Treating lower and upper airway infections in CF

Christiane Knoop

Institut de Mucoviscidose de l’ULB

Hôpital Universitaire Erasme, Brussels,

Belgium

15th South Eastern European Cystic Fibrosis Conference

CFTR protein

2Rowe et al. N Engl J Med 2005; 352:1992.

CFTR protein

3Rowe et al. N Engl J Med 2005; 352:1992.

Pathogenesis of CF lung disease

4

Abnormal CFTR Protein

Defective Ion Transport2

CFTR gene defect

End StageLung Disease

Cycle ofDestruction

InfectionInflammation

Mucus Obstruction

Delayed mucociliary clearance

Abnormal CFTR protein

Airway surface liquid depletion

Defective ion transport

Scarring

5

CF lung disease

� First cause of morbidity and mortality

in CF adults

� →→→→ 75 % hospital admissions

Penketh Thorax 1987

� FEV1 < 30 % predicted values

� paO2 < 55 mmHg ±±±± paCO2 > 50 mmHg

Survival at 2 yrs < 50 %

Kerem N Engl J Med 1992

Symptoms and signs

• Chronic cough

• Expectorations

• Hemoptysis

• Dyspnea

• Exercise intolerance

• Thoracic pain

• Normal auscultation

→ crackles upper lung

zones → disseminated

• Signs of thoracic

hyperinflation

• Cyanosis

• Clubbing

65th South Eastern European Cystic Fibrosis Conference

Bacterial colonizations

7Cystic Fibrosis Foundation Annual Data Report 2011

Types of colonisations/infections

8

• New infection

• Initial infection successfully

eradicated

• Intermittent colonisation

• Chronic colonisation

• Acute pulmonary exacerbation

5th South Eastern European Cystic Fibrosis Conference

9

Follow-up

1) Clinical assessment

2) Lung function tests

3) Microbiology

5th South Eastern European Cystic Fibrosis Conference

10

Microbiology

• Sputum culture or laryngeal swab at each

out-patient visit (1 x / 4-6 weeks)

• Culture for Pseudomonas and other CF –

associated bacteria

Experienced personnel !

• Antibiotic sensitivity to be established for

various colonies

5th South Eastern European Cystic Fibrosis Conference

Conventional treatment of CF lung disease

11

• Physiotherapy

• Mucolytics (DNAse, hypertonic saline, …)

• Bronchodilators – inhaled corticosteroids

• Antibiotics (inhaled, oral, iv)

• Anti-inflammatory medications (azi,

ibuprofen, …)

• Oxygen – Ventilation

• Preventive measures

Döring et al. J Cystic Fibrosis 2012; 11: 461.

Conventional treatment of CF lung disease

12

• Physiotherapy

• Mucolytics (DNAse, hypertonic saline, …)

• Bronchodilators – inhaled corticosteroids

• Antibiotics (inhaled, oral, iv)

• Anti-inflammatory medications (azi,

ibuprofen, …)

• Oxygen – Ventilation

• Preventive measures

Döring et al. J Cystic Fibrosis 2012; 11: 461.

13

Mucolytics

1) DNAse - Pulmozyme

2) Hypertonic saline

Mucoclear 6% ou 3%

Nebusal 7%

14

DNAse:To whom it should be prescribed ?

In all patients

CF lung disease: mild, moderate, severe

Start during a stable phase or during an acute

exacerbation Am J Respir Crit Care Med 1996

Several months trial

2.5 mg / day

Follow-up of symptoms, lung function, number

of acute exacerbations

No clear criteria for efficacy, no long-lasting

effect

Hypertonic saline

15Elkins et al. N Engl J Med 2006; 354:229.

N = 164

~ 60 euro/month

16

Antibiotics

1) New infection with Pseudomonas

aeruginosa

→→→→ Eradication

2) Chronic colonization/ infection with

Pseudomonas aeruginosa

→→→→ Maintenance therapy

3) Treatment of pulmonary exacerbations

Pseudomonas and other

17

Eradication of new Pseudomonas infection

• Left untreated will progress to chronic infection

• worse lung function

• more exacerbations

• higher mortality

• Prompt eradication treatment necessary

(ideally within 4 wks of sputum)

• No regimen superior to others

• Oral cipro + inhaled coli up to 3 months

• Tobramycin solution for inhalation 28 days

• Follow-up cultures !

Smyth A et al. ECFS Standards of Care: Best practice guidelines. J Cyst Fibr 2014; 13: Suppl 1: S23 – S42.

18

Maintenance treatment

19

Chronic Pseudomonas infection

• Long-term inhaled antibiotics

• Tobramycin solution for inhalation ON/OFF > 6 yrs

to be continued indefinitely (US guidelines), all age

groups (European guidelines)

• TIS and tobramycin dry-powder =

• Inhaled aztreonam is an alternative

• Nebulized or dry-powder colistin widely used

Smyth A et al. ECFS Standards of Care: Best practice guidelines. J Cyst Fibr 2014; 13: Suppl 1: S23 – S42.

20

Other chronic infections

• No recommendations

• In practice

• MSSA flucloxacillin, minocyclin, sxt …

Smyth A et al. ECFS Standards of Care: Best practice guidelines. J Cyst Fibr 2014; 13: Suppl 1: S23 – S42.

New (formulations of) inhaled antibiotics

21

• Tobramycin solution for inhalation (TIS) = TOBI 2,042

euro/month

• Aztréonam (AZLI) = Cayston 3,060 euro/month

• Dry-powder formulations

• TIP = TOBIpodhaler 2,083 euro/month

• CDPI = Colobreathe 1,343 euro/month

• Liposomal formulations

• Amikacine

• International comparator study vs. TIS ongoing

• Antibiotics in development

• Levofloxacine dry-powder

• Vancomycin: nebulized and dry-powder

22

Definition of pulmonary exacerbation

Development of ≥≥≥≥ 3 new symptoms/signs:

• ↑↑↑↑ cough

• ↑↑↑↑ expectorations and/or change of colour

• Fever > 1x/week

• Weight loss > 1 kg ou 5 % of weight + anorexia

• ↑↑↑↑ RR

• New crackles

• ↓↓↓↓ exercise tolerance

• ↓↓↓↓ FEV1 ≥≥≥≥ 10 % of basal values

• ↓↓↓↓ saturation ≥≥≥≥ 10 %

• Changes on X-ray

23

Treatment of pulmonary exacerbation

• Gold standard: β β β β-lactamin + aminoside

• (lack of evidence ! Toxicity, allergy, … )

• if MSSA : + oxacilline

N Engl J Med 1996

• ↑↑↑↑ volume of distribution and AB clearance

• →→→→ higher AB doses and/or shortened

• intervals of administration (PI patients !)

• Duration: 10 - 21 days

• Goal: return to baseline clinical situation/

lung function

17 novembre 2014 24

CF SINUS DISEASE

CFpathogens

25

Preventive measures

1) Avoid contact with infected persons

2) Shots� influenza

3) Improve nutrition

4) Avoid tobacco exposure

(active and passive)Gilljam Resp Med 1991

Campbell J Pediat 1992