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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 oen as pulmonares cr nicas

Uso de AzitromicinanasDoençasPulmonaresCrônicas

Dr. Paulo Kussek

PneumologiaPediátrica

Hospital Pequeno Príncipe – Curitiba

farmacocin tica
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)

macrol deo
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.
panbronquiolite difusa
PanbronquioliteDifusa
  • Doençainflamatóriaprogressiva das viasaeríferasdescritaquaseexclusivamenteemLesteAsiáticos.
  • Caracterizada:
    • porinfecçãocrônica das viasaéreasporPseudomonas aeruginosacom sintomas de tosseprodutiva, dispnéia e limitaçãoaofluxoaéreo, sinusitecrônica.

Clearance Mucociliar

Reduzido

InfecçãoAguda/Crônica

InflamaçãoPersistente

panbronquiolite c ochrane
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

doen a
Doença?

Clearance Mucociliar

Reduzido

InfecçãoAguda/Crônica

InflamaçãoPersistente

slide7

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

slide8

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

fibrose c stica cochrane
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

fc pa n egativa
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)

doen a1
Doença?

Clearance mucociliar

Reduzido

InfecçãoAguda/Crônica

InflamaçãoPersistente

doen a pulmonar obstrutiva cr nica dpoc
DoençaPulmonarObstrutivaCrônica (DPOC)
  • Tratamentopadrão:
    • Broncodilatadores LABA - LAMA
    • Costicosteróidesinalatórios
      • São efetivosemreduzirexacerbaçõesematé 40%.
doen a pulmonar obstrutiva cr nica
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.

doen a pulmonar obstrutiva cr nica1
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.

doen a pulmonar obstrutiva cr nica2
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.

doen a2
Doença ?

Clearance Mucociliar

Reduzido

InfecçãoAguda/Crônica

InflamaçãoPersistente

slide18
Asma?
  • DoençaCrônicaInflamatória de ViasAéreas
  • AsmaNeutrofílica – patógenosatípicoscomoMycoplasma pneumoniae e Chlamidophilapneumoniae
asma cochrane
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

doen a3
Doença?

Clearance Mucociliar

Reduzido

InfecçãoAguda/Crônica

InflamaçãoPersistente

rinossinusite cr nica
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;

doen a4
Doença?

Clearance Mucociliar

Reduzido

InfecçãoAguda/Crônica

InflamaçãoPersistente

slide23

Síndrome de BronquioliteObliterante

Pós-Transplante

Bronquiectasia Idiopática

Bronquiolite Viral Aguda

Prevenção de DisplasiaBroncopulmonar

slide24

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.
considera o final
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.