Azithromycin and asthma

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Azithromycin and asthma

  1. 1. Azithromycin and Acute Asthma Exacerbations<br />Sarah Smitherman<br />1-27-2011<br />
  2. 2. Case Presentation<br />Admitting senior on wards<br />Multiple acute asthma exacerbation admissions one day<br />Discussion with co-senior: <br />Should we use azithromycin for added anti-inflammatory benefit in acute asthma exacerbation?<br />
  3. 3. Background Information: Azithromycin and Asthma<br />Inflammation literature:<br />Macrolides & ketolides shown to decrease inflammatory markers in multiple studies.<br />Kraft (Chest, 2002) treated 55 asthmatics with clarithromycin x 6 weeks. <br />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.<br />
  4. 4. Background Information: Azithromycin and Asthma<br />Infection literature:<br />Studies have shown increased rates of colonization of M. pneumoniae & C. pneumoniae in asthmatics vs. controls<br />C. pneumoniae IgA levels shown to be increased in acute asthma exacerbations, and IgA levels do not increase in those without exacerbation. <br />76% of those with exacerbation also had evidence of viral infection, suggesting C. pneumoniae reactivation plays a role in viral-induced acute asthma exacerbations<br />Multiple animal studies suggest link between M. pneumoniae infection and airway remodeling <br />Infection with M. pneumoniae after allergic sensitization was associated with increased collagen deposition in the airway.<br />
  5. 5. Background Information: Azithromycin and Asthma<br />Cochrane review 2008 - Macrolides in Stable Asthma:<br />“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…”<br />“Considering the small number of patients studies, there is insufficient evidence to support or refute the use of macrolides in patients with chronic asthma.”<br />“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”<br />
  6. 6. Background Information: Azithromycin and Asthma<br />Macrolides in Acute Asthma Exacerbations:<br />Current guidelines do not support use of antibiotics in routine asthma exacerbations<br />Researchers argue the evidence on macrolides in asthma gives a theoretical benefit of macrolides in acute exacerbations:<br />decreasing inflammation <br />treating coexistent atypical infection.<br />
  7. 7. PICO<br />Population: <br />Patients presenting with acute asthma exacerbation<br />Intervention: <br />Use of macrolide or ketolide in addition to standard therapy<br /> Comparison: <br />Current standard of care (i.e. no antibiotic used)<br />Outcome: <br />Improvement in lung function and symptoms of acute asthma exacerbation<br />
  8. 8. Clinical Question<br />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?<br />
  9. 9. Literature search<br />Using OVID:<br />“Azithromycin and Asthma” – 37 results<br />“Macrolide and Asthma” – 127 results<br />Filtered to full text, English – 24 results<br />“Antibiotics and Asthma” – 40 results<br />Assistance of Caryn Scoville<br />Similar search results<br />This search yielded multiple results:<br />Many articles helpful, but most were review articles or did not answer the clinical question<br />
  10. 10. Article Selection<br />Macrolide Antibiotics and Asthma Treatment. (J Allergy Clin Immunol 2006;117:1233-6.)<br />Discussed both chronic and acute exacerbations, but was review article<br />Asthma and Atypical Bacterial Infection. (CHEST 2007; 132:1962–1966)<br />Discussed both chronic and acute exacerbations, but was review article<br />Macrolides and Airway Inflammation in Children. (Pediatric Respiratory Reviews 2005; 6, 227-235)<br />Review article, not specific to asthma<br />Read these articles to see if there were any research articles that answered the clinical question. <br />No new articles discovered with this method.<br />
  11. 11. Article Selection <br />The Effect of Telithromycin in Acute Exacerbations of Asthma. N Engl J Med 2006;354:1589-600.<br />Only research article to address macrolide or ketolide use in acute asthma exacerbation. <br />Unfortunately, no pediatric specific article available.<br />Cited repeatedly by the review articles. <br />Every review article, including Cochrane reviews state more research is needed.<br />
  12. 12. Patient Population<br />Patient Population<br />Adults 17-55 yrs<br />Majority white females<br />Dx of Asthma >6 months <br />acute exacerbation @ Urgent Care, ER, or inpatient setting<br />
  13. 13. Inclusion and Exclusion Criteria<br />Inclusion<br />Exclusion<br />Inclusion criteria:<br />Increased wheeze, dyspnea<br />PEF <80% of predicted<br />Ability to complete diary of asthma symptoms & home PEF<br />Ability to give written consent<br />Exclusion criteria<br />Need for immediate ICU care<br />Known allergic precipitant<br />Known lower respiratory tract disease other than asthma<br />Smoking hx >10 pack-yrs<br />Antibiotic use in prior 30 days<br />Overt infection requiring specific antibiotic treatment<br />
  14. 14. Study Design<br />Patients assigned in 1:1 ratio to telithromycin 400 mg daily vs. identical appearing placebo x 10 days<br />Double Blinded<br />Parallel-group<br />Randomized<br />Placebo-controlled<br />Multicenter & Multinational <br />Data held and analyzed by contract research organization<br />
  15. 15. Study Design Continued<br />Primary endpoints – assessed at 6 weeks post treatment with telithromycin:<br />Diary of sxs (rated 0-6) on 4 variables. These scores were averaged to give a “diary symptom score”<br />(1) Frequency of sxs<br />(2) severity of sxs<br />(3) level of activity<br />(4) effect of asthma on activity<br />PEF upon awakening<br />
  16. 16. Study Design Continued<br />Secondary endpoints:<br />PFTs performed in clinic<br />C. pneumoniae and M. pneumoniaedetection (PCR, culture, and antibody testing)<br />Additional information:<br />Safety analysis<br />
  17. 17. Study Design Continued<br />See figure 1: Study Design<br />270 randomized: 136 placebo, 134 telithromycin<br />Placebo arm:<br />Started with 136, lost 7 (withdrew, lost to f/u)<br />129 completed 10 days of treatment<br />Lost additional 10 ( 3 adverse events, 2 lack of efficacy, 2 protocol violation, 3 lost to f/u)<br />119 completed the 6 weeks of follow up.<br />Telithromcyin arm:<br />Started with 134, Lost 8 (adverse event, withdrew, lost to f/u)<br />126 completed 10 days of treatment<br />Lost additional 14 (5 adverse events, 3 withdrew, 5 lost to f/u, 1 “other”)<br />112 completed 6 weeks of follow up.<br />
  18. 18. Study Analysis<br />Power needed for the study was determined by using the symptom score. <br />Needed 120 per group to reach 80% statistical power (at P<0.05) to detect a 0.51 (20%) difference between groups<br />Analysis of covariance model used to analyze efficacy end points <br />Longitudinal analyses were based on averages during the 6 week f/u period. <br />Analysis of covariance used to estimate the means within groups and the between group differences. <br />Between group tests were used to compare the effects of telithromycin with placebo<br />Models were adjusted to account for factors of center, treatment-center interaction, and baseline values as covariates<br />
  19. 19. Study Results: Primary Outcomes<br />Telithromycin pts had significantly greater improvement in asthma symptoms during study period than placebo pts<br />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)<br />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)<br />No difference in PEF rates<br />
  20. 20. Study Results: Secondary Outcomes<br />Researchers evaluated the mean decrease in the asthma symptom score from baseline to end of the treatment. <br />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)<br />This equates to an average reduction of 51.1% for telithromycin group vs. 28.5% for placebo group<br />
  21. 21. Study Results: Secondary Outcomes<br />More symptom free days in the telithromycin group (16% vs. 8 %, p = 0.006)<br />PFT improvements baseline to end of treatment (10 days):<br />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)<br />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)<br />FVC mean difference 0.27L (C.I. 0.08-0.45, p = 0.006)<br />FEF25-75 mean difference of 0.4 L/sec (C.I. 0.13 to 0.67, p = 0.004)<br />
  22. 22. Study Results: Secondary Outcomes<br />NONE of the PFT tests showed a significant treatment effect by the 6th week of the study.<br />
  23. 23. Study Results: Secondary Outcomes<br />61% of patients met a least one criterion for infection with C. pneumoniae, M. pneumoniae, or both. <br />Subgroup analysis:<br />No difference in asthma symptom scores or PEF rates for those with and without evidence of infection<br />The improvement in FEV1 was the same for those with and without evidence of infection. <br />BUT the mean difference of FEV1 improvement was only significant in a subgroup of 131 patients who were positive for infection.<br />For remaining 82 patients, the mean difference in FEV1 was not statistically significant<br />
  24. 24. Post Hoc Analysis: Steroid use<br />Receiving or NOT receiving Oral steroids made no difference in the magnitude of treatment effect:<br />85 pts got steroids: Mean decrease in symptom score not significant (C.I. -0.6 to 0.1, p = 0.09)<br />170 pts did not receive steroids: Mean decrease in symptoms score not statistically significant (CI -0.6 to -0.03, p = 0.03)<br />
  25. 25. Adverse Events<br />No difference between groups for the frequency of adverse events<br />Except nausea in telithromycin group (p=0.01)<br />Elevation in AST and ALT >3x’s Upper limit of normal seen in 2 pts in telithromycin group<br />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)<br />FDA currently evaluating telithromycin and possible liver toxicity<br />None of the 6 serious adverse events during the study and f/u period were considered treatment related<br />4 cases of worsening asthma sxs (2 in each group)<br />PID<br />Serious constipation<br />
  26. 26. Clinical Significance<br />Results generalizable to all ages? <br />Results generalizable to macrolide antibiotics?<br />Results clinically significant?<br />No differences in 6 weeks for PFT markers<br />Difference in asthma symptom score was modest, and difficult to assess in population that did not receive oral steroids (a common mainstay of treatment)<br />Authors note:<br />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<br />Mainstays of treatment (oral steroids & inhaled steroids) not well studied<br />No published studies comparing oral corticosteroids vs. placebo<br />2 RCT showed no evidence of improved outcome with doubling dose of inhaled corticosteroid during exacerbation.<br />
  27. 27. Study Importance<br />Only study to date to evaluate use of an antibiotic for atypical organisms in acute asthma treatment<br />All prior studies on antibiotics in acute asthma treatment did not assess atypical coverage<br />
  28. 28. Study Shortcomings<br />No pediatric study<br />Subgroup analyses <br />Example: FEV1 significant difference only seen in group with evidence for bacterial infection<br />Subgroup analysis may not have adequate power to draw conclusions from the analysis.<br />Did not meet the numbers needed to reach statistical power (120 in each group needed)<br />112 telithromycin, 119 placebo<br />Had calculated a difference in symptom score of 0.51 points (20% difference) between groups to be statistically significant. <br />observed decrease of only 0.3 points <br />
  29. 29. Study Shortcomings<br />Standard therapy in exacerbations often includes oral steroids, but only 85 patients received steroids<br />Makes results less generalizable<br />Would the short term improvement in the FEV1 with telithromycin be seen if all pts had received steroids?<br />Use of telithromcyin<br />New drug, not widely available or widely used<br />Makes less generalizable<br />Authors stated in response to letter to editor: <br />“Chose telithromycin because Sanofi-Aventis was willing to sponsor the study,” <br />“Respiratory pathogens are susceptible to telithromycin, whereas macrolide resistance is widespread.”<br />
  30. 30. Summary<br />Prior research suggests that macrolides and ketolides can:<br />Decrease asthma related inflammation <br />Decrease colonization of atypical respiratory organisms that may exacerbate asthma symptoms.<br />Telithromycin is a ketolide that showed some short term improvement in asthma symptoms and FEV1. <br />Results from this study are not widely generalizable and need to be validated<br />May consider use of atypical coverage in patients with severe cases. Would not recommend for all patients.<br />Use in chronic asthma still being evaluated<br />Further study is needed<br />
  31. 31. References<br />Effect of Telithromycin in Acute Exacerbations of Asthma. N Engl J Med 2006; 354:1589-600.<br />Treating Acute Asthma with Antibiotics – Not Quite Yet. N Engl J Med 2006; 354: 1632-1634<br />Macrolide Antibiotics and Asthma Treatment. J Allergy Clin Immunol 2006;117:1233-6.<br />Asthma and Atypical Bacterial Infection. CHEST 2007; 132:1962–1966<br />Macrolides and Airway Inflammation in Children. Pediatric Respiratory Reviews 2005; 6, 227-235<br />Antibiotics for Acute Asthma. Cochrane Database of Systematic Reviews 2001, Issue 2.<br />Macrolides for Chronic Asthma. Cochrane Database of Systematic Reviews 2005, Issue 4.<br />

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