囊性纤维病抗生素的应用(英文)Inhaled-Antibiotics-in-Cystic-Fi课件.ppt

1、Inhaled Antibiotics in Cystic FibrosisByTony S.Poteat,M.D.Resident Grand RoundsNovember 24,1998Case PresentationnHPI:41 yo WM with cystic fibrosis presents with a seven day history of increased shortness of breath and diaphoresis.nIncreased sputum production.nSputum is thicker and is now green.nHe r

2、eports noncompliance with his pulmozyme and flovent.Case PresentationnHe had finished his 28 day course of inhaled tobramycin 7 days prior to admission.nPMH:Cystic fibrosis diagnosed at age 28.Nasal polypsnAll:TetracyclineCase PresentationnMedications:Inhaled tobramycin 300 mg b.i.d.for 28 days then

3、 off for 28 days.Ventolin 3 puffs t.i.d.Flovent 2 puffs b.i.d.Serevent 2 puffs b.i.d.Pulmozyme 2.5 mg nebulized q.d.Home oxygen 3L by nasal cannula.Pancreatic enzymes with each meal.Case PresentationnSH:10 pack year history of tobacco,quit at age 28.Occasional red wine.Disability since 3/95,was an a

4、uto technician.nROS:Patient feels that he has lost 5-10 pounds over the last month.Case PresentationnPE:Vitals 95.9/107/25/133/90Gen:Anxious WM in mild respiratory distress.HEENT:NC/AT,EOMI,PERRL,OP clearNeck:Supple,no lymphadenopathyCase PresentationCV:tachycardic no murmur,rubs,or gallopsLungs:Cra

5、ckles in the left base,decreased breath sounds and wheezes bilaterallyAbd:BenignExt:Clubbing in all extremities,no edemaCase PresentationnLabs:15.3 17.9 416 71%segs 18%lymphs 10%monosSMAC:WNLABG:7.406/49/49/30/83%on 3L Case PresentationnCXR:Cystic changes,peribronchial thickening,no focal infiltrate

6、s.nSputum culture from 4 months earlier grew 4+Pseudomonas aeruginosa sensitive to Zosyn.nSpirometry from 4 months earlier showed an FEV1 of 18%predicted and a FVC of 45%predicted.Case PresentationnHospital Course:The patients sats improved on 60%face shield and aggressive bronchodilators,and he was

7、 admitted to 8RT.He was begun on IV Zosyn,Cipro,steroids,inhaled Tobramycin,nebulized bronchodilators,and postural drainage.Blood and sputum cultures were sent.Pediatric pulmonology was consulted and recommended continuing the antibiotics,obtaining a nutrition consult and a breathing plus consult.Hi

8、s sputum grew out 4+Pseudomonas aeruginosa sensitive to the current antibiotics.He continued to improve and his oxygen demands returned to baseline.He was discharged after 8 days on PO Cipro,IV Zosyn,inhaled Tobramycin,a Prednisone taper,and his admission medications.IntroductionnCystic fibrosis(CF)

9、was first described in 1936.nTransmitted by an autosomal recessive pattern.The gene is located on chromosome 7,and codes for the CFTR.nIt affects the lung,pancreas,sweat glands,testes,and biliary ducts.nCarrier rate in Caucasians is 1 in 20.IntroductionnIncidence is 1 in 2,500 live births.n34%of the

10、 19,517 patients with CF are 18 years of age or older.n90%of CF patients die of lung disease.nMedian age of survival in 1996 was 31 years.nThe introduction of antibiotics in the 1940s significantly improved the prognosis for CFPathogenesis of CF Lung DiseasenPatients have normal lungs at birth.nInfe

11、ction begins an inflammatory response that continues throughout the disease.nPrimary pathogen is Pseudomonas aeruginosa.nThe cascade of infection and inflammation ultimately destroys airways,impairs gas exchange,and leads to patient death.Mortality in CFnEitan et al.673 patients followed between 197

12、7 and 1989assessed PFTs,ABGs,and nutritional status 190(28%)patients died during the studyFEV1 below 30%predicted and FVC below 40%predicted were both associated with two year mortalities greater than 50%also for every 10%decrease in FEV1 the relative risk for death was 1.8Mortality in CFnEitan et a

13、l.a decrease in the weight-to-height percentage to less than 70%was also associated with a 2-year mortality rate greater than 50%Mortality in CFnFrom these results you can assume that any intervention that slows or stops the decline in PFTs will have a significant impact on the survival of CF patien

14、ts.Why Inhaled Antibiotics?nPseudomonas aeruginosa(Pa)is a major contributor to CF lung disease and its resultant morbidity and mortality.nAminoglycosides active against Pa penetrate the sputum poorly.nPeak sputum concentrations of aminoglycosides are equal to only 12%of serum concentrations.Why Inh

15、aled Antibiotics?nBioactivity of aminoglycosides is further decreased in CF patients by its:binding to DNAbinding to mucinincreased concentrations of divalent cationsWhy Inhaled Antibiotics?nThe lower sputum concentrations of aminoglycosides require larger IV doses of aminoglycosides.nIncreased risk

16、 of ototoxicity and nephrotoxicity.nAerosolized aminoglycosides reach high concentrations in the sputum,and due to their limited absorption from the respiratory tract systemic toxicity is minimized.Techniques of AdministrationnEisenberg et al.jet nebulizers versus ultrasonic nebulizerultrasonic nebu

17、lizer is costly,inconvenient,and high maintenancejet nebulizers were proven to deliver greater than 10 times the MIC of Pseudomonas in 87-93%of patientsTechniques of AdministrationnNikolaizik et al.bronchial constriction after nebulized tobramycin with decreased FEV1 and FVCbeta agonist before admin

18、istration reduced this effect(p0.001)The EvidencenHodson et al.double-blind,randomized,cross-over trial of aerosolized carbenicillin and gentamicin in CF patients with Papurpose was to determine if treatment could halt or slow the decline in lung function and reduce the number of hospitalizations en

19、rolled 20 patients with Pa positive culturesHodson et al.patients were randomly assigned to 6 months of antibiotic or placebothe antibiotics were 1 gram of carbenicillin with 80 mg of gentamicin each b.i.d.3 patients withdrewn1 in the first month with a rashn1 with bilateral pneumothoracies in month

20、 8n1 in month 10 on placebo because she felt much worse than her first 6 monthsHodson et al.nResults:of the 17 patients completed the study the mean FEV1 during antibiotic was 1566 ml versus 1300 ml during placebo(p0.001)FVC was 2656 ml on antibiotic versus 2314 ml on placebo(p0.02)hospitalizations

21、were reduced with 7 during placebo and 3 during treatment but was not significantfourteen patients favored antibiotic,3 were undecided,and no one favored placeboStead et al.nRandomized,crossover study,comparing nebulized ceftazidime versus gentamicin and carbenicillin versus saline in CF patients wi

22、th PanEach treatment was given randomly for 4 months for a total of 12 monthsn18 patients were enrolled into the studynCeftazidime and saline were blindedStead et al.nPurpose was to determine if ceftazidime would be as effective as gentamicin and carbenicillin with possible benefits of:possible use

23、in patients with penicillin allergyless time to nebulizetreat patients who failed to respond to the other regimenStead et al.nOf the 18 patients enrolled 5 were withdrawn during the first 4 months2 were noncompliant(1 on saline,1 on ceftaz)2 on saline had deterioration,and were changed to antibiotic

24、1 could not tolerate the taste of salineStead et al.nResultsFEV1 increased from 1.48 L on saline to 1.70 L on both antibiotic treatments(p0.02 for both)body weight was increased over entry in both antibiotic groups(p0.01)hospital admissions were decreased during the study year compared to the year b

25、efore the study,5 admissions versus 16 admissions respectively(p0.05)Stead et al.nCeftazidime is as efficacious as gent/carbenicillin.nCould be used in patients with penicillin allergy.nUseful in patients infected with organisms resistant to gentamicin or carbenicillin.Maclusky et al.nRandomized con

26、trolled trial comparing long-term inhaled tobramycin(32 months)versus saline.nPurpose was to assess the long-term safety and effectiveness of tobramycin in suppressing pulmonary disease.nPatients were colonized with Pa,had FEV1 greater than 40%,and were receiving bronchodilators.Maclusky et al.nPati

27、ents received either tobramycin 80 mg t.i.d.or normal saline nPatients were aware of their treatment regimen but the physicians were blindedMaclusky et al.n28 patients were enrolled,13 patients in the control group and 15 patients in the treatment groupn1 patient was not colonized with Pa and was ex

28、cluded from analysis,and 1 patient in the control group died at 13 months into the studyMaclusky et al.nResultsFEV1 improved(p0.01)on treatmentFVC improved(p0.05)on treatmentno evidence of nephro-or ototoxicityMaclusky et al.1008060402010080604020FEV1%PredictedFVC%PredictedTreatmentMonths Follow Up0

29、10203040Ramsey et al.n71 patients enrolled into a double-blind,placebo-controlled,three period crossover trial to assess the efficacy and safety of aerosolized tobramycin.nattempted to overcome some limitations of previous studies.double-blindedlarger number of patientscovered the taste of tobramyci

30、nRamsey et al.nPatients had FVCs greater than 40%and were colonized with PanRandomly assigned to either tobramycin 600 mg t.i.d.for 28 days followed by placebo for 56 days(group 1)or placebo for 28 days followed by tobramycin for 56 days(group 2)nTo assess compliance quinine hydrochloride was added

31、to both solutions and random urine samples were taken during the studyRamsey et al.n36 patients were assigned to group 1,and 35 to group 2n66 of the 71 patients completed the studynNoncompliance ranged from 7 to 20%during the study and was comparable between the 2 groupsRamsey et al.nFEV1 and FVC we

32、re both increased over placebo during the first 28 days(p0.015).nDuring the three-period crossover the significance of the increase in FEV1 between treatment and placebo was greater(p0.005).nA significant carryover effect was found for FEV1(p0.009).Ramsey et al.Ramsey et al.nPulmonary exacerbations

33、and antibiotic use were also decreased3%of patients on tobramycin had exacerbations compared to 20%of placebo patients who had exacerbations(p=0.06,number needed to treat is 5.9)15%of tobramycin patients required antibiotics compared to 49%of placebo patients who required antibiotics(p=0.006,number

34、needed to treat is 3)Ramsey et al.nNo renal or ototoxicity was observed.n10 of the 71 patients(14%)developed resistant strains of Pa.nThere was no difference in the emergence of resistant strains between placebo and tobramycin groups.TOBI(Tobramycin Solution for Inhalation)nTwo multicenter,randomize

35、d,placebo-controlled studies on TOBI were recently made available by the Pathogenesis Corporation.nThese studies enrolled a total of 520 cystic fibrosis patients with Pa.nThese studies were designed to look at clinical endpoints(PFTS)and health outcomes(antibiotics,hospitalizations,and work and scho

36、ol days missed).TOBInPlacebo and drug groups were similar in both studiesnPatients received either TOBI 300 mg b.i.d.or taste-masked placebo b.i.d.and were randomized to either three 28-day on drug/28 day off drug cycles or placebo in the same cyclethis design was employed because previous studies h

37、ad found significant carryover effect after 28 day treatmentintermittent therapy may reduce the possibility of increased resistance of Pa to TOBI by the phenomenon of transienceTOBITOBIStudy 1 and study 2 were analyzed separately for FEV1,and together for health outcomesrelative change for FEV1 in s

38、tudy 1(n=223)was 12.02 for drug and-0.52 for placebo(p0.001)for study 2(n=297)the relative change in FEV1 was 8.7 for drug and-2.72 for placebo(p0.001)TOBITOBInSubgroup analysis,by age,gender,disease severity,and rhDNase use,of FEV1 in the two studies demonstrate that TOBI works for a wide variety o

39、f patients.TOBITOBIPatients on drug were 26%less likely to be hospitalized than patients on placebo(p=0.014,relative risk of 0.74)hospital stays were decreased on drug versus placebo,5.1 days versus 8.1 days respectively(p0.001)IV anti-pseudomonal antibiotic use was also decreased on drug(p0.001)TOB

40、ITOBIduring the 24 weeks,days missed from work or school were less on drug versus placebo,5.15 days during drug versus 6.96 days during placebo(p=0.031)compliance was 88%for drug and 93%for placeboTOBInNo ototoxicity or nephrotoxicity was observed.nSerum tobramycin levels remain well below systemic

41、toxicity limits.TOBInThis is also the first study to use the PARA LC PLUS jet nebulizer which has a valve that directs the entire inspiration through the nebulization chamber.nThis design is 2 times more efficient than a standard jet nebulizer.nThe time to nebulize a dose is 15 minutes.ConclusionsnInhaled antibioticsSlow or reverse the decline in pulmonary function.Reduce antibiotic use and hospital days.Effective in a variety of patients of different ages or disease severity.Are safe and have minimal side effects.