03/07/2012. Goiânia Encontro Nacional Infecções Respiratórias e Tuberculose

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1 Goiânia Encontro Nacional Infecções Respiratórias e Tuberculose Bronquiectasias Ñ Fibrocística Medicamentos disponíveis Medicamentos necessários Alexandre Pinto Cardoso Md PhD Professor Pneumologia Fac. Medicina UFRJ Diretor Divisão de Tisio-Pneumologia Coordenador Unidade de Pesquisa Clínica IDT/HUCFF/UFRJ Epidemiologia das Doenças Pulmonares Obstrutivas Crônicas Janeiro 2008 a Setembro 2011 Fonte: Ministério da Saúde - Sistema de Informações Hospitalares do SUS (SIH/SUS) Internações por Região e por Lista de Morbidade Região Norte Região Nordeste Região Sudeste Região Sul Região Centro- Oeste Pneumonia DPOC Asma Bronquiectasia

2 Média de permanência por lista de morbidade do CID , ,4 5,8 4 4, Influenza [gripe] Pneumonia Bronquite enfisema e outr doenç pulm obstr crôn Asma Bronquiectasia Bronquiectasias ñ Fibrocística Alterações da depuração mucociliar são críticas na patogenia da bronquiectasia e no tratamento 2

3 Hipótese do círculo vicioso na patogenia da bronquiectasia Lapa e Silva and Cole Am J resp. Mol. Biology Modelo experimental de bronquiectasias em ratos Lapa e Silva et al. Am J Respir Cell Mol Bio 1989,1, 197 Tratamento Bronquiectasias Farmacológico Antibióticos Anti-inflamatórios Drogas Hiper osmolar Mucolíticos Outros Fisioterapia Respiratória Rehabilitação Educaçãoe suporte emocional 3

4 Hipótese do círculo vicioso na patogenia da bronquiectasia Novo nicho ecológico Lapa e Silva and Cole Am J resp. Mol. Biology 4

5 BRONQUIECTASIAS Etiologia Infecções S. pneumoniae 10,6% H. influenzae 30,1% P. aeruginosa 30,9% BGN 13,0% (moraxella) Mycobacterium 22,0% Staphylo áureus 17,0% Aspergillus 4,9% Macfarlane 2010 Thorax Short and Long Term Antibiotic treatment Reduces Airway and Systemic Inflammation in Non-Cystic Fibrosis Bronchiectasis James D Chalmers1, Maeve P Smith2, Brian J McHugh3, Cathy Doherty4, John R Govan5 and Adam T Hill6 385 pacientes /12 meses / Gentamicina /nebulização 15 tratados ATB venoso Excerbação 35 ATB venoso sem exacerbaçào Marcadoressorológicos: ICAM I, VICAM I Published ahead of print on June 28, 2012, doi: /rccm OC Am. J. Respir. Crit. Care Med. June 28, 2012 rccm oc Short and Long Term Antibiotic treatment Reduces Airway and Systemic Inflammation in Non-Cystic Fibrosis Bronchiectasis James D Chalmers1, Maeve P Smith2, Brian J McHugh3, Cathy Doherty4, John R Govan5 and Adam T Hill6 In stable patients, there was a direct relationship between airway bacterial load and markers of airway inflammation (p< for all analyses). High bacterial loads were associated with higher serum ICAM-1, E-selectin and VCAM-1 (p<0.05 above bacterial load >1 x 107 cfu/ml). In stable patients, there was a direct relationship between bacterial load and the risk of subsequent exacerbations (OR 1.20, ,p<0.0001) and severe exacerbations (OR 1.11, ,p=0.02). Short and long term antibiotic treatments were associated with reductions in bacterial load, airways and systemic inflammation. Published ahead of print on June 28, 2012, doi: /rccm OC Am. J. Respir. Crit. Care Med. June 28, 2012 rccm oc 5

6 Antibióticos Exacerbação Venosos Orais Inalatórios Combinação Colonização Orais Inalados Venosos* Critérios Exacerbação Critérios Exacerbação O Donnel, CHEST 1998 Mudança da produção do catarro Aumento da dispnéia Aumento da tosse Febre Aumento do Chiado Moleza, fadiga,letargia ou redução exercicios Redução da função pulmonar Novo infiltrado radiológico Mudança na ausculta pulmonar Pelo menos 4 destes 6

7 EXACERBAÇÃO. 1) Obter amostra de escarro antes de iniciar tratamento 2). Antibiótico empírico estratificar riscos para pseudomonas. 3). Antibióticos empírico devemos ajustar de acordo com a cultura de escarro. Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 17 (Suppl. 6), E1 E59 BRONQUIECTASIAS Rico de agudização p/ Pseudomonas : Uso recente de ATB Hospitalização Recente Doença Grave Prévio isolamento de Pseudomonas aeruginosa VEF1 menor que 60 % (?) Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 17 (Suppl. 6), E1 E59 Recomendações Terapêuticas 7

8 Antibióticos Empírico Amoxilina 500 TID Co-amoxi TID βlactamase Ciprofloxacina BID(Pseudomonas) Combinação Dependendo da cepa Comentários Duração CurtoXLongo Sensibilidade da cultura Medicamentos IV IMPACTO DA INFECÇÃO CRÔNICA IMPACTO CLÍNICO 8

9 POLVERINO 2011 Critérios para tratamento continuado com Atb e drogas imunomoduladoras Pacientes com 3 exacerbações por ano que necessitaram antibióticos,ou significante morbidade (C) Modulação da carga bacteriana Ciclos de antibioticoterapia VO Antibiótico inalatório (NBZ/pó) Contínuo ou intermitente Uso prolongado de Macrolídeos* 9

10 Prática não é nova PROFILAXIA ANTIBIOTICOS ORAIS Currie et al 1989 Amoxicilina 3g TID/32 semanas Hill SL 1990 Amoxicilina inalada 10 semanas Raynor et al1994 Ciprofloxacino >90 dias TOBRAMICINA INALATÓRIA AJRCCM 2000,162: AUSENCIA DE PSEUDOMONAS NO ESCARRO 35 % EM 6 SEMANAS FUNÇÃO PULMONAR IGUAL 10

11 Am J Respir Crit Care Med Feb 15;183(4): Epub 2010 Sep 24. A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis. Murray MP, Govan JR, Doherty CJ, Simpson AJ, Wilkinson TS, Chalmers JD, Greening AP, Haslett C, Hill AT. METHODS: Sixty-five patients were randomized to either twice-daily nebulized gentamicin, 80 mg, or nebulized 0.9% saline, for 12 months. All were reviewed at three-monthly intervals during treatment and at 3 months' follow-up. GENTAMICINA 11

12 An Optimized Inhaled Ciprofloxacin Formulation DRCFI (Dual Release Ciprofloxacin For Inhalation) Enhances Antibiotic Lung ConcentrationsAnd AntimicrobialEffect In Non-CF Bronchiectasis (Non-CF BE), [PublicationPage: A3659 ATS 2012 San Francisco CFI (Ciprofloxacin for inhalation) [ARD-3100] - Lipoquin and DRCFI (Dual release ciprofloxacin for inhalation) [ARD-3150] - Pulmaquin are once daily inhaled liposomal ciprofloxacin formulations. In addition to the liposomal formulation in CFI, DRCFI also contains free ciprofloxacin solution that produces an initial high peak of ciprofloxacin followed by prolonged ciprofloxacin concentrations in the lung. D.J. Serisier1, D. Bilton2, T. De Soyza3, I. Gonda4 1Brisbane, QLD/AU, 2London/UK, 3Newcastle/UK, 4Hayward, CA/US ORBIT-1 and ORBIT-2 studygroup An Optimized Inhaled Ciprofloxacin Formulation DRCFI (Dual Release Ciprofloxacin For Inhalation) Enhances Antibiotic Lung ConcentrationsAnd AntimicrobialEffect In Non-CF Bronchiectasis (Non-CF BE), [PublicationPage: A3659 ATS 2012 San Francisco In addition to the liposomal formulation in CFI, DRCFI also contains free ciprofloxacin solution that produces an initial high peak of ciprofloxacin followed by prolonged ciprofloxacin concentrations in the lung. DRCFI also achieves high and sustained airway concentrations with once-daily dosing in non- CF BE patients. In placebo-controlled studies in non- CF BE, both formulations produced statistically significant reductions in P. aeruginosa (PA) colony forming units (CFUs), but DRCFI produced greater and more sustained reductions. D.J. Serisier1, D. Bilton2, T. De Soyza3, I. Gonda4 1Brisbane, QLD/AU, 2London/UK, 3Newcastle/UK, 4Hayward, CA/US ORBIT-1 and ORBIT-2 studygroup An Optimized Inhaled Ciprofloxacin Formulation DRCFI (Dual Release Ciprofloxacin For Inhalation) Enhances Antibiotic Lung ConcentrationsAnd AntimicrobialEffect In Non-CF Bronchiectasis (Non-CF BE), [PublicationPage: A3659 ATS 2012 San Francisco A 24 week study of once dailydrcfi (3 cycles of 4 weeks on treatment and 4 weeks off) confirmed significant reductions of PA CFU s after each treatment cycle, as well as a significant difference in median time to first pulmonary exacerbation (DRCFI 134 days vs placebo 58 days, p=0.046). DRCFI also produced excellent safety profiles with no significant changes in FEV1 and no significant adverse effects. The optimization of inhaled ciprofloxacin formulation from CFI to DRCFI has resulted in improvedairwayantibioticconcentration and retention characteristics and antimicrobial efficacy in PAcolonized non-cf BE. D.J. Serisier1, D. Bilton2, T. De Soyza3, I. Gonda4 1Brisbane, QLD/AU, 2London/UK, 3Newcastle/UK, 4Hayward, CA/US ORBIT-1 and ORBIT-2 studygroup 12

13 NOVAS DROGAS INALADAS Erradicação Pseudomonas Torax

14 Respir Med Mar;106(3): Epub 2011 Dec 26. Outcomes of Pseudomonas eradication therapy in patients with non-cystic fibrosis bronchiectasis. White L, Mirrani G, Grover M, Rollason J, Malin A, Suntharalingam J. Source Respiratory Department, Royal United Hospital, Combe Park, Bath, BA1 3NG, United Kingdom. Eradication therapy involved intravenous antibiotics (n = 12), intravenous antibiotics followed by oral ciprofloxacin (n = 13) or ciprofloxacin alone (n = 5), combined with 3 months of nebulised colistin. Pseudomonas was initially eradicated from sputum in 24 patients (80.0%). 13/24 patients remained Pseudomonas-free and 11/24 were subsequently reinfected (median time 6.2 months). Respir Med Mar;106(3): Epub 2011 Dec 26. Outcomes of Pseudomonas eradication therapy in patients with non-cystic fibrosis bronchiectasis. White L, Mirrani G, Grover M, Rollason J, Malin A, Suntharalingam J. Source Respiratory Department, Royal United Hospital, Combe Park, Bath, BA1 3NG, United Kingdom Exacerbation frequency was significantly reduced from 3.93 per year pre-eradication and 2.09 post-eradication (p = 0.002).. This study demonstrates that Pseudomonas can be eradicated from a high proportion of patients, which may lead to prolonged clearance and reduced exacerbation rates. This important outcome requires confirmation in a prospective Macrolideos Ação no biofilme produzido por pseudomonas (iasl,rhl) Retarda a maturação in vitro Propriedades antiinflamatórias Reduz a produççao de NfKβ Reduz produção de Mucina (MUC5AC) Azitromicina 500 2X semana três meses 14

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16 MACROLÍDEOS AZITROMICINA 2 X SEMANA/ 12 PACIENTES/ REDUÇÃO DE EXACERBAÇÕES, REDUÇÃO VOLUME SECREÇÃO Cymbala et al Treat Respir Med (2)

17 CORTICOIDES INALADOS 17

18 Goiânia Encontro Nacional Infecções Respiratórias e Tuberculose Bronquiectasias Ñ Fibrocística Medicamentos disponíveis Medicamentos necessários Alexandre Pinto Cardoso Md PhD Professor Pneumologia Fac. Medicina UFRJ Diretor Divisão de Tisio-Pneumologia Coordenador Unidade de Pesquisa Clínica IDT/HUCFF/UFRJ 18

19 Medicamentos necessários Farmacológico Antibióticos Antibióticos inalados Anti-inflamatórios Corticoide inalados +Agonistasβ adrenérgicos Drogas Hiper osmolar Mucolíticos Outros Fisioterapia Respiratória Rehabilitação Educaçãoe suporte emocional CONGRESSO BRASILEIRO DE PNEUMOLOGIA E TISIOLOGIA RIO 2016 Esperamos por voce! 19

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21 Drugs Today (Barc) May;48(5): Inhaled antibiotics for lower respiratory tract infections: focus on ciprofloxacin. Arch Bronconeumol Jun;47 Suppl 6: [Inhaled antibiotics in the treatment of noncystic fibrosis bronchiectasis] 21

22 i. The study discussed in this paper demonstrates that long-term therapy with inhaled gentamicin can eradicate the infection or reduce the bacterial load, decrease the risk of subsequent infections and improve the quality of life in patients with non-cf bronchiectasis with a minimal risk of side effects Informa UK, Ltd 22

23 Am J Respir Crit Care Med Feb 15;183(4): Epub 2010 Sep 24. A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis. Murray MP, Govan JR, Doherty CJ, Simpson AJ, Wilkinson TS, Chalmers JD, Greening AP, Haslett C, Hill AT. MEASUREMENTS AND MAIN RESULTS: At each review the following were assessed: quantitative and qualitative sputum bacteriology; sputum purulence and 24-hour volume; FEV(1), FVC, and forced expiratory flow, midexpiratory phase; exercise capacity; Leicester Cough Questionnaire and St. George's Respiratory Questionnaire; and exacerbation frequency. Fifty-seven patients completed the study 23

24 Am J Respir Crit Care Med Feb 15;183(4): Epub 2010 Sep 24. A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis. Murray MP, Govan JR, Doherty CJ, Simpson AJ, Wilkinson TS, Chalmers JD, Greening AP, Haslett C, Hill AT.. At the end of 12 months' treatment, compared with the saline group, in the gentamicin group there was reduced sputum bacterial density with 30.8% eradication in those infected with Pseudomonas aeruginosa and 92.8% eradication in those infected with other pathogens; less sputum purulence (8.7% vs. 38.5%; P < ); greater exercise capacity (510 [ ] m vs. 415 [ ] m; P = 0.03); and fewer exacerbations (0 [0-1] vs. 1.5 [1-2]; P < ) with increased time to first exacerbation (120 [ ] d vs [ ] d; P = 0.02) Am J Respir Crit Care Med Feb 15;183(4): Epub 2010 Sep 24. A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis. Murray MP, Govan JR, Doherty CJ, Simpson AJ, Wilkinson TS, Chalmers JD, Greening AP, Haslett C, Hill AT. The gentamicin group had greater improvements in Leicester Cough Questionnaire (81.4% vs. 20%; P < 0.01) and St. George's Respiratory Questionnaire (87.5% vs. 19.2%; P < 0.004) score. No differences were seen in 24-hour sputum volume, FEV(1), FVC, or forced expiratory flow, midexpiratory phase. No P. aeruginosa isolates developed resistance to gentamicin. At follow-up, all outcome measures were similar to baseline. Conclusions: Regular, long-term nebulized gentamicin is of significantbenefitin non-cystic fibrosis bronchiectasis but treatment needs to be continuous for its ongoing efficacy. Clinical trial registered with (NCT ). 24