Azithromycin and asthma

1. Azithromycin and Acute Asthma Exacerbations
Sarah Smitherman
1-27-2011

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.

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.

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

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
Population:
Patients presenting with acute asthma exacerbation
Intervention:
Use of macrolide or ketolide in addition to standard therapy
Comparison:
Current standard of care (i.e. no antibiotic used)
Outcome:
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; 132:19621966)
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
Exclusion
Inclusion criteria:
Increased wheeze, dyspnea
PEF 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
Parallel-group
Randomized
Placebo-controlled
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

Secondary endpoints:
PFTs performed in clinic
C. pneumoniae and M. pneumoniaedetection (PCR, culture, and antibody testing)
Additional information:
Safety analysis

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 P3xs 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)
PID
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; 132:19621966
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.

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Azithromycin and asthma