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REVISION DE FLUOROQUINOLONAS EN LAS INFECCIONES DEL TRACTO RESPIRATORIO
(especial para SIIC © Derechos reservados)
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Autor:
Heather J. Smith
Columnista Experto de SIIC

Artículos publicados por Heather J. Smith 
Coautor George G. Zhanel* 
Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, and Departments of Medicine. Health Sciences Centre, Winnipeg, Manitoba, Canada*


Recepción del artículo: 13 de enero, 2004
Aprobación: 0 de , 0000
Conclusión breve
Las fluoroquinolonas son drogas importantes en el manejo de las infecciones extrahospitalarias del tracto respiratorio; las de última generación ofrecen beneficios en cuanto a su farmacocinética, farmacodinamia y mayor espectro de acción.

Resumen

Las nuevas fluoroquinolonas (clinafloxacina, garenoxacina, gatifloxacina, gemifloxacina, grepafloxacina, levofloxacina, moxifloxacina, sitafloxacina, sparfloxacina y trovafloxacina) tienen excelente actividad contra aerobios gramnegativos y mejor actividad contra organismos grampositivos como Streptococcus pneumoniae y Staphylococcus aureus. Clinafloxacina, garenoxacina, gatifloxacina, gemifloxacina, moxifloxacina, sitafloxacina, sparfloxacina y trovafloxacina tienen mejor actividad contra anaerobios como Bacteroides fragilis. Generalmente, la garenoxacina muestra la mayor actividad contra patógenos atípicos como Chlamydophila pneumoniae y Micoplasma pneumoiae. Las nuevas fluoroquinolonas son agentes terapéuticos cada vez más importantes en el tratamiento de infecciones extrahospitalarias del tracto respiratorio ya que tienen amplio espectro, incluyendo S. pneumoniae resistente a penicilina y a macrólidos, parámetros farmacocinéticos superiores y buena eficacia clínica. Al aumentar el uso de las fluoroquinolonas se informó la aparición de resistencia. Los mecanismos de resistencia comprenden las mutaciones cromosómicas espontáneas en las enzimas blanco, menor acumulación de la droga en la célula bacteriana y eflujo. Es necesario usar las nuevas fluoroquinolonas a conciencia para limitar la aparición de resistencia y preservar esta clase de antibacterianos.

Palabras clave
Flouoroquinolonas

Clasificación en siicsalud
Artículos originales> Expertos del Mundo>
página www.siicsalud.com/des/expertos.php/66273

Especialidades
Principal: Farmacología, Infectología, 
Relacionadas: Medicina Interna, Neumonología, 

Enviar correspondencia a:
George G. Zhanel. Clinical Microbiology, Health Sciences Centre, MS673-820 Sherbrook St., Winnipeg, Manitoba, R3A 1R9, Canada.

A REVIEW OF FLUOROQUINOLONES IN RESPIRATORY TRACT INFECTIONS
Abstract
The newer fluoroquinolones (clinafloxacin, garenoxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, moxifloxacin, sitafloxacin, sparfloxacin, and trovafloxacin) provide excellent activity against gram-negative aerobes and show improved activity against gram-positive organisms such as Streptococcus pneumoniae and Staphylococcus aureus. Clinafloxacin, garenoxacin, gatifloxacin, gemifloxacin, moxifloxacin, sitafloxacin, sparfloxacin, and trovafloxacin display improved activity against anaerobes such as Bacteroides fragilis. Generally, garenoxacin displays the highest activity against atypical pathogens such as Chlamydophila pneumoniae and Mycoplasma pneumoniae. The newer fluoroquinolones are increasingly important therapeutic agents in the treatment of community-acquired respiratory tract infections as they offer broad-spectrum activity, including penicillin and macrolide resistant S. pneumoniae, superior pharmacokinetic parameters, and good clinical efficacy. As use of fluoroquinolones increases, resistance development has been reported. Spontaneous chromosomal mutations in target enzymes, decreased accumulation of drug in the bacterial cell, and efflux comprise the mechanisms of fluoroquinolone resistance. Conscientious use of the newer fluoroquinolones is necessary in order to limit resistance development and preserve this class of antibacterial.
REVISION DE FLUOROQUINOLONAS EN LAS INFECCIONES DEL TRACTO RESPIRATORIO

(especial para SIIC © Derechos reservados)
Artículo completo
 Evolución de las fluoroquinolonas
Con el descubrimiento del ácido nalidíxico (una naftiridina) en 1962, se creó una nueva clase de antibióticos, las quinolonas.1 El ácido nalidíxico mostraba buena actividad contra aerobios gramnegativos; sin embargo, su uso fue limitado porque tenía pobre actividad contra organismos grampositivos, mala farmacocinética y numerosos efectos adversos.1 Alteraciones estructurales en el ácido nalidíxico dieron como resultado las fluoroquinolonas norfloxacina y ciprofloxacina, en los años \'80.1 La norfloxacina y ciprofloxacina mostraron mayor espectro de actividad tanto contra organismos grampositivos como gramnegativos y eran mucho más potentes que los antibióticos precedentes.1 A partir de la adición de varios sustituyentes moleculares a la estructura quinolona básica se siguió introduciendo mejoras a la clase de las fluoroquinolonas. Las nuevas fluoroquinolonas: gatifloxacina, gemifloxacina, grepafloxacina, levofloxacina, moxifloxacina, sitafloxacina, sparfloxacina, trovafloxacina y la desfluoroquinolona en investigación garenoxacina, demostraron actividad mejorada contra organismos grampositivos como Streptococcus pneumoniae así como propiedades farmacocinéticas mejoradas.1Mecanismo de acción
La actividad bactericida de las fluoroquinolonas está mediada por la inhibición de dos topoisomerasas de tipo 2, la ADN girasa y la topoisomerasa IV.1,2 La ADN girasa y la topoisomerasa IV mantienen el estado topológico del ADN al generar roturas sistemáticas de cadena simple en ambas cadenas del cromosoma bacteriano, pasando un segmento intacto de ADN a través de la rotura, seguido de la reparación de las cadenas de ADN rotas.1-4 Se forma un complejo divisible entre la fluoroquinolona, la enzima y las cadenas de ADN rotas.2,4,5 Se liberan las porciones de ADN de cadena doble rotas, produciendo inhibición de la replicación, transcripción, recombinación y reparación del ADN.1,2
La ADN girasa es una proteína tetramérica compuesta por dos dímeros GyrA y dos dímeros GyrB (A2B2), codificados respectivamente por gyrA y gyrB.1,3-5 La ADN girasa es esencial en la replicación ya que elimina los giros superhelicoidales por delante de la horquilla de replicación e introduce superhélices negativas en el ADN.1-4
De igual manera, la topoisomerasa IV es una proteína tetramérica compuesta por dos dímeros ParC y dos ParE (C2E2) codificados por parC y parE, respectivamente.1,3-5 La topoisomerasa IV es esencial para la decatenación de cromátides hermanas durante la segregación de los cromosomas replicados.1,2,4
Mecanismos de resistencia
Los mecanismos de resistencia a fluoroquinolonas comprenden las mutaciones cromosómicas espontáneas en la ADN girasa y en la topoisomerasa IV, la disminución de la acumulación de droga en la célula bacteriana, y el eflujo.1,6-8 Es importante evaluar la aparición de resistencia a fluoroquinolonas en patógenos respiratorios, ya que el objetivo principal de las nuevas fluoroquinolonas es el tratamiento de las infecciones extrahospitalarias del tracto respiratorio.1,9 Generalmente, la incidencia de resistencia a fluoroquinolonas entre los patógenos respiratorios sigue siendo baja;1,10 sin embargo, recientemente se informó resistencia a las fluoroquinolonas en Streptococcus pneumoniae.1,11 Por lo tanto, la discusión en esta sección se basa en la resistencia a fluorouinolonas por parte de S. pneumoniae.
La aparición de resistencia a fluorouinolonas en S. pneumoniae es generalmente debida a mutaciones puntuales espontáneas en las regiones de gyrA y parC determinantes de resistencia a quinolonas.1,5,12,13 El impacto de las mutaciones en gyrB y parE es limitado y controvertido.1,5,12,13 Las mutaciones más frecuentes en los aminoácidos de GyrA en los cultivos de S. pneumoniae resistentes a fluoroquinolonas son Ser-81 y Glu-85.1-3,12,13 Ser-81 es comúnmente sustituida por Phe o Tyr.1-3,12,13 El 69.2% al 78.6% de todas las sustituciones GyrA son Ser-81-Phe.12,13 Glu-85 puede ser mutada a residuos Lys o Gly.2,3,12,13 Las sustituciones de aminoácidos arriba mencionadas de Ser-81 y Glu-85 pueden producir la alteración del la estructura del sitio de unión a quinolonas en el complejo ADN-ADN girasa.3 La resistencia a fluoroquinolonas puede ser debida a reducción de la afinidad de unión al complejo ADN-enzima modificado.3 El aminoácido ParC comúnmente asociado a resistencia a fluoroquinolonas en S. pneumoniae es Ser-79.1-3,12,13 Ser-79 es generalmente mutado a Phe o Tyr.1,3,12,13 El 50%-62.5% de todos los cultivos de S. pneumoniae con mutación ParC son Ser-79-Phe.12,13 Otras mutaciones comúnmente observadas en ParC son Asp-83 (Ala, Gly, Asn, Thr y Tyr),2,12,13 Ser-52-Gly, y Lys-137-Asn, pero las mutaciones Ser-52 y Lys-137 no parecen producir aumentos en la concentración inhibitoria mínima (CIM).12 Los aumentos de la CIM para ciprofloxacina, clinafloxacina, gatifloxacina, gemifloxacina, grepafloxacina, levofloxacina, moxifloxacina y trovafloxacina debidos a mutaciones gyrA y parC se presentan en la tabla 1.
Tabla 1Originalmente se creía que el eflujo de fluoroquinolonas en S. pneumoniae estaba controlado por la bomba de eflujo PmrA.6-8,16-18 Sin embargo, el aumento de la expresión de pmrA no se asocia de manera directa con cultivos con fenotipo de eflujo.16 Adicionalmente, el fenotipo de eflujo no se altera por la inactivación de pmrA.17,18 Actualmente se están investigando otras posibles bombas de eflujo en S. pneumoniae para determinar su papel en el eflujo de fluoroquinolonas.
Actividad microbiológica
La actividad in vitro de las nuevas fluoroquinolonas (clinafloxacina, garenoxacina, gatifloxacina, gemifloxacina, grepafloxacina, levofloxacina, moxifloxacina, sitafloxacina, sparfloxacina y trovafloxacina) contra patógenos clínicamente importantes se compara con la de la ciprofloxacina en las tablas 2 a 5. Esas tablas fueron tomadas de una revisión nuestra, previa.1 Cada tabla presenta la concentración mínima de cada antibiótico que se requiere para inhibir el 50% y el 90% de los cultivos (CIM50 y CIM90) para diferentes grupos de organismos: aerobios grampositivos (tabla 2), aerobios gramnegativos (tabla 3), anaerobios (tabla 4) y patógenos atípicos (tabla 5).
Tabla 2En comparación con la ciprofloxacina, todas las nuevas fluoroquinolonas muestran mayor actividad in vitro contra organismos grampositivos.1,19-86 La gemifloxacina, la garenoxacina y la sitafloxacina muestran la actividad más potente, sobre la base de la CIM90, contra Staphylococcus aureus (sensibles a meticilina), Staphylococcus epidermidis (sensibles a meticilina) y Streptococcus pneumoniae (sensibles o no a penicilina). Staphylococcus aureus y S. pneumoniae tienen sensibilidad similar a las fluoroquinolonas, con un orden de potencia decreciente: gemifloxacina ≥ sitafloxacina ≥ garenoxacina ≥ clinafloxacina = trovafloxacina > grepafloxacina = moxifloxacina ≥ gatifloxacina = sparfloxacina > levofloxacina > ciprofloxacina. En general, las nuevas fluoroquinolonas demostraron mejor actividad contra organismos grampositivos, pero la actividad contra Enterococcus spp. sigue siendo baja, con un intervalo CIM90 de 1-16 μg/ml.
Tabla 3La tabla 3 muestra la actividad in vitro de las nuevas fluoroquinolonas contra aerobios gramnegativos.20,21,24,26,28-43,45,47-51,55-58,61,63,66-68,72-74,79,81-86,87-112 La mayor actividad contra grampositivos no redujo la actividad contra gramnegativos, al comparar con ciprofloxacina. Además de Pseudomonas aeruginosa, las nuevas fluoroquinolonas mostraron gran actividad contra los aerobios gramnegativos, con CIM90 generalmente < 2 μg/ml. La actividad de las nuevas fluoroquinolonas contra P. aeruginosa es de valores de CIM90 de 1-16 μg/ml. El orden de actividad, sobre la base de CIM90, fue clinafloxacina > sitafloxacina > ciprofloxacina > gemifloxacina ≥ trovafloxacina ≥ grepafloxacina ≥ levofloxacina ≥ sparfloxacina ≥ gatifloxacina > moxifloxacina > garenoxacina. El espectro de CIM90 para Haemophylus influenzae y Moraxella catarrhalis para ciprofloxacina y las nuevas fluoroquinolonas fue de 0.004-0.03 y 0.008-0.03 &mug;/ml, respectivamente.
Tabla 4Adicionalmente, las nuevas fluoroquinolonas mostraron mayor actividad contra anaerobios (tabla 4) y patógenos atípicos (tabla 5) en comparación con ciprofloxacina.19,23,27,30,32-34,36,39,41,42,45,48,51,53,55-60,62,69-72,76,77,80,82,83,85,87,88,90-104,106,108,109,112-150 La sitafloxacina fue la más activa contra Bacteroides fragilis, Clostridium difficile y Clostridium perfringens (tabla 4). El intervalo de CIM90 para las nuevas fluoroquinolonas contra B. fragilis y C. perfringes fue de 0.25-8 y 0.06-1 μg/ml, respectivamente. El orden de actividad, basado en los valores de CIM90, contra B. fragilis fue sitafloxacina ≥ garenoxacina > trovafloxacina > clinafloxacina = moxifloxacina > gatifloxacina > gemifloxacina > sparfloxacina > levofloxacina > grepafloxacina = ciprofloxacina. El orden de actividad, basado en los valores de CIM90 contra C. perfringes fue sitafloxacina > clinafloxacina = gemifloxacina > trovafloxacina > gatifloxacina = grepafloxacina = moxifloxacina = sparfloxacina > ciprofloxacina = garenoxacina = levofloxacina.
Tabla 5Las nuevas fluoroquinolonas mostraron mayor actividad in vitro contra patógenos atípicos como Chlamydophila pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae y Ureaplasma urealyticum, en comparación con ciprofloxacina, como lo demuestran sus valores CIM90 (tabla 5). Las CIM90 para C. pneumoniae y U. urealyticum fueron ≤ 1 μg/ml. El intervalo de CIM90 para L. pneumophila y M. pneumoniae fue 0.008-0.3 y 0.03-0.5 μg/ml, respectivamente. El orden de actividad contra C. pneumoniae, basado en valores CIM90, fue garenoxacina > sparfloxacina > grepafloxacina > gatifloxacina ≥ gemifloxacina > levofloxacina = moxifloxacina = trovafloxacina > ciprofloxacina. Todas las fluoroquinolonas son muy activas contra L. pneumophila y tienen valores CIM90 similares. Para M. pneumoniae, el orden de actividad de las fluoroquinolonas fue garenoxacina > clinafloxacina > gatifloxacina = gemifloxacina ≥ moxifloxacina = sparfloxacina > grepafloxacina = trovafloxacina > levofloxacina > ciprofloxacina. El orden de actividad decreciente contra U. urealyticum fue garenoxacina = trovafloxacina > gemifloxacina > moxifloxacina > clinafloxacina = sparfloxacina > gatifloxacina = grepafloxacina = levofloxacina > ciprofloxacina.
Farmacocinética/farmacodinamia
Los parámetros farmacocinéticos de las nuevas fluoroquinolonas en sujetos sanos luego de una dosis única se presentan en la tabla 6.1,31,151-178
Tabla 6Las nuevas fluoroquinolonas son bien absorbidas luego de su administración oral, con un espectro de biodisponibilidad de > 70% para sitafloxacina a 99% para levofloxacina y valores Tmax, tiempo requerido para lograr la concentración plasmática máxima (Cmax), de aproximadamente 1 a 2 horas. Al igual que las otras fluoroquinolonas nuevas, la biodisponibilidad de la garenoxacina es alta (92%). La investigación acerca del efecto de la comida en la farmacocinética de las nuevas fluoroquinolonas indica que los alimentos pueden retardar su absorción, pero no alteran la cantidad absorbida (área bajo la curva [ABC]) ni la biodisponibilidad. Por lo tanto, gatifloxacina, garenoxacina, gemifloxacina, grepafloxacina, levofloxacina, moxifloxacina, sitafloxacina, sparfloxacina, y trovafloxacina pueden ser tomadas por vía oral, con alimentos o sin ellos.
La unión a proteínas para las nuevas fluoroquinolonas va del 5% (clinafloxacina) al 75% (garenoxacina), y el volumen de distribución de 1.1 (levofloxacina) a 7.7 (grepafloxacina) l/kg. La tabla 7 muestra la penetración de las nuevas fluoroquinolonas en determinados líquidos y tejidos. Generalmente, las nuevas fluoroquinolonas tienen buena penetración en los macrófagos alveolares, mucosa bronquial, fluido de recubrimiento epitelial y saliva; sin embargo, la penetración en el líquido cefalorraquídeo es inferior a la de la ciprofloxacina. Las nuevas fluoroquinolonas mostraron penetrar en los líquidos inflamatorios en proporciones séricas de 0.60 (trovafloxacina) a 1.33 (grepafloxacina). La información acerca de la garenoxacina es limitada, pero parece que la tasa de penetración en los tejidos del tracto respiratorio es inferior a la de las otras fluoroquinolonas, con valores de 11.17, 0.72 y 0.95 para los macrófagos alveolares, mucosa bronquial y fluido de recubrimiento epitelial, respectivamente (tabla 7).
Tabla 7La vida media de las nuevas fluoroquinolonas es más larga que la de la ciprofloxacina, y va de 4.7 horas para sitafloxacina a 18.7 horas para sparfloxacina (tabla 7). Clinafloxacina, gatifloxacina, levofloxacina y sitafloxacina son excretadas principalmente por riñón: > 50% del compuesto original es eliminado en la orina. Gemifloxacina, grepafloxacina, moxifloxacina, sparfloxacina y trovafloxacina son excretadas predominantemente a través de vías no renales (tabla 7). Se vio que la garenoxacina se elimina tanto por vías renales como no renales.179 Se requieren ajustes de dosis para clinafloxacina, gatifloxacina, levofloxacina, gemifloxacina y sparfloxacina en pacientes con deterioro renal, si bien las dos últimas se eliminan por vías no renales.1,161,169 Actualmente no hay información disponible acerca de si se requieren ajustes de dosis para garenoxacina o sitafloxacina en pacientes con deterioro renal o hepático.
Los parámetros farmacodinámicos de las moléculas de las drogas describen la relación entre la concentración sérica de la droga y sus efectos farmacológicos y toxicológicos.1
Se utilizan los parámetros farmacodinámicos de los estudios in vitro para determinar el régimen de dosificación óptima del antibiótico que maximice su eficacia clínica, minimice la toxicidad y limite la aparición de resistencia.1 Para obtener resultados clínicamente significativos de potencia y eficacia in vivo se requiere la actividad farmacodinámica de los agentes antibacterianos, basada en la integración de la farmacocinética, actividad microbiológica y concentraciones séricas y tisulares adecuadas.1
Las propiedades farmacodinámicas pueden ser usadas para predecir la respuesta terapéutica de los microorganismos a los antimicrobianos, correlacionando las mediciones de exposición a la droga (Cmax, o ABC en las 24 horas de la administración de la dosis [ABC24]) con mediciones de potencia de la droga (CIM) o evaluando el tiempo (T) durante el cual la concentración de la droga es superior a la CIM.1 Por lo tanto, Cmax/CIM, ABC24/CIM (o el área bajo la curva concentración plasmática inhibitoria-tiempo [ABCI]) y el tiempo por encima de la CIM (T/CIM) son los parámetros farmacocinéticos/farmacodinámicos importantes en la predicción de resultados clínicos.180
Generalmente se considera que las fluoroquinolonas son antibacterianos dependientes de la concentración, por lo que los principales parámetros usados para predecir la actividad antibacteriana y la eficacia clínica son las tasas ABC24/CIM y Cmax/CIM.1 La información obtenida en animales (in vitro) y clínica indica que las tasas ABC24/CIM ≥ 30 son predictoras de erradicación bacteriana en las infecciones extrahospitalarias del tracto respiratorio causadas por S. pneumoniae.164,181,182 Los parámetros farmacocinéticos/farmacodinámicos para las fluoroquinolonas, contra S. penumoniae, se presentan en la tabla 8.
Tabla 8Fracasos del tratamiento
Con el aumento del uso de las fluoroquinolonas se informaron fracasos clínicos durante el tratamiento empírico con estas drogas. Varios informes surgieron a partir del fracaso de la levofloxacina durante el tratamiento de la neumonía neumocócica.5,183 El uso reciente (durante los últimos 3 meses) de terapia con fluoroquinolonas (especialmente ciprofloxacina) ha sido implicado como el principal factor de riesgo de fracaso con las nuevas fluoroquinolonas, y tres de cinco pacientes descritos tenían el antecedente reciente de tratamiento con fluoroquinolonas.5,183 Posteriormente se vio que el S. pneumoniae responsable del fracaso de la levofloxacina en los tres pacientes que habían recibido tratamiento reciente con fluoroquinolonas tenía sustituciones ParC (Ser-79-Phe) y GyrA (Ser-81-Phe/Tyr, Glu-85-Lys).5,183 Los otros dos casos no tenían antecedente de tratamiento con fluoroquinolonas.183 En un caso, el cultivo posterior al tratamiento presentó sustituciones tanto en ParC (Ser-79-Phe) como en GyrA (Ser-81-Phe) si bien en el cultivo inicial no se habían detectado mutaciones ni en ParC ni en GyrA.183 El cultivo inicial del quinto caso (previo a la terapia con levofloxacina) tenía una sustitución Ser-79-Phe en ParC, si bien la CIM indicaba que era susceptible.183 Luego de la terapia, el cultivo tenía mutaciones tanto en ParC (Ser-79-Phe) como en GyrA (Ser-81-Phe).183 Los dos últimos casos son particularmente interesantes ya que los pacientes no habían recibido terapia previa con fluoroquinolonas; uno de los cultivos parece haber desarrollado dos mutaciones (una en ParC y la otra en GyrA) durante el curso del tratamiento, y el otro era considerado sensible, pero tenía una sustitución ParC. El impacto y la frecuencia con que esto ocurre aún debe ser determinado.
Conclusiones
Las nuevas fluoroquinolonas (clinafloxacina, gatifloxacina, gemifloxacina, grepafloxacina, levofloxacina, moxifloxacina, sitafloxacina, sparfloxacina, y trovafloxacina) y la desfluoroquinolona garenoxacina demostraron tener un amplio espectro de actividad contra bacilos gramnegativos, aerobios grampositivos, incluidas algunas cepas resistentes, anaerobios, y patógenos atípicos en comparación con ciprofloxacina. Adicionalmente, estos agentes tienen farmacocinética favorable y una eficacia clínica y bacteriológica excelente. Como tales, las fluoroquinolonas son agentes terapéuticos cada vez más importantes en el tratamiento de las infecciones extrahospitalarias del tracto respiratorio. Es necesario usar a conciencia las nuevas fluoroquinolonas para limitar la aparición de resistencia y preservar esta clase de antibacterianos.
Los autores no manifiestan conflictos.
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