The study found that in adults presenting with acute asthma exacerbations, the addition of the ketolide telithromycin to standard therapy resulted in greater improvement in asthma symptoms and lung function compared to placebo, especially in those who tested positive for atypical bacterial infections like Chlamydia pneumoniae and Mycoplasma pneumoniae. However, the benefits did not persist beyond 10 days of treatment and telithromycin was associated with more nausea.

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.

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 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; 132:1962–1966) 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 Exclusion 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 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

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) 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; 132:1962–1966 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.