Antibióticos para el tracoma
Resumen
Antecedentes
El tracoma es la principal causa infecciosa prevenible de ceguera en el mundo. En 1996, la OMS lanzó la Alliance for the Global Elimination of Trachoma by the year 2020; basada en la estrategia "SAFE" (del inglés surgery, antibiotics, facial cleanliness, and environmental improvement).
Objetivos
Evaluar la evidencia que apoya el brazo de antibióticos de la estrategia SAFE mediante la evaluación de los efectos de los antibióticos sobre el tracoma activo (objetivo primario), la infección de la conjuntiva por Chlamydia trachomatis, la resistencia a los antibióticos y los efectos adversos (objetivos secundarios).
Métodos de búsqueda
Se realizaron búsquedas en las bases de datos electrónicas pertinentes y en los registros de ensayos. La fecha de la última búsqueda fue el 4 de enero de 2019.
Criterios de selección
Se incluyeron ensayos controlados aleatorizados (ECA) que cumplían con cualquiera de los dos criterios: (a) ensayos en los que la administración tópica u oral de un antibiótico se comparó con placebo o ningún tratamiento en personas o comunidades con tracoma, (b) ensayos en los que se comparó un antibiótico tópico con un antibiótico oral en personas o comunidades con tracoma. También se incluyeron los estudios que consideraron diferentes estrategias de dosis en la población.
Obtención y análisis de los datos
Se utilizaron los métodos estándar previstos por Cochrane. La certeza de la evidencia se evaluó mediante los criterios GRADE.
Resultados principales
Se identificaron 14 estudios en los que se asignó al azar a individuos con tracoma y 12 estudios con asignación al azar grupal.
Cualquier antibiótico versus control (individuos)
Nueve estudios (1961 participantes) asignaron al azar a los individuos con tracoma para recibir antibióticos o un control (ningún tratamiento o placebo). Todos estos estudios incluyeron a niños y jóvenes con tracoma activo. Los antibióticos utilizados en estos estudios incluyeron (oxi)tetraciclina tópica (cinco estudios), doxiciclina (dos estudios) y sulfonamidas (cuatro estudios). Cuatro estudios tuvieron más de dos brazos de estudio. En general, estos estudios se informaron de manera deficiente y fue difícil juzgar el riesgo de sesgo.
Estos estudios proporcionaron evidencia de certeza baja de que los pacientes con tracoma activo tratados con antibióticos experimentaron una reducción del tracoma activo a los tres meses (riesgo relativo [RR] 0,78; intervalo de confianza [IC] del 95%: 0,69 a 0,89; 1961 pacientes; nueve ECA; I2 = 73%) y a los 12 meses (RR 0,74; IC del 95%: 0,55 a 1,00; 1035 pacientes; cuatro ECA; I2 = 90%). Hubo evidencia de certeza baja disponible para la infección ocular a los tres meses (RR 0,81; IC del 95%: 0,63 a 1,04; 297 pacientes; cuatro ECA; I2 = 0%) y a los 12 meses (RR 0,25; IC del 95%: 0,08 a 0,78; 129 pacientes; un ECA). Ninguno de estos estudios evaluó la resistencia a los antimicrobianos. En los estudios que informaron los efectos perjudiciales, no se informaron efectos adversos graves (evidencia de certeza baja).
Antibióticos orales versus tópicos (individuos)
Ocho estudios (1583 participantes) compararon los antibióticos orales y tópicos. Solo un estudio incluyó a pacientes mayores de 21 años de edad. Los antibióticos orales incluyeron azitromicina (cinco estudios), sulfonamidas (dos estudios) y doxiciclina (un estudio). Los antibióticos tópicos incluyeron (oxi)tetraciclina (seis estudios), azitromicina (un estudio) y sulfonamida (un estudio). Estos estudios se informaron de manera deficiente y fue difícil juzgar el riesgo de sesgo.
Hubo evidencia de certeza baja de poca o ninguna diferencia en el efecto entre los antibióticos orales y tópicos sobre el tracoma activo a los tres meses (RR 0,97; IC del 95%: 0,81 a 1,16; 953 pacientes; seis ECA; I2 = 63%) y a los 12 meses (RR 0,93; IC del 95%: 0,75 a 1,15; 886 pacientes; cinco ECA; I2 = 56%). Hubo evidencia de certeza muy baja para la infección ocular a los tres o 12 meses. No se evaluó la resistencia a los antimicrobianos. En los estudios que presentaron los efectos adversos, no se informaron efectos adversos graves; un estudio informó de dolor abdominal con azitromicina; un estudio informó dos casos de náuseas con azitromicina; y un estudio informó de tres casos de reacción a las sulfonamidas (evidencia de certeza baja).
Azitromicina oral versus control (comunidades)
Cuatro estudios con asignación al azar grupal compararon el antibiótico con ningún tratamiento o con tratamiento tardío. Se dispuso de datos sobre el tracoma activo a los 12 meses a partir de dos estudios, aunque no se pudieron agrupar debido a las diferencias en los informes. Un estudio en riesgo bajo de sesgo encontró una menor prevalencia del tracoma activo 12 meses después de una dosis única de azitromicina en comunidades con una prevalencia alta de infección (RR 0,58; IC del 95%: 0,52 a 0,65; 1247 pacientes). El otro estudio, de menor calidad, realizado en comunidades de prevalencia baja informó prevalencias medianas similares de la infección a los 12 meses: 9,3% en las comunidades tratadas con azitromicina y 8,2% en las comunidades no tratadas. Esta evidencia sobre una reducción del tracoma activo con el tratamiento se consideró de certeza moderada; se disminuyó en un nivel debido a la inconsistencia entre los dos estudios. Dos estudios informaron infección ocular a los 12 meses y se pudieron agrupar los datos. Hubo una reducción de la infección ocular (RR 0,36; 0,31 a 0,43; 2139 pacientes) 12 meses después del tratamiento masivo con una dosis única en comparación con ningún tratamiento (evidencia de certeza moderada). Hubo evidencia de certeza alta de un mayor riesgo de resistencia de las bacterias Streptococcus pneumoniae, Staphylococcus aureus, y Escherichia coli a la azitromicina, la tetraciclina y la clindamicina en las comunidades tratadas con azitromicina, con riesgo relativos aproximadamente cinco veces mayores a los 12 meses. La evidencia no apoyó un aumento de la resistencia a la penicilina o al trimetoprim‐sulfametoxazol. Ninguno de los estudios midió la resistencia a la C trachomatis. No se informaron eventos adversos graves. El efecto adverso principal observado para la azitromicina (˜10%) fue el dolor abdominal, los vómitos y las náuseas.
Azitromicina oral versus tetraciclina tópica (comunidades)
Tres estudios con asignación al azar por grupos compararon azitromicina oral con tetraciclina tópica. La evidencia fue inconsistente para el tracoma activo y la infección ocular a los tres y 12 meses (evidencia de certeza baja) y no se agrupó debido a la heterogeneidad considerable. No se informó sobre la resistencia a los antimicrobianos ni sobre los efectos adversos.
Diferentes estrategias de dosis
Seis estudios compararon diferentes estrategias para la dosis. Hubo: tratamiento masivo en diferentes intervalos de dosis; aplicación de reglas de interrupción o suspensión del tratamiento masivo; estrategias para aumentar la cobertura del tratamiento masivo. No hubo evidencia sólida para apoyar cualquier variación en el tratamiento masivo anual recomendado.
Conclusiones de los autores
El tratamiento con antibióticos puede reducir el riesgo de tracoma activo e infección ocular en los pacientes con infección por C trachomatis, en comparación con ningún tratamiento/placebo, aunque no se conoce el tamaño del efecto del tratamiento en los individuos. El tratamiento con antibióticos masivos con una dosis única oral de azitromicina reduce la prevalencia del tracoma activo y de la infección ocular en las comunidades. No existe evidencia sólida que apoye cualquier variación en la periodicidad recomendada del tratamiento masivo anual. Hay evidencia de un mayor riesgo de resistencia a los antibióticos a los 12 meses en las comunidades tratadas con antibióticos.
PICO
Resumen en términos sencillos
Antibióticos para el tracoma
¿Cuál es el objetivo de esta revisión?
El objetivo de esta revisión Cochrane fue averiguar si los antibióticos funcionan para el tratamiento del tracoma, ya sea en individuos o en comunidades. Los investigadores Cochrane recopilaron y analizaron todos los estudios pertinentes para responder a esta pregunta y encontraron 26 estudios.
Mensajes clave
La revisión muestra que el tratamiento con antibióticos en pacientes y comunidades con tracoma da lugar a menos infecciones oculares debido al tracoma y a menos enfermedades oculares. El tratamiento masivo con antibióticos en las comunidades se asocia con un aumento de la resistencia a los antimicrobianos.
¿Qué se estudió en la revisión?
El tracoma es causado por un tipo de infección bacteriana de la parte externa del ojo que, si no se trata, puede provocar ceguera. Este germen se conoce como Chlamydia trachomatis, el cual prospera donde escasea el agua y la higiene es deficiente. El tracoma es la causa infecciosa más común de pérdida de la visión y suele afectar a las personas que viven en comunidades de escasos recursos. Los episodios repetidos de conjuntivitis (inflamación de la membrana que cubre la superficie del globo ocular y el interior de los párpados) conocidos como "tracoma activo", que son causados por esta infección ocular, pueden dar lugar a que el párpado superior se voltee hacia adentro. Las pestañas rozan la parte frontal transparente del ojo (córnea), lo que provoca dolor, formación de cicatrices y ceguera.
La Organización Mundial de la Salud (OMS) ha desarrollado la estrategia SAFE (por sus siglas en inglés) para eliminar el tracoma.
‐ Cirugía de los párpados que se voltean hacia adentro
‐ Antibióticos para eliminar la infección ocular
‐ Limpieza facial para detener la transmisión de la infección ocular
‐ Mejoría del medio ambiente, en particular, agua potable y saneamiento
Esta revisión considera la parte A de la estrategia SAFE. Se pueden utilizar antibióticos para tratar la infección ocular, los cuales pueden administrarse como pomadas o por vía oral. Los dos antibióticos utilizados comúnmente para el tratamiento del tracoma son la azitromicina (dosis única por vía oral) y la tetraciclina (pomada aplicada en el ojo durante varias semanas).
¿Cuáles son los principales resultados de la revisión?
Los investigadores Cochrane encontraron 26 estudios relevantes.
Catorce estudios incluyeron a pacientes con tracoma. Estos estudios se realizaron en las siguientes regiones de la OMS (un estudio se realizó en dos regiones): Región de África (tres estudios), Región del Mediterráneo Oriental (cinco estudios), Región de las Américas (cuatro estudios), Región de Asia Sudoriental (un estudio) y Región del Pacífico Occidental (dos estudios). La mayoría de los estudios incluyeron a niños y jóvenes con tracoma activo.
Estos estudios demostraron que:
⇒ los pacientes con tracoma tratados con antibióticos pueden presentar una actividad menor en el tracoma y la infección ocular a los tres y 12 meses después del tratamiento (evidencia de certeza baja);
⇒ puede haber poca o ninguna diferencia en el tracoma activo entre los pacientes que reciben antibióticos orales y tópicos a los tres y 12 meses (evidencia de certeza baja), aunque solo hubo evidencia de certeza muy baja sobre la infección ocular a los tres y 12 meses;
⇒ no hubo informes de efectos adversos graves. El efecto adverso informado con más frecuencia fueron las náuseas con la administración de azitromicina.
Doce estudios incluyeron a comunidades en áreas donde el tracoma es común y trataron a toda la comunidad ("tratamiento masivo"). Estos estudios se realizaron principalmente en la región de África (10 estudios), un estudio en la región del Mediterráneo Oriental (Egipto) y otro en la región del Pacífico Occidental (Vietnam).
Estos estudios demostraron que:
⇒ las comunidades tratadas con azitromicina tuvieron menos tracoma (tracoma activo e infección ocular) 12 meses después de un tratamiento de dosis única (evidencia de certeza moderada);
⇒ no hubo evidencia sólida que apoyara el cambio de la estrategia de tratamiento masivo actualmente recomendada para las comunidades afectadas cada año;
⇒ hubo un mayor riesgo de resistencia a los antimicrobianos en las comunidades tratadas (evidencia de certeza alta).
¿Cuál es el grado de actualización de esta revisión?
Los investigadores Cochrane buscaron estudios publicados hasta el 4 de enero de 2019.
Authors' conclusions
Summary of findings
| Antibiotic versus control for trachoma: individuals | ||||||
| Patient or population: people (any age) with active trachoma | ||||||
| Outcomes | Follow‐up | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Certainty of the evidence | |
| Assumed risk | Corresponding risk | |||||
| Control | Antibiotic | |||||
| Active trachoma Clinical assessment: active trachoma defined as TF, TI, or both | 3 months | Study population | RR 0.78 | 1961 | ⊕⊕⊝⊝ | |
| 800 per 1000 | 624 per 1000 | |||||
| 12 months | Study population | RR 0.74 | 1035 | ⊕⊕⊝⊝ | ||
| 750 per 1000 | 555 per 1000 | |||||
| Ocular C trachomatis infection Positive test for C trachomatis infection identified by culture, staining on conjunctival smears, or nucleic acid amplification methods | 3 months | Study population | RR 0.81 | 297 | ⊕⊕⊝⊝ | |
| 500 per 1000 | 405 per 1000 | |||||
| 12 months | Study population | RR 0.25 | 129 | ⊕⊕⊝⊝ | ||
| 200 per 1000 | 50 per 1000 | |||||
| Antibiotic resistance Proportion of samples showing evidence of resistance to antibiotic | Any time point | None of the studies addressed this outcome. | ||||
| Adverse effects | Any time point | 4 studies made no comment on adverse effects. 3 studies noted no untoward reactions (sulfonamides) or only trivial reactions (tetracycline, sulfonamide). 1 study of 155 students noted 3 adverse reactions to sulfonamide (severe purpura associated with marked thrombocytopenia, 2 cases of drug rash). 1 study of 122 children noted anorexia, nausea, vomiting, or diarrhoea in 3 children. 2 of these children were receiving doxycycline, and the disturbances lasted only a single day in each child, in spite of continuing medication. | 1961 | ⊕⊕⊝⊝ | ||
| *The assumed risk is the median risk in control groups in the included studies (rounded to nearest 10 per 1000). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; TF: trachomatous inflammation‐follicular; TI: trachomatous inflammation‐intense; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded one level for serious limitations in study design (methods of sequence generation, allocation concealment, and masking poorly reported; three studies at high risk of attrition bias) and one level for serious inconsistency (risk ratios ranged from 0.40 to 1.02 and I2 = 73%). | ||||||
| Oral versus topical antibiotic for trachoma: individuals | |||||||
| Patient or population: people (any age) with active trachoma | |||||||
| Outcomes | Follow‐up | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Certainty of the evidence | Comments | |
| Assumed risk | Corresponding risk | ||||||
| Topical antibiotic | Oral antibiotic | ||||||
| Active trachoma Clinical assessment: active trachoma defined as TF, TI, or both | 3 months | Study population | RR 0.97 | 953 | ⊕⊕⊝⊝ low1 | ||
| 600 per 1000 | 582 per 1000 | ||||||
| 12 months | Study population | RR 0.93 | 886 | ⊕⊕⊝⊝ low2 | |||
| 500 per 1000 | 465 per 1000 | ||||||
| Ocular C trachomatis infection Positive test for C trachomatis infection identified by culture, staining on conjunctival smears, or nucleic acid amplification methods | 3 months | See comment | See comment | Not estimable | 298 | ⊕⊝⊝⊝ | No pooled estimate due to high heterogeneity: Darougar 1980 RR 6.05 (95% CI 0.78, 46.95); Dawson 1997 RR 0.57 (0.14, 2.30); Tabbara 1996 RR 1.30 (0.41, 4.11) |
| 12 months | See comment | See comment | Not estimable | 220 | ⊕⊝⊝⊝ | Darougar 1980 RR 2.59 (95% CI 0.28, 23.88); Dawson 1997 RR 0.50 (0.18, 1.43) | |
| Antibiotic resistance Proportion of samples showing evidence of resistance to antibiotic | Any time point | None of the studies addressed this outcome. | |||||
| Adverse effects | Any time point | 3 studies made no comment on adverse effects. 1 study of 155 students noted 3 adverse reactions to sulfonamide (severe purpura associated with marked thrombocytopenia, 2 cases of drug rash). 1 study of 194 people reported abdominal pain more often in azithromycin group (26% versus 16%, P = 0.09). Other effects: diarrhoea, vomiting, fever, headache, body pain were similar between 2 study groups. 1 study of 60 people reported no serious adverse reactions and that both azithromycin and tetracycline were well tolerated. 1 study of 168 children noted that azithromycin was well tolerated and that only 2 children (of 125 treated) complained of nausea. | 1583 | ⊕⊕⊝⊝ | |||
| *The assumed risk is the median risk in control groups in the included studies (rounded to nearest 10 per 1000). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; TF: trachomatous inflammation‐follicular; TI: trachomatous inflammation‐intense; RR: risk ratio | |||||||
| GRADE Working Group grades of evidence | |||||||
| 1Downgraded one level for serious limitations in study design (only one study reported adequate methods for allocation concealment and masking of outcome assessment) and one level for inconsistency (study estimates ranged from 0.65 to 1.37 and I2 = 63%). | |||||||
| Oral azithromycin compared to control for trachoma: communities | ||||||
| Patient or population: people (any age) with active trachoma | ||||||
| Outcomes | Follow‐up | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Certainty of the evidence (GRADE) | Comments |
| Assumed risk | Corresponding risk | |||||
| Control | Oral azithromycin | |||||
| Active trachoma | 3 months | None of the studies addressed this outcome. | ||||
| 12 months | Medium‐risk population | RR 0.58 (0.52 to 0.65) | 1247 | ⊕⊕⊕⊝ moderate1 | One additional study reported data as median community prevalence. At 12 months, the median community prevalence of active trachoma was 9.3% in communities given one single dose of azithromycin (range 0 to 38.9%) and 8.2% in communities that had not been treated (range 0 to 52.9%). | |
| 100 per 1000 | 58 per 1000 (52 to 65) | |||||
| High‐risk population | ||||||
| 300 per 1000 | 174 per 1000 (156 to 195) | |||||
| Ocular C trachomatis infection Positive test for C trachomatis infection identified by culture, staining on conjunctival smears, or nucleic acid amplification methods | 3 months | None of the studies addressed this outcome. | ||||
| 12 months | Medium‐risk population | RR 0.36 | 2139 (2 studies) | ⊕⊕⊕⊝ moderate2 | ||
| 100 per 1000 | 36 per 1000 | |||||
| High‐risk population | ||||||
| 300 per 1000 | 108 per 1000 | |||||
| Antibiotic resistance Proportion of samples showing evidence of resistance to antibiotic | Any time point | There was evidence of an increased risk of resistance of S pneumoniae, S aureus, and E coli to azithromycin, tetracycline, and clindamycin with risk ratios in the order of 5 at 12 months. No evidence to support increased resistance to penicillin or trimethoprim/sulfamethoxazole. | 1354 (4 studies) | ⊕⊕⊕⊕ high | ||
| Adverse effects | Any time point | No serious adverse events reported. Azithromycin associated with reduced mortality in children. Main adverse effect of azithromycin (in approximately 10% of the population) was abdominal pain, vomiting, and nausea. | 3069 | ⊕⊕⊕⊕ high | ||
| *The assumed risk (medium/high risk) were based on prevalence estimates used as the basis for recommendations as set out in WHO 2010. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; TF: trachomatous inflammation‐follicular; TI: trachomatous inflammation‐intense; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded one level for serious inconsistency. | ||||||
| Oral azithromycin compared to topical tetracycline for trachoma: communities | |||||||
| Patient or population: people (any age) with active trachoma | |||||||
| Outcomes | Follow‐up | Illustrative comparative risks (95% CI) | Relative effect | No. of participants | Certainty of the evidence | Comments | |
| Assumed risk | Corresponding risk | ||||||
| Topical tetracycline | Oral azithromycin | ||||||
| Active trachoma | 3 months | See comment | Not estimable | 6002 | ⊕⊕⊝⊝ | ACT 1999 Egypt RR 0.52 (95% CI 0.43, 0.64); ACT 1999 Tanzania RR 1.16 (1.00, 1.36); ACT 1999 The Gambia RR 0.76 (0.50, 1.15) | |
| 12 months | See comment | Not estimable | 5414 | ⊕⊕⊝⊝ | ACT 1999 Egypt RR 0.74 (95% CI 0.61, 0.90); ACT 1999 Tanzania RR 1.19 (1.02, 1.40); ACT 1999 The Gambia RR 0.55 (0.40, 0.75) | ||
| Ocular C trachomatis infection | 3 months | See comment | Not estimable | 5773 | ⊕⊕⊝⊝ | ACT 1999 Egypt RR 0.22 (95% CI 0.11, 0.44); ACT 1999 Tanzania RR 0.68 (0.49, 0.95); ACT 1999 The Gambia RR 0.51 (0.37, 0.70) | |
| 12 months | See comment | Not estimable | 5276 | ⊕⊕⊝⊝ | ACT 1999 Egypt RR 0.48 (95% CI 0.31, 0.74); ACT 1999 Tanzania RR 1.01 (0.76, 1.35); ACT 1999 The Gambia RR 0.62 (0.44, 0.87) | ||
| Antibiotic resistance Proportion of samples showing evidence of resistance to antibiotic | Any time point | None of the studies addressed this outcome. | |||||
| Adverse effects | Any time point | No comment on adverse effects in study reports | 6002 | ‐ | |||
| CI: confidence interval; TF: trachomatous inflammation‐follicular; TI: trachomatous inflammation‐intense; RR: risk ratio | |||||||
| GRADE Working Group grades of evidence | |||||||
| 1Downgraded one level for serious limitations in study design (three cluster‐randomised trials, two of which only randomised two communities to oral/topical antibiotic; assessment of trachoma was not masked, but assessment of ocular infection was; recruitment bias not addressed and problems with incomplete outcome data; some attempt made to adjust for baseline imbalances) and one level for serious inconsistency (results were different in the different studies ‐ see comment column in table). | |||||||
Background
Description of the condition
Trachoma is the world's leading infectious cause of blindness (WHO 2018). In 2015, there were an estimated 398,000 people blind due to trachoma (80% uncertainty intervals 114,000 to 851,000) (Flaxman 2017). Trachoma is a disease of poverty and is associated with poor water supplies and sanitation (Garn 2018). The age‐standardised all‐ages prevalence of blindness due to trachoma varies from 0% in most high‐income countries to 0.23% (0.07% to 0.42%) in East sub‐Saharan Africa and 0.19% (0.06% to 0.35%) in West sub‐Saharan Africa (Flaxman 2017).
There are two phases of trachoma. In the first phase, most frequently seen in infancy and childhood, there are repeated rounds of conjunctivitis caused by the bacterium Chlamydia trachomatis. The conjunctivitis is characterised by the presence of follicles on the under surface of the upper eyelid and by vascular changes and is known as active trachoma. 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. When symptomatic, symptoms may persist for months after the infection is cleared. C trachomatis is thought to be transmitted from child to child and from child to mother and back to child through eye‐finger‐eye contacts, fomites, and via eye‐seeking flies.
Repeated conjunctival infections over a number of years can lead to the second phase of disease, characterised by scarring and shortening of the upper eyelid. Ultimately, the lashes turn inwards to rub on the cornea, causing pain, corneal abrasions, and secondary infection. Treatment at this stage is surgery to reposition the eyelid margin. Blindness results from corneal opacification. The blinding phase affects women more commonly than men (Cromwell 2009), and typically starts in adult life (Burton 2009).
Description of the intervention
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 (topical) or taken orally (systemic). Topically applied antibiotics 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 a low dose 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.
Oral treatment gives a higher dose of antibiotic to sites of infection outside of the eye, but systemic antibiotics can cause various adverse effects in the person taking them. Bacteria anywhere in the body may also develop antibiotic resistance. As the currently recommended oral antibiotic regimen is a single, directly observed dose of azithromycin, as compared to six weeks of twice‐daily topical tetracycline, oral treatment is likely to have a higher compliance rate than a course of topical antibiotic.
Efforts in trachoma control have used various antibiotic treatment regimens and have also been aimed at different subgroups within a trachoma endemic area. Examples of subgroups are: only those individuals with clinical signs of disease (detected actively or passively); active cases together with family contacts; or high‐risk groups including schoolchildren. Because many individuals harbour infection without demonstrating clinical signs, it has been suggested that trachoma elimination cannot be achieved by antibiotic treatment given only to subgroups of a trachoma endemic community (Bailey 1993; Kamiya 1956; Sutter 1983). This led to the concept of community‐based interventions, where 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 trachoma intervention trials is clinically active disease. In some trials a secondary endpoint is laboratory evidence of ocular C trachomatis infection.
Why it is important to do this review
International interest in trachoma was given a boost in 1996 when the World Health Organization (WHO) launched a new initiative for trachoma control, based on the 'SAFE' strategy, and in 1998 the 51st World Health Assembly passed a resolution on "Global elimination of blinding trachoma" (WHA 1998). The components of the SAFE acronym are Surgery, Antibiotics, Facial cleanliness, and Environmental improvement. Cochrane Reviews on surgery for trichiasis (Burton 2015), face washing (Ejere 2015), and environmental sanitary interventions have also been completed (Rabiu 2012).
The WHO recommends the following antibiotic treatment for trachoma: either topical treatment of 1% tetracycline ointment to both eyes, twice daily for six weeks, or azithromycin, given as a single oral dose of 1 g in adults and 20 mg/kg of body weight in children (Solomon 2006).
This review was important to systematically evaluate the safety and effectiveness of these recommended treatment regimens.
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), Chlamydia trachomatis infection of the conjunctiva, antibiotic resistance, and adverse effects (secondary objectives).
(1) What is the effect of antibiotic treatment of the individual on active trachoma and ocular C trachomatis infection?
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What is the effect of antibiotic treatment versus no treatment?
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What is the effect of oral versus topical antibiotic?
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What is the effect of oral azithromycin compared to topical tetracycline?
(2) What is the effect of community treatment with antibiotics on the prevalence of active trachoma and ocular C trachomatis infection?
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What is the effect of mass administration of antibiotic compared to no treatment?
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What is the effect of mass administration of oral azithromycin versus topical tetracycline?
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What is the effect of annual versus different treatment frequencies?
(3) What are the adverse effects of antibiotic treatment?
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What are the adverse effects at the individual level?
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What is the effect of mass administration of oral azithromycin or topical tetracycline on resistance in (i) C trachomatis and (ii) other bacteria?
Methods
Criteria for considering studies for this review
Types of studies
This review includes only randomised controlled trials (RCTs) of antibiotic treatment for active trachoma. We included clinical and community‐based trials. In clinical trials, the unit of randomisation was the individual with active trachoma, and outcomes were reported at an individual level. In community‐based trials, the unit of randomisation was a community, in which some individuals had active trachoma, and outcomes may have been reported at an individual or a community level.
Types of participants
Participants in the trials were people who were usually resident in a trachoma endemic area.
Types of interventions
We included trials in which the interventions were:
-
topical or oral administration of an antibiotic at any dose or frequency compared to placebo or no treatment;
-
topical administration of an antibiotic at any dose or frequency compared to oral administration of an antibiotic at any dose or frequency.
We excluded studies 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.
We also included studies addressing different dosing strategies in the population.
Types of outcome measures
We measured outcomes at three, 12, and 24 months after the start of treatment. Three months was the time at which the maximum effect on active trachoma was expected, given that clinical signs take several months to resolve after the clearance of infection (Grassly 2008). We selected 12 months to represent the period during which recurrence of infection or relapse would most likely occur, and 24 months 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 six weeks to several months.
In order to take into account the fact that studies may not have collected outcomes at these exact times, we defined the following ranges for each:
-
three months, i.e. outcomes measured before six months;
-
12 months, i.e. outcomes measured between six months and 18 months;
-
24 months, i.e. outcomes measured after 18 months.
If more than one outcome measurement in any of these follow‐up ranges was available, then we selected the nearest measurement to three, 12, or 24 months.
Primary outcomes
The primary outcome for this review was active trachoma. There are five main trachoma grading scales (Dawson 1975a; Dawson 1981a; MacCallan 1936; Thylefors 1987; WHO 1962). All these 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 low magnification (usually x 2.5). The Dawson scales subdivide the follicular and papillary activity as F 0 to 3 and P 0 to 3. The Thylefors scale is a simplified version defining active trachoma by the grades TF (trachomatous inflammation‐follicular) and TI (trachomatous inflammation‐intense). The MacCallan scale is not directly comparable with the other scales, as scarring is included as an indicator of active disease. The four more recent scales are broadly comparable. A minor inconsistency between them is that Dawson's F1 is defined as five or fewer follicles in zones two and three, and F2 as "more than 5 follicles in zones 2 and 3 together, but less than 5 in zone 3"; whereas TF is five or more follicles in zones two and three. This means that the divisions between F1 and F2 and 'not TF' and TF do not quite coincide.
In this review we defined the absence of active trachoma as:
-
not TF and not TI (Thylefors scale);
-
(P0 or P1 or P2) AND (F0 or F1) (WHO and Dawson scales).
We defined active trachoma as TF, TI, or both, in the Thylefors scale; or any other grade for P or F in the WHO or Dawson scales.
Secondary outcomes
The secondary outcome for this review was a positive test for C trachomatis infection. A variety of tests have been used to demonstrate presence of the pathogen. Historically, 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 nucleic acid amplification methods. The tests, in order of increasing sensitivity, are:
-
culture by C trachomatis isolation in eggs or tissue culture;
-
staining of conjunctival smears with Giemsa or iodine;
-
direct fluorescent antibody cytology;
-
indirect enzyme immunoassay;
-
nucleic acid test (NAT);
-
nucleic acid amplification tests (NAAT).
For the current update we defined an additional secondary outcome: resistance: proportion of samples showing evidence of resistance to antibiotic in (i) C trachomatis and (ii) other bacteria. We considered any measure of resistance reported in the included studies. This included genotypic and phenotypic measures for all organisms and drug classes. We focused on the proportion of samples that were resistant, but also collected data, where available, on the proportion of isolates that were resistant.
Adverse effects
We recorded all adverse effects reported in the included studies.
Search methods for identification of studies
Electronic searches
The Cochrane Eyes and Vision Information Specialist searched the following electronic databases for randomised controlled trials and controlled clinical trials. There were no restrictions on language or year of publication. The electronic databases were last searched on 4 January 2019.
-
Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 1) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (searched 4 January 2019) (Appendix 1).
-
MEDLINE Ovid (1946 to 4 January 2019) (Appendix 2).
-
Embase Ovid (1980 to 4 January 2019) (Appendix 3).
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International Standard Randomised Controlled Trial Number (ISRCTN) registry (www.isrctn.com/editAdvancedSearch; searched 4 January 2019) (Appendix 4).
-
US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; searched 4 January 2019) (Appendix 5).
-
World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp; searched 4 January 2019) (Appendix 6).
Searching other resources
We used the Science Citation Index to search for articles that cited the included studies. We searched the reference lists of included articles for any other potentially relevant studies. For previous versions of this review, we also contacted experts in the field, either directly or through the membership of the WHO workshops, requesting information on unpublished trials. We did not do this for the current update, however we did contact individual trialists for more information.
Data collection and analysis
Selection of studies
For the first publication of this review (Mabey 2005), one review author assessed the titles identified from the initial searches and selected all titles that made reference to treatment for trachoma. For subsequent updates (Evans 2011 and current update), two review authors screened the search results. The searches also found references to genital C trachomatis infections and to laboratory tests on C trachomatis. We excluded titles that clearly referred to either of these groups at the first screening. Two review authors independently reviewed the full texts of all potentially relevant papers and assessed them according to the Criteria for considering studies for this review.
Data extraction and management
Two review authors independently extracted data. Any discrepancies were resolved before data were entered into Review Manager 5 (Review Manager 2008).
For the 2011 review update, JE checked the original data collection and entry. The changes that were made are summarised in Appendix 7. For the newly identified trials, two review authors (JE, AWS) independently extracted data, resolving any discrepancies by discussion. Data were entered by both review authors onto two spreadsheets and cross‐checked. Data were cut and pasted into RevMan from the spreadsheet (JE). For the current update, the process was repeated by JE/EHE using updated Review Manager 5 (RevMan 5) software (Review Manager 2014).
Assessment of risk of bias in included studies
We assessed risk of bias using Cochrane's 'Risk of bias' assessment tool as described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). We assessed the extent to which bias could have been introduced in the following aspects of study design and execution: sequence generation, allocation concealment, blinding (masking), incomplete outcome data, and selective outcome reporting. We considered two additional criteria for cluster‐randomised trials: recruitment bias and baseline imbalances (Higgins 2011). Two review authors (JE/AWS (2011), JE/EHE (2019)) independently assessed risk of bias, compared results, and resolved any discrepancies by discussion.
Measures of treatment effect
The primary outcome for the review was active trachoma, and the secondary outcomes were ocular C trachomatis infection and antibiotic resistance. These are dichotomous (adverse) outcomes, and our preferred effect measure was the risk ratio.
Unit of analysis issues
This review includes trials in which individuals were randomly allocated to treatment and trials in which communities were the unit of allocation (cluster‐randomised trials). A correct analysis of cluster‐randomised trials includes an adjustment for the fact that people within a cluster tend to be more similar to each other than to people from other clusters (i.e. the observations are not independent). 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).
Our preferred method of analysis of cluster‐randomised studies was as follows: for those studies that reported the effect measure using an analysis that properly accounted for the cluster design, we planned to enter and pool data from different studies using the generic‐inverse variance method in RevMan 5. However, we were aware that cluster‐randomised trials are not always analysed and reported appropriately. We planned that for those studies that did not report such an effect measure, we would perform an approximate analysis (Higgins 2011), as follows:
-
calculate a 'design effect' of 1 + (M − 1) ICC (where ICC = intracluster correlation coefficient and M = average cluster size);
-
multiply the standard error of an analysis at the individual level by the square root of the design effect.
Estimates from the literature suggest that the ICC can vary from 0.05 to 0.2 (Katz 1988; West 1991). We planned sensitivity analyses using ICC estimates of 0.05, 0.1 and 0.2.
Dealing with missing data
The clinical need to change or discontinue antibiotic therapy (for an individual undergoing treatment for a single episode of infection of disease, or a community undergoing a single round of mass treatment) 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 we did not exclude studies on this basis.
Assessment of heterogeneity
We assessed heterogeneity by considering clinical and study design differences between trials and by examining the forest plots. We also considered statistical measures of heterogeneity such as the χ2 test and I2 statistic.
Assessment of reporting biases
As less than 10 trials were included in the meta‐analyses in this version of the review, we did not assess publication bias. In future updates that include more trials, we will assess the possibility of small‐study effects, including publication bias, using a funnel plot (plotting the risk ratio along the x‐axis versus standard error along the y‐axis).
We included all trials irrespective of the language of publication, however we cannot exclude the possibility that negative trials have been published in less accessible journals (see publication bias above).
We did not find any evidence of multiple (duplicate) reporting publication bias. Data from one of our included trials, ACT 1999 The Gambia, were published twice, with ocular C trachomatis infection being the focus of one publication and active trachoma the focus of the other, but the relationship of the data was clear from the publications.
Data synthesis
In the original review, the review authors pooled outcomes from community‐based trials in which non‐affected and affected cases were treated with outcomes from individual‐based trials in which only affected cases were treated. The original protocol planned but did not carry out a sensitivity analysis to determine the effect of using only data from cases that were active at baseline.
In the updates we considered these community‐based and individually randomised trials separately, as we believed that they were asking different questions and were likely to be estimating different treatment effects. The individually randomised studies address the question: what is the effect of antibiotic treatment on individuals? The cluster‐randomised trials address the question: what is the effect of antibiotic treatment on communities? The effect of treatment in individuals in treated communities may be different because as well as the individual‐level effect, there may be an additional impact via reduction in transmission. The following two objectives were identified.
Where appropriate, data were pooled using a random‐effects model. We used a fixed‐effect model if there were three or fewer trials. In cases where there was substantial heterogeneity or inconsistency, that is the individual study estimates were different sides of the null line and/or confidence intervals did not overlap, with corresponding high levels of I2, we did not pool the results.
Subgroup analysis and investigation of heterogeneity
We considered type of antibiotic (oral or topical) to be a potential source of clinical heterogeneity. This subgroup analysis was not specified explicitly but was implied in the objectives of the original protocol, which were to consider oral and topical antibiotics separately, in particular oral azithromycin and topical tetracycline. A further subgroup analysis considered just those trials in which communities were randomised to oral azithromycin, topical tetracycline, or both, where the antibiotic was administered using regimens consistent with WHO guidelines current in 2010, compared either to each other, placebo, or no treatment.
Sensitivity analysis
As set out above in the Unit of analysis issues section, we considered the possible effect of assumptions about the size of the intracluster correlation coefficient (ICC) on the results.
'Summary of findings' table
'Summary of findings' tables were introduced in the current update following new Cochrane guidance. As such, these tables are post hoc, but as fewer than seven outcomes were specified in this review, and we focused on the key comparisons in individuals and communities, there were no significant judgements that may have been influenced by our knowledge of the data in the preparation of these tables. We graded the certainty of the evidence for the comparisons and outcomes included in the 'Summary of findings' tables using the GRADE approach (Schünemann 2017). We considered risk of bias in the studies contributing data, consistency of effects, precision of the effect estimate, directness of the evidence, and possibility of publication bias when grading the evidence. The initial assessment was done by JE, and this was checked by co‐authors.
Results
Description of studies
Results of the search
2011 version
The previous edition of this review published in 2011 included 22 studies. Fourteen of these studies were individually randomised, and a further eight were cluster‐randomised.
2019 update
The searches run in January 2019 yielded a further 1406 records (Figure 1). After removal of 301 duplicates, the Cochrane Information Specialist screened the remaining 1105 records and removed 839 references that were not relevant to the scope of the review. We screened the remaining 266 references and obtained 51 full‐text reports for further assessment. We identified 27 reports of four new cluster‐randomised studies (PRET Niger; PRET Tanzania; PRET The Gambia; Wilson 2018). The searches identified three new reports for the TEF study and nine new reports for the TANA study. The total number of included studies was 26; see Characteristics of included studies for further details.
Study flow diagram.
We will assess two ongoing studies for potential inclusion when data become available (NCT03523156; SWIFT 2017), and one study by Last 2015 is awaiting classification.
We excluded nine reports of the following nine studies: Coulibaly 2013; MORDOR 2018; NCT00286026; NCT00347607; NCT00347776; NCT01178762; NCT01767506; NCT02211729; Schachterle 2014. The total number of excluded studies is 63; see Characteristics of excluded studies for further details.
Included studies
Individually randomised studies
Fourteen individually randomised studies are included in the review (Table 1).
| Study | Country | Inclusion criteria | Number of people randomised | Age | Sex % male | |
| 1 | Egypt | Active trachoma or "undetermined case" | 228 | 6 to 12 years | Not reported | |
| 2 | The Gambia | Active trachoma | 194 | 9 months to 60 years | 51% | |
| 3 | The Gambia | Active trachoma | 314 | 6 months to 10 years | 50% | |
| 4 | Guinea and Pakistan | Active trachoma | 670 | 1 to 10 years | 50% | |
| 5 | Iran | Active trachoma | 147 | Pre‐school | 38% | |
| 6 | USA (Indian reservation) | Active trachoma | 29 | 12 to 21 years | Not reported | |
| 7 | USA (Indian reservation) | Active trachoma | 36 | 12 to 21 years | Not reported | |
| 8 | Egypt | Active trachoma | 168 | 2 to 10 years | 60% | |
| 9 | USA (Indian boarding school) | Active trachoma | 457 | 8 to 20 years | Not reported | |
| 10 | USA (Indian boarding school) | Active trachoma | 120 | 7 to 13 years | Not reported | |
| 11 | Australia (Aboriginal children) | Follicular trachoma | 641 | 5 to 14 years | Not reported | |
| 12 | India | Active trachoma | 349 | 5 to 13 years | Not reported | |
| 13 | Saudi Arabia | Active trachoma | 64 | 6 to 14 years | Not reported | |
| 14 | Taiwan | Active trachoma | 322 | Primary school age | Not reported |
*Dawson 1969 Sherman and Dawson 1969 Stewart were reported in the same paper.
Types of participants
These 14 studies took place in the following countries (according to WHO region) (one study, Cochereau 2007, was conducted in two regions).
African Region
-
The Gambia (Bailey 1993; Bowman 2000)
-
Guinea (Cochereau 2007)
Eastern Mediterranean Region
-
Egypt (Attiah 1973; Dawson 1997)
-
Iran (Darougar 1980)
-
Pakistan (Cochereau 2007)
-
Saudi Arabia (Tabbara 1996)
Region of the Americas
South‐East Asian Region
-
India (Shukla 1966)
Western Pacific Region
-
Australia (Peach 1986)
-
Taiwan (Woolridge 1967)
The participants in these studies had active trachoma. The number of participants randomised ranged from 29, in Dawson 1969 Sherman, to 670, in Cochereau 2007. Almost all of the studies enrolled children and/or young people (21 years or younger) only, with the exception of Bailey 1993, which had a wider age range (9 months to 60 years). Not all studies reported the proportion of males and females, but in those that did there were approximately equal proportions. Participants in the studies in USA and Australia were from Indigenous communities (Native American and Aboriginal, respectively).
Types of interventions
Table 2 summarises the comparisons addressed in these studies.
| Comparison | Intervention | Comparator | ||||||
| Antibiotic | Dose | Duration | Frequency | Intervention | Dose | Duration | Frequency | |
| Studies with a no‐treatment, placebo, or inactive treatment comparator group | ||||||||
| tetracycline derivative GS2989 (topical) | 0.25% | once every school day for 11 weeks | once | no treatment | ‐ | ‐ | ‐ | |
| oxytetracycline (topical) | 1% | twice daily for 7 consecutive days | every month for 12 months | vitamin pills | not reported | single dose | every month for 12 months | |
| tetracycline (topical) | 1% | twice daily for 6 consecutive days | every week for 6 weeks | no treatment | ‐ | ‐ | ‐ | |
| tetracycline (oral) | not reported | daily for 5 days | once a month for 3 months | no treatment | ‐ | ‐ | ‐ | |
| doxycycline | 2.5 to 4.0 mg/kg | once daily for 5 consecutive days | every week up to 28 doses in 40 days | placebo | ‐ | once daily for 5 consecutive days | every week up to 28 doses in 40 days | |
| Shukla 1966*** | Sulfafurazole (topical) + sulfadimethoxine (oral) | 15%/100 mg/kg | twice daily for 5 consecutive days every month for 5 months/bi‐weekly for 5 months | twice daily for 5 consecutive days every month for 5 months/bi‐weekly for 5 months | no treatment | ‐ | ‐ | ‐ |
| trisulfapyrimidines (oral) | 3.5 g/day (in 3 doses) | 21 consecutive days | once | placebo | ‐ | 21 consecutive days | ‐ | |
| Oral versus topical antibiotic | ||||||||
| azithromycin (oral) | 20 mg/kg | single dose | once | tetracycline (topical) | 1% | twice daily for 6 weeks | once | |
| azithromycin (oral) | 20 mg/kg | single dose | once or weekly for 3 weeks or monthly for 6 months | oxytetracycline/polymyxin + oral placebo | oxytetracycline 1%/polymyxin 10,000 units/gram | once daily for 5 consecutive days | every 28 days for 6 months | |
| azithromycin (oral) | 20 mg/kg | single dose | once | tetracycline (topical) | 1% | twice daily for 5 consecutive days | every week for 6 weeks | |
| sulfamethoxypyridazine (oral) | 0.5 g | once daily for 5 consecutive days | every week for 3 weeks | tetracycline (topical) | 1% | 3 times daily on 5 consecutive days | ‐ | |
| Cochereau 2007**** | azithromycin (topical) | 1.5% | twice daily for 2 days | ‐ | azithromycin (oral) | 20 mg/kg | single dose | ‐ |
*Also compared to oxytetracycline (Terramycin) once every school day for 11 weeks.
**Also compared to doxycycline (oral) 5 mg/kg single dose every month for 12 months.
***Also compared to sulfadimethoxine (oral) 100 mg/kg bi‐weekly or weekly dose for 5 months and sulfafurazole (topical) 15% twice daily for 5 consecutive days, every month for 5 months.
****Also compared to azithromycin (topical) 1.5% twice daily for 3 days.
Nine studies compared antibiotic with a no‐treatment or placebo arm. These antibiotics were:
-
tetracycline or oxytetracycline applied topically (Attiah 1973; Darougar 1980; Woolridge 1967);
-
oral tetracycline (Peach 1986);
-
doxycycline (Hoshiwara 1973);
-
sulfonamides (Dawson 1969 Sherman; Dawson 1969 Stewart; Foster 1966; Shukla 1966).
Four studies compared oral azithromycin with topical tetracycline (Bailey 1993; Bowman 2000; Dawson 1997; Tabbara 1996).
One study compared topical azithromycin with oral azithromycin (Cochereau 2007).
Azithromycin was usually given as a single dose of 20 mg/kg up to 1 g (for adults). Topical tetracycline was usually the 1% dose, although there was some variation in treatment schedules. In general, the application of topical tetracycline was supervised, or applied by personnel in the research team. The exceptions were Bailey 1993 and Bowman 2000, where the ointment was administered by carers and was not supervised.
Types of outcome measures
Reporting of the two main outcome measures for this review is presented in Table 3.
| Study | Active trachoma | Ocular infection | |||||
| Classification scheme | 3 months | 12 months | Laboratory assessments | 3 months | 12 months | ||
| 1 | WHO 1962 | ✓ | No follow‐up | No laboratory tests | ‐ | ‐ | |
| 2 | Dawson 1981 | ✓ | ✓ (26 weeks) | IDEIA amplified enzyme‐linked immunosorbent assay (Dako) for genus‐specific lypopolysaccharide antigen | ✓ | ✓ (26 weeks) | |
| 3 | Thylefors 1987 | ✓ | ✓ (6 months) | No laboratory tests | ‐ | ‐ | |
| 4 | Thylefors 1987 | ✓ (2 months) | No follow‐up | Conjuctival swab analysed using PCR | Data not reported | No follow‐up | |
| 5 | Modification of Dawson 1975 | ✓ (4 months) | ✓ | Conjunctival swabs followed by culture in irradiated McCoy cells | ✓ (4 months) | ✓ | |
| 6 | MacCallan 1936 | ✓ (20 weeks) | No follow‐up | No laboratory tests | ‐ | ‐ | |
| 7 | MacCallan 1936 | ✓ (20 weeks) | No follow‐up | No laboratory tests | ‐ | ‐ | |
| 8 | Thylefors 1987 | ✓ | ✓ | Conjunctival specimens; slides stained with direct fluorescent antibody for chlamydial elementary bodies | ✓ | ✓ | |
| 9 | Thygeson 1960 | ✓ | ✓ | No laboratory tests | ‐ | ‐ | |
| 10 | Dawson 1969 | ✓ (5 months) | No follow‐up | IFAT on scrapings of upper tarsal conjunctival epithelium | ✓ (5 months) | No follow‐up | |
| 11 | At least 1 follicle or some papillary hypertrophy | ✓ | No follow‐up | No laboratory tests | ‐ | ‐ | |
| 12 | WHO 1962 | ✓ (5 months) | No follow‐up | No laboratory tests | ‐ | ‐ | |
| 13 | Dawson 1981 | ✓ | No follow‐up | Conjunctival scrapings for inclusion bodies/cells/organisms/mucus; IFAT for free elementary bodies | ✓ | No follow‐up | |
| 14 | Modified McCallan classification | ✓ | ✓ | No laboratory tests | ‐ | ‐ | |
IFAT: immunofluorescence antibody test
PCR: polymerase chain reaction
*Followed up to three years.
All studies provided data at around three months (range two to five months). Six studies had longer follow‐up, ranging from six months (Bailey 1993; Bowman 2000), and 12 months (Darougar 1980; Dawson 1997; Foster 1966) to three years (Woolridge 1967).
All 14 individually randomised studies reported active trachoma at follow‐up. A variety of classification schemes were used for active trachoma. The majority of studies used one of the scales described in Types of outcome measures.
-
MacCallan 1936 (Dawson 1969 Sherman; Dawson 1969 Stewart; Woolridge 1967)
-
WHO 1962 (Attiah 1973; Shukla 1966)
-
Dawson 1975 (Darougar 1980)
-
Dawson 1981 (Bailey 1993; Tabbara 1996)
-
Thylefors 1987 (Bowman 2000; Cochereau 2007; Dawson 1997)
Three studies used different classifications, but these were likely to have been based on a similar assessment (Foster 1966; Hoshiwara 1973; Peach 1986). 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 more or less equivalent in all of the studies, using only the presence of follicles and papillae for diagnosis of active disease.
Six of the 14 studies reported assessment of ocular infection (Bailey 1993; Cochereau 2007; Darougar 1980; Dawson 1997; Hoshiwara 1973; Tabbara 1996), but comparative data on ocular infection between intervention groups were not reported by Cochereau 2007.
None of the studies considered resistance as an outcome. Adverse effects were reported inconsistently.
Cluster‐randomised studies
Twelve community‐based studies are included in the review (Table 4).
|
| Study | Country | Inclusion criteria: communities | Inclusion criteria: people | Number of communities randomised | Number of people randomised | Age | Sex % male | Endemicity | |
| Children | Adults | |||||||||
| 1 | Egypt | trachoma endemic areas | everyone present in community | 2 | 2238 | all ages | not reported | ‐ | All ages: no active trachoma (64%); | |
| 2 | Tanzania | trachoma endemic areas | everyone present in community | 2 | 3261 | all ages | not reported | ‐ | All ages: no active trachoma (47%); mild follicular inflammatory (F1, P1, P2) (22%); follicular trachoma (F2, F3) (15%); severe inflammatory trachoma (P3) (16%) | |
| 3 | The Gambia | trachoma endemic areas | everyone present in community | 8 (pair‐matched) | 1753 | all ages | not reported | Prevalence of active trachoma among 0 to 9 year olds (36%) | No active trachoma (57%); mild follicular inflammatory (F1, P1, P2) (27%); follicular trachoma (F2, F3) (9%); severe inflammatory trachoma (P3) (7%) | |
| 4 | Vietnam | randomly selected from Thanh Hoa Province | everyone present in community older than 6 months was assessed for trachoma and people with trachoma and their household members treated. | 2 | 1851 | 6 months or older | ˜40% | Prevalence of active trachoma: | Prevalence of active trachoma: | |
| 5 | Niger | > 15% prevalence of active trachoma in children | everyone present in community | not reported | 1347 | average age 18 to 19 years | 48% | ‐ | Prevalence of C trachomatis infection (all ages) (7%) | |
| 6 | Niger | population between 250 and 600 and prevalence of 10% or more of active trachoma in children aged 0 to 60 months | everyone present in community | 24 | 12,991 | all ages; sentinel children aged 0 to 5 years | 48% | Prevalence of ocular C trachomatis infection in children aged 5 years or younger (approximately 20%) | Prevalence of TF in people aged 15 years or older (approximately 1%) | |
| 7 | Tanzania | less than 5000 people with an estimated active trachoma prevalence of between 20% and 50% for mesoendemic communities and less than 20% for hypoendemic communities | everyone present in the community | 32 | not reported | all ages; sentinel children aged 0 to 5 years | 50% to 52% | Prevalence of C trachomatis infection in children aged less than 5 years ranged from 18% to 25%. | Prevalence of C trachomatis infection (all ages) (6%) | |
| 8 | The Gambia | trachoma prevalence greater than 5% | everyone present in the community | 48 | all ages; sentinel children 5 years or less | ˜50% | Prevalence of C trachomatis infection in children aged 5 years or younger was 1%. | ‐ | ||
| 9 | Mali | unclear | everyone present in the community | 4 (2 with interventions relevant to this review) | all ages | not reported | ‐ | Prevalence of active trachoma ranged from 15% to 22% (all ages). | ||
| 10 | Ethiopia | all subkebeles (geographical unit with approximately 1400 people) in the study region that were less than | everyone present in the community | 48 | 66,404 | all ages; sentinel group of children and adults | ˜51% | Prevalence of C trachomatis infection in children aged less than 10 years ranged from 8% to 62% (mean approximately 40%). | Prevalence of C trachomatis infection in people aged 10 years or older ranged from 2% to 28% (mean approximately 15%). | |
| 11 | Ethiopia | random sample of peasant associations (standardised administrative unit) | everyone present in the community | 16 | 5410 | all ages; sentinel groups of children aged 1 to 5 years | not reported | Prevalence of C trachomatis infection in children aged 1 to 5 years ranged from 31% to 65% (mean approximately 43%). | ‐ | |
| 12 | Tanzania | not been treated with azithromycin since 2009 and were predicted from prior prevalence surveys to have TF between 5 and 9.9% | not clearly stated but assumed to be everyone in community apart from pregnant women and children under 6 months | 96 | not reported | 6 months or older, only sample of 20 children aged 1 to 9 years assessed | 48% (in children assessed) | Prevalence of Ctrachomatis infection in children aged 1 to 9 years ranged from 0 to 33%, median 0%. | .‐ | |
LCR: ligase chain reaction
TF: trachomatous inflammation–follicular
Types of participants
These 12 studies took place in the following countries (according to WHO region).
African Region
-
The Gambia (ACT 1999 The Gambia; PRET The Gambia)
-
Niger (NCT00618449; PRET Niger)
-
Mali (Resnikoff 1995)
-
Tanzania (ACT 1999 Tanzania; PRET Tanzania; Wilson 2018)
Eastern Mediterranean Region
-
Egypt (ACT 1999 Egypt)
Western Pacific Region
-
Vietnam (Atik 2006)
The inclusion criteria for communities were not always clearly specified in these studies, and varied where they were specified. Some studies randomly selected communities in specific regions (Atik 2006; TEF); some studies specified a cut‐point in terms of prevalence of active trachoma between 5% and 20% (NCT00618449; PRET Niger; PRET Tanzania; PRET The Gambia); one study included communities that had not received azithromycin since 2009 with an estimated prevalence of active trachoma between 5% and less than 10% (Wilson 2018); and others used logistical considerations (TANA).
All the studies (except Atik 2006) evaluated some form of mass drug administration and therefore included everyone present in the communities. The evaluation of the outcome was often done on a random sample of children and adults, termed a "sentinel" sample. Where sex was reported, approximately 50% of the population were male.
Most studies were conducted in trachoma endemic areas with high levels of infection and clinical disease, particularly in children. The exceptions were Atik 2006, NCT00618449, and PRET The Gambia, where active trachoma and ocular infection were less than 20%.
Types of interventions
Table 5 summarises the comparisons addressed in the 12 cluster‐randomised studies. Almost all of these studies evaluated mass drug administration with azithromycin at 20 mg/kg up to 1 g for adults. Resnikoff 1995 assessed topical tetracycline 1%. Atik 2006 only treated people with active trachoma and their household members.
| Intervention | Comparator | |||
| Comparison | Antibiotic* | Frequency | Antibiotic* | Frequency |
| Studies with a no‐treatment or delayed‐treatment comparator group | ||||
| tetracycline ** | every month for 6 months | no treatment | ‐ | |
| azithromycin | once only; annually for 3 years; twice a year for 3 years | delayed treatment | ‐ | |
| azithromycin | every 3 months for 3 years | delayed treatment | ‐ | |
| azithromycin | once only | delayed treatment | ‐ | |
| Studies of azithromycin versus tetracycline | ||||
| azithromycin | once a week for 3 weeks | tetracycline | once daily for 6 weeks | |
| Atik 2006**** | azithromycin | single dose at baseline and 12 months. Non‐index cases received tetracycline, and surgery offered where appropriate. | All patients with active trachoma received topical tetracycline and surgery offered where appropriate. | ‐ |
| Studies of different frequencies of azithromycin | ||||
| azithromycin | for 1 month (Day 0 and Day 30) | azithromycin | Day 0 | |
| azithromycin | annually for 3 years (enhanced coverage) | azithromycin | annually for 3 years (standard coverage) | |
| PRET Niger;***** TANA; TEF | azithromycin | twice a year for 3 years | azithromycin | annually for 3 years |
| azithromycin | annually for 3 years | azithromycin | cessation rule | |
*Azithromycin was given as a single oral dose at 20 mg/kg up to 1 g (adults); tetracycline was given topically 1%.
**One drop four times daily for seven days.
***Once a week for three weeks.
****Treatment of people with active trachoma and their household members only.
*****Only children were treated twice yearly.
Four studies compared antibiotic to no treatment, Resnikoff 1995, or delayed treatment (TANA; TEF; Wilson 2018).
Four studies compared azithromycin and topical tetracycline (ACT 1999 Egypt; ACT 1999 Tanzania; ACT 1999 The Gambia; Atik 2006).
Six studies compared different strategies for mass drug administration:
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NCT00618449 compared azithromycin twice (one month apart) with a single dose of azithromycin;
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the three PRET studies compared enhanced coverage (> 90%) with standard coverage (80% to 90%) (PRET Niger; PRET Tanzania; PRET The Gambia);
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three studies compared azithromycin twice a year for two or three years with azithromycin once a year for two or three years (PRET Niger; TANA; TEF), with only children being treated twice a year in PRET Niger;
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PRET Tanzania and PRET The Gambia compared azithromycin annually for three years with a cessation rule.
Specific exclusion criteria were usually given for pregnant women, children younger than six months, or people with macrolide allergy. Other treatments offered included oral erythromycin or topical tetracycline.
Types of outcome measures
Table 6 summarises the reporting of the main outcome measures for this review in these cluster‐randomised studies. Follow‐up ranged from six months, in Resnikoff 1995, to 42 months, in TANA, with most studies reporting at least to 12 months. Most studies used the classification of trachoma as set out in Thylefors 1987, the exception being the ACT studies (ACT 1999 Egypt; ACT 1999 Tanzania; ACT 1999 The Gambia), which used Dawson 1981a. Almost all studies (except Resnikoff 1995) did some form of assessment of ocular infection using a variety of techniques, but most commonly polymerase chain reaction (PCR). Five studies assessed resistance (PRET Niger; PRET Tanzania; PRET The Gambia; TANA; TEF). None of the studies assessed resistance of C trachomatis to antibiotics, but a number of other bacteria were considered (Streptococcus pneumoniae, Staphylococcus aureas, Escherichia coli), as well as genetic determinants of macrolide resistance.
| Study | Follow‐up | Active trachoma | Ocular infection | Resistance | Adverse effects | |
| 1 | 12 to 14 months | Dawson 1981 | Conjunctival swabs assessed using LCR. | Not studied | Not reported | |
| 2 | 12 to 14 months | Dawson 1981 | Conjunctival swabs assessed using LCR. | Not studied | Not reported | |
| 3 | 12 months | Dawson 1981 | Conjunctival swabs assessed using LCR. | Not studied | Not reported | |
| 4 | 24 months | Thylefors 1987 | Conjuctival samples analysed using polymerase chain reaction (Amplicor‐PCR). | Not studied | Not reported | |
| 5 | 12 months | Not specified | Conjunctival swabs assessed using nucleic acid amplification test. | Not studied | Reported (no adverse events) | |
| 6 | 36 months | Thylefors 1987 | Conjuctival samples analysed using polymerase chain reaction (Amplicor‐PCR). | lytA+ | Not reported | |
| 7 | 36 months | Thylefors 1987 | Conjuctival samples analysed using polymerase chain reaction (Amplicor‐PCR). | E coli | Reported (no serious adverse events) | |
| 8 | 36 months | Thylefors 1987 | Conjuctival samples analysed using polymerase chain reaction (Amplicor‐PCR). | S pneumoniae | Not reported | |
| 9 | 6 months | Thylefors 1987 | No laboratory tests | Not studied | Not reported | |
| 10 | 42 months | Thylefors 1987 | Conjuctival samples analysed using polymerase chain reaction. | S pneumoniae | Reported | |
| 11 | 24 months | Thylefors 1987 | Conjuctival samples analysed using polymerase chain reaction (Amplicor‐PCR). | S pneumoniae | Reported (no serious adverse events) | |
| 12 | 12 months | Thylefors 1986 | Conjuctival samples analysed using polymerase chain reaction. | Not studied | Reported (no serious adverse events) |
LCR: ligase chain reaction
PCR: polymerase chain reaction
Excluded studies
We excluded 63 studies for the following reasons (Characteristics of excluded studies).
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Types of studies: not RCTs (33 studies).
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Types of participants: not people with trachoma or not conducted in a trachoma endemic area (4 studies).
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Types of interventions: not a relevant intervention or comparator (21 studies).
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Types of outcomes: eye outcomes not measured, or assessed effect of antibiotics on trichiasis only (4 studies).
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Other reason: study not done (1 study), trial report not found (1 study).
Risk of bias in included studies
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Allocation
Twelve studies described adequate methods of generating an unpredictable sequence, using either computer‐generated sequences or random number tables. We considered that allocation concealment was not an issue for cluster‐randomised trials, and graded all 12 cluster‐randomised studies as at low risk of bias for this domain. Three of the individually randomised studies reported adequate methods of allocation concealment. The remaining studies reported insufficient detail to judge the risk of selection bias.
Blinding
We considered performance and detection bias together, but separated the two main outcomes (active trachoma and ocular infection) because we considered that masking would have a different impact on these two outcomes. We considered that the issues of performance and detection bias for antimicrobial resistance were likely to be similar to those for ocular infection, as antimicrobial resistance is also assessed using laboratory tests.
Individually randomised studies
Active trachoma
In most of the individually randomised studies the treatments were quite different, either comparisons with no treatment, or comparing oral and topical treatments. Only four studies used placebo treatments to mask the study arms: three studies compared active treatment to placebo (Dawson 1969 Sherman; Dawson 1969 Stewart; Hoshiwara 1973), and one study compared oral and topical azithromycin with equivalent placebo treatments in each arm (Cochereau 2007). We graded these studies as at low risk of bias for performance and detection bias for active trachoma. A number of studies mentioned masking, particularly of outcome assessors. Masking was not well described in general, and we marked these studies as having an unclear risk of bias for performance and detection bias for active trachoma, given that the interventions were so clearly different. We graded studies where masking was not mentioned as at high risk of bias (Shukla 1966).
Ocular infection
Fewer studies measured ocular infection. Where masking was described, these were graded in general as having low risk of bias. Two of the individually randomised studies did not describe masking of laboratory samples and so were graded as at unclear risk of bias (Darougar 1980; Dawson 1997).
Cluster‐randomised studies
Active trachoma
All the comparisons in the cluster‐randomised studies were obviously different, and none of the studies reported using placebos. We therefore graded these studies as at high risk of bias, unless they reported efforts to mask the assessment of trachoma and/or attempted to minimise knowledge of the other arms of the study, in which case we graded them as at unclear risk of bias.
Ocular infection (and antimicrobial resistance where assessed)
We graded the majority of studies that examined these outcomes as at low risk of bias, as efforts to mask the laboratory assessment were generally well described. Three studies described masking procedures in insufficient detail (NCT00618449; PRET Niger; Wilson 2018).
Incomplete outcome data
Only eight studies provided data suggesting that incomplete outcome data were unlikely to bias the results, that is they reported high follow‐up rates (greater than 80%) that were reasonably equal between intervention groups (Bailey 1993; Bowman 2000; Dawson 1997; Peach 1986; PRET Niger; TANA; TEF; Woolridge 1967). We graded seven studies with high or unequal loss to follow‐up as at high risk of attrition bias (ACT 1999 Egypt; ACT 1999 Tanzania; ACT 1999 The Gambia; Atik 2006; Foster 1966; Hoshiwara 1973; Resnikoff 1995). In another study, people were excluded because of inadequate treatment, and it was not clear to which group this applied (Darougar 1980); this study was also graded as at high risk of attrition bias. Attrition bias was difficult to judge for the remaining studies, which we graded as at unclear risk of bias.
Selective reporting
There was little suggestion of selective outcome reporting. Table 3 and Table 6 show the outcome‐reporting grid. In most cases where an outcome was not reported it was because the study follow‐up was not conducted at that time point, which is unlikely to introduce bias. TANA did not publish data on active trachoma, but this information was supplied by the authors. In two studies (Cochereau 2007; NCT00618449), it was clear that data on ocular infection had been collected but not reported.
Other potential sources of bias
Recruitment bias
Recruitment bias can occur when individuals are recruited to the trial after the clusters have been randomised, as the knowledge of whether each cluster is an ‘intervention’ or ‘control’ cluster could affect the types of participants recruited (Higgins 2011). None of the included studies discussed this issue.
Baseline imbalances
When small numbers of clusters are randomised, there is a possibility of chance baseline imbalance between the randomised groups in terms of either the clusters or the individuals (Higgins 2011). This was a problem with some of the cluster‐randomised trials included in this review. Four of the trials randomised only two communities to treatment or control (ACT 1999 Egypt; ACT 1999 Tanzania; Atik 2006; Resnikoff 1995). Reporting of the baseline comparability of clusters or statistical adjustment for baseline characteristics can help reduce concern about the effects of baseline imbalances (ACT 1999 Egypt; ACT 1999 Tanzania), however it is difficult to interpret differences in treatment effect between only two communities because there may be some other unknown confounding factor that explains the difference in effect. In ACT 1999 The Gambia, eight communities were pair‐matched. The more recent cluster‐randomised studies were larger: PRET Niger (24 communities); PRET Tanzania (32 communities); PRET The Gambia (48 communities); TANA (48 communities); TEF (16 communities); Wilson 2018 (96 communities).
Effects of interventions
See: Summary of findings for the main comparison Antibiotic versus control for trachoma: individuals; Summary of findings 2 Oral versus topical antibiotic for trachoma: individuals; Summary of findings 3 Oral azithromycin compared to control for trachoma: communities; Summary of findings 4 Oral azithromycin compared to topical tetracycline for trachoma: communities
Comparison 1: Any antibiotic versus control (individuals)
Primary outcome: active trachoma
Analysis 1.1 shows the effect of any antibiotic treatment on active trachoma at three months. Nine trials randomising 1961 people contributed to this analysis. There was considerable heterogeneity between trials (I2 = 73%). The treatment effects observed in the different trials ranged from a risk ratio of 0.40 (95% confidence interval (CI) 0.20 to 0.79), Dawson 1969 Stewart, to a risk ratio of 1.02 (95% CI 0.83 to 1.25), Darougar 1980. However, most of the trials suggested an apparent beneficial effect of treatment on active trachoma measured at three months follow‐up. The pooled risk ratio was 0.78 (95% CI 0.69 to 0.89). We judged this to be low‐certainty evidence, downgrading for risk of bias and inconsistency (summary of findings Table for the main comparison).
Analysis 1.2 shows the effect of any antibiotic treatment on active trachoma at 12 months. Four trials randomising 1035 people contributed to this analysis. Again there was evidence of considerable heterogeneity between trials (I2 = 90%). The treatment effects observed in the different trials ranged from a risk ratio of 0.50 (95% CI 0.41 to 0.62), Shukla 1966, to a risk ratio of 1.05 (95% CI 0.88 to 1.24), Foster 1966. However, three of the four trials showed a statistically significant beneficial effect of treatment on active trachoma measured at 12 months follow‐up. The pooled risk ratio was 0.74 (95% CI 0.55 to 1.00). We judged this to be low‐certainty evidence, downgrading for serious limitations in study design and inconsistency (summary of findings Table for the main comparison).
Subgroup analysis: oral antibiotics versus control compared with topical antibiotics versus control
Analysis 1.3 shows the results separately for the trials that considered oral antibiotic versus control and the trials that considered topical antibiotic versus control on active trachoma at three months. Although statistical heterogeneity was reduced by considering these trials separately, substantial heterogeneity remained (I2 of 60% and 68%). The pooled estimate of treatment effect for oral antibiotics on active trachoma at three months was 0.81 (95% CI 0.67 to 0.97) and for topical antibiotics 0.82 (95% CI 0.72 to 0.92). A similar picture was seen for active trachoma at 12 months (Analysis 1.4). Subgroup analyses such as these can be misleading because there may be other reasons for differences between trials apart from the type of antibiotic used. Direct comparison of oral versus topical antibiotic within trials is a more reliable estimate of relative effect.
Secondary outcome: C trachomatis infection
Analysis 1.5 shows the effect of any antibiotic treatment on ocular C trachomatis infection at three months. Fewer trials contributed to this analysis (4 trials, n = 297). However, in contrast to the effect on active trachoma, there was no evidence of heterogeneity in treatment effect between trials (I2 = 0%). The treatment effect appeared to be of a similar order of effect as for active trachoma, but did not achieve conventional levels of statistical significance (pooled risk ratio of 0.81, 95% CI 0.63 to 1.04). We judged this to be low‐certainty evidence, downgrading for serious limitations in study design and imprecision (summary of findings Table for the main comparison).
Analysis 1.6 shows the effect of any antibiotic treatment on C trachomatis infection at 12 months. Only one trial provided data on ocular chlamydial infection at 12 months (Darougar 1980). The effect was strong, with a risk ratio of 0.25. Although this was statistically significant, the estimate of treatment effect was imprecise with a wide confidence interval (0.08 to 0.78), reflecting the small sample size of the trial. We judged this to be low‐certainty evidence, downgrading for very serious limitations in study design: one small study at risk of bias.
One source of clinical heterogeneity in these trials was whether oral or topical antibiotic was used. One of the objectives of this review was to compare oral and topical treatment, in particular oral azithromycin and topical tetracycline.
Subgroup analysis: oral antibiotics versus control compared with topical antibiotics versus control
Data were insufficient to make a reliable comparison of the effects of oral and topical antibiotics versus control on C trachomatis infection (Analysis 1.7; Analysis 1.8).
Secondary outcome: antimicrobial resistance
None of the studies assessed antimicrobial resistance.
Adverse effects
Table 7 summarises the information on adverse effects reported in the individually randomised studies. In 5 of the 14 individually randomised studies, there was no mention of adverse effects in the study report.
| Study | Antibiotic (number of people treated) | Report | |
| 1 | Oxytetracycline (77) Tetracycline derivative GS2989 (75) | No comment on adverse effects in report | |
| 2 | Azithromycin (97) Topical tetracycline with oral erythromycin in severe cases (97) | Table 2 on page 454 reports adverse effects. Abdominal pain reported more often in azithromycin group (26% versus 16%, P = 0.09). Other effects: diarrhoea, vomiting, fever, headache, body pain, other similar between study groups. "There were no serious adverse reactions and both treatments were well tolerated. All symptoms resolved spontaneously and none required treatment." 1 study participant died, probably due to malaria. He had received topical tetracycline. | |
| 3 | Azithromycin (160) Tetracycline (154) | No comment on adverse effects in report | |
| 4 | Azithromycin topical 2‐day regimen (222) 3‐day (220) and oral azithromycin (214) | "Ocular adverse events were reported in 10.8%, 8.9% and 13.1% of patients in the 2‐day, 3‐day and oral treatment groups respectively. Systemic adverse events were reported in 2.6%, 10.2% and 9.0% of patients. None of the adverse events were treatment‐related events. One patient (3‐day group) had a serious unrelated adverse events (death due to head injury)." (page 670) | |
| 5 | Doxycycline (44) Oxytetracycline (38) | No comment on adverse effects in report | |
| 6 & 7 | Trisulfapyrimidines (33) | "No untoward reactions to sulfonamides were noted" (page 587) | |
| 8 | Oxytetracycline/polymyxin (43) Azithromycin (125) | "In this trial, azithromycin was well tolerated and only two children (of 125 treated) complained of nausea" (page 367) | |
| 9 | Sulfamethoxypyridazine (112) Tetracycline (106) | "3/155 students who received sulfamethoxypyridazine had adverse reactions to the drug. One girl developed a severe purpura associated with marked thrombocytopenia. She recovered following withdrawal of the drug and administration of corticosteroids. Two cases of diagnosed drug rash necessitated discontinuance of the drug. The nephrotic syndrome developed in one boy three months after completion of sulphonamide therapy, but the relationship of this development to therapy was not determined. No reactions or rashes occurred in the other two treatment groups" (page 453) (note: Table 3/Table 4 report 112 children treated with sulfamethoxypyridazine) | |
| 10 | Doxycycline (49) | "Anorexia, nausea, vomiting or diarrhea occurred in three children between the 15th and 25th days of medication. Two of these children were receiving doxycycline, and the disturbances lasted only a single day in each child, in spite of continuing medication. Between day 21 and 28 of medication, transient macular rashes and one‐day illness with low‐grade fever and anorexia occurred in four children. Two of them had received drug, and two placebo. It is likely that an intercurrent, unrelated illness was responsible. Gross enamel dysplasia or tooth discoloration was not observed on examination 20 weeks after the end of medication." (page 222) | |
| 11 | Tetracycline (932) | No comment on adverse effects in report | |
| 12 | Sulfafurazole (140) Sulfadimethoxine (161) | No comment on adverse effects in report | |
| 13 | Azithromycin (31) Tetracycline (29) | "No adverse effects were noted" (page 844); and "The safety of a single oral dose of azithromycin has been demonstrated in this study. Similar to other clinical studies, no adverse effects developed in any of the patients in the azithromycin group" (page 845) | |
| 14 | Tetracycline (726) Sulfonamide (526) | "No more than trivial reactions were observed in any of these three studies, to vaccine, to oil adjuvant, to eye ointment or to sulfa drug." (page 1581) |
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In Bailey 1993 abdominal pain was reported more often in the azithromycin group (26% versus 16%, P = 0.09). Other effects: diarrhoea, vomiting, fever, headache, body pain, other similar between two study groups.
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Cochereau 2007 reported no treatment‐related adverse events.
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Dawson 1969 Sherman and Dawson 1969 Stewart noted "No untoward reactions to sulfonamides".
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Dawson 1997 reported that azithromycin was well tolerated, and that only two children (of 125 treated) complained of nausea.
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Foster 1966 noted three adverse reactions to sulphamethoxypyridazine in 155 children given the drug.
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Hoshiwara 1973 reported "Anorexia, nausea, vomiting or diarrhoea..." in two children out of 49 receiving doxycycline.
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Tabbara 1996 reported no adverse effects in 31 people given azithromycin and 29 given tetracycline.
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Woolridge 1967 noted only trivial reactions.
Comparison 2: Oral versus topical antibiotics (individuals)
Primary outcome: active trachoma
Analysis 2.1 shows the effect of oral versus topical antibiotic on active trachoma at three months from within‐trial comparisons (6 trials, n = 953). There was considerable statistical heterogeneity (I2 = 63%). The estimates of effect were spread across the null line, with three trials reporting a beneficial effect of oral antibiotics, and three trials reporting a beneficial effect of topical antibiotics. Three of the six trials had findings consistent with no difference in effect (Darougar 1980; Dawson 1997; Foster 1966). We judged this to be moderate‐certainty evidence, downgrading one level for serious limitations in study design and one level for inconsistency as the study estimates ranged from 0.65 to 1.37 (summary of findings Table 2).
Analysis 2.2 shows the effect of oral versus topical antibiotic on active trachoma at 12 months from within‐trial comparisons (5 trials, n = 886). There was considerable statistical heterogeneity (I2 = 56%). The estimates of effect were spread across the null line, with three trials reporting a beneficial effect of oral antibiotics, and two trials reporting a beneficial effect of topical antibiotics. Three of the six trials had findings consistent with no difference in effect (Darougar 1980; Dawson 1997; Foster 1966). We judged this to be low‐certainty evidence, downgrading one level for serious limitations in study design and one level for inconsistency as the study estimates ranged from 0.66 to 1.15 (summary of findings Table 2).
Examining the trials for clinical heterogeneity suggested that the interventions used in Bowman 2000 were different. In particular, this study focused on "practical operational conditions", which meant that the topical treatments were unsupervised. A post hoc analysis excluding this trial from the analyses substantially reduced the observed inconsistency (I2 = 0%) at three months, with a pooled risk ratio for the remaining five included trials of 1.04 (95% CI 0.94 to 1.16). Similar improvements in consistency were seen when Bowman 2000 was excluded from the 12 months' analyses (I2 changed from 56% to 29%, pooled risk ratio 1.01 (95% CI 0.85 to 1.20)). In the other trials, application of topical antibiotics was done by members of the research team or schoolteachers.
Secondary outcome: C trachomatis infection
Similarly for active trachoma at 12 months, there was no consistent evidence to support either oral or topical antibiotics being more effective for C trachomatis infection at three (Analysis 2.3) or 12 months (Analysis 2.4) (summary of findings Table 2).
Secondary outcome: antimicrobial resistance
None of the studies assessed antimicrobial resistance.
Adverse effects
See Comparison 1 above.
Comparison 3: Oral azithromycin versus topical tetracycline (individuals)
Primary outcome: active trachoma
Analysis 3.1 and Analysis 3.2 show the specific comparison between oral azithromycin and topical tetracycline for active trachoma at three and 12 months. There was considerable heterogeneity in the results of these studies for active trachoma (Analysis 3.1). As before, excluding Bowman 2000 from the analyses substantially reduced the inconsistency (I2 = 0%), and the pooled risk ratio of the two remaining trials was 1.01 (95% CI 0.80 to 1.28). Only two trials reported data at 12 months. Bowman 2000 reported a beneficial effect of azithromycin compared to tetracycline (risk ratio 0.66, 95% CI 0.45 to 0.98). Dawson 1997 reported a smaller effect that was not statistically significant (risk ratio 0.90, 95% CI 0.65 to 1.23).
We have not included data from Bailey 1993 in the graphical analyses because they compared oral antibiotic (single dose azithromycin) with a combination of topical/oral antibiotic (topical tetracycline with oral erythromycin for severe cases). A total of 194 people with active trachoma were randomly allocated to treatment, 97 in each group. Approximately 60% of these people were antigen positive at baseline. At 26 weeks, 21/97 had active trachoma in the azithromycin group and 27/97 in the tetracycline/erythromycin group (risk ratio 0.78, 95% CI 0.47 to 1.28). Approximately 42% of each group were antigen positive. We have also not included data from Cochereau 2007 in the meta‐analyses because they compared oral azithromycin with two regimens of topical azithromycin, and treated people accompanying the children to the treatment centre. They found that trachoma resolved in 93.0%, 96.3%, and 96.6% of the two‐day group, three‐day group, and oral treatment group 60 days after treatment.
Secondary outcome: C trachomatis infection
Analysis 3.3 and Analysis 3.4 show the specific comparison between oral azithromycin and topical tetracycline for C trachomatis infection at three and 12 months. Two studies reported this outcome at three months. The results of these studies differed: Dawson 1997 risk ratio 0.57, 95% CI 0.14 to 2.30, favouring azithromycin, and TANA risk ratio 1.30, 95% CI 0.41 to 4.11, favouring tetracycline. At 12 months there were only data from Dawson 1997, but with few events the effect estimate was imprecisely estimated (risk ratio 0.50, 95% 0.18 to 1.43).
Secondary outcome: antimicrobial resistance
None of the studies assessed antimicrobial resistance.
Adverse effects
See Comparison 1 above.
Comparison 4: Oral antibiotics versus control (communities)
Four cluster‐randomised community‐based trials compared antibiotic to no or delayed treatment: three studies of oral azithromycin (TANA; TEF; Wilson 2018) and one study of topical tetracycline (Resnikoff 1995).
Primary outcome: active trachoma
None of the studies followed up at three months.
Two studies published on active trachoma at 12 months (Resnikoff 1995; Wilson 2018) and one study provided unpublished data (TANA).
In TANA, 258/634 sentinel children aged 0 to 9 years in 12 communities treated with a single dose of azithromycin had active trachoma at 12 months compared with 429/613 children in communities where treatment was delayed to 12 months (risk ratio 0.58, 95% CI 0.52 to 0.65). The results of this study were reasonably robust to assumptions about the intracluster correlation coefficient (ICC): adjusting for an ICC of 0.2 gave a 95% CI of 0.41 to 0.83.
Wilson 2018 reported data as median community prevalence. At 12 months, the median community prevalence of active trachoma was 9.3% in communities given one single dose of azithromycin (range 0 to 38.9%) and 8.2% in communities that had not been treated (range 0 to 52.9%).
There are several potential reasons for the difference between TANA and Wilson 2018: (1) The prevalence of active trachoma in the population of Wilson 2018 was low (median 6%). In TANA disease prevalence was much higher: over 70% of children had active trachoma at baseline in the intervention groups; (2) We judged TANA largely at low risk of bias but Wilson 2018 was a mixture of unclear and high risk of bias. In particular, the authors reported that reported that people taking part in the 12‐month follow‐up were less likely to report exposure to a face‐washing educational campaign and were less likely to live within 30 minutes of a water source; (3) the coverage of mass drug administration was lower in Wilson 2018 at 73% whereas in TANA it was over 80%.
In Resnikoff 1995 four villages were randomly allocated in factorial fashion to treatment with 1% oxytetracycline or health education. Individuals treated with tetracycline experienced a higher cure rate than people who were not, and communities treated with tetracycline experienced a lower incidence and prevalence of the disease.
Secondary outcome: C trachomatis infection
TEF and TANA reported C trachomatis infection at 12 months (Analysis 4.2). In both studies communities treated with azithromycin were less likely to have C trachomatis infection at 12 months compared to untreated communities. These studies gave different estimates of effect (0.61 in Atik 2006 and 0.32 in TANA, I2 = 97%). The pooled risk ratio was 0.35 (95% CI 0.21 to 0.60). Although it is likely that the size of the pooled effect estimate is unreliable, given the differences between the studies, both of the studies indicated a statistically significant beneficial effect of antibiotic treatment on C trachomatis infection. Again, we judged this to be moderate‐certainty evidence, downgrading for inconsistency (summary of findings Table 3).
The conclusions did not change as a result of adjusting for the extra variation introduced by the cluster design of the studies. Adjusting for an ICC of 0.2 gave a confidence interval for the pooled risk ratio of 0.20 to 0.63.
In TANA communities were treated at 12 months. However, at a later stage after four years of mass treatment, communities were randomised to continuation versus discontinuation of annual or biannual mass treatment. In the discontinuation arm, the mean prevalence of infection in children aged 0 to 9 years increased from 8.3% (95% CI 4.2% to 12.4%) at baseline (0 months) to 14.7% (95% CI 8.7% to 20.8%, P = 0.04) at 36 months. The prevalence of C trachomatis in communities randomised to continuation of mass treatment was 7.2% (95% CI 3.3% to 11.0%) at baseline and 6.6% (95% CI 1.1% to 12.0%, P = 0.64) at 36 months.
Wilson 2018 reported data as median community prevalence. At 12 months, the median community prevalence of ocular infection was 0% in communities given one single dose of azithromycin (range 0 to 14.3%) and 0% in communities that had not been treated (range 0 to 14.3%).
Secondary outcome: antimicrobial resistance
Five studies, all taking place in Africa, assessed antimicrobial resistance (Table 8) (PRET Niger; PRET Tanzania; PRET The Gambia; TANA; TEF). Three of these studies compared azithromycin with no azithromycin (PRET Tanzania; TANA; TEF). In PRET Tanzania azithromycin was given once a year for three years; in TANA azithromycin was given every three months for one year; and in TEF azithromycin was given twice a year for three years. Two studies compared different frequencies of azithromycin administration. PRET Niger compared azithromycin twice a year for two years to azithromycin once a year for two years. PRET The Gambia compared azithromycin once a year for three years to azithromycin once a year for one year. In all five studies antibiotic resistance was assessed in children, although the age ranges differed.
| Studies* | Country | Intervention | Comparator | Age of participants | Bacteria or genetic determinant | Carriage body reservoir | Sample type | Antibiotic | Follow‐up |
| Niger (Matameye district in the Zinder region) | AZ twice a year for 2 years | AZ once a year for 2 years | 6 months to 12 years | lytA+ | Nasopharynx | Nasopharyngeal swab | Macrolide resistance | Baseline and 24 months | |
| Tanzania (Kongwa district) | AZ once a year for 3 years | No AZ | Less than 3 years | E coli | Gastrointestinal | Rectal swab | AZ | Baseline, 1, 3, and 6 months | |
| The Gambia | AZ once a year for 3 years | AZ once a year for 1 year | Less than 15 years | S pneumoniae | Nasopharynx | Nasopharyngeal swab | AZ | Intervention group: 1 month before and 1 month and 6 months after 3rd annual round of MDA | |
| Ethiopia (Goncho Siso Enese woreda district, Amhara zone) | AZ every 3 months for 12 months | No AZ (control communities treated at 12 months) | 1 to 10 years | S pneumoniae | Nasopharynx | Nasopharyngeal swab | AZ | Baseline and 12 months | |
| Ethiopia (Goro district of the Gurage zone of southern Ethiopia) | AZ twice a year for 3 years | No AZ | 1 to 5 years | S pneumoniae | Nasopharynx | Nasopharyngeal swab | AZ | 24, 36, 42, and 54 months |
AZ: azithromycin
MDA: mass drug administration
TMP‐SMX: trimethoprim‐sulfamethoxazole
*All the studies were cluster‐randomised trials, and AZ was delivered to the whole community (mass drug administration).
None of the studies assessed antibiotic resistance inC trachomatis. Three studies assessed S pneumoniae (PRET The Gambia; TANA; TEF); one study assessed S aureus (PRET The Gambia); and one study assessed E coli (PRET Tanzania). Carriage was nasopharyngeal, with the exception of E coli, which was gastrointestinal. Four studies assessed resistance to azithromycin. PRET Niger and TANA assessed genetic evidence of resistance to macrolides and azithromycin, respectively. Other antibiotics were also considered: erythromycin (PRET Tanzania), clindamycin (PRET The Gambia; TANA), tetracycline (TANA; TEF), penicillin (TANA; TEF), and trimethoprim‐sulfamethoxazole (TMP‐SMX) (TEF).
Maximum follow‐up (after baseline mass drug administration (MDA) treatment) was six months (PRET Tanzania), 12 months (TANA), 24 months (PRET Niger), 30 months (PRET The Gambia), and 54 months (TEF).
Due to the heterogeneity of studies, outcomes, and reporting, we did not perform any meta‐analysis of antimicrobial resistance outcomes.
Antibiotic resistance in S pneumoniae
Table 9 show the results of the studies investigating resistance to S pneumoniae (PRET The Gambia; TANA; TEF).
| Study* | Follow‐up** | Intervention*** | Comparator | Risk ratio | 95% confidence intervals | ||||
| Number of communities | n/N | % | Number of communities | n/N | % | ||||
| AZITHROMYCIN | |||||||||
| 1 month before 3rd annual round of MDA | 2 | 0/415 | 0 | 6 | ‐ | ‐ | ‐ | ‐ | |
| 1 month after 3rd annual round of MDA | 2 | 5/417 | 1.2 | 6 | ‐ | ‐ | ‐ | ‐ | |
| 6 months after 3rd annual round of MDA (intervention group) | 2 | 3/343 | 0.9 | 6 | 1/400 | 0.3 | 3.5 | 0.4 to 33.5 | |
| PRET The Gambia (as a percentage pneumococcal isolates)¶ | 1 month before 3rd annual round of MDA | 2 | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ |
| PRET The Gambia (as a percentage pneumococcal isolates)¶ | 1 month after 3rd annual round of MDA | 2 | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ |
| PRET The Gambia (as a percentage pneumococcal isolates)¶ | 6 months after 3rd annual round of MDA (intervention group) | 2 | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ |
| Baseline | 11 | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ | |
| 12 months | 12 | 56/119 | 46.9 | 12 | 11/120 | 9.2 | 5.1 | 2.8 to 9.3 | |
| TANA (as a percentage pneumococcal isolates)¶ | Baseline | 11 | 5/76 | 6.3 | ‐ | ‐ | ‐ | ‐ | ‐ |
| TANA (as a percentage pneumococcal isolates)¶ | 12 months | 12 | 58/93 | 62.3 | 12 | 11/98 | 11.6 | 5.6 | 3.1 to 9.9 |
| 24 months | 8 | 34/120 | 28.2 | 8 | 1/120 | 0.9 | 34.0 | 4.7 to 244 | |
| 36 months | 8 | 92/120 | 76.8 | 8 | 0/119 | 0 | 183.4 | 11.5 to 2922 | |
| 42 months | 8 | 37/120 | 30.6 | 8 | ‐ | ‐ | ‐ | ‐ | |
| 54 months | 8 | 25/120 | 20.8 | 8 | ‐ | ‐ | ‐ | ‐ | |
| CLINDAMYCIN | |||||||||
| Baseline | 11 | 2/110 | 1.5 | ‐ | ‐ | ‐ | ‐ | ‐ | |
| 12 months | 12 | 16/119 | 13.3 | 12 | 4/120 | 3.3 | 4 | 1.4 to 11.7 | |
| TANA (as a percentage pneumococcal isolates)¶ | Baseline | 11 | 1/76 | 1.5 | ‐ | ‐ | ‐ | ‐ | ‐ |
| TANA (as a percentage pneumococcal isolates)¶ | 12 months | 12 | 14/83 | 16.9 | 12 | 4/98 | 3.9 | 4.1 | 1.4 to 12.1 |
| PENICILLIN | |||||||||
| Baseline | 11 | 0/110 | 0 | ‐ | ‐ | ‐ | ‐ | ‐ | |
| 12 months | 12 | 0/119 | 0 | 12 | 1/120 | 0.8 | 0.34 | 0.01 to 8.2 | |
| TANA (as a percentage pneumococcal isolates)¶ | Baseline | 11 | 0/76 | 0 | ‐ | ‐ | ‐ | ‐ | ‐ |
| TANA (as a percentage pneumococcal isolates)¶ | 12 months | 12 | 0/83 | 0 | 12 | 1/98 | 1.0 | 0.39 | 0.02 to 9.52 |
| 24 months | 8 | 1/120 | 0.9 | 8 | 0/120 | 0 | 3.0 | 0.12 to 72.9 | |
| 36 months | 8 | 0/120 | 0 | 8 | 0/119 | 0 | ‐ | ‐ | |
| 42 months | 8 | 0/120 | 0 | 8 | ‐ | ‐ | ‐ | ‐ | |
| 54 months | 8 | 0/120 | 0 | 8 | ‐ | ‐ | ‐ | ‐ | |
| TETRACYCLINE | |||||||||
| Baseline | 11 | 11/110 | 10.0 | ‐ | ‐ | ‐ | ‐ | ‐ | |
| 12 months | 12 | 34/119 | 28.4 | 12 | 21/120 | 17.5 | 1.6 | 1.01 to 2.6 | |
| TANA (as a percentage pneumococcal isolates)¶ | Baseline | 11 | 12/76 | 15.2 | ‐ | ‐ | ‐ | ‐ | ‐ |
| TANA (as a percentage pneumococcal isolates)¶ | 12 months | 12 | 29/83 | 35.5 | 12 | 21/98 | 21.5 | 1.6 | 1.01 to 2.6 |
| 24 months | 8 | 44/120 | 36.5 | 8 | 23/120 | 18.9 | 1.9 | 1.2 to 3.0 | |
| 36 months | 8 | 82/120 | 68.7 | 8 | 19/119 | 15.7 | 4.3 | 2.8 to 6.6 | |
| 42 months | 8 | 69/120 | 57.2 | 8 | ‐ | ‐ | ‐ | ‐ | |
| 54 months | 8 | 46/120 | 38.7 | 8 | ‐ | ‐ | ‐ | ‐ | |
| TRIMETHOPRIM‐SULFAMETHOXAZOLE | |||||||||
| 24 months | 8 | 0/120 | 0 | 8 | 3/120 | 2.7 | 0.14 | 0.01 to 2.7 | |
| 36 months | 8 | 9/120 | 7.9 | 8 | 8/119 | 6.7 | 1.1 | 0.5 to 2.8 | |
| 42 months | 8 | 11/120 | 8.8 | 8 | ‐ | ‐ | ‐ | ‐ | |
| 54 months | 8 | 8/120 | 6.8 | 8 | ‐ | ‐ | ‐ | ‐ | |
n/N: number of isolates with resistance/total number of isolates
AZ: azithromycin
MDA: mass drug administration
*Studies were all cluster‐randomised controlled trials. PRET The Gambia compared AZ once a year for 3 years with AZ once a year for 1 year; TANA compared AZ every 3 months for 12 months with no AZ; TEF compared AZ twice a year for 3 years with no AZ.
**Follow‐up is months after baseline (i.e. first MDA) unless otherwise indicated.
***TANA and TEF reported average percentages across communities, and these are the percentages reported in this table. We estimated n/N using these percentages and additional information in the text of the paper. Figures for n/N were used to calculate the risk ratio and 95% confidence interval in RevMan 5. There may be minor discrepancies due to rounding between the raw numbers, percentages and risk ratios. The 95% confidence intervals for the risk ratio are are not adjusted for the cluster design.
¶ Denominator is isolates with pneumococcal carriage only.
In PRET The Gambia azithromycin/macrolide resistance was assessed one month before, one month after, and six months after the third annual round of MDA in two communities. This was compared to antibiotic resistance 30 months after one round of MDA in six communities. There were few cases of resistance to azithromycin: no cases one month before the third round of azithromycin MDA; 5/417 (1.2%) one month after; and 3/343 (0.9%) six months after. In the comparator group there was one case of resistance in 400 children (0.3%) 30 months after one annual round of MDA. The risk ratio comparing intervention (six months after the third round of mass treatment) and control (30 months after one annual round of mass treatment) suggested an increased risk of resistance in the intervention communities (risk ratio 3.5, 95% CI 0.4 to 33.5). However, wide confidence intervals, due to the sparse data, were compatible with increased or decreased risk.
TANA compared antibiotic resistance in 12 communities allocated to mass treatment with azithromycin every three months for 12 months, which was compared to antibiotic resistance in 12 communities that did not receive azithromycin for 12 months. At baseline in the intervention communities, on average 3.6% of children were carrying S pneumoniae resistant to azithromycin. At 12 months this had increased to 46.9%. The 12 untreated control communities were not assessed at baseline, but at 12 months had an average azithromycin‐resistant S pneumoniae carriage risk of 9.2% (risk ratio 5.1, 95% CI 2.8 to 9.3). These analyses are based on the proportion of swabbed children who were classified as resistant. Similar findings were seen for analyses of the proportion of pneumococcal isolates that were classified as resistant (risk ratio 5.6, 95% CI 3.1 to 9.9). The confidence intervals around the effect estimate do not take into account the cluster design of the study. In the study report, confidence intervals were only provided for risk estimates by group and not for the risk ratio. Comparing these with confidence intervals calculated ignoring the cluster design suggested that any design effect in this study would be less than 1.5. Repeating the risk ratio calculations assuming a conservative design effect of 2 suggests the lower confidence interval would be not less than 2.
Similar results were seen in TEF. A substantial proportion of children in eight communities treated with azithromycin twice a year for three years were carrying S pneumoniae resistant to azithromycin at follow‐up visits: 28.2% at 24 months and 76.8% at 36 months. This proportion decreased after cessation of azithromycin and was 30.6% at 42 months and 20.8% at 54 months. Data from eight untreated control communities had a lower risk of resistance: 0.9% at 24 months and 0% at 36 months. Risk ratio was 34.0 (95% CI 4.7 to 244) at 24 months and 183.4 (95% CI 11.5 to 2922) at 36 months. Again, repeating analyses assuming a design effect of 2, the lower confidence intervals were always well above 1.
In TANA an increased risk of clindamycin resistance was seen in the intervention communities (risk ratio 4, 95% CI 1.4 to 11.7), but the prevalence of resistance was lower than in other studies: 13.3% in communities treated every three months compared to 3.3% in untreated communities. Similar results were seen for analyses of isolates of S pneumoniae infection.
Both TANA and TEF investigated penicillin resistance in S pneumoniae. There were very few cases (0 or 1 only) in both studies.
Both TANA and TEF investigated tetracycline resistance in S pneumoniae. In TANA 10% of children had tetracycline‐resistant S pneumoniae at baseline; this increased to 28.4% in communities given mass treatment with azithromycin every three months. This was compared to 17.5% resistance in the non‐treated communities at 12 months (risk ratio 1.6, 95% CI 1.01 to 2.6). An analysis with design effect of 2 reduced the lower confidence interval to below 1. Similar results were seen when the analyses were restricted to isolates of S pneumoniae infection. In TEF tetracycline resistance was seen in 36.5%, 68.7%, 57.2%, and 38.7% of samples at 24, 36, 42, and 54 months, respectively. This was compared to 18.9% and 15.7% resistance in the control group at 24 months and 36 months (risk ratio 1.9 (95% CI 1.2 to 3.0) and 4.3 (2.8 to 6.6), respectively). The lower confidence interval for the latter analysis remained above 1 with a design effect of 2.
TEF was the only study to look at TMP‐SMX and found a similar order of magnitude of resistance in intervention (approximately 8%) and comparator groups (approximately 7% at 36 months) (risk ratio 1.1, 95% CI 0.5 to 2.8).
Antibiotic resistance in S aureus
Table 10 shows the results of the studies investigating resistance to S aureus (PRET The Gambia).
| Study* | Follow‐up** | Intervention | Comparator | Risk ratio | 95% confidence interval*** | ||||
| Number of communities | n/N | % | Number of communities | n/N | % | ||||
| AZITHROMYCIN | |||||||||
| 1 month before 3rd annual round of MDA | 2 | 37/414 | 8.9 | 6 | ‐ | ‐ | ‐ | ‐ | |
| 1 month after annual round of MDA | 2 | 142/417 | 34.1 | 6 | ‐ | ‐ | ‐ | ‐ | |
| 6 months after 3rd annual round of MDA (intervention group) | 2 | 25/343 | 7.3 | 6 | 6/375 | 1.6 | 4.6 | 1.9 to 11.0 | |
| PRET The Gambia(as a percentage of isolates)¶ | 1 month before 3rd annual round of MDA | 2 | 37/102 | 36.3 | 6 | ‐ | ‐ | ‐ | ‐ |
| PRET The Gambia(as a percentage of isolates)¶ | 1 month after 3rd annual round of MDA | 2 | 142/161 | 88.2 | 6 | ‐ | ‐ | ‐ | ‐ |
| PRET The Gambia(as a percentage of isolates)¶ | 6 months after 3rd annual round of MDA (intervention group) | 2 | 25/30 | 83.3 | 6 | 6/25 | 24.0 | 3.5 | 1.7 to 7.1 |
| CLINDAMYCIN | |||||||||
| 1 month before 3rd annual round of MDA | 2 | 24/414 | 5.8 | 6 | ‐ | ‐ | ‐ | ‐ | |
| 1 month after 3rd annual round of MDA | 2 | 128/417 | 30.7 | 6 | ‐ | ‐ | ‐ | ‐ | |
| 6 months after 3rd annual round of MDA (intervention group) | 2 | 20/343 | 5.8 | 6 | 3/375 | 0.8 | 7.3 | 2.2 to 24.3 | |
| PRET The Gambia(as a percentage of isolates)¶ | 1 month before 3rd annual round of MDA | 2 | 24/102 | 23.5 | 6 | ‐ | ‐ | ‐ | ‐ |
| PRET The Gambia(as a percentage of isolates)¶ | 1 month after annual round of MDA | 2 | 128/161 | 79.5 | 6 | ‐ | ‐ | ‐ | ‐ |
| PRET The Gambia(as a percentage of isolates)¶ | 6 months after 3rd annual round of MDA (intervention group) | 2 | 20/30 | 66.7 | 6 | 3/25 | 12.0 | 5.6 | 1.9 to 16.5 |
n/N: number of isolates with resistance/total number of isolates
AZ: azithromycin
MDA: mass drug administration
*Studies were all cluster‐randomised controlled trials. PRET The Gambia compared AZ once a year for three years with AZ once a year for one year.
**Follow‐up is months after baseline (i.e. first mass drug administration) unless otherwise indicated.
***The 95% confidence intervals for the risk ratio are are not adjusted for the cluster design.
¶ Denominator is isolates with S.aureus carriage only.
Only one study reported resistance to S aureus (PRET The Gambia). This study compared azithromycin once a year for three years with azithromycin once a year for one year.
Resistance to azithromycin rose from 8.9% one month before the third round of mass treatment to 34.1% one month after and dropped again to 7.3% six months later in two communities. This was higher than the prevalence of resistance in six comparator communities (1.6%) that had received 1 dose of azithromycin 30 months previously (risk ratio 4.6, 95% CI 1.9 to 11.0). A similar change over time was seen with clindamycin (5.8% one month before third round; 30.7% one month after third round; and 5.8% six months after third round), with a low risk in comparator communities (0.8% prevalence 30 months after baseline) risk ratio 7.3 (95% CI 2.2 to 24.3).
Antibiotic resistance in E coli
One study reported resistance to E coli (Table 11) (PRET Tanzania). In the four intervention communities, azithromycin resistance increased from 16.3% at baseline to 61.2% one month after mass treatment, thereafter decreasing to 42.1% at three months, and 31.3% at six months. In the four untreated communities, azithromycin resistance was lower: 20.8%, 18.7%, 15.9%, and 20.0% (risk ratio at six months 1.6, 95% CI 0.8 to 3.0). A similar pattern was seen for erythromycin. In the four intervention communities, erythromycin resistance varied from 26.0% at baseline to 76.0% at one month after mass treatment, to 54.9% at three months, and 38.6% at six months. In the four untreated communities, erythromycin resistance was lower: 22.9%, 28.4%, 23.8%, and 26.0% (risk ratio at six months 1.8, 95% CI 0.8 to 3.9).
| Study* | Follow‐up** | Intervention | Comparator | Risk ratio | 95% confidence intervals*** | ||||
| Number of communities | n/N | % | Number of communities | n/N | % | ||||
| AZITHROMYCIN | |||||||||
| Baseline | 4 | 20/163 | 16.3 | 4 | 20/96 | 20.8 | 0.6 | 0.3 to 1.04 | |
| 1 month | 4 | 79/129 | 61.2 | 4 | 25/134 | 18.7 | 3.3 | 2.3 to 4.8 | |
| 3 months | 4 | 56/133 | 42.1 | 4 | 20/126 | 15.9 | 2.7 | 1.7 to 4.2 | |
| 6 months | 4 | 26/83 | 31.3 | 4 | 10/50 | 20.0 | 1.6 | 0.8 to 3.0 | |
| PRET Tanzania (as a percentage of isolates)¶ | Baseline | 4 | 30/300 | 10.0 | 4 | 39/205 | 19.0 | 0.5 | 0.3 to 0.8 |
| PRET Tanzania (as a percentage of isolates)¶ | 1 month | 4 | 153/347 | 44.1 | 4 | 46/325 | 14.2 | 3.1 | 2.3 to 4.2 |
| PRET Tanzania (as a percentage of isolates)¶ | 3 months | 4 | 104/347 | 30.0 | 4 | 32/324 | 9.9 | 3.0 | 2.1 to 4.4 |
| PRET Tanzania (as a percentage of isolates)¶ | 6 months | 4 | 44/191 | 23.0 | 4 | 14/118 | 11.9 | 1.9 | 1.1 to 3.4 |
| ERYTHROMYCIN | |||||||||
| Baseline | 4 | 32/123 | 26.0 | 4 | 22/96 | 22.9 | 1.2 | 0.6 to 2.2 | |
| 1 month | 4 | 98/129 | 76.0 | 4 | 38/134 | 28.4 | 8.0 | 4.6 to 13.9 | |
| 3 months | 4 | 73/133 | 54.9 | 4 | 30/126 | 23.8 | 3.9 | 2.3 to 6.6 | |
| 6 months | 4 | 32/83 | 38.6 | 4 | 13/50 | 26.0 | 1.8 | 0.8 to 3.9 | |
| PRET Tanzania (as a percentage of isolates)¶ | Baseline | 4 | 51/300 | 17.0 | 4 | 35/205 | 17.1 | 1.0 | 0.6 to 1.6 |
| PRET Tanzania (as a percentage of isolates)¶ | 1 month | 4 | 219/347 | 63.1 | 4 | 65/325 | 20.0 | 6.8 | 4.8 to 9.7 |
| PRET Tanzania (as a percentage of isolates)¶ | 3 months | 4 | 149/347 | 42.9 | 4 | 52/324 | 16.0 | 3.9 | 2.7 to 5.7 |
| PRET Tanzania (as a percentage of isolates)¶ | 6 months | 4 | 61/191 | 31.9 | 4 | 20/118 | 16.9 | 2.3 | 1.3 to 4.1 |
n/N: number of isolates with resistance/total number of isolates
AZ: azithromycin
*Studies were all cluster‐randomised controlled trials. PRET Tanzania compared AZ once a year for three years with no AZ.
**Follow‐up is months after baseline (i.e. first mass drug administration) unless otherwise indicated.
***The 95% confidence intervals for the risk ratio are not adjusted for the cluster design.
¶ Denominator is isolates with E.coli carriage only.
Adverse effects
Table 12 summarises the information on adverse effects reported in the cluster‐randomised studies. In TANA data on adverse effects due to azithromycin were collected systematically:
| Study | Antibiotic (number of communities and people treated) | Report | |
| 1, 2 & 3 | Azithromycin (6 communities, approximately 3800) Tetracycline (6 communities, approximately 2400) | No comment on adverse effects in report | |
| 4 | A total of 4 communities included in the study. Azithromycin (214) Tetracycline (161) | No comment on adverse effects in report | |
| 5 | Azithromycin (1139) | Reported no adverse events on clinical trials register (clinicaltrials.gov/ct2/show/results/NCT00618449) | |
| 6 | Azithromycin (48 communities, approximately 6000) | No comment on adverse effects in report, but "a data and safety monitoring committee met annually to review results and serious adverse events" | |
| 7 | Azithromycin (32 communities, approximately 12,000) | "There were no serious adverse events reported in either arm." | |
| 8 | Azithromycin (48 communities, 29,091) | No comment on adverse effects in report | |
| 9 | Oxytetracycline (346) | No comment on adverse effects in report | |
| 10 | Azithromycin (over 16,000) | "We recorded no reported serious adverse events attributed to study medication. 96 deaths were recorded in subkebeles in the children‐treated group and 126 deaths recorded in those in the control group. At 12 months a survey was undertaken to assess adverse effects in the treated population (n=671, 96 side‐effects reported). [.. ] 56 (11.3%) patients reported abdominal pain, vomiting, and nausea, whereas diarrhoea, constipation and related issues accounted for 16 (2.4%) of complaints. Four (0.6%) patients reported haemorrhoid or other as side effects" (House and colleagues, page 1115). "In a trachoma‐endemic area, mass distribution of oral azithromycin was associated with reduced mortality in children" (Porco and colleagues, conclusion of abstract) | |
| 11 | Azithromycin (16 communities, 4790) | "There were no serious adverse events due to the study medicine reported" | |
| 12 | Azithromycin (48 communities, unclear how many people) | "No serious adverse events were associated with MDA." |
MDA: mass drug administration
-
96/671 individuals treated with azithromycin reported an adverse effect of treatment (14.3%, 95% CI 11.7% to 17.2%); 72 of these 96 people (75%) had gastrointestinal effects (abdominal pain, vomiting, nausea, diarrhoea, constipation, and related issues) (10.7% of total sample of 671 people, 95% CI 8.5% to 13.3%);
-
no serious adverse events were recorded in this study;
-
a specific analysis of childhood mortality suggested that azithromycin treatment reduced the rate of childhood mortality in these communities. The mortality rate for children aged 1 to 9 years was 4.1 per 1000 person‐years (95% CI 3.0 to 5.7) in the treated communities compared to 8.3 per 1000 person‐years (95% CI 5.3 to 13.1) in the untreated communities.
-
NCT00618449, PRET Tanzania, Tabbara 1996, TEF, and Wilson 2018 reported that there were no serious adverse events.
Notably, two other large cluster‐randomised studies of azithromycin did not comment on adverse events (PRET Niger; PRET The Gambia), but in PRET Niger "a data and safety monitoring committee met annually to review results and serious adverse events".
Comparison 5: Oral azithromycin versus topical tetracycline (communities)
Primary outcome: active trachoma
Only one study compared oral and topical community‐based treatment for trachoma, the Azithromycin in Control of Trachoma study (ACT). As this study took place in three different countries in Africa (Egypt, The Gambia, and Tanzania), it is included in the analyses as three separate studies.
Even though all three studies had the same interventions and the one study protocol, there was still considerable heterogeneity of effect. However, it should be noted that in two locations only two communities were randomised to oral versus topical treatment (ACT 1999 Egypt; ACT 1999 Tanzania).
The effect of community‐based treatment with azithromycin versus topical tetracycline on active trachoma is shown in Analysis 5.1 and Analysis 5.2. In ACT 1999 Egypt and ACT 1999 The Gambia, there was some evidence that azithromycin was more effective than topical tetracycline in reducing the risk of active trachoma at three and 12 months. However, these results were not very robust to assumptions about the ICC. Adjusting for an ICC of 0.05 resulted in confidence intervals including 1 for all the results. In ACT 1999 Tanzania, the findings were less consistent, with a risk ratio greater than 1 (favouring topical treatment) for active trachoma at three and 12 months. We judged this to be low‐certainty evidence, downgrading for serious limitations in study design and inconsistency (summary of findings Table 4).
One further study with a more complex design compared targeted azithromycin combined with surgery versus surgery alone. People with active trachoma in the control group received tetracycline, as did non‐index cases in the intervention group (Atik 2006). The proportion of people with active trachoma at 12 months was 21/523 in the intervention group compared with 35/994 in the control (risk ratio 1.14, 95% CI 0.67 to 1.94). The figures for ocular infection were: 23/659 vs 68/1192 (risk ratio 0.61, 95% CI 0.39 to 0.97).
Secondary outcome: C trachomatis infection
The effect of community‐based treatment with azithromycin versus topical tetracycline on active trachoma is shown in Analysis 5.3 and Analysis 5.4. At three months, azithromycin appeared to be more effective than topical tetracycline in reducing the risk of C trachomatis infection. However, these results were not very robust to assumptions about the ICC. Adjusting for an ICC of 0.05 resulted in confidence intervals including 1 for all the results. In ACT 1999 Tanzania, the findings were less consistent, with a risk ratio greater than 1 (favouring topical treatment) for C trachomatis infection at 12 months. We judged this to be low‐certainty evidence, downgrading for serious limitations in study design and inconsistency (summary of findings Table 4).
Secondary outcome: antimicrobial resistance
See Comparison 4 above.
Adverse effects
See Comparison 4 above.
Comparison 6: Annual versus different treatment frequencies
The included studies considered several different dosing strategies. These fall into three broad categories: applying mass treatment at different dosing intervals; applying cessation or stopping rules to mass treatment; and strategies to increase mass treatment coverage.
Mass administration of azithromycin at different dosing intervals
The WHO recommends annual treatment with antibiotics for communities where the prevalence of active trachoma in children aged 1 to 9 years is 10% or more (Solomon 2006; WHO 2014). Four studies compared different dosing intervals with azithromycin versus annual treatment with azithromycin. The different dosing intervals evaluated were as follows.
-
Two doses of azithromycin (day 0 and day 30) compared with one dose (day 0) for one year (NCT00618449).
-
Azithromycin (single dose) every three months for one year (children aged 1 to 10 years only) (TANA).
-
Azithromycin (single dose) every six months for two years (TEF).
-
Azithromycin (single dose) every six months for three years (children aged 0 to 12 years only) (PRET Niger).
-
Azithromycin (single dose) every six months for three years (TANA).
Two doses of azithromycin (day 0 and day 30) compared with one dose (day 0) for one year
NCT00618449 compared two doses of azithromycin (day 0 and day 30) with a single dose of azithromycin (day 0) in 10 communities within the Maradi region of Niger with a high prevalence of clinical active trachoma in children aged 10 years and younger. This study is unpublished, but study results were available on the trials register (clinicaltrials.gov/ct2/show/results/NCT00618449). The results of this study were inconclusive. At one year, 19/679 (2.8%) participants in the two dose arm had C trachomatis infection compared with 12/668 (1.8%) in the single dose arm (risk ratio 1.56, 95% CI 0.76 to 3.18). The investigators reported that "Prevalence of infection in communities was less than predicted, as was return of infection post‐treatment, thus hypothesis could not be evaluated".
Azithromycin (single dose) every three months for 12 months
TANA evaluated the treatment of children aged 1 to 10 years every three months for one year in 12 communities in Ethiopia. Active trachoma was reported for the children‐treated arm only. Table 13 shows results for C trachomatis infection. At 12 months there was a lower prevalence of infection in children age 1 to 10 years in the communities where children were treated every three months (3.6%) compared with the communities where everyone was offered 1 annual dose (14.6%). Similar prevalence of infection at 12 months was observed in the two groups in people age 11 years and above (8.2% versus 6.2%).
|
| Intervention: children aged 1 to 10 years offered single‐dose oral azithromycin every 3 months (n = 12 communities) | Comparator: everyone aged 1 year and older offered single‐dose oral azithromycin at first visit (baseline) (n = 12 communities) | ||
| Prevalence % | 95% confidence interval | Prevalence % | 95% confidence interval | |
| Children aged 1 to 10 years | 3.6 | 0.8 to 6.4 | 14.6 | 7.2 to 22.1 |
| Children and adults aged 11 years and older | 8.2 | 5.1 to 11.4 | 6.2 | 2.9 to 9.4 |
Azithromycin (single dose) every six months
Three studies compared azithromycin mass treatment every six months with annual treatment (PRET Niger; TANA; TEF). In PRET Niger, the treatment every six months was targeted at children aged 0 to 12 years only. PRET Niger and TANA reported active trachoma, and results were similar between communities treated every six months and communities treated annually.
-
In PRET Niger, the prevalence of active trachoma at 36 months was 7.8% (95% CI 5.3% to 11.4%) in the communities where children were treated every six months and 8.0% (95% CI 5.0% to 11.6%) in the communities where everyone was treated annually.
-
In TANA, the prevalence of active trachoma in children aged 0 to 9 years at 42 months was 35.0% (95% CI 23.9% to 46.1%) in communities treated every six months compared with 31.5% (95% CI 21.6% to 41.3%) in communities treated annually. The authors reported that they did not detect a difference at all other time points (12, 18, 24, 30, 36 months) in children aged 0 to 9 years nor in people aged 10 years or older.
All three studies reported results for C trachomatis (see Table 14). Overall, there was some evidence of lower prevalence of C trachomatis infection in communities treated every six months, but the differences were generally small and not statistically significant. These data were not pooled due to differences in follow‐up and age groups considered and in reporting (mean community prevalences).
|
| Intervention: everyone aged 1 year and older offered single‐dose oral azithromycin every 6 months | Comparator: everyone aged 1 year and older offered single‐dose oral azithromycin annually | ||
|
| Prevalence % | 95% confidence interval | Prevalence % | 95% confidence interval |
| PRET Niger | 3.8 | 2.2 to 6.0 | 5.8 | 3.2 to 9.0 |
| PRET Niger | 0.0 | 0 to 7 | 0.3 | 0 to 7 |
| TANA Follow‐up: 12 months | 1.7 | 0.7 to 2.6 | 6.2 | 2.9 to 9.4 |
| TANA | 1.5 | 0.2 to 2.8 | 2.3 | 0.8 to 3.8 |
| TANA | 0.2 | 0.0 to 0.6 | 1.5 | 0.1 to 3.0 |
| TANA Follow‐up: 12 months | 1.7 | 0.7 to 2.6 | 6.2 | 2.9 to 9.4 |
| TANA | 1.5 | 0.2 to 2.8 | 2.3 | 0.8 to 3.8 |
| Children and adults aged 10 years and older | 0.2 | 0.0 to 0.6 | 1.5 | 0.1 to 3.0 |
| TEF | 1.3 | 0.3 to 2.6 | 10.9 | 0.1 to 21.8 |
| TEF | 0.9 | 0.0 to 2.1 | 6.8 | 1.2 to 12.4 |
PRET Niger: 24 communities in each group; only children aged 0 to 12 years treated in intervention group.
TANA: 12 communities in each group.
TEF: 8 communities in each group.
Annual mass drug administration compared to annual mass drug administration if evidence of trachoma in the community (C trachomatis infection or active trachoma)
In PRET Tanzania and PRET The Gambia, annual mass drug administration was also compared to annual mass drug administration if there was evidence of follicular trachoma or infection, that is the lack of infection was to be used as a stopping rule.
In PRET Tanzania the stopping rule was not applied because infection was observed in all communities after dosing.
In PRET The Gambia there was no evidence of any difference according to stopping rule on active trachoma (rate ratio 1.17, 95% CI 0.65 to 1.53) or C trachomatis infection (rate ratio 0.78, 95% CI 0.14 to 4.49) at 36 months, but with wide confidence intervals, indicating considerable uncertainty in the effect estimate. The rate ratios quoted here compare communities allocated to stopping rule, that is that received only one round of mass drug treatment, with communities that received three rounds of mass drug treatment, with confidence intervals adjusted for cluster design. Communities in the stopping‐rule arms only received treatment if there were observed cases of infection or disease in the community in the previous six months, and this rule was implemented for all communities, hence they received only one round of mass drug treatment.
Strategies to improve the coverage of mass treatment with azithromycin
In the three PRET studies (PRET Niger; PRET Tanzania; PRET The Gambia), annual mass drug administration with single dose azithromycin and a standard coverage of 80% to 90% was compared to annual mass drug administration of azithromycin with enhanced coverage of 90% or more. All three studies found little evidence of a benefit of the additional effort to increase the coverage of mass treatment.
-
In PRET Niger, the prevalence of C trachomatis infection at 36 months was 7.1% (95% CI 2.7% to 11.4%) in the enhanced‐coverage communities compared with 4.6% (95% CI 0% to 9.5%) in the standard‐coverage communities.
-
In PRET Tanzania at 36 months (one year after the third mass drug administration), there was no evidence of any difference in the prevalence of C trachomatis infection according to coverage of mass drug administration. The prevalence of infection was 4.0% in the standard‐coverage communities and 5.4% in the enhanced‐coverage communities. The authors reported an adjusted difference of 1.4% (95% CI −1.0% to 3.8%).
-
In PRET The Gambia, there was no evidence for an effect of enhanced coverage on C trachomatis infection (rate ratio 1.03, 95% CI 0.18 to 5.89) or active trachoma (rate ratio 1.15, 95% CI 0.74 to 1.79), but with wide confidence intervals, indicating considerable uncertainty in the effect estimate.
Discussion
Summary of main results
The trials included in this review provide evidence that individuals with trachoma benefit from antibiotic treatment (summary of findings Table for the main comparison). Antibiotic treatment reduces the risk of active trachoma and ocular C trachomatis infection up to 12 months after treatment. The trials included in this review were clinically and statistically heterogeneous, and most had serious limitations in their design. This makes it difficult to estimate the size of the effect ‐ the current best guess would be an approximate 20% risk reduction. We judged the certainty of the evidence to be low. Oral and topical treatments appeared to have similar effects if used as prescribed (summary of findings Table 2). One study compared oral antibiotic and unsupervised topical treatment and found the oral antibiotic to be more effective "under practical operational conditions", which may have been due to poor compliance with the more complex topical treatment regimen (Bowman 2000).
Only three of the more recent trials in individuals used azithromycin, which is the currently recommended oral antibiotic treatment. None of these trials had a no‐treatment group. However, in the individually randomised trials there was no evidence that azithromycin was less effective than topical tetracycline.
We identified four community‐based trials comparing azithromycin versus no treatment. These trials were of variable quality and size, however there was one large, good‐quality trial conducted in Ethiopia providing moderate‐certainty evidence that community‐based treatment with a single dose of azithromycin reduces the prevalence of active trachoma and ocular chlamydial infection in children up to 12 months after treatment (summary of findings Table 3) (TANA).
Only one trial compared oral versus topical community‐based treatment (summary of findings Table 4). This study was conducted in three countries in Africa and was therefore included as three separate studies in this review. Data from this study were inconsistent. In The Gambia and Egypt, there was some evidence that oral azithromycin was more effective than topical tetracycline, particularly with regards to ocular infection. However, after adjustment for the cluster design of the study, these findings were not statistically significant and were not replicated consistently in the Tanzanian arm of the study.
The included studies considered several different dosing strategies. These fall into three broad categories: applying mass treatment at different dosing intervals; applying cessation or stopping rules to mass treatment; and strategies to increase mass treatment coverage. There was no strong evidence to support any variation in the recommended annual mass treatment.
None of the included trials reported any serious adverse events associated with either of the currently used antibiotics, azithromycin and topical tetracycline. However, for many of the trials it was not clear whether data on adverse effects had been collected systematically. In the one trial that did collect and report these data systematically, between 10% and 15% of people experienced symptoms such as nausea and vomiting with azithromycin treatment.
Results from five cluster‐randomised trials of mass treatment with azithromycin provided high‐certainty evidence of an increased risk of resistance of S pneumoniae,S aureus, and E coli to azithromycin, tetracycline, and clindamycin with risk ratios in the order of 5 at 12 months. There was no evidence to support increased resistance to penicillin or trimethoprim‐sulfamethoxazole (TMP‐SMX).
Overall completeness and applicability of evidence
A strength of the evidence is that the included trials come from many different countries and populations. However, it is unfortunate that heterogeneity between trial results meant that we could not estimate with any confidence the size of the effect for treatment of trachoma with oral or topical antibiotics, although it is likely that both oral and topical treatments have a beneficial effect.
The epidemiology of trachoma has changed over time as programmes have implemented the SAFE strategy. In March 2019, the number of people living in areas where the prevalence of trachomatous inflammation–follicular (TF) in children aged 1 to 9 years was ≥ 5% was 142.2 million, down from 1517 million in 2002 (WER 2019). The majority of people living in trachoma endemic areas are in sub‐Saharan Africa. Many of the more recent trials included in this review took place in countries in the African Region. The level of endemicity was relatively high in most of these studies, and the extent to which they are applicable in settings with lower endemicity is unclear.
Almost all the trials in individuals were done in children, and the generalisability of these findings to adults is uncertain. Data were reported for adults and children in the community‐based trials. Given the small number of trials, it was not possible to determine whether the effects are different in these groups, but one study provided data on ocular infection after mass treatment in both children and adults (TANA). The observed risk ratio was 0.32 (95% CI 0.26 to 0.40) in children and 0.49 (95% CI 0.33 to 0.71) in adults.
Where azithromycin is not donated, 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 cured.
Some populations in which trachoma is endemic are subject to migration, which 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.
Quality of the evidence
The included trials were published from 1966 onwards, and their quality was variable. The certainty of evidence for most outcomes was low, particularly for the comparison of antibiotics versus no treatment (summary of findings Table for the main comparison). Reporting of sequence generation and allocation concealment was not good, and it was often difficult to assess the effect of incomplete data due to inadequate reporting. There was considerable heterogeneity of results. However, masking of outcome assessment was reported for laboratory analyses (less so for clinical assessments of active trachoma), and there was little evidence of selective outcome reporting. There was moderate‐certainty evidence for the comparison of oral versus topical antibiotics for the outcome active trachoma (summary of findings Table 2).
The community‐based trials were also of variable methodological quality (summary of findings Table 3; summary of findings Table 4). In some cluster‐randomised studies, only two communities were randomly allocated to treatment. Although adjustment for baseline characteristics can alleviate this problem to some extent, the interpretation of these studies remains problematic. As well as being underpowered, it is difficult to exclude the alternative explanation that there is some characteristic that is different between the communities (apart from treatment of trachoma) and which may be the real cause of any observed differences in outcome. There was also little information on other potential sources of bias in cluster‐randomised trials such as recruitment bias.
Four community‐based trials had a 'delayed treatment' design that involved randomly selecting clusters for treatment and comparing the prevalence of trachoma 12 months after treatment with a random selection of untreated clusters, which are then enrolled in the treatment programme (Resnikoff 1995; TANA; TEF; Wilson 2018). This study design overcomes the ethical dilemma of surveying communities for trachoma and then withholding treatment for 12 months, but has the disadvantage that baseline data on trachoma are not available in the control group.
Potential biases in the review process
This review has been substantially revised for the update. New methods, such as assessment of risk of bias and subgroup and sensitivity analyses, and inclusion of antimicrobial resistance as an outcome, have been incorporated. A new protocol was not written. It is possible that the update could have been influenced by knowledge of the trial results.
We found the classification Atik 2006 problematic. In the last edition of this review we included this trial in the comparison "azithromycin versus no treatment" but on re‐evaluation for the current edition we considered the trial to be "azithromycin versus tetracycline". Although the study was described as azithromycin versus no azithromycin in fact people with active trachoma in the control group received tetracycline. The change in classification of this study did not affect the conclusions of this review.
In the current 2019 update we included studies that compared different treatment strategies. We added in the additional question to our objectives: "What is the effect of annual versus different treatment frequencies?". We did not repeat the searches for this additional question. There may be studies that were not included in previous editions of the review (for example Schemann 2007), that would have been eligible for the current update. We do not anticipate that we will have missed many relevant studies as searches were screened from 2010 onwards.
Agreements and disagreements with other studies or reviews
We identified a number of non‐randomised studies providing data on antimicrobial resistance. Their results are summarised in Table 15. Overall, the non‐randomised studies provided inconsistent evidence on resistance, with some evidence of increased resistance to azithromycin for S pneumoniae. Three studies considered resistance in C trachomatis after mass treatment and suggest little evidence of resistance to azithromycin.
| Citation and location | Study design | Age group | Antibiotic | Follow‐up | Comment |
| C trachomatis | |||||
| Rombo district, Tanzania | Antimicrobial resistance assessed before and after azithromycin treatment in people with C trachomatis infection. | Not reported | Azithromycin Tetracycline | 2 months | 956/978 residents examined at baseline; 56 with eye infection; 43 isolates from these people at baseline. “We conclude that no clinically or programmatically significant changes in C. trachomatis azithromycin or tetracycline susceptibilities were induced" |
| Gurage zone, Ethiopia | Samples taken before and after treatment. | 1 to 5 years | Azithromycin Doxycycline | 18 months after 4 bi‐annual mass treatment (2 years) | Found no significant differences in susceptibilities to azithromycin and doxycycline in 6 post‐treatment and 4 pre‐treatment samples |
| Kongwa district, Tanzania | Isolates obtained before and after mass drug administration. | 0 to 9 years | Azithromycin Doxycycline | 12 months after 3 years of mass treatment | Compared resistance to C trachomatis in children with/without continuing infection and found similar levels of resistance |
| S pneumoniae | |||||
| Northern territory (Aboriginal community), Australia | Antimicrobial resistance assessed before and after azithromycin treatment in children with trachoma. | 5 to 14 years | Azithromycin Erythromycin (results not reported) | 2 to 3 weeks, 2 months, and 6 months following azithromycin treatment | 79 children with trachoma:
|
| Western Nepal | Antimicrobial resistance assessed before and after azithromycin treatment in children. | 1 to 10 years | Azithromycin Penicillin Chloramphenicol Sulfamethoxazole | 10 days and 6 months | At 180 days, 5% of 104 children with 2 previous treatments carriage of azithromycin‐resistant S pneumoniae compared with 0% of children with 1 (150 children) or 0 (149 children) previous treatments |
| Rombe district, northern Tanzania | Antimicrobial resistance assessed before and after azithromycin treatment in children. | 0 to 7 years | Azithromycin Penicillin Erythromycin Cotrimoxazole | 2 months and 6 months | "At the 2‐month and 6‐month points, macrolide‐resistant isolates were 0% and 1%, respectively" |
| Western Nepal | Cross‐sectional survey 1 year after mass distribution of azithromycin | 1 to 10 years | Azithromycin Trimethoprim/sulfamethoxazole | 1 year | No macrolide resistance observed in 50 nasopharyngeal samples positive for S pneumoniae. |
| Kailali district, western Nepal | Cross‐sectional survey 6 months after the 3rd annual treatment with azithromycin or tetracycline or no treatment | 1 to 10 years | Azithromycin Trimethoprim/sulfamethoxazole | 12 months | 5/163 (3%) isolates were resistant to azithromycin in the azithromycin‐treated communities compared with 0 in 126 children in tetracycline‐treated communities and 91 in untreated. Tetracycline resistance was higher in tetracycline‐treated communities (39/126, 31%) compared with 17% and 16% in azithromycin‐treated and untreated communities, respectively. |
| KIlosa district, Tanzania | Cross‐sectional survey 4 years after mass distribution of azithromycin | 1 month to 59 months | Azithromycin | 4 years | Resistance to azithromycin was observed in 14.3%, 29.0%, and 16.6% of the S pneumoniae, S aureus, and E coli isolates, respectively. |
A recent systematic review of community‐level interventions in reducing the prevalence of active trachoma (published as an abstract only) identified a similar number of trials as the current review and came to similar conclusions, that is that mass drug administration reduces active trachoma and ocular chlamydia infection (Bobba 2018). Diab 2018 concluded that azithromycin eye drops twice daily for three days may be as efficient as oral azithromycin in treating active trachoma. This was largely based on the findings of a non‐randomised study, but the authors did identify the one trial on this topic identified in the current review (Cochereau 2007). We agree that the trial identified similar rates of cure over 60 days, but suggest that confirmatory studies are needed to assess longer‐term follow‐up.
A recent systematic review of resistance following mass azithromycin distribution drew similar conclusions to the current review (O'Brien 2019), that is that the available evidence suggests that macrolide resistance to azithromycin is increased after mass azithromycin distribution, particularly for S pneumoniae.
Study flow diagram.
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Comparison 1 Any antibiotic versus control (individuals), Outcome 1 Active trachoma at 3 months.
Comparison 1 Any antibiotic versus control (individuals), Outcome 2 Active trachoma at 12 months.
Comparison 1 Any antibiotic versus control (individuals), Outcome 3 Active trachoma at 3 months (subgroup analysis).
Comparison 1 Any antibiotic versus control (individuals), Outcome 4 Active trachoma at 12 months (subgroup analysis).
Comparison 1 Any antibiotic versus control (individuals), Outcome 5 Ocular C trachomatis infection at 3 months.
Comparison 1 Any antibiotic versus control (individuals), Outcome 6 Ocular C trachomatis infection at 12 months.
Comparison 1 Any antibiotic versus control (individuals), Outcome 7 Ocular C trachomatis infection at 3 months (subgroup analysis).
Comparison 1 Any antibiotic versus control (individuals), Outcome 8 Ocular C trachomatis infection at 12 months (subgroup analysis).
Comparison 2 Oral versus topical antibiotics (individuals), Outcome 1 Active trachoma at 3 months.
Comparison 2 Oral versus topical antibiotics (individuals), Outcome 2 Active trachoma at 12 months.
Comparison 2 Oral versus topical antibiotics (individuals), Outcome 3 Ocular C trachomatis infection at 3 months.
Comparison 2 Oral versus topical antibiotics (individuals), Outcome 4 Ocular C trachomatis infection at 12 months.
Comparison 3 Oral azithromycin versus topical tetracycline (individuals), Outcome 1 Active trachoma at 3 months.
Comparison 3 Oral azithromycin versus topical tetracycline (individuals), Outcome 2 Active trachoma at 12 months.
Comparison 3 Oral azithromycin versus topical tetracycline (individuals), Outcome 3 Ocular C trachomatis infection at 3 months.
Comparison 3 Oral azithromycin versus topical tetracycline (individuals), Outcome 4 Ocular C trachomatis infection at 12 months.
Comparison 4 Oral azithromycin versus control (communities), Outcome 1 Active trachoma at 12 months.
Comparison 4 Oral azithromycin versus control (communities), Outcome 2 Ocular C trachomatis infection at 12 months.
Comparison 5 Oral azithromycin versus topical tetracycline (communities), Outcome 1 Active trachoma at 3 months.
Comparison 5 Oral azithromycin versus topical tetracycline (communities), Outcome 2 Active trachoma at 12 months.
Comparison 5 Oral azithromycin versus topical tetracycline (communities), Outcome 3 Ocular C trachomatis infection at 3 months.
Comparison 5 Oral azithromycin versus topical tetracycline (communities), Outcome 4 Ocular C trachomatis infection at 12 months.
| Antibiotic versus control for trachoma: individuals | ||||||
| Patient or population: people (any age) with active trachoma | ||||||
| Outcomes | Follow‐up | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Certainty of the evidence | |
| Assumed risk | Corresponding risk | |||||
| Control | Antibiotic | |||||
| Active trachoma Clinical assessment: active trachoma defined as TF, TI, or both | 3 months | Study population | RR 0.78 | 1961 | ⊕⊕⊝⊝ | |
| 800 per 1000 | 624 per 1000 | |||||
| 12 months | Study population | RR 0.74 | 1035 | ⊕⊕⊝⊝ | ||
| 750 per 1000 | 555 per 1000 | |||||
| Ocular C trachomatis infection Positive test for C trachomatis infection identified by culture, staining on conjunctival smears, or nucleic acid amplification methods | 3 months | Study population | RR 0.81 | 297 | ⊕⊕⊝⊝ | |
| 500 per 1000 | 405 per 1000 | |||||
| 12 months | Study population | RR 0.25 | 129 | ⊕⊕⊝⊝ | ||
| 200 per 1000 | 50 per 1000 | |||||
| Antibiotic resistance Proportion of samples showing evidence of resistance to antibiotic | Any time point | None of the studies addressed this outcome. | ||||
| Adverse effects | Any time point | 4 studies made no comment on adverse effects. 3 studies noted no untoward reactions (sulfonamides) or only trivial reactions (tetracycline, sulfonamide). 1 study of 155 students noted 3 adverse reactions to sulfonamide (severe purpura associated with marked thrombocytopenia, 2 cases of drug rash). 1 study of 122 children noted anorexia, nausea, vomiting, or diarrhoea in 3 children. 2 of these children were receiving doxycycline, and the disturbances lasted only a single day in each child, in spite of continuing medication. | 1961 | ⊕⊕⊝⊝ | ||
| *The assumed risk is the median risk in control groups in the included studies (rounded to nearest 10 per 1000). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; TF: trachomatous inflammation‐follicular; TI: trachomatous inflammation‐intense; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded one level for serious limitations in study design (methods of sequence generation, allocation concealment, and masking poorly reported; three studies at high risk of attrition bias) and one level for serious inconsistency (risk ratios ranged from 0.40 to 1.02 and I2 = 73%). | ||||||
| Oral versus topical antibiotic for trachoma: individuals | |||||||
| Patient or population: people (any age) with active trachoma | |||||||
| Outcomes | Follow‐up | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Certainty of the evidence | Comments | |
| Assumed risk | Corresponding risk | ||||||
| Topical antibiotic | Oral antibiotic | ||||||
| Active trachoma Clinical assessment: active trachoma defined as TF, TI, or both | 3 months | Study population | RR 0.97 | 953 | ⊕⊕⊝⊝ low1 | ||
| 600 per 1000 | 582 per 1000 | ||||||
| 12 months | Study population | RR 0.93 | 886 | ⊕⊕⊝⊝ low2 | |||
| 500 per 1000 | 465 per 1000 | ||||||
| Ocular C trachomatis infection Positive test for C trachomatis infection identified by culture, staining on conjunctival smears, or nucleic acid amplification methods | 3 months | See comment | See comment | Not estimable | 298 | ⊕⊝⊝⊝ | No pooled estimate due to high heterogeneity: Darougar 1980 RR 6.05 (95% CI 0.78, 46.95); Dawson 1997 RR 0.57 (0.14, 2.30); Tabbara 1996 RR 1.30 (0.41, 4.11) |
| 12 months | See comment | See comment | Not estimable | 220 | ⊕⊝⊝⊝ | Darougar 1980 RR 2.59 (95% CI 0.28, 23.88); Dawson 1997 RR 0.50 (0.18, 1.43) | |
| Antibiotic resistance Proportion of samples showing evidence of resistance to antibiotic | Any time point | None of the studies addressed this outcome. | |||||
| Adverse effects | Any time point | 3 studies made no comment on adverse effects. 1 study of 155 students noted 3 adverse reactions to sulfonamide (severe purpura associated with marked thrombocytopenia, 2 cases of drug rash). 1 study of 194 people reported abdominal pain more often in azithromycin group (26% versus 16%, P = 0.09). Other effects: diarrhoea, vomiting, fever, headache, body pain were similar between 2 study groups. 1 study of 60 people reported no serious adverse reactions and that both azithromycin and tetracycline were well tolerated. 1 study of 168 children noted that azithromycin was well tolerated and that only 2 children (of 125 treated) complained of nausea. | 1583 | ⊕⊕⊝⊝ | |||
| *The assumed risk is the median risk in control groups in the included studies (rounded to nearest 10 per 1000). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; TF: trachomatous inflammation‐follicular; TI: trachomatous inflammation‐intense; RR: risk ratio | |||||||
| GRADE Working Group grades of evidence | |||||||
| 1Downgraded one level for serious limitations in study design (only one study reported adequate methods for allocation concealment and masking of outcome assessment) and one level for inconsistency (study estimates ranged from 0.65 to 1.37 and I2 = 63%). | |||||||
| Oral azithromycin compared to control for trachoma: communities | ||||||
| Patient or population: people (any age) with active trachoma | ||||||
| Outcomes | Follow‐up | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Certainty of the evidence (GRADE) | Comments |
| Assumed risk | Corresponding risk | |||||
| Control | Oral azithromycin | |||||
| Active trachoma | 3 months | None of the studies addressed this outcome. | ||||
| 12 months | Medium‐risk population | RR 0.58 (0.52 to 0.65) | 1247 | ⊕⊕⊕⊝ moderate1 | One additional study reported data as median community prevalence. At 12 months, the median community prevalence of active trachoma was 9.3% in communities given one single dose of azithromycin (range 0 to 38.9%) and 8.2% in communities that had not been treated (range 0 to 52.9%). | |
| 100 per 1000 | 58 per 1000 (52 to 65) | |||||
| High‐risk population | ||||||
| 300 per 1000 | 174 per 1000 (156 to 195) | |||||
| Ocular C trachomatis infection Positive test for C trachomatis infection identified by culture, staining on conjunctival smears, or nucleic acid amplification methods | 3 months | None of the studies addressed this outcome. | ||||
| 12 months | Medium‐risk population | RR 0.36 | 2139 (2 studies) | ⊕⊕⊕⊝ moderate2 | ||
| 100 per 1000 | 36 per 1000 | |||||
| High‐risk population | ||||||
| 300 per 1000 | 108 per 1000 | |||||
| Antibiotic resistance Proportion of samples showing evidence of resistance to antibiotic | Any time point | There was evidence of an increased risk of resistance of S pneumoniae, S aureus, and E coli to azithromycin, tetracycline, and clindamycin with risk ratios in the order of 5 at 12 months. No evidence to support increased resistance to penicillin or trimethoprim/sulfamethoxazole. | 1354 (4 studies) | ⊕⊕⊕⊕ high | ||
| Adverse effects | Any time point | No serious adverse events reported. Azithromycin associated with reduced mortality in children. Main adverse effect of azithromycin (in approximately 10% of the population) was abdominal pain, vomiting, and nausea. | 3069 | ⊕⊕⊕⊕ high | ||
| *The assumed risk (medium/high risk) were based on prevalence estimates used as the basis for recommendations as set out in WHO 2010. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; TF: trachomatous inflammation‐follicular; TI: trachomatous inflammation‐intense; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded one level for serious inconsistency. | ||||||
| Oral azithromycin compared to topical tetracycline for trachoma: communities | |||||||
| Patient or population: people (any age) with active trachoma | |||||||
| Outcomes | Follow‐up | Illustrative comparative risks (95% CI) | Relative effect | No. of participants | Certainty of the evidence | Comments | |
| Assumed risk | Corresponding risk | ||||||
| Topical tetracycline | Oral azithromycin | ||||||
| Active trachoma | 3 months | See comment | Not estimable | 6002 | ⊕⊕⊝⊝ | ACT 1999 Egypt RR 0.52 (95% CI 0.43, 0.64); ACT 1999 Tanzania RR 1.16 (1.00, 1.36); ACT 1999 The Gambia RR 0.76 (0.50, 1.15) | |
| 12 months | See comment | Not estimable | 5414 | ⊕⊕⊝⊝ | ACT 1999 Egypt RR 0.74 (95% CI 0.61, 0.90); ACT 1999 Tanzania RR 1.19 (1.02, 1.40); ACT 1999 The Gambia RR 0.55 (0.40, 0.75) | ||
| Ocular C trachomatis infection | 3 months | See comment | Not estimable | 5773 | ⊕⊕⊝⊝ | ACT 1999 Egypt RR 0.22 (95% CI 0.11, 0.44); ACT 1999 Tanzania RR 0.68 (0.49, 0.95); ACT 1999 The Gambia RR 0.51 (0.37, 0.70) | |
| 12 months | See comment | Not estimable | 5276 | ⊕⊕⊝⊝ | ACT 1999 Egypt RR 0.48 (95% CI 0.31, 0.74); ACT 1999 Tanzania RR 1.01 (0.76, 1.35); ACT 1999 The Gambia RR 0.62 (0.44, 0.87) | ||
| Antibiotic resistance Proportion of samples showing evidence of resistance to antibiotic | Any time point | None of the studies addressed this outcome. | |||||
| Adverse effects | Any time point | No comment on adverse effects in study reports | 6002 | ‐ | |||
| CI: confidence interval; TF: trachomatous inflammation‐follicular; TI: trachomatous inflammation‐intense; RR: risk ratio | |||||||
| GRADE Working Group grades of evidence | |||||||
| 1Downgraded one level for serious limitations in study design (three cluster‐randomised trials, two of which only randomised two communities to oral/topical antibiotic; assessment of trachoma was not masked, but assessment of ocular infection was; recruitment bias not addressed and problems with incomplete outcome data; some attempt made to adjust for baseline imbalances) and one level for serious inconsistency (results were different in the different studies ‐ see comment column in table). | |||||||
| Study | Country | Inclusion criteria | Number of people randomised | Age | Sex % male | |
| 1 | Egypt | Active trachoma or "undetermined case" | 228 | 6 to 12 years | Not reported | |
| 2 | The Gambia | Active trachoma | 194 | 9 months to 60 years | 51% | |
| 3 | The Gambia | Active trachoma | 314 | 6 months to 10 years | 50% | |
| 4 | Guinea and Pakistan | Active trachoma | 670 | 1 to 10 years | 50% | |
| 5 | Iran | Active trachoma | 147 | Pre‐school | 38% | |
| 6 | USA (Indian reservation) | Active trachoma | 29 | 12 to 21 years | Not reported | |
| 7 | USA (Indian reservation) | Active trachoma | 36 | 12 to 21 years | Not reported | |
| 8 | Egypt | Active trachoma | 168 | 2 to 10 years | 60% | |
| 9 | USA (Indian boarding school) | Active trachoma | 457 | 8 to 20 years | Not reported | |
| 10 | USA (Indian boarding school) | Active trachoma | 120 | 7 to 13 years | Not reported | |
| 11 | Australia (Aboriginal children) | Follicular trachoma | 641 | 5 to 14 years | Not reported | |
| 12 | India | Active trachoma | 349 | 5 to 13 years | Not reported | |
| 13 | Saudi Arabia | Active trachoma | 64 | 6 to 14 years | Not reported | |
| 14 | Taiwan | Active trachoma | 322 | Primary school age | Not reported | |
| *Dawson 1969 Sherman and Dawson 1969 Stewart were reported in the same paper. | ||||||
| Comparison | Intervention | Comparator | ||||||
| Antibiotic | Dose | Duration | Frequency | Intervention | Dose | Duration | Frequency | |
| Studies with a no‐treatment, placebo, or inactive treatment comparator group | ||||||||
| tetracycline derivative GS2989 (topical) | 0.25% | once every school day for 11 weeks | once | no treatment | ‐ | ‐ | ‐ | |
| oxytetracycline (topical) | 1% | twice daily for 7 consecutive days | every month for 12 months | vitamin pills | not reported | single dose | every month for 12 months | |
| tetracycline (topical) | 1% | twice daily for 6 consecutive days | every week for 6 weeks | no treatment | ‐ | ‐ | ‐ | |
| tetracycline (oral) | not reported | daily for 5 days | once a month for 3 months | no treatment | ‐ | ‐ | ‐ | |
| doxycycline | 2.5 to 4.0 mg/kg | once daily for 5 consecutive days | every week up to 28 doses in 40 days | placebo | ‐ | once daily for 5 consecutive days | every week up to 28 doses in 40 days | |
| Shukla 1966*** | Sulfafurazole (topical) + sulfadimethoxine (oral) | 15%/100 mg/kg | twice daily for 5 consecutive days every month for 5 months/bi‐weekly for 5 months | twice daily for 5 consecutive days every month for 5 months/bi‐weekly for 5 months | no treatment | ‐ | ‐ | ‐ |
| trisulfapyrimidines (oral) | 3.5 g/day (in 3 doses) | 21 consecutive days | once | placebo | ‐ | 21 consecutive days | ‐ | |
| Oral versus topical antibiotic | ||||||||
| azithromycin (oral) | 20 mg/kg | single dose | once | tetracycline (topical) | 1% | twice daily for 6 weeks | once | |
| azithromycin (oral) | 20 mg/kg | single dose | once or weekly for 3 weeks or monthly for 6 months | oxytetracycline/polymyxin + oral placebo | oxytetracycline 1%/polymyxin 10,000 units/gram | once daily for 5 consecutive days | every 28 days for 6 months | |
| azithromycin (oral) | 20 mg/kg | single dose | once | tetracycline (topical) | 1% | twice daily for 5 consecutive days | every week for 6 weeks | |
| sulfamethoxypyridazine (oral) | 0.5 g | once daily for 5 consecutive days | every week for 3 weeks | tetracycline (topical) | 1% | 3 times daily on 5 consecutive days | ‐ | |
| Cochereau 2007**** | azithromycin (topical) | 1.5% | twice daily for 2 days | ‐ | azithromycin (oral) | 20 mg/kg | single dose | ‐ |
| *Also compared to oxytetracycline (Terramycin) once every school day for 11 weeks. | ||||||||
| Study | Active trachoma | Ocular infection | |||||
| Classification scheme | 3 months | 12 months | Laboratory assessments | 3 months | 12 months | ||
| 1 | WHO 1962 | ✓ | No follow‐up | No laboratory tests | ‐ | ‐ | |
| 2 | Dawson 1981 | ✓ | ✓ (26 weeks) | IDEIA amplified enzyme‐linked immunosorbent assay (Dako) for genus‐specific lypopolysaccharide antigen | ✓ | ✓ (26 weeks) | |
| 3 | Thylefors 1987 | ✓ | ✓ (6 months) | No laboratory tests | ‐ | ‐ | |
| 4 | Thylefors 1987 | ✓ (2 months) | No follow‐up | Conjuctival swab analysed using PCR | Data not reported | No follow‐up | |
| 5 | Modification of Dawson 1975 | ✓ (4 months) | ✓ | Conjunctival swabs followed by culture in irradiated McCoy cells | ✓ (4 months) | ✓ | |
| 6 | MacCallan 1936 | ✓ (20 weeks) | No follow‐up | No laboratory tests | ‐ | ‐ | |
| 7 | MacCallan 1936 | ✓ (20 weeks) | No follow‐up | No laboratory tests | ‐ | ‐ | |
| 8 | Thylefors 1987 | ✓ | ✓ | Conjunctival specimens; slides stained with direct fluorescent antibody for chlamydial elementary bodies | ✓ | ✓ | |
| 9 | Thygeson 1960 | ✓ | ✓ | No laboratory tests | ‐ | ‐ | |
| 10 | Dawson 1969 | ✓ (5 months) | No follow‐up | IFAT on scrapings of upper tarsal conjunctival epithelium | ✓ (5 months) | No follow‐up | |
| 11 | At least 1 follicle or some papillary hypertrophy | ✓ | No follow‐up | No laboratory tests | ‐ | ‐ | |
| 12 | WHO 1962 | ✓ (5 months) | No follow‐up | No laboratory tests | ‐ | ‐ | |
| 13 | Dawson 1981 | ✓ | No follow‐up | Conjunctival scrapings for inclusion bodies/cells/organisms/mucus; IFAT for free elementary bodies | ✓ | No follow‐up | |
| 14 | Modified McCallan classification | ✓ | ✓ | No laboratory tests | ‐ | ‐ | |
| IFAT: immunofluorescence antibody test *Followed up to three years. | |||||||
|
| Study | Country | Inclusion criteria: communities | Inclusion criteria: people | Number of communities randomised | Number of people randomised | Age | Sex % male | Endemicity | |
| Children | Adults | |||||||||
| 1 | Egypt | trachoma endemic areas | everyone present in community | 2 | 2238 | all ages | not reported | ‐ | All ages: no active trachoma (64%); | |
| 2 | Tanzania | trachoma endemic areas | everyone present in community | 2 | 3261 | all ages | not reported | ‐ | All ages: no active trachoma (47%); mild follicular inflammatory (F1, P1, P2) (22%); follicular trachoma (F2, F3) (15%); severe inflammatory trachoma (P3) (16%) | |
| 3 | The Gambia | trachoma endemic areas | everyone present in community | 8 (pair‐matched) | 1753 | all ages | not reported | Prevalence of active trachoma among 0 to 9 year olds (36%) | No active trachoma (57%); mild follicular inflammatory (F1, P1, P2) (27%); follicular trachoma (F2, F3) (9%); severe inflammatory trachoma (P3) (7%) | |
| 4 | Vietnam | randomly selected from Thanh Hoa Province | everyone present in community older than 6 months was assessed for trachoma and people with trachoma and their household members treated. | 2 | 1851 | 6 months or older | ˜40% | Prevalence of active trachoma: | Prevalence of active trachoma: | |
| 5 | Niger | > 15% prevalence of active trachoma in children | everyone present in community | not reported | 1347 | average age 18 to 19 years | 48% | ‐ | Prevalence of C trachomatis infection (all ages) (7%) | |
| 6 | Niger | population between 250 and 600 and prevalence of 10% or more of active trachoma in children aged 0 to 60 months | everyone present in community | 24 | 12,991 | all ages; sentinel children aged 0 to 5 years | 48% | Prevalence of ocular C trachomatis infection in children aged 5 years or younger (approximately 20%) | Prevalence of TF in people aged 15 years or older (approximately 1%) | |
| 7 | Tanzania | less than 5000 people with an estimated active trachoma prevalence of between 20% and 50% for mesoendemic communities and less than 20% for hypoendemic communities | everyone present in the community | 32 | not reported | all ages; sentinel children aged 0 to 5 years | 50% to 52% | Prevalence of C trachomatis infection in children aged less than 5 years ranged from 18% to 25%. | Prevalence of C trachomatis infection (all ages) (6%) | |
| 8 | The Gambia | trachoma prevalence greater than 5% | everyone present in the community | 48 | all ages; sentinel children 5 years or less | ˜50% | Prevalence of C trachomatis infection in children aged 5 years or younger was 1%. | ‐ | ||
| 9 | Mali | unclear | everyone present in the community | 4 (2 with interventions relevant to this review) | all ages | not reported | ‐ | Prevalence of active trachoma ranged from 15% to 22% (all ages). | ||
| 10 | Ethiopia | all subkebeles (geographical unit with approximately 1400 people) in the study region that were less than | everyone present in the community | 48 | 66,404 | all ages; sentinel group of children and adults | ˜51% | Prevalence of C trachomatis infection in children aged less than 10 years ranged from 8% to 62% (mean approximately 40%). | Prevalence of C trachomatis infection in people aged 10 years or older ranged from 2% to 28% (mean approximately 15%). | |
| 11 | Ethiopia | random sample of peasant associations (standardised administrative unit) | everyone present in the community | 16 | 5410 | all ages; sentinel groups of children aged 1 to 5 years | not reported | Prevalence of C trachomatis infection in children aged 1 to 5 years ranged from 31% to 65% (mean approximately 43%). | ‐ | |
| 12 | Tanzania | not been treated with azithromycin since 2009 and were predicted from prior prevalence surveys to have TF between 5 and 9.9% | not clearly stated but assumed to be everyone in community apart from pregnant women and children under 6 months | 96 | not reported | 6 months or older, only sample of 20 children aged 1 to 9 years assessed | 48% (in children assessed) | Prevalence of Ctrachomatis infection in children aged 1 to 9 years ranged from 0 to 33%, median 0%. | .‐ | |
| LCR: ligase chain reaction | ||||||||||
| Intervention | Comparator | |||
| Comparison | Antibiotic* | Frequency | Antibiotic* | Frequency |
| Studies with a no‐treatment or delayed‐treatment comparator group | ||||
| tetracycline ** | every month for 6 months | no treatment | ‐ | |
| azithromycin | once only; annually for 3 years; twice a year for 3 years | delayed treatment | ‐ | |
| azithromycin | every 3 months for 3 years | delayed treatment | ‐ | |
| azithromycin | once only | delayed treatment | ‐ | |
| Studies of azithromycin versus tetracycline | ||||
| azithromycin | once a week for 3 weeks | tetracycline | once daily for 6 weeks | |
| Atik 2006**** | azithromycin | single dose at baseline and 12 months. Non‐index cases received tetracycline, and surgery offered where appropriate. | All patients with active trachoma received topical tetracycline and surgery offered where appropriate. | ‐ |
| Studies of different frequencies of azithromycin | ||||
| azithromycin | for 1 month (Day 0 and Day 30) | azithromycin | Day 0 | |
| azithromycin | annually for 3 years (enhanced coverage) | azithromycin | annually for 3 years (standard coverage) | |
| PRET Niger;***** TANA; TEF | azithromycin | twice a year for 3 years | azithromycin | annually for 3 years |
| azithromycin | annually for 3 years | azithromycin | cessation rule | |
| *Azithromycin was given as a single oral dose at 20 mg/kg up to 1 g (adults); tetracycline was given topically 1%. | ||||
| Study | Follow‐up | Active trachoma | Ocular infection | Resistance | Adverse effects | |
| 1 | 12 to 14 months | Dawson 1981 | Conjunctival swabs assessed using LCR. | Not studied | Not reported | |
| 2 | 12 to 14 months | Dawson 1981 | Conjunctival swabs assessed using LCR. | Not studied | Not reported | |
| 3 | 12 months | Dawson 1981 | Conjunctival swabs assessed using LCR. | Not studied | Not reported | |
| 4 | 24 months | Thylefors 1987 | Conjuctival samples analysed using polymerase chain reaction (Amplicor‐PCR). | Not studied | Not reported | |
| 5 | 12 months | Not specified | Conjunctival swabs assessed using nucleic acid amplification test. | Not studied | Reported (no adverse events) | |
| 6 | 36 months | Thylefors 1987 | Conjuctival samples analysed using polymerase chain reaction (Amplicor‐PCR). | lytA+ | Not reported | |
| 7 | 36 months | Thylefors 1987 | Conjuctival samples analysed using polymerase chain reaction (Amplicor‐PCR). | E coli | Reported (no serious adverse events) | |
| 8 | 36 months | Thylefors 1987 | Conjuctival samples analysed using polymerase chain reaction (Amplicor‐PCR). | S pneumoniae | Not reported | |
| 9 | 6 months | Thylefors 1987 | No laboratory tests | Not studied | Not reported | |
| 10 | 42 months | Thylefors 1987 | Conjuctival samples analysed using polymerase chain reaction. | S pneumoniae | Reported | |
| 11 | 24 months | Thylefors 1987 | Conjuctival samples analysed using polymerase chain reaction (Amplicor‐PCR). | S pneumoniae | Reported (no serious adverse events) | |
| 12 | 12 months | Thylefors 1986 | Conjuctival samples analysed using polymerase chain reaction. | Not studied | Reported (no serious adverse events) | |
| LCR: ligase chain reaction | ||||||
| Study | Antibiotic (number of people treated) | Report | |
| 1 | Oxytetracycline (77) Tetracycline derivative GS2989 (75) | No comment on adverse effects in report | |
| 2 | Azithromycin (97) Topical tetracycline with oral erythromycin in severe cases (97) | Table 2 on page 454 reports adverse effects. Abdominal pain reported more often in azithromycin group (26% versus 16%, P = 0.09). Other effects: diarrhoea, vomiting, fever, headache, body pain, other similar between study groups. "There were no serious adverse reactions and both treatments were well tolerated. All symptoms resolved spontaneously and none required treatment." 1 study participant died, probably due to malaria. He had received topical tetracycline. | |
| 3 | Azithromycin (160) Tetracycline (154) | No comment on adverse effects in report | |
| 4 | Azithromycin topical 2‐day regimen (222) 3‐day (220) and oral azithromycin (214) | "Ocular adverse events were reported in 10.8%, 8.9% and 13.1% of patients in the 2‐day, 3‐day and oral treatment groups respectively. Systemic adverse events were reported in 2.6%, 10.2% and 9.0% of patients. None of the adverse events were treatment‐related events. One patient (3‐day group) had a serious unrelated adverse events (death due to head injury)." (page 670) | |
| 5 | Doxycycline (44) Oxytetracycline (38) | No comment on adverse effects in report | |
| 6 & 7 | Trisulfapyrimidines (33) | "No untoward reactions to sulfonamides were noted" (page 587) | |
| 8 | Oxytetracycline/polymyxin (43) Azithromycin (125) | "In this trial, azithromycin was well tolerated and only two children (of 125 treated) complained of nausea" (page 367) | |
| 9 | Sulfamethoxypyridazine (112) Tetracycline (106) | "3/155 students who received sulfamethoxypyridazine had adverse reactions to the drug. One girl developed a severe purpura associated with marked thrombocytopenia. She recovered following withdrawal of the drug and administration of corticosteroids. Two cases of diagnosed drug rash necessitated discontinuance of the drug. The nephrotic syndrome developed in one boy three months after completion of sulphonamide therapy, but the relationship of this development to therapy was not determined. No reactions or rashes occurred in the other two treatment groups" (page 453) (note: Table 3/Table 4 report 112 children treated with sulfamethoxypyridazine) | |
| 10 | Doxycycline (49) | "Anorexia, nausea, vomiting or diarrhea occurred in three children between the 15th and 25th days of medication. Two of these children were receiving doxycycline, and the disturbances lasted only a single day in each child, in spite of continuing medication. Between day 21 and 28 of medication, transient macular rashes and one‐day illness with low‐grade fever and anorexia occurred in four children. Two of them had received drug, and two placebo. It is likely that an intercurrent, unrelated illness was responsible. Gross enamel dysplasia or tooth discoloration was not observed on examination 20 weeks after the end of medication." (page 222) | |
| 11 | Tetracycline (932) | No comment on adverse effects in report | |
| 12 | Sulfafurazole (140) Sulfadimethoxine (161) | No comment on adverse effects in report | |
| 13 | Azithromycin (31) Tetracycline (29) | "No adverse effects were noted" (page 844); and "The safety of a single oral dose of azithromycin has been demonstrated in this study. Similar to other clinical studies, no adverse effects developed in any of the patients in the azithromycin group" (page 845) | |
| 14 | Tetracycline (726) Sulfonamide (526) | "No more than trivial reactions were observed in any of these three studies, to vaccine, to oil adjuvant, to eye ointment or to sulfa drug." (page 1581) |
| Studies* | Country | Intervention | Comparator | Age of participants | Bacteria or genetic determinant | Carriage body reservoir | Sample type | Antibiotic | Follow‐up |
| Niger (Matameye district in the Zinder region) | AZ twice a year for 2 years | AZ once a year for 2 years | 6 months to 12 years | lytA+ | Nasopharynx | Nasopharyngeal swab | Macrolide resistance | Baseline and 24 months | |
| Tanzania (Kongwa district) | AZ once a year for 3 years | No AZ | Less than 3 years | E coli | Gastrointestinal | Rectal swab | AZ | Baseline, 1, 3, and 6 months | |
| The Gambia | AZ once a year for 3 years | AZ once a year for 1 year | Less than 15 years | S pneumoniae | Nasopharynx | Nasopharyngeal swab | AZ | Intervention group: 1 month before and 1 month and 6 months after 3rd annual round of MDA | |
| Ethiopia (Goncho Siso Enese woreda district, Amhara zone) | AZ every 3 months for 12 months | No AZ (control communities treated at 12 months) | 1 to 10 years | S pneumoniae | Nasopharynx | Nasopharyngeal swab | AZ | Baseline and 12 months | |
| Ethiopia (Goro district of the Gurage zone of southern Ethiopia) | AZ twice a year for 3 years | No AZ | 1 to 5 years | S pneumoniae | Nasopharynx | Nasopharyngeal swab | AZ | 24, 36, 42, and 54 months | |
| AZ: azithromycin *All the studies were cluster‐randomised trials, and AZ was delivered to the whole community (mass drug administration). | |||||||||
| Study* | Follow‐up** | Intervention*** | Comparator | Risk ratio | 95% confidence intervals | ||||
| Number of communities | n/N | % | Number of communities | n/N | % | ||||
| AZITHROMYCIN | |||||||||
| 1 month before 3rd annual round of MDA | 2 | 0/415 | 0 | 6 | ‐ | ‐ | ‐ | ‐ | |
| 1 month after 3rd annual round of MDA | 2 | 5/417 | 1.2 | 6 | ‐ | ‐ | ‐ | ‐ | |
| 6 months after 3rd annual round of MDA (intervention group) | 2 | 3/343 | 0.9 | 6 | 1/400 | 0.3 | 3.5 | 0.4 to 33.5 | |
| PRET The Gambia (as a percentage pneumococcal isolates)¶ | 1 month before 3rd annual round of MDA | 2 | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ |
| PRET The Gambia (as a percentage pneumococcal isolates)¶ | 1 month after 3rd annual round of MDA | 2 | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ |
| PRET The Gambia (as a percentage pneumococcal isolates)¶ | 6 months after 3rd annual round of MDA (intervention group) | 2 | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ |
| Baseline | 11 | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ | |
| 12 months | 12 | 56/119 | 46.9 | 12 | 11/120 | 9.2 | 5.1 | 2.8 to 9.3 | |
| TANA (as a percentage pneumococcal isolates)¶ | Baseline | 11 | 5/76 | 6.3 | ‐ | ‐ | ‐ | ‐ | ‐ |
| TANA (as a percentage pneumococcal isolates)¶ | 12 months | 12 | 58/93 | 62.3 | 12 | 11/98 | 11.6 | 5.6 | 3.1 to 9.9 |
| 24 months | 8 | 34/120 | 28.2 | 8 | 1/120 | 0.9 | 34.0 | 4.7 to 244 | |
| 36 months | 8 | 92/120 | 76.8 | 8 | 0/119 | 0 | 183.4 | 11.5 to 2922 | |
| 42 months | 8 | 37/120 | 30.6 | 8 | ‐ | ‐ | ‐ | ‐ | |
| 54 months | 8 | 25/120 | 20.8 | 8 | ‐ | ‐ | ‐ | ‐ | |
| CLINDAMYCIN | |||||||||
| Baseline | 11 | 2/110 | 1.5 | ‐ | ‐ | ‐ | ‐ | ‐ | |
| 12 months | 12 | 16/119 | 13.3 | 12 | 4/120 | 3.3 | 4 | 1.4 to 11.7 | |
| TANA (as a percentage pneumococcal isolates)¶ | Baseline | 11 | 1/76 | 1.5 | ‐ | ‐ | ‐ | ‐ | ‐ |
| TANA (as a percentage pneumococcal isolates)¶ | 12 months | 12 | 14/83 | 16.9 | 12 | 4/98 | 3.9 | 4.1 | 1.4 to 12.1 |
| PENICILLIN | |||||||||
| Baseline | 11 | 0/110 | 0 | ‐ | ‐ | ‐ | ‐ | ‐ | |
| 12 months | 12 | 0/119 | 0 | 12 | 1/120 | 0.8 | 0.34 | 0.01 to 8.2 | |
| TANA (as a percentage pneumococcal isolates)¶ | Baseline | 11 | 0/76 | 0 | ‐ | ‐ | ‐ | ‐ | ‐ |
| TANA (as a percentage pneumococcal isolates)¶ | 12 months | 12 | 0/83 | 0 | 12 | 1/98 | 1.0 | 0.39 | 0.02 to 9.52 |
| 24 months | 8 | 1/120 | 0.9 | 8 | 0/120 | 0 | 3.0 | 0.12 to 72.9 | |
| 36 months | 8 | 0/120 | 0 | 8 | 0/119 | 0 | ‐ | ‐ | |
| 42 months | 8 | 0/120 | 0 | 8 | ‐ | ‐ | ‐ | ‐ | |
| 54 months | 8 | 0/120 | 0 | 8 | ‐ | ‐ | ‐ | ‐ | |
| TETRACYCLINE | |||||||||
| Baseline | 11 | 11/110 | 10.0 | ‐ | ‐ | ‐ | ‐ | ‐ | |
| 12 months | 12 | 34/119 | 28.4 | 12 | 21/120 | 17.5 | 1.6 | 1.01 to 2.6 | |
| TANA (as a percentage pneumococcal isolates)¶ | Baseline | 11 | 12/76 | 15.2 | ‐ | ‐ | ‐ | ‐ | ‐ |
| TANA (as a percentage pneumococcal isolates)¶ | 12 months | 12 | 29/83 | 35.5 | 12 | 21/98 | 21.5 | 1.6 | 1.01 to 2.6 |
| 24 months | 8 | 44/120 | 36.5 | 8 | 23/120 | 18.9 | 1.9 | 1.2 to 3.0 | |
| 36 months | 8 | 82/120 | 68.7 | 8 | 19/119 | 15.7 | 4.3 | 2.8 to 6.6 | |
| 42 months | 8 | 69/120 | 57.2 | 8 | ‐ | ‐ | ‐ | ‐ | |
| 54 months | 8 | 46/120 | 38.7 | 8 | ‐ | ‐ | ‐ | ‐ | |
| TRIMETHOPRIM‐SULFAMETHOXAZOLE | |||||||||
| 24 months | 8 | 0/120 | 0 | 8 | 3/120 | 2.7 | 0.14 | 0.01 to 2.7 | |
| 36 months | 8 | 9/120 | 7.9 | 8 | 8/119 | 6.7 | 1.1 | 0.5 to 2.8 | |
| 42 months | 8 | 11/120 | 8.8 | 8 | ‐ | ‐ | ‐ | ‐ | |
| 54 months | 8 | 8/120 | 6.8 | 8 | ‐ | ‐ | ‐ | ‐ | |
| n/N: number of isolates with resistance/total number of isolates *Studies were all cluster‐randomised controlled trials. PRET The Gambia compared AZ once a year for 3 years with AZ once a year for 1 year; TANA compared AZ every 3 months for 12 months with no AZ; TEF compared AZ twice a year for 3 years with no AZ. ¶ Denominator is isolates with pneumococcal carriage only. | |||||||||
| Study* | Follow‐up** | Intervention | Comparator | Risk ratio | 95% confidence interval*** | ||||
| Number of communities | n/N | % | Number of communities | n/N | % | ||||
| AZITHROMYCIN | |||||||||
| 1 month before 3rd annual round of MDA | 2 | 37/414 | 8.9 | 6 | ‐ | ‐ | ‐ | ‐ | |
| 1 month after annual round of MDA | 2 | 142/417 | 34.1 | 6 | ‐ | ‐ | ‐ | ‐ | |
| 6 months after 3rd annual round of MDA (intervention group) | 2 | 25/343 | 7.3 | 6 | 6/375 | 1.6 | 4.6 | 1.9 to 11.0 | |
| PRET The Gambia(as a percentage of isolates)¶ | 1 month before 3rd annual round of MDA | 2 | 37/102 | 36.3 | 6 | ‐ | ‐ | ‐ | ‐ |
| PRET The Gambia(as a percentage of isolates)¶ | 1 month after 3rd annual round of MDA | 2 | 142/161 | 88.2 | 6 | ‐ | ‐ | ‐ | ‐ |
| PRET The Gambia(as a percentage of isolates)¶ | 6 months after 3rd annual round of MDA (intervention group) | 2 | 25/30 | 83.3 | 6 | 6/25 | 24.0 | 3.5 | 1.7 to 7.1 |
| CLINDAMYCIN | |||||||||
| 1 month before 3rd annual round of MDA | 2 | 24/414 | 5.8 | 6 | ‐ | ‐ | ‐ | ‐ | |
| 1 month after 3rd annual round of MDA | 2 | 128/417 | 30.7 | 6 | ‐ | ‐ | ‐ | ‐ | |
| 6 months after 3rd annual round of MDA (intervention group) | 2 | 20/343 | 5.8 | 6 | 3/375 | 0.8 | 7.3 | 2.2 to 24.3 | |
| PRET The Gambia(as a percentage of isolates)¶ | 1 month before 3rd annual round of MDA | 2 | 24/102 | 23.5 | 6 | ‐ | ‐ | ‐ | ‐ |
| PRET The Gambia(as a percentage of isolates)¶ | 1 month after annual round of MDA | 2 | 128/161 | 79.5 | 6 | ‐ | ‐ | ‐ | ‐ |
| PRET The Gambia(as a percentage of isolates)¶ | 6 months after 3rd annual round of MDA (intervention group) | 2 | 20/30 | 66.7 | 6 | 3/25 | 12.0 | 5.6 | 1.9 to 16.5 |
| n/N: number of isolates with resistance/total number of isolates *Studies were all cluster‐randomised controlled trials. PRET The Gambia compared AZ once a year for three years with AZ once a year for one year. ¶ Denominator is isolates with S.aureus carriage only. | |||||||||
| Study* | Follow‐up** | Intervention | Comparator | Risk ratio | 95% confidence intervals*** | ||||
| Number of communities | n/N | % | Number of communities | n/N | % | ||||
| AZITHROMYCIN | |||||||||
| Baseline | 4 | 20/163 | 16.3 | 4 | 20/96 | 20.8 | 0.6 | 0.3 to 1.04 | |
| 1 month | 4 | 79/129 | 61.2 | 4 | 25/134 | 18.7 | 3.3 | 2.3 to 4.8 | |
| 3 months | 4 | 56/133 | 42.1 | 4 | 20/126 | 15.9 | 2.7 | 1.7 to 4.2 | |
| 6 months | 4 | 26/83 | 31.3 | 4 | 10/50 | 20.0 | 1.6 | 0.8 to 3.0 | |
| PRET Tanzania (as a percentage of isolates)¶ | Baseline | 4 | 30/300 | 10.0 | 4 | 39/205 | 19.0 | 0.5 | 0.3 to 0.8 |
| PRET Tanzania (as a percentage of isolates)¶ | 1 month | 4 | 153/347 | 44.1 | 4 | 46/325 | 14.2 | 3.1 | 2.3 to 4.2 |
| PRET Tanzania (as a percentage of isolates)¶ | 3 months | 4 | 104/347 | 30.0 | 4 | 32/324 | 9.9 | 3.0 | 2.1 to 4.4 |
| PRET Tanzania (as a percentage of isolates)¶ | 6 months | 4 | 44/191 | 23.0 | 4 | 14/118 | 11.9 | 1.9 | 1.1 to 3.4 |
| ERYTHROMYCIN | |||||||||
| Baseline | 4 | 32/123 | 26.0 | 4 | 22/96 | 22.9 | 1.2 | 0.6 to 2.2 | |
| 1 month | 4 | 98/129 | 76.0 | 4 | 38/134 | 28.4 | 8.0 | 4.6 to 13.9 | |
| 3 months | 4 | 73/133 | 54.9 | 4 | 30/126 | 23.8 | 3.9 | 2.3 to 6.6 | |
| 6 months | 4 | 32/83 | 38.6 | 4 | 13/50 | 26.0 | 1.8 | 0.8 to 3.9 | |
| PRET Tanzania (as a percentage of isolates)¶ | Baseline | 4 | 51/300 | 17.0 | 4 | 35/205 | 17.1 | 1.0 | 0.6 to 1.6 |
| PRET Tanzania (as a percentage of isolates)¶ | 1 month | 4 | 219/347 | 63.1 | 4 | 65/325 | 20.0 | 6.8 | 4.8 to 9.7 |
| PRET Tanzania (as a percentage of isolates)¶ | 3 months | 4 | 149/347 | 42.9 | 4 | 52/324 | 16.0 | 3.9 | 2.7 to 5.7 |
| PRET Tanzania (as a percentage of isolates)¶ | 6 months | 4 | 61/191 | 31.9 | 4 | 20/118 | 16.9 | 2.3 | 1.3 to 4.1 |
| n/N: number of isolates with resistance/total number of isolates *Studies were all cluster‐randomised controlled trials. PRET Tanzania compared AZ once a year for three years with no AZ. ¶ Denominator is isolates with E.coli carriage only. | |||||||||
| Study | Antibiotic (number of communities and people treated) | Report | |
| 1, 2 & 3 | Azithromycin (6 communities, approximately 3800) Tetracycline (6 communities, approximately 2400) | No comment on adverse effects in report | |
| 4 | A total of 4 communities included in the study. Azithromycin (214) Tetracycline (161) | No comment on adverse effects in report | |
| 5 | Azithromycin (1139) | Reported no adverse events on clinical trials register (clinicaltrials.gov/ct2/show/results/NCT00618449) | |
| 6 | Azithromycin (48 communities, approximately 6000) | No comment on adverse effects in report, but "a data and safety monitoring committee met annually to review results and serious adverse events" | |
| 7 | Azithromycin (32 communities, approximately 12,000) | "There were no serious adverse events reported in either arm." | |
| 8 | Azithromycin (48 communities, 29,091) | No comment on adverse effects in report | |
| 9 | Oxytetracycline (346) | No comment on adverse effects in report | |
| 10 | Azithromycin (over 16,000) | "We recorded no reported serious adverse events attributed to study medication. 96 deaths were recorded in subkebeles in the children‐treated group and 126 deaths recorded in those in the control group. At 12 months a survey was undertaken to assess adverse effects in the treated population (n=671, 96 side‐effects reported). [.. ] 56 (11.3%) patients reported abdominal pain, vomiting, and nausea, whereas diarrhoea, constipation and related issues accounted for 16 (2.4%) of complaints. Four (0.6%) patients reported haemorrhoid or other as side effects" (House and colleagues, page 1115). "In a trachoma‐endemic area, mass distribution of oral azithromycin was associated with reduced mortality in children" (Porco and colleagues, conclusion of abstract) | |
| 11 | Azithromycin (16 communities, 4790) | "There were no serious adverse events due to the study medicine reported" | |
| 12 | Azithromycin (48 communities, unclear how many people) | "No serious adverse events were associated with MDA." | |
| MDA: mass drug administration | |||
|
| Intervention: children aged 1 to 10 years offered single‐dose oral azithromycin every 3 months (n = 12 communities) | Comparator: everyone aged 1 year and older offered single‐dose oral azithromycin at first visit (baseline) (n = 12 communities) | ||
| Prevalence % | 95% confidence interval | Prevalence % | 95% confidence interval | |
| Children aged 1 to 10 years | 3.6 | 0.8 to 6.4 | 14.6 | 7.2 to 22.1 |
| Children and adults aged 11 years and older | 8.2 | 5.1 to 11.4 | 6.2 | 2.9 to 9.4 |
|
| Intervention: everyone aged 1 year and older offered single‐dose oral azithromycin every 6 months | Comparator: everyone aged 1 year and older offered single‐dose oral azithromycin annually | ||
|
| Prevalence % | 95% confidence interval | Prevalence % | 95% confidence interval |
| PRET Niger | 3.8 | 2.2 to 6.0 | 5.8 | 3.2 to 9.0 |
| PRET Niger | 0.0 | 0 to 7 | 0.3 | 0 to 7 |
| TANA Follow‐up: 12 months | 1.7 | 0.7 to 2.6 | 6.2 | 2.9 to 9.4 |
| TANA | 1.5 | 0.2 to 2.8 | 2.3 | 0.8 to 3.8 |
| TANA | 0.2 | 0.0 to 0.6 | 1.5 | 0.1 to 3.0 |
| TANA Follow‐up: 12 months | 1.7 | 0.7 to 2.6 | 6.2 | 2.9 to 9.4 |
| TANA | 1.5 | 0.2 to 2.8 | 2.3 | 0.8 to 3.8 |
| Children and adults aged 10 years and older | 0.2 | 0.0 to 0.6 | 1.5 | 0.1 to 3.0 |
| TEF | 1.3 | 0.3 to 2.6 | 10.9 | 0.1 to 21.8 |
| TEF | 0.9 | 0.0 to 2.1 | 6.8 | 1.2 to 12.4 |
| PRET Niger: 24 communities in each group; only children aged 0 to 12 years treated in intervention group. | ||||
| Citation and location | Study design | Age group | Antibiotic | Follow‐up | Comment |
| C trachomatis | |||||
| Rombo district, Tanzania | Antimicrobial resistance assessed before and after azithromycin treatment in people with C trachomatis infection. | Not reported | Azithromycin Tetracycline | 2 months | 956/978 residents examined at baseline; 56 with eye infection; 43 isolates from these people at baseline. “We conclude that no clinically or programmatically significant changes in C. trachomatis azithromycin or tetracycline susceptibilities were induced" |
| Gurage zone, Ethiopia | Samples taken before and after treatment. | 1 to 5 years | Azithromycin Doxycycline | 18 months after 4 bi‐annual mass treatment (2 years) | Found no significant differences in susceptibilities to azithromycin and doxycycline in 6 post‐treatment and 4 pre‐treatment samples |
| Kongwa district, Tanzania | Isolates obtained before and after mass drug administration. | 0 to 9 years | Azithromycin Doxycycline | 12 months after 3 years of mass treatment | Compared resistance to C trachomatis in children with/without continuing infection and found similar levels of resistance |
| S pneumoniae | |||||
| Northern territory (Aboriginal community), Australia | Antimicrobial resistance assessed before and after azithromycin treatment in children with trachoma. | 5 to 14 years | Azithromycin Erythromycin (results not reported) | 2 to 3 weeks, 2 months, and 6 months following azithromycin treatment | 79 children with trachoma:
|
| Western Nepal | Antimicrobial resistance assessed before and after azithromycin treatment in children. | 1 to 10 years | Azithromycin Penicillin Chloramphenicol Sulfamethoxazole | 10 days and 6 months | At 180 days, 5% of 104 children with 2 previous treatments carriage of azithromycin‐resistant S pneumoniae compared with 0% of children with 1 (150 children) or 0 (149 children) previous treatments |
| Rombe district, northern Tanzania | Antimicrobial resistance assessed before and after azithromycin treatment in children. | 0 to 7 years | Azithromycin Penicillin Erythromycin Cotrimoxazole | 2 months and 6 months | "At the 2‐month and 6‐month points, macrolide‐resistant isolates were 0% and 1%, respectively" |
| Western Nepal | Cross‐sectional survey 1 year after mass distribution of azithromycin | 1 to 10 years | Azithromycin Trimethoprim/sulfamethoxazole | 1 year | No macrolide resistance observed in 50 nasopharyngeal samples positive for S pneumoniae. |
| Kailali district, western Nepal | Cross‐sectional survey 6 months after the 3rd annual treatment with azithromycin or tetracycline or no treatment | 1 to 10 years | Azithromycin Trimethoprim/sulfamethoxazole | 12 months | 5/163 (3%) isolates were resistant to azithromycin in the azithromycin‐treated communities compared with 0 in 126 children in tetracycline‐treated communities and 91 in untreated. Tetracycline resistance was higher in tetracycline‐treated communities (39/126, 31%) compared with 17% and 16% in azithromycin‐treated and untreated communities, respectively. |
| KIlosa district, Tanzania | Cross‐sectional survey 4 years after mass distribution of azithromycin | 1 month to 59 months | Azithromycin | 4 years | Resistance to azithromycin was observed in 14.3%, 29.0%, and 16.6% of the S pneumoniae, S aureus, and E coli isolates, respectively. |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Active trachoma at 3 months Show forest plot | 9 | 1961 | Risk Ratio (M‐H, Random, 95% CI) | 0.78 [0.69, 0.89] |
| 2 Active trachoma at 12 months Show forest plot | 4 | 1035 | Risk Ratio (M‐H, Random, 95% CI) | 0.74 [0.55, 1.00] |
| 3 Active trachoma at 3 months (subgroup analysis) Show forest plot | 9 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 3.1 Oral antibiotic | 6 | 599 | Risk Ratio (M‐H, Random, 95% CI) | 0.81 [0.67, 0.97] |
| 3.2 Topical antibiotic | 6 | 1478 | Risk Ratio (M‐H, Random, 95% CI) | 0.82 [0.72, 0.92] |
| 4 Active trachoma at 12 months (subgroup analysis) Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.1 Oral antibiotic | 3 | 429 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.76, 1.00] |
| 4.2 Topical antibiotic | 4 | 724 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.71, 0.88] |
| 5 Ocular C trachomatis infection at 3 months Show forest plot | 4 | 297 | Risk Ratio (M‐H, Random, 95% CI) | 0.81 [0.63, 1.04] |
| 6 Ocular C trachomatis infection at 12 months Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 7 Ocular C trachomatis infection at 3 months (subgroup analysis) Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 7.1 Oral antibiotic | 4 | 259 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.66, 1.11] |
| 7.2 Topical antibiotic | 1 | 85 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.18 [0.02, 1.37] |
| 8 Ocular C trachomatis infection at 12 months (subgroup analysis) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 8.1 Oral antibiotic | 1 | 91 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.10, 1.23] |
| 8.2 Topical antibiotic | 1 | 85 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.14 [0.02, 1.04] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Active trachoma at 3 months Show forest plot | 6 | 953 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.81, 1.16] |
| 2 Active trachoma at 12 months Show forest plot | 5 | 886 | Risk Ratio (M‐H, Random, 95% CI) | 0.93 [0.75, 1.15] |
| 3 Ocular C trachomatis infection at 3 months Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 4 Ocular C trachomatis infection at 12 months Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Active trachoma at 3 months Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2 Active trachoma at 12 months Show forest plot | 2 | 447 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.76 [0.59, 0.99] |
| 3 Ocular C trachomatis infection at 3 months Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 4 Ocular C trachomatis infection at 12 months Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Active trachoma at 12 months Show forest plot | 1 | 1247 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.58 [0.52, 0.65] |
| 2 Ocular C trachomatis infection at 12 months Show forest plot | 2 | 2139 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.31, 0.43] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Active trachoma at 3 months Show forest plot | 3 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Active trachoma at 12 months Show forest plot | 3 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3 Ocular C trachomatis infection at 3 months Show forest plot | 3 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4 Ocular C trachomatis infection at 12 months Show forest plot | 3 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
