“Progress in the Treatment of Chronic
Airway Infection in Cystic Fibrosis”
Gary Albers, MD
Professor of Pediatrics
Division of Pulmonary Medicine
Saint Louis University School of Medicine
St. Louis, MO
Disclosures
According to Accreditation Council for Continuing Medical Education
all individuals in a position to control content must disclose all
associations with proprietary entities that may have a direct
relationship to the subject matter they will be presenting at this activity.
For this activity, the following affiliations/financial interests have been
disclosed:
Gary Albers, MD has received grant/research support from Mpex and
honoraria from Gilead Sciences and Novartis. Patrick Flume, MD
(Content Reviewer) has received grant/research support from Bayer,
Boehringer Ingelheim, Gilead Sciences, Inspire, Mpex, Novartis,
Pharmaxis Ltd., Vertex, the Cystic Fibrosis Foundation and National
Institutes of Health. He has also served as a consultant for Gilead
Sciences and Inspire. David Geller, MD (Content Reviewer) has
received grant/research support from Bayer, Boehringer Ingelheim,
Gilead Sciences, Mpex, Pharmaxis Ltd., and Philips Respironics. He
has served as a consultant for CSL Behring, Genentech, Gilead
Sciences, Novartis and Talecris. Linda O’Connor, PharmD (Medical
Writer) has no relevant financial relationships to disclose. ABcomm
staff has no relevant financial relationships to disclose.
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Learning Objectives
• Identify and diagnose patients with cystic fibrosis (CF).
• Recognize the negative consequences associated with
chronic airways infection in patients with CF.
• Mitigate the negative effects of chronic airways
infection through early, aggressive treatment.
• Review the differences between aerosolized antibiotics
– in terms of efficacy, safety, and delivery device – in
order to choose the most appropriate treatment.
• Adjust therapy when microbial response, pulmonary
function, or patient-reported outcomes (PROs) are
inadequate.
Lecture Overview
•
•
•
•
Epidemiology of cystic fibrosis (CF)
Diagnosis of CF
Pathophysiology and clinical features of CF
Development of chronic airways infection in
CF
• Treatment options for airways infection in CF
Epidemiology
Epidemiology of Cystic Fibrosis
• Prevalence1
• 30,000 in the US
• 70,000 worldwide
• Change in patient demographics
• Life expectancy1
• Pulmonary health2
1 Cystic
Fibrosis Foundation, 2011.
et. al. Pediatr Pulmunol. 2008;43:739-44.
2 VanDevanter
Median Predicted Age of Survival
CFF Patient Registry, 2009
40
38
34
32
30
28
26
'0
9
'0
7
'0
5
'0
3
'0
1
'9
9
'9
7
'9
5
'9
3
'9
1
'8
9
'8
7
24
'8
5
Patient Age
36
Year
Patients With CF
CFF Patient Registry, 2009
Children
Adults
Number of Patients
15000
12000
9000
6000
3000
0
6
'8
8
'8
0
'9
2
'9
4
'9
6
'9
8
'9
0
'0
2
'0
4
'0
6
'0
8
'0
Year
Pulmonary Function Over Time
CFF Patient Registry, 2009
Preserved lung function
Median FEV1 (% Predicted)
100
90
80
70
2009
1990
60
50
40
6
8
10
12
14
16
18
20
22
24
26
28
30 Years
Diagnosis
Diagnosis of CF
Newborn screening
• Performed in all 50 states
• Screening process
 Measurement of the pancreatic enzyme, immunoreactive
trypsinogen (IRT)
 If IRT is elevated, then repeat IRT or genotyping
 If genetic mutation is detected, then sweat chloride test
 If chloride level 30-60 mmol/L, then suggestive of CF and
gene sequencing may be ordered
 If chloride level > 60 mmol/L, then CF is confirmed
CFTR Channel
Normal channel
Absent or defective channel
Chloride ions
Water molecules
Inside of cell
Outside of cell
Mucus is thinned by water
then cleared from airways
MucusMucus
proteins
Lack of chloride ions means less water;
mucus becomes sticky and difficult to clear
14
Diagnosis of CF
Sweat chloride test
• Considered the “gold standard” for
diagnosing CF
• Measures the amount of chloride in sweat
• Results
–
–
–
–
< 30 mmol/L = negative result
30-59 mmol/L = borderline result if < 6 months old
40-59 mmol/L = borderline result if > 6 months old
≥ 60 mmol/L = consistent with CF
Cystic Fibrosis Foundation, 2011.
Diagnosis of CF
Genotyping
• Over 1,500 mutations on the CF
gene  malfunctioning CF
transmembrane conductance
regulator (CFTR)
• Absent CFTR or defective
functioning of CFTR is possible
• CFTR maintains periciliary fluid
level to allow for mucociliary
clearance
Cystic Fibrosis Mutations
Class I:- No synthesis of CFTR protein: These are missense, nonsense or frame shift mutations making the cell devoid
of CFTR protein. The phenotypic effects tend to be more severe.
Class II:- Defective processing of CFTR protein:
Common to this class is ∆F508: This class of mutation is
characterized by faulty processing and lack of transport of CFTR
protein to the apical membrane.
Class III:- Defective Regulation: It is a type of missense
mutation leading to the formation of nonfunctional CFTR at the
apical membrane.
Class IV:- Defective Conductance: It targets the function of
CFTR, reducing the conductance of the chloride ion channel.
Class V:- Reduced production of CFTR: Characterized by
reduced expression of normal CFTR protein, hence mild
phenotypes.
Complexity of Diagnosis in Era of Newborn Screening
Pathophysiology and Clinical
Features
Pathophysiology of CF
Abnormal
CFTR
 Reduced airway surface liquid
 Impaired mucociliary clearance
Infection
Obstruction
Inflammation
Structural damage
Infection
Obstruction
Inflammation
Bronchiectasis
Infection
Inflammation
Obstruction
Pulmonary insufficiency
Respiratory failure
Major Respiratory Pathogens
Over Time
CFF Patient Registry, 2009
100
Patients (%)
80
Pseudomonas aeruginosa
60
S. aureus
40
H. Influenza
MRSA
20
0 to 1
2 to 5
6 to 10
11 to 17
18 to 24
25 to 34
35 to 44
45+ Years
Mucoid P. aeruginosa
Predicts Poor Survival
Proportion Surviving
1.0
No Pa (n = 12)
0.9
Nonmucoid Pa (n = 19)
0.8
0.7
0.6
Mucoid Pa (n = 50)
0.5
0.4
0
0
20
40
60
80
Time (mo)
Henry RL, et al. Pediatr Pulmonol 1992; 12:158-161
100
Pseudomonas Infection in CF
• Most prevalent respiratory
bacterial pathogen
• Associated with significant
morbidity
• Can produce a selfprotective, extracellular
matrix of glycoproteins
 Resistance to host immune
response
 Resistance to antibiotic
therapy
Starner, et. al. Ann Int Med. 2005;143:816-22.
Chmiel, et. al. Clin Rev Allergy Immunol. 2002;23:5-27.
Evolution of Pa Infection in CF
2nd Pa +
culture
Birth
1st Pa + Pa
negative
culture
culture
Abnormal
Immune
response
Intermittent
infection
Mucoidy
Anti-Pa antibodies
Consecutive
Pa positive
cultures
Chronic
infection
Classification of
P. aeruginosa Infection
Leeds Criteria
Respiratory cultures obtained in the last 12
months (based on at least 4 cultures/year)
• > 50% positive
• < 50% positive
Chronic infection
intermittent infection
• None positive
Negative
Lee TW, et al. J Cyst Fibros 2003; 2:29-34
Prevalence (%)
Prevalence of Pseudomonas
Phenotype Over Time
Li, et. al. JAMA. 2005;293:581-8.
Treatment of Pseudomonas Infection
Newborn
Prevention of infection:
 Avoidance
 Antibiotic prophylaxis?
Intermittent infection
Treatment of early infection:
Eradication
Chronic infection
Treatment of chronic infection:
Suppression
Prevention of Initial
Pseudomonas Infection
• Hygienic measures
– e.g., Decontamination of
medical equipment
• Patient segregation
– To minimize cross infection
• Vaccination
– Experimental
Eber, et. al. Thorax. 2010;65(10):849-51.
Prevention of Initial
Pseudomonas Infection
Continuous Antibiotic Prophylaxis
Retrospective, observational studies (no control groups were used)
Gentamicin inhalation1
80 mg or 120 mg twice daily
Treatment period = 3 years
N= 28
Tobramycin or amikacin inhalation2
Prophylactic or early treatment of
95% of pediatric patients at CF center
N= 116
Long-term prophylaxis delayed
acquisition of Pseudomonas
and was associated with better
lung function
Treatment was associated with a low rate
of Pseudomonas colonization and better
lung function
Observation period = 15 years
1Heinzl,
et. al. Pediatr Pulmonol. 2002;33:32-7.
et al. J Cyst Fibros. 2006;5:237-44.
2Lebecque,
Prevention of Initial
Pseudomonas Infection
Cycled Antibiotic Prophylaxis
• Study design
– Randomized, double-blind, placebo-controlled study
– N = 65 patients without Pseudomonas infection
– Colistin inhalation 80 mg twice daily plus oral ciprofloxacin
10 mg/kg twice daily
– 3 weeks of treatment every 3 months for 3 years
• Study results
– No significant differences between treatment and placebo
groups with regard to: percent of patients with positive
cultures and median time to acquisition of infection
Tramper-Stranders, et. al. Thorax. 2010;65(10):915-20.
Treatment Goal: Eradication
• Various strategies have been used in non-controlled,
small-scale studies
• Historical strategies include:
– IV anti-Pseudomonal antibiotics
– Oral antibiotics (e.g., ciprofloxacin) and inhaled antibiotics
(e.g., TIS)
– Inhaled antibiotics (e.g., TIS)
• Results
– Variable response rates
– Long-term efficacy and safety need further evaluation
Treggiari, et. al. Pediatr Pulmonol. 2007;42:751-6.
Tobramycin for Eradication
ELITE Clinical Trial
• Study design
– Randomized, open-label, multicenter study
– Patients with early-onset Pseudomonas infection
– Tobramycin 300 mg twice daily for 28 days (N =
45) or 56 days (N = 43)
– Long-term observation (follow-up on month 27)
Ratjen, et al. Thorax. 2010;65(4):286-91.
Tobramycin for Eradication
ELITE Clinical Trial
% Patients free of
Pseudomonas 1
month after end of
treatment
Median time to
recurrence of
Pseudomonas
infection
% Patients free of
Pseudomonas at 27
months
Tobramycin
300 mg twice
daily for 28 days
93%
26.12 months
66%
Tobramycin
300 mg twice
daily for 56 days
92%
25.82 months
69%
Treatment
group
Ratjen, et al. Thorax. 2010;65(4):286-91.
Eradication of Pseudomonas Infection
EPIC Clinical Trial
Culture-based therapy
N= 150
Clinical study
N= 300
Cycled therapy
N= 150
Tobramycin inhalation + placebo
Twice daily for 28 days; repeated when
quarterly cultures are positive for Pseudomonas
Tobramycin inhalation + ciprofloxacin oral
Twice daily for 28 days; repeated when
quarterly cultures are positive for Pseudomonas
Tobramycin inhalation + placebo
Twice daily for 28 days then 56 days off; for 6
consecutive quarterly cycles
Tobramycin inhalation + ciprofloxacin oral
Twice daily for 28 days then 56 days off; for 6
consecutive quarterly cycles
Available at www.clinicaltrials.gov/ct2/show/NCT00097773. Accessed January, 2011.
Treggiari, et al. Contemp Clin Trials. 2009;30(3):256-68.
Treatment Goal:
Chronic Suppression
Early treatment goal:
Late treatment goal:
Eradication
Chronic suppression
 Reduce the bacterial load
 Improve lung function
 Reduce symptoms
 Reduce exacerbation(s)
 Reduce morbidity and mortality
Geller. Respir Care. 2009;54(5):658-70.
Assessing Response to Treatment
in Patients with CF
•
•
•
•
Microbial response
Pulmonary function
Pulmonary exacerbations
Clinical symptoms
Pulmonary Function
• Measure: change in
FEV1 percent predicted
• Most common primary
endpoint in clinical trials
• Younger patients and
those with milder
disease – less
pronounced
improvement in
pulmonary function
Pulmonary Exacerbations
• Measure: time to need
additional antibiotics
• Common endpoint in
clinical trials
• Definition varies among
clinical trials
Clinical Symptoms
•
•
•
•
•
•
Quality of life measure
Clinician-reported outcomes
Observer-reported outcomes (parents)
Patient-reported outcomes (PROs)
Role in clinical trials
Role in patient monitoring
Patient-Reported Outcomes (PROs)
• Definition
“Any outcome based on data provided
by the patient or patient proxy.”
• Characteristics
– Patient’s subjective experience
– Impact of illness and treatment
– Patient’s well-being and daily functioning
Acquadro, et al. Value in Health. 2003;6:522-31.
Cystic Fibrosis Questionnaire-Revised
(CFQ-R)
Pulmonary
Signs
and Symptoms
Decreased Exercise Tolerance
Frequency of Cough
Increased Work of Breathing
Productive Cough
Cough
Wheezing
Day Cough
Sputum Volume
Night Cough
Change in Sputum Color
Chest Congestion
Goss, et. al. Proc Am Thorac Soc. 2007;4:378-86.
Aerosolized Antibiotics
• Rationale for use
– To deliver a high dose of medication to the
location of disease (airways)
– To minimize systemic exposure and toxicity
– To overcome sputum binding (aminoglycoside
antibiotics)
– To optimize pharmacokinetic / pharmacodynamic
parameters
Geller. Respir Care. 2009;54(5):658-70.
History of Aerosolized Antibiotic
Delivery for CF
IV antibiotic solutions used off-label in jet nebulizers
Tobramycin used in ultrasonic nebulizer (600 mg)
Tobramycin used in Pari LC Plus® jet nebulizer (300 mg)
Aztreonam used in vibrating mesh eFlow® device
Tobramycin and ciprofloxacin being studied for use in
dry powder inhalers
TIS for Chronic Airways Infection
Change in Pulmonary Function (From Baseline to Week 24)
Tobramycin 300 mg
twice daily for 28 days,
3 on/off cycles
N = 520
Ramsey, et. al. NEJM. 1999;340:23-30.
TIS for Chronic Airways Infection
Change in Pulmonary Function in Adolescents
Tobramycin 300 mg
twice daily for 28 days,
12 on/off cycles
N = 93 adolescents
Moss, et. al. Chest. 2002;121:55-63.
TIS for Chronic Airways Infection
Change From Baseline to Week 24
IV Antibiotic Use
Hospitalization
40%
60%
45%
37%
30%
20%
10%
0%
Ramsey, et. al. NEJM. 1999;340:23-30.
Patients Receiving 1 or More
Courses of IV Antibiotics (%)
Patients Hospitalized
at Least Once (%)
50%
52%
50%
39%
40%
30%
20%
10%
0%
Tobramycin
Placebo
AZLI for Chronic Airways Infection
AIR-CF-1 Clinical Trial
Change in Sputum Pseudomonas Density from Baseline
0.4
0
Baseline
Day 14
Day 28
Day 42
-0.4
-0.8
-1.2
-1.6
-2
Retsch-Bogart, et al. Chest. 2009;135(5):1223-32.
Aztreonam
Placebo
P < 0.05
AZLI for Chronic Airways Infection
AIR-CF-1 Clinical Trial
Change in FEV1 (% of Predicted Value) from Baseline
15
10
5
Aztreonam
Placebo
0
Baseline
Day 14
Day 28
Day 42
P < 0.05
-5
-10
Retsch-Bogart, et al. Chest. 2009;135(5):1223-32.
Treatment difference on
day 28 = 10.3 %
AZLI for Chronic Airways Infection
AIR-CF-1 Clinical Trial
Change in CFQ-R Score (from Baseline to Day 28)
6
5
4
3.9
3.6
3.6
2
2.3
0
2.1
-1.3
Aztreonam
Placebo
-2
-4
-4.2
-4.7
-4.8
-6
-8
-4.4
-6.9
Eating
Emotional
functioning
Health
perceptions
Physical
functioning
Retsch-Bogart, et al. Chest. 2009;135(5):1223-32.
Role/ School
Vitality
AZLI for Chronic Airways Infection
AIR-CF-1 Clinical Trial
Change in CFQ-R Respiratory Score from Baseline
10
8
6
4
2
0
-2
Baseline
Day 14
Day 28
-4
-6
-8
-10
Retsch-Bogart, et al. Chest. 2009;135(5):1223-32.
Day 42
Aztreonam
Placebo
P < 0.05
Treatment difference on
day 28 = 9.7 points
Aerosolized Antibiotic
Development Pipeline
Preclinical
Tobramycin (TIS)
Aztreonam (AZLI)
Tobramycin (TIP)
Levofloxacin
Liposomal Amikacin
Fosfomycin/
Tobramycin
Ciprofloxacin DPI
Liposomal
Ciprofloxacin
Cystic Fibrosis Foundation, 2011.
Phase I
Phase II
Phase III
Clinically available
to patients
Aerosolized Antibiotics
Device
Antibiotics
Features
Jet nebulizer –
T-piece unvented
Off-label and
compounded from IV
formulations
Low delivery efficiency, time-consuming
Noisy, less portable device
Intensive cleaning and maintenance
Jet nebulizer –
Breath-enhanced
Tobramycin (TIS)
Liposomal ciprofloxacin*
Improved delivery efficiency compared to
unvented
T-piece nebulizer
Breath-enhanced nebulizer
* Investigational. Geller. Respir Care. 2009;54(5):658-70. Geller, et al. Respir Care. 2009;54(6):796-800.
Kesser, et al. Respir Care. 2009;54(6):754-68. Cystic Fibrosis Foundation, 2011.
Aerosolized Antibiotics
Device
eFlow®
technology
platform
Antibiotics
Aztreonam
Fosfomycin / tobramycin*
Levofloxacin*
Liposomal amikacin*
Tobramycin (TIS)*
Features
High-delivery efficiency vs. jet nebulizer
Less time-consuming delivery
Quiet, battery-operated, portable device
Cleaning and disinfection still required
* Investigational. Geller. Respir Care. 2009;54(5):658-70. Geller, et al. Respir Care. 2009;54(6):796-800.
Kesser, et al. Respir Care. 2009;54(6):754-68. Cystic Fibrosis Foundation, 2011.
Aerosolized Antibiotics
Device
Dry powder
inhalers (DPI)
Antibiotics
Tobramycin (TIP)*
Ciprofloxacin*
Colistin*
Features
High-delivery efficiency vs. jet nebulizer
Reduced time burden
Small, portable device, no power needed
No complicated cleaning needed
High payload of powder may increase
risk of local irritation and cough
* Investigational. Geller. Respir Care. 2009;54(5):658-70. Geller, et al. Respir Care. 2009;54(6):796-800.
Kesser, et al. Respir Care. 2009;54(6):754-68. Cystic Fibrosis Foundation, 2010.
Aerosolized Antibiotic Delivery
• Improvements
–
–
–
–
Efficiency, speed of use
Portability
Cleaning, maintenance
Greater payload of antibiotic to lungs
• Limitations
– No device works for all patients
– Novel drug delivery devices are being approved quicker than
antibiotics; therefore, temptation to use newer, more efficient
devices for existing antibiotics without adequate study
Summary
• Greater understanding of the pathophysiolgic
cascade of events in patients with CF
• Early, aggressive treatment of Pseudomonas
infection
• Reduced treatment burden with new
formulations and aerosol delivery systems
• Improved patient outcomes
Unanswered Questions
• Which inhaled antibiotic is the treatment of
choice?
• When will an evidence-based treatment
algorithm be developed?
• What treatment regimen is best (intermittent,
continuous, alternating)?
• What other bacterial pathogens need to be
targeted in patients with CF?
Therapeutic Pipeline for CF
“Cure”
Primary Treatment
“Secondary Treatment”