration: 3 daily during 3 consecutive weeks.

COMPARISON: lactose-placebo.
Administration: oral.
Dose: not reported.
Duration: 3 daily for 3 consecutive weeks.

OutcomesPrimary: active trachoma.
Secondary: positive IFAT (1 - 5 identifiable inclusions per 100 - 1,000 cells).
NotesParticipants from Indian reservations.
Numbers need to be read from figures, some not very clear.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Dawson 1997

Methods

Type of trial: clinical.

Allocation: random.
Unit of randomisation: blocks of eight.

Masking:
participant: for azithromycin,
provider: no,
outcome: yes.

Exclusions after randomisation: no.
Losses to follow-up: absence in village/not found.
Attrition bias: no.
ITT analysis: yes.

Unusual study design: oral placebo for different azithromycin regimens, no placebo for topical treatment.

Validity rating: B.

Participants

Country: Egypt.

Number randomised: 168.
Age (ave.): 2 to 10 years (4).
Sex: 59.5% male.

Clinical grading: Thylefors 1987.
Lab tests: Thylefors 1987; Dawson 1981.

Inclusion criteria: active trachoma, two to 10 years, resident in a study village.
Exclusion criteria: missing baseline record.

Interventions

TREATMENT: azithromycin.
Administration: oral.
Dose: 20 mg/kg BW.
Duration: 1 dose, or 3 times 1 dose at weekly intervals, or 6 times 1 dose at 28 day intervals.

COMPARISON: Oxytet/polymyxin + oral placebo.
Administration: topical.
Dose: oxytet 1%/polymyxin 10,000 U/g
Duration: once daily for 5 consecutive days every 28 days for 6 times.

OutcomesPrimary: active trachoma.
Secondary: elementary bodies < = 200 or > 200 on conjunctival smears.
Adverse effects: -
NotesEpidemic of purulent conjunctivitis at 8/12 years; cut-off for positivity not justified.
Three azithromycin regimens analysed together.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Foster 1966

Methods

Type of trial: clinical.

Allocation: random.
Unit of randomisation: individuals.

Masking:
participant: no,
provider: no,
outcome: yes.

Exclusions after randomisation: not reported.
Losses to follow-up: yes.
Attrition bias: not clear.
ITT analysis: no.

Validity rating: C.

Participants

Country: USA.

Number randomised: approx. 305.
Age (ave.): 8 to 20 years.
Sex: not reported.

Clinical grading: Thygeson 1960.
Lab tests: -

Inclusion criteria: active trachoma, studying in a study school.
Exclusion criteria: none.

Interventions

TREATMENT 1: Sulphamethoxypyridazine.
Administration: oral.
Dose: 0.5 g.
Duration: once daily for 5 consecutive days every week for 3 weeks.

TREATMENT 2 : tetracycline.
Administration: topical.
Dose: 1%.
Duration: 3 times daily on 5 consecutive days every week for 6 weeks.

COMPARISON: no treatment.

OutcomesPrimary: active trachoma.
Secondary: none.
Adverse effects: not recorded.
NotesParticipants boarding.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Hoshiwara 1973

Methods

Allocation: random.
Unit of randomisation: individual.

Masking:
participant - yes,
provider - yes,
outcome - yes.

Exclusions after randomisation: no
Losses to follow-up: poor compliance, lack of sample.
Attrition bias: yes.
ITT analysis: no.

Validity rating: C.

Participants

Country: USA.

Number randomised: 120.
Age (ave.): 7 to 13 years (9.9).
Sex: not reported.

Clinical grading: Dawson 1969.
Lab tests: IFAT on scrapings of upper tarsal conjunctival epithelium.

Inclusion criteria: active disease, boarding at study school.
Exclusion criteria: none

Interventions

TREATMENT: doxycycline.
Administration: oral.
Dose: 2.5-4.0 mg/kg.
Duration: once daily for 5 consecutive days every week up to 28 doses in 40 days.

COMPARISON: placebo.
Administration: oral.
Duration: once daily for 5 consecutive days every week up to 28 doses in 40 days.

Outcomes

Primary: active trachoma.
Secondary: TRIC-positive immunofluorescent inclusions.

Adverse effects: anorexia, nausea, vomiting or diarrhoea.

NotesParticipants boarding.
Placebo with 'strong beneficial effect'.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Peach 1986

Methods

Type of trial: public health.

Allocation: stratified randomisation.
Unit of randomisation: community but analysed as individuals.

Masking:
participant - no,
provider - no,
outcome: no.

Exclusions after randomisation: no.
Losses to follow up: yes.
Attrition bias: no.
ITT analysis: yes.

Validity rating: C.

Participants

Country: Australia.

Number randomised: 641.
Age: children 5 to 14 years (plus 5% under 5 and 5% over 14).
Sex: not reported.
Grading: local version with at least one follicle or some papillary hypertrophy being positive.
No lab tests.

Interventions

TREATMENT: oily tetracycline daily for 5 days once a month for 3 months.

COMPARISON: no treatment.

OutcomesPrimary: active trachoma.
NotesOne arm of a larger trial with components face washing and facewashing plus antibiotics.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Schachter 1999i

Methods

Type of trial: public health.

Allocation: random within one matched pair.
Unit of randomisation: village.

Masking:
participant - no,
provider - no,
outcome - no.

Exclusions after randomisation: no.
Losses to follow-up: yes, temporary absence.
Attrition bias: yes.
ITT analysis: no.

Unusual study design: only one pair of villages hence randomness of assignment very limited.

Validity rating: C.

Participants

Country: Egypt.

Number randomised: 2238.
Age (ave.): all ages.
Sex: not reported.

Clinical grading: Dawson 1981.
Lab tests: LCR.

Inclusion criteria: all villagers present.
Exclusion criteria: none, but alternative treatment for azithromycin-allocated women at childbearing age.

Interventions

TREATMENT: azithromycin.
Administration: oral.
Dose: 20 mg/kg up to 1g.
Duration: once a week for 3 weeks. Women of childbearing age erythromycin for 14 days, 500 mg twice daily or 250 mg four times daily (amoxicillin in case of intolerance).

COMPARISON: oxytetracycline.
Administration: topical.
Dose: 1%.
Duration: once daily for 6 weeks.

OutcomesPrimary: active trachoma.
Secondary: infection.
NotesSurvey compliance:
E: 93% (A), 71% (T); I: 91% (A), 83% (T).
Treatment compliance = at least one dose of azithromycin or 28 applications of Tetracycline
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Schachter 1999ii

Methods

Type of trial: public health.

Allocation: random within four matched pairs.
Unit of randomisation: village.

Masking:
participant - no,
provider - no,
outcome - no.

Exclusions after randomisation: no.
Losses to follow-up: yes, temporary absence.
Attrition bias: yes.
ITT analysis: no.

Validity rating: C.

Participants

Country: The Gambia.

Number randomised: 1753.
Age (ave.): all ages.
Sex: not reported.

Clinical grading: Dawson 1981.
Lab tests: LCR.

Inclusion criteria: all villagers present.
Exclusion criteria: none, but alternative treatment for azithromycin-allocated women at childbearing age.

Interventions

TREATMENT: azithromycin.
Administration: oral.
Dose: 20 mg/kg up to 1g.
Duration: once a week for 3 weeks. Women of childbearing age erythromycin for 14 days, 500 mg twice daily or 250 mg four times daily (amoxicillin in case of intolerance).

COMPARISON: oxytetracycline.
Administration: topical.
Dose: 1%.
Duration: once daily for 6 weeks.

OutcomesPrimary: active trachoma.
Secondary: infection.
NotesVery high migration rate.
Survey compliance:
E: 90% (A), 94% (T); I: 74% (A), 63% (T).
Treatment compliance = at least one dose of azithromycin or 28 applications of Tetracycline
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Schachter 1999iii

Methods

Type of trial: public health.

Allocation: random within one matched pair.
Unit of randomisation: village.

Masking:
participant - no,
provider - no,
outcome - no.

Exclusions after randomisation: none
Losses to follow-up: yes, temporary absence.
Attrition bias: yes.
ITT analysis: no.

Unusual study design: only one pair of villages hence randomness of assignment very limited.

Validity rating: C.

Participants

Country: Tanzania.

Number randomised: 3261.
Age (ave.): all ages.
Sex: not reported.

Clinical grading: Dawson 1981.
Lab tests: LCR.

Inclusion criteria: all villagers present.
Exclusion criteria: none, but alternative treatment for azithromycin-allocated women at childbearing age.

Interventions

TREATMENT: azithromycin.
Administration: oral.
Dose: 20 mg/kg up to 1g.
Duration: once a week for 3 weeks. Women of childbearing age erythromycin for 14 days, 500 mg twice daily or 250 mg four times daily (amoxicillin in case of intolerance).

COMPARISON: oxytetracycline.
Administration: topical.
Dose: 1%.
Duration: once daily for 6 weeks.

OutcomesPrimary: active trachoma.
Secondary: infection.
NotesHigh population movement.
Survey compliance:
E: 71% (A), 95% (T); I: 63% (A), 84% (T).
Treatment compliance = at least one dose of azithromycin or 28 applications of Tetracycline
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Shukla 1966

Methods

Type of trial: clinical.

Allocation: random.
Unit of randomisation: individual.

Masking:
participant - no,
provider - no,
outcome: - unclear.

Exclusions after randomisation: no.
Losses to follow-up: none.
Attrition bias: no.
ITT analysis: no.

Unusual study design: four-armed trial with factorial design.

Validity rating: C.

Participants

Country: India.

Number randomised: 349.
Age (ave.): 5 to 13 years.
Sex: not reported.

Clinical grading: WHO 1962.
Lab tests: none.

Inclusion criteria: active trachoma, schooling at a study school.
Exclusion criteria: none.

Interventions

TREATMENT 1: sulphafurazole + sulphadimethoxine.
Administration: topical + oral.
Dose: 15%/100 mg/kg.
Duration: twice daily for 5 consecutive days every month for 5 months/bi-weekly for 5 months.

TREATMENT 2: sulphadimethoxine.
Administration: oral.
Dose: 100 mg/kg.
Duration: biweekly or weekly dose for 5 months.

TREATMENT 3: sulphafurazole.
Administration: topical.
Dose: 15%.
Duration: twice daily for 5 consecutive days every month for 5 months.

COMPARISON: no treatment.

OutcomesPrimary: active trachoma.
Secondary: -
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Tabbara 1996

Methods

Type of trial: clinical.

Allocation: random.
Unit of randomisation: individual.

Masking:
participant - no,
provider - no,
outcome - yes.

Exclusions after randomisation: no
Losses to follow-up: absence.
Attrition bias: no.
ITT analysis: yes.

Validity rating: C.

Participants

Country: Saudi Arabia.

Number randomised: 64.
Age (ave.): 6 to 14 years (11.1).
Sex: not reported.

Clinical grading: Dawson 1981.
Lab tests: conjunctival scrapings for inclusion bodies/cells/organisms/mucus; IFAT for free elementary bodies.

Inclusion criteria: active trachoma, schooling in study village.
Exclusion criteria: none

Interventions

TREATMENT: azithromycin.
Administration: oral.
Dose: 20 mg/kg.
Duration: 1 dose.

COMPARISON: tetracycline.
Administration: topical.
Dose: 1%.
Duration: twice daily for 5 consecutive days per week over 6 weeks.

OutcomesPrimary: active trachoma.
Secondary: intraepithelial cell inclusion bodies, free elementary bodies.
Adverse effects: none.
NotesCase definition not clear (probable diagnosis of trachoma based on cytology, definitive diagnosis of trachoma based on microscopical assessment of scrapings).
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Woolridge 1967

  1. a

    ITT - intention to treat
    mg/kg - milligrams per kilogram of body weight
    LCR - Ligase chain reaction
    Ave. - average

Methods

Type of trial: clinical.

Allocation: random.
Unit of randomisation: individual.

Masking:
participant: no,
provider: no,
outcome: yes.

Exclusions after randomisation: unclear.
Losses to follow-up: unclear.
Attrition bias: unclear.
ITT analysis: unclear.

Unusual study design: combined vaccine and therapy trial. Review considers groups with placebo-vaccine.

Validity rating: C.

Participants

Country: Taiwan.

Number randomised: 322.
Age (ave.): primary school age.
Sex: not reported.

Clinical grading: Modified McCallan classification.
Lab tests: none.

Inclusion criteria: active trachoma.
Exclusion criteria: none.

Interventions

TREATMENT: tetracycline.
Administration: topical.
Dose: 1%.
Duration: twice daily for 6 consecutive days per week for 6 weeks.

COMPARISON: no treatment.

Outcomes

Primary: active trachoma.
Secondary: none.

Adverse effects: not assessed.

NotesOnly trachoma-positives included, but table does not show this. Numbers for analysis calculated from percentages given.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Assaad 1968Concealment of allocation: C (twice randomisation among two groups).
Babbar 1982No comparison group receiving placebo or no treatment.
Bailey 1993bOral erythromycin added to topical treatment in severe cases.
Bietti 1967Review only.
Cerulli 1983No evidence of randomisation.
Chumbley 1988No comparison group receiving placebo or no treatment.
Daghfous 1974No evidence of randomisation.
Daghfous 1985No comparison group receiving placebo or no treatment.
No evidence of randomisation.
Darougar 1980aNo comparison group receiving placebo or no treatment.
Darougar 1981No comparison group.
Dawson 1967aAllocation concealment inadequate (alternation).
Dawson 1967bAllocation concealment inadequate (alternation).
Dawson 1968No evidence of randomisation.
Dawson 1971Allocation concealment inadequate (alternation).
Dawson 1972aNo evidence of randomisation.
Dawson 1972bNo evidence of randomisation.
Dawson 1974aNo evidence of randomisation.
Dawson 1974bAllocation concealment inadequate.
Dawson 1975aAllocation concealment inadequate.
Dawson 1981aNo proper control group (previously treated children who did not receive treatment during actual trial).
Dawson 1982No comparison group receiving placebo or no treatment.
Gupta 1966No evidence of randomisation.
Gupta 1968No comparison group receiving placebo or no treatment.
Guzey 2000Inclusion criteria of participants non-specific. They had bilateral trachoma or showed symptoms (not described).
Hasan 1976No comparison group receiving placebo or no treatment.
Isenberg 2002Study not carried out in a trachoma endemic area.
Ji 1986No trial report.
Kamiya 1956Lack of comparison villages.
Litricin 1968No comparison group.
Mohan 1982No evidence of randomisation.
Nabli 1988No comparison group.
Nisbet 1979Placebo invalid.
Obikili 1988No comparison group.
Reinhards 1959No comparison group.
Resnikoff 1994No comparison group.
Resnikoff 1995Randomisation included health education.
Tabbara 1988Randomisation was by eye and not patient. It was not possible to determine the individual patient outcome.
Toufic 1968Report of control campaigns not trials.
Wadia 1980No comparison group.
Werner 1977No comparison group.
No evidence of randomisation.
Whitcher 1974No evidence of randomisation.

Ancillary