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.

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 T_max, tiempo requerido para lograr la concentración plasmática máxima (C_max), 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 (C_max, 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, C_max/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 C_max/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.

Bibliografía del artículo

1. Zhanel GG, Ennis K, Vercaigne, et al. A critical review of the fluoroquinolones: focus on respiratory tract infections. Drugs. 2002; 62: 13-59.
2. Drlica K, Zhao X. DNA gyrase, topoisomerase IV, and the 4-quinolones. Microbiol. Mol. Biol. Rev. 1997; 61: 377-392.
3. Hooper DC. Mechanism of FQ res. In Gram Positive Pathogens; Fischetti VA, Novick RP, Ferretti JJ, Portnoy DA, Rood JI, Eds.; American Society of Microbiology: Washington, D.C., 2000; 685-693.
4. Yague G, Morris JE, Pan XS et al. Cleavable-complex formation by wild-type and quinolone-resistant Streptococcus pneumoniae type II topoisomerases mediated by gemifloxacin and other fluoroquinolones. Antimicrob. Agents Chemother. 2002; 46: 413-419.
5. Kays MB, Smith DW, Wack MF, et al. Levofloxacin treatment failure in a patient with fluoroquinolone-resistant Streptococcus pneumoniae pneumonia. Pharmacother. 2002; 22: 395-399.
6. Brenwald NP, Gill MJ, Wise R. Prevalence of a putative efflux mechanism among fluoroquinolone-resistant clinical isolates of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 1998; 42: 2032-5.
7. Zeller V, Janoir C, Kitzis MD, et al. Active efflux as a mechanism of resistance to ciprofloxacin in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 1997; 41: 1973-8.
8. Gill MJ, Brenwald NP, Wise R. Identification of an efflux pump gene, pmrA, associated with fluoroquinolone resistance in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 1999; 43: 187-9.
9. Roblin D. The clinical development of quinolone antibacterials. Int. J. Pharm. Med. 1999; 13: 83-90.
10. Sahm DF, Jones ME, Hickey ML, et al. Resistance surveillance of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis isolated in Asia and Europe, 1997-1998. J Antimicrob. Chemother. 2000; 45: 457-66.
11. Chen DK, McGeer A, de Azavedo JC, et al. Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. N Engl. J. Med. 1999; 341: 233-9.
12. Bast DJ, Low DE, Duncan CL, et al. Fluoroquinolone resistance in clinical isolates of Streptococcus pneumoniae: contributions of type II topoisomerase mutations and efflux to levels of resistance. Antimicrob. Agents Chemother. 2000; 44: 3049-3054.
13. Zhanel GG, Walkty A, Nichol K, et al. Molecular characterization of fluoroquinolone resistant Streptococcus pneumoniae clinical isolates obtained from across Canada. Diag. Microbiol. Infect. Dis. 2003; 45: 63-67.
14. Morris JE, Pan X, Fisher LM, et al. Grepafloxacin, a Dimethyl Derivative of Ciprofloxacin, Acts Preferentially through Gyrase in Streptococcus pneumoniae: Role of the C-5 Group in Target Specificity. Antimicrob. Agents Chemother. 2002; 46: 582-585.
15. Jorgensen JH, Weigel LM, Swenson JM, et al. Activities of Clinafloxacin, Gatifloxcin, Gemifloxacin, and Trovafloxacin against Recent Clinical Isolates of Levofloxacin-Resistant Streptococcus pneumoniae. Antimicrob. Agents Chemother. 2000; 44: 2962-2968.
16. Piddock LJV, Johnson MM, Simjee S, et al. Expression of efflux pump gene pmrA in fluoroquinolone-resistant and –susceptible clinical isolates of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 2002; 46: 808-812.
17. Brenwald NP, Appelbaum P, Davies T, et al. Evidence for efflux pumps, other than PmrA, associated with fluoroquinolone resistance in Streptococcus pneumoniae. Clin. Microbiol. Infect. 2003; 9: 140-143.
18. Pestova E, Millichap JJ, Siddiqui F, et al. Non-PmrA-mediated multidrug resistance in Streptococcus pneumoniae. J. Antimicrob. Chemother. 2002; 49: 553-559.
19. (NCCLS), N. C. C. L. S. 2000. Performance standards for antimicrobial susceptibility testing: Polgar PE, editor. 10th informational supplement, NCCLS. Pennsylvania.
20. Abbanat D, Macielag M, Bush K. Novel antibacterial agents for the treatment of serious Gram-positive infections. Expert Opin. Investig. Drugs. 2003; 12:379-99.
21. Barry AL, Fuchs PC, Brown SD. Antibacterial activity of moxifloxacin (Bay 12-8039) against aerobic clinical isolates, and provisional criteria for disk susceptibility tests. Eur. J Clin. Microbiol. Infect. Dis. 1999; 18:305-9.
22. Bassetti M, Dembry LM, Farrel PA, et al. Antimicrobial activities of BMS-284756 compared with those of fluoroquinolones and beta-lactams against gram-positive clinical isolates. Antimicrob. Agents Chemother. 2002; 46:234-8.
23. Betriu C, Redondo M, Palau ML, et al. Comparative in vitro activities of linezolid, quinupristin-dalfopristin, moxifloxacin, and trovafloxacin against erythromycin-susceptible and-resistant Streptococci. Antimicrob. Agents Chemother. 2000; 44:1838-41.
24. Biedenbach DJ, Barrett MS, Croco MA, et al. BAY 12-8039, a novel fluoroquinolone: activity against important respiratory tract pathogens. Diagn Microbiol. Infect. Dis. 1998; 32:45-50.
25. Biedenbach DJ, Jones R, Dipersio J. Fluoroquinolone resistance in H. influenzae (HFLU) and M. catarrhalis (MCAT): frequency of occurrence and strain characteristics in the SENTRY Antimicrobial Surveillance Program (1997-1999; North America) [poster no.54]. 1999 Sep 26-29. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco (CA).
26. Biedenbach DJ, Jones RN, Pfaller MA. Activity of BMS284756 against 2,681 recent clinical isolates of Haemophilus influenzae and Moraxella catarrhalis: Report from The SENTRY Antimicrobial Surveillance Program (2000) in Europe, Canada and the United States. Diagn. Microbiol. Infect. Dis. 2001; 39:245-50.
27. Casellas JM, Gilardoni M, Tome G, et al. Comparative in-vitro activity of levofloxacin against isolates of bacteria from adult patients with community-acquired lower respiratory tract infections. J. Antimicrob. Chemother. 1999; 43:37-42.
28. Coyle EA, Kaatz GW, Rybak MJ. Activities of newer Fluoroquinolones against ciprofloxacin-resistant Streptococcus pneumoniae. Antimicrob. Agents Chemother. 2001; 45:1654-1659.
29. Davies TA, Kelly LM, Pankuch GA. Antipneumoccocal activity of gatifloxacin compared to those of nine other agents. Antimicrob. Agents Chemother. 2000; 44:304-10.
30. Dembry LM, Roberts JC, Schock KD, et al . Comparison of in vitro activity of trovafloxacin against gram-positive and gram-negative organisms with quinolones and beta-lactam antimicrobial agents. Diagn. Microbiol. Infect. Dis. 1998; 31:301-11.
31. Deshpande DJ, Diekema DJ, Jones RN. Comparative activity of clinafloxacin and nine other compounds tested against 1000 contemporary clinical isolates from patients in United States hospitals. Diagn. Microbiol. Infect. Dis. 1999; 35:81-8.
32. Diekema DJ, Jones RN, Rolston KV. Antimicrobial activity of gatifloxacin compared to seven other compounds tested against gram-positive organisms isolated at 10 cancer-treatment centers. Diagn. Microbiol. Infect. Dis. 1999; 34:37-43.
33. Drlica K. A strategy for fighting antibiotic resistance. ASM News. 2001; 67:27-33.
34. Felmingham D, Robbins MJ, Ingley K, et al. In-vitro activity of trovafloxacin, a new fluoroquinolone, against recent clinical isolates. J. Antimicrob. Chemother. 1997; 39:43-9.
35. Fung-Tomc J, Minassian B, Kolek B, et al. In vitro antibacterial spectrum of a new broad-spectrum 8-methoxy fluoroquinolone, gatifloxacin. J. Antimicrob. Chemother. 2000; 45:437-46.
36. Fung-Tomc JC, Minassian B, Kolek B, et al. Antibacterial spectrum of a novel des-fluoro(6) quinolone, BMS-284756. Antimicrob. Agents Chemother. 2000; 44:3351-6.
37. Giamarellos-Bourboulis EJ, Sambatakou H, Grecka P et al. In vitro activity of quinupristin/dalfopristin and newer quinolones combined with gentamicin against resistant isolates of Enterococcus faecalis and Enterococcus faecium. Eur J Clin Microbiol. Infect. Dis. 1998; 17:657-61.
38. Gordon KA, Pfaller MA, Jones RN. BMS284756 (formerly T-3811, a des-fluoroquinolone) potency and spectrum tested against over 10,000 bacterial bloodstream infection isolates from the SENTRY antimicrobial surveillance programme (2000). J. Antimicrob. Chemother. 2002; 49:851-5.
39. Hardy D, Amsterdam D, Mandell LA et al. Comparative in vitro activities of ciprofloxacin, gemifloxacin, grepafloxacin, moxifloxacin, ofloxacin, sparfloxacin, trovafloxacin, and other antimicrobial agents against bloodstream isolates of gram-positive cocci. Antimicrob. Agents. Chemother. 2000; 44:802-5.
40. Hoban DJ, Zhanel GG, Karlowsky JA. In vitro activity of the novel ketolide HMR 3647 and comparative oral antibiotics against Canadian respiratory tract isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Diagn. Microbiol. Infect. Dis. 1999; 35:37-44.
41. Hoellman DB, Lin G, Jacobs MR, et al. Anti-pneumococcal activity of gatifloxacin compared with other quinolone and non-quinolone agents. J. Antimicrob. Chemother. 1999; 43:645-9.
42. Hoogkamp-Korstanje JA. In-vitro activities of ciprofloxacin, levofloxacin, lemofloxacin, ofloxacin, pefloxacin, sparfloxacin and trovafloxacin against gram-positive and gram-negative pathogens from respiratory tract infections. J. Antimicrob. Chemother. 1997; 40:427-31.
43. Hoogkamp-Korstanje JA, Roelofs-Willemse J. Comparative in vitro activity of moxifloxacin against Gram-positive clinical isolates. J. Antimicrob. Chemother. 2000; 45:31-9.
44. Ieven M, Goossens W, De Wit S, et al. In vitro activity of gemifloxacin compared with other antimicrobial agents against recent clinical isolates of streptococci. J. Antimicrob. Chemother. 2000; 45:51-3.
45. Johnson DM, Jones RN, Erwin ME. Anti-streptococcal activity of SB-265805 (LB20304), a novel fluoronaphthyridone, compared with five other compounds, including quality control guidelines. Diagn. Microbiol. Infect. Dis. 1999; 33:87-91.
46. Jones RN, Pfaller MA, Doern GV. Comparative antimicrobial activity of trovafloxacin tested against 3049 Streptococcus pneumoniae isolates from the 1997-1998 respiratory infection season. Diagn. Microbiol. Infect. Dis. 1998; 32:119-26.
47. Jones RN, Pfaller MA, Stilwell M. Activity and spectrum of BMS 284756, a new des-F (6) quinolone, tested against strains of ciprofloxacin-resistant Gram-positive cocci. Diagn. Microbiol. Infect. Dis. 2001; 39:133-5.
48. Keller N, Smollen G, Davidson Y, et al. The susceptibility of Streptococcus pneumoniae to levofloxacin and other antibiotics. J. Antimicrob. Chemother. 1999; 43:1-3.
49. King A, May J, French G, et al. Comparative in vitro activity of gemifloxacin. J. Antimicrob. Chemother. 2000; 45:1-12.
50. Kirby JT, Mutnick AH, Jones RN, et al. Geographic variations in garenoxacin (BMS284756) activity tested against pathogens associated with skin and soft tissue infections: report from the SENTRY Antimicrobial Surveillance Program (2000). Diagn. Microbiol. Infect. Dis. 2002; 43:303-9.
51. Kolek B, Warr G, Bonner D, et al. Intracellular penetration and bactericidal activity of the novel des- fluoro(6) quinolone, BMS-284756. J. Antimicrob. Chemother. 2001; 48:445-6.
52. Ling TK, Liu EY, Cheng AF. In vitro activity of trovafloxacin (CP 99,219), a new fluoroquinolone against hospital isolates. Chemotherapy. 1999; 45:22-7.
53. Low DE, Muller M, Duncan CL, et al. Activity of BMS-284756, a novel des-fluoro(6) quinolone, against Staphylococcus aureus, including contributions of mutations to quinolone resistance. Antimicrob. Agents Chemother. 2002; 46:1119-21.
54. Marshall SA, Jones RN, Murray PR, et al. In-vitro comparison of DU-6859a, a novel fluoroquinolone, with other quinolones and oral cephalosporins tested against 5086 recent clinical isolates. J. Antimicrob. Chemother. 1993; 32:877-84.
55. Martinez-Martinez L, Joyanes P, Suarez AI. Activity of gemifloxacin against clinical isolates of Listeria monocytogenes and Coryneform bacteria [poster 1504]. 1999 Sep 26-29. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco (CA).
56. Martinez-Martinez L, Pascual A, Suarez AI, et al. In-vitro activity of levofloxacin, ofloxacin, and D-ofloxacin against coryneform bacteria and Listeria monocytogenes. J. Antimicrob. Chemother. 1999; 43:27-32.
57. McCloskey L, Moore T, Niconovich N, et al. In vitro activity of gemifloxacin against a broad range of recent clinical isolates from the USA. J. Antimicrob. Chemother. 2000; 45:13-21.
58. Mikamo H, Kawazoe K, Sato Y, et al. In vitro and in vivo antibacterial activities of AM-1155 in the fields of obstetrics and gynecology. Chemotherapy. 1998; 44:238-42.
59. Milatovic D, Schmitz FJ, Brisse S, et al. In Vitro Activities of Sitafloxacin (DU-6859a) and Six Other Fluoroquinolones against 8,796 Clinical Bacterial Isolates. Antimicrob. Agents Chemother. 2000; 44:1102-1107.
60. Miyashita N, Niki Y, Kishimoto T, et al. In vitro and in vivo activities of AM-1155, a new fluoroquinolone, against Chlamydia spp. Antimicrob. Agents Chemother. 1997; 41:1331-4.
61. Montanari MP, Mingoia M, Marchetti F, et al. In vitro activity of levofloxacin against gram-positive bacteria. Chemotherapy. 1999; 45:411-7.
62. Montanari MP, Prenna M, Mingoia M, et al. In vitro antibacterial activity of trovafloxacin and five other fluoroquinolones. Chemotherapy. 1998; 44:85-93.
63. Nagai A, Miyazaki M, Morita T, et al. Comparative articular toxicity of garenoxacin, a novel quinolone antimicrobial agent, in juvenile beagle dogs. J. Toxicol. Sci. 2002; 27:219-28.
64. Niki Y, Yamashita Y, Otoh H. In vitro activities of sitafloxacin (DU-6859a) against major pathogens of community-acquired pneumonia. Kurashiki, Japan. Kawasaki Medical School. 1999.
65. Odland BA, Jones RN, Verhoef J, et al. Antimicrobial activity of gatifloxacin (AM-1155, CG5501), and four other fluoroquinolones tested against 2,284 recent clinical strains of Streptococcus pneumoniae from Europe, Latin America, Canada, and the United States. The SENTRY Antimicrobial Surveillance Group (Americas and Europe). Diagn. Microbiol. Infect. Dis. 1999; 34:315-20.
66. Pankuch GA, Hoellman DB, Jacobs MR, et al. Antipneumococcal activity of MEN 10700, a new penem, compared with other compounds, by MIC and time-kill kinetics. J. Antimicrob. Chemother. 1999; 44:381-4.
67. Pong A, Thomson KS, Moland ES, et al. Activity of moxifloxacin against pathogens with decreased susceptibility to ciprofloxacin. J. Antimicrob. Chemother. 1999; 44:621-7.
68. Rittenhouse S, McCloskey L, Broskey J, et al. In vitro antibacterial activity of gemifloxacin and comparator compounds against common respiratory. J. Antimicrob. Chemother. 2000; 45:23-7.
69. Rolston KV, Ho DH, LeBlanc B, et al. In-vitro activity of trovafloxacin against clinical bacterial isolates from patients with cancer. J. Antimicrob. Chemother. 1997; 39:15-22.
70. Snydman DR, Jacobus NV, McDermott LA, et al. In vitro activities of newer quinolones against Bacteroides group organisms. Antimicrob. Agents Chemother. 2002; 46:3276-9.
71. Stein GE. Pharmacokinetics and pharmacodynamics of newer fluoroquinolones. Clin. Infect. Dis. 1996; 23:S19-24.
72. Struwig MC, Botha PL, Chalkley LJ. In vitro activities of 15 antimicrobial agents against clinical isolates of South African enterococci. Antimicrob. Agents Chemother. 1998; 42:2752-5.
73. Takahata M, Mitsuyama J, Yamashiro Y, et al. In vitro and in vivo antimicrobial activities of T-3811ME, a novel des-F-(6)-quinolone. Antimicrob. Agents Chemother. 1999; 43:1077-84.
74. Thomson KS, Sanders CC. The effects of increasing levels of quinolone resistance on in-vitro activity of four quinolones. J. Antimicrob. Chemother. 1998; 42:179-87.
75. Thornsberry C, Ogilvie PT, Holley Jr HP, et al. Survey of susceptibilities of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis isolates to 26 antimicrobial agents: a prospective US study. Antimicrob. Agents Chemother. 1999; 43:2612-23.
76. Traub WH, Leonhard B. Susceptibility of Moraxella catarrhalis to 21 antimicrobial drugs: validity of current NCCLS criteria for the interpretation of agar disk diffusion antibiograms. Chemotherapy. 1997; 43:159-67.
77. Verhaegen J, Verbist, L. In-vitro activities of 16 non-beta-lactam antibiotics against penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae. J. Antimicrob. Chemother. 1999; 43:563-7.
78. Von Eiff C, Peters G. Comparative in-vitro activities of moxifloxacin, trovafloxacin, quinupristin/dalfopristin and linezolid against staphylococci. J. Antimicrob. Chemother. 1999; 43:569-73.
79. Wagstaff AJ, Balfour JA. Grepafloxacin. Drugs. 1997; 53:817-27.
80. Watanabe A, Tokue Y, Takahashi H, et al. In vitro activity of HSR-903, a new oral quinolone, against bacteria causing respiratory infections. Antimicrob. Agents Chemother. 1999; 43:1767-8.
81. Weiss K, Laverdier M, Restieri C. Comparative activity of trovafloxacin and Bay 12-8039 against 452 clinical isolates of Streptococcus pneumoniae. J. Antimicrob. Chemother. 1998; 42:5232-5.
82. Wise R, Andrews, JM. The activity of grepafloxacin against respiratory pathogens in the UK. J. Antimicrob. Chemother. 1997; 40:27-30.
83. Wise R, Andrews JM. The in-vitro activity and tentative break-point of gemifloxacin, a new fluoroquinolone. J. Antimicrob. Chemother. 1999; 44:679-88.
84. Woodcock JM, Andrews JM, Boswell FJ, et al. In vitro activity of BAY 12-8039, a new fluoroquinolone. Antimicrob. Agents Chemother. 1997; 41:101-6.
85. Wootton M, Bowker KE, Janowska A, et al. In-vitro activity of HMR 3647 against Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and beta-haemolytic streptococci. J. Antimicrob. Chemother. 1999; 44:445-53.
86. Zhanel GG, Walkty A, Vercaigne L. The new fluoroquinolones: a critical review. Can. J. Infect. Dis. 1999; 10:207-38.
87. Biedenbach DJ, Beach ML, Jones RN. Antimicrobial activity of gatifloxacin tested against Neisseria gonorrhoeae using three methods and a collection of fluoroquinolone-resistant strains. Diagn. Microbiol. Infect. Dis. 1998; 32:307-11.
88. Biedenbach DJ, Croco MA, Barrett TJ, et al. Comparative in vitro activity of gatifloxacin against Stenotrophomonas maltophilia and Burkholderia species isolates including evaluation of disk diffusion and E test methods. Eur. J. Clin. Microbiol. Infect. Dis. 1999; 18:428-31.
89. Biedenbach DJ, Jones RN, Pfaller MA. Activity of BMS284756 against 2,681 recent clinical isolates of Haemophilus influenzae and Moraxella catarrhalis: Report from The SENTRY Antimicrobial Surveillance Program (2000) in Europe, Canada and the United States. Diagn. Microbiol. Infect. Dis. 2001; 39:245-50.
90. Cormican MG, Jones RN. Antimicrobial activity and spectrum of LB20304, a novel fluoronaphthyridone. Antimicrob. Agents Chemother. 1997; 41:204-11.
91. Davies TA, Kelly LM, Hoellman DB, et al. Activities and postantibiotic effects of gemofloxacin compared to those of 11 other agents against Haemophilus influenzae and Moraxella catarrhalis. Antimicrob. Agents Chemother. 2000; 44:633-9.
92. Diekema DJ, Pfaller MA, Jones RN, et al. Survey of blood-stream infections due to gram-negative bacilli: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, and Latin America for the SENTRY Antimicrobial Surveillance Program, 1997. Clin. Infect. Dis. 1999; 29:595-607.
93. Frechette, R. T-3811 Toyama/Bristol-Myers Squibb. Curr. Opin. Investig. Drugs. 2001; 2:1706-1711.
94. Fuchs PC, Barry AL, Brown SD. In vitro activities of clinafloxacin against contemporary clinical bacterial isolates from 10 North American centers. Antimicrob. Agents Chemother. 1998; 42:1274-7.
95. Gales AC, Jones RN, Gordon KA, et al. Activity and spectrum of 22 antimicrobial agents tested against urinary tract infection pathogens in hospitalized patients in Latin America: report from the second year of SENTRY antimicrobial surveillance program (1998). J. Antimicrob. Chemother. 2000; 45:295-303.
96. Goldstein EJ, Citron DM, Merriam CV, et al. Activity of gatifloxacin compared to those of five other quinolones versus aerobic and anaerobic isolates from skin and soft tissue samples of human and animal bite wound infections. Antimicrob. Agents Chemother. 1999. 43:1475-9.
97. Hecht DW, Osmolski JR. Activities of garenoxacin (BMS-284756) and other agents against anaerobic clinical isolates. Antimicrob. Agents Chemother. 2003; 47:910-6.
98. Hoban DJ, Bouchillon SK, Johnson JL, et al. Comparative in vitro activity of gemifloxacin, ciprofloxacin, levofloxacin and ofloxacin in a North American surveillance study. Diagn. Microbiol. Infect. Dis. 2001; 40:51-57.
99. Howard W, Biedenbach DJ, Jones RN. Comparative antimicrobial spectrum and activity of the desfluoroquinolone BMS284756 (T-3811) tested against non-fermentative Gram-negative bacilli. Clin. Microbiol. Infect. 2002; 8:340-4.
100. Isenberg HD, Alperstein P, France K. In vitro activity of ciprofloxacin, levofloxacin, and trovafloxacin, alone and in combination with beta-lactams, against clinical isolates of Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Burkholderia cepacia. Diagn. Microbiol. Infect. Dis. 1999; 33:81-6.
101. Jones RN, Biedenbach DJ, Erwin ME, et al. Activity of gatifloxacin against Haemophilus influenzae and Moraxella catarrhalis, including susceptibility test development, E-test comparisons, and quality control guidelines for H. influenzae. J. Clin. Microbiol. 1999; 37:1999-2002.
102. Rhomberg PR, Biedenbach DJ, Jones RN. Activity of BMS284756 (T-3811) tested against anaerobic bacteria, Campylobacter jejuni, Helicobacter pylori and Legionella spp. Diagn. Microbiol. Infect. Dis. 2001; 40:45-9.
103. Roblin PM, Hammerschlag MR. In vitro activity of a new 8-methoxyquinolone, BAY 12-8039, against Chlamydia pneumoniae. Antimicrob. Agents Chemother. 1998; 42:951-2.
104. Rolston KV, Frisbee-Hume S, LeBlanc BM, et al. Antimicrobial activity of a novel des-fluoro (6) quinolone, garenoxacin (BMS-284756), compared to other quinolones, against clinical isolates from cancer patients. Diagn. Microbiol. Infect. Dis. 2002; 44:187-94.
105. Sader HS, Jones RN, Gales AC, et al. Antimicrobial susceptibility patterns for pathogens isolated from patients in latin american medical centers with a diagnosis of pneumonia: analysis of results from the SENTRY Antimicrobial Surveillance Program (1997). SENTRY Latin American Study Group. Diagn. Microbiol. Infect. Dis. 1998; 32:289-301.
106. Traub WH, Leonhard B. Susceptibility of Moraxella catarrhalis to 21 antimicrobial drugs: validity of current NCCLS criteria for the interpretation of agar disk diffusion antibiograms. Chemotherapy. 1997; 43:159-67.
107. Valdezate S, Vindel A, Baquero F, et al. Comparative in vitro activity of quinolones against Stenotrophomonas maltophilia. Eur. J. Clin. Microbiol. Infect. Dis. 1999; 18:908-11.
108. Waites KB, Crabb DM, Bing X, et al. In vitro susceptibilities to and bactericidal activities of garenoxacin (BMS-284756) and other antimicrobial agents against human Mycoplasmas and Ureaplasmas. Antimicrob. Agents Chemother. 2003; 47:161-5.
109. Weiss K, Restieri C, De Carolis E, et al. Comparative activity of new quinolones against 326 clinical isolates of Stenotrophomonas maltophilia. J. Antimicrob. Chemother. 2000; 45:363-5.
110. Weller TM, Andrews JM, Jevons G, et al. The in vitro activity of BMS-284756, a new des-fluorinated quinolone. J. Antimicrob. Chemother. 2002; 49:177-84.
111. Woodcock JM, Andrews JM, Boswell FJ, et al. In vitro activity of BAY 12-8039, a new fluoroquinolone. Antimicrob. Agents. Chemother. 1997; 41:101-6.
112. Wu P, Barrett JF, Denbleyker DL, et al. Target-based activity of BMS-284756 as measured by the supercoiling inhibition and cleavable complex assay. 40th ICAAC Abstracts. 2000 September 17-20:81 (751).
113. Ackerman G, Schaumann R, Pless B, et al. Comparative activity of moxifloxacin in vitro against obligately anaerobic bacteria. Eur. J. Clin. Microbiol. Infect. Dis. 2000; 19:228-32.
114. Aldridge KE, Ashcraft DS. Comparison of the in vitro activities of Bay 12-8039, a new quinolone, and other antimicrobials against clinically important anaerobes. Antimicrob. Agents Chemother. 1997; 41:709-11.
115. Andersson MI, MacGowan AP. Development of the quinolones. J. Antimicrob. Chemother. 2003; 51 (Suppl 1):1-11.
116. Bebear CM, Renaudin H, Boudjadja A, et al. In vitro activity of BAY 12-8039, a new fluoroquinolone against mycoplasmas. Antimicrob. Agents Chemother. 1998; 42:703-4.
117. Bebear CM, Renaudin H, Schaeverbeke T, et al. In-vitro activity of grepafloxacin, a new fluoroquinolone, against mycoplasmas. J. Antimicrob. Chemother. 1999; 43:711-4.
118. Betriu C, Gomez M, Palau ML, et al. Activities of new antimicrobial agents (trovafloxacin, moxifloxacin, sanfetrinem, and quinupristin-dalfopristin) against Bacteroides fragilis group: comparison with the activities of 14 other agents. Antimicrob. Agents Chemother. 1999; 43:2320-2.
119. Cohen MA, Huband MD. In-vitro susceptibilities of Mycoplasma pneumoniae, Mycoplasma hominis and Ureaplasma urealyticum to clinafloxacin, PD 131628, ciprofloxacin and comparator drugs [letter]. J. Antimicrob. Chemother. 1997; 40:308-9.
120. Credito KL, Jacobs MR, Appelbaum PC. Time-kill studies of the antianaerobe activity of garenoxacin compared with those of nine other agents. Antimicrob. Agents Chemother. 2003; 47:1399-402.
121. Donati M, Pollini GM, Sparacino M, et al. Comparative in vitro activity of garenoxacin against Chlamydia spp. J. Antimicrob. Chemother. 2002; 50:407-10.
122. Donati M, Rodriguez M, Fermepin, et al. Comparative in-vitro activity of moxifloxacin, minocycline and azithromycin against Chlamydia spp. J. Antimicrob. Chemother. 1999; 43:825-7.
123. Dubois J, St-Pierre C. Comparative in vitro activity and post-antibiotic effect of gemifloxacin against Legionella spp. J. Antimicrob. Chemother. 2000; 45:41-6.
124. Dubois J, St-Pierre C. In vitro activity of gatifloxacin, compared with ciprofloxacin, clarithromycin, erythromycin and rifampin, against Legionella species. Diagn. Microbiol. Infect. Dis. 1999; 33:261-5.
125. Dubois J, St-Pierre C. In vitro susceptibility study of BMS-284756 against Legionella species. Diagn. Microbiol. Infect. Dis. 2001; 41:79-82.
126. Duffy LB, Crabb D, Searcey K, et al. Comparative potency of gemifloxacin, new quinolones, macrolides, tetracycline and clindamycin against Mycoplasma spp. J. Antimicrob. Chemother. 2000; 45:29-33.
127. Edlund C, Sabouri S, Nord CE. Comparative in vitro activity of BAY 12-8039 and five other antimicrobial agents against anaerobic bacteria. Eur. J. Clin. Microbiol. Infect. Dis. 1998; 17:193-5.
128. Ednie LM, Jacobs MR, Appelbaum PC. Activities of gatifloxacin compared to those of seven other agents against anaerobic organisms. Antimicrob. Agents Chemother. 1998; 42:2459-62.
129. Goldstein EJ, Citron DM, Hudspeth M, et al. Trovafloxacin compared with levofloxacin, ofloxacin, ciprofloxacin, azithromycin and clarithromycin against unusual aerobic and anaerobic human and animal bite-wound pathogens. J. Antimicrob. Chemother. 1998; 41:391-6.
130. Goldstein EJ, Citron DM, Hunt Gerardo S, et al. Comparative in vitro activities of DU-6859a, levofloxacin, ofloxacin, sparfloxacin, and ciprofloxacin against 387 aerobic and anaerobic bite wound isolates. Antimicrob. Agents Chemother. 1997; 41:1193-5.
131. Goldstein EJ, Citron DM, Merriam CV, et al. In vitro activities of the des-fluoro(6) Quinolone BMS-284756 against aerobic and anaerobic pathogens isolated from skin and soft tissue animal and human bite wound infections. Antimicrob. Agents Chemother. 2002; 46:866-70.
132. Goldstein EJ, Citron DM, Perriam CV, et al. Activities of telithromycin (HMR 3647, RU 66647) compared to those of erythromycin, azithromycin, clarithromycin, roxithromycin, and other antimicrobial against against unusual anaerobes. Antimicrob. Agents Chemother. 1999; 43:2801-5.
133. Goldstein EJ, Citron DM, Warren Y, et al. In vitro activity of gemifloxacin (SB 265805) against anaerobes. Antimicrob. Agents Chemother. 1999; 43:2231-5.
134. Hoellman DB, Kelly LM, Jacobs MR, et al. Comparative anti-anaerobic activity of BMS 284756. Antimicrob. Agents Chemother. 2001; 45:589-92.
135. Kato N, Tanaka K, Kato H, et al. In vitro activity of R-95867, the active metabolite of a new oral carbapenem, CS-834, against anaerobic bacteria. J. Antimicrob. Chemother. 2000; 45:357-61.
136. Malay S, Roblin PM, Reznik T, et al. In vitro activities of BMS-284756 against Chlamydia trachomatis and recent clinical isolates of Chlamydia pneumoniae. Antimicrob. Agents Chemother. 2002; 46:517-8.
137. Miyashita N, Niki Y, Matsushima T. In vitro and in vivo activities of sitafloxacin against Chlamydia spp. Antimicrob. Agents Chemother. 2001; 45:3270-3272.
138. Nielsen K, Bangsborg JM, Hoiby N. Susceptibility of Legionella species to five antibiotics and development of resistance by exposure to erythromycin, ciprofloxacin, and rifampicin. Diagn. Microbiol. Infect. Dis. 2000; 36:43-8.
139. Nightingale CH. Moxifloxacin, a new antibiotic designed to treat community-acquired respiratory tract infections: a review of microbiologic and pharmacokinetic-pharmacodynamic characteristics. Pharmacotherapy. 2000; 20:245-56.
140. Ridgway GL, Salman H, Robbins MJ, et al. The in-vitro activity of grepafloxacin against Chlamydia spp., Mycoplasma spp., Ureaplasma urealyticum and Legionella spp. J. Antimicrob. Chemother. 1997; 40:31-4.
141. Roblin PM, Hammerschlag MR. In-vitro activity of gatifloxacin against Chlamydia trachomatis and Chlamydia pneumoniae. J. Antimicrob. Chemother. 1999; 44:549-51.
142. Roblin PM, Kutlin A, Hammerschlag MR. In vitro activity of trovafloxacin against Chlamydia pneumoniae. Antimicrob. Agents Chemother. 1997; 41:2033-4.
143. Roblin PM, Reznik T, Hammerschlag MR. In vitro activity of garenoxacin against recent clinical isolates of Chlamydia pneumoniae. Int. J. Antimicrob. Agents. 2003. Article in Press.
144. Roblin PM, Reznik T, Kutlin A. In vitro activities of gemifloxacin (SB 265805, LB20304) against recent clinical isolates of Chlamydia pneumoniae. Animicrob. Agents Chemother. 1999; 43:2806-7.
145. Rodvold K, Neuhauser M. Pharmacokinetics and pharmacodynamics of fluoroquinolones. Pharmacotherapy. 2001; 21:S233-252.
146. Saravolatz L, Manzor O, Pawlak J, et al. Antimicrobial activity of BMS 284756, a novel des-fluoro (6) quinolone and seven fluoroquinolones against Streptococcus pneumoniae. Clin. Microbiol. Infect. 2001; 7:572-3.
147. Schaumann R, Ackerman G, Pless B, et al. In vitro activities of gatifloxacin, two other quinolones, and five nonquinolone antimicrobials against obligately anaerobic bacteria. Antimicrob. Agents Chemother. 1999; 43:2783-6.
148. Schmitz FJ, Boos M, Mayer S, et al. Increased in vitro activity of the novel des-fluoro(6) quinolone BMS- 284756 against genetically defined clinical isolates of Staphylococcus aureus. J. Antimicrob. Chemother. 2002; 49:283-7.
149. Ullmann U, Schubert S, Krausse R. Comparative in-vitro activity of levofloxacin, other fluoroquinolones, doxycycline and erythromycin against Ureaplasma urealyticum and Mycoplasma hominis. J. Antimicrob. Chemother. 1999; 43:33-6.
150. Wexler HM, Molitoris E, Molitoris D, et al. In vitro activity of levofloxacin against a selected group of anaerobic bacteria isolated from skin and soft tissue infections. Antimicrob. Agents Chemother. 1998; 42:984-6.
151. Abramowicz ME. Gatifloxacin and moxifloxacin: two new fluoroquinolones. The Medical Letter. 2000; 42:15-7.
152. Andrews JM, Honeybourne D, Brenwald NP, et al. Concentrations of trovafloxacin in bronchial mucosa, epithelial lining fluid, alveolar macrophages and serum after administration of single or multiple oral doses to patients undergoing fibre-optic broncoscopy. J. Antimicrob. Chemother. 1997; 39:797-802.
153. Andrews JM, Honeybourne D, Jevons G, et al. Concentration of levofloxacin (HR 355) in the respiratory tract following a single dose in patients undergoing fibre-optic bronchoscopy. J. Antimicrob. Chemother. 1997; 40:573-7.
154. Bron NJ, Dorr MB, Mant TG, et al. The tolerance and pharmacokinetics of clinafloxacin (CI-960) in healthy subjects. J. Antimicrob. Chemother. 1996; 38:1023-9.
155. Chien SC, Rogge MC, Gisclon LG, Curtin, et al. Pharmacokinetic profile of levofloxacin following once-daily 500-milligram oral or intravenous doses. Antimicrob. Agents Chemother. 1997; 41:2256-60.
156. Child J, Andrews JM, Wise R. Pharmacokinetics and tissue penetration of the new fluoroquinolone grepafloxacin. Antimicrob. Agents Chemother. 1995; 39:513-5.
157. Cutler NR, Vincent J, Jhee SS, et al. Penetration of trovafloxacin into cerebrospinal fluid in humans following intravenous infusion of alatrofloxacin. Antimicrob. Agents Chemother. 1997; 41:1298-1300.
158. Davis R, Markham A, Balfour JA. Ciprofloxacin: an updated review of its pharmacology, therapeutic efficacy and tolerability. Drugs. 1996; 51:1019-74.
159. Efthymiopoulos C, Bramer SL, Maroli A. Effect of food and gastric pH on the bioavailability of grepafloxacin. Clin. Pharmacokinet. 1997; 33:S18-24.
160. Efthymiopoulos C, Bramer SL, Maroli A. Effect of renal impairment on the pharmacokinetics of grepafloxacin. Clin. Pharmacokinet. 1997; 33:S32-8.
161. Fish DN, Chow AT. The clinical pharmacokinetics of levofloxacin. Clin. Pharmacokinet. 1997; 32:101-19.
162. Gotfried MH, Danzinger LH, Rodvold K. Steady state plasma and intrapulmonary concentrations of levofloxacin and ciprofloxacin in healthy adult subjects. Chest. 2001; 119:1114-22.
163. Kozawa O, Uematsu T, Matsuno H, et al. Comparative study of pharmacokinetics of two new fluoroquinolones, balofloxacin and grepafloxacin, in elderly subjects. Antimicrob. Agents Chemother. 1996; 40:2824-8.
164. Lister PD, Sanders CC. Pharmacodynamics of levofloxacin and ciprofloxacin against Streptococcus pneumoniae. J. Antimicrob. Chemother. 1999; 43:1118-23.
165. Melnik G, Schwesinger WH, Teng R, et al. Hepatobiliary elimination of trovafloxacin and metabolites following single oral doses in healthy volunteers. Eur. J. Clin. Microbiol. Infect. Dis. 1998; 17:424-6.
166. Naber KG, Theuretzbacher U, Moneva-Koucheva G, et al. Urinary excretion and bactericidal activity of intravenous ciprofloxacin compared with oral ciprofloxacin. Eur. J. Clin. Microbiol. Infect. Dis. 1999; 18:783-9.
167. Nakashima M, Uematsu T, Kosuge K, et al. Single- and multiple-dose pharmacokinetics of AM-1155, a new 6-fluoro-8-methoxt quinolone, in humans. Antimicrob. Agents Chemother. 1995; 39:2635-40.
168. Randinitis EJ, Brodfuehrer J, Vassos AB. Pharmacokinetics of clinafloxacin following oral and intravenous single and multiple dosing in volunteers [abstract]. 1998 Sep 25-27. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego (CA).
169. Randinitis EJ, Koup JR, Rausch G. Single-dose clinafloxacin pharmacokinetics in subjects with various degrees of renal function [abstract]. 1998 Sept 25-27. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego (CA).
170. Saliba F, Isaac L, Barker PJ. The pharmacokinetics and tolerability of a single oral dose of gemifloxacin in patients with mild or moderate hepatic impairment [poster]. 2000 May 7-11. 3rd European Congress of Chemotherapy. Madrid, Spain.
171. Schuler P, Zemper K, Borner K, et al. Penetration of sparfloxacin and ciprofloxacin into alveolar macrophages, ephithelial lining fluid, and polymorphonuclear leucocytes. Eur. Respir. J. 1997; 10:1130-6.
172. Stass H, Halabi A, Delesen H. No dose adjustment needed for patients with renal impairment receiving oral BAY 12-8039 [abstr]. 1998 Sep 25-27. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego (CA).
173. Stass H, Kubitza D. Pharmacokinetics and elimination of moxifloxacin after oral and intravenous administration in man. J. Antimicrob. Chemother. 1999; 43:83-90.
174. Teng R, Liston TE, Harris SC. Oral bioavailability of trovafloxacin with and without food in healthy volunteers. J. Antimicrob. Chemother. 1997; 39:87-92.
175. Vincent J, Dogolo L, Baris BA, et al. Single- and multiple-dose administration, dosing regimens, and pharmacokinetics of trovafloxacin and alatrofloxacin in humans. Eur. J. Clin. Microbiol. Infect. Dis. 1998; 17:427-30.
176. Vincent J, Teng R, Dalvie DK, et al. Pharmacokinetics and metabolism of single oral doses of trovafloxacin. Am. J. Surg. 1998; 176:8S-13S.
177. Wise R, Ashby JP, Andrews JM. In vitro activity of PD 127, 391, an enhanced-spectrum quinolone. Antimicrob. Agents Chemother. 1988; 32:1251-6.
178. Wise R, Jones S, Das I, et al. Pharmacokinetics and inflammatory fluid penetration of clinafloxacin. Antimicrob. Agents Chemother. 1998; 42:428-30.
179. Bello A, Farmer J, O\'Mara E, et al. Pharmacokinetics and disposition of garenoxacin in healthy adult male subjects. ASHP Midyear Clinical Meeting. 2002; 37:P321E.
180. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin. Infect. Dis. 1998; 26:1-12.
181. Hershberger E, Rybak MJ. Activities of trovafloxacin, gatifloxacin, clinafloxacin, sparfloxacin, levofloxacin, and ciprofloxacin against penicillin-resistant Streptococcus pneumoniae in an in vitro infection model. Antimicrob. Agents Chemother. 2000; 44:598-601.
182. Zhanel GG, Noreddin AM. Pharmacokinetics and pharmacodynamics of the new fluoroquinolones: focus on respiratory infections. Curr. Opin. Pharmacol. 2001; 1:459-463.
183. Davidson R, Cavalcanti R, Brunton JL, et al. Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N. Engl. J. Med. 2002; 346: 747-750.
184. Wilson APR, Grunenberg RN. Ciprofloxacin: 10 years of clinical experience. Somerset: Maxim Medical. 1997.
185. Garcia-Saenz MC, Arias-Puente A, Fresnadillo-Martinez MJ, et al. Human aqueous humor levels of oral ciprofloxacin, levofloxacin, and moxifloxacin. J. Cataract Refract. Surg. 2001; 27:1969-1974.
186. Shimada J, Nogita T, Ishibashi Y. Clinical pharmacokinetics of sparfloxacin. Clin. Pharmacokinet. 1993; 25:358-69.
187. Vance-Bryan K, Guay DR, Rotschafer JC. Clinical pharmacokinetics of ciprofloxacin. Clin. Pharmacokinet. 1990; 19:434-61.
188. Rodriguez-Cerrato V, Ghaffar F, Saavedra J, et al. BMS-284756 in experimental cephalosporin-resistant pneumococcal meningitis. Antimicrob. Agents Chemother. 2001; 45:3098-103.
189. Cottagnoud P, Acosta F, Cottagnoud M, et al. Gemifloxacin Is Efficacious against Penicillin-Resistant and Quinolone-Resistant Pneumococci in Experimental Meningitis. Antimicrob. Agents Chemother. 2002; 46:1607-9.
190. Smirnov A, Wellmer A, Gerber J, et al. Gemifloxacin is Effective in Experimental Pneumococcal Meningitis. Antimicrob. Agents Chemother. 2000; 44:767-770.
191. Fish DN, North DS. Gatifloxacin, an Advanced 8-Methoxy Fluoroquinolone. Pharmacotherapy. 2001; 21:35-59.
192. Tanimura H, Uchiyama K, Kashiwagi H. Gallbladder tissue concentrations, biliary excretion and pharmacokinetics of OPC-17116. Drugs. 1995; 49:341-3.
193. Ohnishi H, Tanimura H, Ichimiya G. Excretion of levofloxacin into bile and gallbladder tissue [abstract]. Drugs. 1993; 45:260-1.
194. Wise R. A reveiw of the clinical pharmacology of moxifloxacin, a new 8-methoxy quinolone and its potential relationship to therapeutic efficacy. Clin. Drug Invest. 1999; 17:365-87.
195. Johnson JH, Cooper MA, Andrews JM, et al. Pharmacokinetics and inflammatory fluid penetration of sparfloxacin. Antimicrob. Agents Chemother. 1992; 36:2444-6.
196. Wise R, Gee T, Marshall G, et al. Single-dose pharmacokinetics and penetration of BMS 284756 into an inflammatory exudate. Antimicrob. Agents Chemother. 2002; 46:242-4.
197. Gee T, Andrews JM, Ashby JP, et al. Pharmacokinetics and tissue penetration of gemifloxacin following a single oral dose. J. Antimicrob. Chemother. 2001; 47:431-434.
198. Wise R, Andrews JM, Ashby JP, et al. A study to determine the pharmacokinetics and inflammatory fluid penetration of gatifloxacin following a single oral dose. J. Antimicrob. Chemother. 1999; 44:701-4.
199. Muller M, Stass H, Brunner M, et al. Penetration of moxifloxain into peripheral compartments in humans. Antimicrob. Agents Chemother. 1999; 43:2345-9.
200. Wise R, Andrews JM, Marshall G, et al. Pharmacokinetics and inflammatory-fluid penetration of moxifloxacin following oral or intravenous administration. Antimicrob. Agents Chemother. 1999; 43:1508-10.
201. Wise R, Mortiboy D, Child J, et al. Pharmacokinetics and penetration into inflammatory fluid of trovafloxacin (CP-99,219). Antimicrob. Agents Chemother. 1996; 40:47-9.
202. Takahashi Y, Itoh Y, Doi T. Penetration of OPC-17116, a new quinolone compound, into male genital tracts and its in vitro antibacterial activity [abstract]. 1991 Sep 29-Oct 2. 31st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago (IL).
203. Naber CK, Steghafner M, Kinzig-Schippers M, et al. Concentrations of Gatifloxacin in Plasma and Urine and Penetration into Prostatic and Seminal Fluid, Ejaculate, and Sperm Cells after Single Oral Adminstrations of 400 Milligrams to Volunteers. Antimicrob. Agents Chemother. 2001; 45:293-297.
204. Rodvold K, Neuhauser M. Pharmacokinetics and Pharmacodynamics of Fluoroquinolones. Pharmacotherapy. 2001; 21:S233-252.
205. Childs S, Gleason D, Immergut M. Penetration of trovafloxacin into prostatic tissue following multiple dosing in man [abstract]. 1997 Sep 28 - Oct 1. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto (ON).
206. Wise R, Honeybourne D. A review of the penetration of sparfloxacin into the lower respiratory tract and sinuses. J. Antimicrob. Chemother. 1996; 37:S57-63.
207. Honeybourne D, Andrews JM, Cunningham B, et al. The concentrations of clinafloxacin in alveolar macrophages, epithelial lining fluid, bronchial mucosa and serum after administration of single 200 mg oral doses to patients undergoing fibre-optic bronchoscopy. J. Antimicrob. Chemother. 1999; 43:153-5.
208. Andrews J, Honeybourne D, Jevons G et al. Concentrations of garenoxacin in plasma, bronchial mucosa, alveolar macrophages and epithelial lining fluid following a single oral 600 mg dose in healthy adult subjects. J. Antimicrob. Chemother. 2003; 51:727-30.
209. Cook PJ, Andrews JM, Wise R, et al. Concentrations of OPC-17116, a new fluoroquinolone antibacterial, in serum and lung compartments. J. Antimicrob. Chemother. 1995; 35:317-26.
210. Andrews J, Honeybourne D, Jevons G. Penetration of BAy 12-8039 into bronchial, mucosa, epithelial lining [abstract]. 1998 Sep 25-27. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego (CA).
211. Soman A, Honeybourne D, Andrews J, et al. Concentrations of moxifloxacin in serum and pulmonary compartments following a single 400 mg dose in patients undergoing fibre-optic bronchoscopy. J. Antimicrob. Chemother. 1999; 44:835-8.
212. Peleman RA, Van De Velde V, Germonpre PR, et al. Trovafloxacin concentration in airway fluids of patients with severe community-acquired pneumonia. Antimicrob. Agents Chemother. 2000; 44:178-80.