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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.