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Uso de Azitromicina nas D oenças Pulmonares Crônicas

Uso de Azitromicina nas D oenças Pulmonares Crônicas. Dr. Paulo Kussek Pneumologia Pediátrica Hospital Pequeno Príncipe – Curitiba. Farmacocinética. Macrolídeo - A zitromicina . M embrana celular > L isossomo dos leucócitos . 37 % da medicação é absorvida em 2-3 hrs

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Uso de Azitromicina nas D oenças Pulmonares Crônicas

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  1. Uso de AzitromicinanasDoençasPulmonaresCrônicas Dr. Paulo Kussek PneumologiaPediátrica Hospital Pequeno Príncipe – Curitiba

  2. Farmacocinética • Macrolídeo- Azitromicina. • Membranacelular > Lisossomo dos leucócitos. • 37% da medicaçãoéabsorvidaem 2-3 hrs • ½ via plasmaticaaté14 horas. • Niveissanguíneosaté 6 dias. • Penetraçãotissularaté 30 dias. • Excretadaemsecreçãobrônquica ( até 40 x maiorquenívelplasmático) e saliva. • Linear correlação com dose oral . • Espectroantibacteriano contra Chlamydia, Mycoplasma e Legionella. Azithromycin Maintenance Therapy in Patients With Cystic Fibrosis: A Dose Advice Based on a Review of Pharmacokinetics, Efficacy, and Side Effects .Erik B. Wilms, Daniel J. Touw, Harry G.M. Heijerman,Cornelis K. van der Ent.Pediatric Pulmonology 47:658–665 (2012)

  3. Macrolídeo • Efeitos: • Antiinflamatório. • Modulaçãodo mecanismo de defesa do hospedeiro= imunomodulador. • Regula a funcão do leucócitosreduzindo o acúmuloporredução das citocinaspró-inflamatórias. • Controle da hipersecreção do muco e suaviscosidade. • Meados de 1980 – muda a história natural da Panbronquiolitedifusa.

  4. PanbronquioliteDifusa • Doençainflamatóriaprogressiva das viasaeríferasdescritaquaseexclusivamenteemLesteAsiáticos. • Caracterizada: • porinfecçãocrônica das viasaéreasporPseudomonas aeruginosacom sintomas de tosseprodutiva, dispnéia e limitaçãoaofluxoaéreo, sinusitecrônica. Clearance Mucociliar Reduzido InfecçãoAguda/Crônica InflamaçãoPersistente

  5. Panbronquiolite -Cochrane The primary outcomes were five-year survival rate, lung function and clinical response. Main results:  Only one RCT (19 participants) with significant methodological limitations was included in this review. It found that the computerised tomography images of all participants treated with a long-term, low-dose macrolide (erythromycin) improved from baseline, while the images of 71.4% of participants in the control group (with no treatment) worsened and 28.6% remained unchanged. Adverse effects were not reported. Authors' conclusions:  There is little evidence for macrolides in the treatment of DPB. We are therefore unable to make any new recommendations. It may be reasonable to use low-dose macrolides soon after diagnosis is made and to continue this treatment for at least six months, according to current guidelines. This record should be cited as:  Yang M, Dong BR, Lu J, Lin X, Wu HM. Macrolides for diffuse panbronchiolitis. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD007716. DOI: 10.1002/14651858.CD007716.pub3 Assessed as up to date:  July 25, 2012

  6. Doença? Clearance Mucociliar Reduzido InfecçãoAguda/Crônica InflamaçãoPersistente

  7. FibroseCística • Staphylococcus aureus (estágiosiniciais) • P. aeruginosa (estágiosfinais) • Produzalginato e crescecomo um biofilme. • Azitromicina 250 or 500 mg - 3 diasporsemana. • Função: • Altera Biofilme da PA com redução da virulência. • Reduz a aderênciabacteriananascelulasepiteliais. • Inibe a motilidadebacteriana. Defeito CFTR Movimento anormal de sodio, cloro e agua através da célula Muco seco e espesso espessamento do muco Obstrução brônquica infecção Liberação DNA dos leucocitos inflamação Destruição pulmonar progressiva Falha respiratória Azithromycin for cystic fibrosis.K.W. Southern, Barker. EurRespir J 2004; 24: 834–838

  8. Fibrose Cística • Resultados: • 45 pacientes (idademédia29 anos) • 1 ano de azitromicina • Peso médioaumentou de 63.1 kg do pré-tratamentopara63.9 kg durante o tratamento( p=0.01). • Perda de funçãopulmonarpré-tratamentoFEV1 - 4.1% e FVC -3.0% para+0.8% ( p =0.001) e+1.6% ( p=0.01), respectivamente. • 90% das amostras de escarroeram PA+, reduzindopara81% durante o tratamento(p=0.003). Long-term azitromycin treatment of cystic fibrosis patients with chronic Pseudomonas aeruginosa infection; an observational cohort study. Christine RønneHansena,T, TacjanaPresslera, Christian KochF, NielsHøibybJournal of Cystic Fibrosis 4 (2005) 35–40

  9. FibroseCística - Cochrane Main results:  Ten of 31 studies identified were included (959 patients). Demonstrated consistent improvement in forced expiratory volume in one second over six months. Patients treated with azithromycin were approximately twice as likely to be free of pulmonary exacerbation at six months. With respect to secondary outcomes, there was a significant reduction in need for oral antibiotics and greater weight gain in those taking azithromycin.  Adverse events were uncommon and not obviously associated with azithromycin, although a once-weekly high dose regimen was associated with more frequent gastrointestinal adverse events Treatment with azithromycin was associated with reduced identification of Staphylococcus aureus on respiratory culture, but also a significant increase in macrolide resistance. Authors' conclusions:  This review provides evidence of improved respiratory function after six months of azithromycin. Data beyond six months were less clear, although reduction in pulmonary exacerbation was sustained.  Treatment appeared safe over a six-month period; however, emergence of macrolide resistance was a concern. Assessed as up to date: February 29, 2012

  10. FC – PA Negativa • Uso de azitromicinapor 6 -12 mesesresultaemmelhoraclínica com redução das exacerbações e melhora do ganho de peso empacientes com FC infectadosounãopor PA, mas benefícios a longoprazoaindasãoindeterminados. Open-Label, Follow-on Study of Azithromycin in Pediatric Patients With CF Uninfected With Pseudomonas aeruginosa- Lisa Saiman, Nicole Mayer-Hamblett, Michael Anstead, Larry C. Lands, Margaret Kloster, Christopher H. Goss, Lynn M. Rose, Jane L. Burns, Bruce C. Marshall, Felix Ratjen- Pediatric Pulmonology 47:641–648 (2012)

  11. Doença? Clearance mucociliar Reduzido InfecçãoAguda/Crônica InflamaçãoPersistente

  12. DoençaPulmonarObstrutivaCrônica (DPOC) • Tratamentopadrão: • Broncodilatadores LABA - LAMA • Costicosteróidesinalatórios • São efetivosemreduzirexacerbaçõesematé 40%.

  13. DoençaPulmonarObstrutivaCrônica • Azitromicinana dose de 250 mg diariamente x placebo = 1 ano. 1142 participantespelomenos 40 anos de idade, diagnóstico de DPOC, VEF1 e CVF<70%. Azithromycin for Prevention of Exacerbations of COPD. Richard K. Albert, John Connett, William C. Bailey, Richard Casaburi,J. Allen D. Cooper, Gerard J. Criner, Jeffrey L. Curtis, Mark T. Dransfield, MeiLan K. Han, Stephen C. Lazarus, Barry Make, Nathaniel Marchetti, Fernando J. Martinez, Nancy E. Madinger, Charlene McEvoy, Dennis E. Niewoehner, Janos Porsasz, , Connie S. Price, John Reilly, Paul D. Scanlon, Frank C. Sciurba, Steven M. Scharf, George R. Washko, Prescott G. Woodruff, Nicholas R. Anthonisen. N Engl J Med 2011;365:689-98.

  14. DoençaPulmonarObstrutivaCrônica • Exacerbações Azithromycin for Prevention of Exacerbations of COPD. Richard K. Albert, John Connett, William C. Bailey, Richard Casaburi,J. Allen D. Cooper, Gerard J. Criner, Jeffrey L. Curtis, Mark T. Dransfield, MeiLan K. Han, Stephen C. Lazarus, Barry Make, Nathaniel Marchetti, Fernando J. Martinez, Nancy E. Madinger, Charlene McEvoy, Dennis E. Niewoehner, Janos Porsasz, , Connie S. Price, John Reilly, Paul D. Scanlon, Frank C. Sciurba, Steven M. Scharf, George R. Washko, Prescott G. Woodruff, Nicholas R. Anthonisen. N Engl J Med 2011;365:689-98.

  15. DoençaPulmonarObstrutivaCrônica Azithromycin for Prevention of Exacerbations of COPD. Richard K. Albert, John Connett, William C. Bailey, Richard Casaburi,J. Allen D. Cooper, Gerard J. Criner, Jeffrey L. Curtis, Mark T. Dransfield, MeiLan K. Han, Stephen C. Lazarus, Barry Make, Nathaniel Marchetti, Fernando J. Martinez, Nancy E. Madinger, Charlene McEvoy, Dennis E. Niewoehner, Janos Porsasz, , Connie S. Price, John Reilly, Paul D. Scanlon, Frank C. Sciurba, Steven M. Scharf, George R. Washko, Prescott G. Woodruff, Nicholas R. Anthonisen. N Engl J Med 2011;365:689-98.

  16. DoençaPulmonarObstrutivaCrônica- Cochrane

  17. Doença ? Clearance Mucociliar Reduzido InfecçãoAguda/Crônica InflamaçãoPersistente

  18. Asma? • DoençaCrônicaInflamatória de ViasAéreas • AsmaNeutrofílica – patógenosatípicoscomoMycoplasma pneumoniae e Chlamidophilapneumoniae

  19. Asma - Cochrane Main results:  Seven studies recruiting a total of 416 participants met the inclusion criteria. We assembled findings from studies comparing macrolide treatment for at least 4 weeks in adult and pediatric patients treated for chronic asthma. Four studies showed a positive effect on symptoms of macrolides in different types of asthmatic patients. There were limited data available for meta-analysis. There was no significant difference in FEV1 for either parallel or crossover trials. However, there were significant differences in eosinophilic inflammation and symptoms. Authors' conclusions:  Considering the small number of patients studied, there is insufficient evidence to support or to refute the use of macrolides in patients with chronic asthma. Further studies are needed in particular to clarify the potential role of macrolides in some subgroups of asthmatics such as those with evidence of chronic bacterial infection. This record should be cited as:  Richeldi L, Ferrara G, Fabbri L, Lasserson TJ, Gibson PG. Macrolides for chronic asthma. Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD002997. DOI10.1002/14651858.CD002997.pub3 Assessed as up to date: May 21, 2007

  20. Doença? Clearance Mucociliar Reduzido InfecçãoAguda/Crônica InflamaçãoPersistente

  21. RinossinusiteCrônica • Afeta 15% da população, duraçãoacima de 12 semanas. • Melhora dos pacientes • 5% em 2 semanas. • 48% em 4 semanas • 63% em 8 semanas • 71% em 12 semanas. Macrolides for the Treatment of Chronic Sinusitis, Asthma, and COPD* Mark H. Gotfried – Chest2004 Feb 125(2 Suppl):52S-60S;

  22. Doença? Clearance Mucociliar Reduzido InfecçãoAguda/Crônica InflamaçãoPersistente

  23. Síndrome de BronquioliteObliterante Pós-Transplante Bronquiectasia Idiopática Bronquiolite Viral Aguda Prevenção de DisplasiaBroncopulmonar

  24. Riscos do UsoProlongado de Macrolídeos • Resistênciabacteriana do Staphylococcus aureusacima de 83% em 1 ano, 97% após 2 anos e 100% após 3 anos de uso de azitromicina. • Ototoxidade. • Cardiotoxicidade- aumento do intervalo QT> fibrilação e morte. • InteraçãoMedicamentosa a longoprazo.

  25. Consideração Final • Porseuefeitoimunomodulatador e antimicrobiano, e pelofato de alcançaraltasconcentraçõesnostecidos do tratorespiratório, osmacrolídeosassumem o papel do candidato ideal aomanejo das doençaspulmonarescrônicas, inflamatóriasou/e infecciosas. • Mas aindaprecisamos de estudosquecomprovemestesbenefícios a longoprazo.

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