Macrolidos en Asma

Macrólidos para el asma crónica
Richeldi L, Ferrara G, Fabbri LM, Lasserson TJ, Gibson PG
Reproducción de una revisión Cochrane, traducida y publicada en La Biblioteca Cochrane Plus, 2008, Número 2
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ÍNDICE DE MATERIAS
RESUMEN...................................................................................................................................................................1
RESUMEN EN TÉRMINOS SENCILLOS....................................................................................................................2
ANTECEDENTES........................................................................................................................................................2
OBJETIVOS.................................................................................................................................................................2
CRITERIOS PARA LA VALORACIÓN DE LOS ESTUDIOS DE ESTA REVISIÓN......................................................2
ESTRATEGIA DE BÚSQUEDA PARA LA IDENTIFICACIÓN DE LOS ESTUDIOS....................................................3
MÉTODOS DE LA REVISIÓN.....................................................................................................................................3
DESCRIPCIÓN DE LOS ESTUDIOS..........................................................................................................................3
CALIDAD METODOLÓGICA.......................................................................................................................................4
RESULTADOS.............................................................................................................................................................4
DISCUSIÓN.................................................................................................................................................................4
CONCLUSIONES DE LOS AUTORES........................................................................................................................5
AGRADECIMIENTOS..................................................................................................................................................6
POTENCIAL CONFLICTO DE INTERÉS.....................................................................................................................6
FUENTES DE FINANCIACIÓN....................................................................................................................................6
REFERENCIAS...........................................................................................................................................................6
TABLAS........................................................................................................................................................................8
Characteristics of included studies.......................................................................................................................8
Characteristics of excluded studies....................................................................................................................10
Table 01 Summary of included studies' characteristics......................................................................................24
Table 02 Narrative of individual study results......................................................................................................31
CARÁTULA................................................................................................................................................................34
RESUMEN DEL METANÁLISIS.................................................................................................................................35
GRÁFICOS Y OTRAS TABLAS..................................................................................................................................37
01 Macrolide versus placebo - crossover studies...............................................................................................37
01 VEF1 (L/minuto)......................................................................................................................................37
02 CVF........................................................................................................................................................37
03 Síntomas (escala estandarizada)...........................................................................................................38
04 PCE esputo............................................................................................................................................38
05 PCE sérica..............................................................................................................................................38
06 Eosinófilos en sangre.............................................................................................................................39
07 Neutrófilos en sangre.............................................................................................................................39
08 Eosinófilos en esputo.............................................................................................................................39
09 Neutrófilos en esputo..............................................................................................................................40
10 PC20 (metacolina)..................................................................................................................................40
11 PC20 (sulpirina)......................................................................................................................................40
02 Macrólido versus placebo - estudios de grupos paralelos.............................................................................41
01 VEF1 (L/minuto)......................................................................................................................................41
02 VEF1 (escala estandarizada).................................................................................................................41
Macrólidos para el asma crónica i
Copyright © John Wiley & Sons Ltd. Usado con permiso de John Wiley & Sons, Ltd.
ÍNDICE DE MATERIAS
03 VEF1 % teórico.......................................................................................................................................41
04 Cambio en el FEM vespertino................................................................................................................42
05 Cambio en el FEM matutino...................................................................................................................42
06 Síntomas diurnos....................................................................................................................................42
07 Reducción del uso de esteroides (continuos).........................................................................................43
08 Reducción del uso de esteroides (dicotómicos).....................................................................................43
09 Exacerbaciones......................................................................................................................................43
10 Retiros de los estudios...........................................................................................................................44
11 Náuseas.................................................................................................................................................44
12 Diarrea....................................................................................................................................................44
13 Cambios en las pruebas de la función hepática.....................................................................................44
ii Macrólidos para el asma crónica
Richeldi L, Ferrara G, Fabbri LM, Lasserson TJ, Gibson PG
Esta revisión debería citarse como:

Richeldi L, Ferrara G, Fabbri LM, Lasserson TJ, Gibson PG. Macrólidos para el asma crónica (Revisión Cochrane traducida).
En: La Biblioteca Cochrane Plus, 2008 Número 2. Oxford: Update Software Ltd. Disponible en: http://www.update-software.com.
(Traducida de The Cochrane Library, 2008 Issue 2. Chichester, UK: John Wiley & Sons, Ltd.).
Fecha de la modificación más reciente: 22 de noviembre de 2004
Fecha de la modificación significativa más reciente: 06 de junio de 2005
RESUMEN
Antecedentes
El asma es una enfermedad crónica de las vías aéreas en la cual la inflamación de la mucosa respiratoria juega un papel fundamental.
Los mecanismos responsables del mantenimiento de esta respuesta inflamatoria sólo se conocen parcialmente y existen pruebas
de que la infección crónica por patógenos intracelulares (como la Chlamydia pneumoniae) puede jugar un papel. Los macrólidos
son antibióticos con actividad tanto antimicrobiana como antiinflamatoria y su uso en pacientes asmáticos puede llevar a la
reducción de la inflamación de las vías aéreas y por lo tanto mejorar los síntomas y la función pulmonar.
Objetivos
Determinar la eficacia de los macrólidos en el tratamiento de pacientes con asma crónica.
Estrategia de búsqueda
Se buscó en el Registro Especializado de Ensayos Controlados del Grupo Cochrane de Vías Respiratorias (Cochrane Airways
Group) hasta mayo de 2005. Esta búsqueda también se complementó con búsquedas bibliográficas manuales de revisiones
publicadas con anterioridad, actas de congresos, y contacto con los autores del estudio. En la búsqueda inicial, se incluyeron
todos los idiomas.
Criterios de selección
Ensayos clínicos controlados, aleatorios que involucraran tanto a niños como a pacientes adultos con asma crónica tratados con
macrólidos durante más de 4 semanas, versus placebo.
Recopilación y análisis de datos
Dos revisores examinaron de manera independiente todos los artículos identificados. Dos revisores revisaron de forma independiente
los textos completos de los artículos potencialmente relevantes.
Resultados principales
Siete estudios que reclutaron un total de 416 participantes, cumplieron los criterios de inclusión. La calidad del informe de la
metodología del estudio fue generalmente baja. Se evaluaron los hallazgos de los estudios que el tratamiento con macrólidos
durante al menos 4 semanas en pacientes adultos y pediátricos tratados por asma crónica. Cuatro estudios revelaron un efecto
positivo sobre los síntomas de los macrólidos en diferentes tipos de pacientes asmáticos. Hubo datos limitados disponibles para
el metanálisis. No hubo diferencias significativas en el VEF1 para los ensayos paralelos o cruzados (crossover). Sin embargo,
hubo diferencias significativas en la inflamación eosinofílica y en los síntomas. Un ensayo de grupos paralelos amplio informó
diferencias significativas en el flujo máximo, pero estas diferencias se redujeron después de 6 meses de tratamiento.
Conclusiones de los autores

Teniendo en cuenta el pequeño número de pacientes evaluado, no existen pruebas suficientes para apoyar o refutar el uso de los
macrólidos en pacientes con asma crónica. Se necesitan estudios adicionales, en especial para aclarar el posible papel de los
macrólidos en algunos subgrupos de asmáticos como aquellos con indicios de infección bacteriana crónica.
✦
Página 1
RESUMEN EN TÉRMINOS SENCILLOS
El asma es un trastorno inflamatorio crónico de las vías respiratorias. Los antibióticos macrólidos son fármacos antiinflamatorios
potenciales que pueden ser útiles para el asma. Esta revisión sistemática examinó varios ensayos clínicos controlados aleatorios
de tratamiento antibiótico con macrólidos para el asma. Si bien los resultados apoyan un efecto antiinflamatorio de esta clase de
fármacos para el asma, no hubo beneficios claros para los participantes con asma. Esto pudo deberse a que el diseño del estudio
no fue óptimo. Se necesitan más investigaciones para examinar el papel de los macrólidos en el tratamiento del asma.
✦
ANTECEDENTES
El asma es una enfermedad inflamatoria de las vías aéreas OBJETIVOS

caracterizada por inflamación crónica, hiperreactividad
El objetivo de esta revisión es determinar la eficacia de los
bronquial y sibilancias paroxísticas. Afecta a personas de
macrólidos en el tratamiento de pacientes con asma crónica.
cualquier edad, pero con frecuencia la enfermedad se presenta
en la infancia, especialmente en pacientes alérgicos. Si la
aparición del asma es más tardía, durante la vida adulta, ésta CRITERIOS PARA LA VALORACIÓN DE LOS
puede ser más severa y requerir tratamiento antiinflamatorio ESTUDIOS DE ESTA REVISIÓN
agresivo.
Tipos de estudios
El tratamiento del asma se basa en el uso de medicamentos
antiinflamatorios preferiblemente administrados en forma local La revisión se restringió a ensayos clínicos controlados
o por vía oral, dependiendo de la gravedad de la enfermedad, aleatorios (ECA) que facilitaran pruebas sólidas para la eficacia
con el objetivo de controlar los síntomas respiratorios y de cualquier tratamiento médico. Se prefirieron los ensayos
disminuir la inflamación de las vías aéreas (GINA 2002). Los doble ciego, pero también se revisaron estudios abiertos y
fármacos comúnmente utilizados para el asma son los simple ciego para su posible inclusión. Se consideraron los
broncodilatadores y los corticosteroides. Los tratamientos más estudios publicados en otros idiomas además del inglés sí el
recientes incluyen antileucotrienos para el asma leve a moderada resumen traducido indicaba que el estudio era un ECA de
y fármacos inmunosupresores que solamente se usan en el asma tratamiento con macrólidos para el asma y se solicitó un
no tratable grave y resistente a los esteroides. (Barnes 1996). traductor.
Los macrólidos son antibióticos que son ampliamente utillizados Tipos de participantes
en el tratamiento de varias enfermedades infecciosas, incluyendo Niños y pacientes adultos con asma crónica.
las infecciones respiratorias (Alvarez-Elcoro 1999). Los
Tipos de intervención
informes publicados han revelado un efecto antiinflamatorio
en esta clase de antibióticos, mediante el cual los macrólidos Macrólidos, administrados durante más de 4 semanas, versus
parecen disminuir la hiperreactividad bronquial asociada con placebo. Se agruparon los datos de estudios que compararon
la inflamación eosinofílica (Amayasu 2000), pero no se hallaron diferentes tratamientos con macrólidos.
pruebas sobre una relación fructífera con el tratamiento con Tipos de medidas de resultado
esteroides (Nelson 1993). Sin embargo, los macrólidos como
Se evaluó al menos una de estas medidas de resultado primarias:
la roxitromicina ejercen un efecto importante en el mecanismo
- síntomas asmáticos (incluyendo puntuaciones de síntomas)
molecular de la inflamación asmática. En estudios in vivo e in
- necesidad de medicación para el asma
vitro de modelos humanos y animales se ha demostrado que
- función pulmonar (incluido el flujo espiratorio máximo, FEV1
los macrólidos suprimen la producción de citoquinas como
y el volumen de gas torácico)
IL-5, IL-8, IL-6 y GM CSF, e inhiben la adhesión de neutrófilos
- hiperreactividad bronquial no específica (a la histamina o la
a las células epiteliales, la irrupción respiratoria de neutrófilos
metacolina)
y la secreción de mucus en las vías respiratorias humanas
- menor dosis de corticosteroide en pacientes asmáticos que
(Adachi 1996Konno 1994Koyama 1998).
requieren esteroides
Además, un posible factor desencadenante de la inflamación Medidas de resultado secundarias:
bronquial es la infección crónica por Chlamydia pneumoniae, - número y tipo de efectos secundarios
como se demostró con métodos serológicos en los pacientes - número de retiros del estudio
con asma (Gencay 2001), que puede tratarse con tratamiento - recuento de eosinófilos en muestras sanguíneas periféricas
de macrólidos (Black 1997, Kawasaki 1998, Black 2000). y/o en muestras de esputo
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- mediciones de proteína catiónica eosinofílica (PCE) en suero Consideraciones estadísticas

y esputo. Cuando fue apropiado, los resultados de los ensayos incluidos
se combinaron usando el software Review Manager.
ESTRATEGIA DE BÚSQUEDA PARA LA Las variables de datos continuos se agruparon con diferencia
IDENTIFICACIÓN DE LOS ESTUDIOS de medias ponderada de efectos fijos (DMP) para los ensayos
de grupos paralelos y con una varianza inversa genérica de
La identificación de los ensayos se realizó con el Registro efectos fijos (VIG) para los estudios cruzados (crossover), o
Especializado de Ensayos Controlados del Grupo Cochrane de para los estudios paralelos donde sólo estaban disponibles las
Vías Respiratorias, que se deriva de búsquedas sistemáticas en diferencias de medias.
bases de datos bibliográficas como el Registro Cochrane Central
Los datos de medidas de resultado dicotómicas se agruparon
de Ensayos Controlados (Cochrane Central Register of
con el cociente de riesgo (CR) de efectos fijos.
Controlled Trials [CENTRAL]), MEDLINE, EMBASE y
CINAHL, y búsquedas manuales en revistas respiratorias y Cuando era apropiado se realizaron análisis de sensibilidad
resúmenes de congresos. Para esta revisión, se buscó en el basados en la calidad del estudio. Se realizaron pruebas de
registro usando los siguientes términos: macrolide* OR heterogeneidad. Cuando se observó heterogeneidad (I2 superior
clarithromycin OR troleandomycin OR erythromycin OR a 0%) el agrupamiento se realizó con el modelo de efectos fijos
josamycin OR azithromycin OR roxithromycin y de efectos aleatorios.
Se examinaron las bibliografías y los artículos de revisión Se realizó un análisis de subgrupos basado en la respuesta
identificados a partir de estos trabajos primarios en busca de serológica a la Chlamydia pneumoniae: seropositivo versus
ECA y referencias adicionales. seronegativo
La búsqueda más reciente se efectuó en mayo de 2005.
DESCRIPCIÓN DE LOS ESTUDIOS
MÉTODOS DE LA REVISIÓN La búsqueda de estudios utilizando la estrategia descrita
identificó 99 estudios. Una evaluación preliminar identificó 25
Se comprobaron los resúmenes de los artículos identificados
estudios potencialmente elegibles para su inclusión en la
usando la estrategia de búsqueda anteriormente señalada, y se
revisión sistemática. Entre ellos, los revisores coincidieron al
recuperaron en su totalidad los artículos que parecían cumplir
identificar 7 estudios como ECA, que comparaban el tratamiento
los criterios de inclusión. En el estudio debía incluirse los datos
con macrólidos durante al menos 4 semanas en pacientes adultos
de al menos una de las medidas primarias de resultado.
y pediátricos tratados por asma crónica. Los restantes 18
Cada artículo identificado se recuperó y categorizó dentro de
estudios se excluyeron porque incluían pacientes que no eran
uno de los siguientes grupos:
asmáticos, porque no eran controlados, o eran estudios in vitro,
- incluido: ECA o ECC que cumple con los criterios de inclusión
o debido al corto periodo de tratamiento con macrólidos (menos
descritos y aquellos que no pueden definirse a partir del
de 4 semanas). En la versión inicial de esta revisión había 5
resumen, el título o los títulos MESH;
estudios incluidos. La actualización de esta revisión contiene
- excluido: ensayos que no fueran ECA o ECC.
2 nuevos estudios (Kraft 2002; Kostadima 2004).
Cuando hubo alguna duda, un segundo revisor evaluó el artículo
y se llegó a un consenso. Para descripciones breves de los detalles de los estudios, ver
Se evaluó la calidad metodológica de cada ensayo según una tabla "Características de los estudios incluidos". Para ver los
escala de 0 a 5 basada en el método descrito por Jadad (Jadad detalles completos de cada estudio que se informaron
1996) y se resumió del siguiente modo: narrativamente ver Tabla 01.
1. ¿El estudio es descrito como aleatorio? (sí=1; no=0)
Diseño
2. ¿El estudio es descrito como doble ciego? (sí=1; no=0)
Todos los estudios fueron aleatorios y doble ciego. Hubo 6
3. ¿Hubo una descripción de los retiros y abandonos? (sí=1;
estudios de grupos paralelos (Black 2001; Nelson 1993; Kamada
no=0)
1993; Kostadima 2004; Kraft 2002) y 2 estudios cruzados
4. ¿Se describió adecuadamente y fue apropiado el método de
(crossover) (Shoji 1999; Amayasu 2000).
asignación al azar? (sí=1; no=0)
5. ¿Se describió correctamente y era adecuado el método de Participantes
doble cegamiento? (sí=1; no=0) Se reclutó un total de 416 participantes en los estudios de la
6. Resta 1 punto sí los métodos de asignación al azar o revisión. Se describió a todos los participantes como pacientes
cegamiento fueron inapropiados. con asma. Sólo un estudio evaluó los efectos del tratamiento
Además, cada estudio se evaluó con respecto a la fiabilidad del con macrólidos en el asma pediátrica (Kamada 1993), los
diagnóstico de asma utilizando los criterios preespecificados restantes estudios reclutaron pacientes con asma de más de 18
(véase más arriba). años de edad. Según los criterios de GINA 2002 sobre la
Página 3
gravedad del asma, los estudios eran heterogéneos. La gravedad (diferencia media: -0,05 litros [IC del 95%: -0,31 a 0,21];
inicial del asma de los participantes en los estudios se clasificó Amayasu 2000; Shoji 1999).
como: intermitente (Amayasu 2000); leve (Shoji 1999); leve
FEM: No se pudieron realizar metanálisis para esta medida de
persistente (Kostadima 2004); moderada intermitente (Kraft
resultado. Black 2001 informó una diferencia significativa al
2002) y grave (Nelson 1993;Kamada 1993). La clasificación
término de las 6 semanas de tratamiento de 6 L/minuto para el
de Black 2001 no fue posible por una notificación inadecuada
FEM matutino (P = 0,04); y 8 L/minuto para el FEM vespertino
de los fármacos al inicio.
(P = 0,02). Sin embargo, hubo un posterior aumento de los
Intervenciones valores del FEM matutino y vespertino en ambos grupos en los
Dos estudios compararon roxitromicina con placebo (Black 6 meses posteriores a la finalización del tratamiento, donde la
2001; Shoji 1999), 2 estudios compararon claritromicina con magnitud de la mejoría en ambos grupos resultó en una
placebo (Amayasu 2000; Kraft 2002), un estudio evaluó los diferencia no significativa 6 meses después del abandono del
efectos de la claritromicina (Kostadima 2004), y 2 estudios mismo.
evaluaron los efectos de la troleandomicina además del
Consumo de corticosteroides: No hubo diferencias significativas
tratamiento con esteroides orales como parte de un protocolo
en la cantidad de esteroides orales consumidos (DME -0,32 [IC
de reducción de esteroides (Kamada 1993; Nelson 1993).
del 95%: - 0,81 a 0,18]), Nelson 1993; Kamada 1993).
Medidas de resultado
Medidas de resultado secundarias
Todos los estudios midieron la función pulmonar como FEV1,
Síntomas diurnos y nocturnos: No se pudo realizar un
CVF, FEM o como una prueba de provocación del alérgeno. metanálisis con estas medidas de resultado. Black 2001 informó
Todos los estudios midieron los síntomas con la excepción de que tanto las puntuaciones de síntomas diurnos como nocturnos
Kostadima 2004 y Kraft 2002. exhibieron una mejoría no significativa en el grupo tratado en
comparación con el grupo placebo en el periodo de estudio de
6 meses.
CALIDAD METODOLÓGICA
Síntomas: Hubo una diferencia a favor del macrólido en la
De acuerdo con la puntuación de Jadad, la calidad de la reducción de síntomas (-1,25 unidades de DE [IC del 95%: -1,8
metodología informada en los estudios fue generalmente baja a -0,7]; Amayasu 2000; Shoji 1999).
(Jadad 1996). Solamente un estudio obtuvo una calificación de
3, dos una calificación de 2 y dos una calificación de 1 (Nelson Tolerabilidad al fármaco y retiros: no se informaron diferencias
1993. ECA: puntuación de Jadad: 2;Kamada 1993. ECA: significativas en los estudios individuales en cuanto los retiros
puntuación de Jadad: 3; Shoji 1999. ECA: puntuación de Jadad: (Kostadima 2004) o para los eventos gastrointestinales (Black
1; Amayasu 2000. ECA: puntuación de Jadad: 1; Black 2001. 2001). No hubo diferencias significativas en la cantidad de
ECA: puntuación de Jadad: 2; Kraft 2002. ECA: puntuación de participantes que experimentaron cambios en la función hepática
Jadad: 1; Kostadima 2004. ECA: puntuación de Jadad: 2). (CR: 4,66 [IC del 95%: 0,88 a 24,6]; Black 2001; Kamada
1993). NB para los datos de Kamada 1993, se combinaron los
datos de todos los participantes que tomaron un macrólido en
RESULTADOS dos grupos de tratamiento activo (macrólido más
metilprednisolona [N = 6], y macrólido más prednisona [N =
Los datos se presentaron según la medición de resultado antes 7]).
descrita. Se analizaron los datos de los estudios que compararon
macrólidos con placebo. Los datos narrativos completos de Amayasu 2000 y Kostadima 2004 informaron que fue necesario
cada estudio se presentaron en la Tabla 02. un aumento de la metacolina para causar una disminución del
20% en el VEF1 en pacientes asmáticos después del tratamiento
Medidas de resultado primarias
con claritromicina. Lamentablemente, los diferentes métodos
VEF1: No hubo diferencias estadísticamente significativas entre
para la prueba de provocación de metacolina que se utilizaron
macrólidos y placebo para los estudios cruzados (crossover) en los dos grupos y la forma distinta de informar los datos no
(diferencia de medias: 0 Litros [IC del 95%: -0,33 a 0,34], permiten realizar un metanálisis sobre esta medida de resultado.
Amayasu 2000; Shoji 1999; Kraft 2002). Black 2001 no informó El estudio Shoji 1999 usó una prueba específica de provocación
diferencias significativas en el VEF1 entre ambos grupos de distinta en un subgrupo especial de pacientes asmáticos
tratamiento. Se utilizó una medida estandarizada para analizar (asmáticos intolerantes a la aspirina), y no reveló efectos de la
los datos de dos ensayos de grupos paralelos. La estimación del roxitromicina en esta prueba.
efecto agrupado no fue significativa (unidades de DE: -0,22
[IC del 95%: -0,6 a 0,16]; Kraft 2002; Kostadima 2004).
DISCUSIÓN
CVF: Sin diferencias estadísticamente significativas entre los
macrólidos y el placebo para los estudios cruzados (crossover) Los macrólidos se propusieron como agentes ahorradores de
esteroide desde 1974 (Spector 1974) para el tratamiento de
Página 4
pacientes asmáticos que requieren esteroides. Los efectos de hipersensibilidad bronquial después del tratamiento con
antiinflamatorios de la roxitromicina y la claritromicina son claritromicina, y destacaron un efecto clínico potencial apoyado
bien conocidos y estos fármacos por lo tanto podrían ser útiles por la disminución de marcadores proinflamatorios. Se necesitan
para el tratamiento de la enfermedad inflamatoria crónica del estudios más amplios bien diseñados para evaluar este posible
asma bronquial (Black 1997). Además, recientemente se ha efecto beneficioso, si se considera que: la cantidad de pacientes
indicado el empleo del efecto antimicrobiano de los macrólidos en los dos estudios fue limitada, los métodos utilizados fueron
para el tratamiento de la infección respiratoria crónica, debido diferentes y que una prueba específica de provocación (Shoji
a la infección concomitante por Chlamydia pneumoniae en 1999) no se vio afectado por el tratamiento con roxitromicina.
pacientes asmáticos como una intervención terapéutica
No se han informado efectos secundarios significativos. Sin
potencialmente relevante (Black 2000; Gencay 2001).
embargo, el escaso número de sujetos en estos estudios limita
A pesar de estos antecedentes, existen pocas pruebas sobre la la generalizabilidad de los hallazgos y su uso en la atención
utilidad clínica de los macrólidos en el asma a partir de los ECA clínica de rutina.
disponibles. La interpretación de los datos provenientes de los
Además, la mayoría de los estudios indican que las
7 ECA incluidos en la presente revisión también se ve
intervenciones educacionales serían muy útiles en la aplicación
obstaculizada por tres factores:
del mejor tratamiento antiasmático que se requiera. Estudios
Primero, se han usado diferentes tipos de intervenciones en los que utilizaron troleandomicina (Nelson 1993; Kamada 1993)
diferentes estudios. La troleandomicina (Nelson 1993 y Kamada informaron una disminución significativa en las dosis de
1993) no mostró un efecto economizador de esteroides y fue corticosteroides orales necesarias para controlar los síntomas,
retirada por los efectos secundarios hepáticos. Roxitromicina con una reducción significativa en la hipersensibilidad
(Shoji 1999; Black 2001) y claritromicina (Amayasu 2000; bronquial. El aumento en los indicadores de efectos secundarios
Kostadima 2004; Kraft 2002) son antibióticos macrólidos más como el colesterol y la glucemia en ayunas, y la reducción
recientes que parecen tener efectos antiinflamatorios. Su efecto menos significativa en la densitometría ósea descrita por Nelson
ahorrador de esteroide no ha sido evaluado. 1993, no confirmaron la utilidad del efecto de ahorro de
esteroides de la troleandomicina, pero también revelaron un
Segundo, se incluyeron varios tipos de pacientes asmáticos, lo
efecto perjudicial con el aumento de los efectos adversos
que implica diferentes subgrupos de asmáticos y de esta manera
potenciales del tratamiento con esteroides.
los hallazgos son menos aplicables a los pacientes de asma
"habituales". Dos estudios incluyeron pacientes asmáticos que Por último, los resultados de un amplio estudio multicéntrico
requerían esteroides orales, los cuales se pueden considerar que multinacional (Black 2001), parecen indicar un efecto de la
representan a los pacientes afectados por asma persistente grave roxitromicina sobre la función pulmonar en pacientes asmáticos
(Kamada 1993; Nelson 1993), mientras que un estudio incluyó con evidencia serológica de Chlamydia pneumoniae, incluso
pacientes asmáticos con intolerancia a la aspirina (Shoji 1999), cuando el estudio no da respuesta a numerosas preguntas acerca
otro incluyó pacientes con asma alérgicos, que sufrían asma del papel de las infecciones crónicas sobre el asma (Johnston
intermitente (GINA 2002) y 2 estudios (Black 2001 y Kraft 2001). Por consiguiente, los resultados de este estudio no
2002) incluyeron pacientes asmáticos con pruebas serológicas establecen claramente las funciones relativas de los efectos
de una infección por Chlamydia pneumoniae. antimicrobianos y antiinflamatorios de los macrólidos en los
pacientes asmáticos. Sin embargo, este primer ensayo aleatorio
Tercero, las medidas de resultado fueron heterogéneas entre
reveló que posiblemente la roxitromicina cumpla una función
los estudios. En cada estudio, sólo se registraron síntomas de
en el tratamiento de los pacientes con asma crónica, aún cuando
asma (mediante diferentes escalas); por lo general se realizaron
los efectos del tratamiento parecen ser de escasa magnitud y
pruebas de la función pulmonar y pruebas de provocación de
sólo se presentan durante el tratamiento continuo.
metacolina con diferentes metodologías o parámetros.
A pesar de estas limitaciones, todos los estudios indicaron
algunos efectos de los macrólidos sobre la reducción de los CONCLUSIONES DE LOS AUTORES
síntomas y la mejoría de la función pulmonar. En particular, el
Implicaciones para la práctica
metanálisis de 2 estudios diferentes (Amayasu 2000; Shoji
1999), aunque en dos subgrupos diferentes de pacientes Aunque algunos datos clínicos indican un efecto positivo de
(alérgicos e intolerantes a la aspirina) y utilizando diferentes los macrólidos en pacientes asmáticos en ausencia de efectos
moléculas (roxitromicina y claritromicina) indicó una mejoría secundarios de relevancia, por el momento, estos datos son
en la puntuación de los síntomas, una reducción significativa insuficientes para recomendar el uso sistemático de macrólidos
de los marcadores de inflamación eosinofílica (recuento de para controlar el asma.
eosinófilos, PCE en sangre o en esputo), por lo que añade Implicaciones para la investigación
pruebas adicionales de un posible efecto antiinflamatorio de
Se necesitan estudios adicionales para evaluar la utilidad clínica
los macrólidos en los pacientes asmáticos. Dos estudios
tanto del efecto antiinflamatorio como del antimicrobiano de
(Kostadima 2004 y Amayasu 2000) informaron una supresión
Página 5
los macrólidos en poblaciones más grandes de pacientes, POTENCIAL CONFLICTO DE INTERÉS

seleccionando pacientes con una mejor estratificación según la
gravedad del asma, con especial énfasis en los asmáticos con Ninguno conocido.
marcadores de infección por agentes intracelulares y para la
evaluación de la seguridad a largo plazo. Más aún, los estudios
futuros se deberían focalizar en subgrupos de personas FUENTES DE FINANCIACIÓN
"sensibles al tratamiento" y dirigirse hacia aspectos de la
Recursos externos
duración del tratamiento y el posible surgimiento de bacterias
resistentes al fármaco. • Consorzio Ferrara Ricerche ITALY
• Associazione per la Ricerca e la Cura dell'Asma (ARCA)
ITALY
AGRADECIMIENTOS
Recursos internos
Los autores desean agradecer a Makiko Meguro su ayuda gentil
en la traducción de documentos japoneses y a Toby Lasserson • La información sobre los recursos de apoyo no está
sus sugerencias en el proceso de actualización. disponible
✦
REFERENCIAS Referencias de los estudios excluidos de esta revisión
Referencias de los estudios incluidos en esta revisión Andrade 1983

Andrade WP, Renard RL, Nelson HS. The effect of troleandomycin and
Amayasu 2000 {published data only} methylprednisolone alone and in combination on bronchial sensitivity to
*Amayasu H, Yashida S, Ebana S, Yamamoto Y, Nishikawa T, Shoji T, methacholine. Annals of Allergy 1983;51:515-7.
et al. Clarithromycin suppress bronchial hyperresponsiveness associated
with eosinophilic inflammation in patients with asthma. Annals of Allergy, Ball 1990
Asthma and Immunology 2000;84(6):594-8. Ball BD, Hill MR, Brenner M, Sanks R, Szefler SJ. Effect of low-dose
troleandromycin on glucocorticoid pharmacokinetics and airway
Black 2001 {published data only} hyperresponsiveness in severily asthmatic children. Ann Allergy
*Black P, Jenkins CR, Scicchitano R, Blasi F, Allegra L, Mills G, et al. 1990;65:37-45.
Randomised, controlled trial of roxithromycin for the treatment of asthma
in subjects with serological evidence of infection with Chlamydia Cogo 1994
pnaumoniae. American Journal of Respiratory and Critical Care Medicine Cogo R, Caiazzo G, De Luca P, Boddi V, De Luca M, Casini A. Effect of
2001;164(4):536-41. miocamycin and amoxicillin/clavulonate on total serum immunoglobulin
E levels in patients with infectious exacerbations of allergic asthma: a
Kamada 1993 {published data only} crossover trial. Current Therapeutic Research 1994;55:184-98.
*Kamada AK, Hill MR, Iklé DN, Brenner AM, Szefler SJ. Efficacy and
safety of low-dose troleandomycin therapy in children with severe, Ebling 1984
steroid-requiring asthma. Journal of Allergy and Clinical Immunology Ebling WF, Szefler SJ, WJ Jusko. Analysis of cortisol, methylprednisolone,
1993;91:873-82. and methylprednisolone hemisuccinate. Absence of effects of
troleandomycin on ester hydrolysis. Journal of Chromatography
Kostadima 2004 {published data only} 1984;105:271-80.
*Kostadima E, Tsiodras S, Alexopoulos EI, Kaditis AG, Mavrou I,
Georgatou N, Papamichalopoulos A. Clarithromycin reduces the severity Feldman 1997
of bronchial hyperresponsiveness in patients with asthma. European Feldman C, Anderson R, Theron AJ, Ramafi G, Cole PJ, Wilson R.
Respiratory Journal 2004;23(5):714-7. Roxithromycin, clarithromycin, and azithromycin attenuate the injurious
effects of bioactive phospholipids on human respiratory epithelium in vitro.
Kraft 2002 {published data only} Inflammation 1997;21(6):655-65.
*Kraft M, Cassell GH, Pak J, Martin RJ. Mycoplasma pneumoniae and
Chlamydia pneumoniae in asthma: effect of clarithromicyn. Chest Gotfried 2004
2002;121(6):1782-8. Gotfried MH, Jung R, Messick CR, Rubinstein I, Garey KW, Rodvold KA,
Danzinger LH. Effects of six-week clarithromycin therapy in
Nelson 1993 {published data only} corticosteroid-dependent asthma: a randomized, double-blind,
*Nelson HS, Hamilos DL, Corsello PR, Levesque NV, Buchmeier AD, placebo-controlled pilot study. Current Therapeutic Research
Bucker BL. A double-blind study of troleandomycin and methylprednisolone 2004;65(1):1-12.
in asthmatic subjects who require daily corticosteroids. American Review
of Respiratory Disease 1993;147:398-404. Hueston 1991
Hueston WJ. A comparison of albuterol and erythromycin for the treatment
Shoji 1999 {published data only} of acute bronchitis. Journal of Family Practice 1991;33:476-80.
*Shoji T, Yoshida S, Sakamoto H, Hasegawa H, Nakagawa H, Amayasu
H. Anti-inflammatory effect of roxithromycin in patients with Itkin 1970
aspirin-intolerant asthma. Clinical and Experimental Allergy 1999;29:950-6. Itkin IH, Menzel ML. The use of macrolide antibiotic substances in the
treatment of asthma. Journal of Allergy 1970;45(3):146-62.
Página 6
Kaplan 1958 Black 2000

Kaplan. Antibiotics Annual 1958-1959:273-6. Black PN, Scicchitano R, Jenkins CR, Blasi F, Allegra L, Wlodarczyk J,
Cooper BC. Serological evidence of infection with Chlamidia pneumoniae
Koh 1997 is related to the severity of asthma. European Respiratory Journal
Koh YY, Lee MH, Sun YH, Sung KW, Chae JH. Effect of roxithromycin 2000;15:254-9.
on airway responsiveness in children with bronchiectasis: a double-blind,
placebo-controlled study. European Respiratory Journal 1997;10:994-9. Eitches 1985
Eitches RW, Rachelefsky GS, Katz RM, Mendoza GR, Siegel SC.
Spector 1974a Methylprednisolone and troleandomycin in treatment of steroid-dependent
Spector SL, Katz FH, Farr RS. Troleandomycin: effectiveness in asthmatic children. American Journal of Diseases of Children
steroid-dependent asthma and bronchitis. Journal of Allergy and Clinical 1985;139:264-8.
Immunology 1974;54(6):367-79.
Gencay 2001
Szefler 1980 Gencay M, Rudiger JJ, Tamm M, Solér M, Perruchoud AP, Roth M.
Szefler SJ, Rose JQ, Ellis EF, Spector SL, Green AW, Jusko WJ. The effect Increased frequency of Chlamydia pneumoniae antibodies in patients with
of troleandomycin on methylprednisolone elimination. Journal of Allergy asthma. American Journal of Respiratory and Critical Care Medicine
and Clinical Immunology 1980;66(6):447-51. 2001;163:1097-100.
Szefler 1982 GINA 1995
Szefler SJ, Brenner M, Jusko WJ, Spector SL, Flesher KA, Ellis EF. Dose- NHLBI/WHO Workshop Report. Global strategy for asthma management
and time-related effect of troleandomycin on methylprednisolone and prevention. Global Initiative for Asthma. 1995.
elimination. Clinical Pharmacology and Therapeutics 1982;32(2):166-71.
GINA 2002
Szefler 1982a NHLBI/WHO. Global Strategy for Asthma Management and Prevention.
Szefler SJ, Ellis EF, Brenner M, Rose JQ, Spector SL, Yurchak AM, et al. Global Initiative for Asthma. 2002.
Steroid-specific and anticonvulsivant interaction aspects of
troleandomycin-steroid therapy. Journal of Allergy and Clinical Immunology Hann 1998
1982;69(5):455-60. Hann DL, Bukstein D, Luskin A, Zeitz H. Evidence for Chlamydia
pneumoniae infection in steroid-dependent asthma. Annals of Allergy Asthma
Takamura 2001 and Immunology 1998;80:45-9.
Takamura M, Odashima Y, Iikura H. Continuous low-dosage macrolide
therapy in children with bronchial asthma. Japanese Journal of Antibiotics Jadad 1996
2001;54(Suppl C):9-11. Jadad A, Moore RA, Carroll D, Jenkson C, Reynolds JM, Gavaghan DJ,
McQuay HJ. Assessing the quality of reports of randomised controlled
Wald 1986 trials: is blinding necessary?. Controlled Clinical Trials 1996;17:1-12.
Wald JA, Friedman BF, Farr RS. An improved protocol for the use of
troleandomycin (TAO) in the treatment of steroid-requiring asthma. Journal Johnston 2001
of Allergy and Clinical Immunology 1986;78:36-43. Johnston SL. Is Chlamydia pneumoniae important in asthma?. American
Journal of Respiratory and Critical Care Medicine 2001;164(4):513-4.
Weinberger 1977
Weinberger MW, Hudgel D, Spector S, Chidsey C. Inhibition of Kawasaki 1998
theophylline clearence by troleandomycin. Journal of Allergy and Clinical Kawasaki S, Takizawa H, Ohtoshi T, Takeuchi N, Kohyama T, Nakamura
Immunology 1977;59(3):228-31. H, et al. Roxithromycin inhibits cytokine production by and neutrophil
attachment to human bronchial epithelial cells in vitro. Antimicrobial Agents
Zeiger 1980 and Chemotherapy 1998;42(6):1499-502.
Zeiger RS, Schatz M, Sperling W, Simon RA, Stevenson DD. Efficacy of
troleandomycin in outpatients with severe, corticosteroid-dependent asthma. Konno 1994
Journal of Allergy and Clinical Immunology 1980;66(6):438-46. Konno S, Asano K, Kurokawa M, Ikeda K, Okamoto K, Adachi M.
Antiasthmatic activity of a macrolide antibiotic, roxithromycin: analysis
Referencias adicionales of possible mechanisms in vitro and in vivo. International Archives of
Allergy and Immunology 1994;105(3):308-16.
Adachi 1996
Adachi T, Motojima S, Hirata A. Eosinophil apoptosis caused by Koyama 1998
theophylline, glucocorticoids, and macrolides after stimulation with IL-5. Koyama T, Takizawa, Kawasaki S, Takami K, Otoshi T, Ito K. Effects of
Journal of Allergy and Clinical Immunology 1996;98:S207-S215. various drugs on IL-8 production by eosinophils collected from patients
with allergic inflammation. Japanese Journal of Antibiotics 1998;51:131-3.
Alvarez-Elcoro 1999
Alvarez-Elcoro S, Enzler MJ. The macrolides: erythromycin, clarithromycin, Nelson 1993
and azithromycin. Mayo Clinic Proceedings 1999;74(6):613-34. Nelson HS, Hamilos DL, Corsello PR, Levesque NV, Buchmeier AD,
Bucher BL. A double-blind study of troleandomycin and methylprednisolone
ATS 1987 in asthmatic subjects who require daily corticosteroids. American Review
ATS Scientific Assembly on Clinical Problems. Standards for the diagnosis of Respiratory Disease 1993;147:398-404.
and care of patients with chronic obstructive pulmonary disease (COPD)
and asthma. American Review of Respiratory Disease 1987;136:225-44. Spector 1974
Spector SL, Katz FH, Farr RS. Troleandomycin: effectiveness in
Barnes 1996 steroid-dependent asthma and bronchitis. Journal of Allergy and Clinical
Barnes PJ. Immunomodulation as asthma therapy: where do we stand?. Immunology 1974;54:367-9.
European Respiratory Journal. Supplement 1996;22:154s-159s.
Black 1997 * El asterisco señala los documentos más importantes para este estudio
Black PN. Anti-inflammatory effects of macrolide antibiotics. European
Respiratory Journal 1997;10:971-2.
Página 7
TABLAS
Characteristics of included studies

Study Amayasu 2000
Methods Randomised controlled trial, double blind, placebo controlled. Crossover study -
Statistical analysis: Student's paired t test.
Participants 17 adult patients with allergy-induced asthma
Interventions Clarithromycin 200 mg twice a day) vs placebo
Outcomes Blood eosinophils, blood neutrophils, serum ECP, sputum eosinophils, sputum
neutrophils, sputum ECP, symptom score, FVC, FEV1, methacoline challenge
Notes
Allocation concealment A
Study Black 2001
Methods Randomised controlled trial, double blind, placebo controlled, multicenter, multinational
Participants 219 asthmatic patients
Interventions Roxithromycin vs placebo
Outcomes Symptoms, PEFR
Notes
Allocation concealment A
Study Kamada 1993
Methods Randomised controlled trial, double blind, placebo controlled
Participants 19 patients (ages 6 to 17 years)
Interventions Troleandomycin (250 mcg) + methylprednisolone once daily vs troleandomycin (250
mcg) + prednisolone once daily vs placebo + methylprednisolone once daily
Outcomes Symptoms score, metacholine PD20, glucocorticoid dose reduction, FEV1
Notes
Allocation concealment B
Study Kostadima 2004
Participants 75 patients (aged 18-70 yrs)
Interventions -Group A: charitromycin 250 mg b.i.d. for 8 weeks
-Group B: chlaritromycin 250 t.i.d. for 8 weeks
-Group C: placebo dextrose tablets for 8 weeks.
Outcomes methacoline PD20
Notes
Study Kraft 2002
Página 8
Characteristics of included studies

Participants 55 patients, 31 of them with evidence of C. pneumomiae or M. pneumoniae infection
(aged 33.4 SD 1.2)
Interventions -clarithromycin 500 mg bid for 6 weeks
-placebo for 6 weeks
Outcomes Lung function, cytokine in situ production
Notes
Study Nelson 1993
Participants 75 asthmatic adult patients
Interventions Troleandomycin (250 mcg) + methylprednisolone vs placebo + methylprednisolone
Outcomes Symptoms score, corticosteroids dose, blood eosinophil count, IgG, fasting blood sugar,
metacholine P20
Notes
Study Shoji 1999
Methods Randomised controlled trial, double blind, placebo controlled. Crossover study -
Statistical analysis: Student's paired t test
Participants 14 adult patients with aspirin-intolerant asthma
Interventions Roxithromycin (150 mg twice a day) vs placebo
Outcomes Blood eosinophils, blood neutrophils, serum ECP, sputum eosinophils, sputum
neutrophils, sputum ECP, symptom score, FVC, FEV1, methacoline challenge
Notes
Página 9
Characteristics of excluded studies

Study Reason for exclusion
Andrade 1983 Study period too short (6 days) and randomisation method not adequate.
The study was designed to assess the effect of troleandomycin and methylprednisolone
alone or in combination on bronchial hyper responsiveness in mild asthmatic patients. RCT:
Jadad score: 1. Patients: 8 patients (4 males and 4 females) aged 20 to 42 years, all with
symptoms of mild chronic obstructive airways disease, with FEV1 > 80% of predicted, and
with a fall in FEV1 equal or greater than 20% of predicted were enrolled. Treatment required
by patients was not reported, but all patients were able to discontinue therapy for 7 days with
no change in lung function tests. Using the GINA score system (GINA 2002), all patients
could be classified in the milder class of asthma (1th group, intermittent asthma). Type of
interventions: each patient was assigned to 4 treatments groups in a random order: placebo
/ placebo; methylprednisolone (4 mg QID) / placebo; troleandomycin (250 mg QID) / placebo;
troleandomycin (250 mg QID) / methylprednisolone (4 mg QID). All patients took medications
4 times daily for 5 days and once in the sixth day. A wash out period of five to seven days
followed each drug combination. Methacholine test was performed at the sixth day of
treatment, as well as pulmonary function tests and complete blood count, liver function tests
and electrolytes. Data was analysed by two ways analysis of variance. Outcome
measurements. Bronchial hyper responsiveness: sensitivity to inhaled methacholine was not
significantly altered by any of the drug combinations used. Data were not clearly reported.
Side effects: authors reported a mild increase in liver function tests in the period of
administration of troleandomycin. Not explained in how many patients side effects were
recorded. No change in blood count was reported. Authors concluded that the combination
of methylprednisolone and troleandomycin failed to reduce methacholine sensitivity in mild
asthmatic patients. The short period of 6 days of treatment was justified by previous
observations that an effect in severe asthmatic patients was described in few days. Exclusion
criteria: this study was excluded because the shortness of the treatment period and for a not
clear method of randomisation of patients.
Página 10

Ball 1990
Página 11

Study period too short (2 weeks).
Designed to assess the effect of troleandomycin on glucocorticoid pharmacokinetics and on
asthma symptoms and lung function tests in a group of severe asthmatic patients requiring
chronic steroid therapy. RCT: Jadad score: 2. Patients: 18 severe asthmatic children requiring
daily dose of systemic steroids for poorly controlled asthmatic symptoms with conventional
treatments including (theophylline, inhaled beta-agonists 4 times daily, a dose of oral
prednisone > 20 mg/daily). Using the GINA score system (GINA 2002), all patients were
classified in the more severe class of asthma (4th group, severe persistent asthma). Exclusion
criteria included: clinical evidence of viral infections 4 weeks before study onset, abnormal
hepatic or renal function, pregnancy, smoking, anaemia, thrombocytopenia, concurrent
therapy with anticonvulsives, erythromycin, rifampin, oral contraceptives, ergotamine; all
conditions of complicating illness not adequately treated, including severe psychiatric
disorders. Non-compliance to study treatments. Types of interventions: patients were
randomised in three groups: troleandomycin (250 mg)/methylprednisolone (minimal dose of
maintenance reached in every patient, 4/5 of the equivalent prednisolone dose) once daily;
troleandomycin (250 mg)/prednisolone (minimal dose of maintenance reached in every
patient) once daily; placebo/methylprednisolone (minimal dose of maintenance reached in
every patient, 4/5 of the equivalent prednisolone dose) once daily; all patients continued their
optimal conventional antiasthmatic concurrent therapy. Steroids dose was tapered by 20%
every two days for a period of two weeks. Results: 3 patients were discontinued, 2 for
concurrent upper airways viral infections, 1 for concurrent abdominal surgery (not indicated
the group of randomisation). 15 patients (5 for each group) completed the 2 weeks trial (6
females, 9 males, age between 9.5 and 18 years, history of asthma of minimum of 2.5 years,
requiring oral steroids from at least 6 months to a maximum of 13 years). 1 patient in the
troleandomycin/prednisolone group required surgery on day 12, remaining in the study
although she required daily prednisone for two days prior to surgery. Outcome measures:
clinical response and required asthma medications: all patients have been able to tolerate
a 50% reduction in their steroid dose in all the three groups. No patient required more than
1 extra inhaled beta-agonist treatment per week.
Only 1 patient in the placebo group showed a deterioration of the symptoms score (not
specified scale of evaluation). Pulmonary function tests: body plethysmography performed
at the start and the end of the 2 week trial: reported a trend for improvement in the
troleandomycin/methylprednisolone, no change in the 2 other groups, despite steroids dose
reduction. FEV1 showed the greatest improvement in the troleandomycin/methylprednisolone.
No statistical analysis was reported. Methacholine response: 4 of the 5 patients in the
troleandomycin/methylprednisolone group, 2 of the 5 patients in the
troleandomycin/prednisolone group showed a decrease of airways hyper-responsiveness to
methacholine from 3 to 30 fold at the end of study. Kruskall-Wallis test demonstrated a not
significant difference (p=0.26) in the changes of these parameters, probably due to the
inadequate sample size as well as for variability in the response. Laboratory analyses: no
change in liver function was reported. Total circulating eosinophils were reduced in 3 of 5
patients in the troleandomycin/methylprednisolone group, in 1 patient in the
troleandomycin/prednisolone group and in 1 patient treated with placebo. The count raised
in all the other patient. No statistical analyses were performed, data of 1 patient lost in the
troleandomycin/prednisolone group. Pharmacokinetics: troleandomycin reduced the
methylprednisolone clearance of 62%. No effect on prednisolone elimination. Adverse effects:
three adverse clinical experiences were reported: 1 patient in the troleandomycin/prednisolone
group developed acute appendicitis. One patient in the troleandomycin/methylprednisolone
was dropped for an acute abdomen requiring surgery. One patient who was receiving high
dose of steroids developed an increased intraocular pressure in the placebo group, requiring
methylprednisolone treatment, not otherwise specified. After end of the study period, remaining
in the troleandomycin/prednisolone treatment, 1 patient developed a psychotic depression
(history of psychiatric disorders in the past was present). The Authors concluded that a low
dosage of troleandomycin resulted in a significant reduction of methylprednisolone clearance.
Página 12

However, the clinical response to troleandomycin / methylprednisolone therapy was considered
to be greater than if only due to this effect on steroid level and an independent effect on
airways hyper-responsiveness is important to define, although in the lack of statistical
significance in the study. The ability of all the patients to tolerate a reduction of 50% of the
dose of steroid was explained with the hypothesis of its distribution in the airways with an
accumulation effect. The Authors recognised the need for well designed, targeted to
"troleandomycin responders", and longer studies to test the utility of troleandomycin in
asthmatic patients. Exclusion criteria: the study was excluded due to the short (2 weeks)
period of treatment.
Página 13

Cogo 1994 Lack of blinding, study of inadequate duration, lack of outcome measures.
The study by Cogo 1994 and coworkers assessed the clinical efficacy and effect on total
serum immunoglobulin E (IgE) of miocamycin compared to amoxicillin/clavulanate in the
treatment of infectious exacerbations of bronchial asthma. This is not a RCT. Open,
randomised crossover trial, Jadad score: 0. Patients: 42 patients with pollen asthma and
infectious exacerbation, probably of bacterial origin were enrolled. Inclusion criteria were:
fever, increase in frequency and seriousness of cough, increased expectoration of
mucopurulent sputum with possible haemoptysis and increased dyspnoea and wheezing.
Exclusion criteria were: radioallergosorbent test for penicillin and/or other macrolides,
pharmacologic therapy with drugs able to induce IgE production. No classification of patients
in classes of severity is possible because the lack of symptoms and treatment assessment.
Types of interventions. Each patient underwent two antibiotic treatments with each of the
test drug, in the occasion of two successive infectious exacerbations, according to a crossover
design; the treatments were: 5 - 10 days therapy with miocamycin (1.8 gm/day in three
administrations); 5 - 10 days therapy with amoxicillin/clavulanate (2 gm/day in two
administrations). A 25 - 30 days washout period was required between treatments.
Measurements of total serum IgE at the day 0-15-35 and 50 was performed in the same
laboratory. At the same time hematochemic and clinical tests were performed (not specified).
Non parametric tests were used for statistical analyses (Wilcoxon-Mann-Whitney test). To
evaluate the different effect of the treatments on total serum IgE level, data for analyses were
first transformed following Clayton-Hills procedure.
9 patients were lost at the first follow-up. Among the 33 remaining, 16 (9 M and 7 F, mean
age 24.9 years) were assigned to miocamycin group, while 17 (11 M and 6 F, mean age 23.6
years) were assigned to amoxicillin/clavulanate group. 17 resulted to be un assessable, either
because absence or a second infectious exacerbation, or because the IgE measurements
were not done. The remaining 16 patients completed the protocol, 9 ( were assigned to the
miocamycin group, 7 in the amoxicillin-clavulanate group. Outcomes measurements. Baseline
IgE levels were not significantly different between treatment groups (p=0.21). as at the start
of the second treatment period (p=0.21). Miocamycin group showed a median IgE value of
300 IU at the end of the first period and 320 IU at the end of the second treatment with
amoxicillin/clavulanate. Amoxicillin/clavulanate showed a median value of 428 IU at the end
of the first period, and of 410 IU at the end of the retreatment with miocamycin. Differences
among levels at baseline and at the end of each period were calculated (as medians and
standard deviation). Transformations for calculated values were performed following
Clayton-Hills procedure. A significant difference were found between the overall effect of the
treatments on IgE level (p<0.05). No differences were reported for symptoms and blood
chemistry analysis. 5 patients among 26 (19%) treated with miocamycin reported gastralgia,
while 9 among 28 (32%) patients in amoxicillin/clavulanate treatment experienced side effects:
1 gastralgia, the other increased frequency or intensity of asthma attacks (data not showed).
Authors concluded that because treatment of infectious exacerbations of asthmatic attacks
with amoxicillin/clavulanate caused a significant increased of IgE levels and was likelier to
cause adverse effects, the use of miocamycin was preferable in asthmatic patients, with an
equivalent clinical efficacy. Exclusion criteria: this trial was excluded because the lack of a
blindness, for the too short period of treatments and for lack of outcomes measurements
considered in the review.
Ebling 1984 Basic science study.
Study focuses on a high performance liquid chromatographic assay for the simultaneous
measurement of cortisol and methylprednisolone using dexamethasone as the internal
standard. This assay has been applied in pharmacokinetic studies in 1 patient with severe
steroid requiring asthma regarding troleandomycin-methylprednisolone interactions: Although
methylprednisolone elimination is reduced in the presence of troleandomycin therapy, no
effect was found on the pharmacokinetic of methylprednisolone sodium succinate. Exclusion
criteria: basic science study.
Página 14

Feldman 1997 Basic science in vitro study.
This in vitro study was conducted with the aim to demonstrate a protective effect of 3
macrolides (roxithromycin, clarithromycin and azithromycin) on bronchial epithelium against
pro-inflammatory action of bio active phospholipids (PL), platelet-activating factor (PAF),
lyso-PAF and lysophosphatidylcholine (LPC).
Cultures of human ciliated epithelium were incubated with the three pro-inflammatory agents
and ciliary beat frequency (CBF) and epithelial damage (ED) were assessed using
standardised methods. Those agents caused a dose-depending slowing of CBF and ED.
Neither anti oxidative enzymes catalase and superoxide dismutase, alone or in combination,
or the addiction of the three macrolides showed to be able to reduce slowing effect and ED.
If polymorphonuclear leukocytes (PMNL) were added to the cultures, a protective effects of
macrolides were found, resulting in a significant reduction of CBF slowing and of ED.
Authors concluded that this anti-inflammatory effect of macrolides/azalides can provide a
further therapeutic approach to management of asthmatic patients by decreasing airways
inflammation and by protecting against ciliary dysfunction.
Exclusion criteria: this is an in vitro study of basic science.
Gotfried 2004 The study was suspended because the slow enrollement of patients, the clarithromycina and
placebo groups were unequal in size and the final analysis was performed only within the
treatment group, analysing data before and after the macrolide therapy within the same
patients.
Página 15

Hueston 1991 Patients not affected by asthma.
This study assessed the effect of albuterol compared to erythromycin in the treatment of
acute bronchitis in patients without other pulmonary or cardiac disease, comprised asthma.
RCT: Jadad score: 3
Patients: 45 patients were eligible for the study, all with a productive cough of less than 30
days duration, between 18 and 65 years of age; exclusion criteria adopted were: pregnancy,
history of chronic obstructive pulmonary disease or asthma or of cardiac disease, allergy to
erythromycin or albuterol, evidence of pneumonia in the past 6 months, fever>39.5°C or
administration of antibiotics in the 14 days before the study.
Types of interventions: 3 patients decline to participate. 42 patients remaining were randomly
assigned to: albuterol group (2 mg/5 ml) (20 patients); erythromycin group (400 mg / 5 ml)
(22 patients) both administered as a teaspoonful of liquid every 6 hours for 7 days. Regarding
demographic features, albuterol group showed a greater proportion of males and older mean
age than erythromycin, with no significant difference. Albuterol group showed a significant
proportion of smokers than erythromycin group (p=0.09). No difference was found for severity
of symptoms and physical examination features. Each patients was provided with a daily
diary to note frequency of cough and time and severity of coughing (as during night). Patients
noted their general feeling following a 5 step scale (Likert scale) and if they needed other
additional medications. After 7 days, patients were examined by a physician and scores were
recorded. 2 patients for each group were withdrawn from the study because of medications
side effects. 2 patients in the erythromycin and 1 in the albuterol group failed to follow-up at
the seventh day. Outcomes measurements. Patients in the albuterol group demonstrated a
minor proportion of patients still coughing and less patients with productive cough than
erythromycin group (p=0.004 and p=0.002, respectively). No differences were noted for other
symptoms features. Sub analysis for smoker patients were performed cause of the greater
proportion in the albuterol group. Again, albuterol group showed a better outcome than
erythromycin (p=0.03). also in nonsmokers was found a little difference favour to albuterol
(p=0.02). No differences were reported within the groups between smokers and non smokers.
6 patients in the albuterol group experienced nervousness or tremulousness, while 6 patients
in the erythromycin group reported gastrointestinal side effects. Author concluded that albuterol
showed a significant action in reducing days and features of cough in acute bronchitis patients
when compared to erythromycin. Although its action can be referred to the effect on bronchial
reaction due to infection, 2 limits of the study were recognized: the small samples size, failing
to investigate little differences between the groups and proportion of productive cough, and
route of administration used for albuterol, that can influence side effect proportion. Exclusion
criteria: this study was excluded because it did not include asthmatic patients and there was
no asthmatic features clearly valuable.
Página 16

Itkin 1970 Lack of clearly reported randomisation and short (2 weeks) duration.
Double-blind, cross over study carried out to assess the utility and safety of macrolides in
severe asthmatic patients after that some case reports demonstrated a useful action on
symptoms and lung function in some selected patients. The authors also reported experience
in 3 normal subjects to assess the interaction of troleandomycin with the metabolism of
steroids. Patients: 12 asthmatic patients hospitalised at the asthma service of the National
Jewish Hospital were enrolled, all with a diagnosis of reversible obstructive lung disease.
Lack of clear data regarding symptoms frequency, drugs needed and lung function makes
difficult to classify patients following the GINA criteria. Types of interventions: after an
observational 2 weeks period patients were assigned to 4 treatments groups in a random
order (not a clear randomisation were explained): troleandomycin 125 mg, 2 capsules 4 times
daily oleandomycin 250 mg, 2 capsules 4 times daily tetracycline 125 mg, 2 capsules 4 times
daily; placebo, 2 capsules 4 times daily
All treatments were continued for 2 weeks. Wash out periods were not reported. Lung function
testes were performed twice daily, patients underwent an interview daily regarding asthmatic
symptoms with a quantitative estimation using a 4 grade scale. Body weight was recorded
daily, while a full-face picture was taken at the end of the 2 weeks period. Sputum for
microbiological and cytological analyses was collected daily, as blood analyses were done
weekly. 1 patient was withdrawn for the occurrence of a pharyngitis, other 2 patients needed
a reduction of drug dosage but data were kept in the analyses. Outcome measurements:
data were compared as means for every treatment group. A significant difference in mean
FEV1 between troleandomycin and control period (p<0.005) and oleandomycin and control
period (p<0.005) was recorded. Significant differences in mean FEV1 (p<0.01) were reported
for troleandomycin vs placebo, troleandomycin vs tetracyclines, oleandomycin vs placebo
and oleandomycin vs tetracyclines. No differences were noted between troleandomycin vs
oleandomycin and placebo vs tetracyclines. Symptoms score improved significantly when
comparing troleandomycin vs control, oleandomycin vs control (p<0.001) and tetracyclines
vs control (p<0.01). Percentage of eosinophils in the blood decreased significantly when
patients were treated with troleandomycin (p<0.0005) or oleandomycin (p<0.005) when
compared with control period. A significant decrease in the absolute number was reported
for troleandomycin (p<0.001), oleandomycin (p<0.01) and tetracyclines (p<0.01) vs control
period. Lymphocytes absolute number decreased significantly while patients were taking
troleandomycin (p<0.001) or oleandomycin (p<0.01) compared to control period. Side effects:
6 patients in the troleandomycin period and 2 in the oleandomycin period had an abnormal
liver function test, only 1 among these reported gastrointestinal symptoms, all the abnormality
resolved spontaneously without discontinuation of the drug. In 1 patient an increase in the
Cushing appearance were noted, in 2 patients sputum cultures were positive for Mycoplasma.
Authors concluded that troleandomycin can be a clinically useful adjunct to the usual
medication to improve symptoms in severe asthmatic patients; adverse effects on liver function
test were mild and reversible; data suggest that macrolides have an effect other than
antimicrobial, likely connected with steroid metabolism. Exclusion criteria: lack of a clearly
reported method of randomisation and treatment period shorter than 4 weeks.
Página 17

Kaplan 1958 Not a RCT study.
The study was performed to assess the utility of troleandomycin (triacetyloleandomycin) in
a group of patients with chronic asthma and evidence of airways infection. Patients: 44
patients with evidence of wheezing were selected from 5 groups: 1) emphysema with infection,
2) chronic bronchitis, 3) bronchiectasis 4) allergic rhinitis, sinusitis and polyps; 5) asthma
superimposed on an acute allergic episode e/o acute upper respiratory infection. Because
the lack on data regarding lung function and symptoms, it was not possible to confirm a clear
diagnosis and to classify patients following GINA criteria (GINA 2002). Types of intervention:
all patients were treated with troleandomycin 250 mg 4 times daily for a week and, then, 1
capsule daily. Sputum samples for microbiological analyses were collected prior to therapy
and every 7 days. Organisms were identified by usual bacteriological techniques. Test for
susceptibility to oleandomycin was performed with the disc method. Outcomes measurement:
despite the most of organisms isolated were susceptible to oleandomycin, there were no
profound changes in the bacterial flora before and after the therapy. 84% of patients reported
a reduction of cough, expectoration, and wheezing. The improvement in patient's condition
could not be correlated with the bacteriological findings. The authors reported also 5 case
reports of patients with asthma associated to other conditions who took profound benefits
from oleandomycin therapy.The authors concluded that oleandomycin caused a rapid change
in the amount and type of sputum that doesn't correlate with the change of bacterial flora,
maybe for a bias in collecting samples; other antibiotics can have a possible role in "infectious
asthma", especially if used on the basis of susceptibility test. Exclusion criteria: this is not a
RCT.
Página 18

Koh 1997 Patients are children with bronchiectasis; for the 7 asthmatic children, insufficient data were
reported.
The study by Koh 1997 and coworkers is a randomised, placebo controlled, double-blind
study carried out to assess the effect of roxithromycin on airways responsiveness in children
with bronchiectasis and documented airway hyper responsiveness.
RCT: Jadad score: 2. Patients. 27 children affected by bronchiectasis of various causes, with
a documented bronchial hyper responsiveness, was eligible for the study. 2 were withdrawn
for noncompliance. 25 children, 14 boys and 11 girls, with a mean age of 13 years, 7 with a
diagnosis of asthma, nine reported as atopic were enrolled. Causes of bronchiectasis were:
measles (1), tuberculosis (5), ciliary dyskinesias (6), idiopathic (13). All of them were in clinical
stable conditions and continued their therapy during the study. No other drugs, as cromolyn
sodium or inhaled corticosteroids has been used. No one received antibiotics or corticosteroids
within 1 month prior to enter in the study or had an history of upper respiratory tract infection
within 4 weeks before entering.
Types of interventions. Patients underwent a preliminary methacholine provocation test before
start treatment, then they were randomly assigned to two treatment groups:
roxithromycin 4 mg/kg twice a day
placebo
for 12 weeks. During the treatment period, they underwent an assessment every 3 weeks,
and a researcher examined sputum following a 3 grades scale of evaluation, according to
the presence of purulence and a stain was performed to obtain a count of polymorphonuclear
leucocytes and to assign a score following a 3 grades score. In every visit, FEV1 was
measured and data recorded. At the end of the 12 weeks period, 24 hours after stopped
roxithromycin, patients underwent a new methacholine provocation test. Outcomes
measurements. There were no differences between the two groups for demographic features,
atopy and cause of bronchiectasis. 3 asthmatic patients were in the roxithromycin group, 4
in the placebo. There were no differences in baseline FEV1 PD 20 and maximal response
to methacholine expressed as percentage fall in FEV1 between the two groups. No significant
differences were noted in FEV1 measurements throughout the study period. Patients in the
antibiotic group showed a significant improvement in the sputum purulence score by the sixth
week (p<0.05) as in the sputum leucocytes score. All patients, excluding 2 in the placebo
group didn't reported infectious exacerbations. In the roxithromycin group, PD 20 geometric
mean value was significantly increased compared to that before treatment (p<0.01). No
significant changed occurred in the placebo group (p>0.1). All the three asthmatic in the
antibiotic group experienced an increase of PD 20, while the 4 in the placebo group didn't.
Mean value of maximal variation of FEV1 after provocation test was significantly increased
in the roxithromycin group (p<0.01), the change was not significant in the placebo group.
Authors concluded that was not possible to establish from this study whether the improvement
in airways responsiveness was due to treating infections or to the anti-inflammatory action
of roxithromycin. They declaimed that the association among sputum features, airway
responsiveness wasn't investigated cause the great variability of those features at baseline
and cause the small sample size. Further studies were considered necessary to determine
the mechanisms by which the antibiotic caused the reduction of airways responsiveness in
bronchiectasis and its clinical utility. Exclusion criteria: this study was excluded because it
has been performed on an population of children with bronchiectasis; for the 7 asthmatic
patients, not sufficient data were reported regarding disease features and impossibility to
classify in defined classes of severity.
Página 19

Spector 1974a Not randomised.
Crossover, double-blind study conducted to evaluate the effect of troleandomycin in steroid
dependent asthmatic patients and bronchitis. Patients: patients with "asthma" defined as
obstructive airways disease with a reversibility of at least 15% in FEV1 after bronchodilators,
requiring high doses of steroids for symptoms control or with a poor controlled disease despite
treatments with bronchodilators and course of steroids were included. Cough and mucus
production for more than 3 months during the year for at least 2 years were not an exclusion
criteria, while significant hepatic and renal diseases were contraindications to enter the study.
Using the GINA score system (GINA 2002), despite the lack of cleat data about treatments
employed, patients can be classified as moderate persistent or severe persistent asthmatics
(3th and 4th group). Type of interventions: no clear protocol for drugs administration and
steroid tapering was reported in the study. Patients enrolled were assigned to one of the 2
groups: troleandomycin at a starting dose of 14 mg/Kg/day; placebo. Treatment phase was
continued for 2-4 weeks, after a 1-2 weeks baseline period of treatment with
methylprednisolone. the wash-out period was not reported. All patients continued their
previous therapy (including other antibiotics). Methacholine or histamine challenge were
performed after 2 weeks of treatment, pulmonary function tests twice daily, hematologic and
chemistry analyses were performed weekly. A symptoms score questionnaire was
administered to the last 20 patients enrolled in the study. 76 patients were enrolled in the
study. 2 withdrawn, 1 on her own decision, without having side-effects, another for significant
liver function tests alterations. Outcome measurements. Patients were classified in three
groups in relation to the ability of tapering steroid dose: 50 (67%) were marked responders:
oral corticosteroids changed from daily to alternate-day dosage with the alternate-day morning
dose <2 * former daily dosage or the alternate-day dose decreased >50%. 13 (18%) were
probable responders: already established alternate-day dose decreased 15 to 50% 11 (15%)
were non responders: daily oral corticosteroids could not be changed to alternate-day dosage
or alternate-day dose decreased <15%. No statistically significant difference were found for
demographic data. Pulmonary function tests: data for analyses was available for 57 patients.
A significant increase in FEV1(differences mean value) was observed during treatment with
troleandomycin when compared with placebo (mean improvement 0.42 L vs 0.16 L, p<0.001).
Similar results were reported in the cross-over treatment period. Because methacholine
challenge was performed only in the best clinical conditions, data was reported only for 14
patients before and after troleandomycin treatment: 6 show a marked improvement (increase
of the dose required to produce a 20% fall in FEV1), 5 improved for less higher concentrations
and 3 remained quite at the same responsiveness (only 1 patients was a non responder).
Subjective evaluation: 18 of 20 patients were able to fill the questionnaire. A significant
improvement in the mean score reported was seen after troleandomycin therapy when
compared with placebo (p<0.01).The questionnaire comprised questions about drugs needed
and sputum characteristics. Better results were reported by marked responders. Side effects:
19 patients shown a mild, transient elevation of liver function tests, especially for sGOT,
usually during the second week of treatment with troleandomycin. 69 patients treated with
the antibiotic shown a significant increase in serum cholesterol (p<0.001). One patient on
troleandomycin developed urticaria and another a maculopapular rash. One patient had a
clinical picture of temporal arteritis, one a possible viral myocarditis and another an increase
in heart size. Nausea, vomiting, diarrhoea and rush also developed in a few patients during
treatment with troleandomycin. An increase in Cushingoid features occurred in some patients
who did not tapper steroids. Authors concluded that troleandomycin, given with
methylprednisolone, was very effective in approximately 70% and probably effective in an
additional 15%, with a considerable reduction in the steroid dose in some patients. Despite
some side effects, troleandomycin has proved to be an effective addition for a particular
subgroup of severe, asthmatic patients. Exclusion criteria: this study was excluded because
the lack of a randomisation. Also the treatment period was too short.
Página 20

Szefler 1980 Not a RCT study.
Conducted to evaluate the effect of troleandomycin on methylprednisolone pharmacokinetic.
Patients: 10 severe steroid dependent asthmatic patients were enrolled. Types of intervention:
plasma levels of methylprednisolone were evaluated at time 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10,
12, 18 and 24 hr after the administration before and after a week of treatment with
troleandomycin. Model independent pharmacokinetic parameters were determined.
Outcome measurements: mean values of clearance of methylprednisolone was significantly
reduced from the baseline level after the macrolide treatment (from 406 SD 139 ml/min/1.73
m2 l week to 146 SD 57 ml/min/1.73 m2 l week, p<0.001). Methylprednisolone half life was
significantly increased (2.46 SD 0.75 hr to 4.63 SD 1.35 hr, p<0.001) after a week of treatment.
3 patients were evaluated after at least 1 month of antibiotic therapy, and the same effect
was found on kinetic parameters. The authors concluded that the inhibition of
methylprednisolone clearance may contribute to the beneficial effect observed with the
combination of troleandomycin and this steroid. Further studies are needed to discover the
mechanisms and the best dosage to use this interaction for clinical purposes. Exclusion
criteria: not a RCT study.
Szefler 1982 Not a RCT study.
Performed to assess the effect of troleandomycin on steroids pharmacokinetic with and
without the association of anti convulsivant drugs.
Patients: 6 severe asthmatic patients were enrolled, 3 of them in treatment with anticonvulsant
drugs. Types of intervention: 3 patients received methylprednisolone and prednisolone in a
only morning dose and plasma levels were tested at time 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12
hr after the administration before and after a week of treatment with troleandomycin.
Methylprednisolone was also tested in the three patients taking phenobarbital. Model
independent pharmacokinetic parameters were determined. PEF and symptoms were recorded
daily. Outcomes measurements: troleandomycin altered the elimination of methylprednisolone
with a significant increase of plasma levels and reduction of the clearance. No effect were
reported on prednisolone pharmacokinetics, while troleandomycin demonstrated to reduce
the effect of anti convulsivant drugs on the methylprednisolone clearance, reducing the steroid
elimination. The authors concluded that the effect of troleandomycin on steroid metabolism
is steroid specific. The antibiotic is also capable to reduce the effect of anticonvulsant drugs
on methylprednisolone and these effects have to be considered in the treatment of severe
asthmatic patients who require association therapy. Exclusion criteria: not a RCT study.
Szefler 1982a Not a RCT study.
Takamura 2001 The study by Takamura 2001 is a cross-over study comparing the effect of erythromycin and
clarithromycin in asthmatic patients. It was excluded by the review because it is not described
as randomised.
Página 21

Wald 1986 Not randomised.
Carried out to assess the efficacy of a new protocol for the use of troleandomycin as steroid
sparing agent, using lower dose of the antibiotic to avoid hepatic toxicity and a rapid steroid
taper. This is not a RCT but an open label trial without a control group. Patients. 15 patients
were enrolled to enter the protocol: 13 females and 2 males, with a story of steroid dependent
asthma, all previously treated with an aggressive medical regimen including theophylline,
inhaled bronchodilators, both oral and inhaled steroids, all with documented reversible
obstructive lung disease. Using the GINA score system (GINA 2002), all patients were
classified in the more severe class of asthma (4th group, severe persistent asthma). None
oh the patients was taking antibiotic or drugs known to interfere with steroids metabolism,
all underwent an educational program for the management of asthma. Types of interventions.
All 15 patients received troleandomycin 250 mg twice daily if liver function tests were normal,
or once daily in patients with two or more abnormal alterated liver function test. The last 3
patients entered in the study received antibiotic 250 mg once daily. Theophyllines dosage
was reduced by approximately 25% in all patients. Methylprednisolone was rapidly tapered
(2 to 20 mg) every 2 days. Once a patient was receiving alternate day steroid, troleandomycin
was reduced to 250 mg on alternate day regimen. Steroid taper was continued until the dose
was believed to be safe or the patients spirometry values fell by 10% from their previous best
functions. Beta-agonists were decreased when appropriate. Blood analyses were performed
twice weekly, inpatients underwent daily spirometry and blood pressure measurement, as
outpatients recorded daily peak flow and underwent spirometry and blood pressure
measurement. Outcomes measurements. 13 patients were able to reach an alternate day
steroids regimen, with a marked improvement in clinical course (no symptoms score reported).
2 patients were unable to reduce steroids to an alternate day dosage, required bursts of
methyl prednisone and discontinued troleandomycin after 3 weeks. Those patients were
considered partial responders.
Within 3 weeks, 13 of 15 patients tolerated an alternate day steroids with a statistically
significant reduction of steroid dosage (p<0.001) with the mean alternate day dose of methyl
prednisone 25.2 mg. All 13 patients were able to maintain the regimen for a follow-up period
of meanly 6.4 months. A further reduction to 14.8 mg bi daily was possible in all 13 patients,
with an high significant difference when compared to baseline steroid dose (p<0.001). Lung
function measured by spirometry improved. Changes obtained in 3 weeks of treatments were
significant both for FEV1 and FVC (p<0.001). Adverse effects were classified as following:
enhancement of steroid related side effect: 3 patients experienced an increased glucose
intolerance; 1 of those experienced also elevation of blood pressure and in intraocular
pressure; all side effects resolved with steroid tapering; effect related to rapid steroid reduction:
4 patients complained of severe leg pain. Adverse reaction relating to troleandomycin itself:
4 patients experienced transient elevation of liver enzymes, all when receiving 500 mg daily.
Levels reduced when antibiotic tapered. Baseline data was not significantly different from
those of pre discharge.
theophyllines toxicity was nor observed, with no significant difference between theophyllines
serum level baseline and pre discharge. 1 patient, previously affected by deep venous
thromboembolia, died for pulmonary embolism 8 months after starting protocol. Authors
concluded that this protocol, using lower dose of troleandomycin respect all proved in the
past, can be useful in patients with steroids requiring asthma. It is able to reduce significantly
steroid requirement to an alternate day administration with fewer side effects (related both
to antibiotic and to chronic steroid use). Authors, furthermore, considered sufficient a starting
dose of troleandomycin of 250 mg than 500 mg, cause the surprising data reported in the
first days of the study (last 4 patients use with starting dose without worsening) and considered
a 4 weeks period of trial with the antibiotic sufficient to distinguish responders from
non-responders patients. Moderate liver function test elevation was not considered a
contraindication to treatment. Exclusion criteria: this study wasn't a randomised controlled
trial.
Página 22

Weinberger 1977 Not a RCT study.
Conducted to assess the effect of troleandomycin on theophylline clearance. Patients: 8
severe asthmatic patients. Types of intervention: patients were administered troleandomycin
250 mg 4 times daily during intravenous or oral administration of theophylline in therapeutic
dosages. Serum theophylline levels were assayed before, after 10 days of start and after 10
days of discontinuation of the antibiotic. Outcome measurements: theophylline level were
found higher than in the control period and mean clearance was twice the normal value. A
patient experienced a gran mal seizure 10 days after troleandomycin administration. Liver
function testes shown only mild and reversible alterations. The Authors concluded that an
action of the macrolide on theophylline metabolism can be really important and it have to be
considered when associations of multiple drugs are needed in severe patients.
Exclusion criteria: not a RCT study.
Zeiger 1980 Not a RCT study.
Prospective, open, therapeutic trial on the effect of troleandomycin in outpatients with severe
steroid-dependent asthma. Patients: 16 severe steroid dependent asthmatic patients were
enrolled in the ambulatory of the Kaiser-Permanent Medical Center (San Diego), all in
treatment with the maximal bronchodilator therapy and with frequent need of steroid courses,
and with daily symptoms. Using the GINA score system (GINA 2002) patients can be
considered severe persistent asthmatic patients (4th group of GINA). Types of intervention:
all patients were treated with an initial dose of troleandomycin of 1 gm/day (14 mg/kg) for 1
or 2 weeks, then tapered to 250 mg or less with a weekly tapering of 250 mg. Steroids in use
were passed to an equivalent dose of methylprednisolone and theophylline dosage reduced
25-50%. Methylprednisolone dosage was reduced progressively to the minimal dose required
to maintain clinical well-being. All patients underwent a visit weekly for the first 3 months and
after monthly. Liver function tests were performed weekly, lung function tests at every visit
and cortisol levels after the institution of an alternate day administration of drugs. Outcome
measurements: patients had from 4 to 18 months follow-up since starting troleandomycin.
A patient discontinued the study at the 4th month for a flare of asthma which required higher
doses of steroids with side effects associated with the troleandomycin treatment. Clinical
findings: all patients experienced a marked improvement in their quality of life (no scale of
evaluation was used). None of the study patients has required hospitalisation since starting
the antibiotic, in contrast to many admissions the year prior to troleandomycin. Spirometric
findings: mean values of FEV1 and FEV25%-75% improved during troleandomycin therapy,
with a mean increase of 14% and 43% respectively after tapering of troleandomycin and
methylprednisolone. Steroid requirement: most patients experienced at least a four to fivefold
reduction in methylprednisolone requirements. 13 of 15 patients were able to tolerate an
alternate day administration of steroid. 13 patients were able to taper troleandomycin to a
250 mg dose on alternate days. Side effects: all patients initially experienced an increase in
steroid-induced side effects (cushingoid features, weight gain, fluid retention, reversible with
the tapering of steroid dose. No significant change in liver function were reported.Theophylline
levels rose to levels greater than 20 mg/ml only in patients with an inadequate reduction of
its dosage. 1 patients experienced a bilateral submandibular gland enlargement within the
first week of the study. The authors concluded that troleandomycin in association with
methylprednisolone can be useful in the treatment of severe asthmatic patients and proposed
a protocol with a fast dose tapering to reduce the incidence of side-effects. They also
highlighted that treatment must be individualized to obtain the best results. Exclusion criteria:
not a RCT study.
Página 23
TAB LAS ADICIONALES
Table 01 Summary of included studies' characteristics

Study ID Design Participants Interventions Outcomes
Nelson Designed to assess Patients: 75 patients Type of interventions: The principal analysis was by
1993 the ability of enrolled, all with a patients were randomised to comparison of group means
troleandomycin to fluctuation of at least 15% 2 treatment groups: by Student's t test or
reduce the daily of FEV1 values occurring troleandomycin (250 distribution by chi-square
steroid treatment either spontaneously or mg)/methylprednisolone (37 testing. When indicated
required for asthma after bronchodilation with patients); because of non normal
control and the steroid inhaled beta-agonists, placebo/methylprednisolone distribution , Wilcoxon's
long term side effects requiring a minimum dosage (38 patients). rank-sum test was employed
in asthmatic patients of 15 mg of prednisone per Both groups were also and when insufficient numbers
requiring daily day or an equivalent dose treated with calcium in a of individuals cells made
corticosteroid therapy. of another steroid over the dose of 1500 mg per day to chi-square inappropriate,
preceding 3 months with reduce bone loss effects, if Fisher's exact test was
history of deterioration of not contraindicated by history substituted.
symptoms when steroid of renal calculi or designed to assess the ability
dose was tapered. Patients hyper-calcaemia. of troleandomycin to reduce
using inhaled sodium The 2 groups were not the daily steroid treatment
cromolyn or steroids were significantly different for required for asthma control
required to discontinue demographic data. The and the steroid long term side
these medications before dosage of daily theophylline effects in asthmatic patients
enrolment in the study. treatment was reduced 25% requiring daily corticosteroid
Patients using anti in all study subjects. Steroid therapy.
convulsivant therapy, dose reduction was initiated Patients: 75 patients enrolled,
significant hepatic disease immediately with a 25% all with a fluctuation of at least
or smokers were also reduction in the alternate day 15% of FEV1 values occurring
excluded. Using the GINA dose, at intervals of 6 days either spontaneously or after
score system (GINA 2002) and, subsequently, 2 weeks. bronchodilation with inhaled
all patients were classified General guidelines for steroid beta-agonists, requiring a
in the more severe class of tapering were that symptoms minimum dosage of 15 mg of
asthma (4th group, severe should remain well controlled prednisone per day or an
persistent asthma). and peak flow should remain equivalent dose of another
if possible within 10% of the steroid over the preceding 3
level recorded during the months with history of
baseline period of optimum deterioration of symptoms
asthma control. Acute when steroid dose was
exacerbations were treated tapered. Patients using
in the majority of cases by inhaled sodium cromolyn or
guidelines indications; during steroids were required to
exacerbations discontinue these medications
troleandomycin treatment before enrolment in the study.
was temporally stopped, Patients using anti
methylprednisolone in a dose convulsivant therapy,
of at least 16 mg twice day, significant hepatic disease or
until optimal control of smokers were also excluded.
symptoms. The study Using the GINA score system
protocol was then restarted (GINA 2002) all patients were
following symptoms classified in the more severe
class of asthma (4th group,
severe persistent asthma).
Página 24

resolution. The majority of Type of interventions: patients
steroid adjustments were were randomised to 2
made under the supervision treatment groups:
of the Principal Investigator. troleandomycin (250
18 patients failed to complete mg)/methylprednisolone (37
the 1 year of double-blind patients);
participation (7 in the placebo/methylprednisolone
troleandomycin and 11 in the (38 patients).
placebo group, p value not Both groups were also treated
significant). When with calcium in a dose of 1500
considering asthma control, mg per day to reduce bone
dropouts didn't differed loss effects, if not
significantly from those contraindicated by history of
completing 1 year of renal calculi or
participation and were not hyper-calcaemia.
considered as treatment The 2 groups were not
failures. significantly different for
Among the 30 patients demographic data. The
remaining in the dosage of daily theophylline
troleandomycin group, 17 treatment was reduced 25%
completed a 2 year period in in all study subjects. Steroid
double-blind. In the placebo dose reduction was initiated
group, 27 completed the 1 immediately with a 25%
year and 8 completed the 2 reduction in the alternate day
year period of the study. dose, at intervals of 6 days
and, subsequently, 2 weeks.
General guidelines for steroid
tapering were that symptoms
should remain well controlled
and peak flow should remain
if possible within 10% of the
level recorded during the
baseline period of optimum
asthma control. Acute
exacerbations were treated in
the majority of cases by
guidelines indications; during
exacerbations troleandomycin
treatment was temporally
stopped, methylprednisolone
in a dose of at least 16 mg
twice day, until optimal control
of symptoms. The study
protocol was then restarted
following symptoms
resolution. The majority of
steroid adjustments were
made under the supervision
of the Principal Investigator.
18 patients failed to complete
the 1 year of double-blind
participation (7 in the
troleandomycin and 11 in the
placebo group, p value not
Página 25

significant). When considering
asthma control, dropouts
didn't differed significantly
from those completing 1 year
of participation and were not
considered as treatment
failures.
Among the 30 patients
remaining in the
troleandomycin group, 17
completed a 2 year period in
double-blind. In the placebo
group, 27 completed the 1
year and 8 completed the 2
year period of the study.
Outcome measures.
The principal analysis was by
comparison of group means
by Student's t test or
distribution by chi-square
testing. When indicated
because of non normal
distribution , Wilcoxon's
rank-sum test was employed
and when insufficient numbers
of individuals cells made
chi-square inappropriate,
Fisher's exact test was
substituted.
Kamada Carried out to assess Patients: 19 patients, ages Types of intervention. The Outcome measures
1993 the efficacy and the 6 to 17 years, all affected by patients were randomised in Data were summarized as
safety of low dose reversible obstructive three treatment groups: means and standard errors
troleandomycin in airways disease (ATS troleandomycin (250 mg) / within groups, and, where
severe, steroid 1987), all requiring methylprednisolone once applicable, 95% confidence
requiring children, prednisone at a daily dose daily (6 patients); intervals are computed on
especially to test the of at least 20 mg, using troleandomycin (250 mg) / individual treatment effects.
use of this macrolide inhaled bronchodilator at prednisolone once daily (8 The analysis for treatment
for a 12 week time least 4 times daily, taking patients); differences was performed
period. theophylline and with a placebo / methylprednisolone with one-way analysis of
previously failed treatment once daily (5 patients); variance on the differences
with cromolyn sodium. All Randomisation was stratified between 12 weeks of
patients were receiving on 2 levels of severity of treatments and base-line for
inhaled glucocorticoid asthma. After a single-blind all variables except
therapy (during the study all run-in period of at least 1 methacholine PC20,
patients used flunisolide in week, patients were glucocorticoid dose reduction
dose of 2 to 4 puff twice randomised to receive one and symptoms score.
daily). Using the GINA of the three above treatments Methacholine PC20 was
scoring system (GINA in a double blind fashion analysed as the ratio of 12
2002), all patients were using two identically week measurement to the
classified in the more appearing capsules and one base-line reduction and
severe class of asthma (4th white capsule.
group, severe persistent Steroid doses were tapered
asthma). using a previously published
Página 26

Exclusion criteria: protocol (Eitches 1985) to percent symptoms score
pregnancy, viral upper achieve dosing on every reduction were calculated as
airways infections within 4 other day or a 50% reduction (baseline-final)/baseline*100.
weeks of enrolment; during the first 2 weeks. Analysis for changes within
abnormal hepatic or renal Investigators who were not groups was performed with
function, inadequately blinded to the data, tapered one-sample t tests. Multiple
controlled cardiac sinus or the doses of steroid on the comparisons among the
thyroid disease or basis of reported symptoms treatment groups means were
gastroesophageal reflux, and FEV1 and/or PEF performed with Fisher's
severe psychologic values, as recommended by protected least significant
disorders, current use of investigators blinded to data; difference procedure with an
anticonvulsants, doses were tapered in alpha level of 0.05.
erythromycin, oral general by 2.5 to 5 mg per
contraceptives, rifampin, week.
ergotamine, haemoglobin Short courses of
<12 gm/dl or platelet <150 supplemental prednisone
k/µl or other complicating were allowed if FEV1 or PEF
pulmonary disease. measurements dropped
Among the 19 patients below 65% of predicted
enrolled, 2 were values, or if extra inhaled
discontinued; 1 receiving bronchodilator treatments
troleandomycin-prednisone within a 6-hour period or
because of failure to three extra treatments within
maintain adequate lung 24-hours period were
function after 8 week of required. Study medications
treatment. Data from this were discontinued during
patient is included in the these courses and were
analysis because a restarted at a dose
follow-up evaluation was equivalent to that when the
obtained before termination. patient was clinically stable.
A second patient, also in the Differences among groups
troleandomycin-prednisone were significant for height
group, was dropped after 3 between
week of treatment for an troleandomycin-methyl
elevation of liver enzymes prednisone and methyl
level, which necessitated prednisone alone. The
discontinuation of the troleandomycin-methyl
antibiotic. This patient was prednisone group also had
excluded in the final an higher symptom scores
analysis. and steroids requirement
during the baseline period,
likely result of the stratified
randomisation procedure.
Shoji 1999 Designed to 14 patients, with clinical Types of interventions A symptoms score (including
investigate the effect history of aspirin-intolerant Patients were randomised in 4 step of symptoms severity)
of roxithromycin on asthma, with a positive two blocks: was recorded every week by
airways sulpyrine and/or lysine roxithromycin (150 mg twice physicians.
responsiveness to the aspirin provocation test, non a day) Outcome measurements
sulpyrine provocation smokers, with a diagnosis placebo (twice a day) All PC20 values were
test and to investigate of mild or moderate asthma for 8 weeks. FEV1, FVC, logarithmically transformed
the effect on urinary following ATS 1987 criteria blood analyses was before analysis and summary
performed at the start and
the end of period.
Página 27

aspirin-induced (ATS 1987) were included. After a 4 weeks washout statistics were all expressed
excretion of All were stable and free of period, the subjects crossed as means and standard
leukotriene E4 and on symptoms of respiratory over to receive the deviations. Student's paired
eosinophilic infection for at least 6 alternative treatment for 8 t-test was used to compare
inflammation. weeks. Patients using weeks. mean differences. Wilcoxon's
antiasthmatic drugs other All patients underwent a signed rank test was used for
than beta agonists, and/or sulpyrine provocation test comparison of the two
roxithromycin were after each 8 week treatment treatment groups at the same
excluded. Using the GINA course with either time point regarding FEV1
score system (GINA 2002), roxithromycin or placebo in and leukotrienes values.
all patients were classified a double-blind manner,
in the 1st group, intermittent performing spirometry before
asthma, based on current and after 5, 10 and 15
treatment used. An minutes after inhalation. The
evaluation on the frequency urinary level of leukotriene
of asthmatic symptoms was E4 was measured before and
not possible, because after antibiotic use and
baseline symptoms were provocation testing.
not reported in the paper.
Amayusu Designed to evaluate 17 patients affected by Patients were randomly Outcome measurements
2000 the effect of allergy-induced asthma assigned to 2 treatment All PC20 values were
clarithromycin on were enrolled in this study. groups: logarithmically transformed
bronchial hyper All patients met the ATS clarithromycin (200 mg twice before analysis and summary
responsiveness and 1987 criteria (ATS 1987) for a day) statistics were all expressed
eosinophilic mild or moderate asthma, placebo (twice a day) as means and standard
inflammation in they were treated with for 8 weeks. Blood samples deviations. Student's paired
patients with allergy beta-agonists only to control for cell counts and serum t-test was used to compare
induced asthma. asthmatic symptoms. Based eosinophilic cationic protein mean differences. Wilcoxon's
on the current treatment, measurements were taken signed rank test was used for
patients could be classified before and after the 8 week comparison of the two
as intermittent asthma period and sputum analyses treatment groups at the same
following GINA 2002 were performed following a time point regarding FEV1
recommendations (GINA standard protocol. and ECP values.
2002). Elsewhere, there Methacholine provocation
was no clear indication testing was performed after
about the frequency and the 8 weeks, with lung
severity of asthmatic function measurements
symptoms before starting performed before and after
the trial. 5, 10, 15 minutes of the
Patients were excluded if provocation test.
there was evidence on viral Patients previously
infection in the 6 weeks randomised in the two group
prior to the study, if they underwent a crossover
were treated with period with the same type of
anti-asthmatic drugs other intervention and, then, were
than beta-agonists, or with resubmitted to the study
clarithromycin. analyses.
A symptoms score was
assessed weekly following a
4 grade scale of severity.
Black 1999 Multicenter Patients Types of intervention: Outcome measures:
multinational study on 232 patients 18-60 yrs of patients were randomly symptoms and morning and
the effect of a age, with a defined evening PEF were recorded
Página 28

roxithromycin in diagnosis of asthma, with assigned to 2 treatment during treatment and for the
asthmatic patients with FEV1 50-90% of predicted groups: following 6 months. The
serological evidence of were enrolled in four roxithromycin 150 mg bd Asthma Quality of Life
Chlamydia different Countries placebo Questionnaire (AQLQ) was
pneumoniae infection. (Australia, New Zealand, for 6 weeks. administered at
Italy and Argentina). randomisation, at week 2, 6,
Patients had serological 12 and 24 after the beginning
evidence of Chlamydia if the treatment. A the same
pneumoniae infection, as times a spirometry was
demonstrated by IgG and performed.
IgA antibody titres. 13 patients randomised to
Exclusion criteria were: treatment withdrew from the
previous treatment with study. Among the remaining
macrolides, quinolone and 219, 105 were in the
tetracycline in the 4 weeks roxythromycin and 114 in the
before entering the study, placebo group. No significant
use of ergot alkaloids, differences between the 2
terfenadine or astemizole, groups were recorded for
smoking history of 20 pack demographic and lung
years or more, function tests.
bronchiectasis, other
serious systemic disease,
hypersensitivity to
macrolides or any significant
change in asthma
medication in the previous
month, respiratory tract
infection during the run-in
period or abnormal liver or
kidney function test. Due to
the lack in the paper of a
complete description of
symptoms or drugs needed
to control symptoms for
each patient, a classification
following the GINA score
(GINA 2002) was not
possible.
Kraft 2002 The study by Kraft Patients: 55 asthmatic Interventions: The patients Outcome measures.
2002 was designed to patients, whose 31 had an were randomised in a double Presence or absence of a
assess the effect of evidence of infection by M. blind fashion into two arms: positive PCR for M.
the treatment with pneumoniae or C. -clarithromycin 500 mg bid pneumoniae or C.
clarithromycin on pneumoniae were recruited for 6 weeks pneumoniae between with 2
pulmonary function in the study. All were -placebo for 6 weeks arms was compared by Fisher
tests and inflammation classified as asthmatic No clear limitation of the use exact test. The outcome
in asthmatic patients following the ATS 1987 of other drugs (especially variables (FEV1, changes in
with an evidence of criteria. According to the oral steroids) was included FEV1, FVC and levels of
infection by M. ATS 1987 criteria, all in the protocol for the cytokines in the BAL) were
pneumoniae or C. subjects were considered duration of the treatment. compared using unpaired t
pneumoniae. asthmatics of moderate 3 patients were excluded test or Wilcoxon sign rank,
severity. No clear from the treatment analysis, depending on the distribution
classification based on the but it is not clearly reported of the data. Within-group
severity of asthma is in which arm of the study comparisons were performed
Página 29

reported in the study; based they were allocated. using the t test or Wilcoxon
on the percent predicted Twenty-six patients were rank sum. Data were
FEV1 and drugs used at the reported as allocated to each presented as mean±SEM or
baseline (about 69% in both of the study's arms. The median. All tests were
PCR+ and PCR- subjects), number of patients with a two-sided with a level of
the patients are likely to be positive PCR for either M. significance p?0.05.
for the most part moderate pneumoniae or C.
persistent asthmatics (Class pneumoniae at the baseline
III of the GINA 2002). One was similar in the
patient was reported to be chlarithromycin and in the
continuously treated with placebo group (13 vs 14,
oral steroids, and, thus, respectively), as well as no
considered a severe significant difference was
persistent asthmatic (GINA reported for the FEV1 mean
2002). values in the two groups
Exclusion criteria included (2.72±0.17 L in the
the inpatient status, upper clarithromycin vs 2.52±0.13
or lower respiratory tract L in the placebo group,
infections and/or use of p=0.37). No other
macrolides, tetracyclines or demographic data were
quinolones within 3 months reported to better compare
from the beginning of the the two arms of the study.
study, smoking history > 5
pack/years or any cigarette
within the previous 2 years,
other significant respiratory
diseases or other medical
problems.
Kostadima Designed to evaluate Patients: 75 patients were Interventions: the patients Statistics: results are
2004 the effect of enrolled, aged 18-70 years, were randomised in a double presented as either median
clarithromycin on with a diagnosis of mild blind fashion in 3 arms: (interquartile range) or
bronchial persistent asthma for more -Group A: clarithromycin 250 mean±SD. PD 20 and
hyper-responsiveness then 1 year according to the mg b.i.d. for 8 weeks spirometric indices before and
to methacholine in GINA 2002, and a -Group B: clarithromycin 250 after the treatment were
patients with a provocative dose of t.i.d. for 8 weeks compared using a Wilcoxon
diagnosis of asthma. methacholine causing a -Group C: placebo dextrose signed-rank test or a
20% fall in FEV1 (PD 20) of tablets for 8 weeks. two-tailed paired t test.
<20 mg. During the study no Bronchodilators were Changes in PD 20 in the
other medications were discontinued at least 12 treatment groups were
allowed, and exclusion hours before the provocation compared using the
criteria included: history of tests. Mann-Whitney test.
allergic rhinitis or Side effects were recorded
occupational asthma, and assessed by total blood
smoking habit (past or count, renal function and liver
current), exacerbations function. Some patients
requiring oral steroids or underwent serum free
upper tract infections in the cortisol levels at the baseline
4 weeks before the trial, a and at the end of the study.
FEV1<50% of the predicted The allocation method is not
value or <1 L at the described in details and ir
baseline, other systemic seems to be questionable: a
diseases, use of research nurse, who was
beta-blockers or pregnancy declared to do not had other
Página 30

or nursing mothers. roles in the study, was in
Exacerbations during the charge of randomising the
study were a criteria for patients in the 3 groups.
withdrawn. Demographic data are
reported for every arm of the
study, without including the
drop outs.
-group A: 22 patients (3 drop
outs, 1 for exacerbation 2 for
not adherence to the
protocol) were 48±16 year
old, 6 (27%) females. At the
baseline, the mean FEV1%
value was 85±12, with a
median PD 20 of 0.3 (0.1-1)
mg.
-group B: 20 patients (5 drop
outs, 3 for exacerbations, 1
for a gastrointestinal
disorder, 1 for not adherence
to the protocol) were 42±12
year old, 12 (60%) females.
At the baseline, the mean
FEV1% value was 85±13,
with a median PD 20 of 0.4
(0.1-0.9) mg.
-group C: 21 patients (4 drop
outs, 3 exacerbations and 1
not adherent to the protocol)
were 41±16 year old, 15
(71%) females, with a mean
FEV1% value of 86±14 and
a median PD 20 of 0.3
(0.1-0.6) mg.
Age and pulmonary function
test values were similar
among the three groups.
Table 02 Narrative of individual study results

Study ID Detail of results
Nelson Symptom control: Significant reduction in the requirement for hospitalisation and steroid boost relative
1993 to the year before the study in both active and placebo groups. Similar results were reported during the
2 years of follow-up, with non-significant differences between the 2 groups. The authors remarked that
the tapering of steroid dose was performed only in situations of complete symptom control and that
symptom control was not an evaluable outcome.
Corticosteroid dose: the mean steroid dose at enrolment was not significantly different between the 2
groups. The mean dose reported in the placebo group during the year preceding the study entry was
significantly higher than in the troleandomycin group (22.8 mg/day, SD 1.9 mg/day vs 17.6 mg/day SD
1.5 mg/day p=0.02). A significant reduction from the previous corticosteroid usage was reported for the
lowest stable dose in both groups, with troleandomycin treated patients reaching a lower dose (10.4
mg/day SD 1.3 mg/day vs 6.3 mg/day SD 1.3 mg/day p=0.03). Neither the 1 year nor the 2 years
reduction of the dose was significantly different in the 2 groups.
Página 31

Corticosteroid effects: eosinophil counts were significantly increased at the time of the 1 year evaluation
in both groups. Similarly, the 60 minutes stimulated cortisol levels rose during the study, and after 1
year the difference was significant in both groups, but not between groups.
Dual-photon densitometry of the L2-4 vertebrae showed a continued decline in both groups of bone
density when adjusted for age-matched controls. The mean decline during 1 and 2 years was twice as
greater, but significant only in the troleandomycin group (1 year p=0.01, 2 years p=0.001).
Significant differences between the 2 groups were reported for the following 3 parameters:
Mean IgG level decreased in the troleandomycin group, and this change was not observed in the placebo
group (2 years p=0.03).
Fasting blood sugar increased in the troleandomycin group, and decreased in the placebo group (2
years p=0.02).
Mean cholesterol level increased in the troleandomycin group, although not significantly; it was lower
in the placebo group after 1 and 2 years (p=0.03 and p=0.01 respectively), with a significant difference
between the 2 groups (p=0.02 and p=0.03 in the 2 years, respectively).
Methacholine challenge was performed only in 11 patients in the placebo and in 13 in the treatment
group. The dose producing a 20% fall in FEV1 rose in the troleandomycin group, indicating less airway
responsiveness (0.55 mg/ml in the placebo vs 1.86 mg/ml in the macrolides group, p=0.08).
Three subjects died during the study, 2 in the treated group and 1 in the placebo group, none for asthma.
The authors highlighted the importance of adequate education of the patients regarding the use of
antiasthmatic drugs, especially steroids. Although the study showed a significant difference in the lower
stable dose reached in the troleandomycin group, the increase in indicators of side effects as cholesterol
and fasting blood sugar, as a less significant reduction in the bone densitometry, did not confirm the
utility of the steroid sparing effect of troleandomycin, but showed a detrimental action with increasing
the potential for adverse effects of steroid treatment.
Kamada A significant glucocorticoid dosage reduction was recorded in all 3 groups. The maximum tolerated
1993 percent dosage reductions were 80% ± 6% in the troleandomycin-methyl prednisone group (p<0.001),
55% ± 8% 8 (p<0.001) for the troleandomycin-prednisone group, 44% ± 14% (p=0.041) for methyl
prednisone group; a significant difference was present only between troleandomycin-methyl prednisone
group and methyl prednisone group.
No statistically significant difference was reported for days of supplemental prednisone for exacerbations.
Symptom score was reduced by nearly 50% in patients receiving troleandomycin-methyl prednisone
(p=0.025). There were no significant differences in the other two groups. Pulmonary function test were
slightly reduced in all groups, with a significant reduction of pre bronchodilator FEV1 and FEF25-75 in
the troleandomycin-prednisone group (p=0.026 and p=0.012, respectively). Methacholine PC 20 was
significantly reduced only in the troleandomycin-methyl prednisone group and slightly increased in the
troleandomycin-prednisone group, but the difference may be a reflection of glucocorticoid dosage taper
and supplemental prednisone before the final evaluation.
Safety aspects: 13 patients received troleandomycin. 1 patient in the troleandomycin-prednisone group
experienced an elevation of liver enzymes that needed the discontinuation of troleandomycin and
resolved subsequently. Another patient, in the troleandomycin-methyl prednisone group, reported a mild
elevations of liver enzymes, that resolved spontaneously, without discontinuation of the treatment. No
significant alteration of serum and urine cortisol concentrations were observed, whereas an increase
was observed in the methyl prednisone group. Bone density was unchanged in all groups. A slightly
decrease (NS) in bone density was observed in the two groups receiving troleandomycin. One patient,
in the troleandomycin-prednisone group , was severely osteopenic before the start of the study, and
experienced a vertebral compression fracture that was attributed to her previous glucocorticoid exposure.
Another patient in the troleandomycin-prednisone group developed marked striae on the arms and trunk.
She was also affected by Marfan syndrome.
The authors concluded that, despite the absence of a control group with only prednisone and the poor
number of subjects for each group, some conclusions could be drawn from this study: it is not possible
to improve lung function by tapering the steroid dose; the only goal reached is to keep the same level
of lung function when reducing the dose of steroids, without severe adverse effect.
Página 32

Kostadima A significant increase of the FEV1% was reported only in the group B (from 85±13 at the baseline to
2004 88±12 at the end of the study period, p<0.05). In the other 2 groups the predicted values were 85±14
and 86±14 at the baseline and 85±12 and 88±15 in group A and C, respectively, differences not
statistically significant.
Compared to the baseline, there was a significant increase in the median PD 20 in groups A and B
(receiving the macrolide) but not in the placebo group. Median (interquartile range) in the 3 groups were
before and after the treatment were: group A: 0.3 (0.1-1) and 1.3 (0.6-2) mg (p<0.001); group B: 0.4
(0.1-0.9) mg (p<0.001); and group C: 0.4 (0.1-0.9) and 0.3 (0.1-0.6) mg (p=NS).
No side effects were clearly reported, but a patient in the group B withdrawn for a gastrointestinal disorder
(no further details were reported). Cortisol levels were measured in 40 patients, no alteration was found
at the baseline and after the treatment with the macrolide.
Shoji 1999 Symptom score significantly decreased after roxithromycin treatment (1.63 SD 0.48 vs 0.87 SD 0.70
p<0.05 ). No subject got worse.
No statistically significant differences were observed in the lung function tests between roxithromycin
and placebo treated patients both after the 8 weeks period, and after provocation testing with sulpyrine.
There were no differences between the 2 groups in the PC20-sulpyrine values of the provocation test,
nor in the leukotriene E4 elimination in the urine.
Mean ECP and eosinophils count both in serum both in sputum showed a significant decrease after the
8 weeks period of treatment with the antibiotic (blood eosinophils p<0.01, serum eosinophils and ECP,
sputum ECP p<0.05).
None of the patients reported any adverse effect.
The authors concluded that roxithromycin demonstrated an anti-inflammatory effect associated with
reduced eosinophil infiltration in patients with aspirin-intolerant asthma, although it did not have effects
on pulmonary function and leukotrienes production, providing interesting therapeutic possibilities for
further trials.
Amayusu 15 of the 17 patients improved their symptom score, 2 reported no improvement. The mean symptom
2000 score decreased significantly after treatment with clarithromycin (1.64 SD 0.48 vs 0.88 SD 0.72 p<0.05).
FVC and FEV1 did not show a significant variation during the time of clarithromycin therapy. This study
failed to confirm the bronchodilating effect of the macrolide. Blood eosinophil count as well as serum
and sputum ECP levels were significantly decreased after clarithromycin treatment. (blood eosinophils
46.3 SD 6.9 vs 12.0 SD 2.4 p<0.1, sputum eosinophils 90 SD 32 vs 11 SD 6 p<0.05, both serum and
sputum ECP p<0.05, 15.2 SD 7.3 vs 3.7 SD 1.5 and 1.7 SD 0.9 vs 0.4 SD 0.1, respectively).
Methacholine provocation test caused an obstructive reaction in all patients independently of the
treatment. PC20-methacholine was higher in the clarithromycin than in the placebo group (mean log
PC20 methacholine was 2.96 SD 0.57 in clarithromycin vs 2.60 SD 0.51 in placebo p<0.01).
No statistically significant association was found between increased PC20 methacholine and ECP levels.
No adverse reaction was reported during the treatment with clarithromycin.
The authors concluded that clarithromycin has not only antibacterial, but also an anti-inflammatory
activity, associated with a reduction of the eosinophilic infiltration in patients with asthma. It is able to
improve symptoms and bronchial hyper responsiveness, but further trials are needed to investigate its
clinical utility.
Black 2001 At the end of the 6 weeks of treatment, the increase of the mean values of morning PEF was significantly
higher in the treated group (14 L/min) compared to the placebo group (8 L/min).There was a subsequent
increase of the morning PEF values in both groups over the following 6 months after the end of treatment,
where the improvement over baseline was 18 L/min in the roxithromycin group, compared to 12 L/min
in the placebo group (p=ns). For evening PEF values, roxithromycin significantly improved PEF values
(15 L/min vs 3 L/min in the placebo group) at the end of the treatment (p=0.02), but not at later time
points.
Both the day time and the night time symptom scores showed a non significant improvement in the
treated group compared to the placebo group over the 6 month study period.
There was a non-significant trend for improved AQLQ score with treatment. No statistically significant
difference was recorded for the day time and night time symptoms scores.
Página 33

No difference was found for rescue medications, as well as for Chlamydia antibody titres measured
during the study.
No difference was reported for side effects between the 2 groups. Only mild and reversible liver function
test alterations were recorded in 2 patients treated with roxythromycin.
The authors concluded that the (not statistically significant) trend of improvement of pulmonary function
test as seen in the 3 months following end of treatment in the roxithromycin group compared to the
placebo group, suggest that the effect of the macrolide therapy on PEF values could be due more to
the antimicrobial effect, than to the antiinflammatory effect of the drug, and that the onset time and
persistence of the effect could be due to a suppression more than a eradication of the C. Pneumoniae
infection. The authors also propose a study with the use of 2 antibiotics active against C. pneumoniae.
Kraft 2002 No change in the FEV1 mean values between clarithromycin and placebo was reported reported at the
end of the treatment (2.64±0.14 L vs 2.69±0.16, respectively, p=.75). A sub-analysis for PCR status the
subjects with a positive PCR for M. pneumoniae or C. pneumoniae showed a significant increase from
their baseline after the therapy with clarithromycin (from a FEV1 mean value of 2.50±0.16 to 2.69±0.16,
p=0.05, N=14), whilst this change was not observed in subjects with a positive or negative PCR who
received placebo (data are not reported in the paper) or with a negative PCR who received the macrolide
(baseline FEV1 mean value 2.59±0.24 L vs 2.54±0.18 L after the treatment, p=0.85, N=12).
In the 14 patients with a positive PCR for an intracellular pathogen who underwent the treatment with
clarithromycin, a decrease in the expression of IL-5, IL-12 and TNF-alpha in BAL cells was observed
by in situ hybridizations. These results would suggest a possible effect of the treatment with macrolides
on the inflammation and pathophysiology of asthma in subjects with an evidence of infection by M.
pneumoniae or C. pneumoniae, but they need to be confirmed with more sensitive techniques and larger
cohort of patients.
It is unclear why the patients underwent a sinus CT evaluation, if they were not affected by chronic
sinusitis and if one of the exclusion criteria was an history of upper airways infection in the last 3 months
before the study.
CARÁTULA
Titulo Macrólidos para el asma crónica
Autor(es) Richeldi L, Ferrara G, Fabbri LM, Lasserson TJ, Gibson PG
Contribución de los autores Luca Richeldi: Autor principal, realizó el borrador del protocolo y de la revisión.
Gianni Ferrara: Extracción de datos, introducción e interpretación
Peter Gibson: Realizó la identificación de preguntas de la revisión; ofreció apoyo
editorial en todo momento
Leonardo Fabbri: Co-autor de la revisión
Toby Lasserson (actualización 2004): realizó la conversión de datos cruzados
(crossover); revisión del texto según los datos de nuevos ensayos
Número de protocolo publicado 2000/1

inicialmente
Número de revisión publicada 2001/3

inicialmente
Fecha de la modificación más

22 noviembre 2004
reciente"
Página 34
"Fecha de la modificación
06 junio 2005
SIGNIFICATIVA más reciente
Cambios más recientes Esta revisión contiene datos de 2 nuevos estudios (Kostadima 2004; Kraft
2002) identificados a partir de búsquedas electrónicas realizadas en mayo
2005. El diseño de estos estudios no permite la acumulación de estos
datos nuevos con los de estudios anteriores. Una nueva medida de
resultado agrupada sobre el VEF1 no reveló diferencias significativas. Los
datos de los ensayos cruzados (crossover) que se agruparon anteriormente
con análisis de las medidas de resultado continuas ahora se convirtieron
en datos de varianza inversa genéricos.
Fecha de búsqueda de nuevos

El autor no facilitó la información
estudios no localizados
Fecha de localización de nuevos

estudios aún no El autor no facilitó la información
incluidos/excluidos
Fecha de localización de nuevos

01 mayo 2005
estudios incluidos/excluidos
Fecha de modificación de la
sección conclusiones de los El autor no facilitó la información
autores
Dirección de contacto Dr Luca Richeldi

Divisione di Pneumologia
Policlinico di Modena
Via del Pozzo, 71
Modena
41100
ITALY
Télefono: + 39-059-4222655
E-mail: richeldi.luca@unimo.it
Facsimile: + 39-059-4224231
Número de la Cochrane Library CD002997
Grupo editorial Cochrane Airways Group
Código del grupo editorial HM-AIRWAYS
RESUMEN DEL METANÁLISIS
01 Macrolide versus placebo - crossover studies

Resultado Nº de Nº de Método estadístico Tamaño del efecto
estudios participantes
01 VEF1 (L/minuto) 2 Litros (efectos fijos) IC del 0.11 [-0.47, 0.69]
95%
02 CVF 2 Litros (efectos fijos) IC del -0.05 [-0.31, 0.21]
95%
Página 35
01 Macrolide versus placebo - crossover studies

03 Síntomas (escala 2 62 Unidades de DE (efectos -1.25 [-1.80, -0.70]
estandarizada) fijos) IC del 95%
04 PCE esputo 2 62 mg/L (efectos fijos) IC del -1.45 [-1.78, -1.11]
95%
05 PCE sérica 2 62 mg/L (efectos fijos) IC del -12.84 [-15.67, -10.00]
95%
06 Eosinófilos en sangre 2 62 10(4)/mL (efectos fijos) IC -33.50 [-36.11, -30.90]
del 95%
07 Neutrófilos en sangre 2 62 10(4)/mL (efectos fijos) IC -42.94 [-75.70, -10.19]
del 95%
08 Eosinófilos en esputo 2 62 10(4)/mL (efectos fijos) IC -78.48 [-90.83, -66.14]
del 95%
09 Neutrófilos en esputo 2 62 10(4)/mL (efectos fijos) IC -70.08 [-108.25,
del 95% -31.91]
10 PC20 (metacolina) Número de dosis (efectos Totales no
fijos) IC del 95% seleccionados
11 PC20 (sulpirina) Número de dosis (efectos Totales no
02 Macrólido versus placebo - estudios de grupos paralelos

Resultado Nº de Nº de Método estadístico Tamaño del efecto
estudios participantes
01 VEF1 (L/minuto) Litros (efectos fijos) IC del Totales no
95% seleccionados
02 VEF1 (escala estandarizada) 2 115 Unidades de DE (efectos -0.22 [-0.60, 0.16]
fijos) IC del 95%
03 VEF1 % teórico Diferencia de medias Totales no
ponderada (efectos fijos) IC seleccionados
del 95%
04 Cambio en el FEM vespertino Diferencia de medias Totales no
del 95%
05 Cambio en el FEM matutino Diferencia de medias Totales no
del 95%
06 Síntomas diurnos Diferencia de medias Totales no
del 95%
07 Reducción del uso de 2 67 Diferencia de medias -0.32 [-0.81, 0.18]
esteroides (continuos) estandarizada (efectos fijos)
IC del 95%
08 Reducción del uso de Riesgo Relativo (efectos Totales no
esteroides (dicotómicos) fijos) IC del 95% seleccionados
Página 36
02 Macrólido versus placebo - estudios de grupos paralelos

09 Exacerbaciones Diferencia de medias Totales no
del 95%
10 Retiros de los estudios Riesgo Relativo (efectos Totales no
11 Náuseas Riesgo Relativo (efectos Totales no
12 Diarrea Riesgo Relativo (efectos Totales no
13 Cambios en las pruebas de la 2 250 Riesgo Relativo (efectos 4.66 [0.88, 24.60]
función hepática fijos) IC del 95%
GRÁFICOS Y OTRAS TABLAS
Fig. 01 Macrolide versus placebo - crossover studies

01.01 VEF1 (L/minuto)
01.02 CVF
Página 37
01.03 Síntomas (escala estandarizada)
01.04 PCE esputo
01.05 PCE sérica
Página 38
01.06 Eosinófilos en sangre
01.07 Neutrófilos en sangre
01.08 Eosinófilos en esputo
Página 39
01.09 Neutrófilos en esputo
01.10 PC20 (metacolina)
01.11 PC20 (sulpirina)
Página 40
Fig. 02 Macrólido versus placebo - estudios de grupos paralelos

02.01 VEF1 (L/minuto)
02.02 VEF1 (escala estandarizada)
02.03 VEF1 % teórico
Página 41
02.04 Cambio en el FEM vespertino
02.05 Cambio en el FEM matutino
02.06 Síntomas diurnos
Página 42
02.07 Reducción del uso de esteroides (continuos)
02.08 Reducción del uso de esteroides (dicotómicos)
02.09 Exacerbaciones
Página 43
02.10 Retiros de los estudios
02.11 Náuseas
02.12 Diarrea
02.13 Cambios en las pruebas de la función hepática
Página 44

Macrolidos en Asma

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Macrólidos para el asma crónica

Richeldi L, Ferrara G, Fabbri LM, Lasserson TJ, Gibson PG

Si desea suscribirse a "La Biblioteca Cochrane Plus", contacte con:

Macrólidos para el asma crónica i

ii Macrólidos para el asma crónica

Richeldi L, Ferrara G, Fabbri LM, Lasserson TJ, Gibson PG

Esta revisión debería citarse como:

Conclusiones de los autores

RESUMEN EN TÉRMINOS SENCILLOS

El asma es una enfermedad inflamatoria de las vías aéreas OBJETIVOS

- mediciones de proteína catiónica eosinofílica (PCE) en suero Consideraciones estadísticas

los macrólidos en poblaciones más grandes de pacientes, POTENCIAL CONFLICTO DE INTERÉS

Referencias de los estudios incluidos en esta revisión Andrade 1983

Kaplan 1958 Black 2000

Characteristics of included studies

Characteristics of included studies

Characteristics of excluded studies

Characteristics of excluded studies

Characteristics of excluded studies

Characteristics of excluded studies

Characteristics of excluded studies

Characteristics of excluded studies

Characteristics of excluded studies

Characteristics of excluded studies

Characteristics of excluded studies

Characteristics of excluded studies

Characteristics of excluded studies

Characteristics of excluded studies

Characteristics of excluded studies

Characteristics of excluded studies

TAB LAS ADICIONALES

Table 01 Summary of included studies' characteristics

Table 01 Summary of included studies' characteristics

Table 01 Summary of included studies' characteristics

Table 01 Summary of included studies' characteristics

Table 01 Summary of included studies' characteristics

Table 01 Summary of included studies' characteristics

Table 01 Summary of included studies' characteristics

Table 01 Summary of included studies' characteristics

Table 02 Narrative of individual study results

Table 02 Narrative of individual study results

Table 02 Narrative of individual study results

Table 02 Narrative of individual study results

Titulo Macrólidos para el asma crónica

Autor(es) Richeldi L, Ferrara G, Fabbri LM, Lasserson TJ, Gibson PG

Número de protocolo publicado 2000/1

Número de revisión publicada 2001/3

Fecha de la modificación más

Fecha de búsqueda de nuevos

Fecha de localización de nuevos

Fecha de localización de nuevos

Dirección de contacto Dr Luca Richeldi

Número de la Cochrane Library CD002997

Grupo editorial Cochrane Airways Group

Código del grupo editorial HM-AIRWAYS

RESUMEN DEL METANÁLISIS

01 Macrolide versus placebo - crossover studies

01 Macrolide versus placebo - crossover studies

02 Macrólido versus placebo - estudios de grupos paralelos

02 Macrólido versus placebo - estudios de grupos paralelos

GRÁFICOS Y OTRAS TABLAS

Fig. 01 Macrolide versus placebo - crossover studies

01.03 Síntomas (escala estandarizada)