Inhaled Antibiotics in Cystic Fibrosis

1
Inhaled Antibiotics in Cystic Fibrosis

• By
• Tony S. Poteat, M.D.
• Resident Grand Rounds
• November 24, 1998

2
Case Presentation

• HPI 41 yo WM with cystic fibrosis presents with
  a seven day history of increased shortness of
  breath and diaphoresis.
• Increased sputum production.
• Sputum is thicker and is now green.
• He reports noncompliance with his pulmozyme and
  flovent.

3
Case Presentation

• He had finished his 28 day course of inhaled
  tobramycin 7 days prior to admission.
• PMH Cystic fibrosis diagnosed at age 28.
• Nasal polyps
• All Tetracycline

4
Case Presentation

• Medications Inhaled tobramycin 300 mg b.i.d.
  for 28 days then 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.

5
Case Presentation

• SH 10 pack year history of tobacco, quit at age
  28.
• Occasional red wine.
• Disability since 3/95, was an auto technician.
• ROS Patient feels that he has lost 5-10
  
  pounds over the last month.

6
Case Presentation

• PE Vitals 95.9 / 107 / 25 / 133/90
• Gen Anxious WM in mild respiratory distress.
• HEENT NC/AT, EOMI, PERRL, OP clear
• Neck Supple, no lymphadenopathy

7
Case Presentation

• CV tachycardic no murmur, rubs, or gallops
• Lungs Crackles in the left base, decreased
  breath sounds and wheezes bilaterally
• Abd Benign
• Ext Clubbing in all extremities, no edema

8
Case Presentation

• Labs 15.3
• 17.9 416 71 segs
• 18 lymphs
• 10 monos
• SMAC WNL
• ABG 7.406/49/49/30/83 on 3L

9
Case Presentation

• CXR Cystic changes, peribronchial thickening,
  no focal infiltrates.
• Sputum culture from 4 months earlier grew 4
  Pseudomonas aeruginosa sensitive to Zosyn.
• Spirometry from 4 months earlier showed an FEV1
  of 18 predicted and a FVC of 45 predicted.

10
Case Presentation

• Hospital Course The patients sats improved on
  60 face shield and aggressive bronchodilators,
  and he was 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. His 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.

11
Introduction

• Cystic fibrosis (CF) was first described in 1936.
• Transmitted by an autosomal recessive pattern.
  The gene is located on chromosome 7, and codes
  for the CFTR.
• It affects the lung, pancreas, sweat glands,
  testes, and biliary ducts.
• Carrier rate in Caucasians is 1 in 20.

12
Introduction

• Incidence is 1 in 2,500 live births.
• 34 of the 19,517 patients with CF are 18 years
  of age or older.
• 90 of CF patients die of lung disease.
• Median age of survival in 1996 was 31 years.
• The introduction of antibiotics in the 1940s
  significantly improved the prognosis for CF

13
Pathogenesis of CF Lung Disease

• Patients have normal lungs at birth.
• Infection begins an inflammatory response that
  continues throughout the disease.
• Primary pathogen is Pseudomonas aeruginosa.
• The cascade of infection and inflammation
  ultimately destroys airways, impairs gas
  exchange, and leads to patient death.

14
Mortality in CF

• Eitan et al.
• 673 patients followed between 1977 and 1989
• assessed PFTs, ABGs, and nutritional status
• 190 (28) patients died during the study
• FEV1 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 1.8

15
Mortality in CF

• Eitan et al.
• a decrease in the weight-to-height percentage to
  less than 70 was also associated with a 2-year
  mortality rate greater than 50

16
Mortality in CF

• From 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 patients.

17
Why Inhaled Antibiotics?

• Pseudomonas aeruginosa (Pa) is a major
  contributor to CF lung disease and its resultant
  morbidity and mortality.
• Aminoglycosides active against Pa penetrate the
  sputum poorly.
• Peak sputum concentrations of aminoglycosides are
  equal to only 12 of serum concentrations.

18
Why Inhaled Antibiotics?

• Bioactivity of aminoglycosides is further
  decreased in CF patients by its
• binding to DNA
• binding to mucin
• increased concentrations of divalent cations

19
Why Inhaled Antibiotics?

• The lower sputum concentrations of
  aminoglycosides require larger IV doses of
  aminoglycosides.
• Increased risk of ototoxicity and nephrotoxicity.
• Aerosolized aminoglycosides reach high
  concentrations in the sputum, and due to their
  limited absorption from the respiratory tract
  systemic toxicity is minimized.

20
Techniques of Administration

• Eisenberg et al.
• jet nebulizers versus ultrasonic nebulizer
• ultrasonic nebulizer is costly, inconvenient, and
  high maintenance
• jet nebulizers were proven to deliver greater
  than 10 times the MIC of Pseudomonas in 87-93 of
  patients

21
Techniques of Administration

• Nikolaizik et al.
• bronchial constriction after nebulized tobramycin
  with decreased FEV1 and FVC
• beta agonist before administration reduced this
  effect (p

22
The Evidence

• Hodson et al.
• double-blind, randomized, cross-over trial of
  aerosolized carbenicillin and gentamicin in CF
  patients with Pa
• purpose was to determine if treatment could halt
  or slow the decline in lung function and reduce
  the number of hospitalizations
• enrolled 20 patients with Pa positive cultures

23
Hodson et al.

• patients were randomly assigned to 6 months of
  antibiotic or placebo
• the antibiotics were 1 gram of carbenicillin with
  80 mg of gentamicin each b.i.d.
• 3 patients withdrew
• 1 in the first month with a rash
• 1 with bilateral pneumothoracies in month 8
• 1 in month 10 on placebo because she felt much
  worse than her first 6 months

24
Hodson et al.

• Results
• of the 17 patients completed the study the mean
  FEV1 during antibiotic was 1566 ml versus 1300 ml
  during placebo (p
• FVC was 2656 ml on antibiotic versus 2314 ml on
  placebo (p
• hospitalizations were reduced with 7 during
  placebo and 3 during treatment but was not
  significant
• fourteen patients favored antibiotic, 3 were
  undecided, and no one favored placebo

25
Stead et al.

• Randomized, crossover study, comparing nebulized
  ceftazidime versus gentamicin and carbenicillin
  versus saline in CF patients with Pa
• Each treatment was given randomly for 4 months
  for a total of 12 months
• 18 patients were enrolled into the study
• Ceftazidime and saline were blinded

26
Stead et al.

• Purpose was to determine if ceftazidime would be
  as effective as gentamicin and carbenicillin with
  possible benefits of
• possible use in patients with penicillin allergy
• less time to nebulize
• treat patients who failed to respond to the other
  regimen

27
Stead et al.

• Of the 18 patients enrolled 5 were withdrawn
  during the first 4 months
• 2 were noncompliant (1 on saline, 1 on ceftaz)
• 2 on saline had deterioration, and were changed
  to antibiotic
• 1 could not tolerate the taste of saline

28
Stead et al.

• Results
• FEV1 increased from 1.48 L on saline to 1.70 L on
  both antibiotic treatments (p
• body weight was increased over entry in both
  antibiotic groups (p
• hospital admissions were decreased during the
  study year compared to the year before the study,
  5 admissions versus 16 admissions respectively
  (p

29
Stead et al.

• Ceftazidime is as efficacious as
  gent/carbenicillin.
• Could be used in patients with penicillin
  allergy.
• Useful in patients infected with organisms
  resistant to gentamicin or carbenicillin.

30
Maclusky et al.

• Randomized controlled trial comparing long-term
  inhaled tobramycin (32 months) versus saline.
• Purpose was to assess the long-term safety and
  effectiveness of tobramycin in suppressing
  pulmonary disease.
• Patients were colonized with Pa, had FEV1 greater
  than 40, and were receiving bronchodilators.

31
Maclusky et al.

• Patients received either tobramycin 80 mg t.i.d.
  or normal saline
• Patients were aware of their treatment regimen
  but the physicians were blinded

32
Maclusky et al.

• 28 patients were enrolled,13 patients in the
  control group and 15 patients in the treatment
  group
• 1 patient was not colonized with Pa and was
  excluded from analysis, and 1 patient in the
  control group died at 13 months into the study

33
Maclusky et al.

• Results
• FEV1 improved (p
• FVC improved (p
• no evidence of nephro- or ototoxicity

34
Maclusky et al.
100
80
FVC Predicted
60
40
20
Treatment
100
80
FEV1 Predicted
60
40
20
0
10
20
30
40
Months Follow Up
35
Ramsey et al.

• 71 patients enrolled into a double-blind,
  placebo-controlled, three period crossover trial
  to assess the efficacy and safety of aerosolized
  tobramycin.
• attempted to overcome some limitations of
  previous studies.
• double-blinded
• larger number of patients
• covered the taste of tobramycin

36
Ramsey et al.

• Patients had FVCs greater than 40 and were
  colonized with Pa
• Randomly 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)
• To assess compliance quinine hydrochloride was
  added to both solutions and random urine samples
  were taken during the study

37
Ramsey et al.

• 36 patients were assigned to group 1, and 35 to
  group 2
• 66 of the 71 patients completed the study
• Noncompliance ranged from 7 to 20 during the
  study and was comparable between the 2 groups

38
Ramsey et al.

• FEV1 and FVC were both increased over placebo
  during the first 28 days (p
• During the three-period crossover the
  significance of the increase in FEV1 between
  treatment and placebo was greater (p
• A significant carryover effect was found for FEV1
  (p

39
Ramsey et al.
40
Ramsey et al.

• Pulmonary exacerbations and antibiotic use were
  also decreased
• 3 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 needed to treat is
  3)

41
Ramsey et al.

• No renal or ototoxicity was observed.
• 10 of the 71 patients (14) developed resistant
  strains of Pa.
• There was no difference in the emergence of
  resistant strains between placebo and tobramycin
  groups.

42
TOBI (Tobramycin Solution for Inhalation)

• Two multicenter, randomized, placebo-controlled
  studies on TOBI were recently made available by
  the Pathogenesis Corporation.
• These studies enrolled a total of 520 cystic
  fibrosis patients with Pa.
• These studies were designed to look at clinical
  endpoints (PFTS) and health outcomes
  (antibiotics, hospitalizations, and work and
  school days missed).

43
TOBI

• Placebo and drug groups were similar in both
  studies
• Patients 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 cycle
• this design was employed because previous studies
  had found significant carryover effect after 28
  day treatment
• intermittent therapy may reduce the possibility
  of increased resistance of Pa to TOBI by the
  phenomenon of transience

44
TOBI
45
TOBI

• Study 1 and study 2 were analyzed separately for
  FEV1, and together for health outcomes
• relative change for FEV1 in study 1 (n 223) was
  12.02 for drug and -0.52 for placebo (p
• for study 2 (n 297) the relative change in FEV1
  was 8.7 for drug and -2.72 for placebo (p

46
TOBI
47
TOBI

• Subgroup analysis, by age, gender, disease
  severity, and rhDNase use, of FEV1 in the two
  studies demonstrate that TOBI works for a wide
  variety of patients.

48
TOBI
49
TOBI

• Patients on drug were 26 less likely to be
  hospitalized than patients on placebo (p0.014,
  relative risk of 0.74)
• hospital stays were decreased on drug versus
  placebo, 5.1 days versus 8.1 days respectively
  (p
• IV anti-pseudomonal antibiotic use was also
  decreased on drug (p

50
TOBI
51
TOBI

• during 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
  (p0.031)
• compliance was 88 for drug and 93 for placebo

52
TOBI

• No ototoxicity or nephrotoxicity was observed.
• Serum tobramycin levels remain well below
  systemic toxicity limits.

53
TOBI

• This 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.
• This design is 2 times more efficient than a
  standard jet nebulizer.
• The time to nebulize a dose is 15 minutes.

54
Conclusions

• Inhaled antibiotics
• Slow 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.