MICROBIOLOGY OF BRONCHIECTASIS

AND ANTIBIOTIC TREATMENT

Prof. Dr. Abdullah Sayıner, Ege UMS Dept. of Chest Diseases

Conflict of interest

• Pfizer• Novartis• Bayer• Abdi İbrahim

Vicious circle hypothesis

Damage şn the bronchial wall and epithelium

Dysfunction in mucociliary clearance

Colonization of lower respiratory tractand frequent exacerbations

Chronic and exacerbatinginflammation

Cole PJ. Clin Ther 1991; 13: 194-8

Aims of antibiotic treatment

• In stable period, eradication of colonizing bacteria

• In exacerbations, treatment of acute infection

In exacerbations, colonizing bacteria increase in number or a new strain develops.

Monso E, Am J Respir Crit Care Med 1995; 152: 1316-20Sethi S, New Eng J Med 2002; 347: 465

Hemophilus influenzae• Colonizes 15-50% of the patients• Can adhere to the respiratory mucus and

epithelial cells using adhesion molecules and pyli, resulting in colonization.

• Through genetic mutations or horizontal gene transfer, can change its phenotype or surface antigens, thus can avoid immune response and oxidative stress.

• Can form a biofilm (amorphous matrix) in the respiratory tract, which surrounds the colonies. It can decrease its metabolism and growth rate in this environment.

Foweraker JE. Eur Respir Mon 2011; 52: 68-96Gilsdorf JR. Infect Immun 2004; 72: 2457-61Starner TD. Am J Respir Crit Care Med 2006; 174: 213-220

Pseudomonas aeruginosa

• Colonizes 10-40% of the patients• More frequently isolated in patients

in whom the disease is diagnosed before 14 years of age, FEV1 level is low, sputum volume is high and there is saccular bronchiectasis.

• More frequent exacerbations and hospitalizations, worse quality of life, faster decline in pulmonary function

Ho PL. Chest 1998; 114: 1594-98Kömüs N. Tuberk Toraks 2006; 54: 355-62

Survival of Pseudomonas in the respiratory tract

• Biofilm formation• Bacteria with different phenotypes – alginate

production, lowered metabolic rate, frequent mutations etc – can coexist within the same patient. → Easy adaptation to changes in the environment

• Natural resistance to several antibiotics + acquired resistance to several others through chromosomal mutations or gene transfer

• Difficulties in bacteriologic diagnosis because of the existence of multiple phenotypes in the chronic infection environment.

Gillham MI. J Antimicrob Chemother 2009; 63: 728-32

Biofilm

• Biofilm formation: Alginate and proteins + DNA fragments from host cells + various metabolites

→ protection against phagocytosis by neutrophils and macrophages

→ Anaerobic environment under the biofilm surface → Effectiveness of aminoglycosides → Metabolic activity → Effectiveness of beta-lactams ve quinolones

Yang L. J Bacteriol 2008; 190: 2767-76Walters MC. Antimicrob Agents Chemother 2003; 47: 317-23

• Streptococcus pneumoniae: Particularly, in patients with Ig or complement deficiencies

• Moraxella catarrhalis• Staphylococcus aureus• Viruses• Mycobacteria other than tuberculosis

Other microorganisms

Sputum culture

Determination of thecausative agent and itssusceptibility to drugs

Possibility of isolated bacterianot being the phenotype causingthe infection

Sputum culture

• Sputum sample must be obtained prior to the initiation of antibiotic treatment.

• Useful if the empiric treatment is not successful or if there is a possibility of deescalation (narrowing of antibiotic spectrum).

Antibiotic treatment

• Some patients with bronchiectasis may produce large amounts of and purulent sputum in stable period. Therefore, when deciding on antibiotic treatment, symptoms during stable period and additional evidence of infection should carefully be questioned.

• There is no randomized, controlled study evaluating effectiveness of antibiotic treatment in exacerbations of bronchiectasis.

• IV ceftazidime (n=18) vs oral levofloxacin (n=17) for 10 days in exacerbations of bronchiectasis

• Evaluation of clinical parameters before and after treatment

Tsang KW ve ark. Eur Respir J 1999;14:1206

Ceftazidime Levofloxacin

Day 1 Day 10 P value Day 1 Day 10 P value

Fever 37.5 36.8 0.0006 37.4 36.6 0.02

WBC count

11.2 7.0 0.0001 10.7 7.8 0.01

Sputum volume (ml)

60 20 0.0002 72.5 16 0.002

Purulence

4 1 0.0007 3 1.5 0.03

Cough 3 1 0.0005 2 1 0.002

Dyspnea

1 0.5 0.001 2 1 0.002

Addition of ciprofloxacin to inhaled tobramycin

Patients with PseudomonasinfectionMulticenter, randomized,placebo controlled studyTreatment for 14 daysNo difference in clinical findings

% Plcb Tobra

Improvement

44.4 34.6

Failure 18.5 11.5

Relapse 18.5 11.5

Bilton D. Chest 2006;130:1503

Oral treatment Parenteral treatment

Patients without any risk factors for Pseudomonas infection

Beta-lactam + beta-lactamase inhibitorRespiratory fluoroquinolone

Beta-lactam + beta-lactamase inhibitor3rd generation non-Pseudomonas cephalosporinRespiratory fluoroquinolone

Patients with risk factors for Pseudomonas infection

Ciprofloxacin Ciprofloxacin3. or 4. gen anti-pseudomonal cephalosporinCarbapenemPiperacillin-tazobactamAnti-pseudomonal beta-lactam + FQ or aminoglycoside

Turkish Thoracic Society recommendations

Risk factors for Pseudomonas infection

• Hospitalization within the preceding month

• Antibiotic use for four times or more during the preceding year or once during the preceding month

• Severe (resulting in respiratory failure) exacerbation

• Isolation of P. aeruginosa in previous exacerbation or in stable period

Oral treatment Parenteral treatment

Patients without any risk factors for Pseudomonas infection

Beta-lactam + beta-lactamase inhibitorRespiratory fluoroquinolone

Beta-lactam + beta-lactamase inhibitor3rd generation non-Pseudomonas cephalosporinRespiratory fluoroquinolone

Patients with risk factors for Pseudomonas infection

Ciprofloxacin Ciprofloxacin3. or 4. gen anti-pseudomonal cephalosporinCarbapenemPiperacillin-tazobactamAnti-pseudomonal beta-lactam + FQ or aminoglycoside

Turkish Thoracic Society recommendations

Macrolides – anti-inflamatory effects

• Decrease in mucus secretion in airways• Inhibition of production of proinflammatory

cytokines (IL-8) and adhesion molecules, resulting in decreased neutrohil chemotaxis

• Disrution of biofilm which is formed by and which protects P.aeruginosa and prevention of its reformation

• There is not enough clinical evidence supporting these positive effects.

BUT• Potential for development of resistance• Adverse effects on cardiac signal transmission

Amsden GW. JAC 2005;55:10Crosbie PAJ. Eur Respir J 2009;33:171

Macrolides: Clinical studies in bronchiectasis

Design Drug Adults / children

Duration Effect Adverse events

RCT Clarithro

0/34 3 mo SputumFEV1

?

RCT Roxithro

0/25 12 wk BHRFEV1

?

Open Azithro3/hf

39/0 10 mo ExacSymp

LFTDiarrhea

RCT Erithro2x500

21/0 8 wk FEV1Sputum

Rash

R, open, crossover

Azithro2/wk

11/0 6 mo Exac Sputum

Diarrhea 25%

Retrospect

Azithro3/hf

56/0 9 mo ExacFEV1

?

Crosbie PAJ. Eur Respir J 2009;33:171

Inhaled tobramycin• Inhalation using a nebulizer (300mg bid)• 28-day treatment cycles followed by 28-day off-

drug periods• Outcomes in patients with cystic fibrosis colonized

with P. aeruginosa to whom this treatment is administered: placebo-controlled study (3 cycles) 10% increase in FEV1 levels (vs 2% decrease in plcb group) 1 log decrease in concentration of colonizing Pseudomonas 23% decrease in hospitalizations Increase in prevalence of drug-resistant strains (25%32%)

Ramsey BW. N Engl J Med 1999;340:23

• 74 patients colonised with P. aeruginosa

• Randomized, placebo-controlled trial • Inhaled tobramycin (IT) / placebo for

four weeks• Eradication in 13/37 IT patients

Barker AF ve ark. AJRCCM 2000;162:481

Barker AF ve ark. AJRCCM 2000;162:481

Barker AF ve ark. AJRCCM 2000;162:481

Inhaled tobramycin: Adverse events (%)

Tobramycin Placebo

Increased cough 41 24

Dyspnea 32* 8

Increased sputum 22 14

Chest pain 19* 0

Wheeze 16* 0

Fatigue 14 16

Fever 11 16

Barker AF ve ark. AJRCCM 2000;162:481

Summary

• Bronchial colonization / infection have an adverse effect on the course and prognosis of bronchiectasis.

• H. influenzae and P. aeruginosa more frequently colonizes patients with worse pulmonary function and saccular bronchiectasis.

• In spite of some theoretic problems, bacteriologic examination of the sputum should be done.

• There is weak evidence that the use of antibiotics during exacerbations is associated with limited benefits.

• Long-term macrolide treatment can be considered in patients with frequent exacerbations. Inhaled tobramycin does not seem to be very effective in patients with non-cystic fibrosis bronchiectasis.