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Azithromycin and asthma



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  • 1. Azithromycin and Acute Asthma Exacerbations
    Sarah Smitherman
  • 2. Case Presentation
    Admitting senior on wards
    Multiple acute asthma exacerbation admissions one day
    Discussion with co-senior:
    Should we use azithromycin for added anti-inflammatory benefit in acute asthma exacerbation?
  • 3. Background Information: Azithromycin and Asthma
    Inflammation literature:
    Macrolides & ketolides shown to decrease inflammatory markers in multiple studies.
    Kraft (Chest, 2002) treated 55 asthmatics with clarithromycin x 6 weeks.
    In patients positive for M. pneumoniaeor C pneumoniae, there was a reduction in TNF alpha, IL-5, and IL-12. There was also an improvement in FEV1.
  • 4. Background Information: Azithromycin and Asthma
    Infection literature:
    Studies have shown increased rates of colonization of M. pneumoniae & C. pneumoniae in asthmatics vs. controls
    C. pneumoniae IgA levels shown to be increased in acute asthma exacerbations, and IgA levels do not increase in those without exacerbation.
    76% of those with exacerbation also had evidence of viral infection, suggesting C. pneumoniae reactivation plays a role in viral-induced acute asthma exacerbations
    Multiple animal studies suggest link between M. pneumoniae infection and airway remodeling
    Infection with M. pneumoniae after allergic sensitization was associated with increased collagen deposition in the airway.
  • 5. Background Information: Azithromycin and Asthma
    Cochrane review 2008 - Macrolides in Stable Asthma:
    “While results support an anti-inflammatory effect of (macrolides) in asthma, there were no clear benefits to participants with asthma. This may have been because the study design was not optimal. More research is needed…”
    “Considering the small number of patients studies, there is insufficient evidence to support or refute the use of macrolides in patients with chronic asthma.”
    “Further studies are needed to clarify the potential role of macrolides in some subgroups of asthmatics such as those with evidence of chronic bacterial infections”
  • 6. Background Information: Azithromycin and Asthma
    Macrolides in Acute Asthma Exacerbations:
    Current guidelines do not support use of antibiotics in routine asthma exacerbations
    Researchers argue the evidence on macrolides in asthma gives a theoretical benefit of macrolides in acute exacerbations:
    decreasing inflammation
    treating coexistent atypical infection.
  • 7. PICO
    Patients presenting with acute asthma exacerbation
    Use of macrolide or ketolide in addition to standard therapy
    Current standard of care (i.e. no antibiotic used)
    Improvement in lung function and symptoms of acute asthma exacerbation
  • 8. Clinical Question
    In patients presenting with an acute asthma exacerbation, does the addition of a macrolide or ketolide to standard therapy result in an improvement in lung function or symptoms of acute asthma exacerbation when compared to the current standard of care?
  • 9. Literature search
    Using OVID:
    “Azithromycin and Asthma” – 37 results
    “Macrolide and Asthma” – 127 results
    Filtered to full text, English – 24 results
    “Antibiotics and Asthma” – 40 results
    Assistance of Caryn Scoville
    Similar search results
    This search yielded multiple results:
    Many articles helpful, but most were review articles or did not answer the clinical question
  • 10. Article Selection
    Macrolide Antibiotics and Asthma Treatment. (J Allergy Clin Immunol 2006;117:1233-6.)
    Discussed both chronic and acute exacerbations, but was review article
    Asthma and Atypical Bacterial Infection. (CHEST 2007; 132:1962–1966)
    Discussed both chronic and acute exacerbations, but was review article
    Macrolides and Airway Inflammation in Children. (Pediatric Respiratory Reviews 2005; 6, 227-235)
    Review article, not specific to asthma
    Read these articles to see if there were any research articles that answered the clinical question.
    No new articles discovered with this method.
  • 11. Article Selection
    The Effect of Telithromycin in Acute Exacerbations of Asthma. N Engl J Med 2006;354:1589-600.
    Only research article to address macrolide or ketolide use in acute asthma exacerbation.
    Unfortunately, no pediatric specific article available.
    Cited repeatedly by the review articles.
    Every review article, including Cochrane reviews state more research is needed.
  • 12. Patient Population
    Patient Population
    Adults 17-55 yrs
    Majority white females
    Dx of Asthma >6 months
    acute exacerbation @ Urgent Care, ER, or inpatient setting
  • 13. Inclusion and Exclusion Criteria
    Inclusion criteria:
    Increased wheeze, dyspnea
    PEF <80% of predicted
    Ability to complete diary of asthma symptoms & home PEF
    Ability to give written consent
    Exclusion criteria
    Need for immediate ICU care
    Known allergic precipitant
    Known lower respiratory tract disease other than asthma
    Smoking hx >10 pack-yrs
    Antibiotic use in prior 30 days
    Overt infection requiring specific antibiotic treatment
  • 14. Study Design
    Patients assigned in 1:1 ratio to telithromycin 400 mg daily vs. identical appearing placebo x 10 days
    Double Blinded
    Multicenter & Multinational
    Data held and analyzed by contract research organization
  • 15. Study Design Continued
    Primary endpoints – assessed at 6 weeks post treatment with telithromycin:
    Diary of sxs (rated 0-6) on 4 variables. These scores were averaged to give a “diary symptom score”
    (1) Frequency of sxs
    (2) severity of sxs
    (3) level of activity
    (4) effect of asthma on activity
    PEF upon awakening
  • 16. Study Design Continued
    Secondary endpoints:
    PFTs performed in clinic
    C. pneumoniae and M. pneumoniaedetection (PCR, culture, and antibody testing)
    Additional information:
    Safety analysis
  • 17. Study Design Continued
    See figure 1: Study Design
    270 randomized: 136 placebo, 134 telithromycin
    Placebo arm:
    Started with 136, lost 7 (withdrew, lost to f/u)
    129 completed 10 days of treatment
    Lost additional 10 ( 3 adverse events, 2 lack of efficacy, 2 protocol violation, 3 lost to f/u)
    119 completed the 6 weeks of follow up.
    Telithromcyin arm:
    Started with 134, Lost 8 (adverse event, withdrew, lost to f/u)
    126 completed 10 days of treatment
    Lost additional 14 (5 adverse events, 3 withdrew, 5 lost to f/u, 1 “other”)
    112 completed 6 weeks of follow up.
  • 18. Study Analysis
    Power needed for the study was determined by using the symptom score.
    Needed 120 per group to reach 80% statistical power (at P<0.05) to detect a 0.51 (20%) difference between groups
    Analysis of covariance model used to analyze efficacy end points
    Longitudinal analyses were based on averages during the 6 week f/u period.
    Analysis of covariance used to estimate the means within groups and the between group differences.
    Between group tests were used to compare the effects of telithromycin with placebo
    Models were adjusted to account for factors of center, treatment-center interaction, and baseline values as covariates
  • 19. Study Results: Primary Outcomes
    Telithromycin pts had significantly greater improvement in asthma symptoms during study period than placebo pts
    Mean symptom scores decrease by 1.3 points with telithromycin vs. decrease of 1 with placebo (C.I. -0.5 to -0.1, p = 0.004)
    This difference shows telithromycin group had 40.4% reduction vs. 26.5% reduction with placebo. (C.I. -23.4 to -4.3, p=0.005)
    No difference in PEF rates
  • 20. Study Results: Secondary Outcomes
    Researchers evaluated the mean decrease in the asthma symptom score from baseline to end of the treatment.
    The Mean of the decrease was 1.7 for telithromycin and 1.3 in placebo group (C.O. -0.7 to -0.2, p= 0.002)
    This equates to an average reduction of 51.1% for telithromycin group vs. 28.5% for placebo group
  • 21. Study Results: Secondary Outcomes
    More symptom free days in the telithromycin group (16% vs. 8 %, p = 0.006)
    PFT improvements baseline to end of treatment (10 days):
    Telihtromycin 0.63 L improvement in FEV1 vs. 0.34 L improvement with placebo. (mean difference 0.29, C.I. 0.12-0.46, p= 0.001)
    Telithromycin group showed improved PEF vs. placebo, with a mean difference of 26.9L between the groups C.I.1.8-52.1, p = 0.04)
    FVC mean difference 0.27L (C.I. 0.08-0.45, p = 0.006)
    FEF25-75 mean difference of 0.4 L/sec (C.I. 0.13 to 0.67, p = 0.004)
  • 22. Study Results: Secondary Outcomes
    NONE of the PFT tests showed a significant treatment effect by the 6th week of the study.
  • 23. Study Results: Secondary Outcomes
    61% of patients met a least one criterion for infection with C. pneumoniae, M. pneumoniae, or both.
    Subgroup analysis:
    No difference in asthma symptom scores or PEF rates for those with and without evidence of infection
    The improvement in FEV1 was the same for those with and without evidence of infection.
    BUT the mean difference of FEV1 improvement was only significant in a subgroup of 131 patients who were positive for infection.
    For remaining 82 patients, the mean difference in FEV1 was not statistically significant
  • 24. Post Hoc Analysis: Steroid use
    Receiving or NOT receiving Oral steroids made no difference in the magnitude of treatment effect:
    85 pts got steroids: Mean decrease in symptom score not significant (C.I. -0.6 to 0.1, p = 0.09)
    170 pts did not receive steroids: Mean decrease in symptoms score not statistically significant (CI -0.6 to -0.03, p = 0.03)
  • 25. Adverse Events
    No difference between groups for the frequency of adverse events
    Except nausea in telithromycin group (p=0.01)
    Elevation in AST and ALT >3x’s Upper limit of normal seen in 2 pts in telithromycin group
    But both of these patients started out with higher than normal liver enzymes (baseline 2.8-3 x upper limit of normal, end of study 3 to 4.9 x upper limit of normal)
    FDA currently evaluating telithromycin and possible liver toxicity
    None of the 6 serious adverse events during the study and f/u period were considered treatment related
    4 cases of worsening asthma sxs (2 in each group)
    Serious constipation
  • 26. Clinical Significance
    Results generalizable to all ages?
    Results generalizable to macrolide antibiotics?
    Results clinically significant?
    No differences in 6 weeks for PFT markers
    Difference in asthma symptom score was modest, and difficult to assess in population that did not receive oral steroids (a common mainstay of treatment)
    Authors note:
    Cochrane review of 2 studies for antibiotics in acute asthma attacks did not show a benefit, but neither study assessed antibiotics effective against atypical bacteria
    Mainstays of treatment (oral steroids & inhaled steroids) not well studied
    No published studies comparing oral corticosteroids vs. placebo
    2 RCT showed no evidence of improved outcome with doubling dose of inhaled corticosteroid during exacerbation.
  • 27. Study Importance
    Only study to date to evaluate use of an antibiotic for atypical organisms in acute asthma treatment
    All prior studies on antibiotics in acute asthma treatment did not assess atypical coverage
  • 28. Study Shortcomings
    No pediatric study
    Subgroup analyses
    Example: FEV1 significant difference only seen in group with evidence for bacterial infection
    Subgroup analysis may not have adequate power to draw conclusions from the analysis.
    Did not meet the numbers needed to reach statistical power (120 in each group needed)
    112 telithromycin, 119 placebo
    Had calculated a difference in symptom score of 0.51 points (20% difference) between groups to be statistically significant.
    observed decrease of only 0.3 points
  • 29. Study Shortcomings
    Standard therapy in exacerbations often includes oral steroids, but only 85 patients received steroids
    Makes results less generalizable
    Would the short term improvement in the FEV1 with telithromycin be seen if all pts had received steroids?
    Use of telithromcyin
    New drug, not widely available or widely used
    Makes less generalizable
    Authors stated in response to letter to editor:
    “Chose telithromycin because Sanofi-Aventis was willing to sponsor the study,”
    “Respiratory pathogens are susceptible to telithromycin, whereas macrolide resistance is widespread.”
  • 30. Summary
    Prior research suggests that macrolides and ketolides can:
    Decrease asthma related inflammation
    Decrease colonization of atypical respiratory organisms that may exacerbate asthma symptoms.
    Telithromycin is a ketolide that showed some short term improvement in asthma symptoms and FEV1.
    Results from this study are not widely generalizable and need to be validated
    May consider use of atypical coverage in patients with severe cases. Would not recommend for all patients.
    Use in chronic asthma still being evaluated
    Further study is needed
  • 31. References
    Effect of Telithromycin in Acute Exacerbations of Asthma. N Engl J Med 2006; 354:1589-600.
    Treating Acute Asthma with Antibiotics – Not Quite Yet. N Engl J Med 2006; 354: 1632-1634
    Macrolide Antibiotics and Asthma Treatment. J Allergy Clin Immunol 2006;117:1233-6.
    Asthma and Atypical Bacterial Infection. CHEST 2007; 132:1962–1966
    Macrolides and Airway Inflammation in Children. Pediatric Respiratory Reviews 2005; 6, 227-235
    Antibiotics for Acute Asthma. Cochrane Database of Systematic Reviews 2001, Issue 2.
    Macrolides for Chronic Asthma. Cochrane Database of Systematic Reviews 2005, Issue 4.