Comment
Science Photo Library
Azithromycin for patients with frequent COPD exacerbations
Published Online April 16, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70087-6 See Articles page 361
340
Discovery of azithromycin in the early 1980s was a landmark achievement that was later recognised by the American Chemical Society with a Heroes of Chemistry award to the research scientists who developed it. Azithromycin is a remarkable second-generation macrolide antibiotic with many immunomodulatory properties.1 The drug accumulates efficiently in neutrophils and other phagocytes resulting in intracellular concentrations that can be more than 200 times higher than extracellular concentrations. The neutrophils can then be recruited to sites of injury or infection within minutes, as part of the innate immune response. Hence, azithromycin is able to be delivered rapidly and in high concentrations to the airways of patients with chronic obstructive pulmonary disease (COPD). Furthermore, the long plasma half-life of oral azithromycin of about 70 h allows sustained exposure of the inflamed airways to the drug.1 In The Lancet Respiratory Medicine, Sevim Uzun and colleagues2 report results from their randomised, placebo-controlled COLUMBUS trial, in which they assessed the effects of azithromycin (500 mg three times a week) in patients with COPD with a history of three or more exacerbations in the previous year. Azithromycin treatment for 1 year resulted in a significant reduction in exacerbation rate versus placebo (0·58, 95% CI 0·42–0·79; p=0·001) and increased the median time to first exacerbation by 71 days (130 days [95% CI 28–232] vs 59 days [95% CI 31–87]; p=0·001). No significant effects on lung function, hospital admission, or overall health-related quality of life were noted. The effect of azithromycin on exacerbations was in line with findings from a meta-analysis of studies about prophylactic antibiotic treatment for COPD, which showed a 27% relative reduction in exacerbation rates with macrolide treatment.3 However, the COLUMBUS study differed from previous studies in one important aspect—all patients enrolled in the study were frequent exacerbators. Frequent COPD exacerbations are associated with impaired quality of life, disease progression, and increased mortality,4 and patients with frequent exacerbations are now recognised as a distinct and
important phenotype.5 In the ECLIPSE study, patients with frequent exacerbations were defined as having two or more exacerbations a year.6 This frequent exacerbation phenotype was fairly stable over 3 years and the best predictor of future exacerbations was a history of exacerbations in the previous year. The COLUMBUS study targeted prolonged azithromycin treatment at patients with frequent exacerbations (three or more a year). These patients were highly likely to have a further exacerbation and only 7% of those in the control group did not have an exacerbation during the study. Therefore, a strategy of limiting treatment to patients with three or more exacerbations a year is likely to result in fewer patients being exposed to prolonged macrolide treatment unnecessarily, and a reduced risk of inducing macrolide-resistant organisms. Antimicrobial resistance is a great concern and high rates of macrolide resistance in community populations are strongly linked to the use of macrolides by individuals and communities.7 The unrestricted use of long-term macrolide treatment for a common disorder such as COPD would have a major effect on development of macrolide-resistance in the community. However, the risk of macrolideresistant organisms to an individual is not clear, and adverse events directly related to macrolide resistance have not been reported in clinical trials of macrolide treatment in patients with COPD, cystic fibrosis, or non-cystic-fibrosis bronchiectasis. Azithromycin treatment is well-tolerated and although gastrointestinal adverse events are increased, they are generally mild. Hearing impairment8 and cardiovascular toxic effects9 are potentially important adverse events that were not addressed in the COLUMBUS study and require vigilance, especially if given to elderly patients with comorbidities. A strength of the COLUMBUS study was the exclusion of patients with bronchiectasis by CT scanning. However, only five (1%) of 433 patients screened for eligibility had coexisting bronchiectasis, whereas the prevalence of radiological bronchiectasis in patients with COPD in other studies varied from 4% in the ECLIPSE cohort10 to 58% in Martinez-Garcia and colleagues’ study.11 Further studies are needed www.thelancet.com/respiratory Vol 2 May 2014
Comment
to assess the prevalence and clinical importance of coexisting COPD and bronchiectasis. Another approach to reducing the risk of antimicrobial resistance is to shorten the duration of macrolide treatment. A post-hoc analysis of the COLUMBUS data showed that patients in the azithromycin group were significantly more likely to remain free of exacerbations after 6 months of treatment than were those in the placebo group. Whether the beneficial effects of azithromycin also extend beyond the treatment period, as noted in patients with non-cystic-fibrosis bronchiectasis,12 also warrants further study. Azithromycin treatment in patients with COPD is effective for prevention of pulmonary exacerbations, with the phenotype of frequent exacerbators showing the most benefit. In the COLUMBUS study, the number needed to treat to prevent one patient from exacerbating was five. The decision to treat with prolonged macrolide antibiotic treatment is affected by several important factors including efficacy, development of antimicrobial resistance, prevalence of the disorder, and adverse events. Do the beneficial effects of macrolide treatment for patients with COPD outweigh the risks to the community? This question remains a dilemma at present, but it seems sensible, in our opinion, to minimise the risk to the community by limiting macrolide treatment to patients who have three or more exacerbations a year.
*Conroy Wong, Samantha Herath Counties Manukau District Health Board, Department of Respiratory Medicine, Middlemore Hospital, Otahuhu, Auckland 2025, New Zealand (CW); and McGill University, Department of Respiratory Medicine, Montreal Chest Institute, Montreal, Canada (SH) [email protected] We declare that we have no competing interests. 1
2
3.
4 5
6 7
8 9 10 11 12
Parnham MJ, Haber VE, Giamarellos-Bourboulis EJ, Perletti G, Verleden GM, Vos R. Azithromycin: mechanisms of action and their relevance for clinical applications. Pharmacol Ther 2014; published online March 11. DOI:10.1016/j.pharmthera.2014.03.003. Uzun S, Djamin RS, Kluytmans JAJW, et al. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2014; published online April 16. http://dx.doi.org/10.1016/S2213-2600(14)70019-0. Herath SC, Poole P. Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev 2013; 11: CD009764. Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet 2007; 370: 786–96. Han MK, Agusti A, Calverley PM, et al. Chronic obstructive pulmonary disease phenotypes: the future of COPD. Am J Respir Crit Care Med 2010; 182: 598–604. Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 2010; 363: 1128–38. Serisier DJ. Risks of population antimicrobial resistance associated with chronic macrolide use for inflammatory airway diseases. Lancet Respir Med 2013; 1: 262–74. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011; 365: 689–98. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012; 366: 1881–90. Agusti A, Calverley PM, Celli B, et al. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res 2010; 11: 122. Martinez-Garcia MA, Soler-Cataluna JJ, Donat Sanz Y, et al. Factors associated with bronchiectasis in patients with COPD. Chest 2011; 140: 1130–37. Wong C, Jayaram L, Karalus N, et al. Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet 2012; 380: 660–67.
As recently as 15 years ago, critical illnesses such as severe sepsis and acute respiratory distress syndrome were regarded as acutely life-threatening events that resulted in no long-term problems for those patients who were lucky enough to survive. Within this framework, physicians strived to reduce the case fatality rate. Investigators dutifully reported short-term mortality rates in clinical trials, and congratulated themselves on decreasing in-hospital mortality for these two disorders.1,2 However, as the number of survivors of critical illness grew, it became clear that something was not right. Survivors were not the same after critical illness. Rather, they had new weaknesses, cognitive impairment, www.thelancet.com/respiratory Vol 2 May 2014
depression, and early death. The consequences of critical illness have now become so widely acknowledged that they have their own name, post-intensive care syndrome.3 The growing recognition of the burdens associated with survival from critical illness has spurred several new questions. What factors are most responsible for long-term outcomes? To what extent does the acute illness itself or the treatment received during or after critical illness affect outcomes? Do some problems precede critical illness but go unrecognised until intensive care—a time of decreased reserve and increased scrutiny? And, most importantly, what are the best ways to prevent or treat the common burdens faced by survivors of critical illness?
A Benoist/Science Photo Library
Somatic symptoms in survivors of critical illness
Published Online April 7, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70071-2 See Articles page 369
341
Science Photo Library
Azithromycin for patients with frequent COPD exacerbations
Published Online April 16, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70087-6 See Articles page 361
340
Discovery of azithromycin in the early 1980s was a landmark achievement that was later recognised by the American Chemical Society with a Heroes of Chemistry award to the research scientists who developed it. Azithromycin is a remarkable second-generation macrolide antibiotic with many immunomodulatory properties.1 The drug accumulates efficiently in neutrophils and other phagocytes resulting in intracellular concentrations that can be more than 200 times higher than extracellular concentrations. The neutrophils can then be recruited to sites of injury or infection within minutes, as part of the innate immune response. Hence, azithromycin is able to be delivered rapidly and in high concentrations to the airways of patients with chronic obstructive pulmonary disease (COPD). Furthermore, the long plasma half-life of oral azithromycin of about 70 h allows sustained exposure of the inflamed airways to the drug.1 In The Lancet Respiratory Medicine, Sevim Uzun and colleagues2 report results from their randomised, placebo-controlled COLUMBUS trial, in which they assessed the effects of azithromycin (500 mg three times a week) in patients with COPD with a history of three or more exacerbations in the previous year. Azithromycin treatment for 1 year resulted in a significant reduction in exacerbation rate versus placebo (0·58, 95% CI 0·42–0·79; p=0·001) and increased the median time to first exacerbation by 71 days (130 days [95% CI 28–232] vs 59 days [95% CI 31–87]; p=0·001). No significant effects on lung function, hospital admission, or overall health-related quality of life were noted. The effect of azithromycin on exacerbations was in line with findings from a meta-analysis of studies about prophylactic antibiotic treatment for COPD, which showed a 27% relative reduction in exacerbation rates with macrolide treatment.3 However, the COLUMBUS study differed from previous studies in one important aspect—all patients enrolled in the study were frequent exacerbators. Frequent COPD exacerbations are associated with impaired quality of life, disease progression, and increased mortality,4 and patients with frequent exacerbations are now recognised as a distinct and
important phenotype.5 In the ECLIPSE study, patients with frequent exacerbations were defined as having two or more exacerbations a year.6 This frequent exacerbation phenotype was fairly stable over 3 years and the best predictor of future exacerbations was a history of exacerbations in the previous year. The COLUMBUS study targeted prolonged azithromycin treatment at patients with frequent exacerbations (three or more a year). These patients were highly likely to have a further exacerbation and only 7% of those in the control group did not have an exacerbation during the study. Therefore, a strategy of limiting treatment to patients with three or more exacerbations a year is likely to result in fewer patients being exposed to prolonged macrolide treatment unnecessarily, and a reduced risk of inducing macrolide-resistant organisms. Antimicrobial resistance is a great concern and high rates of macrolide resistance in community populations are strongly linked to the use of macrolides by individuals and communities.7 The unrestricted use of long-term macrolide treatment for a common disorder such as COPD would have a major effect on development of macrolide-resistance in the community. However, the risk of macrolideresistant organisms to an individual is not clear, and adverse events directly related to macrolide resistance have not been reported in clinical trials of macrolide treatment in patients with COPD, cystic fibrosis, or non-cystic-fibrosis bronchiectasis. Azithromycin treatment is well-tolerated and although gastrointestinal adverse events are increased, they are generally mild. Hearing impairment8 and cardiovascular toxic effects9 are potentially important adverse events that were not addressed in the COLUMBUS study and require vigilance, especially if given to elderly patients with comorbidities. A strength of the COLUMBUS study was the exclusion of patients with bronchiectasis by CT scanning. However, only five (1%) of 433 patients screened for eligibility had coexisting bronchiectasis, whereas the prevalence of radiological bronchiectasis in patients with COPD in other studies varied from 4% in the ECLIPSE cohort10 to 58% in Martinez-Garcia and colleagues’ study.11 Further studies are needed www.thelancet.com/respiratory Vol 2 May 2014
Comment
to assess the prevalence and clinical importance of coexisting COPD and bronchiectasis. Another approach to reducing the risk of antimicrobial resistance is to shorten the duration of macrolide treatment. A post-hoc analysis of the COLUMBUS data showed that patients in the azithromycin group were significantly more likely to remain free of exacerbations after 6 months of treatment than were those in the placebo group. Whether the beneficial effects of azithromycin also extend beyond the treatment period, as noted in patients with non-cystic-fibrosis bronchiectasis,12 also warrants further study. Azithromycin treatment in patients with COPD is effective for prevention of pulmonary exacerbations, with the phenotype of frequent exacerbators showing the most benefit. In the COLUMBUS study, the number needed to treat to prevent one patient from exacerbating was five. The decision to treat with prolonged macrolide antibiotic treatment is affected by several important factors including efficacy, development of antimicrobial resistance, prevalence of the disorder, and adverse events. Do the beneficial effects of macrolide treatment for patients with COPD outweigh the risks to the community? This question remains a dilemma at present, but it seems sensible, in our opinion, to minimise the risk to the community by limiting macrolide treatment to patients who have three or more exacerbations a year.
*Conroy Wong, Samantha Herath Counties Manukau District Health Board, Department of Respiratory Medicine, Middlemore Hospital, Otahuhu, Auckland 2025, New Zealand (CW); and McGill University, Department of Respiratory Medicine, Montreal Chest Institute, Montreal, Canada (SH) [email protected] We declare that we have no competing interests. 1
2
3.
4 5
6 7
8 9 10 11 12
Parnham MJ, Haber VE, Giamarellos-Bourboulis EJ, Perletti G, Verleden GM, Vos R. Azithromycin: mechanisms of action and their relevance for clinical applications. Pharmacol Ther 2014; published online March 11. DOI:10.1016/j.pharmthera.2014.03.003. Uzun S, Djamin RS, Kluytmans JAJW, et al. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2014; published online April 16. http://dx.doi.org/10.1016/S2213-2600(14)70019-0. Herath SC, Poole P. Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev 2013; 11: CD009764. Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet 2007; 370: 786–96. Han MK, Agusti A, Calverley PM, et al. Chronic obstructive pulmonary disease phenotypes: the future of COPD. Am J Respir Crit Care Med 2010; 182: 598–604. Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 2010; 363: 1128–38. Serisier DJ. Risks of population antimicrobial resistance associated with chronic macrolide use for inflammatory airway diseases. Lancet Respir Med 2013; 1: 262–74. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011; 365: 689–98. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012; 366: 1881–90. Agusti A, Calverley PM, Celli B, et al. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res 2010; 11: 122. Martinez-Garcia MA, Soler-Cataluna JJ, Donat Sanz Y, et al. Factors associated with bronchiectasis in patients with COPD. Chest 2011; 140: 1130–37. Wong C, Jayaram L, Karalus N, et al. Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet 2012; 380: 660–67.
As recently as 15 years ago, critical illnesses such as severe sepsis and acute respiratory distress syndrome were regarded as acutely life-threatening events that resulted in no long-term problems for those patients who were lucky enough to survive. Within this framework, physicians strived to reduce the case fatality rate. Investigators dutifully reported short-term mortality rates in clinical trials, and congratulated themselves on decreasing in-hospital mortality for these two disorders.1,2 However, as the number of survivors of critical illness grew, it became clear that something was not right. Survivors were not the same after critical illness. Rather, they had new weaknesses, cognitive impairment, www.thelancet.com/respiratory Vol 2 May 2014
depression, and early death. The consequences of critical illness have now become so widely acknowledged that they have their own name, post-intensive care syndrome.3 The growing recognition of the burdens associated with survival from critical illness has spurred several new questions. What factors are most responsible for long-term outcomes? To what extent does the acute illness itself or the treatment received during or after critical illness affect outcomes? Do some problems precede critical illness but go unrecognised until intensive care—a time of decreased reserve and increased scrutiny? And, most importantly, what are the best ways to prevent or treat the common burdens faced by survivors of critical illness?
A Benoist/Science Photo Library
Somatic symptoms in survivors of critical illness
Published Online April 7, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70071-2 See Articles page 369
341
