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Adverse and Beneficial Secondary Effects of Mass Treatment with Azithromycin to Eliminate Blindness Due to Trachoma in Nepal

  1. A. M Fry1,2,
  2. H. C Jha4,
  3. T. M Lietman3,
  4. J. S. P Chaudhary4,
  5. R. C Bhatta4,
  6. J Elliott1,
  7. T Hyde1,2,
  8. A Schuchat1,
  9. B Gaynor3, and
  10. S. F Dowell1
  1. 1Respiratory Diseases Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, Atlanta, Georgia
  2. 2Epidemic Intelligence Service, Centers for Disease Control and Prevention, Atlanta, Georgia
  3. 3Proctor Foundation, University of California, San Francisco
  4. 4Geta Eye Hospital, Dhanghedi, Nepal
  1. Reprints or correspondence: Dr. Alicia Fry, Centers for Disease Control and Prevention, 1600 Clifton Rd. NE, Mailstop E-10, Atlanta, GA 30333 (afry{at}cdc.gov)
 
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Abstract

Mass administration of azithromycin to eliminate blindness due to trachoma has raised concerns regarding the emergence of antimicrobial resistance. During 2000, we compared the antimicrobial resistance of nasopharyngeal pneumococcal isolates recovered from and the prevalence of impetigo, respiratory symptoms, and diarrhea among 458 children in Nepal before and after mass administration of azithromycin. No azithromycin-resistant pneumococci were isolated except from 4.3% of children who had received azithromycin during 2 previous mass treatments (P <.001). There were decreases in the prevalence of impetigo (from 14% to 6% of subjects; adjusted odds ratio [OR], 0.41; 95% confidence interval [CI], 0.21–0.80) and diarrhea (from 32% to 11%; adjusted OR, 0.26; 95% CI, 0.14–0.43) 10 days after azithromycin treatment. The absence of macrolide-resistant isolates after 1 mass treatment with azithromycin is encouraging, although the recovery of azithromycin-resistant isolates after 2 mass treatments suggests the need for resistance monitoring when multiple rounds of antimicrobial treatment are given

The World Health Organization and international partners have initiated a global campaign to eliminate blindness due to trachoma by the year 2020 (the Global Elimination of Blindness due to Trachoma [GET2020] program) [1]. The strategy to control endemic trachoma and prevent the resulting blindness includes improvement of hygiene and mass administration of antimicrobial agents. Azithromycin is the most effective agent that has been tested for this purpose; a single dose or short course of azithromycin has been shown to decrease the prevalence of endemic trachoma among children [2–5]. One concern with the mass administration of a long-acting, broad-spectrum antimicrobial agent such as azithromycin is that it may lead to the emergence of antimicrobial resistance, both in Chlamydia trachomatis and in other bacterial pathogens. Because the global trachoma campaign has recently been initiated, it is an opportune time to document the potential for adverse effects that might inadvertently be caused by this elimination strategy

Monitoring antimicrobial resistance in C. trachomatis remains technically challenging and has not been done after mass antimicrobial treatment. However, results from several small studies have raised concerns that azithromycin-resistant Streptococcus pneumoniae isolates are rapidly selected after mass chemoprophylaxis with azithromycin [6, 7]. S. pneumoniae is a leading bacterial cause of pneumonia, meningitis, and bloodstream infections in many parts of the world, and a correlation between increasing macrolide use in the community and increasing macrolide resistance among streptococci has been reported [8, 9]. Also, macrolide resistance in S. pneumoniae is often associated with resistance to other classes of antimicrobials, including sulfa and penicillin agents [10], which are recommended for the treatment of childhood infections in countries where trachoma is endemic [11]. This may have important implications if mass administration of azithromycin leads to the emergence of resistance to the drugs available for treatment of pneumonia in countries targeted by GET2020

In addition to reducing the prevalence of trachoma, mass treatment with azithromycin may have other beneficial outcomes [12, 13]. Organisms that are susceptible to broad-spectrum macrolides will likely be affected by a mass treatment campaign, including those that cause a variety of skin diseases, diarrhea, and acute respiratory infections [14]. We studied the secondary effects of mass treatment with azithromycin for the elimination of blindness due to trachoma in Nepal, including the community prevalence of antimicrobial-resistant pneumococci, impetigo, and symptoms of respiratory and gastrointestinal illness

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Methods

Setting Our study was conducted between May and November 2000 in 8 wards in the districts of Kailali and Kanchanpur, in the Seti and Mahakali zones, in far-western Nepal. Herein, Nepalese wards are referred to as “villages.” The prevalence of trachoma in the districts of Kailali and Kanchanpur ranges from 3% to 39% [15]. This study was coordinated with an ongoing project, initiated in November 1998, to administer a single dose of azithromycin (20 mg/kg) annually to all village children aged 1–10 years [15]. Azithromycin was distributed to the children in the 8 study villages in an incremental manner (figure 1). The 1-time oral ingestion of azithromycin by each child was supervised by project managers [15]

Figure 1
Figure 1

Flow chart distinguishing groups according to receipt of azithromycin treatment and method of data collection. Circles containing the abbreviation “Az” indicate the time of mass administration of azithromycin to all children 1–10 years of age as part of an ongoing project described elsewhere [15]. Shaded swab symbol, time nasopharyngeal swab obtained, questionnaire administered, and skin examination performed. “Study period” refers to the present study to determine the secondary effects of mass administration of azithromycin

Participants We randomly selected 60 children from each of the 8 villages during the follow-up eye examinations, an organized event during which all children gathered in 1 location. Written informed consent was obtained from parents or guardians for each child, and the study protocol was approved by the Nepal Health Research Council and Social Welfare Council and Centers for Disease Control and Prevention (CDC) institutional review board and was performed in accordance with the ethical standards of the Helsinki Declaration of 1975, as revised in 1983

We collected data at 3 time points: day 0 (i.e., the day of azithromycin administration), day 10, and day 180. At the time our study began, the children in the 8 villages were classified into 3 groups according to their history of exposure to azithromycin (figure 1). On day 0, after data collection was complete, all children aged 1–10 years living in the 3 villages who had never been exposed to azithromycin received a single dose of azithromycin for the first time (these children comprised the current treatment group). None of the children in the other villages received mass treatment with azithromycin at this time. We did not collect data on day 10 from the group with 2 previous exposures because of logistical constraints

Data collection We obtained nasopharyngeal swabs from each child at each visit and used skim milk–tryptone-glucose-glycerin medium for preservation and transport of the swabs, as described elsewhere [16]. A skin examination of each child was done by a physician at each of the 3 time points. The presence of impetigo was recorded, according to clinical appearance, as “definite,” “possible,” or “none” only those lesions recorded as “definite” were included in the analysis. The parent or guardian of each child was interviewed in the local language (Rana Tharu, Dangaura Tharu, or Nepali dialects) by an interviewer previously trained in interviewing techniques. We collected personal and household information on day 0 and information regarding antimicrobial use and symptoms that the child experienced during the previous 2 weeks at each time point. Diarrhea was defined as ⩾3 loose stools per day. We inquired about skin lesions consistent with impetigo by showing parents a color photograph of a lower-extremity impetigo lesion

Laboratory studies All nasopharyngeal swab specimens were stored at -20°C or -70°C, transported on ice, and processed at the CDC, as described elsewhere [16]. To test the efficiency of the transportation process, we processed a portion of the first 50 and the third 50 specimens in Nepal and the remaining portion at the CDC, and we compared the respective proportions of specimens from which S. pneumoniae were isolated. Antibiotic susceptibilities for azithromycin, penicillin, chloramphenicol, trimethoprim, sulfamethoxazole, clindamycin, and cefuroxime were determined by broth dilution MIC testing. We used National Committee for Clinical Laboratory Standards break points for nonsusceptibility (which included the categories “intermediately susceptible” and “resistant”) to azithromycin, penicillin, chloramphenicol, trimethoprim, sulfamethoxazole, clindamycin, and cefuroxime [17]. Serotypes were determined by Quellung reaction

Statistical analysis All data were double-entered, and discrepancies were verified against the original record. For comparison of data for 2 time points, crude 2-tailed P values were calculated with the χ2 test for dichotomous variables or the Wilcoxon sign-rank test for continuous variables. For comparison within 1 group of data from 2 time points, crude P values were calculated by use of McNemar's paired analysis to account for repeated measures for the same individual. P ⩽.05 was considered statistically significant. Missing values were excluded from the analysis. Multivariate models were investigated by use of generalized estimating equations with exchangeable working correlations to account for the repeated assessment of the same subjects. SUDAAN software, version 7 (Research Triangle Institute), was used to account for the clustered study design. The current treatment group at day 0 was the reference group. Risk factors were included in the multivariate analysis if they were determined to be potential confounders on the basis of previously published information or significantly (P ⩽.05) associated with illness in this investigation. All 2-way interactions were evaluated

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Results

Comparison of groups We enrolled 458 children. Parents were unavailable to sign consent forms for 22 children. At day 0, the 3 groups were similar with regard to sex and age distribution (table 1). On the basis of parents's reports, the 3 groups were also similar with respect to the proportion who had received antimicrobial agents other than azithromycin in the previous month (current treatment group, 32% of subjects; 1 previous treatment group, 33%; 2 previous treatments group, 26%). None of the parents were able to recall the name of the antimicrobial agent or to produce a container with a medication identification label; therefore, we were unable to verify the use of antibiotic agents in the previous month. The groups who had received 1 and 2 previous treatments tended to include fewer children who lived in homes with >3 children <11 years of age than did the current treatment group, although the differences were not statistically significant (P =.06 and P =.08, respectively). The proportion of children with impetigo that was documented by skin examination was the same at baseline in all 3 groups, as was the proportion of children with cough and diarrhea during the 2 weeks previous to baseline. There was good participation during follow-up visits at day 10 (current treatment group, 95% of subjects; 1 previous treatment group, 91% of subjects) and day 180 (current treatment group, 89%; 1 previous treatment group, 86%; 2 previous treatments group, 90%)

Figure 2
Figure 2

Comparison of proportions of children with symptoms of gastrointestinal illness (reported during interview) and impetigo (detected by skin examination) at days 0, 10, and 180 after administration of azithromycin. NA, not applicable because no nasopharyngeal swabs were obtained at day 10. *P <.05 for comparison with day 0

Table 1
Table 1

Demographic and clinical characteristics of children in 3 groups at baseline (day 0) in study of secondary effects of mass treatment with azithromycin

S. pneumoniae carriage and antimicrobial susceptibility of isolates Pneumococci were isolated from similar proportions of the 100 naspharyngeal swab specimens tested both in Nepal and at the CDC (86 samples vs. 90). The prevalence of nasopharyngeal carriage of S. pneumoniae in the 3 groups ranged from 80% to 89% of subjects (table 2). In the group treated with azithromycin on day 0, the proportion of subjects who had carriage of S. pneumoniae decreased from 85% before treatment to 42% 10 days after azithromycin treatment (adjusted P <.001). The prevalence of carriage did not change between day 0 and day 10 in the group that was not currently receiving antimicrobial treatment

Table 2
Table 2

Rates of nasopharyngeal carriage and antimicrobial resistance for Streptococcus pneumoniae isolates from children in study of secondary effects of mass treatment with azithromycin

For the current treatment group, we did not recover azithromycin-resistant S. pneumoniae from the samples obtained before treatment or the samples obtained 10 days or 6 months after a single treatment (table 2). Nor did we recover azithromycin-resistant pneumococci from samples obtained 6 months or 1 year after a single treatment from the group who had 1 previous exposure to azithromycin. However, in the group with 2 previous exposures to azithromycin, 2 (2%) of 92 pneumococcal isolates had resistance to azithromycin documented at day 0 (P =.05 vs. the other 2 groups), which was 6 months after they received their second treatment, and 4 (4.5%) of 88 isolates had azithromycin resistance documented at day 180 (P =.002 vs. the other 2 groups) 1 year after they received their second treatment. Both of the azithromycin-resistant isolates recovered from samples obtained at day 0 were serotype 19A; they were recovered from children in different households but in the same village. Of the 4 azithromycin-resistant isolates documented at day 180, 3 were recovered from children in the same village; 1 of these children had a resistant isolate on day 0. Two isolates were serotype 19A, and 1 isolate was serotype 11A. The other azithromycin-resistant isolate, which was recovered from a child in another village, was serotype 11A. Because 1 child carried a resistant strain both documented at day 0 and at day 180, the overall prevalence of azithromycin-resistant pneumococci in the group with 2 previous exposures was 4.3% (5 of 115 subjects; P <.001 vs. the other 2 groups). There was no difference in the number of azithromycin-resistant isolates at day 0 and at day 180 in the group with 2 previous azithromycin exposures (P =.63). All azithromycin-resistant isolates were susceptible to clindamycin; pneumococcal strains with inducible ermB methylase gene are usually susceptible to clindamycin

Sulfamethoxazole resistance in the pneumococcal isolates was common. Resistance to chloramphenicol and penicillin was less common; all 7 of the chloramphenicol-resistant isolates were also resistant to sulfamethoxazole (table 2). None of the azithromycin-resistant isolates were resistant to sulfamethoxazole, penicillin, or chloramphenicol

Beneficial effects In the current treatment group, the proportion of children with impetigo had decreased significantly at day 10 after the administration of azithromycin (table 3) and had returned to the baseline value 6 months later (figure 2). No difference was seen in the proportion of children with impetigo between day 0 and day 10 in the group that was not currently receiving treatment. Similarly, fewer children in the current treatment group were reported by parents to have skin lesions on day 10 than did on day 0 (2 [1%] of 164 children vs. 10 [6%] of 166; adjusted OR, 0.20; 95% CI, 0.05–0.80). No differences were noted in the proportion of children with skin lesions (as reported by parents) in the untreated group (4 [2%] of 163 vs. 5 [3%] of 174; adjusted OR, 0.83; 95% CI, 0.30–2.28). At day 180, the proportion of children with impetigo was similar to the proportion at day 0 in both the current treatment group (13% of subjects; adjusted OR, 1.01; 95% CI, 0.54–1.89) and the 1 previous treatment group (22% of subjects; adjusted OR, 1.23; 95% CI, 0.73–2.06). These results were not confounded by receipt of antibiotics by the child or siblings during the previous month

Table 3
Table 3

Proportions of children with impetigo (detected by skin examination) and symptoms of illness (reported during interview) on days 0 and 10

The proportions of children with reported diarrhea, abdominal pain, and vomiting in the current treatment group had decreased at day 10 (table 3). There were no differences in the proportions of children with diarrhea, abdominal pain, or vomiting between day 0 and day 10 in the group that did not receive azithromycin 10 days earlier. Antibiotic use by the child or siblings during the previous month did not confound these results. Diarrhea was less commonly reported in the winter (i.e., at day 180) than in the spring (i.e., at day 0) in all groups (figure 2). There were no differences between groups in the proportions of children reported to have cough, shortness of breath, fever, headache, or general illness. When parents were asked whether they knew why azithromycin was administered to their child, few identified illness of the eye, skin, respiration, or digestive system as a reason (current treatment group: at day 0, 7% of subjects; at day 180, 3%; 1 previous treatment group: at day 0, 5% of subjects; at day 180, 3%; 2 previous treatments group: at day 0, 26% of subjects; at day 180, 7%)

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Discussion

In rural Nepal, we found no macrolide resistance among pneumococcal isolates recovered from specimens obtained from children before administration of a single mass treatment with azithromycin, and we found none 10 days and 6 months after the mass treatment. In children from 2 villages that had received 2 consecutive mass treatments, a small number of macrolide-resistant pneumococci persisted 1 year after the second treatment. We did not find a change in the proportion of pneumococci recovered after azithromycin treatment that were resistant to sulfa or penicillin agents, relative to the proportion recovered before azithromycin treatment. Because no intervention has been shown to be as effective as administration of antimicrobial agents in reducing the prevalence of endemic trachoma [2–5, 18], mass treatment with azithromycin will be critical in reducing the prevalence of endemic trachoma and achieving the GET2020 goal of eradication. Therefore, our results are encouraging for the initial phase of the GET2020 campaign

It is estimated that ∼6 million cases of blindness worldwide are due to trachoma [19]. The reduction of the prevalence of endemic trachoma by means of azithromycin therapy is a cornerstone of the GET2020 strategy and is anticipated to be the principal long-term beneficial effect of such mass treatment. We found short-term beneficial effects as well, including a reduction in the number of children with symptoms of diarrhea and children with impetigo. Investigators in The Gambia, a region with high rates of malaria transmission, also noted fewer episodes of fever and headache, symptoms consistent with acute malaria, as well as less diarrhea and vomiting among children who received azithromycin for the reduction of blindness due to trachoma [10]. Diarrhea is a leading cause of childhood mortality in many countries where trachoma is endemic [20]. Also, in some children, impetigo caused by group A streptococci can be complicated by glomerulonephritis. Antibiotic prophylaxis has been used to reduce the frequency of group A streptococcal infections among military recruits in the United States [21, 22]. Although the rate of malaria transmission is low in Nepal, malaria is a leading cause of childhood mortality in other regions in which trachoma is endemic. We have no evidence that these transient effects of azithromycin use result in any lasting health benefits. Although these small benefits alone do not warrant mass treatment with azithromycin, parents may appreciate these additional benefits, especially if the distribution of azithromycin coincides with the seasonal peak for these syndromes

In Western countries, the increasing prevalence of macrolide resistance in Streptococcus species in the community has been correlated with increasing macrolide use in the community [8, 9]. Two mechanisms can explain an increase in the proportion of pneumococci that are antimicrobial resistant: selective expansion of resistant clones that already exist in the community or induction of new resistant isolates [23]. In far-western Nepal, a survey of pharmacies and pharmaceutical distribution centers indicated that macrolide antibiotic use was uncommon [24]; therefore, macrolide antimicrobial pressure is placed on pneumococci in these communities only once a year, when the single mass treatment is administered. From our study, it appears that 2 consecutive annual treatments may be enough to induce a small number of macrolide-resistant pneumococcal strains in the community. If annual treatments were continued in these communities, which now have circulating resistant organisms, it is unclear what the effect on the prevalence of antimicrobial resistance would be

In a trachoma control study among Aboriginal children in Australia, azithromycin-resistant strains were present in a small proportion of children (1.3% of those examined) before treatment with azithromycin was initiated [6]. Azithromycin treatment resulted in a statistically significant increase in the prevalence of nasopharyngeal carriage of macrolide-resistant S. pneumoniae 3–4 weeks and 2 months after treatment (to 15.8% and 27% of children, respectively). At 6 months, the prevalence of carriage of resistant isolates had decreased (to 5.1% of children). These findings differ from ours, most likely because azithromycin-resistant pneumococci were already circulating in the Australian community before initiation of mass treatment. Together, these study results suggest that the effect of mass treatment on the prevalence of antimicrobial resistance in communities that will require multiple mass treatments or communities with macrolide-resistant organisms circulating before treatment may warrant future investigation

Because the potential exists to induce antimicrobial-resistant pneumococci after multiple mass treatments, methods that maintain the beneficial effects of azithromycin and reduce the need for multiple treatments may become increasingly important in the campaign to eradicate trachoma. Improvements in environmental hygienic conditions may minimize the prevalence of trachoma in communities [25]; however, more research is needed to better define C. trachomatis reservoirs and modes of transmission. Efforts to identify and optimize environmental factors that facilitate the eradication effort may minimize the need for multiple mass antimicrobial treatments and the need for expensive monitoring systems

Although it is unlikely that our primary finding, the prevalence of antimicrobial-resistant pneumococci, was influenced by potential biases, some of our results should be interpreted cautiously. One-third of parents from all villages reported that their children had received antimicrobial agents in the month previous to the study; we were unable to determine which agents were used in each village or to verify that the medication was an antimicrobial agent. Therefore, it is possible that antimicrobial agents other than azithromycin could account for the beneficial effects that we noted. However, the addition of the factor “use of an antimicrobial agent” into the multivariate analysis did not alter our findings, and all villages had a similar prevalence of resistance to antimicrobial agents other than azithromycin, which suggests the availability of similar antimicrobial agents. Therefore, it seems less likely that other antimicrobial agents account for our findings

Our questionnaire data may have been influenced by better parent recall at day 10 than at day 0, a bias that may explain the decrease in frequency of reported respiratory symptoms, headache, and fever in both the treated and untreated groups at day 10, compared with at day 0. Also, the data obtained by interview were possibly influenced by parental perception of the effects of azithromycin. However, because no parent perceived gastrointestinal illness to be a reason for azithromycin distribution, it seems unlikely that our results suggesting that azithromycin has a beneficial effect on the incidence of diarrhea, vomiting, and abdominal pain were significantly influenced by this bias. The questionnaire data may also be biased because of interviewers who were not blinded to the treatment status of the village; however, if this were the case, we would expect all symptoms, not only gastrointestinal and skin-related symptoms, to be consistently better in treated villages

Finally, we were unable to have a skin examination for impetigo performed by a person blinded to the treatment groups. To evaluate the potential effect of this bias, we had assessed the frequency of skin lesions separately, by asking for a report from parents, and these data were consistent with the skin examination results, which suggests that bias was unlikely to be an important explanation for our findings

Mass administration of antimicrobial agents is a key component in several global disease elimination or control campaigns in addition to the campaign to eliminate blindness due to trachoma. These include programs to eliminate or control onchocerciasis with use of ivermectin, to prevent opportunistic infections in AIDS patients with use of cotrimoxazole, and others [26–29]. Such interventions may have secondary effects, both adverse and beneficial, and efforts to quantify adverse effects should be integrated into disease-elimination campaigns. The present study provides some reassurance that the trachoma elimination campaign will not rapidly induce the emergence of antimicrobial resistance in pneumococci in regions where the prevalence of resistance is low at baseline and where <2 mass antimicrobial treatments will be needed. However, other questions about secondary effects remain unanswered. To maintain public confidence and ensure the long-term success of such global campaigns, studies such as this one should be routinely integrated into all phases of global control programs that use mass chemoprophylaxis as a major component

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Acknowledgments

We acknowledge the following for their invaluable assistance in the field: the staff of Geta Eye Hospital (Dhanghedi, Nepal), including B. K. Jamuna, L. R. Panta, R. B. Chaudhary, B. S. Dhami, A. Rana, M. Gurung, and B. Gurung; Helen Keller International, including G. Rana, B. B. Chuadhary, and L. Upadhaya; the Proctor Foundation, including S. O. Holmes and L. Freidly; and the Respiratory Diseases Branch, Centers for Disease Control and Prevention (CDC; Atlanta, GA), including M. Brondson, R. Downey, and I. Chuang. We also thank the following for their assistance and support through out the study: H. S. Bista, Norwegian Association of the Blind and Partially Sighted (Kathmandu, Nepal); D. S. Rijal and R. P. Pokhrel, Nepalese Society for Comprehensive Eye Care (Kathmandu); L. Tapert and B. B. Thapa, Helen Keller International; R. M. Scott and M. N. Viadya, Walter Reed/AFRIMS Research Unit (Kathmandu); R. Facklam, D. Jackson, and E. Zell, Respiratory Diseases Branch, CDC; D. Negrel, Prevention of Blindness program, and R. Williams, Anti-Infective Drug Resistance Surveillance and Containment Department of Communicable Disease Surveillance and Response, World Health Organization (Geneva, Switzerland)

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Footnotes

  • Financial support: United States Agency for International Development, Antimicrobial Resistance Initiative

  • Received January 7, 2002.
  • Revision received March 4, 2002.
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References

  1. ↵
    1. World Health Organization
    . 51st World Health Assembly. Resolution 51.11.1998. Available at: http://who.int/pbd/trachoma/wha51-e.htm. Accessed 25 June 2002.
  2. ↵
    1. Bailey RL,
    2. Whittle HC,
    3. Mabey D
    . Randomised controlled trial of single-dose azithromycin in treatment of trachoma. Lancet 1993;342:453-6.
    CrossRefMedlineWeb of Science
    1. Tabbara KF,
    2. al-Omar O,
    3. Choudhury AH,
    4. al-Faisal Z
    . Single-dose azithromycin in the treatment of trachoma: a randomised, controled study. Ophthalmology 1996;103:842-6.
    MedlineWeb of Science
    1. Dawson CR,
    2. Sallam S,
    3. Sheta A,
    4. et al
    . A comparison of oral azithromycin with topical oxytetracycline/polymyxin for the treatment of trachoma in children. Clin Infect Dis 1997;24:363-8.
    Abstract/FREE Full Text
  5. ↵
    1. Schachter J,
    2. Mabey DCW,
    3. Dawson CW,
    4. et al
    . Azithromycin in control of trachoma. Lancet 1999;354:630-5.
    CrossRefMedlineWeb of Science
  6. ↵
    1. Leach AJ,
    2. Mayo M,
    3. Gratten M,
    4. et al
    . A prospective study of the impact of community-based azithromycin treatment of trachoma on carriage and resistance of Streptococcus pneumoniae. Clin Infect Dis 1997;24:356-62.
    Abstract/FREE Full Text
  7. ↵
    1. Chern KC,
    2. Cevallos V,
    3. Dhami HL,
    4. et al
    . alterations in the conjunctival bacterial flora following a single dose of azithromycin in a trachoma endemic area. Br J Ophthalmol 1999;83:1332-5.
    Abstract/FREE Full Text
  8. ↵
    1. Hyde TB,
    2. Gay K,
    3. Stephens RS,
    4. et al
    . Macrolide resistance among invasive Streptococcus pneumoniae isolates. JAMA 2001;286:1857-62.
    Abstract/FREE Full Text
  9. ↵
    1. Seppala H,
    2. Klaukka T,
    3. Vuopio-Varkila J,
    4. et al
    . The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. Finnish study group for antimicrobial resistance. N Engl J Med 1997;337:441-6.
    CrossRefMedlineWeb of Science
  10. ↵
    1. Whitney CG,
    2. Farley MM,
    3. Hadler J,
    4. et al
    . Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United States. N Engl J Med 2000;343:1917-24.
    CrossRefMedlineWeb of Science
  11. ↵
    1. World Health Organization
    . Integrated management of the sick child. Bull World Health Organ 1995;73:735-40.
    MedlineWeb of Science
  12. ↵
    1. Adegbola RA,
    2. Bailey R,
    3. Secka O,
    4. et al
    . Effect of azithromycin on pharyngeal microflora. Pediatr Infect Dis J 1995;14:335-6.
    CrossRefMedlineWeb of Science
  13. ↵
    1. Whitty JM,
    2. Glasgow KW,
    3. Sadiq ST,
    4. et al
    . Impact of community-based mass treatment for trachoma with oral azithromycin on general morbidity in Gambia children. Pediatr Infect Dis J 1999;18:955-8.
    CrossRefMedlineWeb of Science
  14. ↵
    1. Tarlow MJ,
    2. Harris J,
    3. Kolokathis A
    . Future indications for macrolides. Pediatr Infect Dis J 1997;16:457-62.
    CrossRefMedlineWeb of Science
  15. ↵
    1. Holms SO,
    2. Bhatta RC,
    3. Chaudhary JS,
    4. et al
    . Comparison of two azithromycin distribution strategies for controlling trachoma in Nepal. Bull World Health Organ 2001;79:194-200.
    MedlineWeb of Science
  16. ↵
    1. O'Brien KL,
    2. Dagan R,
    3. Yagupsky P,
    4. et al
    . Evaluation of a medium (STGG) for transport and optimal recovery of Streptococcus pneumoniae from nasopharyngeal secretions collected during field studies. J Clin Microbiol 2001;39:1021-4.
    Abstract/FREE Full Text
  17. ↵
    1. National Committee for Clinical Laboratory Standards (NCCLS)
    . Performance standards for antimicrobial susceptibility testing: approved standard. NCCLS document M100-S9. Wayne, PA: NCCLS; 1999.
  18. ↵
    1. Bowman RJ,
    2. Van Den C,
    3. Goode VM,
    4. et al
    . Operational comparison of single-dose azithromycin and topical tetracycline for trachoma. Invest Ophthalmol Vis Sci 2000;41:4074-9.
    Abstract/FREE Full Text
  19. ↵
    1. Thylefors B,
    2. Negrel A,
    3. Pararajasegarem R,
    4. Dadzie K
    . Global data on blindness. Bull World Health Organ 1995;73:115-21.
    MedlineWeb of Science
  20. ↵
    1. Cheney CP
    . Acute infectious diarrhea. Med Clin North Am 1993;77:1169-96.
    MedlineWeb of Science
  21. ↵
    1. Thomas RJ,
    2. Conwill DE,
    3. Morton DE,
    4. et al
    . Penicillin prophylaxis for streptococcal infections in the United States Navy and Marine Corps recruitment camps, 1951–;1985. Rev Infect Dis 1988;10:125-30.
    MedlineWeb of Science
  22. ↵
    1. Gray GC,
    2. McPhate DC,
    3. Leinonen M,
    4. et al
    . Weekly oral azithromycin as prophylaxis for agents causing acute respiratory disease. Clin Infect Dis 1998;26:103-10.
    Abstract/FREE Full Text
  23. ↵
    1. Schrag SJ,
    2. Bealle B,
    3. Dowell SF
    . Limiting the spread of resistant pneumococci: biological and epidemiologic evidence for the effectiveness of alternative interventions. Clin Microbiol Rev 2000;13:588-601.
    Abstract/FREE Full Text
  24. ↵
    1. Scheidler VF,
    2. Bhatta RC,
    3. Miao Y
    . Antibiotic use patterns in a trachoma-epidemic region of Nepal. Ophthalmic Epidemiol. in press.
  25. ↵
    1. Emerson PM,
    2. Bailey RL,
    3. Mabey DCW
    . Review of the evidence base for the “F” and “E” components of the SAFE strategy for trachoma control. Trop Med Int Health 2000;5:515-27.
    CrossRefMedlineWeb of Science
  26. ↵
    1. UNAIDS [United Nations Programme on HIV/AIDS]
    . Accelerating access to HIV care, support and treatment: opportunistic infections. 2001. Available at: http://www.unaids.org/acc_access/opportunistic_infections/index.html. Accessed 25 June 2002.
    1. Gilles HM
    . The conquest of “river blindness”. Ann Trop Med Parasitol 1991;85:97-101.
    MedlineWeb of Science
    1. Burnham GM
    . Adverse reactions to ivermectin treatment for onchocerciasis. Results of a placebo-controlled, double-blind trial in Malawi. Trans R Soc Trop Med Hyg 1993;87:313-7.
    CrossRefMedlineWeb of Science
  29. ↵
    1. Pacque M,
    2. Greene BM,
    3. Taylor HR
    . Community-based treatment of onchocerciasis with ivermectin: safety, efficacy, and acceptability of yearly treatment. J Infect Dis 1991;163:381-5.
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  1. Clin Infect Dis. (2002) 35 (4): 395-402. doi: 10.1086/341414
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