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- 1. Exacerbación de EPOC Dr. J. Javier Díaz Castañón Hospital Dr. Angel Leaño
- 7. Inflamación Neutrofilica AJ White Thorax:2003:58;1,73-80
- 12. Exacerbacion: Etiología Bacteriana ? Estudios de cultivo de esputo Gump et al. ARRD 1976,113:465-473 25 pacientes Consultas cada 2 semanas por 4 años Cultivo de esputo 1886 consultas 116 exacerbaciones 1870 estables Estable Exacerbacion 0 10 20 30 40 50 60 SP HI % 33.1 59.9 57.0 37.2
- 13. Etiología Infecciosa Principales Patógenos en Exacerbaciones (esputo) Obaji & Sethi. Drugs and Aging; 2001;18:1-11 9614 687 140 – 2180 14 estudios 48.6 53.7 28.1 – 88.6 Esputo Total Media Rango Comentario No. de pacientes % Cultivo + 31.2 13 – 50 No tipificable H. influenzae 14 4 – 21 M. catarrhalis 14.2 7 – 26 S. pneumoniae Porcentaje de aislamientos totales
- 14. Etiología Infecciosa Otros Patógenos en Exacerbaciones (esputo) Obaji & Sethi. Drugs and Aging; 2001;18:1-11 Media Rango Comentario 5.8 1 – 13 UCI Exacerbación recurrente P. aeruginosa 6.4 1 – 20 Papel ? S. aureus 11.4 3 – 19 UCI Exacerbación recurrente Entero- bacterias Porcentaje de aislamientos totales 9.4 0 – 32 aislado frecuente Colonisación Oral Papel ? H. parainfluenzae
- 15. Exacerbación de EPOC: Etiología Viral Gump et al. ARRD 1976; Buscho et al. JID 1978; Smith et al. ARRD 1980 La Infección viral se asocia con el 30% Exacerbaciones Cuadruplica titulos de anticuerpos Cultivo de secresión respiratoria Proporción de exacerbaciones virales 35 25 20 15 7.5 7.5 0 5 10 15 20 25 30 35 40 Inf Para Rhino Corona Adeno VSR
- 16. Los Antibioticos Mejoran la evolución de las Exacerbaciones Tipo I-III Anthonisen et al. Ann Intern Med 1987;106:196-204 Placebo Antibiotico p <0.01 Todas Tipo I Tipo II Tipo III 55 43 60 70 68 63 70 74 Exito (%) 0 25 50 75
- 18. Etiología Infecciosa Estudios de muestras x broncoscopía en exacerbaciones de EPOC Sethi S, Murphy TF Clin Microbiol Rev 2001;14(2):336-63 Patógenos aislados - 1 10 2 1 52.5 Cepillo protegido 40 externos Pela 9 - 4 4 11 56 Cepillo protegido LBA, aspirado endotraq 50 UCI y V.M. Soler 2 - 3 2 10 51.7 Cepillo protegido 29 externos Monso 3 11 7 3 6 50 Cepillo protegido 50 UCI y V.M. Fagon P. Aeruginosa H. Parainfluenzae S. Pneumoniae M. Catarrhalis H. Influenzae % bacterias Metodo diagnostico Sujetos Estudio
- 19. Broncoscopia en Exacerbación Monso et al. AJRCCM 1995: 1316-20 % positivos 10,000 ufc/ml 25.0 51.7 5.0 24.1 0 10 20 30 40 50 60 Estable Exacerbación p <0.04 p <0.03 %
- 21. ex ex ex Epidemiología Molecular Paciente X seguimiento HI HI HI HI HI 10 8 10 6 10 6 10 8 10 7 1 2 3 4 5 6 7 8 9 10 11 12 13 Sethi et al. NEJM 2002, 347:465-71 1 mes
- 22. Tipificación molecular Sethi et al. NEJM 2002, 347:465-71 H. influenzae asilamiento de esputo Lisados bacterianos enteros Analisados en un gel SDS -PAGE
- 23. Paciente X: seguimiento 1 2 3 4 5 6 7 8 9 10 11 12 13 ex ex ex HI HI HI HI HI 10 8 10 6 10 6 10 8 10 7 A A B C C 1 mes
- 24. Paciente Y: Seguimiento Sethi et al. NEJM 2002, 347:465-71 ex ex ex ex ex ex ex 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 MC MC MC MC MC 10 6 10 7 10 8 10 9 10 7 1 mes
- 25. Tipificación de M. catarrhalis M. catarrhalis Aislada de esputo ADN Genomico purificado Analisis CHEF Sethi et al. NEJM 2002, 347:465-71
- 26. Paciente Y: Seguimiento Sethi et al. NEJM 2002, 347:465-71 ex ex ex ex ex ex ex 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 MC MC MC MC MC 10 6 10 7 10 8 10 9 10 7 A B C D E 1 mes
- 27. Aislamiento de nuevas cepas y exacerbación 33 15.4 26.2 17.1 48.8 16.6 32 18 13.6 18.2 0 10 20 30 40 50 Todos HInt MC SP PA * * * * Riesgo Relativo (95% CI) de exacerbación: Todos 2.15 (1.83-2.63) HInt 1.69 (1.37-2.09) MC 2.96 (2.39-3.67) SP 1.77 (1.14-2.75) PA 0.61 (0.21-1.82) Sethi et al. NEJM 2002, 347:465-71 Nueva cepa + Nueva cepa – *p<0.05 Frecuencia de exacerbación
- 30. Inflamación de la Vía Aérea Paciente X: seguimiento 1 2 3 4 5 6 7 8 9 10 11 12 13 ex ex ex HI HI HI HI HI 10 8 10 6 10 6 10 8 10 7 A A B C C SP 0 0 0 0 0 0 1 mes
- 31. Elastasa de Neutrofilos en Exacerbaciones: Muestras Pareadas Sethi et al. Chest 2000; 118:1557-65 100000 10000 1000 100 10 1 Patógeno + EN (mU/mL) Patógeno – p=0.004
- 35. Estudios Randomizados de Corticoesteroides Douglas C. McCrory,et al CHEST 2001; 119:1190–1209 Benefico P < 0.05 Aumento Vef1 días Hospital Metilprednisolona 125 mgs cada 6 hrs IV x 3 dias y post prednisona en disminución 271 Niewoehner et al / 1999 Benefico p < 0.05 Aumento Vef1 Prebd. Metilprednisolona 35 mgs IV cada 6 hrs.x 3 dias 44 Albert et al / 1980 No benefico Dias hospital Aumento Vef1 Metilprednisolona 100 mgs IV DU 100 Emerman et al / 1989 Benefico P < 0.05 Aumento del VEF1 Prednisona 60 mgs/dia x 3 dias luego diminuyendo 27 Thompson et al / 1996 Benefico p < 0.05 Aumento del Vef1 preBd y Menos días hospital Prednisolona 30 mgs/dia x 14 dias 56 Davies et al /1999 No Benefico Aumento del VEF1 de 0–6 hrs. Hidrocortizona 100 mgs IV DU 138 Bullard et al /1996 efecto Parametro medido Corticoide utilizado Tamaño de la muestra Estudio / año
- 38. Tratamiento de las Exacerbaciones Meta-analisis de estudios de antibióticos controlados con placebo Saint et al. JAMA 1995; 273:957 – 1.0 1.0 – 0.5 1.5 0 0.5 Elmes et al . 1957 Berry et al . 1960 Fear and Edwards. 1962 Elmes et al . 1965 Petersen et al . 1967 Pines et al . 1972 Nicotra et al . 1982 Anthonisen et al . 1987 Jorgensen et al . 1992 Todos Favorece placebo Favorece antibiotico Tamaño del efecto
- 39. Tiempo a la siguiente exacerbación Curación Clínica Baja y alta en carga bacteriana Tiempo a recaida Carga Bacteriana (Ufc/ml) Tiempo(dias) Horizonte Clínico AB1 AB2 AB3 Exac. AB Cura Cura Cura Termina AB Miravitlles. Eur Respir J 2002;20 (suppl 36):9-19
- 41. Estudio MOSAIC Estudio prospectivo, multicentrico, multinacional, aleatorizado, doble-ciego para comparar la efectividad de M oxifloxacina tabletas O rales vs tratamiento antibiotico oral S tandard administrado como manejo de primera linea en pacientes externos con Exacerbación A guda I nfecciosa de bronquitis C ronica. CHEST 125:3, Marzo 2004
- 42. VEF 1 a la inclusión 13.5 13.8 29.9 29.9 27.0 29.2 29.6 27.2 0 5 10 15 20 25 30 <30 30 - <50 50 - <70 > 70 VEF 1 (% del valor predicho) % Pacientes protocolo Moxifloxacina Comparador Moxifloxacina Comparador promedio (SD) 53.6 (19.5) 52.9 (19.7) (p= 0.53)
- 43. Tratamiento Comparativo Amoxillina 500 mg tid Claritromicina 500 mg bid acetil Cefuroxima 250 mg bid 65 (21.8%) 95 (31.9%) 138 (46.3%) n=298 Población de protocolo
- 44. Patógenos aislados en la aleatorización Población microbiologicamente valida H. influenzae (62) S. pneumoniae (26) M. catarrhalis (25) Enterobacteriaceae (15) Other Gram negative (12) H. parainfluenzae (16) S. aureus (7) 4.3% 38.0% 16.0% 15.3% 9.2% 7.4% 9.8%
- 45. Respuesta Clínica Eficacia a los 7-10 días post-tratamiento Resolución Clinica 70.9 62.8 69.7 62.1 56 58 60 62 64 66 68 70 72 ITT PP (95% CI; 1.40, 14.87) (95% CI; 0.26, 15.95) % Moxifloxacina Comparador
- 46. Antibióticos administrados debido a fracaso en el tratamiento ITT PP p=0.006 p=0.030 % 7.6 14.1 8.8 14.8 0 2 4 6 8 10 12 14 16 Moxifloxacina Comparador
- 47. Seguimiento a largo plazo Tiempo a la siguiente exacerbación Promedio del numero de días a la siguiente exacerbación Desde la aleatorización a la nueva exacerbación o a los 9 meses. 132.8 118.0 110 115 120 125 130 135 p=0.03 Todos los pacientes Moxifloxacina Comparador
- 49. Patrones de Sensibilidad de Gérmenes Respiratorios mas habituales en Latinoamérica Datos del programa SENTRY 14. (234 cepas) y del programa Protekt 15 (514 cepas) 100 98.4 100 Telitromicina 100 100 99.6 Moxifloxacino 100 100 99.6 Levofloxacino 96.9 98.3 74.4 Tetraciclina 100 91.7 86.2 Claritromicina 100 100 87.2 Azitromicina 96.9 60.3 58.1 Cotrimoxazol 100 100 88.9 Cefotaxima 99 98.8 81.2 Cefuroxima 100 99.6 85.5 Amoxi-Ac.clavulanico 6.2 87.2 85.5 Amoxicilina - - 71.4 Penicilina M.catarrhalis H.influenzae S.pneumoniae
- 50. Clasificación de la EPOC con los patógenos causantes de las exacerbaciones y tratamiento antibiótico ambulatorio recomendado ALAT 2004 SPRP S. Pneumoniae resistete a penicilina, a o ampicilina-sulbactam, amoxicilina-sulbactam b los factores de riesgo Tabla 4. Moxifloxacina Gatifloxacina Levofloxacina Ciprofloxacina ( sospecha de P. Aeruginosa ) Amoxicilina-acido clavulanico (si alergia a quinolonas) H.influenzae SRPR Gram(-) entericos P.aeruginosa < 35% EPOC severa Moxifloxacina Gatifloxacina Levofloxacina Telitromicina Amoxicilina-acido clavulanico H.influenzae M.catarrhalis SRPR Gram(-) entericos 35-50% EPOC moderada Los anteriores + Moxifloxacina, Gatifloxacina, Levofloxacina Telitromicina H.influenzae M.catarrhalis SPRP > 50% EPOC leve con factores de riesgo b Amoxicilina-acido clavulanico a Cefuroxima Azitromicina o Claritromicina H.influenzae M.catarrhalis S.pneumoniae C.pneumoniae M.pneumoniae > 50% EPOC leve sin factores de riesgo Tratamiento Recomendado Patógenos mas frecuentes VEF1
- 51. Características Clínicas de Gravedad ALAT 2004 * Cardiopatia isquemica, cor pulmonale, Insuficiencia renal o hepática, o diabetes mellitus insulina dependiente Factores de Riesgo Si Si No Antibioticos en los ultimos 15 dias >1 1 0 Hospital año previo >4 >4 <4 Exacerb. año previo Si No No Oxigeno en casa Si Si No Comorbilidad * Si Si No Tabaquismo activo Pequeños esfuerzos Medianos esfuerzos Grandes esfuerzos Disnea basal >70 60-70 <60 Edad (años) Severa Moderada Leve Características
- 54. VPPNI para Falla respiratoria en exacerbaciones de EPOC: Revisión Cochrane y Metaanálisis Riesgo de falla en el tratamiento BMJ VOLUME 326 25 JANUARY 2003
Notas del editor
- MOSAIC: The Study &quot;MOSAIC&quot; is the abbreviation of the study title: A multicentre, multinational, prospective, randomised, double blind study to compare the effectiveness of M oxifloxacin O ral tablets to S tandard oral antibiotic regimen given as first-line therapy in out-patients with A cute I nfective exacerbations of C hronic bronchitis.
- MOSAIC: FEV 1 at inclusion (PP population) FEV 1 stands for forced expiratory volume in one second, a common measure of airways obstruction. The predicted FEV 1 is calculated based on factors such as age and body mass. A low percent of predicted FEV 1 is associated with increased risk of lower respiratory tract infection (Kanner et al., 2001. Am J Respir Crit Care Med. 164: 358 - 364), and is a major prognostic factor for the outcome of AECB. In the per protocol population of the MOSAIC study, the categorical distribution of the percent of predicted FEV 1 showed no difference between groups: 27-30% of patients in both treatment groups were categorised as having a predicted FEV 1 of 30-50%, 50-70% and 70% or more, and approximately 14% had a predicted FEV 1 of less than 30%. The distribution of FEV 1 values was similar in the ITT population.
- MOSAIC: Comparator regimen in PP population In order to provide for the best possible result for comparators, investigators were allowed to choose one of three well established treatments, based on their clinical experience as well as factors such as local epidemiology and in-vitro pathogen susceptibilities. These comparator options corresponded to the recommendations of US, Canadian and European treatment guidelines. Comparator options were: Amoxicillin: one 500 mg capsule three times daily for 7 days, or Clarithromycin: two 250 mg tablets two times daily for 7 days, or Cefuroxime-axetil: one 250 mg tablet two times daily for 7 days. Matching placebo capsules were included in the blister packs to ensure double-blinding. In the comparator arm, 138 (46%) patients received cefuroxime-axetil, 95 (32%) patients received clarithromycin, and 65 (22%) patients received amoxicillin. The most frequent reasons given for comparator choice in both treatment groups were clinical presentation of the patient (50%) and local resistance patterns of suspected pathogens (22%). The distribution of comparator prescription was similar in the ITT population: i n the comparator arm, 174 (46%) patients received cefuroxime-axetil, 114 (30%) patients received clarithromycin, and 88 (23%) patients received amoxicillin.
- MOSAIC: Causative organisms isolated at randomisation (Microbiologically valid population) Sputum samples were available both before and after treatment in 71 patients in the moxifloxacin arm and 79 in the comparator arm, and these patients comprise the microbiologically valid population. The most common organisms detected in these patients were H. influenzae (38.0%), S. pneumoniae (16.0%) and M. catarrhalis (15.3%).
- MOSAIC: Clinical response Main message: Moxifloxacin is significantly superior to standard treatments . The statistically significant treatment group difference in favour of moxifloxacin was achieved with a shorter length of treatment and with a convenient once-daily dose. Background: Clinical cure assessed 7-10 days after the end of treatment was defined as the return to pre-exacerbation status, with no additional antimicrobial therapy required. After 5 days of treatment with moxifloxacin vs. 7 days with comparator, clinical cure was seen in 251/ 354 (70.9%) patients in the moxifloxacin and 236/376 (62.8%) in the comparator arm of the ITT population (95% CI 1.4, 14.9; p=0.05), and 191/274 (69.7%) vs. 185/298 (62.1%) in the per protocol population (95% CI 0.3, 15.6; p=0.02).
- MOSAIC: Post-therapy systemic antimicrobials given for current AECB Main message: Significantly more antibiotics were used for AECB in the comparator group during the follow up period. Background: In the event of clinical treatment failure at the end of treatment, patients could be prescribed a commercially available antibiotic for their symptoms of AECB. In both the ITT and per protocol populations, significantly higher proportions of patients in the comparator arm (14.1% and 14.8% in the two populations) required further antibiotic treatment than in the moxifloxacin arm (7.6% and 8.8%, p=0.006 and 0.030). The distribution of antibiotic prescriptions is summarised in the table below (click on text block): ITT population PP population Moxifloxacin 27 / 354 (7.6%) 24 / 274 (8.8%) Comparator 53 / 376 (14.1%) 44 / 298 (14.8%) p-value 0.006 0.030 Beta-lactams 43.2% 42.7% Quinolone antibacterials 23.9% 26.7% Macrolides/lincosamides 23.9% 20.0% Other antibacterials 9.0% 10.6%
- MOSAIC: Long-term follow-up assessment In the ITT population, a new AECB was documented in 179/324 patients in the moxifloxacin arm and in 176/319 patients in the comparator arm (excludes patients with further antibiotic for ongoing AECB). In that population, median times to the next AECB were 131.0 (range 18-289) days and 103.5 (range 14-280) days for moxifloxacin and comparator, respectively. Mean (SD) times to the next AECB were 132.8 (67.5) days and 118.0 (67.9) days for moxifloxacin and comparator respectively and the difference was statistically significant (p= 0.03).