Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES)

Eku Oben, Mercer University College of Pharmacy

Macrolides have been used to treat asthma, but a review states that they are not better than placebo (OR 0.98, 95% CI 0.13 to 7.23) or steroids (OR 0.82, 95% CI 0.43 to 1.57) in treating asthma. [1] The asthma guidelines state that using daily long-term medications is the most effective way to control asthma. The recommendation is to use inhaled corticosteroids (ICS), leukotriene modifiers, long-acting beta agonists, combination inhalers, and theophylline as options to treat long-term persistent asthma. [2] However, the guidelines do not state the use of macrolide antibiotics, specifically azithromycin, for asthma. A review states that macrolides such as azithromycin may help reduce symptoms in patients with persistent asthma, as it helps improve lung function. [3]

Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomized, double-blond, placebo-controlled trial.
Design Multicenter, randomized double-blind, placebo controlled parallel group trial. N= 420
Objective To test whether patients with symptomatic asthma who are on maintenance therapy would have reduced exacerbations from azithromycin
Study Groups Azithromycin (n= 213); placebo (n= 207)
Methods Patients were randomized in a 1:1 ratio, where they either received 500mg azithromycin or placebo three times a well for 48 weeks
Duration 48 weeks
Primary Outcome Measure Total number of asthma exacerbations over 48 weeks (whether moderate or severe)
Baseline Characteristics
Placebo n= 207 Azithromycin n= 213
Age (yrs) 60.01 (49.58- 67.98) 61.02 (50.62- 68.74)
Sex
Female 121 (58%) 134 (63%)
Male 86 (42%) 79 (37%)
Atopy 163 (80%) 156 (74%)
Ex-smoker 81 (39%) 80 (38%)
Pack years 7.5 (1.5- 18) 7.6 (1.75- 26)
Body-mass index (kg/m2) 28.1 (25.48- 33.11) 29.90 (25.81- 34.86)
Asthma history
Age asthma syptoms began 13 (4- 40) 17 (5- 40)
Age asthma diagnosed 20 (5- 44) 21 (5- 42)
ACQ6 score 1.55 (0.79) 1.56 (0.79)
AQLQ score 5.35 (0.89 5.36 (0.93)
Asthma history past year
Emergency room visit or hospital admission 0 (0-0) 0 (0-0)
Unscheduled doctor visits 1 (0-3) 1 (0-2)
Oral corticosteroid courses 1 (0-2) 1 (0-2)
Medications
Inhaled corticosteroid daily dose, beclomethasone equivalent
Low dose (<400 µg/day) 4 (2%) 5 (2%)
Moderate dose (400- <800 µg/day) 26 (13%) 23 (11%)
High dose (≥800 µg/day) 176 (85%) 185 (87%)
Long-acting beta agonist 205 (99%) 208 (98%)
Leukotriene modifier 6 (3%) 8 (4%)
Long-acting anti muscarinic 33 (16%) 40 (19%)
Theophylline (slow-release) 6 (3%) 7 (3%)
Oral corticosteroid 6 (3%) 8 (4%)
Pre B2 spirometry N= 205 N= 210
Pre B2 FEV1 % 73.58 (18.83) 72.33 (20.70)
Pre B2 FVC% 82.95 (15.14) 82.74 (16.06)
Pre B2 FEV1/FVC % 68.26 (11.90) 67.46 (12.90)
Sputum cell counts N= 166 N= 165
Total cell count (x106) per mL 4.05 (2.16- 8.90) 4.05 (2.34- 7.29)
Neutrophils (%) 33.25 (16.25- 55) 36.75 (17.25- 56.75)
Eosinophils (%) 2.38 (0.5- 10.5) 1.75 (0.5- 7.5)
Sputum phenotype
Eosinophilic 77 (46%) 67 (41%)
Neutrophilic 25 (15%) 21 (13%)
Paucigranulocytic 55 (33%) 70 (42%)
Mixed 9 (5%) 7 (4%)
Blood eosinophils (x109) per L 0.28 (0.16- 0.41) 0.2 (0.11- 0.40)
AQLQ= Asthma Quality of Life Questionnaire

ACQ6= Asthma Control Questionnaire

FEV1= Forced Expiratory Volume in 1s

FVC= Forced Vital Capacity

Results
Placebo Azithromycin
Primary endpoints
Asthma exacerbation rate
Number of patients analyzed 207 213
Rae estimate (95% CI) 1.86 (1.54 to 2.18) 1.07 (0.85 to 1.29
Absolute difference estimate (95% CI) -0.46 (-0.79 to -0.14)
Incidence rate ratio vs. placebo (95% CI) 0.59 (0.47 to 0.74)
                                                                                         P<0.0001
Quality of life
Number of patients analyzed 204 209
AQLQ mean score end of treatment (mean, 95% CI) 5.55 (5.40 to 5.70) 5.73 (5.58 to 5.88)
AQLQ mean score end of treatment difference vs. placebo (adj mean, 95% CI) 0.36 (0.21 to 0.52)
                                                                                          P= 0.001
Adverse Events Common Adverse Events:

Placebo (n= 207) Azithromycin (n= 213)
Nausea 20 (10%) 31 (15%)
Diarrhea 39 (19%) 72 (34%)
Abdominal pain 30 (15%) 38 (18%)
Other gastrointestinal tract 7 (3%) 7 (3%)
Headache 6 (3%) 6 (3%)
Vertigo 0 1 (<1%)
Tinnitus 2 (1%) 2 (1%)
Hearing loss 7 (9%) 6 (6%)
Abnormal liver function test 3 (1%) 1 (<1%)
Oral thrush 2 (1%) 7 (3%)
Allergy 0 1 (<1%)
Rash 10 (5%) 11 (5%)
QTc prolongation 2 (3%) 5 (5%)
Other adverse events 27 (13%) 41 (19%)
Serious Adverse Events

Placebo (n= 207) Azithromycin (n= 213)
Cardiac 8; 6 (3%) 7;5 (2%)
Gastrointestinal tract 5; 4 (2%) 5;5 (2%)
Other health issue 10;8 (4%) 9;3 (1%)
Possible infectious serious adverse event 8; 8 (4%) 5; 3 (1%)
Percentage Discontinued due to Adverse Events: Azithromycin group= 7% Placebo group= 5%
Study Author Conclusions Three times a week of 500mg azithromycin decreased asthma exacerbations and improved quality of life in symptomatic patients with no other abnormalities.

Despite azithromycin’s use in patients with asthma exacerbations who have persistent asthma, it is useful in reducing patient symptoms and improving lung function. However, the guidelines do not recommend it for this patient group. In addition, its use brings the issue of antibiotic resistance into question. Asthma is a narrowing of the airways, not an infection. As such, it does not need to be treated with an antibiotic. The guidelines should be followed when looking to treat asthma. A limitation of this article was that multiple authors either received grants from the sponsors, which could pose some bias.

References:

[1]Kew K, Undela K, Kotortsi I, Ferrara G. Macrolides for chronic asthma. Cochrane Databases of Systematic Reviews. 2015. http://www.cochrane.org/CD002997/AIRWAYS_should-macrolides-be-used-chronic-asthma. Updated September 15, 2015. Accessed August 10, 2017

[2] Managing asthmalong term. NIH. 2007. http://www.nhlbi.nih.gov/files/docs/guidelines/08_sec4_lt_ovw.pdf. Updated August 28, 2007. Accessed August 11, 2017

[3] Ferrara G, Losi M, Franco F, Corbetta L, Fabbri L, Richeldi L. Macrolides in the treatment of asthma and cystic fibrosis. ESV. 2005;99(1):1-10

[4] Gibson P, Yang I, Upham J et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. LCT. 2017;390(10095):659-668

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