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Antibioticoterapia para la disentería por Shigella
Prince RH Christopher, Kirubah V David, Sushil M John, Venkatesan Sankarapandian
Esta revisión debería citarse como: Prince RH Christopher, Kirubah V David, Sushil M John, Venkatesan Sankarapandian. Antibioticoterapia para la disentería por Shigella (Revision Cochrane traducida). En: Biblioteca Cochrane Plus 2009 Número 4. Oxford: Update Software Ltd. Disponible en: http://www.update-software.com. (Traducida de The Cochrane Library, 2009 Issue 4 Art no. CD006784. Chichester, UK: John Wiley & Sons, Ltd.).

Resumen

Antecedentes

La disentería por Shigella es una enfermedad relativamente común a nivel mundial, que ocasionalmente causa la muerte. Los síntomas leves son autolimitantes pero, en casos más graves, se recomiendan antibióticos para la curación y prevención de la recaída. Los antibióticos recomendados son diversos, presentan diferencias regionales en cuanto a la sensibilidad, y tienen efectos secundarios.

Objetivos

Evaluar la eficacia y la seguridad de los antibióticos para el tratamiento de la disentería por Shigella.

Estrategia de búsqueda

En junio 2009, se identificaron todos los ensayos relevantes de las siguientes bases de datos: Registro Especializado de Ensayos Controlados del Grupo Cochrane de Enfermedades Infecciosas (Cochrane Infectious Diseases Group); Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials, CENTRAL) (The Cochrane Library 2008, número 4), MEDLINE, EMBASE, LILACS y el metaRegister of Controlled Trials (mRCT). También se verificaron las actas de congresos para obtener resúmenes pertinentes, y se estableció contacto con investigadores, organizaciones y compañías farmacéuticas.

Criterios de selección

Ensayos controlados aleatorios de antibióticos para la disentería por Shigella.

Obtención y análisis de los datos

Cuatro autores, en grupos de dos, evaluaron de forma independiente la elegibilidad del ensayo, la calidad metodológica, y extrajeron los datos. Se calcularon los cocientes de riesgos (CR) con intervalos de confianza (IC) del 95% para los datos dicotómicos, y se utilizó el modelo de efectos aleatorios para la heterogeneidad significativa. Se exploraron las posibles fuentes de heterogeneidad, cuando estaba presente, en los análisis de subgrupos de edad del participante y porcentaje de participantes con infección por Shigella confirmada.

Resultados principales

Dieciséis ensayos (1 748 participantes), que comprendían cuatro décadas y con sensibilidad dispar a las cepas de Shigella, cumplieron con los criterios de inclusión. Se consideró que siete presentaban riesgo de sesgo debido a la ocultación inadecuada de la asignación o el cegamiento, y 12 debido al informe incompleto de los datos de resultado. Los datos limitados de un ensayo de tres brazos de pacientes con enfermedad moderadamente grave indican que los antibióticos reducen los episodios de diarrea durante el seguimiento (furazolidona versus ningún fármaco: CR 0,21, IC del 95%: 0,09 a 0,48; 73 participantes; cotrimoxazol versus ningún fármaco: CR 0,30, IC del 95%: 0,15 a 0,59; 76 participantes).

No hubo pruebas suficientes para considerar alguna clase de antibiótico superior en eficacia al tratar la disentería por Shigella, pero la heterogeneidad para algunas comparaciones limita la confianza en los resultados. Todos los antibióticos estudiados fueron seguros. Hubo pruebas insuficientes con respecto a la función de los antibióticos en la prevención de recaídas.

Conclusiones de los autores

Los antibióticos reducen la duración de la disentería por Shigella.

Se requieren patrones de sensibilidad a los antibióticos locales o regionales actualizados regularmente para diferentes especies y cepas de Shigella para guiar el tratamiento empírico. Se necesitan más ensayos que se adhieran a las guías estándar para evaluar la función de los antibióticos en el tratamiento de las formas severas de la disentería por Shigella y en los grupos con alto riesgo de complicaciones.

Resumen en términos sencillos

Antibioticoterapia para la disentería por Shigella

La shigelosis es una infección bacteriana del colon que puede causar diarrea, disentería (diarrea con sangre y/o moco) y provocar la muerte. Ocurre principalmente en países de ingresos bajos y medios donde existe sobrepoblación y saneamiento deficiente, y puede provocar alrededor de 1,1 millones de muertes por año a nivel global, principalmente en niños menores de cinco años.

La intención de administrar antibióticos en la shigelosis es acelerar la recuperación, reducir la gravedad de la enfermedad, y reducir el período de tiempo en el que los pacientes son infecciosos. Sin embargo, algunos antibióticos pueden tener efectos secundarios graves, mientras que otros pueden no ser eficaces contra las bacterias Shigella.

La revisión examinó tanto la efectividad como la seguridad de los antibióticos en el tratamiento de la disentería por Shigella. Si bien los antibióticos aquí probados parecían seguros y eficaces, no hubo pruebas suficientes para sugerir qué antibióticos eran superiores. Más ensayos bien diseñados ayudarán a informar la toma de decisiones.

Antecedentes

Descripción de la condición

La shigelosis es una infección bacteriana del colon que causa diarrea y puede provocar la muerte. La disentería (heces mucoides o sanguinolentas frecuentes), cuando es causada por Shigella, se denomina disentería por Shigella. Se estima que alrededor de 164,7 millones de episodios de diarrea por Shigella ocurren a nivel global cada año, de los cuáles la mayoría ocurre en países en desarrollo (99%) y principalmente en niños (69%) (WHO 2006). De las 1,1 millones de muertes debidas a Shigella, el 69% afecta a niños menores de cinco años. (Kotloff 1999; WHO 2006).

Microbiología y modalidad de la propagación

Shigella dysenteriae, S. flexneri, S. sonnei, y S. boydii son las cuatro especies de bacilos gramnegativos, pequeños, no móviles, que causan shigelosis y todos menos S. sonnei tienen más de un subtipo genéticamente diferente (serotipo) (von Seidlein 2006). La distribución de las especies varía a nivel global; por ejemplo, se informó que S. flexneri es más prevalente en la India (58%, Dutta 2002) y Ruanda (68%, Bogaerts 1983), mientras que S. sonnei fue la especie detectada con mayor frecuencia en Tailandia (85%, von Seidlein 2006), Israel (48.8%, Mates 2000), y los EE.UU. (75%, Gupta 2004; Shiferaw 2004).

Las shigellas son transmitidas por la vía fecal-oral, por el contacto directo de persona a persona, y por los alimentos, el agua, y objetos inanimados. Sólo se necesita un pequeño número de bacterias ingeridas para producir la enfermedad. La enfermedad es transmisible mientras una persona infectada excrete el organismo en las heces, que puede extenderse hasta cuatro semanas desde el inicio de la enfermedad. Las tasas de ataque secundarias, el número de personas expuestas que contraen la enfermedad dentro de uno a cuatro días después de la exposición al caso primario (Park 2005), pueden llegar a ser hasta del 40% entre los contactos familiares (Sur 2004).

La shigelosis ocurre predominantemente en los países en desarrollo y es más frecuente donde existe sobrepoblación y saneamiento deficiente. Ocurre en áreas densamente pobladas e instituciones donde las poblaciones están en estrecho contacto entre sí, como los centros de atención de día, los cruceros, las instituciones para las personas con problemas mentales o psicológicos, y los cuarteles militares (Shane 2003; Gupta 2004).

Características clínicas

La manifestación clínica de la shigelosis varía de una enfermedad asintomática a la bacteriemia y la sepsis. Los síntomas incluyen fiebre, diarrea y disentería con calambres abdominales, y esfuerzo ineficaz y doloroso al defecar o al orinar (Niyogi 2005). La shigelosis puede asociarse con complicaciones leves a potencialmente mortales, como prolapso rectal, artralgia (articulaciones dolorosas), artritis, perforación intestinal, y megacolon tóxico (inflamación y distensión extrema del colon), trastornos nerviosos centrales, convulsiones, enteropatía (enfermedad que causa la pérdida de proteínas de los intestinos), desequilibrio electrolítico de sales, y sepsis (Sur 2004; WHO 2005b). Cerca del 3% de las personas con infección por S. flexneri y con una predisposición genética pueden desarrollar el síndrome de Reiter (dolores en las articulaciones, irritación de los ojos, y micción dolorosa) que puede causar dificultad para tratar la artritis crónica (CDC 2005). El síndrome urémico hemolítico (una complicación que resulta en insuficiencia renal, hemorragia, y anemia) y la reacción leucemoide (resultados sanguíneos que se asemejan a la leucemia) complican la infección debida a S. dysenteriae tipo 1 y pueden ser mortales (Sinha 1987). La S. dysenteriae tipo 1 es la única especie de Shigella con genes cromosómicos que codifican la proteína conocida como toxina Shiga (Thorpe 2001).

Diagnosis

Las características clínicas de la fiebre con diarrea con sangre y moco asociados con el dolor abdominal indican que la etiología de la diarrea es Shigella. La microscopía habitual de las heces frescas es una prueba de detección sencilla que es económica, rápida y fácil de realizar; y la visualización de numerosas células polimorfonucleares sugiere una etiología bacteriana. Sólo puede realizarse un diagnóstico definitivo de la shigelosis mediante el cultivo de heces (WHO 2005a). Sin embargo, la especie de Shigella muere rápidamente en ambientes desfavorables y el cultivo de heces debería ser idealmente complementado por intentos de identificar ADN Shigella mediante la reacción en cadena de la polimerasa (RCP) (von Seidlein 2006).

Recaída

Es posible que ocurra una recaída clínica. Este hecho se manifiesta como una mejoría clínica inicial o curación aparente con el tratamiento, seguida de la recurrencia de la diarrea una vez completo el tratamiento farmacológico. En algunos casos, se ha buscado la presencia continua de Shigella en cultivos de heces después del tratamiento, independientemente de la recuperación clínica aparente y se han documentado como fracasos bacteriológicos (Martin 2000), que indican la posibilidad de recaída. La recaída es un indicador importante del fracaso del tratamiento, aunque es clínicamente difícil diferenciar una recaída de la infección con la misma especie o serotipo de Shigella sin pruebas adicionales para el ADN Shigella mediante el análisis de RCP (von Seidlein 2006).

Mortalidad

Se calcula que la tasa de mortalidad es menor al 1% entre los pacientes con enfermedad leve (WHO 2005a), que por lo general es autolimitante (CDC 2005), y los afectados normalmente reciben tratamiento ambulatorio. Sin embargo, la mortalidad llega a ser de hasta un 15% entre los pacientes con S. dysenteriae tipo 1 que requieren hospitalización; esta tasa se ve incrementada por la llegada y el tratamiento tardíos con antibióticos ineficaces. Los neonatos, los niños no lactantes, los niños que se recuperan del sarampión, los niños desnutridos y los adultos mayores de 50 años tienen una enfermedad más grave y un mayor riesgo de muerte (WHO 2005a).

Shigella e infección por VIH

La infección por el virus de inmunodeficiencia humana (VIH) puede ser un factor de riesgo importante para la infección por Shigella. Especialmente en las personas con VIH positivo, la shigelosis se asocia con una enfermedad extensiva, incluida la septicemia por Shigella, y mayores gastos de asistencia sanitaria. El diagnóstico de shigelosis en un adulto sin otro tipo de enfermedad y sin riesgo aparente de exposición para Shigella debe impulsar la consideración de la posibilidad de infección por VIH (Huebner 1993; Baer 1999).

Descripción de la intervención

La Organización Mundial de la Salud (OMS) recomienda que todos los presuntos casos de shigelosis basados en características clínicas sean tratados con antimicrobianos eficaces (antibióticos). La elección del fármaco antimicrobiano ha cambiado con el transcurso de los años debido a que se ha producido resistencia a los antibióticos, con diferentes patrones de resistencia informados en todo el mundo. Se utilizaron los siguientes antibióticos para tratar la disentería por Shigella:

  • clase: betalactámicos: ampicilina, amoxicilina, cefalosporinas de primera y segunda generación (cefixima, ceftriaxona) y pivmecilinam;

  • clase: quinolonas: ácido nalidíxico, ciprofloxacina, norfloxacina, ofloxacina;

  • clase: macrólidos: azitromicina; otros: sulfonamidas, tetraciclina, cotrimoxazol y furazolidona.

En la actualidad, la OMS recomienda que los casos de disentería por Shigella clínicamente diagnosticados sean tratados con ciprofloxacina como tratamiento de primera línea, y pivmecilinam, ceftriaxona, o azitromicina como tratamiento de segunda línea y menciona a los otros como ineficaces (WHO 2005a). Sin embargo, la resistencia a las quinolonas también se ha observado desde finales de los años noventa, y algunos autores han cuestionado la efectividad de esta clase para Shigella (Datta 2003; Sarkar 2003; Sur 2003; Pazhani 2004; Talukder 2004).

Por qué es importante realizar esta revisión

Cuando se administra un antibiótico eficaz, se prevé una mejoría clínica en un plazo de 48 horas (WHO 2005a). Este hecho reduce el riesgo de complicaciones graves y muerte, acorta la duración de los síntomas, y acelera la eliminación de Shigella y la posterior propagación de la infección (WHO 2005a). Debido a que los antibióticos utilizados para el tratamiento de la shigelosis pueden tener efectos adversos (Tabla 1; BNF 2007), algunos potencialmente mortales, el médico se enfrenta con un dilema al elegir un fármaco apropiado para tratar la shigelosis. Este fármaco debe ser eficaz, disponible localmente a costos asequibles, estar asociado con efectos adversos mínimos y ser sensible a las cepas y especies de Shigella locales. Se realizó esta revisión con la esperanza de identificar tal fármaco o grupo de fármacos.Ver Tabla 1

Objetivos

Evaluar la eficacia y la seguridad de los antibióticos para el tratamiento de la disentería por Shigella.

Métodos

Criterios para la valoración de los estudios para esta revisión

Tipos de estudios

Ensayos controlados con asignación al azar (ECAs).

Tipos de participantes

Adultos y niños con síntomas clínicos que sugieren disentería por Shigella. Se incluyeron tanto los participantes hospitalizados como los no hospitalizados.

Tipos de intervenciones

Intervención

Antibióticos, independientemente de la dosis o vía de administración.

Control

Otro antibiótico de una clase diferente (independientemente de la dosis o vía de administración), placebo, o ningún fármaco.

Se incluyeron ensayos que utilizaban intervenciones adicionales si las intervenciones se utilizaban en todos los brazos del tratamiento.

Tipos de medida de resultado

Resultados primarios

  • Diarrea en el seguimiento.

  • Recaída, definida como la reaparición de la diarrea asociada con Shigella en las heces o la disentería durante el seguimiento.

Resultados secundarios

  • Fiebre en el seguimiento: definida como una temperatura corporal mayor a 37,0 ºC o 98,6 ºF.

  • Tiempo hasta el cese de la fiebre.

  • Tiempo hasta el cese de la diarrea.

  • Tiempo hasta el cese de la sangre en las heces.

  • Número total de heces por día.

  • Cura bacteriológica: definida como un cultivo negativo de heces al final de un período de tiempo específico después del tratamiento.

  • Duración de la estancia hospitalaria

  • Desarrollo de complicaciones graves

  • Muerte

  • Eventos adversos graves (es decir, aquellos que son potencialmente mortales o requieren hospitalización); aquellos que llevan a la interrupción del tratamiento; otros tipos de eventos adversos.

Métodos de búsqueda para la identificación de los estudios

Se identificaron todos los ensayos relevantes independientemente del idioma o del estado de la publicación (publicado, no publicado, en prensa y en curso).

Búsquedas electrónicas

Se realizaron búsquedas en las siguientes bases de datos mediante las estrategias y los términos de búsqueda enumerados en la Tabla 2: el Registro Especializado de Ensayos Controlados del Grupo Cochrane de Enfermedades Infecciosas (Cochrane Infectious Diseases Group); Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials, CENTRAL) (The Cochrane Library 2008, número 4); MEDLINE (1966 hasta junio 2009); EMBASE (1974 hasta junio 2009); y LILACS (1982 hasta junio 2009). También se hicieron búsquedas en el metaRegister of Controlled Trials (mRCT) utilizando 'shigell*' como término de búsqueda (junio 2009). Ver Tabla 2

Búsqueda de otros recursos

En Tabla 3se enumeran las búsquedas realizadas en los resúmenes de congresos para obtener los resúmenes pertinentes, los contactos establecidos con los investigadores individuales que trabajan en esta área, los contactos establecidos con las organizaciones y compañías farmacéuticas para identificar los ensayos no publicados y en curso, junto con las fechas en las que se realizó todo esto. También se verificaron las listas de referencias de todos los estudios identificados por los métodos anteriores.Ver Tabla 3

Obtención y análisis de los datos

Selección de los estudios

Dos pares de autores (PC y KVD, y SMJ y VS) evaluaron de forma independiente los resultados de la búsqueda bibliográfica para determinar si el título o el resumen de cada ensayo citado era un ECA. Se recuperaron los informes completos de todos los ensayos considerados como potencialmente relevantes por uno o ambos pares de autores, así como los que estaban poco claros a partir del análisis de los resúmenes. Cada par utilizó un formulario de elegibilidad estándar basado en los criterios de inclusión y exclusión para evaluar los ensayos. Los desacuerdos se resolvieron mediante discusión. Si la elegibilidad era incierta debido a información poco clara o inadecuada, se intentó establecer contacto con los autores del ensayo para obtener aclaraciones. Las razones para excluir los estudios se notificaron en la tabla "Características de los estudios excluidos". Se analizó cada informe de ensayos para asegurar que las publicaciones múltiples del mismo ensayo estén incluidas sólo una vez, y todos los informes estaban vinculados al informe del ensayo original en la lista de referencias de los estudios incluidos.

Extracción y manejo de los datos

Los pares de autores extrajeron de forma independiente los datos de los ensayos mediante el uso de formularios de extracción de datos probados previamente. Se extrajeron los datos sobre los criterios de inclusión y exclusión para los participantes, la intervención de tratamiento administrada, el número total de participantes asignados al azar, el número de participantes en cada grupo para todos los resultados, los abandonos y retiros, y los números que experimentaron cada resultado. Para cada resultado, se extrajo el número analizado y el número asignado al azar en cada grupo de tratamiento para permitir la evaluación de las pérdidas durante el seguimiento. Las discrepancias sobre los datos extraídos se resolvieron mediante consulta al informe del ensayo y mediante discusión. Cuando faltaban datos o no eran suficientes, se intentó establecer contacto con los autores del ensayo.

Para los resultados continuos, se extrajeron los valores medios aritméticos, las desviaciones estándar, y el número de participantes en los que se evaluó el resultado en cada uno de los dos grupos. Se observó si los números evaluados en el ensayo eran el número de participantes que completaron el ensayo o el número asignado al azar. Si se informaban las medianas se extraían los rangos, o los rangos intercuartiles.

Evaluación del riesgo de sesgo en los estudios incluidos

Los pares de autores evaluaron de forma independiente el riesgo de sesgo de cada ensayo incluido para los siguientes seis componentes: generación de secuencia, ocultación de la asignación, cegamiento o enmascaramiento, datos de resultado incompletos, informe selectivo de los resultados, y otras fuentes de sesgo. Para cada uno de estos componentes, se asignó una evaluación con respecto al riesgo de sesgo como "sí", "no", o "incierto" (Higgins 2008). El seguimiento se consideraba adecuado si más del 90% de los participantes asignados al azar estaban incluidos en el análisis final, inadecuado si el número era menor o igual al 90%, o incierto si esta información no estaba disponible a partir del informe o de los autores del ensayo. Estas evaluaciones se registraron en la tabla estándar en RevMan 5 (Review Manager 2008), y se resumieron en las tablas "Riesgo de sesgo" y un gráfico (Figura 1; Figura 2). Cuando fue apropiado, se utilizaron estas evaluaciones para realizar un análisis de sensibilidad basado en la calidad metodológica. Cuando los detalles metodológicos eran inciertos, se intentó establecer contacto con los autores del ensayo en búsqueda de aclaraciones. Las diferencias se resolvieron mediante discusión y al contactar a un Editor con el Grupo de Revisión Cochrane de Enfermedades Infecciosas (Cochrane Infectious Diseases Review Group).

Medidas del efecto del tratamiento

Las medidas del efecto del tratamiento utilizadas fueron el cociente de riesgos (CR) para los resultados dicotómicos y la diferencia de medias (DM) para los resultados continuos, con intervalos de confianza (IC) del 95%.

Manejo de los datos que faltaban

Cuando fue posible, se extrajeron los datos para permitir un análisis por intención de tratar (intention-to-treat analysis) en el que se analizaran todos los participantes en los grupos al que fueron asignados al azar originalmente. Si había discrepancia en el número de los asignados al azar y el número analizado en cada grupo de tratamiento, se calculó el porcentaje de casos perdidos durante el seguimiento en cada grupo y se reportó esta información. Para los resultados dicotómicos, se registró el número de participantes que presentó el evento y el número analizado en cada grupo de tratamiento. A aquellos participantes perdidos durante el seguimiento se les asignó el peor resultado, con excepción del resultado de muerte, ya que sería poco razonable suponer que todos los que se perdieron durante el seguimiento murieron.

Evaluación de la heterogeneidad

Se determinó la presencia de heterogeneidad estadística entre las mismas intervenciones al inspeccionar el diagrama de bosque (forest plot) y al realizar una prueba de ji2para la heterogeneidad con un valor de p de 0,10 para determinar la significación estadística. La estadística I2se utilizó para cuantificar la incongruencia entre los ensayos y un valor superior al 50% se consideró como heterogeneidad significativa. (Deeks 2005).

Evaluación del sesgo de descripción selectiva de los resultados

En todos los estudios se evaluó la adecuación del informe de los datos para las medidas de resultado preestablecidas y para el informe selectivo de los resultados. Se observaron los juicios en base al riesgo del informe selectivo en la tabla "Riesgo de sesgo" para cada estudio en la tabla "Características de los estudios incluidos".

De haber habido suficientes ensayos, se habría evaluado la asimetría en el gráfico en embudo (funnel plot) como una indicación de sesgo de publicación.

Síntesis de los datos

Los primeros dos autores introdujeron los datos en Review Manager 2008con doble entrada de los mismos. PC resumió los datos, que los co-autores verificaron. Todos los resultados se presentan con IC del 95%. Las comparaciones principales fueron entre cualquier fármaco antibiótico y placebo, y entre cualquier fármaco antibiótico y otro fármaco antibiótico de una clase diferente.

Los datos dicotómicos se resumieron mediante CR ponderados y agrupados. Los datos continuos resumidos con medias aritméticas y desviaciones estándar se combinaron mediante diferencias de medias ponderadas.

Si la heterogeneidad no era significativa, se utilizaba el modelo de efectos fijos para resumir los datos. Cuando había heterogeneidad significativa y la misma no podía explicarse por el análisis de subgrupos, los datos se resumieron mediante el modelo de efectos aleatorios y se recomendó una interpretación cautelosa del resultado agrupado.

Análisis de subgrupos e investigación de la heterogeneidad

Cuando había heterogeneidad estadísticamente significativa, se exploraron las posibles fuentes mediante los siguientes análisis de subgrupos: edad de los participantes (adultos versus niños) y porcentaje de participantes con infección por Shigella confirmada.

Análisis de sensibilidad

Se realizaron análisis de sensibilidad para las medidas de resultado primarias con el fin de evaluar la solidez de los metanálisis entre las mismas intervenciones mediante el cálculo de los resultados de todos los ensayos y luego la exclusión de los ensayos de una calidad metodológica inferior (es decir, ensayos con generación de la secuencia de asignación y ocultación de la asignación inadecuadas, ensayos que no fueron doble ciego, y ensayos donde se analizó a menos del 90% de los participantes asignados al azar).

Resultados

Descripción de los estudios

Ver: Características de los estudios incluidos; Características de los estudios excluidos; Características de los estudios en espera de clasificación.

Resultados de la búsqueda

De los 265 estudios recuperados por la búsqueda, se obtuvieron los textos completos de 123 estudios. Los demás fueron excluidos ya que no eran ni ECAs ni estudios de antibioticoterapia para Shigella. De los 123 estudios, 16 ensayos con asignación al azar de individuos, de grupos paralelos, cumplieron con los criterios de inclusión (ver "Características de los estudios incluidos") y se resumen a continuación. Las razones para la exclusión de los otros 106 ensayos se registran en la tablaCaracterísticas de los estudios excluidos. Un estudio está a la espera de evaluación. (Carbo 1981).

Estudios incluidos

Lugar, contexto y duración del seguimiento

Siete ensayos se realizaron en Bangladesh, todos en el International Centre for Diarrhoeal Disease Research (ICDDR,B). Dos ensayos eran de los Estados Unidos de América (Haltalin 1973; Nelson 1976a) y uno de los siguientes países: India (Dutta 1995), Sri Lanka (Bibile 1961), Peru (Gotuzzo 1989), Israel (Leibovitz 2000), Guatemala (Prado 1993), Mexico (Rodriguez 1989), y Kenia (Shanks 1999). Doce ensayos se realizaron en pacientes hospitalizados, tres en pacientes ambulatorios y uno no mencionó el contexto. Los ensayos utilizaron diferentes duraciones del seguimiento: ocho ensayos se realizaron durante seis días, tres ensayos durante cinco días, dos ensayos durante 14 días, un ensayo durante siete días, uno durante diez días, y otro durante seis meses.

Participantes

Los ensayos incluyeron un total de 1 748 participantes. Todos los ensayos excepto uno (Haltalin 1973) se asignaron al azar en base a los síntomas clínicos de la disentería y antes de la confirmación bacteriológica. Se excluyeron los pacientes sin sangre o moco en las heces. Haltalin 1973asignaron al azar a los participantes después de una confirmación presuntiva de Shigella por el estudio de inmunofluorescencia de los hisopados rectales. Dutta 1995no buscó la confirmación microbiológica para Shigella mediante el cultivo de muestras de heces o hisopos rectales. En los restantes ensayos, sólo se informaron los datos de los participantes con Shigella confirmada microbiológicamente y, por lo tanto, sólo esos datos se incluyeron en los análisis. Diez ensayos se realizaron sólo en niños, cinco en adultos, y uno incluyó ambos. Entre los diez ensayos en niños, sólo uno (Dutta 1995) incluyó niños desnutridos (11 de 72) pero no proporcionó datos sobre ellos por separado. Dos ensayos excluyeron niños con desnutrición y los siete ensayos restantes no proporcionaron tal información. Ninguno de los ensayos informó el estado del VIH de los participantes. Los otros criterios de inclusión fueron bastante similares entre todos los ensayos.

Intervenciones

Dos ensayos (Kabir 1986; Rodriguez 1989) compararon antibióticos y placebo o ningún fármaco. Ambos fueron ensayos de tres brazos. Rodriguez 1989comparó furazolidona, cotrimoxazol, y ningún fármaco. Kabir 1986comparó ceftriaxona, ampicilina, y placebo. Seis ensayos compararon fluoroquinolonas y betalactámicos (Alam 1994, pivmecilinam y ácido nalidíxico; Bennish 1990, ciprofloxacina y ampicilina; Haltalin 1973, ácido nalidíxico y ampicilina; Leibovitz 2000, ciprofloxacina y ceftriaxona; Salam 1988, ácido nalidíxico y ampicilina; Salam 1998, ciprofloxacina y pivmecilinam). Dos ensayos compararon fluoroquinolonas y macrólidos (Khan 1997a; Shanks 1999),ambos compararon azitromicina y ciprofloxacina). Dos ensayos compararon cotrimoxazol y betalactámicos (Prado 1993, pivmecilinam y cotrimoxazol; Nelson 1976a, cotrimoxazol y ampicilina). Gotuzzo 1989comparó cotrimoxazol y fluoroquinolonas (norfloxacina). Dutta 1995comparó furazolidona y ácido nalidíxico. Islam 1994comparó gentamicina oral y ácido nalidíxico. Bibile 1961fue un ensayo de cuatro brazos: los tres primeros tenían diferentes tipos de sulfonamidas: sulfamidina, sulfametoxipiridazina, "Streptotriad" y el cuarto brazo era la tetraciclina. Cada comprimido de Streptotriad contenía sulfato de estreptomicina, sulfamerazina, sulfadiazina y sulfatiazol. Este brazo no se incluyó en el análisis (sulfonamida versus tetraciclina) debido a que contenía un fármaco no sulfonamida, la estreptomicina.

Resultados

Esta revisión tuvo dos medidas de resultado de eficacia primarias. La primera medida de resultado primaria, la diarrea en el seguimiento, fue informada en todos menos tres ensayos (Kabir 1986; Gotuzzo 1989; Islam 1994); la duración del seguimiento fue de cinco días en 10/13 ensayos. La segunda medida de resultado primaria, la recaída, se informó en cuatro ensayos (Haltalin 1973; Salam 1998; Shanks 1999; Leibovitz 2000); la duración del seguimiento para este resultado varió de diez a 20 días. Entre las medidas de resultado secundarias, la fiebre en el seguimiento se informó en cuatro ensayos, el tiempo hasta el cese de la fiebre se informó en cinco ensayos, el tiempo hasta el cese de la diarrea se informó en seis ensayos, el tiempo hasta el cese de la sangre en las heces se informó en tres ensayos, el fracaso o la cura bacteriológica se informó en 11 ensayos, y el desarrollo de complicaciones graves se informó en sólo un ensayo. La duración de la estancia hospitalaria no fue un resultado medido por los ensayos. Un ensayo (Kabir 1986) informó el número medio de heces por día en un gráfico que no permitió la extracción de datos para el análisis. Los eventos adversos se informaron en todos menos cuatro ensayos (Haltalin 1973; Alam 1994; Islam 1994; Dutta 1995). Solamente Leibovitz 2000informó los eventos adversos graves relacionados con la antibioticoterapia que llevaba a la hospitalización. Ningún ensayo informó muertes.

Estudios excluidos

Se excluyeron 107 estudios por las siguientes razones. Veintinueve estudios no eran ECAs. En 59 estudios los criterios de inclusión para los participantes no fue la disentería. Dieciocho estudios compararon antibióticos de la misma clase, lo que debe ser el tema de otra revisión. Un ensayo se excluyó porque las intervenciones no eran antibióticos (Raqib 2008). Carbo 1981)se encuentra en espera de evaluación ya que no proporcionó datos sobre los números asignados a las intervenciones y se aguarda una respuesta de los autores.

Riesgo de sesgo en los estudios incluidos

Ver Figura 1para obtener un resumen del "riesgo de sesgo" en cada estudio incluido y Figura 2para obtener un gráfico resumido de la calidad metodológica expresada como porcentajes entre los ensayos incluidos. El riesgo de sesgo para cada estudio se resume de forma adicional enCaracterísticas de los estudios incluidos'.

Asignación

Entre los estudios incluidos, el 81% (13/16) tenía bajo riesgo de sesgo en la generación de la secuencia de asignación. De éstos, cuatro ensayos (Bibile 1961; Prado 1993; Salam 1998; Leibovitz 2000) utilizaron listas de números aleatorios. Los ensayos restantes (Nelson 1976a; Kabir 1986; Salam 1988; Gotuzzo 1989; Bennish 1990; Alam 1994; Islam 1994; Dutta 1995; Khan 1997a) utilizaron técnicas de asignación al azar en bloques. Sin embargo, sólo 9/16 (56%) de los estudios informaron claramente una ocultación adecuada de la asignación (Salam 1988; Bennish 1990; Prado 1993; Alam 1994; Islam 1994; Dutta 1995; Khan 1997a; Salam 1998; Leibovitz 2000).

Cegamiento

Once ensayos (69%) tenían bajo riesgo de sesgo para el componente de cegamiento. Salam 1988, Khan 1997a, Salam 1998, Shanks 1999 y Leibovitz 2000habían cegado al participante, al profesional, y al evaluador de resultados. Kabir 1986, Bennish 1990, Prado 1993, Alam 1994 y Islam 1994habían cegado al participante y al profesional. Dutta 1995sólo había cegado al evaluador de resultados. Bibile 1961, Haltalin 1973, Nelson 1976a, Gotuzzo 1989 y Rodriguez 1989fueron ensayos abiertos.

Seguimiento y exclusiones

Se consideró que sólo el 25% (4/16) de los ensayos (Bibile 1961; Haltalin 1973; Nelson 1976a; Kabir 1986) habían abordado adecuadamente los datos incompletos de los resultados. Los 12 ensayos restantes no abordaron adecuadamente los datos incompletos de los resultados porque excluyeron a los participantes del análisis de los datos después de la asignación al azar ya que posteriormente los cultivos de heces fueron negativos para Shigella. Este hecho representa una falla metodológica grave (verSesgos potenciales en el proceso de revisión').

Descripción selectiva de los resultados de interés

Ningún estudio presentó informe selectivo.

Otras fuentes potenciales de sesgo

Más del 90% (15/16) de los estudios no tenían ninguna otra posible fuente de sesgo. Un estudio (Rodriguez 1989) presentaba un desequilibrio inicial significativo ya que los participantes en uno de los brazos del estudio tuvieron menos días de diarrea que los otros brazos.

Efectos de las intervenciones

Ver: Resumen de los hallazgos para la comparación principal Antibiótico versus ningún fármaco o placebo para la disentería por Shigella; Resumen de los hallazgos 2 Fluoroquinolonas versus betalactámicos para la disentería por Shigella; Resumen de los hallazgos 3 Fluoroquinolonas versus macrólidos para la disentería por Shigella; Resumen de los hallazgos 4 Cotrimoxazol versus betalactámicos para la disentería por Shigella; Resumen de los hallazgos 5 Cotrimoxazol versus fluoroquinolonas (norfloxacina) para la disentería por Shigella; Resumen de los hallazgos 6 Cotrimoxazol versus furazolidona para la disentería por Shigella; Resumen de los hallazgos 7 Gentamicina oral versus ácido nalidíxico para la disentería por Shigella; Resumen de los hallazgos 8 Sulfonamidas versus tetraciclina para la disentería por Shigella

Se propuso preparar metanálisis separados para los ensayos de: (1) un fármaco antibiótico versus otro fármaco antibiótico perteneciente a la misma o a diferente clase de fármaco; (2) fármacos antibióticos agrupados por clase de fármaco versus otros fármacos antibióticos pertenecientes a una clase diferente de fármaco; y (3) monoterapia con cualquier fármaco antibiótico versus combinación del tratamiento con fármacos con dos o más fármacos diferentes administrados juntos o secuencialmente. Sin embargo, sólo fue posible resumir los datos de los ensayos que comparaban antibióticos simples de diferentes clases y de los antibióticos agrupados por clase. Las comparaciones de antibióticos dentro de la misma clase se difirieron a una revisión posterior y, por lo tanto, 17 ensayos potenciales de esta comparación fueron excluidos de esta revisión y se presentan como tales en lasCaracterísticas de los estudios excluidos'. No se identificaron los ensayos de un fármaco antibiótico versus combinación del tratamiento con fármacos con dos o más fármacos diferentes administrados juntos o secuencialmente.

Se presentan los resultados del ensayo agrupados como ocho conjuntos de comparaciones.

1. Versus ningún fármaco o placebo (dos ensayos)

Diarrea en el seguimiento (resultado primario):

Rodriguez 1989comparó furazolidona y cotrimoxazol orales con ningún tratamiento. Menos pacientes en el grupo de antibióticos tenían diarrea en el seguimiento (para furazolidona; CR 0,21, IC del 95%: 0,09 a 0,48; 73 participantes; y para cotrimoxazol versus ningún tratamiento; CR 0,30, IC del 95%: 0,15 a 0,59; 76 participantes, Análisis 1.1).

Kabir 1986comparó ceftriaxona intravenosa (n = 64) y ampicilina intravenosa (n = 60) con placebo (n = 30). No se detectaron diferencias en el tiempo hasta la resolución de la diarrea (Análisis 1.3), la resolución de la fiebre (Análisis 1.2), y el tiempo hasta la resolución de la sangre en las heces (Análisis 1.4), o eventos adversos (Análisis 1.5).

(VerResumen de los resultados para la comparación principal')

2. Fluoroquinolonas versus betalactámicos (seis ensayos)

Diarrea en el seguimiento (resultado primario):

Seis ensayos midieron este resultado, y los efectos comparativos variaron considerablemente entre los ensayos, sin tendencia evidente (686 participantes, seis ensayos, Análisis 2.1; Haltalin 1973; Salam 1988; Bennish 1990; Alam 1994; Salam 1998; Leibovitz 2000). Esta variabilidad aún estaba presente después de la exclusión de los ensayos con un mayor riesgo de sesgo (Haltalin 1973; Bennish 1990; Alam 1994; Salam 1988). La mayoría de los ensayos era en niños; un ensayo era en adultos (Bennish 1990).

En los ensayos donde se confirmaba que el 90% o más de los pacientes incluidos presentaban Shigella, los betalactámicos fueron más eficaces que las fluoroquinolonas (CR 4,68, IC del 95%: 1,74 a 12,59; 257 niños, dos ensayos, (Análisis 2.1). (Haltalin 1973; Leibovitz 2000); en los cuatro ensayos con menos del 90% de los pacientes con Shigella positiva confirmada los resultados no mostraron ningún patrón obvio (Análisis 2.1). (Salam 1988; Bennish 1990; Alam 1994; Salam 1998).

Recaída:

No se observó ningún patrón evidente en los tres ensayos que examinaban este resultado ( Análisis 2.1; Haltalin 1973; Salam 1998; Leibovitz 2000) y el análisis de subgrupos no proporcionó información adicional.

Fiebre en el seguimiento:

Los datos heterogéneos de dos ensayos (Alam 1994; Salam 1998) no mostraron diferencias significativas entre los grupos (191 participantes, Análisis 2.2). No se realizó el análisis de subgrupos debido a que ambos ensayos se realizaron en niños y tenían menos del 90% de participantes con Shigella en cultivo de heces.

Fracaso bacteriológico:

Los datos heterogéneos agrupados de cinco ensayos (Haltalin 1973; Salam 1988; Bennish 1990; Alam 1994; Salam 1998) no mostraron diferencias entre los dos grupos para este resultado (450 participantes, Análisis 2.4). Sin embargo, en el análisis de subgrupos basado en la edad del participante, el único estudio realizado en adultos (Bennish 1990) mostró que las fluoroquinolonas eran mejores que los betalactámicos al producir curas bacteriológicas (CR 0,28, IC del 95%: 0,08 a 0,95; 127 participantes, Análisis 2.4). Aunque los datos del subgrupo de niños (Haltalin 1973; Salam 1988; Alam 1994; Salam 1998) eran homogéneos, no hubo diferencias entre los dos grupos (223 participantes, Análisis 2.4). La heterogeneidad persistió en el análisis de subgrupos basado en el número de participantes con Shigella comprobada incluidos en el análisis.

Desarrollo de complicaciones graves:

Datos de dos ensayos (Haltalin 1973; Salam 1988) no mostraron diferencias entre los dos grupos para este resultado (90 participantes, Análisis 2.5). Aunque las pruebas formales no revelaron heterogeneidad significativa, es importante considerar las diferencias del tamaño y dirección del efecto del tratamiento para los dos ensayos al interpretar este resultado.

Eventos adversos:

Para los eventos adversos graves, Leibovitz 2000no mostró diferencias entre los dos grupos (Análisis 2.6, n=221); Bennish 1990no detectó una diferencia en los eventos adversos que llevaban a la interrupción del tratamiento (127 participantes, Análisis 2.7); para otros eventos adversos, no se detectaron diferencias en cuatro ensayos que informaban este dato (Análisis 2.8). ( Salam 1988; Bennish 1990; Salam 1998; Leibovitz 2000).

(VerResumen de los hallazgos 2').

3. Fluoroquinolonas versus macrólidos (dos ensayos)

Diarrea en el seguimiento (medidas de resultado primarias):

Datos de dos ensayos (Khan 1997a; Shanks 1999) no mostraron diferencias entre los dos grupos (189 participantes, Análisis 3.1). No se pudo evaluar la heterogeneidad debido a que los resultados de Shanks 1999no eran estimables (ningún paciente tuvo diarrea durante el seguimiento en ambos brazos) y, en consecuencia, no se realizó el análisis de subgrupos ni el análisis de sensibilidad.

Recaída:

Shanks 1999informó la recaída pero los resultados no eran estimables ya que ningún paciente había experimentado recaída.

Fiebre en el seguimiento:

Los datos homogéneos de dos ensayos (Khan 1997a; Shanks 1999) no mostraron diferencias entre los dos grupos (189 participantes, Análisis 3.2).

Tiempo hasta el cese de la sangre en las heces:

Un ensayo (Shanks 1999) que informaba este resultado no mostró diferencias entre los dos grupos (113 participantes, Análisis 3.3).

Fracaso bacteriológico:

Un ensayo (Khan 1997a) no mostró diferencias entre los dos grupos (76 participantes, Análisis 3.4).

Eventos adversos:

Khan 1997ano mostró diferencias entre los dos grupos (76 participantes, Análisis 3.5).

(VerResumen de los hallazgos 3').

4. Cotrimoxazol versus betalactámicos (dos ensayos)

Diarrea en el seguimiento (resultado primario):

Los datos homogéneos de dos ensayos (Nelson 1976a; Prado 1993) no mostraron diferencias entre los dos grupos (89 participantes, Análisis 4.1). La exclusión del ensayo de calidad más deficiente (Nelson 1976a) no afectó los resultados en el análisis de sensibilidad.

Fracaso bacteriológico:

Un ensayo (Nelson 1976a) que comparaba este resultado no mostró diferencias entre los dos grupos (28 participantes, Análisis 4.2).

Tiempo hasta el cese de la diarrea:

Un ensayo (Prado 1993) que comparaba este resultado no mostró diferencias significativas entre los dos grupos (61 participantes, Análisis 4.3).

Tiempo hasta el cese de la fiebre:

Un ensayo (Prado 1993) informó este resultado y no hubo diferencia entre los dos grupos (61 participantes, Análisis 4.4).

Tiempo hasta el cese de la sangre en las heces:

Un ensayo (Prado 1993) que comparaba este resultado no mostró diferencias entre los dos grupos (61 participantes, Análisis 4.5).

Eventos adversos:

Los datos homogéneos de dos ensayos (Nelson 1976a; Prado 1993) no mostraron diferencias entre los dos grupos para los eventos adversos (89 participantes, Análisis 4.6).

(Ver "Tabla de resumen de los hallazgos 4").

5. Cotrimoxazol versus fluoroquinolonas (un ensayo)

Fracaso bacteriológico:

Un ensayo (Gotuzzo 1989) que comparaba este resultado no mostró diferencias entre los grupos (62 participantes, Análisis 5.1).

Eventos adversos:

Gotuzzo 1989, el único ensayo para esta comparación, no mostró diferencias entre los grupos (62 participantes, Análisis 5.2).

(VerResumen de los hallazgos 5').

6. Cotrimoxazol versus furazolidona (un ensayo)

Diarrea en el seguimiento (resultado primario):

Un ensayo de tres brazos (Rodriguez 1989), furazolidona, cotrimoxazol, y ningún fármaco) informó este resultado y no hubo diferencias significativas entre los grupos (101 participantes, Análisis 6.1).

(VerResumen de los hallazgos 6').

7. Gentamicina oral versus ácido nalidíxico (un ensayo)

Diarrea en el seguimiento (medida de resultado primaria):

Un ensayo (Islam 1994) que informaba este resultado no mostró diferencias entre los dos grupos (79 participantes, Análisis 7.1).

Fiebre en el seguimiento:

Islam 1994informó este resultado y halló que el ácido nalidíxico era más eficaz que la gentamicina oral al reducir el número de pacientes con fiebre en el seguimiento (CR 2,37, IC del 95%: 1,11 a 5,07; 79 participantes, Análisis 7.2). Si bien ambos antibióticos eran eficaces contra la Shigella in vitro, el ácido nalidíxico fue más eficaz in vivo debido a una mejor absorción al ser administrado por vía oral.

Fracaso bacteriológico:

Islam 1994informó que el ácido nalidíxico era más eficaz que la gentamicina oral al lograr curas bacteriológicas (CR 2,10, IC del 95%: 1,29 a 3,42; 79 participantes, Análisis 7.4).

(Ver "Tabla de resumen de los hallazgos 7")

8. Sulfonamidas versus tetraciclinas (un ensayo)

Diarrea en el seguimiento (resultado primario):

Un ensayo (Bibile 1961) que comparaba este resultado no mostró diferencias entre los dos grupos (60 participantes, Análisis 8.1).

Fracaso bacteriológico:

Bibile 1961no informó diferencias significativas entre los grupos (60 participantes, Análisis 8.2).

(VerResumen de los hallazgos 8').

Discusión

Resumen de los resultados principales

Esta revisión identificó 16 ensayos realizados durante cuatro décadas que asignaron al azar 1748 participantes para evaluar la seguridad y la eficacia de los antibióticos en el tratamiento de la disentería por Shigella. La mayoría de los ensayos estuvo en riesgo de sesgo debido a las limitaciones en la información de los detalles de la asignación al azar o la ocultación de la asignación o el cegamiento, pero la fuente de sesgo más frecuente ocurrió al no informar los detalles de resultados para los participantes que se asignaron al azar pero en los que Shigella no pudo ser aislado del cultivo de heces.

Esta revisión se centró en los ensayos realizados con antibióticos pertenecientes a diferentes clases, en comparación con placebo o ningún tratamiento o entre sí. Se hallaron pruebas limitadas para apoyar el uso de antibióticos en niños y adultos con disentería por Shigella, en comparación con ningún tratamiento o placebo. Un ensayo informó que los antibióticos son eficaces al reducir la proporción de aquellos participantes con diarrea, pero no informó la recaída. Otro ensayo indicó que los antibióticos eran eficaces al reducir la duración de la fiebre, aunque no reducían el tiempo hasta el cese de la diarrea o las heces sanguinolentas.

No se hallaron pruebas sólidas para sugerir que los antibióticos de una clase particular eran mejores que los que pertenecían a una clase diferente. Sin embargo, hubo datos limitados de un subgrupo de estudios para sugerir que una fluoroquinolona (ciprofloxacina) era más eficaz que un betalactámico (ampicilina) al reducir la diarrea entre los adultos, y que los betalactámicos eran más eficaces que las fluoroquinolonas al reducir la diarrea entre los niños con disentería por Shigella comprobada. También se informó que la gentamicina oral era inferior al ácido nalidíxico en lograr la cura bacteriológica y reducir la fiebre en un ensayo pequeño. Los ensayos en esta revisión informan que en varios períodos de tiempo diferentes antibióticos han sido eficaces contra las cepas de la disentería por Shigella (Tabla 4) en diversas partes del mundo. Estos antibióticos son: ampicilina, cotrimoxazol, ácido nalidíxico, fluoroquinolonas como la ciprofloxacina, pivmecilinam, ceftriaxona y azitromicina. Sin embargo, la gentamicina oral fue relativamente ineficaz debido a la pobre absorción al ser administrada por vía oral, en comparación con el ácido nalidíxico y, por lo tanto, no se recomienda. No se hallaron pruebas suficientes para formular observaciones sobre el uso de tetraciclinas, sulfonamidas, y cloranfenicol.Ver Tabla 4

Tampoco existen pruebas suficientes para indicar que cualquier clase de antibiótico previene la recaída de la disentería por Shigella.

Ninguno de los antibióticos estudiados en los ensayos se asoció con eventos adversos principales que estaban relacionados con el fármaco.

Cumplimiento y aplicabilidad general de las pruebas

En lo que se refiere a los objetivos de la revisión, esta revisión halló pruebas limitadas de que los antibióticos reducen la diarrea y la duración de la fiebre, en comparación con ningún antibiótico. Sin embargo, no es posible recomendar un antibiótico o una clase de antibiótico para el tratamiento de la disentería por Shigella. Los estudios identificados no pudieron tratar suficientemente la recaída. Todos los antibióticos estudiados en esta revisión fueron seguros.

Los estudios se dirigieron tanto a adultos como a niños. Sin embargo, las poblaciones en riesgo de disentería por Shigella complicada, como las poblaciones con infección por VIH y los niños desnutridos, no estaban incluidas (o representadas adecuadamente) en los ensayos que se identificaron.

En la práctica actual, los antibióticos se recomiendan y se utilizan en el tratamiento de la disentería por Shigella. Las conclusiones de esta revisión confirman estas recomendaciones y la práctica actual. Sin embargo, esta revisión no puede recomendar un antibiótico o grupo de antibióticos específico como universalmente eficaz para el tratamiento de la disentería por Shigella.

Aunque se considera que las formas leves de la disentería por Shigella son autolimitantes, esta revisión no puede formular observaciones sobre la necesidad de antibióticos en este grupo ya que los ensayos incluidos no calificaron a los pacientes en lo que se refiere a la gravedad de la enfermedad.

Esta revisión no incluyó estudios que utilizaban fármacos pertenecientes a clases similares de antibióticos. Se necesita otra revisión para estudiar las diferencias entre los antibióticos pertenecientes a la misma clase y también entre esquemas de dosis de antibióticos diferentes, y tratamiento de corta duración versus duración más prolongada del mismo antibiótico.

Calidad de las pruebas

El conjunto de pruebas identificado no permite una conclusión consistente con respecto a los objetivos de la revisión o recomendaciones sólidas con respecto a la elección de los antibióticos preferidos. De los 16 ensayos (1 748 participantes) incluidos en la revisión, la mayoría tenía limitaciones metodológicas que incluían el informe inadecuado de la generación de la secuencia de asignación, la ocultación inadecuada de la asignación, y la ausencia de cegamiento. Muchos ensayos excluyeron a los participantes después de la asignación al azar debido a que no desarrollaban Shigella en su cultivo de heces y no habían informado su resultado. Éste es un error metodológico grave. Por lo tanto, la mayoría de los ensayos se calificó de baja o muy baja calidad y la investigación adicional puede cambiar los cálculos de eficacia y la confianza en estos cálculos.

Sesgos potenciales en el proceso de revisión

Se seleccionaron los ensayos que comparaban la eficacia y la seguridad de antibióticos de diferentes clases solamente y se difirió la inclusión de los ensayos que evaluaban los antibióticos de la misma clase de fármaco a una actualización u otra revisión. Diecisiete ensayos se excluyeron sobre la base de este hecho. Este hecho puede haber sesgado los resultados y las conclusiones de esta revisión. Tampoco se incluyeron comparaciones de diferentes dosis, vías de administración, o duración del tratamiento del mismo antibiótico en la disentería por Shigella.

Se seleccionaron los ensayos que incluían participantes con pruebas clínicas de disentería. Sin embargo, la infección por Shigella también puede presentarse como diarrea en hasta tres cuartos de las infecciones, particularmente en los países asiáticos (von Seidlein 2006). La exclusión de tales pacientes en los ensayos de antibióticos en Shigella y la exclusión de los ensayos mediante una definición más amplia que la utilizada en esta revisión podrían haber sesgado las pruebas presentadas. Muchos ensayos en esta revisión también excluyeron participantes asignados al azar para recibir antibióticos si sus heces no desarrollaban cepas de Shigella. Sin embargo, las cepas y especies de Shigella son sumamente sensibles a ambientes hostiles y el fracaso en desarrollar Shigella en el cultivo no descarta la infección por Shigella (von Seidlein 2006). Ninguno de los ensayos incluidos utilizó técnicas de diagnóstico, sensibles, alternativas o adicionales, como la identificación de ADN Shigella mediante la RCP en tiempo real. Es probable que la exclusión de los datos de tales participantes en estos ensayos, y la exclusión de criterios de inclusión más estrictos para el diagnóstico de la disentería por Shigella en esta revisión hayan introducido sesgos de informe y de selección, respectivamente.

Acuerdos y desacuerdos con otros estudios o revisiones

Los resultados globales de esta revisión sugieren que la mayoría de los antibióticos utilizados fueron eficaces. Sin embargo, sólo diez de los 16 ensayos incluidos informaron la proporción de participantes que fueron sensibles a los antibióticos utilizados. Los resultados en estos ensayos se correlacionaron con los patrones de sensibilidad de los antibióticos utilizados.

La OMS recomendó el ácido nalidíxico como el tratamiento de primera línea para la disentería por Shigella hasta 2004 cuando la completa resistencia al ácido nalidíxico en gran parte de China y Bangladesh resultó en recomendaciones de la OMS para evitar el uso de ácido nalidíxico totalmente en la disentería por Shigella (Legros 2004; WHO 2005a). Sin embargo, el ácido nalidíxico sigue siendo una opción potencial en partes del mundo donde la resistencia a este fármaco no es, hasta ahora, un problema generalizado, como la región Dakar de Senegal, donde la resistencia a la ampicilina, el cloranfenicol, la tetraciclina y el cotrimoxazol es frecuente (Sire 2008). Sin embargo, el uso generalizado del ácido nalidíxico puede aumentar la resistencia a la ciprofloxacina debido a la resistencia cruzada de algunas cepas de Shigella y, por lo tanto, tiene una utilidad limitada (WHO 2005a). La OMS recomienda el uso de ciprofloxacina como el antibiótico de primera línea en disentería por Shigella presunta, pero también indica que esta elección debe basarse en patrones de sensibilidad de las cepas de Shigella recientemente aisladas en el área (WHO 2005a). Los cambios temporales y geográficos en las cepas de Shigella se informan en diferentes partes del mundo (von Seidlein 2006) y la vigilancia y evaluación regular de la sensibilidad antimicrobiana a las cepas locales y regionales son necesarias para determinar la elección del antibiótico a ser utilizado como primera línea en la disentería por Shigella. La emergente resistencia del fármaco a la ciprofloxacina y a fármacos de segunda línea como el pivmecilinam, la ceftriaxona y la azitromicina se informa cada vez más en muchas partes del mundo, ya que es resistencia a múltiples fármacos (Kosek 2008; Kuo 2008; Pazhani 2008). Los resultados de esta revisión proporcionan pruebas sistemáticamente evaluadas de que los antibióticos más frecuentemente utilizados son potencialmente eficaces contra la disentería por Shigella, siempre que las cepas y especies locales de Shigella sean susceptibles. Se necesita una evaluación de las cepas regular, de sensibilidad periódica al antibiótico con el fin de guiar el tratamiento empírico local para la disentería por Shigella.

Conclusiones de los autores

Implicaciones para la práctica

Se recomienda el uso de antibióticos para la disentería por Shigella moderada a grave. La elección del antibiótico para usar como primera línea contra la disentería por Shigella debe regirse por patrones de cepas de Shigella, de sensibilidad a los antibióticos locales, actualizados periódicamente. También deben implementarse otras medidas preventivas y de apoyo recomendadas por la OMS (WHO 2005a; WHO 2005b) junto con los antibióticos (p.ej. educación sanitaria y lavado de manos).


Implicaciones para la investigación

Se necesitan ensayos controlados aleatorios que cumplan con las guías CONSORT (CONSORT 2008) para abordar muchos de los temas, como la necesidad de antibióticos en la disentería por Shigella leve, la clase o clases de antibióticos más convenientes contra Shigella en las poblaciones en riesgo de mortalidad alta como niños desnutridos, adultos mayores, pacientes que presentan complicaciones graves debidas a la shigelosis, e individuos con infección por VIH.

Los ensayos deben estratificar a los participantes según la gravedad del cuadro clínico e informar los efectos de los antibióticos por separado para cada grupo. Los ensayos deben informar los resultados para todos los participantes asignados al azar, incluidos los que presentan Shigella confirmada y aquellos con cultivo negativo. Los patrones de sensibilidad a los antibióticos también deben estudiarse e informarse. Los datos con respecto a los resultados presentados en los gráficos e imágenes también deben expresarse en números. Ver Tabla 5para obtener las características sugeridas de un futuro ensayo.Ver Tabla 5


Agradecimientos

Se reconoce el apoyo de Prathap Tharyan, Katherine Abba, Paul Garner, Sara Bhattacharji, Gagandeep Kang y Thambu David Sudarsanam en diversos estadios de esta revisión. Este protocolo y revisión son el producto de talleres realizados por el South Asian Cochrane Network & Centre que fueron financiados en parte por el Effective Health Care Research Programme Consortium (con fondos del Department for International Development [DFID], Reino Unido). Los criterios expresados no son necesariamente los de DFID.

Datos y análisis

Comparación 1. Antibiótico versus ningún fármaco o placebo

Título del subgrupo o resultado

Nº de estudiantes

Nº de participantes

Método estadístico

Tamaño del efecto

1 Diarrea en el seguimiento

1

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

Subtotales solamente

1.1 Furazolidona versus ningunos fármaco

1

73

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

0.21 [0.09, 0.48]

1.2 Cotrimoxazol versus ningún fármaco

1

76

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

0.30 [0.15, 0.59]

2 Tiempo hasta el cese de la fiebre (en días)

1

Diferencia de medias (IV, efectos fijos, IC del 95%)

Subtotales solamente

2.1 Ceftriaxona (IV) versus placebo

1

64

Diferencia de medias (IV, efectos fijos, IC del 95%)

-1.20 [-2.20, -0.20]

2.2 Ampicilina (IV) versus placebo

1

60

Diferencia de medias (IV, efectos fijos, IC del 95%)

-1.50 [-2.41, -0.59]

3 Tiempo hasta el cese de la diarrea (en días)

1

Diferencia de medias (IV, efectos fijos, IC del 95%)

Subtotales solamente

3.1 Ceftriaxona (IV) versus placebo

1

64

Diferencia de medias (IV, efectos fijos, IC del 95%)

-0.30 [-1.41, 0.81]

3.2 Ampicilina (IV) versus placebo

1

60

Diferencia de medias (IV, efectos fijos, IC del 95%)

-0.30 [-1.37, 0.77]

4 Tiempo hasta el cese de la sangre en las heces (en días)

1

Diferencia de medias (IV, efectos fijos, IC del 95%)

Subtotales solamente

4.1 Ceftriaxona (IV) versus placebo

1

64

Diferencia de medias (IV, efectos fijos, IC del 95%)

-0.30 [-1.43, 0.83]

4.2 Ampicilina (IV) versus placebo

1

60

Diferencia de medias (IV, efectos fijos, IC del 95%)

-0.30 [-1.41, 0.81]

5 Otros eventos adversos

1

94

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

1.43 [0.06, 34.13]



Comparación 2. Fluoroquinolonas versus betalactámicos

Título del subgrupo o resultado

Nº de estudiantes

Nº de participantes

Método estadístico

Tamaño del efecto

1 Diarrea en el seguimiento

6

Cociente de riesgos (M-H, efectos aleatorios, IC del 95%)

Subtotales solamente

1.1 Todos los ensayos

6

686

Cociente de riesgos (M-H, efectos aleatorios, IC del 95%)

1.03 [0.45, 2.37]

1.2 Adultos (subgrupo)

1

127

Cociente de riesgos (M-H, efectos aleatorios, IC del 95%)

0.14 [0.04, 0.44]

1.3 Niños (subgrupo)

5

559

Cociente de riesgos (M-H, efectos aleatorios, IC del 95%)

1.46 [0.64, 3.34]

1.4 Shigella confirmada > 90% (subgrupo)

2

257

Cociente de riesgos (M-H, efectos aleatorios, IC del 95%)

4.68 [1.74, 12.59]

1.5 Shigella confirmada < 90% (subgrupo)

4

429

Cociente de riesgos (M-H, efectos aleatorios, IC del 95%)

0.65 [0.29, 1.42]

2 Fiebre en el seguimiento

2

191

Cociente de riesgos (M-H, efectos aleatorios, IC del 95%)

0.87 [0.25, 3.06]

3 Recaída

3

Cociente de riesgos (M-H, efectos aleatorios, IC del 95%)

Subtotales solamente

3.1 Todos los ensayos

3

357

Cociente de riesgos (M-H, efectos aleatorios, IC del 95%)

0.91 [0.11, 7.55]

3.2 Shigella confirmada > 90% (subgrupo)

2

237

Cociente de riesgos (M-H, efectos aleatorios, IC del 95%)

0.91 [0.11, 7.55]

3.3 Shigella confirmada < 90% (subgrupo)

1

120

Cociente de riesgos (M-H, efectos aleatorios, IC del 95%)

No estimable

4 Fracaso bacteriológico

5

1350

Cociente de riesgos (M-H, efectos aleatorios, IC del 95%)

0.74 [0.50, 1.11]

4.1 Todos los ensayos

5

450

Cociente de riesgos (M-H, efectos aleatorios, IC del 95%)

0.73 [0.33, 1.62]

1.2 Adultos (subgrupo)

1

127

Cociente de riesgos (M-H, efectos aleatorios, IC del 95%)

0.28 [0.08, 0.95]

4.3 Niños (subgrupo)

4

323

Cociente de riesgos (M-H, efectos aleatorios, IC del 95%)

0.95 [0.43, 2.09]

4.4 Shigella confirmada > 90% (subgrupo)

1

36

Cociente de riesgos (M-H, efectos aleatorios, IC del 95%)

5.56 [0.29, 108.16]

4.5 Shigella confirmada < 90% (subgrupo)

4

414

Cociente de riesgos (M-H, efectos aleatorios, IC del 95%)

0.65 [0.29, 1.43]

5 Desarrollo de complicaciones graves

2

90

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

0.89 [0.28, 2.85]

6 Eventos adversos graves

1

221

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

10.90 [0.61, 194.82]

7 Eventos adversos que llevan a la interrupción del tratamiento

1

127

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

1.02 [0.27, 3.89]

8 Otros eventos adversos

4

570

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

1.03 [0.77, 1.39]



Comparación 3. Fluoroquinolonas versus macrólidos

Título del subgrupo o resultado

Nº de estudiantes

Nº de participantes

Método estadístico

Tamaño del efecto

1 Diarrea en el seguimiento

2

189

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

0.6 [0.24, 1.49]

2 Fiebre en el seguimiento

2

189

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

0.33 [0.08, 1.35]

3 Tiempo hasta el cese de la sangre en las heces

1

113

Diferencia de medias (IV, efectos fijos, IC del 95%)

-0.20 [-0.68, 0.28]

4 Fracaso bacteriológico

1

76

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

0.33 [0.07, 1.55]

5 Otros eventos adversos

1

76

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

1.33 [0.32, 5.56]



Comparación 4. Cotrimoxazol versus betalactámicos

Título del subgrupo o resultado

Nº de estudiantes

Nº de participantes

Método estadístico

Tamaño del efecto

1 Diarrea en el seguimiento

2

89

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

0.59 [0.23, 1.49]

2 Fracaso bacteriológico

1

28

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

0.75 [0.20, 2.75]

3 Tiempo hasta el cese de la diarrea (horas)

1

61

Diferencia de medias (IV, efectos fijos, IC del 95%)

-0.20 [-15.10, 14.70]

4 Tiempo hasta el cese de la fiebre (horas)

1

61

Diferencia de medias (IV, efectos fijos, IC del 95%)

5.90 [-5.30, 17.10]

5 Tiempo hasta el cese de sangre visible en las heces

1

61

Diferencia de medias (IV, efectos fijos, IC del 95%)

2.80 [-12.71, 18.31]

6 Otros eventos adversos

2

89

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

0.81 [0.27, 2.45]



Comparación 5. Cotrimoxazol versus fluoroquinolonas (norfloxacino)

Título del subgrupo o resultado

Nº de estudiantes

Nº de participantes

Método estadístico

Tamaño del efecto

1 Fracaso bacteriológico

1

62

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

1.69 [0.64, 4.47]

2 Otros eventos adversos

1

62

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

2.82 [0.12, 66.62]



Comparación 6. Cotrimoxazol versus furazolidona

Título del subgrupo o resultado

Nº de estudiantes

Nº de participantes

Método estadístico

Tamaño del efecto

1 Diarrea en el seguimiento

1

101

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

0.71 [0.27, 1.84]



Comparación 7. Gentamicina oral versus ácido nalidíxico

Título del subgrupo o resultado

Nº de estudiantes

Nº de participantes

Método estadístico

Tamaño del efecto

1 Diarrea en el seguimiento

1

79

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

1.71 [0.98, 2.97]

2 Fiebre en el seguimiento

1

79

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

2.37 [1.11, 5.07]

3 Recaída bacteriológica

1

79

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

1.95 [0.64, 5.95]

4 Fracaso bacteriológico

1

79

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

2.1 [1.29, 3.42]



Comparación 8. Sulfonamidas versus tetraciclina

Título del subgrupo o resultado

Nº de estudiantes

Nº de participantes

Método estadístico

Tamaño del efecto

1 Diarrea en el seguimiento

1

60

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

7.68 [0.46, 128.12]

2 Fracaso bacteriológico

1

60

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

11.78 [0.73, 190.30]



Antecedentes

Primera publicación del protocolo: Número 4, 2007
Primera publicación de la revisión: Número 4, 2009

Contribuciones de los autores

PC concibió la revisión y redactó el protocolo. KVD, SMJ y SV ayudaron a desarrollar el protocolo. Dos equipos de autores (PC y KVD & SMJ y SV) seleccionaron los ensayos de forma independiente, evaluaron la calidad, extrajeron e introdujeron los datos. Todos los autores analizaron e interpretaron los resultados y redactaron la revisión final.

Declaraciones de interés

Ninguno conocido.

Fuentes de financiación

Recursos internos

  • Low Cost Effective Care Unit, Christian Medical College, Vellore, India.

  • South Asian Cochrane Network & Centre, Vellore, India.

Recursos externos

  • Department for International Development (DFID), UK.

  • Indian Council of Medical Research, India.

    For support and funding for the Prof. BV Moses and ICMR Advanced Centre for Research & Training in Evidence-Informed Healthcare

Diferencias entre el protocolo y la revisión

We intended to analyse combinations of an antibiotic drug versus another antibiotic drug of the same class or different drug classes. Comparisons of antibiotics within the same class were deferred to a subsequent review and thus 17 potential trials of this comparison were excluded from this review. The protocol was developed using Review Manager (RevMan) 4.2 and the review using RevMan 5 (Review Manager 2008). We intended to assess methodological quality of included studies using the methods described in Juni 2001. However, since the introduction of RevMan 5 (Review Manager 2008), a more detailed assessment of the risk of bias in included trials was undertaken, reported in 'Risk of bias' tables for each trial and graphically summarized in Figure 1 and Figure 2. We also used the GRADE profiler, version 3.2 (GRADE 2004) to create 'Summary of findings' tables for the primary outcomes in the review.

Had continuous data been summarised using geometric means, we would have combined them on the log scale using the generic inverse variance method and reported them on the natural scale.

Had outcomes been reported both at baseline and at a follow up or at trial endpoints, we would have extracted both the mean change from baseline and the standard deviation of this mean for each treatment group. We would also have extracted the means and standard deviation at baseline and follow up in each treatment group. If the data had been reported using geometric means, we would have recorded this information and extracted a standard deviation on the log scale.

Had count data been reported in trials, we intended to extract the total number of events in each group and the total amount of person-time at risk in each group. We also intended to record the total number of participants in each group. If this information was not available, we would have extracted alternative summary statistics such as rate ratios and confidence intervals if available. Again, if count data were presented as dichotomous outcomes, we would have extracted the number of participants in each intervention group and the number of participants in each intervention group who experienced at least one event. If count data were presented as continuous outcomes or as a time-to-event outcomes, we would have extracted the same information as outlined for continuous and time-to-event outcomes. Count data would have been compared using rate ratios when the total number of events in each group and the total amount of person-time at risk in each group are available, or by relative risks or weighted mean difference had the data been presented in dichotomous or continuous forms respectively. Hazard ratios from survival data would have been combined on the log scale using the inverse variance method and presented on the natural scale.

Had time-to-event outcomes been reported, we would have extracted the estimates of the log hazard ratio and its standard error. If standard errors were not available we would have extracted alternative statistics such as CIs or P values.

Información de contacto

Authors: Prince RH Christopher1, Kirubah V David2, Sushil M John2, Venkatesan Sankarapandian2


1Christian Medical College, Family Medicine, , Vellore, India

2Christian Medical College, LCECU, , Vellore, India

Contact: Prince RH Christopher1 prince.christopher@gmail.com. Editorial group: Cochrane Infectious Diseases Group (HM-INFECTN)

Referencias

( * indica la publicación principal del estudio)

Referencias de los estudios incluidos en esta revisión

Alam 1994 {published data only}

Alam AN, Islam MR, Hossain MS, Mahalanabis D, Hye HKMA. Comparison of pivmecillinam and nalidixic acid in the treatment of acute shigellosis in children. Scandinavian Journal of Gastroenterology 1994; 29(4): 313-7.

Bennish 1990 {published data only}

Bennish ML, Salam MA, Haider R, Barza M. Therapy for shigellosis. II. Randomized, double-blind comparison of ciprofloxacin and ampicillin. Journal of Infectious Diseases 1990; 162(3): 711-6.

Bibile 1961 {published data only}

Bibile SW, Cooray MPM, Balasubramaniam K, Gulasekaram J. Comparative trial of drugs in bacillary dysentery. Journal of Tropical Medicine and Hygeine 1961; 64: 300-2.

Dutta 1995 {published data only}

Dutta P, Sett A, Sarkar A, Mitra U, Saha D, Manna B, et al. Comparative efficacy of furazolidone and nalidixic acid in the empirical treatment of acute invasive diarrhoea: randomised clinical trial. Indian Pediatrics 1995; 32(1): 13-9.

Gotuzzo 1989 {published data only}

Gotuzzo E, Oberhelman RA, Maguina C, Berry SJ, Yi A, Guzman M, et al. Comparison of single-dose treatment with norfloxacin and standard 5-day treatment with trimethoprim-sulphamethoxazole for acute shigellosis in adults. Antimicrobial Agents and Chemotherapy 1989; 33(7): 1101-4.

Haltalin 1973 {published data only (unpublished sought but not used)}

Haltalin KC, Nelson JD, Kusmiesz HT. Comparative efficacy of nalidixic acid and ampicillin for severe shigellosis. Archives of Disease in Childhood 1973; 48(4): 305-12.

Islam 1994 {published data only}

Islam MR, Alam AN, Hossain , MS , Mahalanabis D, Hye HK. Double-blind comparison of oral gentamicin and nalidixic acid in the treatment of acute shigellosis in children. Journal of Tropical Pediatrics 1994; 40(6): 320-5.

Kabir 1986 {published data only}

Kabir I, Butler T, Khanam A. Comparative efficacies of single intravenous doses of ceftriaxone and ampicillin for shigellosis in a placebo-controlled trial. Antimicrobial Agents and Chemotherapy 1986; 29(4): 645-8.

Khan 1997a {published data only}

Khan WA, Seas C, Dhar U, Salam MA, Bennish ML. Treatment of shigellosis: V. Comparison of Azithromycin and Ciprofloxacin: A Double-Blind, Randomized, Controlled Trial. Annals of Internal Medicine 1997; 126(9): 697-703.

Leibovitz 2000 {published data only}

Leibovitz E, Janco J, Piglansky L, Press J, Yagupsky P, Reinhart H, et al. Oral ciprofloxacin vs. intramuscular ceftriaxone as empiric treatment of acute invasive diarrhoea in children. Pediatric Infectious Disease Journal 2000; 19(11): 1060-7.

Nelson 1976a {published data only}

Nelson JD, Kusmiesz H, Jackson LH, Woodman E. Trimethoprim-sulfamethoxazole therapy for shigellosis. JAMA 1976; 235(12): 1239-43.

Prado 1993 {published data only}

Prado D, Liu H, Velasquez T, Cleary TG. Comparative efficacy of pivmecillinam and cotrimoxazole in acute shigellosis in children. Scandinavian Journal of Infectious Diseases 1993; 25(6): 713-9.

Rodriguez 1989 {published data only (unpublished sought but not used)}

Rodriguez RS, Chavez AZ, Galindo E. A randomised, controlled, single-blind study comparing furazolidone with trimethoprim-sulphamethoxazole in the empirical treatment of acute invasive diarrhoea. Scandinavian Journal of Gastroenterology. Supplement 1989; 169: 47-53.

Salam 1988 {published and unpublished data}

Salam MA, Bennish ML. Therapy for shigellosis. I. Randomised, double-blind trial of nalidixic acid in childhood shigellosis. Journal of Pediatrics 1988; 113(5): 901-7.

Salam 1998 {published data only}

Salam MA, Dhar U, Khan WA, Bennish ML. Randomised comparison of ciprofloxacin suspension and pivmecillinam for childhood shigellosis. Lancet 1998; 352: 522-7.

Shanks 1999 {published data only (unpublished sought but not used)}

Shanks GD, Smoak BL, Aleman GM, Oundo J, Waiyaki PG, Dunne MW, et al. Single dose of azithromycin or three-day course of ciprofloxacin as therapy for epidemic dysentery in Kenya. Clinical Infectious Diseases 1999; 29(4): 942-3.

Referencias de los estudios excluidos de esta revisión

Aoki 1987 {published data only}

Aoki T, Shimizu N, Tomizawa I, Takizawa Y, Matsubara Y, Seo T, et al. Comparison of clinical efficacy of norfloxacin (NFLX) and pipemidic acid (PPA) in the treatment of infectious enteritis by a double-blind method. Journal of the Japanese Association for Infectious Diseases 1987; 61(7): 830-48.

Aoki 1989 {published data only}

Aoki T, Shimizu N, Tomizawa I, Takizawa Y, Matsubara Y, Nitta Y, et al. Comparison of clinical efficacy of lomefloxacin (LFLX, NY-198) and pipemidic acid (PPA) in the treatment of infectious enteritis by a double-blind method. Journal of the Japanese Association for Infectious Diseases 1989; 63(6): 606-22.

Ashkenazi 1993 {published data only}

Ashkenazi S, Amir J, Waisman Y, Rachmel A, Garty BZ, Samra Z, et al. A randomised, double-blind study comparing cefixime and trimethoprim-sulphamethoxazole in the treatment of childhood shigellosis. The Journal of Pediatrics 1993; 123(5): 817-21. [: ISSN: CN-00096970]

Barada 1980 {published data only}

Barada FA, Guerrant RL. Sulfamethoxazole-trimethoprim versus ampicillin in treatment of acute invasive diarrhoea in adults. Antimicrobial Agents and Chemotherapy 1980; 17(6): 961-4.

Bassily 1994 {published data only}

Bassily S, Hyams K C, el Masry NA, Farid Z, Cross E, Bourgeois AL, Ayad E, Hibbs RG. Short-course norfloxacin and trimethoprim-sulphamethoxazole treatment of shigellosis and salmonellosis in Egypt. American Journal of Tropical Medicine and Hygiene 1994; 51(2): 219-23.

Basualdo 2003 {published data only}

Basualdo W, Arbo A. Randomized comparison of azithromycin versus cefixime for treatment of shigellosis in children. Pediatric Infectious Disease Journal 2003; 22(4): 374-7.

Bennish 1992 {published data only}

Bennish ML, Salam MA, Khan WA, Khan AM. Treatment of shigellosis: III. Comparison of one- or two-dose ciprofloxacin with standard 5-day therapy. A randomised, blinded trial. Annals of Internal Medicine 1992; 117(9): 727-34.

Bezjak 1966 {published data only}

Bezjak B, Breitenfeld V. Therapy of shigellosis and chronic intestinal amoebiasis with enterosediv [Die Therapie der Shigellose und der chronischen Intestinal amoebiasis mit Enterosediv]. Therapie Der Gegenwart 1966; 103(9): 1129-36.

Bhattacharya 1991 {published data only}

Bhattacharya SK, Bhattacharya MK, Dutta P, Sen D, Rasaily R, Moitra A, et al. Randomized clinical trial of norfloxacin for shigellosis. American Journal of Tropical Medicine and Hygiene 1991; 45(6): 683-7.

Bhattacharya 1992 {published data only}

Bhattacharya MK, Nair GB, Sen D, Paul M, Debnath A, Nag A, et al. Efficacy of norfloxacin for shigellosis: a double-blind randomised clinical trial. Journal of Diarrhoeal Diseases Research 1992; 10(3): 146-50.

Bhattacharya 1997 {published data only}

Bhattacharya K, Bhattacharya MK, Dutta D, Dutta S, Deb M, Deb A, et al. Double-blind, randomised clinical trial for safety and efficacy of norfloxacin for shigellosis in children. Acta Paediatrica 1997; 86(3): 319-20.

Bogaerts 1985 {published data only}

Bogaerts J, Habyalimana JB, Chevolet T, Vandepitte J. Treatment of severe bacillary dysentery with trimethoprim alone. Transactions of the Royal Society of Tropical Medicine and Hygiene 1985; 79(2): 203-5.

Browne 1983 {published data only}

Robins-Browne RM, Coovadia HM, Bodasing MN, Mackenjee MKR. Treatment of acute nonspecific gastroenteritis of infants and young children with erythromycin. American Journal of Tropical Medicine and Hygiene. 1983; 32(4): 886-90.

Brugel 1950 {published data only}

Brügel H. On the treatment of bacillary dysentery with phages specific for the endemic infection [Über die Behandlung der Bazillen-Ruhr mit epidemiespezifischen Ruhrphagen]. Deutsche Medizinische Wochenschrift 1950; 75(51): 1751-2.

Butler 1993 {published data only}

Butler T, Lolekha S, Rasidi C, Kadio A, del Rosal PL, Iskandar H, et al. Treatment of acute bacterial diarrhoea: a multicenter international trial comparing placebo with fleroxacin given as a single dose or once daily for 3 days. American Journal of Medicine 1993; 94(3A): 187S-194S.

Cabada 1992 {published data only}

de la Cabada FJ, DuPont HL, Gyr K, Mathewson JJ. Antimicrobial therapy of bacterial diarrhoea in adult residents of Mexico - lack of an effect. Digestion 1992; 53(3-4): 134-41.

Camacho 1989 {published data only}

Camacho JLP. A comparison of furazolidone and ampicillin in the treatment of invasive diarrhoea. Scandinavian Journal of Gastroenterology. 1989; 16(Suppl): 954-9.

CDC 2006 {published data only}

Centers for Disease Control and Prevention. Update on emerging infections: news from the Centers for Disease Control and Prevention. Annals of Emergency Medicine 2006; 47(1): 106-9.

Chang 1977 {published data only}

Chang MJ, Dunkle LM, Van Reken D, Anderson D, Wong ML, Feigin RD. Trimethoprim-sulfamethoxazole compared to ampicillin in the treatment of shigellosis. Pediatrics 1977; 59(5): 726-9.

de Olarte 1974 {published data only}

Garcia de Olarte D, Trujillo H, Agudelo N, Nelson JD, Haltalin KC. Treatment of diarrhoea in malnourished infants and children. A double-blind study comparing ampicillin and placebo. American Journal of Diseases of Children 1974; 127(3): 379-88.

Dryden 1996 {published data only}

Dryden MS, Gabb RJ, Wright SK. Empirical treatment of severe acute community-acquired gastroenteritis with ciprofloxacin. Clinical Infectious Diseases 1996; 22(6): 1019-25.

Dumitriu 1992 {published data only}

Dumitriu S, Dumitriu M, Dimitriu SM, Turcu T, Grigore L, Dumitriu D, et al. Bioactive polymers: in vitro and in vivo study of controlled release neomycin. Journal of Biomaterials Applications 1992; 6(3): 251-60.

DuPont 1973 {published data only}

DuPont HL, Hornick RB. Adverse effect of lomotil therapy in shigellosis. JAMA 1973; 226(13): 1525-8.

DuPont 1982 {published data only}

DuPont HL, Reves RR, Galindo E, Sullivan PS, Wood LV, Mendiola JG. Treatment of travellers' diarrhoea with trimethoprim/sulphamethoxazole and with trimethoprim alone. New England Journal of Medicine 1982; 307(14): 841-4.

DuPont 1983 {published data only}

Dupont HL, Ericsson CD, Galindo E, Dupont MW, Mendiola Gomez J. Antimicrobial therapy of travellers' diarrhoea. Scandinavian Journal of Gastroenterology 1983; 84(Suppl): 99-105.

DuPont 1984 {published data only}

DuPont HL, Ericsson CD, Galindo E, Wood LV, Morgan D, Bitsura JA, et al. Furazolidone versus ampicillin in the treatment of traveller's diarrhoea. Antimicrobial Agents and Chemotherapy 1984; 26(2): 160-3.

DuPont 1986 {published data only}

DuPont HL, Ericsson CD, Reves RR, Galindo E. Antimicrobial therapy for travellers' diarrhoea. Reviews of Infectious Diseases 1986; 8(Suppl 2): S217-22.

DuPont 1992 {published data only}

DuPont HL, Ericsson CD, Mathewson JJ, DuPont MW. Five versus three days of ofloxacin therapy for traveller's diarrhoea: a placebo-controlled study. Antimicrobial Agents and Chemotherapy 1992; 36(1): 87-91.

DuPont 1992a {published data only}

DuPont HL, Ericsson CD, Mathewson JJ, de la Cabada FJ, Conrad DA. Oral aztreonam, a poorly absorbed yet effective therapy for bacterial diarrhoea in US travellers to Mexico. JAMA 1992; 267(14): 1932-5.

Ekwall 1984 {published data only}

Ekwall E, Jonsson M. A comparison of the combination pivmecillinam/pivampicillin and co-trimoxazole in the treatment of convalescent carriers of Salmonella and Shigella. Scandinavian Journal of Infectious Diseases 1984; 16(1): 99-102.

Ericsson 1983 {published data only}

Ericsson CD, DuPont HL, Sullivan P, Galindo E, Evans DG, Evans DJJr. Bicozamycin, a poorly absorbable antibiotic, effectively treats travellers' diarrhoea. Annals of Internal Medicine 1983; 98(1): 20-5.

Ericsson 1992 {published data only}

Ericsson CD, Nicholls-Vasquez I, DuPont HL, Mathewson JJ. Optimal dosing of trimethoprim-sulphamethoxazole when used with loperamide to treat traveller's diarrhoea. Antimicrobial Agents and Chemotherapy 1992; 36(12): 2821-4.

Fakouhi 1971 {published data only}

Fakouhi T, Post C, Dutz W. Clinical trial with sulphamethoxazole-trimethoprim in infantile gastroenteritis. Current Therapeutic Research, Clinical and Experimental 1971; 13(1): 13-7.

Gendrel 1997 {published data only}

Gendrel D, Moreno JL, Nduwimana M, Baribwira C, Raymond J. One-dose treatment with pefloxacin for infection due to multidrug-resistant Shigella dysenteriae type I in Burundi. Clinical Infectious Diseases 1997; 24(1): 83.

Gilman 1980 {published data only}

Gilman RH, Koster F, Islam S, McLaughlin J, Rahaman MM. Randomized trial of high- and low-dose ampicillin therapy for treatment of severe dysentery due to Shigella dysenteriae type 1. Antimicrobial Agents and Chemotherapy 1980; 17(3): 402-5.

Gilman 1981 {published data only}

Gilman RH, Spira W, Rabbani H, Ahmed W, Islam A, Rahaman MM. Single-dose ampicillin therapy for severe shigellosis in Bangladesh. Journal of Infectious Diseases 1981; 143(2): 164-9.

Goodman 1990 {published data only}

Goodman LJ, Trenholme GM, Kaplan RL, Segreti J, Hines D, Petrak R, et al. Empiric antimicrobial therapy of domestically acquired acute diarrhoea in urban adults. Archives of Internal Medicine 1990; 150(3): 541-6.

Ha 2008 {unpublished data only}

Ha V. A randomised controlled trial of gatifloxacin versus ciprofloxacin for the treatment of bacillary dysentery in children. http://isrctn.org/ISRCTN55945881 (accessed 14 October 2008). [: ISRCTN55945881; Wellcome Trust reference: 061330]

Haltalin 1967 {published data only}

Haltalin KC, Nelson JD, Ring R, Sladoje M, Hinton LV. Double-blind treatment study of shigellosis comparing ampicillin, sulphadiazine, and placebo. Journal of Pediatrics 1967; 70(6): 970-81.

Haltalin 1968 {published data only}

Haltalin KC, Nelson JD, Hinton LV, Kusmiesz HT, Sladoje M. Comparison of orally absorbable and non-absorbable antibiotics in shigellosis. A double-blind study with ampicillin and neomycin. The Journal of Pediatrics 1968; 72(5): 708-20.

Haltalin 1968a {published data only}

Haltalin KC, Nelson JD, Kusmiesz HT, Hinton LV. Comparison of intramuscular and oral ampicillin therapy for shigellosis. Journal of Pediatrics 1968; 73(4): 617-22.

Haltalin 1969 {published data only}

Haltalin KC, Nelson JD, Kusmies , HT , Hinton LV. Optimal dosage of ampicillin for shigellosis. The Journal of Pediatrics 1969; 74(4): 626-31.

Haltalin 1972 {published data only}

Haltalin KC, Nelson JD. Failure of furazolidone therapy in shigellosis. American Journal of Diseases of Children 1972; 123(1): 40-4.

Haltalin 1972a {published data only}

Haltalin KC, Kusmiesz HT, Hinton LV, Nelson JD. Treatment of acute diarrhoea in outpatients. Double-blind study comparing ampicillin and placebo. American Journal of Diseases of Children 1972; 124(4): 554-61.

Han 1998 {published data only}

Han CR, Li SL, Luo DD. Comparation of rufloxacin with homefloxacin in 30 cases of bacillary dysentery. Journal of Clinical Internal Medicine 1998; 15(2): 88.

Hansson 1981 {published data only}

Hansson HB, Barkenius G, Cronberg S, Juhlin I. Controlled comparison of nalidixic acid or lactulose with placebo in shigellosis. Scandinavian Journal of Infectious Diseases 1981; 13(3): 191-3.

Helvaci 1998 {published data only}

Helvaci M, Bektaslar D, Ozkaya B, Yaprak I, Umurtak B, Ertugrul A. Comparative efficacy of cefixime and ampicillin-sulbactam in shigellosis in children. Acta Paediatrrica Japonica 1998; 40: 131-4.

Hiraishi 1980 {published data only}

Hiraishi K, Matsubara Y. Comparison of clinical efficacy of fosfomycin (FOM) and kanamycin (KM) in bacillary dysentery by double blind method. Kansenshogaku Zasshi. Journal of the Japanese Association for Infectious Diseases 1980; 54(7): 343-52.

Imagawa 1988 {published data only}

Imagawa Y, Tomizawa I, Takizawa Y, Ito K, Matsubara Y, Seo T, et al. Comparison of clinical efficacy of ciprofloxacin (CPFX, BAY o 9867) and pipemidic acid (PPA) in the treatment of infectious enteritis by a double-blind method. Journal of the Japanese Association for Infectious Diseases 1988; 62(4): 322-39.

Iushchuk 2007 {published data only}

Iushchuk ND, Maev IV, Mar'ianovskaia TV, Gagarina IV. Using neosmectin in the complex therapy of patients with acute intestinal infections. Experimental & Clinical Gastroenterology 2007; 2: 126-30.

Jiang 1994 {published data only}

Jiang SC, Wang XF, Miao JZ. Clinical efficacy of ciprofloxacin and ofloxacin. Chinese Journal of Internal Medicine 1994; 33(7): 444-8.

Jiang 2000 {published data only}

Jiang XP, Ye Y. Therapeutic effect of phosphonomycin combined with another antibiotic on shigellosis. Journal of Clinical Internal Medicine 2000; 17(1): 48.

Jinhua 1992 {published data only}

Jinhua L, Ziaofeng W, Suchum J. Effect observation of pefloxacin in treatment of 64 patients with acute bacillary dysentery. Chinese Journal of Infectious Diseases 1992; 10(Suppl 2): 116-8.

Kabir 1984 {published data only}

Kabir I, Rahaman MM, Ahmed SM, Akhter SQ, Butler T. Comparative efficacies of pivmecillinam and ampicillin in acute shigellosis. Antimicrobial Agents and Chemotherapy 1984; 25(5): 643-5.

Legros 2004 {published data only}

Legros D, Fontaine O. Shigellosis: report of a workshop, held at ICDDR,B: Centre for Health and Population Research, Dhaka, Bangladesh, on 16-18 February 2004. Journal of Health, Population & Nutrition 2004; 22(4): 445-9.

Lexomboon 1972 {published data only}

Lexomboon U, Mansuwan P, Duangmani C, Benjadol P, M'cMinn MT. Clinical evaluation of cotrimoxazole and furazolidone in treatment of shigellosis in children. British Medical Journal 1972; 3(5817): 23-6.

Lionel 1969 {published data only}

Lionel ND, Abeyasekera FJ, Samarasinghe HG, Goonewardena CV, Tawil GS. A comparison of a single dose and a five day course of tetracycline therapy in bacillary dysentery. Journal of Tropical Medicine and Hygiene 1969; 72(7): 170-2.

Lolekha 1988 {published data only}

Lolekha S, Patanachareon S, Thanangkul B, Vibulbandhitkit S. Norfloxacin versus co-trimoxazole in the treatment of acute bacterial diarrhoea: a placebo controlled study. Scandinavian Journal of Infectious Diseases. Supplementum 1988; 56: 35-45.

Lolekha 1991 {published data only}

Lolekha S, Vibulbandhitkit S, Poonyarit P. Response to antimicrobial therapy for shigellosis in Thailand. Reviews of Infectious Diseases 1991; 13(Suppl 4): S342-6.

Mabadeje 1974 {published data only}

Mabadeje AF. A controlled clinical trial of trimethoprim-sulphamethoxazole in shigella dysentery. Journal of Tropical Medicine and Hygiene 1974; 77(3): 50-4.

Mahllooji 2004 {published data only}

Mahllooji KH. A comparative study of cefixime and nalidixic acid, against Shigella in Children Hospital Medical Center of Ali Asghar in Tehran-Iran during 1999. International Journal of Infectious Diseases 2004; 8(Suppl 1): S17.

Martin 2000 {published data only}

Martin JM, Pitetti R, Maffei R, Tritt J, Smail K, Wald ER. Treatment of shigellosis with cefixime: two days vs. five days. Pediatric Infectious Diseases Journal 2000; 19: 522-6.

Matsuoka 1995 {published data only}

Matsuoka Y, Irimajiri S, Obana M, Tomizawa I, Takizawa Y, Nitta Y, et al. Clinical study on the effects of grepafloxacin on infectious enteritis assessment of the fecal drug level and intestinal bacterial flora in a patient with infectious enteritis. Japanese Journal of Chemotherapy 1995; 43(Suppl 1): 319-32.

Miles 1977 {published data only}

Miles RN. Bacillary dysentery in Cyprus. Journal of the Royal Army Medical Corps 1977; 12: 342-4.

Mol 1987 {published data only}

De Mol P, Mets T, Lagasse R, Vandepitte J, Mutwewingabo A, Butzler JP. Treatment of bacillary dysentery: a comparison between enoxacin and nalidixic acid. Journal of Antimicrobial Chemotherapy 1987; 19(5): 695-8.

Moolasart 1999 {published data only}

Moolasart P, Eampokalap B, Ratanasrithong M. Comparison of the efficacy of ceftibuten and norfloxacin in the treatment of acute gastrointestinal infection in children. Southeast Asian Journal of Tropical Medicine and Public Health 1999; 30(4): 764-9.

Morisawa 1970 {published data only}

Morisawa T. Clinical effects of Diromo on intestinal diseases (studies by double blind test). Japanese Archives of Internal Medicine 1970; 17(4): 99-102.

Motohiro 1982 {published data only}

Motohiro T, Sakata Y, Fujimoto T. Evaluation of the effect of pipemidic acid on enteritis. A double blind controlled study compared with piromidic acid. Chemotherapy 1982; 30(2): 125-48.

Nelson 1975 {published data only}

Nelson JD, Haltalin KC. Comparative efficacy of cephalexin and ampicillin for shigellosis and other types of acute diarrhoea in infants and children. Antimicrobial Agents and Chemotherapy 1975; 7(4): 415-20.

Nelson 1976 {published data only}

Nelson JD, Kusmiesz H, Jackson LH. Comparison of trimethoprim-sulphamethoxazole and ampicillin therapy for shigellosis in ambulatory patients. Journal of Pediatrics 1976; 89(3): 491-3.

Nikorowitsch 1978 {published data only}

Nikorowitsch E. Length of stay in the hospital in shigella and salmonella infections treated with furazolidone and without any antimicrobial chemotherapy [Krankenhausverweildauer von Shigellosen und Salmonellosen bei Behandlung mit Furazolidon und ohne antimikrobielle Chemotherapie]. Zeitschrift Für Die Gesamte Innere Medizin Und Ihre Grenzgebiete 1978; 33(2): 51-4.

Oldfield 1987 {published data only}

Oldfield EC, Bourgeois AL, Omar AK, Pazzaglia GL. Empirical treatment of Shigella dysentery with trimethoprim: five day course vs. single dose. American Journal of Tropical Medicine and Hygiene 1987; 37(3): 616-23.

Orenstein 1981 {published data only}

Orenstein WA, Ross L, Overturf GD, Wilkins J, Redfield DR, Underman A. Antibiotic treatment of acute shigellosis: failure of cefamandole compared with trimethoprim-sulphamethoxazole and ampicillin. American Journal of the Medical Sciences 1981; 282(1): 27-33.

Ostrower 1979 {published data only}

Ostrower VG. Comparison of cefaclor and ampicillin in the treatment of shigellosis. Postgraduate Medical Journal 1979; 55(Suppl): 482-4.

Petruccelli 1992 {published data only}

Petruccelli BP, Murphy GS, Sanchez JL, Walz S, DeFraites R, Gelnett J, et al. Treatment of traveller's diarrhoea with ciprofloxacin and loperamide. Journal of Infectious Diseases 1992; 165(3): 557-60.

Pichler 1986 {published data only}

Pichler H, Diridl G, Wolf D. Ciprofloxacin in the treatment of acute bacterial diarrhoea: a double blind study. European Journal of Clinical Microbiology 1986; 5(2): 241-3.

Pichler 1987 {published data only}

Pichler HE, Diridl G, Stickler K, Wolf D. Clinical efficacy of ciprofloxacin compared with placebo in bacterial diarrhoea. American Journal of Medicine 1987; 82(4A): 329-32.

Prado 1981 {published data only}

Prado V, Cohen J, Harun A, Aguirre X, Diaz C. Comparative randomised study on the clinico-bacteriological effectiveness of mecillinam versus cotrimoxazole in shigellosis. Revista Chilena de Pediatría 1981; 52(2): 118-24.

Prado 1992 {published data only}

Prado D, Lopez E, Liu H, Devoto S, Woloj M, Contrini M, et al. Ceftibuten and trimethoprim-sulphamethoxazole for treatment of Shigella and enteroinvasive Escherichia coli disease. Pediatric Infectious Disease Journal 1992; 11(8): 644-7.

Rabbani 1982 {published data only}

Rabbani GH, Gilman RH, Spira WM. Single dose ampicillin therapy for the treatment of Shigellosis in Bangladesh. Southeast Asian Journal of Tropical Medicine and Public Health 1982; 13(3): 505-6.

Rakhmanova 1996 {published data only}

Rakhmanova AG, Kulikov VP. Treatment of Flexner's dysentery with ofloxacin [Lechenie dizenterii Fleksnera ofloksatsinom]. Antibiotiki i Khimioterapii 1996; 41(9): 95.

Raqib 2008 {unpublished data only}

Raqib R. Therapeutic induction of endogenous antibiotics for improved recovery in shigellosis. http://clinicaltrials.gov/show/NCT00800930 (accessed 9 December 2008).

Rogerie 1986 {published data only}

Rogerie F, Ott D, Vandepitte J, Verbist L, Lemmens P, Habiyaremye I. Comparison of norfloxacin and nalidixic acid for treatment of dysentery caused by Shigella dysenteriae type 1 in adults. Antimicrobial Agents and Chemotherapy 1986; 29(5): 883-6.

Sagara 1993 {published data only}

Sagara H, Tomizawa I, Takizawa Y, Yamaguchi T, Masuda G, Negishi I, et al. Clinical study of temafloxacin on infectious enteritis. Chemotherapy 1993; 41(Suppl. 5): 464-78.

Sagara 1994 {published data only}

Sagara H, Tomizawa I, Takizawa Y, Nitta Y, Tsunoda T, Yamaguchi T, et al. Basic and clinical studies of fleroxacin on infectious enteritis. Research Group of AM-833 on infectious enteritis. Kansenshogaku Zasshi. Journal of the Japanese Association for Infectious Diseases 1994; 68(11): 1390-408.

Saito 1983 {published data only}

Saito M, Tomizawa I, Konishi K, Takizawa Y, Matsubara Y, Seo T, et al. Comparison of clinical efficacy of pipemidic acid (PPA) and kanamycin (KM) in bacillary dysentery by double blind method. Kansenshogaku Zasshi 1983; 57(4): 303-17.

Saito 1984 {published data only}

Saito M, Seo T, Matsubara Y, Tomizawa I, Takizawa Y, Ito K, et al. Comparison of clinical efficacy of ofloxacin COFLX: DL-8280) and pipemidic acid (PPA) in acute infectious diarrhoea by a double-blind method. Kansenshogaku Zasshi. Journal of the Japanese Association for Infectious Diseases 1984; 58(10): 965-81.

Salam 1995 {published data only}

Salam MA, Seas C, Khan WA, Bennish ML. Treatment of shigellosis: IV. Cefixime is ineffective in shigellosis in adults. Annals of Internal Medicine 1995; 123(7): 505-8.

Salam 1999 {published data only}

Salam MA, Khan WA, Dhar U, Ronan A, Rollins NC, Bennish ML, et al. Vitamin A for treating shigellosis. BMJ 1999; 318(7188): 939-40.

Sepp 1995 {published data only}

Sepp E, Tamm E, Torm S, Lutsar I, Mikelsaar M, Salminen S. Impact of a Lactobacillus probiotic on the faecal microflora in children with Shigellosis. Microecology and Therapy 1995; 23: 74-80.

Seto 1992 {published data only}

Seto WH, Lau FL, Gotuzzo EH, Carillo C. Lomefloxacin versus trimethoprim/sulphamethoxazole in the treatment of adults with acute bacterial diarrhoea. International Journal of Antimicrobial Agents 1992; 2(1): 61-6.

Soares 1994 {published data only}

Soares JL, Arendt V, Coue JC, Milleliri JM, Philips B, Regis R, et al. Short-term ciprofloxacin treatment of bacillary dysentery due to Shigella dysenteriae type 1 in Rwandan refugees [Traitement court par la ciprofloxacine de la dysenterie bacillaire à Shigella dysenteriae type 1 chez des réfugiés Ruandais]. Médecine Tropicale: Revue Du Corps De Santé Colonial 1994; 54(4): 319-23.

Soares 1996 {published data only}

Soares JL, Milleliri JM, Pigny N, Dupoux J, Coue JC. Efficacy of bacillare dysentery's treatment by lomefloxacine amongst Rwandese refugees in North Zaire [Efficacité du traitement de la dysenterie bacillaire par lomefloxacine chez des refugies au Nord-Zaire]. Medecine et Maladies Infectieuses 1996; 26(2): 141-4.

Study Group 2002 {published data only}

Zimbabwe , Bangladesh , South Africa (Zimbasa) Dysentery Study Group. Multicenter, randomised, double blind clinical trial of short course versus standard course oral ciprofloxacin for Shigella dysenteriae type 1 dysentery in children. Pediatric Infectious Disease Journal 2002; 21(12): 1136-41.

Tian 1986 {published data only}

Tian HY, Zhang XM, Zhou JQ. Effectiveness of swertia davidi and TMP in treating 75 cases of acute bacillary dysentery. Chinese Journal of Integrated Traditional and Western Medicine 1986; 6(1): 34-5.

Tong 1970 {published data only}

Tong MJ, Martin DG, Cunningham JJ, Gunning JJ. Clinical and bacteriological evaluation of antibiotic treatment in shigellosis. JAMA 1970; 214(10): 1841-4.

Varsano 1991 {published data only}

Varsano I, Eidlitz-Marcus T, Nussinovitch M, Elian I. Comparative efficacy of ceftriaxone and ampicillin for treatment of severe shigellosis in children. Journal of Pediatrics 1991; 118(4 (Pt 1)): 627-32.

Vinh 2000 {published data only}

Vinh H, Wain J, Chinh MT, Tam CT, Trang PT, Nga D, et al. Treatment of bacillary dysentery in Vietnamese children: two doses of ofloxacin versus 5-days nalidixic acid. Transactions of the Royal Society of Tropical Medicine and Hygiene 2000; 94(3): 323-6.

Wistrom 1992 {published data only}

Wistrom J, Jertborn M, Ekwall E, Norlin K, Soderquist B, Stromberg A, et al. Swedish study Group. Empiric treatment of acute diarrhoeal disease with norfloxacin. A randomised, placebo-controlled study.. Annals of Internal Medicine 1992; 117(3): 202-8.

Xiouying 1986 {published data only}

Xiouying WU, Juanfeng LU, Ruiyun YE. Therapeutic effect of pipemidic acid in the treatment of bacillary dysentery in children. Chinese Journal of Infectious Diseases 1986; 4(Suppl 4): 736-7.

Yamamoto 1973 {published data only}

Yamamoto T, Tsunoda O, Sugiyama S, Nakajima K, Akao M. Effects of lividomycin on bacillary dysentery and related disorders. Comparison with the effects of kanamycin by a double blind method. Kansenshogaku Zasshi. Journal of the Japanese Association for Infectious Diseases 1973; 47(2): 35-43.

Ye 1990 {published data only}

Ye XL, Cao YX, Xu JS, Wu KY, Shi XY. Multi-drug-resistant Shigella infections in Fujian Province, China. Journal of Diarrhoeal Diseases Research 1990; 8(3): 99.

Yin 1998 {published data only}

Lu Y, Cheng GX. A clinical investigation of treatment of acute bacillary dysentery with ceftriaxone in 84 children. New Chinese Medicine 1998; 29(3): 130-1.

Yunus 1982 {published data only}

Yunus M, Rahman ASMM, Farooque AS, Glass RI. Clinical trial of ampicillin v. trimethoprim sulphamethoxazole in the treatment of Shigella dysentery. Journal of Tropical Medicine and Hygiene 1982; 85(5): 195-9.

Yuying 1995 {published data only}

Yuying M, Guirong L, Guiqing D, Shuying Y. Clinical efficacy of ciprofloxacin in the treatment of 29 cases acute bacterial dysentery. Chinese Journal of Antibiotics 1995; 20(2): 110-1.

Zhang 1991 {published data only}

Zhang YY, Zhun BY, Jiang SC. Clinical evaluation of enoxacin. Chinese Journal of Internal Medicine 1991; 30(8): 480-3, 521.

Referencias de los estudios en espera de evaluación

Carbo 1981 {published data only}

Carbo L. Report of a clinical study of the therapeutic agent Ro/12/2510 vs. ampicillin in acute bacillary dysentery by Shigella [Reporte del estudio clinico del agente terapeutico Ro-12-2510 vs. ampicilina en cuadros de disenteria bacilar aguda por Shigella]. Investigación Médica Internacional 1981; 8(2): 191-3.

Referencias adicionales

Baer 1999

Baer JT, Vugia DJ, Reingold AL, Aragon T, Angulo FJ, Bradford WZ. HIV infection as a risk factor for shigellosis. Emerging Infectious Diseases 1999; 5(6): 820-3.

BNF 2007

British National Formulary (BNF 53). www.bnf.org/bnf March 2007 (accessed 13 June 2007).

Bogaerts 1983

Bogaerts J, Verhaegen J, Munyabikali JP, Mukantabana B, Lemmens P, Vandeven J, et al. Antimicrobial resistance and serotypes of Shigella isolates in Kigali, Rwanda (1983 to 1993): increasing frequency of multiple resistance. Diagnostic Microbiology and Infectious Disease 1997; 28(4): 165-71.

CDC 2005

Center for Disease Control and Prevention, Division of Bacterial and Mycotic Diseases. Shigellosis. www.cdc.gov/node.do/id/0900f3ec8000755c 13 October 2005 (accessed 13 June 2007).

CONSORT 2008

The CONSORT Statement. Available at http://www.consort-statement.org (accessed 15 November 2008).

Datta 2003

Datta D, Bhattacharya MK, Dutta S, Daatta A, Sarkar D, Bhandra B. Emergence of multidrug resistant Shigella dysenteriae type 1 causing sporadic outbreak in and around Kolkata, India. Journal of Health, Population, and Nutrition 2003; 21(1): 79-80.

Deeks 2005

Deeks JJ, Higgins , JPT , Altman DG, editors. Analysing and presenting results. In: Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions 4.2.5 [updated May 2005]; Section 8. www.cochrane.org/resources/handbook/hbook.htm (accessed 31 May 2005).

Dutta 2002

Dutta S, Rajendran K, Roy S, Chatterjee A, DuttaP , Nair GB, et al. Shifting serotypes, plasmid profile analysis and antimicrobial resistance pattern of shigellae strains isolated from Kolkata, India during 1995-2000. Epidemiology and infection 2002; 129(2): 235-43.

GRADE 2004

Jan Brozek, Andrew Oxman, Holger Schünemann. GRADEpro. 3.2 for Windows. GRADE Working Group, 2004.

Gupta 2004

Gupta A, Polyak CS, Bishop RD, Sobel J, Mintz ED. Laboratory-confirmed shigellosis in the United States, 1989-2002: epidemiologic trends and patterns. Clinical Infectious Diseases 2004; 38(10): 1372-7.

Higgins 2008

Higgins JPT, Altman DG (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 (updated September 2008). The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org.

Huebner 1993

Huebner J, Czerwenka W, Gruner E, von Graevenitz A. Shigellemia in AIDS patients: case report and review of the literature. Infection 1993; 21(2): 122-4.

Juni 2001

Juni P, Altman DG, Egger M. Systematic reviews in health care: assessing the quality of controlled clinical trials. BMJ 2001; 323(7303): 42-6.

Kosek 2008

Kosek M, Yori PP, Pan WK, Olortegui MP, Gilman RH, Perez J, et al. Epidemiology of highly endemic multiply antibiotic-resistant shigellosis in children in the Peruvian Amazon. Pediatrics 2008; 122: e541-9.

Kotloff 1999

Kotloff KL, Winickoff JP, Ivanoff B, Clemens JD, Swerdlow DL, Sansonetti PJ, et al. Global burden of Shigella infections: implications for vaccine development and implementation of control strategies. Bulletin of the World Health Organization 1999; 77(8): 651-66.

Kuo 2008

Kuo CY, Su LH, Perera J, Carlos C, Tan BH, Kumarasinghe G, et al. Antimicrobial susceptibility of Shigella isolates in eight Asian countries, 2001-2004. Journal of Microbiology, Immunology and Infection 2008; 41: 107-11.

Mates 2000

Mates A, Eyny D, Philo S. Antimicrobial resistance trends in Shigella serogroups isolated in Israel, 1990 - 1995. European Journal of Clinical Microbiology & Infectious Diseases 2000; 19(2): 108-11.

Niyogi 2005

Niyogi SK. Shigellosis. Journal of Microbiology 2005; 43(2): 133-43.

Park 2005

Park K. Park's textbook of preventive and social medicine. . Jabalpur: M/S Banarsidas Bhanot Publishers, 2005.

Pazhani 2004

Pazhani GP, Sarkar B, Ramamurthy T, Bhattacharya SK, Takeda Y, et al. Clonal multidrug-resistant Shigella dysenteriae type 1 strains associated with epidemic and sporadic dysenteries in eastern India. Antimicrobial Agents and Chemotherapy 2004; 48(2): 681-4.

Pazhani 2008

Pazhani GP, Niyogi SK, Singh AK, Sen B, Taneja N, Kundu M, et al. Molecular characterization of multidrug-resistant Shigella species isolated from epidemic and endemic cases of shigellosis in India. Journal of Medical Microbiology 2008; 57: 856-63.

Review Manager 2008

The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.0. The Nordic Cochrane Centre, The Cochrane Collaboration, 2008.

Sarkar 2003

Sarkar K, Ghosh S, Nujogi SK, Bhattacharya SK. Shigella dysenteriae type 1 with reduced susceptibility to flouroquinolones. Lancet 2003; 361(9359): 785.

Shane 2003

Shane AL, Tucker NA, Crump JA, Mintz ED, Painter JA. Sharing Shigella: risk factors and costs of a multi-community outbreak of shigellosis. Archives of Pediatric and Adolescent Medicine 2003; 157(6): 601-3.

Shiferaw 2004

Shiferaw B, Shallow S, Marcus R, Segler S, Soderlund D, Hardnett FP, et al. Emerging Infections Program FoodNet Working Group. Trends in population-based active surveillance for shigellosis and demographic variability in FoodNet sites, 1996-1999. Clinical Infectious Diseases 2004; 38 Suppl 3: 175-80.

Sinha 1987

Sinha AK, Bhattacharya SK, Sen D, Sengupta PG, Pal SC. Leukemoid reaction in Shigella dysenteriae type 1 infections. Indian Journal of Medical Research 1987; 85: 500-2.

Sire 2008

Sire JM, Macondo EA, Clude JDPG, Siby T, Bahsoun I, Seck A, et al. Antimicrobial resistance in Shigella species isolated in Dakar, Senegal (2004-2006). Japanese Journal of Infectious Disease 2008; 61: 307-9.

StatCalc 2006

Krishnamurthy K. StatCalc 2.0. University of Louisiana at Lafayette, 2006.

Sur 2003

Sur D, Niyogi SK, Sur S, Datta KK, Takeda Y, Nair GB, et al. Multidrug resistant Shigella dysenteriae type 1: forerunners of a new epidemic strain in eastern India?. Journal of Emerging Infectious Diseases 2003; 9(3): 404-5.

Sur 2004

Sur D, Ramamurthy T, Deen J, Bhattacharya SK. Shigellosis: challenges and management issues. Indian Journal of Medical Research 2004; 120(5): 454-62.

Talukder 2004

Talukder KA, Khajanchi BK, Islam MA, Dutta DK, Islam Z, et al. Genetic relatedness of ciprofloxacin-resistant Shigella dysenteriae type 1 strains isolated in south Asia. Journal of Antimicrobial Chemotherapy 2004; 54(4): 730-4.

Thorpe 2001

Thorpe CM, Smith WE, Hurley BP, Acheson DW. Shiga toxins induce, superinduce, and stabilize a variety of C-X-C chemokine mRNAs in intestinal epithelial cells, resulting in increased chemokine expression. Infections and Immunity 2001; 69: 6140-7.

von Seidlein 2006

von Seidlein L, Kim DR, Ali M, Lee H, Wang X, Thiem VD, et al. A multi centre study of Shigella diarrhoea in six Asian countries: disease burden, clinical manifestations, and microbiology. PLoS Medicine 2006; 3(9): e353.

WHO 2005a

World Health Organization. Dept. of Child and Adolescent Health and Development. Guidelines for the control of Shigellosis, including epidemics due to Shigella dysenteriae type 1. Geneva: World Health Organization, 2005.

WHO 2005b

World Health Organization. Shigellosis: disease burden, epidemiology and case management. Weekly Epidemiological Record 2005; 80(11): 94-9.

WHO 2006

World Health Organization. Shigella: Disease burden. www.who.int/vaccine_research/diseases/shigella/en (accessed 15 September 2006).

Tablas

Características de los estudios

Características de los estudios incluidos [ordenados por ID del estudio]

Alam 1994

Methods

Randomized controlled trial
Generation of allocation sequence: block randomization technique
Allocation concealment: drugs were stored in bottles, identical in appearance
Blinding: participants and provider blinded
Inclusion of all randomized participants: inadequate, 89%

Duration: not mentioned

Participants

Number of participants enrolled: 80
Number of participants analysed: 71
Loss to follow up: none
Inclusion criteria: children of both sexes between 1 and 8 years of age; having bloody diarrhoea lasting less than 72 hours
Exclusion criteria: taken drugs for shigellosis; with systemic illnesses; severe malnutrition;

Interventions

(1) Pivmecillinam (50 mg/kg/day, by mouth, in 4 divided doses, for 5 days)
(2) Nalidixic acid (60 mg/kg/day, by mouth, in 4 divided doses, for 5 days)

Outcomes

(1) Treatment failure (diarrhoea at follow up) by day 5
(2) Bacteriological failure on day 5
(3) Temperature > 37.8 ºC (fever on day 5)

Not included in this review:
(4) Abdominal pain or tenderness on day 5

Notes

Location: Bangladesh

Setting: all patients hospitalized in the study ward for the study period

Follow-up period: 6 days

Antibiotic sensitivity pattern of Shigella isolates: 71/71, 100%, were sensitive to pivmecillinam; 26/37, 45%, in the nalidixic group sensitive to nalidixic acid. Nalidixic acid sensitivity is not reported in the pivmecillinam group.

Funding source(s):

  1. United States Agency for International Development (USAID);

  2. International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B);

  3. Leo Pharmaceutical Products, Copenhagen and M/S Opsonin Chemical industries Ltd., Bangladesh provided the study drugs.

Risk of bias

Item

Authors' judgement

Description

Adequate sequence generation?

Yes

"Block randomisation technique". Probably done.

Allocation concealment?

Yes

"...patients were randomly allocated to treatment groups". There is no clear mention that allocation was concealed. Probably done as drugs were stored in serially numbered bottles (see below).

Blinding?
All outcomes

Yes

"Drugs were stored in bottles, identical in appearance, flavour and weight; labels on the bottles contained only the name of the study and the serial number of the patient who used the bottle." Participant and assessor blinding.

Incomplete outcome data addressed?
All outcomes

No

80 entered the study; 71 had Shigella in culture; no data regarding participants with non-Shigella dysentery (9) who were randomized according to the inclusion criteria. Outcomes reported only for all 71 (89%) with culture confirmed Shigella dysentery.

Free of selective reporting?

Yes

The study's prespecified outcomes which were of interest in this review, have been reported

Free of other bias?

Yes

The study appears to be free of other sources of bias



Bennish 1990

Methods

Randomized controlled trial
Generation of allocation sequence: block randomization, random number table
Allocation concealment: medications and placebo packaged in identical appearing capsules
Blinding: participants, investigators, and assessor blinded
Inclusion of all randomized participants: inadequate, 75%

Duration: 1 year and 3 months, from June 1986 to September 1987

Participants

Number of participants enrolled: 161
Number of participants analysed: 121
Loss to follow up: 6
Inclusion criteria: dysentery less than 72 hours duration; adult males; age 18 to 60 years; no prior treatment with antimicrobial agent effective against shigellosis; absence of trophozoites of Entamoeba histolytica on stool microscopy
Exclusion criteria: any other systemic illness additional to diarrhoea

Interventions

(1) Ciprofloxacin (500 mg orally every 12 hours for 5 days)
(2) Ampicillin (500 mg orally every 6 hours for 5 days)

Outcomes

(1) On day 5, resolution of illness (patients with less than 3 stools, none watery, afebrile)
(2) On day 5, marked improvement (patients with less than 6 stools, less than 1 watery stool)
(3) On day 5, slight improvement (less than 9 stools, less than 2 watery stools)
(4) On day 5, treatment failure (febrile, less than 10 stools, less than 3 watery stools)
(5) Bacteriological cure (if Shigella species could not be cultured from a stool or rectal swab on study day 3 or after)
(6) Mean stool frequency on day 3
(7) Adverse events (those that required discontinuation of the drug)
(8) Other adverse events

Notes

Location: Bangladesh

Setting: all patients hospitalized in the study ward for 6 days after the first dose of medication

Follow-up period: 13 days

Antibiotic sensitivity pattern of Shigella isolates: 121/121, 100%, were sensitive to ciprofloxacin; 34/60, 56.6%, in the ciprofloxacin group and 26/61, 42.6%, in the ampicillin group was sensitive to ampicillin

Funding source(s):

  1. Danish International Development Agency

  2. Applied Diarrheal Disease Research Project of the United States Agency for International Development (to M.L. Bennish)

  3. Miles Pharmaceuticals.

Risk of bias

Item

Authors' judgement

Description

Adequate sequence generation?

Yes

"Randomisation was done with block randomisation technique using a random number table and block size four". Probably done.

Allocation concealment?

Yes

Not described but both drugs were identically packaged (see below); possibly concealed

Blinding?
All outcomes

Yes

"...both medications and placebo were packaged in identical-appearing capsules, and patients, physicians, and nursing staff were blinded to their contents". Participant, investigator and assessor blinded.

Incomplete outcome data addressed?
All outcomes

No

Total randomized 161. Outcomes reported only for all 121 (75%) with culture confirmed Shigella dysentery. No data regarding participants with non-Shigella dysentery (34) who were randomized according to the inclusion criteria.

Free of selective reporting?

Yes

The study's prespecified outcomes, which were of interest in this review, have been reported

Free of other bias?

Yes

The study appears to be free of other sources of bias



Bibile 1961

Methods

Randomized controlled trial
Generation of allocation sequence: previously prepared list of random numbers
Allocation concealment: no
Blinding: not blinded
Inclusion of all randomized participants: unclear

Duration: not mentioned

Participants

Number of participants enrolled: unclear
Number of participants analysed: 80
Loss to follow up: unclear
Inclusion criteria: 3 or more unformed stools per day with blood and mucus; tenesmus; no previous treatment; macroscopic and microscopic appearance of the stool comparable with bacillary not amoebic dysentery
Exclusion criteria: amoebic dysentery

Interventions

(1) Sulphadimidine (2 g immediately, followed by 1 g every 6 hours orally for 5 days)
(2) Sulpha methoxy pyridazine (1 g on first day and 0.5 g daily orally for a further 4 days)
(3)Tetracycline (250 mg orally every 6 hours for 5 days)
(4) "Strepto triad" (3 tablets three times daily, orally for 5 days; each tablet of streptotriad contains streptomycin 65 mg, sulphamerazine 65 mg, sulphadiazine 100 mg, and sulphathiazole 100 mg). This group was not included in the analysis (sulphonamides versus tetracycline) as it contains a non-sulphonamide drug - streptomycin.

Other interventions: Injection pethidine given to one participant for severe tenesmus

Outcomes

(1) Number clinically cured by day 5
(2) Number bacteriologically cured
(3) Mean duration of fever in days
(4) Mean duration of abnormal stool in days

Notes

Location: Sri Lanka

Setting: not reported

Follow-up period: 8 days

Antibiotic sensitivity pattern of Shigella isolates: not reported

Funding source(s): Supplies of drugs from:

  1. Imperial Chemical Industries for sulphadimidine ("Sulphamethazine");

  2. Lederle Laboratories for tetracycline ("Achromycon") and sulphamethoxazole ("Lederkyn");

  3. May & Baker Ltd. for "Streptotriad".

Risk of bias

Item

Authors' judgement

Description

Adequate sequence generation?

Yes

"...listed in a random order"

Allocation concealment?

No

"...previously prepared list of random numbers". Probably not done.

Blinding?
All outcomes

No

Not mentioned; probably not done

Incomplete outcome data addressed?
All outcomes

Yes

No missing outcome data

Free of selective reporting?

Yes

The study's prespecified outcomes, which were of interest in this review, have been reported

Free of other bias?

Yes

The study appears to be free of other sources of bias



Dutta 1995

Methods

Randomized controlled trial
Generation of allocation sequence: random number table; permuted blocks of block length 8
Allocation concealment: sealed envelopes
Blinding: outcome assessor blinded; others unclear
Inclusion of all randomized participants: inadequate, 88%

Duration: 8 months, from December 1992 to July 1993

Participants

Number of participants enrolled: 72
Number of participants analysed: 63
Loss to follow up: 9
Inclusion criteria: children; both sexes; aged up to 5 years; with clinical diagnosis of dysentery (loose stool more than 3 times per day)
Exclusion criteria: no prior antibiotic therapy, no systemic illness

Interventions

(1) Furazolidone (7.5 mg/kg/day orally in 4 divided doses for 5 days)
(2) Nalidixic acid (55 mg/kg/day orally in 4 divided doses for 5 days)

Outcomes

(1) Clinical cure on day 3 and day 5 (no blood in stool, no fever, semisolid stools less than 3 times for last 24 hours, or no stool for last 18 hours)
(2) Treatment failure on day 3 or day 5 (deterioration or no improvement in clinical parameters, for example fever, presence of blood, and mucus in stool or frequency of stool on day 5)

Notes

Location: India

Setting: participants were hospitalized during the trial period

Follow-up period: 5 days

Antibiotic sensitivity pattern of Shigella isolates: not reported

Funding source(s): none mentioned

Risk of bias

Item

Authors' judgement

Description

Adequate sequence generation?

Yes

"Patients were randomised into two treatment groups...... in accordance with a random number table, using permuted block of block length eight"

Allocation concealment?

Yes

"...sealed envelopes were used for treatment allocation"

Blinding?
All outcomes

Yes

"One of the investigators who had no knowledge of the drug administered monitored the clinical response"; only outcome assessor blinded.

Incomplete outcome data addressed?
All outcomes

No

"Two patients in furazolidone group and seven patients in the nalidixic acid group dropped out"; no reasons given. 87.4% follow up.

Free of selective reporting?

Yes

The study's prespecified outcomes, which were of interest in this review, have been reported

Free of other bias?

Yes

The study appears to be free of other sources of bias.



Gotuzzo 1989

Methods

Randomized controlled trial
Generation of allocation sequence: block randomization with a random number table
Allocation concealment: unclear
Blinding: nil
Inclusion of all randomized participants: inadequate, 32%

Duration: not reported

Participants

Number of participants enrolled: 174
Number of participants analysed: 55
Loss to follow up: 7
Inclusion criteria: adults; dysentery; duration of illness less than 24 hours; informed consent
Exclusion criteria: antibiotic therapy within 48 hours

Interventions

(1) Cotrimoxazole (160/800 mg twice a day for 5 days)
(2) Norfloxacin (800 mg single dose)

Outcomes

(1) Days to last unformed stool
(2) Number of culture positive follow up

Notes

Location: Peru

Setting: participants were not hospitalized but followed up in the out-patients

Follow-up period: 2 weeks

Antibiotic sensitivity pattern of Shigella isolates: 84% in the cotrimoxazole group and 86% in the norfloxacin group were sensitive to cotrimoxazole; 100% sensitivity in both groups to norfloxacin

Funding source(s): in part by the International Collaboration in Infectious Disease Research grant 5 P01 A120130 from the National Institute of Allergy and Infectious Diseases

Risk of bias

Item

Authors' judgement

Description

Adequate sequence generation?

Yes

Block randomization with a random number table

Allocation concealment?

Unclear

Not mentioned

Blinding?
All outcomes

No

Not mentioned but unlikely to be blinded as the dosage regimens of interventions were different

Incomplete outcome data addressed?
All outcomes

No

174 entered the study; analysis was done on 55 (32%) patients; 62 had Shigella in culture; no data regarding participants with non-Shigella dysentery (112) who were randomized according to the inclusion criteria. 7 patients were excluded from the culture Shigella positive 62 (5 from cotrimoxazole group due to drug resistance to the allocated drug and 2 others not mentioned).

Free of selective reporting?

Yes

The study's prespecified outcomes, which were of interest in this review, have been reported

Free of other bias?

Yes

The study appears to be free of other sources of bias



Haltalin 1973

Methods

Randomized controlled trial
Generation of allocation sequence: unclear
Allocation concealment: no
Blinding: unclear
Inclusion of all randomized participants: adequate, 100%

Duration: not reported

Participants

Number of participants enrolled: 36
Number of participants analysed: 36
Loss to follow up: nil
Inclusion criteria: infants and children; acute diarrhoeal disease; presumptive bacteriologic diagnosis of shigellosis; written informed consent from responsible legal guardian
Exclusion criteria: infants under 1 month of age; known drug allergy; requiring specific antimicrobial therapy for concurrent infection

Interventions

(1) Nalidixic acid (13.75 mg/kg, orally, every 6 hours for 5 days)
(2) Ampicillin (25 mg/kg, orally, every 6 hours for 5 days)

Other interventions:
Symptomatic treatment for fever and convulsions was ordered as necessary and was similar for both groups
Fluid and electrolyte therapy and oral alimentation were given according to ward routine and was similar for both groups

Outcomes

(1) Number culture positive > 48 hours after start of treatment
(2) Number culture positive > 5 days after start of treatment
(3) Relapse
(4) Number of days until culture negative
(5) Diarrhoea > 5 days after start of treatment
(6) Removed from protocol due to worsening
(7) Number of days diarrhoea after start of treatment
(8) Days until afebrile after start of treatment

Notes

Location: United States of America

Setting: hospital, in-patient based trial

Follow-up period: 5 days

Antibiotic sensitivity pattern of Shigella isolates: 17/17, 100%, in the nalidixic acid group were sensitive to nalidixic acid and 19/19, 100%, in the ampicillin group were sensitive to ampicillin. Nalidixic acid sensitivity in the ampicillin group and ampicillin sensitivity in the nalidixic group is not reported.

Funding source(s):

  1. John A. Hartford Foundation

  2. Sterling-Winthrop Research Institute.

Risk of bias

Item

Authors' judgement

Description

Adequate sequence generation?

Unclear

"...randomly assigned"; but the method of sequencing not mentioned. In a previous trial done by the same author (Haltalin 1967) randomization was done based on the terminal digit number of the hospital record. The author could not be contacted for details since there was no mail ID. The journal's present editorial team did not have any details of the study.

Allocation concealment?

Unclear

Not mentioned

Blinding?
All outcomes

Unclear

Not mentioned

Incomplete outcome data addressed?
All outcomes

Yes

No missing outcome data

Free of selective reporting?

Yes

The study's prespecified outcomes, which were of interest in this review, have been reported

Free of other bias?

Yes

The study appears to be free of other sources of bias



Islam 1994

Methods

Randomized controlled trial
Generation of allocation sequence: block randomization
Allocation concealment: was done by sequentially numbered identical containers. "Test drug and the standard drug were packed in identical bottles, were identical in appearance, flavour, and weight; the label of the bottles contained only the name of the study and the serial number of the patient for whom the bottle was used".
Blinding: participant and provider blinded
Inclusion of all randomized participants: inadequate, 89%

Duration: 2 years, from January 1989 to December 1990

Participants

Number of participants enrolled: 79
Number of participants analysed: 69
Loss to follow up: 10
Inclusion criteria: children between 1 and 8 years; bloody diarrhoea; duration of illness, less than 72 hours; absence of trophozoites of E. histolytica; with informed consent
Exclusion criteria: systemic illness; severe malnutrition; taken effective anti-Shigella drugs before coming to hospital

Interventions

(1) Gentamicin (30 mg/kg, orally in 4 divided doses for 5 days)
(2) Nalidixic acid (60 mg/kg, orally in 4 divided doses for 5 days)

Outcomes

(1) Temperature > 37.8 ºC on post treatment days 1
(2) Temperature > 37.8 ºC on post treatment days 3
(3) Temperature > 37.8 ºC on post treatment days 5
(4) Isolation rates of Shigella species from stool/rectal swabs on post treatment days 1
(5) Isolation rates of Shigella species from stool/rectal swabs on post treatment days 2
(6) Isolation rates of Shigella species from stool/rectal swabs on post treatment days 3
(7) Isolation rates of Shigella species from stool/rectal swabs on post treatment days 4
(8) Isolation rates of Shigella species from stool/rectal swabs on post treatment days 5
(9) Bacteriologic relapse
(10) Lack of clinical improvement
(11) Lack of bacteriologic cure

Notes

Location: Bangladesh

Setting: participants were admitted in the study ward during the follow-up period

Follow-up period: 5 days

Antibiotic sensitivity pattern of Shigella isolates: all in both groups were sensitive to gentamicin; 26/37, 70%, in the nalidixic acid group were sensitive to nalidixic acid. Nalidixic acid sensitivity in the gentamicin group was not reported.

Funding source(s):

  1. United States Agency for International Development (USAID);

  2. International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B);

  3. M/S Opsonin Chemical industries Ltd., Bangladesh provided the study drugs.

Risk of bias

Item

Authors' judgement

Description

Adequate sequence generation?

Yes

"...randomly allocated to two treatment groups using a block randomisation technique."

Allocation concealment?

Yes

"...packaged in identical bottles... The labels on the bottles contained only the name of the study and the serial number of the patient for whom the bottle was used"

Blinding?
All outcomes

Yes

Participant and provider

Incomplete outcome data addressed?
All outcomes

No

7/40 missing from the gentamicin group (5 failed to grow Shigella species; 1 developed severe broncho pneumonia and another required blood transfusion for severe anaemia and were excluded from the study); 3/39 missing from nalidixic acid group since they failed to grow Shigella species); 87% follow up

Free of selective reporting?

Yes

The study's prespecified outcomes, which were of interest in this review, have been reported

Free of other bias?

Yes

The study appears to be free of other sources of bias



Kabir 1986

Methods

Randomized controlled trial
Generation of allocation sequence: random numbers table
Allocation concealment: no
Blinding: participant and provider blinded
Inclusion of all randomized participants: adequate, 100%

Duration: not reported

Participants

Number of participants enrolled: 94
Number of participants analysed: 94
Loss to follow up: nil
Inclusion criteria: adult males; dysentery duration of illness less than 48 hours, more than 20 fecal leukocytes per high powered field; no trophozoites of E. histolytica in stool
Exclusion criteria: other illnesses; history of allergy to penicillin; history of recent antibiotic therapy

Interventions

(1) Ceftriaxone (1 g, intravenous, single dose)
(2) Ampicillin (4 g, intravenous, single dose)
(3) Placebo

Outcomes

(1) Mean duration in days of diarrhoea
(2) Mean duration in days of blood in stool
(3) Mean duration in days of fever
(4) Mean duration in days of positive stool culture

Notes

Location: Bangladesh

Setting: patients were requested to stay in the hospital for 7 days

Follow-up period: 7 days

Antibiotic sensitivity pattern of Shigella isolates: all were sensitive to ceftriaxone; 34/34, 100%, in the ceftriaxone group, 24/30, 80%, in the ampicillin group and 28/30, 93%, in the placebo group were sensitive to ampicillin

Funding source(s):

  1. United Nations Development Program;

  2. The World Health Organization

  3. Roche Research Foundation Far East

Risk of bias

Item

Authors' judgement

Description

Adequate sequence generation?

Yes

"...randomly allocated"

Allocation concealment?

Unclear

Not mentioned

Blinding?
All outcomes

Yes

Participants and provider blinded

Incomplete outcome data addressed?
All outcomes

Yes

No missing outcome data. Outcomes reported for all 94 with culture confirmed Shigella dysentery.

Free of selective reporting?

Yes

The study's prespecified outcomes, which were of interest in this review, have been reported

Free of other bias?

Yes

The study appears to be free of other sources of bias



Khan 1997a

Methods

Randomized controlled trial
Generation of allocation sequence: random number table; block randomization with a block size of 6
Allocation concealment: adequate; the randomization list was developed and kept by a person not involved in the care or evaluation or in data analysis
Blinding: participant, provider and outcome assessor blinded
Inclusion of all randomized participants: inadequate, 83%

Duration: not reported

Participants

Number of participants enrolled: 85
Number of participants analysed: 70
Loss to follow up: 6
Inclusion criteria: adult men aged 18 to 60 years; grossly bloody-mucoid stool, tenesmus; duration of illness less than 72 hours; informed consent
Exclusion criteria: taken an effective antimicrobial agent for current illness; co-existing illness requiring antimicrobial therapy; had trophozoites of E. histolytica

Interventions

(1) Azithromycin (500 mg, orally on day 1 followed by 250 mg orally for next 4 days)
(2) Ciprofloxacin (500 mg, orally, every 12 hours for 5 days)

Outcomes

(1) Clinical failure
(2) Bacteriologic failure
(3) Fever > 24 hours

Notes

Location: Bangladesh

Setting: patients were asked to stay in the hospital for a period of 6 days

Follow-up period: 6 days

Antibiotic sensitivity pattern of Shigella isolates: all were sensitive to both antibiotics in both groups

Funding source(s):

  1. International Centre for Diarrhoeal Disease Research, Bangladesh

  2. Pfizer, Inc.

  3. Dr Seas was supported by a fellowship from the Swedish Agency for Research Cooperation with Developing Countries

Risk of bias

Item

Authors' judgement

Description

Adequate sequence generation?

Yes

"...patients were given a consecutive study number to which treatment had been randomly pre assigned by use of a random number table...block randomisation method with a block size six was used"

Allocation concealment?

Yes

"...randomisation list was developed and kept by a person not involved study"

Blinding?
All outcomes

Yes

"...double dummy technique"; participants, provider and outcome assessor blinded

Incomplete outcome data addressed?
All outcomes

No

9/85 participants were excluded from analysis as their rectal swab cultures did not grow Shigella; further, 6 of the remaining 76 were removed due to withdrawal from study (4 in the azithromycin group and 2 in the ciprofloxacin group). 83% follow up.

Free of selective reporting?

Yes

The study's prespecified outcomes, which were of interest in this review, have been reported

Free of other bias?

Yes

The study appears to be free of other sources of bias



Leibovitz 2000

Methods

Randomized controlled trial
Generation of allocation sequence: computer list of random numbers
Allocation concealment: the list of random numbers was created by a person uninvolved in the study
Blinding: participant, provider and outcome assessor blinded
Inclusion of all randomized participants: adequate, 91%

Duration: 1 year and 6 months, from July 1996 to December 1997

Participants

Number of participants enrolled: 221
Number of participants analysed: 201
Loss to follow up: 5
Inclusion criteria: ambulatory infants and children; 6 months to 11 years; community acquired; acute invasive diarrhoea; illness that started less than 7 days before enrolment; grossly bloody-mucoid stools on examination; more than or equal to soft or liquid stools within the last 24 hours; temperature more than or equal to 38 ºC, more than 15 white blood cells/high-power microscopic field; able to take oral medications
Exclusion criteria: were unable to take oral drugs; were receiving antibiotic therapy for the current illness, unless clinical failure was documented; were receiving antimicrobial treatment for more than 3 days for a concomitant infectious disease; needed hospitalization; had a known previous history of renal impairment, liver damage, cardiac disease or seizures; had a known hypersensitivity to either of the study drugs

Interventions

(1) Ciprofloxacin suspension (10 mg/kg, every 12 hours for 3 days + placebo intramuscular injection, one shot per day for 3 days)
(2) Ceftriaxone (intramuscular injection, 50 mg/kg/day, once daily for 3 days, maximal dose of 1 g per day + placebo suspension, one dose every 12 hours for 3 days)

Outcomes

(1) Failure at end of therapy (day 4 to 5)
(2) Relapse at end of follow up (day 21 +/- 5)

Notes

Location: Israel

Setting: not reported

Follow-up period: 21 +/- 5 days

Antibiotic sensitivity pattern of Shigella isolates: all were sensitive to both antibiotics

Funding source(s): in part by Bayer Corp., USA

Risk of bias

Item

Authors' judgement

Description

Adequate sequence generation?

Yes

"Patients were randomly assigned to one of the therapies according to the computerized list provided by Pharma clinical limited"

Allocation concealment?

Yes

"The randomisation list was developed and kept by a person not involved in the care or evaluation of the patients or in data analysis"

Blinding?
All outcomes

Yes

Blinding was done by "double dummy technique". Participant, provider and outcome assessor blinded.

Incomplete outcome data addressed?
All outcomes

No

"Sixteen and four patients from the ciprofloxacin and ceftriaxone group respectively, were excluded from the efficacy analysis because they are withdrawn from the study before its completion". 91% follow up.

Free of selective reporting?

Yes

The study's prespecified outcomes, which were of interest in this review, have been reported

Free of other bias?

Yes

The study appears to be free of other sources of bias



Nelson 1976a

Methods

Randomized controlled trial
Generation of allocation sequence: random number tables
Allocation concealment: no
Blinding: nil
Inclusion of all randomized participants: adequate, 100%

Duration: not reported

Participants

Number of participants enrolled: 28
Number of participants analysed: 28
Loss to follow up: nil
Inclusion criteria: infants and children, diarrhoeic form of shigellosis (abrupt onset with high fever, prostration followed by large volume watery stools containing mucus, no blood); dysenteric form of shigellosis (onset is less abrupt, with a 1- to 3-day period of increasing loose stools with blood, abdominal cramps and tenesmus)
Exclusion criteria: none reported

Interventions

(1) Cotrimoxazole suspension (40 mg trimethoprim and 200 mg sulphamethoxazole in each 5 ml, by mouth 1.25 ml/kg, daily in 2 doses every 12 hours for 5 days, total 10 doses)
(2) Ampicillin trihydrate suspension, by mouth, 100 mg/kg/day in divided doses every 6 hours for 5 days, total 20 doses

Other interventions:
Fluid and electrolyte therapy and diet were given according to ward routine
Drugs were used in the management of high fever or convulsions

Outcomes

(1) Culture positive after > 48 hours
(2) Diarrhoea > 5 days
(3) Number of days until diarrhoea stopped
(4) Adverse events

Notes

Location: United States of America

Setting: participants were admitted in the hospital for 5 days and then discharged and followed up in the out-patients

Follow-up period: 14 to 21 days

Antibiotic sensitivity pattern of Shigella isolates: all in both groups were sensitive to cotrimoxazole; 10/14, 71%, in the ampicillin group and 9/14, 64%, in the cotrimoxazole group were sensitive to ampicillin

Funding source(s): Hoffmann-La Roche, Inc.

Risk of bias

Item

Authors' judgement

Description

Adequate sequence generation?

Yes

"Assignment was made according to a list generated from random number tables"

Allocation concealment?

Unclear

Not mentioned

Blinding?
All outcomes

No

Ampicillin was given 4 times a day and cotrimoxazole was given 2 times a day without dummies

Incomplete outcome data addressed?
All outcomes

Yes

No missing outcome data. All randomized participants were used in analysis.

Free of selective reporting?

Yes

The study's prespecified outcomes, which were of interest in this review, have been reported

Free of other bias?

Yes

The study appears to be free of other sources of bias



Prado 1993

Methods

Randomized controlled trial
Generation of allocation sequence: randomization list
Allocation concealment: randomization list was kept with WHO, Geneva and was broken only after the study was completed
Blinding: participant, investigator, and outcome assessor blinded by double dummy technique
Inclusion of all randomized participants: inadequate, 40%

Duration: 2 years and 3 months, from November 1989 to January 1992

Participants

Number of participants enrolled: 150
Number of participants analysed: 59
Loss to follow up: 2
Inclusion criteria: acute diarrhoea less than 3 days; children, age range 6 months to 13 years; clinical syndrome of dysentery (visible blood in stools and presence of sheets of polymorphonuclear white cells on stool examination or acute diarrhoea (passage of 3 liquid motions within 24 hours) with the presence of polymorphonuclear white cells on stool microscopy); weight for height index above 70%
Exclusion criteria: treatment with antibiotics within 2 days prior to entry into the study; any life threatening illness due to Shigella; any concurrent disease that required treatment with antibiotics other than the drugs being studied; known hypersensitivity to penicillin or cotrimoxazole; presence of trophozoites of Entamoeba histolytica in stools

Interventions

(1) Pivmecillinam (40 mg/kg/day in 4 doses per day)
(2) Cotrimoxazole (40 mg/kg/day in 4 doses per day)

Other interventions:
Dehydration was corrected with orally administered fluids as recommended by WHO

Outcomes

(1) Treatment failure
(2) Duration of diarrhoea
(3) Duration of fever
(4) Duration of grossly visible blood in stools
(5) Duration of positive stool culture
(6) Adverse events

Notes

Location: Guatemala

Setting: participants were hospitalized for 5 days and then followed up in the out-patients

Study period: 11 to 13 days

Antibiotic sensitivity pattern of Shigella isolates: 26/29 in pivmecillinam group and 25/30 in the cotrimoxazole group were sensitive to pivmecillinam; 23/29 in the pivmecillinam group and 24/30 in the cotrimoxazole group were sensitive to cotrimoxazole

Funding source(s): World Health Organization

Risk of bias

Item

Authors' judgement

Description

Adequate sequence generation?

Yes

"Randomisation list"

Allocation concealment?

Yes

"...randomisation list was kept with WHO, Geneva and was broken only after the study was completed"

Blinding?
All outcomes

Yes

Participant and provider blinded by "double dummy technique"

Incomplete outcome data addressed?
All outcomes

No

59/150 (39%) of randomized participants were not included in the analysis as Shigella strains not isolated. 2 patients who withdrew from the study on first day of treatment were not included in the analysis.

Free of selective reporting?

Yes

The study's prespecified outcomes, which were of interest in this review, have been reported

Free of other bias?

Yes

The study appears to be free of other sources of bias



Rodriguez 1989

Methods

Randomized controlled trial
Generation of allocation sequence: unclear
Allocation concealment: no
Blinding: nil
Inclusion of all randomized participants: adequate, 100%

Duration: 1 year and 7 months, from January 1987 to July 1988

Participants

Number of participants enrolled: 125
Number of participants analysed: 123
Loss to follow up: nil
Inclusion criteria: children, aged 2 months to 59 months; passage of 3 or more watery stools in the previous 24 hours; history of diarrhoea up to 5 days before admission; and polymorphonuclear leucocytes and blood in stool samples

Exclusion criteria: received in the previous 48 hours any antimicrobials, antidiarrhoeals or any other drug capable of modifying the course of the disease; who had amoeba in stools; any severe concomitant disease; any intolerance to the drug; any known allergy to the study drugs

Interventions

(1) Furazolidone (7.5 mg/kg/day, in 4 equally divided doses)
(2) Cotrimoxazole (Trimethoprim (8 mg/kg/day) + sulphamethoxazole (40 mg/kg/day)) in 2 equally divided doses
(3) Control group (no antimicrobials)

Outcomes

(1) Cure/treatment success (in initial culture positive cases it is defined as both clinical cure, absence of diarrhoea and alleviation of all signs and symptoms by day 3 plus a bacteriological cure, a negative stool culture; in initial culture negative patients only clinical cure on day 3)
(2) Adverse events

Notes

Location: Mexico

Setting: out-patient study

Follow-up period: 6 days

Antibiotic sensitivity pattern of Shigella isolates: not reported

Funding source(s): Norwich Eaton Pharmaceuticals, Inc. (a Proctor and Gamble company)

Risk of bias

Item

Authors' judgement

Description

Adequate sequence generation?

Unclear

"...randomised into three groups" but the method not mentioned. Neither the author nor the journal could be contacted for clarifications.

Allocation concealment?

Unclear

Not mentioned

Blinding?
All outcomes

No

"Single blind"; not mentioned which group was blinded; blinding of the dosage schedules of the trial drugs in the 3 arms not done

Incomplete outcome data addressed?
All outcomes

No

"...two patients in the control group were voluntarily withdrawn from the study". They were not included in the analysis. 98% follow up.

Free of selective reporting?

Yes

The study's prespecified outcomes, which were of interest in this review, have been reported

Free of other bias?

No

Baseline imbalance, patients in furazolidone group had fewer days with diarrhoea (P value < 0.02)



Salam 1988

Methods

Randomized controlled trial
Generation of allocation sequence: random number table; block randomization with block size of 16
Allocation concealment: unclear in the published data but a personal communication from the author revealed that allocation concealment was done
Blinding: participant, provider, and outcome assessor blinded
Inclusion of all randomized participants: inadequate, 71%

Duration: not reported

Participants

Number of participants enrolled: 90
Number of participants analysed: 64
Loss to follow up: 5
Inclusion criteria: age between 6 months and 12 years; history of blood, mucoid diarrhoea and a stool specimen that had grossly visible blood and mucus; illness duration less than 72 hours
Exclusion criteria: severe malnutrition; with systemic illnesses in addition to shigellosis; who had received allopathic medications other than anti pyretics

Interventions

(1) Nalidixic acid (55 mg/kg/day, in 4 equally divided doses for 5 days)
(2) Ampicillin (100 mg/kg/day in 4 equally divided doses for 5 days)

Outcomes

(1) Stool frequency
(2) Clinical cure
(3) Rectal prolapse
(4) Fever
(5) Bacteriological failure on day 3
(6) Bacteriological failure on day 6
(7) Adverse events

Notes

Location: Bangladesh

Setting: participants were hospitalized for 6 days

Follow-up period: 6 days

Antibiotic sensitivity pattern of Shigella isolates: all in both groups were sensitive to nalidixic acid. 25/40 in the ampicillin group were sensitive to ampicillin. Ampicillin sensitivity in the nalidixic acid group is not reported.

Funding source(s):

  1. United Nations Children Fund (UNICEF);

  2. Dr Bennish is supported by grants from the Danish International Developmental Agency (DANIDA) and the U.S. Agency for International Development (UASAID)

  3. Chinoin Pharmaceutical and Chemical Works Ltd., Budapest, Hungary and Ambee Pharmaceuticals Ltd., Dhaka, Bangaldesh supplied the study drugs

Risk of bias

Item

Authors' judgement

Description

Adequate sequence generation?

Yes

"...random number table and block randomisation method with block size of 16".

Allocation concealment?

Yes

"...patients were randomly assigned to receive either nalidixic acid or ampicillin" but the concealment method was not mentioned in the published data. Personal communication from the author revealed that allocation concealment was done. The drug was administered to the participating children by the research ward nurses, and the investigators only knew the random
number pre-assigned to one of the 2 drugs, by the randomization process.

Blinding?
All outcomes

Yes

"...drugs were administered as syrups that had similar colour, consistency, and flavour, and the concentration of each drug was adjusted so that patients received the same volume... patients, staff and investigators were unaware of which drug was being given."

Incomplete outcome data addressed?
All outcomes

No

"data were analysed only from patients with culture-confirmed cases of shigellosis who remained in the study for at least 24 hours." 90 enrolled, 74 eligible for analysis, 64 analysed. 10 drop-outs - 6 withdrawn by their parents, reasons not provided, 4 withdrawn because of lack of clinical improvement. 82% follow up.

Free of selective reporting?

Yes

The study's prespecified outcomes, which were of interest in this review, have been reported

Free of other bias?

Yes

The study appears to be free of other sources of bias



Salam 1998

Methods

Randomized controlled trial
Generation of allocation sequence: computer generated list of random numbers
Allocation concealment: allocated by Bayer AG Pharma and not available to researchers, double dummy technique
Blinding: participants, providers and outcome assessor blinded
Inclusion of all randomized participants: inadequate, 84%

Duration: 1 year and 8 months, from August 1995 to March 1997

Participants

Number of participants enrolled: 143
Number of participants analysed: 120
Loss to follow up: 10
Inclusion criteria: children aged 2 years to 15 years; dysentery (passage of grossly bloody-mucoid stools for 72 hours or less); who had not received any antimicrobial treatment (agent known to be effective in vivo against shigellosis and active in vitro against the Shigella strain isolated from the patient); gave informed consent
Exclusion criteria: co-existing disorders that required antimicrobial therapy

Interventions

  1. Ciprofloxacin suspension (10 mg/kg, every 12 hours, maximum of 500 mg, for 5 days, total 10 doses with placebo of pivmecillinam)

  2. Pivmecillinam (15 to 20 mg/kg, maximum of 300 mg, every 8 hours for 5 days, total 15 doses with placebo of ciprofloxacin)

Outcomes

(1) Clinical failure (if patient did not have persistent dysentery on day 3, and if on day 5 a patient had 6 stools or less, no bloody-mucoid stools, no more than 1 watery stool and no fever)
(2) Bacteriological failure (bacteriological success: if the initial Shigella species could not be identified in culture on day 3 or later)
(3) Fever less than 24 hours
(4) Number of patients with bloody-mucoid stools more than 3 days
(5) Relapse
(6) Adverse event - limp (one of the adverse reactions to the antibiotic therapy could be a LIMP on walking due to joint pain caused by the antibiotics)
(7) All adverse events

Notes

Location: Bangladesh

Setting: participants were hospitalized for 6 days after the first dose and then discharged for follow up

Follow-up period: 180 days

Antibiotic sensitivity pattern of Shigella isolates: all in both groups were sensitive to ciprofloxacin. 58/60, in the ciprofloxacin group and 57/60 in the pivmecillinam group were sensitive to pivmecillinam.

Funding source(s):

  1. Bayer AG, Wuppertal, Germany

  2. ICDDR, Bangladesh

Risk of bias

Item

Authors' judgement

Description

Adequate sequence generation?

Yes

"Drug allocation used a computer-generated list of random numbers".

Allocation concealment?

Yes

"...list of random numbers, which was not available to the researchers".

Blinding?
All outcomes

Yes

"...double dummy technique". Participant, provider and outcome assessor blinded.

Incomplete outcome data addressed?
All outcomes

No

13/143 (6 in the ciprofloxacin group and 7 in the pivmecillinam group) were excluded from analysis because they were found not eligible (12 did not grow Shigella in their stool culture and 1 had taken nalidixic acid before study entry). Further 10 (5 in each group) withdrew before study completion. 84% follow up.

Free of selective reporting?

Yes

The study's prespecified outcomes, which were of interest in this review, have been reported

Free of other bias?

Yes

The study appears to be free of other sources of bias



Shanks 1999

Methods

Randomized controlled trial
Generation of allocation sequence: unclear
Allocation concealment: not mentioned
Blinding: participants, providers and outcome assessor blinded; double dummy
Inclusion of all randomized participants: inadequate, 87%

Duration: not reported

Participants

Number of participants enrolled: 137
Number of participants analysed: 113
Loss to follow up: 17
Inclusion criteria: adults; acute dysentery (visible blood on recently passed unformed stools); not receiving antibiotics likely to be effective against Shigella species; if female and not pregnant as confirmed by urine testing; able to take oral medications; no study drug allergy; no alternative cause for dysentery; informed consent

Exclusion criteria: not reported

Interventions

  1. Azithromycin (1 g single dose with placebo of ciprofloxacin

  2. Ciprofloxacin (500 mg twice a day with placebo of azithromycin)

Outcomes

  1. Time to clearance of dysentery

  2. Number of participants with dysentery on day 10

  3. Number of days until resolution of dysentery

  4. Number of days until resolution of fever

  5. Number of days of therapeutic support

  6. Relapse after 10 days

  7. Adverse events

Notes

Location: Kenya

Setting: participants were hospitalized for 3 days after the first dose and then discharged for follow up in out-patients

Follow-up period: 10 days

Antibiotic sensitivity pattern of Shigella isolates: not reported

Funding source(s): none mentioned

Risk of bias

Item

Authors' judgement

Description

Adequate sequence generation?

Unclear

"Volunteers were... randomised to receive...". Mentioned randomized but not how generated. Author could not be contacted via e-mail.

Allocation concealment?

Unclear

Not mentioned

Blinding?
All outcomes

Yes

Participants, providers and outcome assessor blinded; double dummy

Incomplete outcome data addressed?
All outcomes

No

17/130 were withdrawn as they left the hospital before completion of the study drug regimen. 87% follow up.

Free of selective reporting?

Yes

The study's prespecified outcomes, which were of interest in this review, have been reported

Free of other bias?

Yes

The study appears to be free of other sources of bias



Características de los estudios excluidos [ordenados por ID del estudio]

Study

Reason for exclusion

Aoki 1987

Not dysentery

Aoki 1989

Not dysentery

Ashkenazi 1993

Not dysentery

Barada 1980

Not dysentery

Bassily 1994

Not dysentery

Basualdo 2003

Not dysentery

Bennish 1992

Same antibiotic in all arms; quinolone, ciprofloxacin; 3-arm trial, 1 g single dose versus 1 g at admission and 2nd dose at 24 hours versus 500 mg twice daily for 5 days

Bezjak 1966

Not a RCT

Bhattacharya 1991

Same class of drugs in all arms; quinolones; norfloxacin versus nalidixic acid

Bhattacharya 1992

Same class of drugs in all arms; quinolones; norfloxacin versus nalidixic acid

Bhattacharya 1997

Same class of drugs in all arms; quinolones; norfloxacin versus nalidixic acid

Bogaerts 1985

Not a RCT

Browne 1983

Not dysentery

Brugel 1950

Not a RCT

Butler 1993

Not dysentery

Cabada 1992

Not dysentery

Camacho 1989

Not dysentery

CDC 2006

Not a RCT

Chang 1977

Not dysentery

de Olarte 1974

Not dysentery

Dryden 1996

Not dysentery

Dumitriu 1992

Not dysentery

DuPont 1973

Not dysentery

DuPont 1982

Not dysentery

DuPont 1983

Not dysentery

DuPont 1984

Not dysentery

DuPont 1986

Not dysentery

DuPont 1992

Not dysentery

DuPont 1992a

Not dysentery

Ekwall 1984

Not dysentery

Ericsson 1983

Not dysentery

Ericsson 1992

Not dysentery

Fakouhi 1971

Not a RCT

Gendrel 1997

Not a RCT

Gilman 1980

Same antibiotic in all arms; beta-lactams; ampicillin, high-dose (150 mg/kg/day) versus low-dose (50 mg/kg/day)

Gilman 1981

Same antibiotic in all arms; beta-lactam; ampicillin, single dose (150 mg/kg; 1 dose) versus multiple doses (150 mg/kg/day for 5 days)

Goodman 1990

Not dysentery

Ha 2008

Same class of drugs in all arms; quinolones; ciprofloxacin versus gatifloxacin

Haltalin 1967

Not dysentery

Haltalin 1968

Not dysentery

Haltalin 1968a

Not a RCT

Haltalin 1969

Not a RCT

Haltalin 1972

Not a RCT

Haltalin 1972a

Not a RCT

Han 1998

Same class of drugs in all arms; quinolones; rufloxacin versus homefloxacin

Hansson 1981

Not dysentery

Helvaci 1998

Same class of drugs in all arms; beta-lactam; cefixime versus ampicillin-sulbactam

Hiraishi 1980

Not dysentery

Imagawa 1988

Not dysentery

Iushchuk 2007

Not a RCT

Jiang 1994

Not a RCT

Jiang 2000

Not a RCT

Jinhua 1992

Not a RCT

Kabir 1984

Same class of drugs in all arms; beta-lactam; pivmecillinam versus ampicillin

Legros 2004

Not a RCT

Lexomboon 1972

Not dysentery

Lionel 1969

Same antibiotic in all arms; macrolide; tetracycline; single-dose (2.5 g single-dose) versus multiple doses (250 mg, 6-hourly for 5 days)

Lolekha 1988

Not dysentery

Lolekha 1991

Not dysentery

Mabadeje 1974

Not dysentery

Mahllooji 2004

Not dysentery

Martin 2000

Not dysentery

Matsuoka 1995

Not a RCT

Miles 1977

Not a RCT

Mol 1987

Same class of drugs in all arms; quinolones, enoxacin versus nalidixic acid

Moolasart 1999

Not dysentery

Morisawa 1970

Not dysentery

Motohiro 1982

Not dysentery

Nelson 1975

Not dysentery

Nelson 1976

Not dysentery

Nikorowitsch 1978

Not a RCT

Oldfield 1987

Not dysentery

Orenstein 1981

Not dysentery

Ostrower 1979

Not dysentery

Petruccelli 1992

Not dysentery

Pichler 1986

Not dysentery

Pichler 1987

Not dysentery

Prado 1981

Not dysentery

Prado 1992

Not dysentery

Rabbani 1982

Not a RCT

Rakhmanova 1996

Not a RCT

Raqib 2008

Not antibiotics

Rogerie 1986

Not a RCT

Sagara 1993

Not a RCT

Sagara 1994

Not a RCT

Saito 1983

Not dysentery

Saito 1984

Not dysentery

Salam 1995

Same class of drugs in all arms; beta-lactams, cefixime versus pivamdinocillin

Salam 1999

Not a RCT

Sepp 1995

Not dysentery

Seto 1992

Not dysentery

Soares 1994

Same class of drugs in all arms; quinolones; ciprofloxacin, short course (2 days) versus long course (5 days)

Soares 1996

Same class of drugs in all arms; quinolones; 3-arm trial, ciprofloxacin versus lomefloxacin long course versus lomefloxacin short course

Study Group 2002

Same antibiotic in all arms; quinolone; ciprofloxacin 15 mg/kg/every 12 hours, short course (3 days) versus standard course (5 days)

Tian 1986

Not a RCT

Tong 1970

Not dysentery

Varsano 1991

Not dysentery

Vinh 2000

Same class of drugs in all arms; quinolones, ofloxacin versus nalidixic acid

Wistrom 1992

Not dysentery

Xiouying 1986

Not a RCT

Yamamoto 1973

Not dysentery

Ye 1990

Not a RCT

Yin 1998

Same class of drugs in all arms; beta-lactams; ceftriaxone made in China versus ceftriaxone made outside China

Yunus 1982

Not dysentery

Yuying 1995

Not a RCT

Zhang 1991

Not dysentery

'Not dysentery' means that not all participants have blood or mucus or both in stools at randomization.
RCT = randomized controlled trial



Características de los estudios en espera de evaluación [ordenados por ID del estudio]

Carbo 1981

Methods

Randomized controlled trial (used a "randomisation table")

Allocation concealment: not described
Blinding: not specified
Inclusion of all randomized participants: not reported

Duration: unclear

Participants

Number of participants enrolled: not reported
Number of participants analysed: not reported
Loss to follow up: unclear
Inclusion criteria: children over 6 years of age (age limit not mentioned); symptoms and positive bacterial culture
Exclusion criteria: prior renal or hepatic disease

Interventions

Ampicillin: variable doses according to body weight for 7 days; number allocated not reported

Ro-12-2510: 2 tablets every 24 hours; duration unclear; number allocated not reported

Outcomes

Clinical failure
Microbiological failure
Relapse

Notes

No numerical data provided on number randomized to each arm or for outcomes

Further details from author awaited



Resumen de los hallazgos

Summary of findings for the main comparison. Antibiotic versus no drug or placebo for Shigella dysentery

Antibiotic versus no drug or placebo for Shigella dysentery

Patient or population: patients with Shigella dysentery
Settings: Mexico and Bangladesh
Intervention: Antibiotic versus no drug or placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Antibiotic versus no drug or placebo

Diarrhoea on follow up - Furazolidone versus no drug
clinical criteria
Follow-up: 6 days

58 per 100

12 per 100
(5 to 28)

RR 0.21
(0.09 to 0.48)

73
(1 study)

⊕⊝⊝⊝
very low 1,2,3

Antibiotic sensitivity of Shigella isolates not reported; Trial done in 1989

Diarrhoea on follow up - Cotrimoxazole versus no drug
clinical criteria
Follow-up: 6 days

58 per 100

17 per 100
(9 to 34)

RR 0.3
(0.15 to 0.59)

76
(1 study)

⊕⊝⊝⊝
very low 1,2,4

Same trial as above; had three arms

Relapse - not reported

See comment

See comment

Not estimable

-

See comment

The two trials for this comparison were too short in follow up duration (6-7 days) to estimate relapses and none were reported.

Serious adverse events - not reported

See comment

See comment

Not estimable

-

See comment

None of the two trials for this comparison reported serious adverse events

Other adverse events
clinical criteria
Follow-up: 7 days

0 per 100

0 per 100
(0 to 0)

RR 1.43
(0.06 to 34.13)

94
(1 study)

⊕⊝⊝⊝
very low 5,6,7

Data from a three armed trial; only one non-serious adverse event in the antibiotic arms and none in placebo arm

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Very serious limitations: The method of randomization was not described and there were baseline imbalances in duration of diarrhoea. Allocation concealment and blinding were not reported and this increases the risk of bias in the detection and reporting of some adverse events, though not for other primary outcomes that were objectively ascertained.
2 Serious indirectness: The single trial included only children and hence the evidence for effectiveness of antibiotics over no antibiotics in adults is uncertain. Though the trial did not exclude participants who were malnourished, it is unclear if any participant was malnourished.
3 No imprecision: Both limits of the point estimate of the trial indicated benefit with furazolidine over not receiving an antibiotic
4 No imprecision: Both limits of the point estimate showed appreciable benefit with cotrimoxazole over not receiving an antibiotic
5 Very serious limitations: Allocation was not concealed and there were baseline imbalances in antibiotic sensitivity to those allocated to ceftriaxone (100%) and ampicillin (80%)
6 Serious indirectness: The trial randomized only adults. The antibiotics assessed were ceftriaxone and ampicillin.
7 Very serious imprecision: The 95% CI of the point estimate of the trial includes appreciable risk of adverse events for antibiotics over placebo with no significant differences between interventions.



Summary of findings 2 Fluoroquinolones versus beta-lactams for Shigella dysentery See Summary of findings 2

Summary of findings 3 Fluoroquinolones versus macrolides for Shigella dysentery See Summary of findings 3

Summary of findings 4 Cotrimoxazole versus beta-lactams for Shigella dysentery See Summary of findings 4

Summary of findings 5 Cotrimoxazole versus fluoroquinolones (norfloxacin) for Shigella dysentery See Summary of findings 5

Summary of findings 6 Cotrimoxazole versus furazolidone for Shigella dysentery See Summary of findings 6

Summary of findings 7 Oral gentamicin versus nalidixic acid for Shigella dysentery See Summary of findings 7

Summary of findings 8 Sulphonamides versus tetracycline for Shigella dysentery See Summary of findings 8

Summary of findings 2. Fluoroquinolones versus beta-lactams for Shigella dysentery

Fluoroquinolones versus beta-lactams for Shigella dysentery

Patient or population: patients with Shigella dysentery
Settings: Bangladesh (4 trials), Israel (1 trial), USA (1 trial)
Intervention: Fluoroquinolones versus beta-lactams

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Fluoroquinolones versus beta-lactams

Diarrhoea on follow up - All trials
clinical criteria
Follow-up: 5 to 180 days

251 per 1000

259 per 1000
(113 to 595)

RR 1.03
(0.45 to 2.37)

686
(6 studies)

⊕⊝⊝⊝
very low 1,2,3,4

One trial from 1973; four trials in the 1990s; only one trial after 2000. The fluoroquinolones evaluated were nalidixic acid, and ciprofloxacin and the beta-lactams evaluated were ampicillin, (intra-muscular) ceftriaxone and pivmecillinam.

Relapse - All trials
clinical criteria
Follow-up: 5 to 180 days

70 per 1000

64 per 1000
(8 to 529)

RR 0.91
(0.11 to 7.55)

357
(3 studies)

⊕⊝⊝⊝
very low 5,6,7,8

One trial from 1973, one from 1990 and one from 2000. Only two reported relapse.

Serious adverse events
clinical criteria
Follow-up: 16 to 21 days

0 per 100

0 per 100
(0 to 0)

RR 10.9
(0.61 to 194.82)

221
(1 study)

⊕⊝⊝⊝
very low 9,10,11

Only seen in 4.5% of those allocated to fluoroquinolones and not in those given beta-lactams

Adverse events leading to discontinuation of treatment

62 per 1000

64 per 1000
(17 to 245)

RR 1.02
(0.27 to 3.89)

127
(1 study)

⊕⊝⊝⊝
very low 12,13,14

Other adverse events
clinical criteria
Follow-up: 5 to 180 days

177 per 1000

182 per 1000
(136 to 246)

RR 1.03
(0.77 to 1.39)

570
(4 studies)

⊕⊝⊝⊝
very low 15,16,17,18

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 No serious limitations: Four of the six trials in this comparison had limitations in reporting outcomes for some participants but a sensitivity analysis did not appreciably alter the results
2 Serious inconsistency: I squared for the pooled data from six trials was 83% but could be partially explained by subgroup analyses of adults and children and by culture-confirmed versus unconfirmed diagnosis of Shigella dysentery and resultant sensitivity patterns. The one trial in adults showed that a fluoroquinolone (ciprofloxacin) was superior (no imprecision) to a beta-lactam (ampicillin) when sensitivity of the Shigella isolates was 100% for the former and 43% for the latter . Homogenous data (I squared 0%) from two trials in children showed that beta-lactams (ampicillin and intra-muscular ceftriaxone) were superior to fluoroquinolones (nalidixic acid and ciprofloxacin) when >90% of participants had culture-confirmed Shigella dysentery with 100% sensitivity to the antibiotic used (no imprecision).
3 No serious indirectness: The six trials included children and adults and only two excluded severely malnourished children. The fluoroquinolones used included nalidixic acid and ciprofloxacin and the macrolides used included ampicillin, ceftriaxone and pivmecillinam.
4 Very serious imprecision: The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with both interventions.
5 No serious limitations: One of the three trials for this comparison had limitations in reporting the method of randomization and allocation concealment but exclusion of this trial in sensitivity analysis did not alter results.
6 Serious inconsistency: The I squared for the pooled data was 63% and could not explained by subgroup analyses.
7 Serious indirectness: The trials that reported this outcome only included children; hence the effects of antibiotics in preventing relapses in adults is unclear.
8 Very serious imprecision: The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with both interventions
9 No serious limitations: There were imbalances in those excluded from analysis in the single trial but randomization, allocation concealment and blinding were free of the risk of bias and follow up included 91% of participants
10 Serious indirectness: The trial included only infants and children and the applicability of the results for this outcome in adults is uncertain.
11 Very serious imprecision: The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with ceftriaxone and ciprofloxacin.
12 Serious limitations: This outcome was reported only for 75% of randomized participants with culture-confirmed Shigella dysentery.
13 Serious indirectness: The trial that reported this outcome included only adults
14 Very serious imprecision: The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with ampicillin and ciprofloxacin in this single trial.
15 Serious limitations: Three of the four trials that reported this outcome reported on less than 85% of those randomised.
16 No inconsistency: I squared was 0%
17 No serious indirectness: The four trials included adults and children and two did not specifically exclude malnourished children.
18 Very serious imprecision: The 95% CI of the pooled estimate indicated appreciable harm and non-appreciable benefit with beta-lactams (ampicillin, ceftriaxone and pivmecillinam) over fluoroquinolones (ciprofloxacin and nalidixic acid)



Summary of findings 3. Fluoroquinolones versus macrolides for Shigella dysentery

Fluoroquinolones versus macrolides for Shigella dysentery

Patient or population: patients with Shigella dysentery
Settings: Bangladesh and Kenya
Intervention: Fluoroquinolones versus macrolides

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Fluoroquinolones versus macrolides

Diarrhoea on follow up
clinical criteria
Follow-up: 6 to 10 days

105 per 1000

63 per 1000
(25 to 156)

RR 0.6
(0.24 to 1.49)

189
(2 studies)

⊕⊝⊝⊝
very low 1,2,3,4

One trial reported that none of the participants had diarrhoea on day 10 and in the other 16/76 had diarrhoea on the sixth day

Relapse - not reported

See comment

See comment

Not estimable

-

See comment

Duration of follow up in both trials were too short (6 to 10 days) to assess relapse and none were reported.

Serious adverse events - not reported

See comment

See comment

Not estimable

-

See comment

None of the two trials reported that any participant developed serious adverse events

Other adverse events
clinical criteria
Follow-up: 6 days

Study population

RR 1.33
(0.32 to 5.56)

76
(1 study)

⊕⊝⊝⊝
very low 5,6,7

79 per 1000

105 per 1000
(25 to 439)

Medium risk population

79 per 1000

105 per 1000
(25 to 439)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Serious limitations: One of the two included trials had limitations in allocation concealment and both reported outcomes for less than 90% of those randomized (82% and 87%)
2 No serious inconsistency: One of the trials had no participants with this outcome and hence risk ratios were estimated for only one trial.
3 Serious indirectness: Both trials randomized only adults. Effects of fluoroquinolones over macrolides in children, especially those who are malnourished are unclear. Antibiotics used were azithromycin and ciprofloxacin in both trials.
4 Very serious imprecision: The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with ciprofloxacin and azithromycin.
5 Very serious limitation: The trial reported this outcome only for 82% of randomized participants.
6 Serious indirectness: The trial included only adults. The antibiotics studied were ciprofloxacin and azithromycin.
7 Very serious imprecision:The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with ciprofloxacin and azithromycin.



Summary of findings 4. Cotrimoxazole versus beta-lactams for Shigella dysentery

Cotrimoxazole versus beta-lactams for Shigella dysentery

Patient or population: patients with Shigella dysentery
Settings: Guatemala and USA
Intervention: Cotrimoxazole versus beta-lactams

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Cotrimoxazole versus beta-lactams

Diarrhoea on follow up
clinical criteria
Follow-up: 11 to 21 days

227 per 1000

134 per 1000
(52 to 338)

RR 0.59
(0.23 to 1.49)

89
(2 studies)

⊕⊝⊝⊝
very low 1,2,3,4

One trial was reported in 1976 and the other in 1993. The antibiotics compared with cotrimoxazole were ampicillin and pivmecillinam respectively.

Relapse - not reported

See comment

See comment

Not estimable

-

See comment

The two trials followed participants for 11 to 21 days but did not report any relapses in this time.

Serious adverse events - not reported

See comment

See comment

Not estimable

-

See comment

No serious adverse events leading to death or hospitalization were reported in either trial.

Other adverse events
clinical criteria
Follow-up: 11 to 21 days

136 per 1000

110 per 1000
(37 to 333)

RR 0.81
(0.27 to 2.45)

89
(2 studies)

⊕⊝⊝⊝
very low 1,2,3,5

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Serious limitations: Inadequate allocation concealment in one trial and inadequate outcome data reporting (for 39% of randomized participants whose cultures were negative for Shigella) in the other
2 No inconsistency: I squared was 0% and the direction of effect favoured cotrimoxazole in both trials.
3 Serious indirectness: Both trials included only infants and children. The antibiotics compared were cotrimoxazole versus ampicillin and pivmecillinam.
4 Very serious imprecision: The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with cotrimoxazole and ampicillin and pivmecillinam.
5 Very serious imprecision: The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with beta-lactams and cotrimoxazole.



Summary of findings 5. Cotrimoxazole versus fluoroquinolones (norfloxacin) for Shigella dysentery

Cotrimoxazole versus fluoroquinolones (norfloxacin) for Shigella dysentery

Patient or population: patients with Shigella dysentery
Settings: Peru
Intervention: Cotrimoxazole versus fluoroquinolones (norfloxacin)

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Cotrimoxazole versus fluoroquinolones (norfloxacin)

Diarrhoea on follow up - not reported

See comment

See comment

Not estimable

-

See comment

Outcome assessed as number of days to last unformed stool. Data not available for proportions with diarrhoea on follow up.

Relapse - not reported

See comment

See comment

Not estimable

-

See comment

The trial followed up participants for 14 days. Relapses were not reported in this time.

Serious adverse events - not reported

See comment

See comment

Not estimable

-

See comment

No participant is reported to have developed serious adverse events leading to death or hospitalisation.

Other adverse events
clinical criteria
Follow-up: 2 weeks

0 per 1000

0 per 1000
(0 to 0)

RR 2.82
(0.12 to 66.62)

62
(1 study)

⊕⊝⊝⊝
very low 1,2,3

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Very serious limitations: Inadequate allocation concealment and blinding and very inadequate outcome data reporting (for only 32% of 174 randomized). Baseline imbalance in antibiotic sensitivity (100% sensitivity in norfloxacin arm and 84% in the cotrimoxazole arm).
2 Serious indirectness: The trial included only adults.
3 Very serious imprecision: The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with cotrimoxazole and norfloxacin.



Summary of findings 6. Cotrimoxazole versus furazolidone for Shigella dysentery

Cotrimoxazole versus furazolidone for Shigella dysentery

Patient or population: patients with Shigella dysentery
Settings: Mexico
Intervention: Cotrimoxazole versus furazolidone

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Cotrimoxazole versus furazolidone

Diarrhoea on follow up
clinical criteria
Follow-up: 6 days

173 per 1000

123 per 1000
(47 to 318)

RR 0.71
(0.27 to 1.84)

101
(1 study)

⊕⊝⊝⊝
very low 1,2,3

Trial reported in 1989; antimicrobial sensitivity to Shigella isolates not reported

Relapse - not reported

See comment

See comment

Not estimable

-

See comment

Follow up duration too short (6 days) in the sole trial for this comparison

Serious adverse events

Medium risk population

RR 0
(0 to 0)

0
(0)

See comment

No participant is reported to have developed serious adverse events leading to death or hospitalization.

Other adverse events - not reported

See comment

See comment

Not estimable

-

See comment

No adverse effects reported; unclear if formally evaluated

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Very serious limitations: Risk of bias likely due to inadequate allocation concealment and blinding. Baseline imbalances in participant characteristics (significantly fewer days of diarrhoea in those allocated to furazolidone- P =0.02).
2 Serious indirectness: The single trial included only infants and children.
3 Very serious imprecision: The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with cotrimoxazole over furazolidone.



Summary of findings 7. Oral gentamicin versus nalidixic acid for Shigella dysentery

Oral gentamicin versus nalidixic acid for Shigella dysentery

Patient or population: patients with Shigella dysentery
Settings: Bangladesh
Intervention: Oral gentamicin versus nalidixic acid

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Oral gentamicin versus nalidixic acid

Diarrhoea at follow up
clinical criteria
Follow-up: 5 days

308 per 1000

527 per 1000
(302 to 915)

RR 1.71
(0.98 to 2.97)

79
(1 study)

⊕⊝⊝⊝
very low 1,2,3

Data from a single trial reported in 1994. Antimicrobial sensitivity for Shigella isolates was 100% in those allocated to oral gentamicin and 70% to those allocated to nalidixic acid.

Relapse - not reported

See comment

See comment

Not estimable

-

See comment

Follow up duration too short (5 days) to assess.

Serious adverse events - not reported

See comment

See comment

Not estimable

-

See comment

No participant is reported to have developed serious adverse events

Other adverse events - not reported

See comment

See comment

Not estimable

-

See comment

No adverse effects reported; unclear if systematically assessed.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Very serious limitations: Though randomization, allocation and blinding were adequate, data were reported only for 87% randomized and there were baseline imbalances in antibiotic sensitivity (100% sensitive in gentamicin arm and 70% in nalidixic acid arm).
2 Serious indirectness: The trial randomized only infants and children and specifically excluded those severely malnourished.
3 Serious imprecision: The 95% CI for the point estimate from the trial includes appreciable and non-appreciable benefit for nalidixic acid over oral gentamicin.



Summary of findings 8. Sulphonamides versus tetracycline for Shigella dysentery

Sulphonamides versus tetracycline for Shigella dysentery

Patient or population: patients with Shigella dysentery
Settings: Sri Lanka
Intervention: Sulphonamides versus tetracycline

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Sulphonamides versus tetracycline

Diarrhoea at follow up
clinical criteria
Follow-up: 8 days

0 per 1000

0 per 1000
(0 to 0)

RR 7.68
(0.46 to 128.12)

60
(1 study)

⊕⊝⊝⊝
very low 1,2,3

Trial reported in 1961. Antimicrobial sensitivity not reported

Relapse - not reported

See comment

See comment

Not estimable

-

See comment

Duration of follow up too short (8 days) to assess relapse

Serious adverse events - not reported

See comment

See comment

Not estimable

-

See comment

No participant is reported to have developed serious adverse events.

Other adverse events - not reported

See comment

See comment

Not estimable

-

See comment

Not reported or pre-stated as an outcome; unclear if assessed.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. 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; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Very serious limitations: Risk of bias likely due to inadequate allocation concealment and blinding and unclear reporting of numbers randomized and numbers analysed.
2 Unclear indirectness: Unclear from report if trial included adults and children; malnourished participants were not specifically excluded.
3 Very serious imprecision: The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with tetracycline and sulphonamides.



Table 1. Known adverse effects of antibiotics used to treat Shigella dysentery^

Antibiotic

Life threatening

Discontinuation^^

Other

Tetracycline

Anaphylaxis

Oesophageal irritation, antibiotic-associated colitis, headache and visual disturbances

In children under 12 years of age causes dental hypoplasia and staining, benign intracranial hypertension

Chloramphenicol

Blood disorders, peripheral and optic neuritis, erythema multiforme

Dyspepsia

Ampicillin

Hypersensitivity reactions

Diarrhoea

Co-trimoxazole or trimethoprim - sulphamethoxazole

Stevens-Johnson syndrome

Diarrhoea, rash

Fluoroquinolones

Hypersensitivity

Dyspepsia, headache, hypotension

Pruritis, tachycardia

Norfloxacin

Dyspepsia, headache, hypotension

Euphoria, tinnitus, polyneuropathy

Ciprofloxacin

Dyspepsia, headache, hypotension

Hot flushes, sweating, tenosynovitis

Ofloxacin

Dyspepsia, headache, hypotension

Anxiety, unsteady gait

Azithromycin

Hypersensitivity

Dyspepsia, flatulence, headache

Ceftriaxone

Hypersensitivity reactions

Diarrhoea, headache, abdominal discomfort

Nalidixic acid

Same as in fluoroquinolones

Toxic psychosis, increased intracranial tension, cranial nerve palsy

Rifaximin

Allergic reactions

Allergic reactions

Cefixime

Hypersensitivity reactions

Flatulence, headache, abdominal pain, defecation urgency, nausea, constipation, pyrexia, vomiting

Pivmecillinam

Same as ampicillin, dyspepsia

^Source: BNF 2007.
^^Can result in discontinuation of treatment.



Table 2. Detailed search strategies

Search set

CIDG SR^

CENTRAL

MEDLINE^^

EMBASE^^

LILACS^^

1

Shigell*

Shigell*

Shigell*

Shigell$

Shigell*

2

Dysentery

DYSENTERY, BACILLARY

DYSENTERY, BACILLARY

SHIGELLOSIS

Dysentery

3

1 or 2

1 or 2

1 or 2

DYSENTERY

1 or 2

4

antibiotic*

ANTI-BACTERIAL AGENTS/THERAPEUTIC USE

ANTI-BACTERIAL AGENTS/THERAPEUTIC USE

1 or 2 or 3

antibiotic*

5

tetracycline*

ANTI-INFECTIVE AGENTS/THERAPEUTIC USE

ANTI-INFECTIVE AGENTS/THERAPEUTIC USE

tetracycline$

tetracycline*

6

chloramphenicol

antibiotic*

antibiotic*

chloramphenicol

chloramphenicol

7

ampicillin*

tetracycline*

tetracycline*

ampicillin

ampicillin

8

co-trimoxazole

chloramphenicol

chloramphenicol

co-trimoxazole

co-trimoxazole

9

fluoroquinolone*

ampicillin

ampicillin

fluoroquinolone$

fluoroquinolone*

10

quinolone*

co-trimoxazole

co-trimoxazole

quinolone$

quinolone*

11

norfloxacin

fluoroquinolone*

fluoroquinolone*

norfloxacin

norfloxacin

12

ciprofloxacin

quinolone*

quinolone*

ciprofloxacin

ciprofloxacin

13

ofloxacin

norfloxacin

norfloxacin

ofloxacin

ofloxacin

14

azithromycin

ciprofloxacin

ciprofloxacin

azithromycin

azithromycin

15

ceftriaxone

ofloxacin

ofloxacin

ceftriaxone

ceftriaxone

16

nalidixic acid

azithromycin

azithromycin

nalidixic acid

nalidixic acid

17

pivmecillinam

ceftriaxone

ceftriaxone

rifaximin

rifaximin

18

4-17/or

nalidixic acid

nalidixic acid

cefixime

cefixime

19

3 and 18

rifaximin

rifaximin

trimethoprim-sulfamethoxazole

trimethoprim-sulfamethoxazole

20

cefixime

cefixime

antibiotic$

pivmecillinam

21

trimethoprim-sulfamethoxazole

trimethoprim-sulfamethoxazole

pivmecillinam

4-20/or

22

pivmecillinam

pivmecillinam

5-21/or

3 and 21

23

4-22/or

4-22/or

Limit 22 to human

24

3 and 23

3 and 23

25

Limit 24 to human

^Cochrane Infectious Diseases Group Specialized Register.
^^Search terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Higgins 2006); upper case: MeSH or EMTREE heading; lower case: free text term.



Table 3. Search strategy: proceedings, organizations, and pharmaceutical companies

Type

Detail

Conference proceeding

- Commonwealth Congress on Diarrhoea and Malnutrition: 8th, Dhaka, Bangladesh, 6 to 8 February 2006 (searched on 12 April 2007)
- Asian Conference on Diarrhoeal Diseases and Nutrition: 10th, Dhaka, Bangladesh, 7 to 9 December 2003 (searched on 13 April 2007)
- Annual Scientific Conference: 10th Dhaka, Bangladesh, 11 to 13 June 2002 (searched on 13 April 2007)
- Annual Meeting of Infectious Disease Society of America: 44th, Toronto, Ontario, Canada, 12 to 15 October 2006; 43rd, San Francisco, California, 6 to 9 October 2005; 42nd, Boston, Massachusetts, USA, 30 September to 3 October 2004 (searched on 18 March 2008)
- Interscience Conference on Antimicrobial Agents and Chemotherapy: 46th, San Francisco, California, 27 to 30 September 2006; 45th, Washington DC, USA, 16 to 19 December 2005; 44th, Washington DC, USA, 30 October to 2 November, 2004 (searched on 18 March 2008)
- European Congress of Clinical Microbiology and Infectious Diseases: 16th, Nice, France, 1 to 4 April 2006; 15th, 2 to 5 April 2005 (searched on 18 March 2008)
- International Congress on Infectious Diseases: 12th, Lisbon, Portugal, 15 to 18 June 2006; 11th, Cancun, Mexico, 4 to 7 March 2004 (searched on 18 March 2008)
- Annual Meeting of The European Society for Paediatric Infectious Disease: 24th, Basel, Switzerland, 3 to 5 May 2006 (searched on 18 March 2008)
- Western Pacific Congress of Chemotherapy and Infectious Diseases: 10th, Fukuoka, Japan, 3 to 6 December 2006 (searched on 18 March 2008)
- European Congress of Chemotherapy and Infection: 8th, Budapest, Hungary, 25 to 28 October 2006 (searched on 18 March 2008)

Organizations

- Liverpool School of Tropical Medicine (contacted on 11 April 2007)
- World Health Organization (contacted on 17 March 2008)
- American Society of Tropical Medicine and Hygiene (contacted on 15 April 2007)
- International Society of Tropical Pediatrics (contacted on 15 April 2007)
- South East Asian Ministers Education Organization (SEAMEO) TROPMED Network (contacted on 17 March 2008)
- International Center for Diarrhoeal Disease Research in Bangladesh (contacted on 21 April 2007)

Pharmaceutical companies

- Goldshield Pharmaceuticals Ltd (tetracycline, Deteclo; chloramphenicol, Chloromycetin) - contacted on 17 March 2008
- Chemidex (ampicillin, Penbritin) - contacted on 17 March 2008
- GlaxoSmithKline (co-trimoxazole, Septrin) - contacted on 17 March 2008
- Merck Sharp & Dohme Ltd (norfloxacin, Utinor) - contacted on 17 March 2008
- Bayer (ciprofloxacin, Ciproxin) - contacted on 20 April 2007
- Aventis Pharma (ofloxacin, Tarivid) - contacted on 15 April 2007
- Pfizer (azithromycin, Zithromax) - contacted on 17 March 2008
- Roche (ceftriaxone, Rocephin) - contacted on 20 April 2007
- Rosemont Pharmaceuticals Ltd (nalidixic acid, Uriben) - contacted on 13 April 2007
- Salix Pharmaceuticals (rifaximin, Xifaxan) - contacted on 17 March 2008
- Rhone-Poulenc Rorer (cefixime, Suprax) - contacted on 17 March 2008
- LEO pharma (pivmecillinam, Selexid) - contacted on 17 March 2008



Table 4. Sensitivity patterns of the Shigella isolates reported in included trials

Study ID

Group 1

Group 2

Group 3

Alam 1994

Pivmecillinam group:

All were sensitive to pivmecillinam

Nalidixic acid sensitivity not reported

Nalidixic acid group:

All were sensitive to pivmecillinam

26/37, 45%, were sensitive to nalidixic acid

Nil

Bennish 1990

Ciprofloxacin group:

All were sensitive to ciprofloxacin; 34/60, 56.6%, were sensitive to ampicillin

Ampicillin group:

All were sensitive to ciprofloxacin; 26/61, 42.6%, were sensitive to ampicillin.

Nil

Bibile 1961

This is a 4-armed trial with sulphadimidine, sulpha methoxy pyridazine, Strepto triad, and tetracycline in each group respectively

Sensitivity patterns not reported for any group

Dutta 1995

Furazolidone and nalidixic acid

Sensitivity patterns not reported for any group

Gotuzzo 1989

Cotrimoxazole group:

27/32, 84%, were sensitive to cotrimoxazole; all were sensitive to norfloxacin

Norfloxacin group:

26/30, 86%, were sensitive to cotrimoxazole; all were sensitive to norfloxacin

Nil

Haltalin 1973

Nalidixic acid group:

All were sensitive to nalidixic acid; ampicillin sensitivity not reported.

Ampicillin group:

All were sensitive to ampicillin; nalidixic acid sensitivity not reported

Nil

Islam 1994

Nalidixic acid group:

26/37, 70%, were sensitive to nalidixic acid; all were sensitive to gentamicin

Oral gentamicin:

Nalidixic acid sensitivity not reported; all were sensitive to gentamicin

Nil

Kabir 1986

Ceftriaxone group:

All were sensitive to ceftriaxone; all were sensitive to ampicillin

Ampicillin group:

All were sensitive to ceftriaxone; 24/30, 80%, were sensitive to ampicillin

Placebo:

All were sensitive to ceftriaxone; 28/30, 93%, were sensitive to ampicillin

Khan 1997a

Azithromycin group:

All were sensitive to both antibiotics

Ciprofloxacin group:

All were sensitive to both antibiotics

Nil

Leibovitz 2000

Ciprofloxacin group:

All were sensitive to both antibiotics

Ceftriaxone group:

All were sensitive to both antibiotics

Nil

Nelson 1976a

Cotrimoxazole group:

All were sensitive to cotrimoxazole; 9/14, 64%, were sensitive to ampicillin

Ampicillin group:

All were sensitive to cotrimoxazole 10/14, 71%, were sensitive to ampicillin

Nil

Prado 1993

Cotrimoxazole group;

24/30, 80%, were sensitive to cotrimoxazole; 25/30, 83.3%, were sensitive to pivmecillinam

Pivmecillinam group:

23/29, 79.3%, were sensitive to cotrimoxazole; 26/29, 89.7%, were sensitive to pivmecillinam

Nil

Rodriguez 1989

3-armed trial with furazolidone, cotrimoxazole and a control (no antimicrobials) respectively

Sensitivity patterns not reported for any group

Nil

Salam 1988

Nalidixic acid group:

All were sensitive to nalidixic acid; ampicillin sensitivity not reported

Ampicillin group:

All were sensitive to nalidixic acid; 25/40, 62.5%, were sensitive to ampicillin

Nil

Salam 1998

Ciprofloxacin group:

All were sensitive to ciprofloxacin; 58/60, 96.7%, were sensitive to pivmecillinam

Pivmecillinam group:

All were sensitive to ciprofloxacin; 57/60, 95%, were sensitive to pivmecillinam

Nil

Shanks 1999

Azithromycin and ciprofloxacin

Sensitivity patterns not reported for any group

Nil

Sensitivity patterns not reported by 4 trials (Bibile 1961; Rodriguez 1989; Dutta 1995; Shanks 1999).



Table 5. Suggestions for a trial of antibiotic for Shigella dysentery

Methods

Participants

Interventions

Outcomes

Notes

Allocation:
Centralized sequence generation with table of random numbers or computer generated lists

Stratified by severity of illness

Sequence concealed until interventions are assigned

Blinding:
Those recruiting and assigning participants, those administering the intervention, and those assessing the outcomes, must all be blind to the allocated group; the administered drugs have to be identical or a double dummy technique has to be used. Liquid medications have to be in similar looking bottles, identical in shape and weight; the medications must themselves be similar in colour and flavour.

Duration:
Minimum of 4 weeks after completion of therapy to assess relapse

Entry criteria can be clinical dysentery, i.e. acute onset frequent loose stools with blood or mucus or both lasting for less than 72 hours and at least 3 stools per day. Other features, such as fever and tenesmus at presentation, have to be recorded but need not be necessary for inclusion into study.

If it is possible to presumptively or decisively detect Shigella in stool before inclusion into study, it should be done. Real-time PCR is a rapid but expensive method to diagnose Shigella early (Legros 2004).

Sample size:
(See Table 6). Age group: trials should be separately done for adults and children (less than 15 years of age) or at least presented separately if they are in the same trial. In children, infants must be a separate group.

Setting: in- or out-patients. The number of participants, if hospitalized for standardization of administration of the interventions, have to be reported separately from those hospitalized due to complications.

Sex: men and women.

Special groups (those who have higher risk of complications:

  • Malnourished children

  • HIV positive individuals

  • Adults more than 50 years of age

  • Infants

Exclusion criteria:
Allergy to the drug studied; history of antibiotic use for this episode of illness in the previous 48 hours; pregnant and lactating women; clinical presence of another infection needing antimicrobials

  1. Any antibiotic studied for efficacy and safety

  2. Any other antibiotic that is the standard for the treatment of Shigella dysentery at that period of time in that country

Others: placebos or probiotics to be studied only on those with no risk of complications and those who have mild illness

Primary outcomes:

  1. Number of patients with diarrhoea on follow up.

  2. Clinical relapse

  3. Adverse effects of antibiotics

  4. Duration of fever

  5. Duration of blood in stools

Secondary outcomes:

  1. Removed from study due to clinical worsening

  2. Fever on follow up

  3. Abdominal pain on follow up

  4. Bacteriological cure

  5. Bacteriological relapse

  6. Duration of diarrhoea

  7. Duration of abdominal pain

  8. Number of days of hospitalisation

Once patients are randomized into the treatment groups, they should not be removed until final analysis. The trial author(s) must publish the outcome findings of the whole group first and then present data for those positive for Shigella by stool or rectal swab culture or PCR and those negative for Shigella. The data have to be presented according to the severity of illness the patients presented with.

Antibiotic sensitivity patterns have to be reported for all antibiotics studied and in all groups

Response to treatment stratified by in vitro antibiotic sensitivity also needs to be reported

Drop-outs:
The patients who drop out after randomization due to loss of follow up, withdrawal from protocol or consent withdrawal etc have to be reported and accounted in the final analysis (intention-to-treat analysis).



Table 6. Sample size suggestions for trial of antibiotics in Shigella dysentery

SAMPLE SIZES

Antibiotic versus no drug or placebo (placebo response at 45%)

or

Antibiotic versus another antibiotic

1 sided α

10% difference: 310

20% difference: 75

25% difference: 50

30% difference: 30

40% difference: 15

2 sided α

10% difference: 390

20% difference: 95

25% difference: 60

30% difference: 40

40% difference: 20

1. The sample size required to detect the assumed difference in improvement or worsening with 80% power and 5% significance level using the outcome of 'diarrhoea at follow up' from this review using StatCalc 2006.
2. The sample size mentioned is for each arm of the study.



Figuras

Figure 1

Methodological quality summary: review authors' judgments about each methodological quality item for each included study.


Figure 1


Figure 2

Methodological quality graph: review authors' judgments about each methodological quality item presented as percentages across all included studies.


Figure 2


Analysis 1.1

Comparison 1 Antibiotic versus no drug or placebo, Outcome 1 Diarrhoea on follow up.


Analysis 1.1


Analysis 1.2

Comparison 1 Antibiotic versus no drug or placebo, Outcome 2 Time to cessation of fever (in days).


Analysis 1.2


Analysis 1.3

Comparison 1 Antibiotic versus no drug or placebo, Outcome 3 Time to cessation of diarrhoea (in days).


Analysis 1.3


Analysis 1.4

Comparison 1 Antibiotic versus no drug or placebo, Outcome 4 Time to cessation of blood in stools (in days).


Analysis 1.4


Analysis 1.5

Comparison 1 Antibiotic versus no drug or placebo, Outcome 5 Other adverse events.


Analysis 1.5


Analysis 2.1

Comparison 2 Fluoroquinolones versus beta-lactams, Outcome 1 Diarrhoea on follow up.


Analysis 2.1


Analysis 2.2

Comparison 2 Fluoroquinolones versus beta-lactams, Outcome 2 Fever at follow up.


Analysis 2.2


Analysis 2.3

Comparison 2 Fluoroquinolones versus beta-lactams, Outcome 3 Relapse.


Analysis 2.3


Analysis 2.4

Comparison 2 Fluoroquinolones versus beta-lactams, Outcome 4 Bacteriological failure.


Analysis 2.4


Analysis 2.5

Comparison 2 Fluoroquinolones versus beta-lactams, Outcome 5 Development of severe complications.


Analysis 2.5


Analysis 2.6

Comparison 2 Fluoroquinolones versus beta-lactams, Outcome 6 Serious adverse events.


Analysis 2.6


Analysis 2.7

Comparison 2 Fluoroquinolones versus beta-lactams, Outcome 7 Adverse events leading to discontinuation of treatment.


Analysis 2.7


Analysis 2.8

Comparison 2 Fluoroquinolones versus beta-lactams, Outcome 8 Other adverse events.


Analysis 2.8


Analysis 3.1

Comparison 3 Fluoroquinolones versus macrolides, Outcome 1 Diarrhoea on follow up.


Analysis 3.1


Analysis 3.2

Comparison 3 Fluoroquinolones versus macrolides, Outcome 2 Fever at follow up.


Analysis 3.2


Analysis 3.3

Comparison 3 Fluoroquinolones versus macrolides, Outcome 3 Time to cessation of blood in stools.


Analysis 3.3


Analysis 3.4

Comparison 3 Fluoroquinolones versus macrolides, Outcome 4 Bacteriological failure.


Analysis 3.4


Analysis 3.5

Comparison 3 Fluoroquinolones versus macrolides, Outcome 5 Other adverse events.


Analysis 3.5


Analysis 4.1

Comparison 4 Cotrimoxazole versus beta-lactams, Outcome 1 Diarrhoea on follow up.


Analysis 4.1


Analysis 4.2

Comparison 4 Cotrimoxazole versus beta-lactams, Outcome 2 Bacteriological failure.


Analysis 4.2


Analysis 4.3

Comparison 4 Cotrimoxazole versus beta-lactams, Outcome 3 Time to cessation of diarrhoea (hours).


Analysis 4.3


Analysis 4.4

Comparison 4 Cotrimoxazole versus beta-lactams, Outcome 4 Time to cessation of fever (hours).


Analysis 4.4


Analysis 4.5

Comparison 4 Cotrimoxazole versus beta-lactams, Outcome 5 Time to cessation of visible blood in stools.


Analysis 4.5


Analysis 4.6

Comparison 4 Cotrimoxazole versus beta-lactams, Outcome 6 Other adverse events.


Analysis 4.6


Analysis 5.1

Comparison 5 Cotrimoxazole versus fluoroquinolones (norfloxacin), Outcome 1 Bacteriological failure.


Analysis 5.1


Analysis 5.2

Comparison 5 Cotrimoxazole versus fluoroquinolones (norfloxacin), Outcome 2 Other adverse events.


Analysis 5.2


Analysis 6.1

Comparison 6 Cotrimoxazole versus furazolidone, Outcome 1 Diarrhoea on follow up.


Analysis 6.1


Analysis 7.1

Comparison 7 Oral gentamicin versus nalidixic acid, Outcome 1 Diarrhoea at follow up.


Analysis 7.1


Analysis 7.2

Comparison 7 Oral gentamicin versus nalidixic acid, Outcome 2 Fever at follow up.


Analysis 7.2


Analysis 7.3

Comparison 7 Oral gentamicin versus nalidixic acid, Outcome 3 Bacteriological relapse.


Analysis 7.3


Analysis 7.4

Comparison 7 Oral gentamicin versus nalidixic acid, Outcome 4 Bacteriological failure.


Analysis 7.4


Analysis 8.1

Comparison 8 Sulphonamides versus tetracycline, Outcome 1 Diarrhoea at follow up.


Analysis 8.1


Analysis 8.2

Comparison 8 Sulphonamides versus tetracycline, Outcome 2 Bacteriological failure.


Analysis 8.2