REVIEW URRENT C OPINION
Severe acute exacerbations of chronic obstructive pulmonary disease: does the dosage of corticosteroids and type of antibiotic matter? Tyree H. Kiser a and R. William Vandivier b
Purpose of review Severe acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are significant events that result in substantial morbidity and mortality. Antibiotic therapy and systemic corticosteroids are important treatments for patients with severe AECOPD. The objective of this review is to summarize the most recent evidence concerning antibiotic and corticosteroid therapy, with a focused evaluation on the contribution of antibiotic type and corticosteroid dosage on patient outcomes. Recent findings Macrolides should be considered the antibiotic of choice for prevention of AECOPD in patients who qualify for therapy. Macrolides, fluoroquinolones, and beta-lactams are all reasonable treatment options for severe AECOPD and the decision to use one over the other should be based upon patient characteristics and institutional or regional antimicrobial susceptibility patterns. The best available evidence now suggests that higher-dose corticosteroids are not superior to treatment with lower-dose corticosteroids in patients with severe AECOPD. Additionally, longer durations of systemic corticosteroid therapy do not improve clinical outcomes. Summary Several antibiotic options are efficacious in the management of severe AECOPD and drug selection should be patient-specific. Recent studies suggest that lower dosages and shorter durations of corticosteroid treatment may be prudent. Keywords acute exacerbation, antibiotic therapy, COPD, dosage, systemic corticosteroids
INTRODUCTION Moderate-to-severe chronic obstructive pulmonary disease (COPD) affects more than 65 million people worldwide and accounts for greater than 3 million deaths annually [1]. The mortality rates associated with COPD are increasing and the World Health Organization estimates that COPD will become the third leading cause of death by 2030 [1]. In the United States alone, up to 24 million people may have COPD and it costs $50 billion per year to treat [2,3]. Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is defined as an acute event characterized by a worsening of respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication [4]. AECOPDs are among the most significant events in COPD disease because they result in alterations of lung function that may take several weeks to www.co-pulmonarymedicine.com
recover, reduce patient quality of life and ultimately accelerate the decline of lung function [2,4–7]. AECOPD is a significant indicator of poor prognosis, and patients with three or more exacerbations in a year are at the greatest mortality risk [8]. The severity of AECOPD varies and can range from mild to life-threatening. Patients with severe a
Department of Clinical Pharmacy and bDepartment of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, COPD Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA Correspondence to Tyree H. Kiser, PharmD, FCCM, FCCP, BCPS, Associate Professor, Department of Clinical Pharmacy, University of Colorado Anschutz Medical Campus, 12850 E Montview Blvd, Campus Box C238, Pharmacy and Pharmaceutical Sciences Building, Aurora CO 80045, USA. Tel: +1 303 724 2883; fax: +1 303 724 0979; e-mail: [email protected] Curr Opin Pulm Med 2015, 21:142–148 DOI:10.1097/MCP.0000000000000142 Volume 21 Number 2 March 2015
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Corticosteroids and antibiotics in severe AECOPD Kiser and Vandivier
KEY POINTS Azithromycin is the antibiotic with the best evidence for preventing severe AECOPD. The antibiotic choice for treatment of AECOPD is complex and should consider patient characteristics and antimicrobial susceptibility patterns. High-dose corticosteroids (>80 mg/day of prednisone equivalents) are not associated with improved efficacy compared with lower doses and may increase the risk for adverse events. Continuing corticosteroids beyond 5–7 days does not improve treatment success or reduce re-exacerbations.
and Enterobacteriaceae [17,18]. Treatment with antibiotics may effectively decrease the bacterial load and the risk of progression to pneumonia. Additionally, resolution of airway inflammation via bacterial eradication from the airways is important for exacerbation resolution [19]. The impact of antibiotics on treatment failure varies depending on disease severity, with the magnitude of benefit increasing with worsening AECOPD severity. Patients with severe AECOPD requiring hospital treatment [relative risk (RR) 0.77; 95% confidence interval (CI) 0.65–0.91] and those admitted to the intensive care unit (RR 0.19; 95% CI 0.08–0.45) are more likely to benefit from early antimicrobial therapy than patients with mild-to-moderate exacerbations (RR 0.80; 95% CI 0.63–1.01) [20,21 ]. The most commonly utilized antibiotics for the treatment of severe AECOPD are macrolides, fluoroquinolones, and beta-lactams (e.g., aminopenicillin with clavulanic acid or third-generation cephalosporins). The major differences in these antibiotic choices surround their antimicrobial activity against infecting pathogens and potentially beneficial pleotropic effects. Macrolide antibiotics have anti-inflammatory and immunomodulatory effects in addition to their antibacterial activity [22]. Additionally, macrolide antibiotics may increase the response to corticosteroids by improving the recruitment of histone deacetylase 2 (HDAC-2), which is a major contributor to the inflammatory gene repression produced by corticosteroids in patients with COPD [23]. Respiratory fluoroquinolones have a broader spectrum of activity and a greater likelihood of covering more resistant pathogens than macrolides. Beta-lactam antibiotics, particularly third-generation cephalosporins, have greater activity against macrolideresistant Streptococcus pneumoniae, but lack activity against atypical pathogens. The antibiotic choice for treatment of AECOPD is complex and encompasses many factors. At a minimum, previous antibiotic use, patient risk factors (e.g., age, type of residence, comorbidities, severity of airflow limitation, previous intubation, long term steroid treatment, and frequency of exacerbations), AECOPD severity, and regional prevalence of microorganisms have to be considered. Clinical efficacy and microbiological response differences between antibiotic choices would help guide therapy; however, the majority of recent prospective studies have included less severely ill outpatients with AECOPD and have involved a noninferiority or primary safety outcome design [24–28]. The preponderance of recent evidence for severe AECOPD has focused on comparisons of macrolides, fluoroquinolones, and cephalosporins evaluated in large observational &
AECOPD have respiratory failure with hypoxemia requiring hospitalization [9]. These exacerbations are responsible for more than 715 000 hospitalizations annually in the United States, and the cost of treating patients with AECOPD is 10-fold greater than in COPD patients who do not experience exacerbations [3,10]. Severe AECOPD is associated with significant morbidity, and in-hospital mortality rates approach 15–30% in patients requiring mechanical ventilation [4,11,12,13 ,14]. Therefore, it is critically important to provide treatment interventions that can improve outcomes in patients with AECOPD. In addition to oxygen and shortacting bronchodilators, systemic corticosteroids and antibiotics are part of the preferred pharmacotherapy treatment approaches for patients hospitalized with AECOPD. The objective of this review is to summarize the most recent evidence regarding antibiotic and corticosteroid therapy in patients with severe AECOPD. This review specifically aims to elucidate whether the type of antibiotic utilized and the corticosteroid dosage prescribed impact clinically relevant patient outcomes. &
ANTIBIOTIC THERAPY Approximately eight out of every ten AECOPD events are caused by microbial pathogens, including bacteria, viruses, and fungi [15–17]. Bacterial infections account for over half of the microbial-induced exacerbations. Therefore, antibacterials are generally recommended in patients with dyspnea and increased sputum volume or purulence [4,9]. Common organisms associated with exacerbations include Streptococcus pneumoniae, Hemophilus influenzae, Moraxella catarrhalis, and atypical bacteria. However, patients with certain risk factors and those with more severe exacerbations can have more resistant bacteria including Pseudomonas aeruginosa
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cohorts (Table 1) [20,29]. An observational study of 19 608 hospitalized AECOPD patients treated with either a macrolide or fluoroquinolone demonstrated a lower associated risk of treatment failure with macrolide therapy (6.8 versus 8.1%); however, this finding was no longer significant in the multivariate analysis [odds ratio (OR) 0.89; 95% CI 0.78–1.01] [29]. No differences were observed between therapies for hospital length of stay or costs. Macrolide therapy was associated with a lower incidence of late mechanical ventilation and antibiotic-associated diarrhea when compared with fluoroquinolones [29]. A more recent observational evaluation of 53 900 patients compared fluoroquinolone therapy with macrolide therapy with or without a cephalosporin. The type of antibiotic prescribed had no effect on in-hospital mortality. However, patients treated with fluoroquinolones had higher 30-day readmission rates. Patients treated with macrolides had shorter hospital length of stay, lower costs, decreased incidence of diarrhea, and fewer re-admissions for Clostridium difficile colitis [21 ]. The results of available studies in severe AECOPD do not provide conclusive evidence for a superior efficacy advantage based upon the choice &
of a macrolide, fluoroquinolone, or beta-lactam antibiotic. Therefore, all three antibiotic classes remain a reasonable option for patients with severe AECOPD. The empiric choice of antibiotic still remains dependent on patterns of antimicrobial resistance and clinical characteristics of the patients being treated. Although there has not been clearly demonstrated superiority with one antibiotic over another, the potential for reduced adverse effects, C. difficile infection, and reduction in 30-day re-admission rates make the use of macrolides an intriguing choice for AECOPD patients that are not already chronically receiving azithromycin and those that do not have significant risk factors for macrolideresistant pathogens. The use of a beta-lactam with high activity against Streptococcus pneumoniae should be considered in these patients in which azithromycin monotherapy may be ineffective. Although an equally effective choice, given the emergence of fluoroquinolone resistance in a variety of pathogens, it may be prudent to reserve the use of respiratory fluoroquinolones to patients with betalactam allergies or those who have risk factors for infections with pathogens likely to be resistant to macrolides or beta-lactams.
Table 1. Evaluations of antibiotic choice and outcomes for patients with severe AECOPD Reference
Design
Treatment Groups
Outcomes
Results
Group 1
1o Outcome
1o Outcome
2 groups N ¼ 19 608 Inclusion: AECOPD Exclusion: other infections
Macrolide therapy Group 2 Fluoroquinolone therapy
Treatment failure: Death COPD readmission Mechanical ventilation 2o Outcomes Hospital cost Hospital LOS Allergic reactions Antibiotic-associated diarrhea
Macrolides were associated with lower treatment failure in the univariate analysis, but this finding was not significant in the multivariate analysis 2o Outcomes No difference in cost or LOS Fluoroquinolones associated with higher rates of antibiotic-associated diarrhea and mechanical ventilation
Observational
Group 1:
1o Outcome
1o Outcome
2 groups N ¼ 53 900 Inclusion: AECOPD Exclusion: ICU, ventilation, other infections
Antibiotic therapy on day 1 or 2 Group 2: No antibiotic therapy on day 1 or 2 Subgroups: Fluoroquinolone versus macrolide Fluoroquinolone versus macrolide þ cephalosporin Macrolide versus macrolide þ cephalosporin
In-hospital mortality 2o Outcomes Late ventilation Hospital readmission Hospital LOS Hospital cost Allergic reactions Antibiotic-associated diarrhea
Antibiotics reduced in-hospital mortality No differences in in-hospital mortality were observed between antibiotic subgroups 2o Outcomes Fluoroquinolones associated with higher 30-day re-admissions Macrolides associated with lower costs, LOS, diarrhea, and readmission for C. difficile colitis
Rothberg et al. [29] Observational
Stefan et al. [21 ] &
AECOPD, acute exacerbation of chronic obstructive pulmonary disease; LOS, length of stay.
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Corticosteroids and antibiotics in severe AECOPD Kiser and Vandivier
The use of antimicrobials for prevention of AECOPD is intriguing because many patients with COPD may be colonized with potentially pathogenic bacteria leading to chronic bronchial infection [30]. This presence of bacterial colonization is linked to airway inflammation and macrolide therapy is effective at reducing the associated neutrophillic bronchitis [31]. Azithromycin 250 mg daily has demonstrated efficacy in preventing AECOPD by a rate of approximately 0.4 exacerbations per patient year [32]. Azithromycin appears most effective at preventing severe AECOPD that requires both antibiotic and steroid treatment. Additionally, there may be a particular benefit in elderly patients and those with lower Global Initiative for Chronic Obstructive Lung Disease stages. Interestingly, azithromycin may have a reduced treatment effect in active smokers [33 ]. The most prominent adverse effects associated with utilizing azithromycin 250 mg daily for an extended duration are a largely reversible ototoxicity and QTc prolongation leading to a possible increase in cardiac deaths [32,34]. Given the lack of evidence for other antimicrobials, azithromycin is the drug of choice for prevention of AECOPD in patients that meet criteria for therapy [35]. However, some controversies surrounding azithromycin use still remain. Given the pharmacokinetics of azithromycin, which yields high lung concentrations and extended half-lives in tissues, some argue that 250 mg three times weekly would provide adequate prevention of exacerbations and reduce the risk of adverse effects [36]. Although theoretical, the evidence for thrice weekly azithromycin is marginal and it is unknown whether this strategy would maintain a favorable benefit to risk ratio compared with daily therapy [35]. Therefore, this strategy should be reserved for patients who are intolerant to daily therapy. Additionally, whether the benefit of azithromycin prophylaxis is maintained beyond 12 months is unknown. At a minimum, patients should be evaluated at the end of 12 months to ascertain the success of therapy and the emergence of macrolide-resistant bacteria, to determine whether continued prophylactic therapy is likely to be beneficial. &
SYSTEMIC CORTICOSTEROID THERAPY Systemic corticosteroids are a cornerstone of treatment for patients with severe AECOPD. A recent evaluation of nine studies (n ¼ 917) by the Cochrane group determined that, in comparison with placebo, the use of corticosteroids was associated with a more than 50% reduction in treatment failure (OR 0.48; 95% CI 0.35–0.67), making it only necessary to treat nine people to avoid a treatment failure [37 ]. &&
Reductions in 30-day relapse rates were also observed (hazard ratio 0.78; 95% CI 0.63–0.97). Hospitalized patients treated with corticosteroids had shorter hospital lengths of stay (1.22 days; 95% CI 2.26 to 0.18), but corticosteroids were not associated with a reduction in 30-day mortality. Corticosteroids were not without risk, and one adverse event occurred for every six people treated (OR 2.33; 95% CI 1.59–3.43) [37 ]. The choice of systemic corticosteroid for severe AECOPD includes medications with predominant glucocorticoid effects (e.g. prednisone, prednisolone, or methylprednisolone). These options are the most studied for AECOPD and are considered preferred to other systemic corticosteroid therapies that have more mineralocorticoid effects (e.g., hydrocortisone) [38]. Several clinical studies have evaluated corticosteroids for severe AECOPD (Table 2) [12,13 ,39,40 ,41 ]. However, owing to the variety of corticosteroid dosing regimens utilized in these studies, considerable debate still exists regarding the most appropriate dose, route, and duration of corticosteroids in severe AECOPD. In patients that can tolerate oral therapy, the use of oral treatment results in similar rates of treatment failure, relapse rates, and mortality when compared with parenteral corticosteroid therapy [37 ,42]. However, given the severity of exacerbations in patients admitted to the hospital or intensive care unit, many physicians still choose to initiate parenteral corticosteroid therapy and transition to oral therapy later in the hospitalization [13 ,41 ,42]. Initial corticosteroid dosages in patients with severe AECOPD have ranged from prednisone 40 mg daily [41 ] to methylprednisolone 500 mg daily (125 mg every 6 h) [39]. An evaluation of patients admitted to the intensive care unit for AECOPD from 2003 to 2008 demonstrated that in US hospitals, there is an almost universal preference for initiating parenteral therapy with two-thirds of patients receiving greater than 240 mg of methylprednisolone daily [13 ]. The use of high-dose methylprednisolone is frequently justified by the severity of exacerbation and the resulting morbidity and mortality. Corticosteroid resistance and reduced clinical response in these patients are additional concerns [23]. It is also likely that the results of the Department of Veteran’s Affairs Cooperative Study published in 1999 (methylprednisolone 125 mg intravenous every 6 h) drove the dosing practices over much of the last decade [39]. However, studies published after 2008 have questioned the need to use such high doses because despite the wide range of corticosteroid dosages utilized, the major clinical outcome results are not substantially different among most recent studies [12,39,41 ]. &&
&
&
&&
&&
&
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&&
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&&
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Design
Treatment groups
Outcomes
Results
Niewoehner et al. [39] RCT 3 Groups N ¼ 271 Inclusion: AECOPD Exclusion: ventilation
Group 1: Methylprednisolone 125 mg IV q6h on days 1–3 Prednisone taper on days 4–14 Group 2: Methylprednisolone 125 mg IV q6h on days 1–3 Prednisone taper on days 4–56 Group 3: Placebo
1o Outcome Treatment failure: Death Intubation COPD readmission Intensified therapy 2o Outcomes Hospital LOS Hyperglycemia
1o Outcome Both steroid regimens decreased treatment failure 2o Outcomes Steroids decreased hospital LOS Steroids increased hyperglycemia
Alia et al. [12]
RCT 2 Groups N ¼ 83 Inclusion: AECOPD, ventilation
Group 1: Methylprednisolone 0.5 mg/kg IV q6h on days 1–3 Methylprednisolone taper on days 4–10 Group 2: Placebo
1o Outcome Ventilation time ICU LOS Noninvasive ventilation failure 2o Outcomes Hospital LOS Hospital mortality Hyperglycemia
1o Outcome Steroids decreased ventilation time Steroids decreased noninvasive ventilation failure 2o Outcomes Steroids did not alter: Hospital LOS Hospital mortality Steroids increased hyperglycemia
Leuppi et al. [41 ]
RCT 2 Groups Noninferiority N ¼ 256 Inclusion: AECOPD
Group 1: Prednisone 40 mg daily 5 days Group 2: Prednisone 40 mg daily 14 days
1o Outcome Time to next AECOPD within 6 months 2o Outcomes Mortality Hospital LOS Need for ventilation Open-label steroids Hyperglycemia
1o Outcome No effect on time to next AECOPD 2o Outcomes No effect on Mortality Ventilation Open-label steroids Hyperglycemia Short-course steroids decreased hospital LOS
Abroug et al. [40 ]
RCT 2 Groups N ¼ 217 Inclusion: AECOPD, ventilation
Group 1: Prednisone 1 mg/kg/ day until discharge or 10 days Group 2: Usual care/no steroids
1o Outcome ICU mortality 2o Outcomes Ventilation time ICU LOS Noninvasive ventilation failure Hyperglycemia
1o Outcome Steroids did not alter ICU mortality 2o Outcomes Steroids did not alter Ventilation time ICU LOS Noninvasive failure Steroids increased hyperglycemia
Kiser et al. [13 ]
Observational 2 Groups N ¼ 17 239 Inclusion: AECOPD, ICU
Group 1: High dose: >240 mg/ day in methylprednisolone equivalent within first 48 h Group 2: Lower dose: 240 mg/ day in methylprednisolone equivalent within first 48 h
1o Outcome Hospital mortality 2o Outcomes Hospital LOS ICU LOS Total cost Hyperglycemia
1o Outcome Lower-dose steroids were not associated with decreased mortality 2o Outcomes Lower-dose steroids associated with: Lower hospital LOS Lower ICU LOS Lower total cost Increased hyperglycemia
&&
&
&
AECOPD, acute exacerbation of chronic obstructive pulmonary disease; LOS, length of stay; RCT, randomized controlled trial.
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Corticosteroids and antibiotics in severe AECOPD Kiser and Vandivier
A recent meta-analysis of 12 studies involving 1172 patients with AECOPD was unable to demonstrate any clinical benefit to initiating systemic corticosteroids at a dose 80 mg/day or higher of prednisone equivalents [43]. In the most critically ill patients requiring ventilator support, initial methylprednisolone dosages of 0.5 mg/kg every 6 h were sufficient for achieving improved clinical outcomes (decreased length of stay, decreased length of ventilation, and lower failure rates for noninvasive ventilation) [12]. In addition to efficacy endpoints, adverse effects of systemic corticosteroids in patients with AECOPD can be significant and are dose-related and durationrelated. The predominant adverse effect is hyperglycemia, but other potentially significant effects include skeletal muscle weakness or myopathy, neurological effects (e.g., anxiety, delirium), infection, hypertension, and gastrointestinal bleed. The mechanisms behind corticosteroid function make it difficult to optimize beneficial effects while minimizing adverse events in patients with AECOPD. There appears to be dissociation between repression of inflammatory genes and activation of off-target genes, which could ultimately result in amplified risk of adverse effects without additional clinical benefits as steroid doses are increased [44,45]. A recent evaluation of high-dose versus lower-dose corticosteroids in severe AECOPD found associations with increased rates of hyperglycemia, need for insulin therapy, and increased rates of invasive fungal infections in patients treated with more than 240 mg/day of methylprednisolone [13 ]. Similarly, an open-label placebo-controlled prospective study of AECOPD patients requiring ventilatory support highlights the increased risk of hyperglycemia that requires initiation or alteration of insulin therapy, and questions whether the risks of steroids outweigh the potential beneficial effects on patient outcomes [40 ]. Taking into account the efficacy and safety conclusions from the available studies, the majority of patients with severe AECOPD should be managed with systemic corticosteroid dosages of 40–80 mg/ day (prednisone equivalents). Dosages greater than 2 mg/kg/day do not appear to be clinically indicated, even in patients requiring mechanical ventilation. The duration of corticosteroid treatment in clinical trials has ranged from 5 days to 8 weeks [39,41 ]. Similar to the trends with corticosteroid dosage, more recent evidence has suggested that a change in clinical practice patterns regarding the duration of corticosteroid therapy utilized for severe AECOPD should be considered. A Cochrane review evaluating studies of 7 days or less compared with greater than 7 days of therapy was unable to demonstrate any difference in treatment failure rates &
&
&&
based upon duration of corticosteroid therapy (OR 0.82; 95% CI 0.24–2.79) [46]. The REDUCE trial, which evaluated prednisone 40 mg/day for 5 days versus 14 days, demonstrated that short-term therapy was noninferior to a longer duration (OR 0.95; 90% CI 0.68–1.26) [41 ]. There were no differences in time to death, re-exacerbations, or recovery of lung function based upon treatment duration. Patients receiving only 5 days of therapy had shorter hospital length of stay (median 8 versus 9 days, P ¼ 0.04) [41 ]. This evidence clearly suggests that there is no additional benefit to treating patients for greater than 5–7 days of systemic corticosteroid therapy during an AECOPD. &&
&&
CONCLUSION Severe AECOPD is an especially concerning event that results in significant morbidity and mortality. Antibiotic therapy is an important intervention for patients with severe AECOPD and increased sputum production or purulence, as they reduce treatment failure rates. Macrolides, fluoroquinolones, and beta-lactams are all reasonable treatment choices and the decision to use one over the other should be based upon patient characteristics and institutional or regional antimicrobial susceptibility patterns. Macrolides should be considered the antibiotic of choice for prevention of AECOPD in patients that qualify for therapy. Recent data also suggest that macrolide-based treatment regimens for AECOPD may have beneficial effects on morbidity, readmission rates, and adverse events compared with other antibiotics; however, more rigorous prospective studies are needed before definitive conclusions can be made. The best available evidence now suggests that higher-dose corticosteroids are not superior to treatment with lower-dose corticosteroids in patients with severe AECOPD. Additionally, longer durations of systemic corticosteroid therapy do not improve clinical outcomes. Based upon the current available evidence, a corticosteroid dose of 40–80 mg/day (prednisone equivalents) for 5–7 days may provide the best approach to managing severe AECOPD in the majority of patients. Acknowledgements None. Financial support and sponsorship This work is unfunded. Conflicts of interest The authors report no conflicts of interest related to this manuscript.
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This study provides further analysis of the large prospective study of azithromycin for prevention of AECOPD and identifies patient and disease characteristics that are associated with response to azithromycin therapy. 34. Ray WA, Murray KT, Hall K, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012; 366:1881–1890. 35. Donath E, Chaudhry A, Hernandez-Aya LF, Lit L. A meta-analysis on the prophylactic use of macrolide antibiotics for the prevention of disease exacerbations in patients with chronic obstructive pulmonary disease. Respir Med 2013; 107:1385–1392. 36. Foulds G, Shepard RM, Johnson RB. The pharmacokinetics of azithromycin in human serum and tissues. J Antimicrob Chemother 1990; 25 (Suppl A):73– 82. 37. Walters JA, Tan DJ, White CJ, et al. Systemic corticosteroids for acute && exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2014; 9:CD001288. This publication critically evaluates and synthesizes the available evidence to support the use of systemic corticosteroids for AECOPD. The analysis describes the magnitude of both beneficial and harmful effects of corticosteroid therapy. 38. Aggarwal P, Wig N, Bhoi S. Efficacy of two corticosteroid regimens in acute exacerbation of chronic obstructive pulmonary disease. Int J Tuberc Lung Dis 2011; 15:687–692. 39. Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med 1999; 340:1941–1947. 40. Abroug F, Ouanes-Besbes L, Fkih-Hassen M, et al. Prednisone in COPD & exacerbation requiring ventilatory support: an open-label randomised evaluation. Eur Respir J 2014; 43:717–724. This prospective open-label study evaluated prednisone 1 mg/kg/day versus placebo for up to 10 days in patients with AECOPD requiring ventilator support. 41. Leuppi JD, Schuetz P, Bingisser R, et al. Short-term vs conventional gluco&& corticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA 2013; 309:2223– 2231. This randomized controlled trial is the largest study to date evaluating short-course corticosteroids compared with conventional durations. 42. Lindenauer PK, Pekow PS, Lahti MC, et al. Association of corticosteroid dose and route of administration with risk of treatment failure in acute exacerbation of chronic obstructive pulmonary disease. JAMA 2010; 303:2359–2367. 43. Cheng T, Gong Y, Guo Y, et al. Systemic corticosteroid for COPD exacerbations, whether the higher dose is better? A meta-analysis of randomized controlled trials. Clin Respir J 2013; 7:305–318. 44. Schacke H, Schottelius A, Docke WD, et al. Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects. Proc Natl Acad Sci U S A 2004; 101:227–232. 45. Schacke H, Docke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther 2002; 96:23–43. 46. Walters JA, Wang W, Morley C, et al. Different durations of corticosteroid therapy for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2011; 10:CD006897.
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Severe acute exacerbations of chronic obstructive pulmonary disease: does the dosage of corticosteroids and type of antibiotic matter? Tyree H. Kiser a and R. William Vandivier b
Purpose of review Severe acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are significant events that result in substantial morbidity and mortality. Antibiotic therapy and systemic corticosteroids are important treatments for patients with severe AECOPD. The objective of this review is to summarize the most recent evidence concerning antibiotic and corticosteroid therapy, with a focused evaluation on the contribution of antibiotic type and corticosteroid dosage on patient outcomes. Recent findings Macrolides should be considered the antibiotic of choice for prevention of AECOPD in patients who qualify for therapy. Macrolides, fluoroquinolones, and beta-lactams are all reasonable treatment options for severe AECOPD and the decision to use one over the other should be based upon patient characteristics and institutional or regional antimicrobial susceptibility patterns. The best available evidence now suggests that higher-dose corticosteroids are not superior to treatment with lower-dose corticosteroids in patients with severe AECOPD. Additionally, longer durations of systemic corticosteroid therapy do not improve clinical outcomes. Summary Several antibiotic options are efficacious in the management of severe AECOPD and drug selection should be patient-specific. Recent studies suggest that lower dosages and shorter durations of corticosteroid treatment may be prudent. Keywords acute exacerbation, antibiotic therapy, COPD, dosage, systemic corticosteroids
INTRODUCTION Moderate-to-severe chronic obstructive pulmonary disease (COPD) affects more than 65 million people worldwide and accounts for greater than 3 million deaths annually [1]. The mortality rates associated with COPD are increasing and the World Health Organization estimates that COPD will become the third leading cause of death by 2030 [1]. In the United States alone, up to 24 million people may have COPD and it costs $50 billion per year to treat [2,3]. Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is defined as an acute event characterized by a worsening of respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication [4]. AECOPDs are among the most significant events in COPD disease because they result in alterations of lung function that may take several weeks to www.co-pulmonarymedicine.com
recover, reduce patient quality of life and ultimately accelerate the decline of lung function [2,4–7]. AECOPD is a significant indicator of poor prognosis, and patients with three or more exacerbations in a year are at the greatest mortality risk [8]. The severity of AECOPD varies and can range from mild to life-threatening. Patients with severe a
Department of Clinical Pharmacy and bDepartment of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, COPD Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA Correspondence to Tyree H. Kiser, PharmD, FCCM, FCCP, BCPS, Associate Professor, Department of Clinical Pharmacy, University of Colorado Anschutz Medical Campus, 12850 E Montview Blvd, Campus Box C238, Pharmacy and Pharmaceutical Sciences Building, Aurora CO 80045, USA. Tel: +1 303 724 2883; fax: +1 303 724 0979; e-mail: [email protected] Curr Opin Pulm Med 2015, 21:142–148 DOI:10.1097/MCP.0000000000000142 Volume 21 Number 2 March 2015
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Corticosteroids and antibiotics in severe AECOPD Kiser and Vandivier
KEY POINTS Azithromycin is the antibiotic with the best evidence for preventing severe AECOPD. The antibiotic choice for treatment of AECOPD is complex and should consider patient characteristics and antimicrobial susceptibility patterns. High-dose corticosteroids (>80 mg/day of prednisone equivalents) are not associated with improved efficacy compared with lower doses and may increase the risk for adverse events. Continuing corticosteroids beyond 5–7 days does not improve treatment success or reduce re-exacerbations.
and Enterobacteriaceae [17,18]. Treatment with antibiotics may effectively decrease the bacterial load and the risk of progression to pneumonia. Additionally, resolution of airway inflammation via bacterial eradication from the airways is important for exacerbation resolution [19]. The impact of antibiotics on treatment failure varies depending on disease severity, with the magnitude of benefit increasing with worsening AECOPD severity. Patients with severe AECOPD requiring hospital treatment [relative risk (RR) 0.77; 95% confidence interval (CI) 0.65–0.91] and those admitted to the intensive care unit (RR 0.19; 95% CI 0.08–0.45) are more likely to benefit from early antimicrobial therapy than patients with mild-to-moderate exacerbations (RR 0.80; 95% CI 0.63–1.01) [20,21 ]. The most commonly utilized antibiotics for the treatment of severe AECOPD are macrolides, fluoroquinolones, and beta-lactams (e.g., aminopenicillin with clavulanic acid or third-generation cephalosporins). The major differences in these antibiotic choices surround their antimicrobial activity against infecting pathogens and potentially beneficial pleotropic effects. Macrolide antibiotics have anti-inflammatory and immunomodulatory effects in addition to their antibacterial activity [22]. Additionally, macrolide antibiotics may increase the response to corticosteroids by improving the recruitment of histone deacetylase 2 (HDAC-2), which is a major contributor to the inflammatory gene repression produced by corticosteroids in patients with COPD [23]. Respiratory fluoroquinolones have a broader spectrum of activity and a greater likelihood of covering more resistant pathogens than macrolides. Beta-lactam antibiotics, particularly third-generation cephalosporins, have greater activity against macrolideresistant Streptococcus pneumoniae, but lack activity against atypical pathogens. The antibiotic choice for treatment of AECOPD is complex and encompasses many factors. At a minimum, previous antibiotic use, patient risk factors (e.g., age, type of residence, comorbidities, severity of airflow limitation, previous intubation, long term steroid treatment, and frequency of exacerbations), AECOPD severity, and regional prevalence of microorganisms have to be considered. Clinical efficacy and microbiological response differences between antibiotic choices would help guide therapy; however, the majority of recent prospective studies have included less severely ill outpatients with AECOPD and have involved a noninferiority or primary safety outcome design [24–28]. The preponderance of recent evidence for severe AECOPD has focused on comparisons of macrolides, fluoroquinolones, and cephalosporins evaluated in large observational &
AECOPD have respiratory failure with hypoxemia requiring hospitalization [9]. These exacerbations are responsible for more than 715 000 hospitalizations annually in the United States, and the cost of treating patients with AECOPD is 10-fold greater than in COPD patients who do not experience exacerbations [3,10]. Severe AECOPD is associated with significant morbidity, and in-hospital mortality rates approach 15–30% in patients requiring mechanical ventilation [4,11,12,13 ,14]. Therefore, it is critically important to provide treatment interventions that can improve outcomes in patients with AECOPD. In addition to oxygen and shortacting bronchodilators, systemic corticosteroids and antibiotics are part of the preferred pharmacotherapy treatment approaches for patients hospitalized with AECOPD. The objective of this review is to summarize the most recent evidence regarding antibiotic and corticosteroid therapy in patients with severe AECOPD. This review specifically aims to elucidate whether the type of antibiotic utilized and the corticosteroid dosage prescribed impact clinically relevant patient outcomes. &
ANTIBIOTIC THERAPY Approximately eight out of every ten AECOPD events are caused by microbial pathogens, including bacteria, viruses, and fungi [15–17]. Bacterial infections account for over half of the microbial-induced exacerbations. Therefore, antibacterials are generally recommended in patients with dyspnea and increased sputum volume or purulence [4,9]. Common organisms associated with exacerbations include Streptococcus pneumoniae, Hemophilus influenzae, Moraxella catarrhalis, and atypical bacteria. However, patients with certain risk factors and those with more severe exacerbations can have more resistant bacteria including Pseudomonas aeruginosa
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cohorts (Table 1) [20,29]. An observational study of 19 608 hospitalized AECOPD patients treated with either a macrolide or fluoroquinolone demonstrated a lower associated risk of treatment failure with macrolide therapy (6.8 versus 8.1%); however, this finding was no longer significant in the multivariate analysis [odds ratio (OR) 0.89; 95% CI 0.78–1.01] [29]. No differences were observed between therapies for hospital length of stay or costs. Macrolide therapy was associated with a lower incidence of late mechanical ventilation and antibiotic-associated diarrhea when compared with fluoroquinolones [29]. A more recent observational evaluation of 53 900 patients compared fluoroquinolone therapy with macrolide therapy with or without a cephalosporin. The type of antibiotic prescribed had no effect on in-hospital mortality. However, patients treated with fluoroquinolones had higher 30-day readmission rates. Patients treated with macrolides had shorter hospital length of stay, lower costs, decreased incidence of diarrhea, and fewer re-admissions for Clostridium difficile colitis [21 ]. The results of available studies in severe AECOPD do not provide conclusive evidence for a superior efficacy advantage based upon the choice &
of a macrolide, fluoroquinolone, or beta-lactam antibiotic. Therefore, all three antibiotic classes remain a reasonable option for patients with severe AECOPD. The empiric choice of antibiotic still remains dependent on patterns of antimicrobial resistance and clinical characteristics of the patients being treated. Although there has not been clearly demonstrated superiority with one antibiotic over another, the potential for reduced adverse effects, C. difficile infection, and reduction in 30-day re-admission rates make the use of macrolides an intriguing choice for AECOPD patients that are not already chronically receiving azithromycin and those that do not have significant risk factors for macrolideresistant pathogens. The use of a beta-lactam with high activity against Streptococcus pneumoniae should be considered in these patients in which azithromycin monotherapy may be ineffective. Although an equally effective choice, given the emergence of fluoroquinolone resistance in a variety of pathogens, it may be prudent to reserve the use of respiratory fluoroquinolones to patients with betalactam allergies or those who have risk factors for infections with pathogens likely to be resistant to macrolides or beta-lactams.
Table 1. Evaluations of antibiotic choice and outcomes for patients with severe AECOPD Reference
Design
Treatment Groups
Outcomes
Results
Group 1
1o Outcome
1o Outcome
2 groups N ¼ 19 608 Inclusion: AECOPD Exclusion: other infections
Macrolide therapy Group 2 Fluoroquinolone therapy
Treatment failure: Death COPD readmission Mechanical ventilation 2o Outcomes Hospital cost Hospital LOS Allergic reactions Antibiotic-associated diarrhea
Macrolides were associated with lower treatment failure in the univariate analysis, but this finding was not significant in the multivariate analysis 2o Outcomes No difference in cost or LOS Fluoroquinolones associated with higher rates of antibiotic-associated diarrhea and mechanical ventilation
Observational
Group 1:
1o Outcome
1o Outcome
2 groups N ¼ 53 900 Inclusion: AECOPD Exclusion: ICU, ventilation, other infections
Antibiotic therapy on day 1 or 2 Group 2: No antibiotic therapy on day 1 or 2 Subgroups: Fluoroquinolone versus macrolide Fluoroquinolone versus macrolide þ cephalosporin Macrolide versus macrolide þ cephalosporin
In-hospital mortality 2o Outcomes Late ventilation Hospital readmission Hospital LOS Hospital cost Allergic reactions Antibiotic-associated diarrhea
Antibiotics reduced in-hospital mortality No differences in in-hospital mortality were observed between antibiotic subgroups 2o Outcomes Fluoroquinolones associated with higher 30-day re-admissions Macrolides associated with lower costs, LOS, diarrhea, and readmission for C. difficile colitis
Rothberg et al. [29] Observational
Stefan et al. [21 ] &
AECOPD, acute exacerbation of chronic obstructive pulmonary disease; LOS, length of stay.
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Corticosteroids and antibiotics in severe AECOPD Kiser and Vandivier
The use of antimicrobials for prevention of AECOPD is intriguing because many patients with COPD may be colonized with potentially pathogenic bacteria leading to chronic bronchial infection [30]. This presence of bacterial colonization is linked to airway inflammation and macrolide therapy is effective at reducing the associated neutrophillic bronchitis [31]. Azithromycin 250 mg daily has demonstrated efficacy in preventing AECOPD by a rate of approximately 0.4 exacerbations per patient year [32]. Azithromycin appears most effective at preventing severe AECOPD that requires both antibiotic and steroid treatment. Additionally, there may be a particular benefit in elderly patients and those with lower Global Initiative for Chronic Obstructive Lung Disease stages. Interestingly, azithromycin may have a reduced treatment effect in active smokers [33 ]. The most prominent adverse effects associated with utilizing azithromycin 250 mg daily for an extended duration are a largely reversible ototoxicity and QTc prolongation leading to a possible increase in cardiac deaths [32,34]. Given the lack of evidence for other antimicrobials, azithromycin is the drug of choice for prevention of AECOPD in patients that meet criteria for therapy [35]. However, some controversies surrounding azithromycin use still remain. Given the pharmacokinetics of azithromycin, which yields high lung concentrations and extended half-lives in tissues, some argue that 250 mg three times weekly would provide adequate prevention of exacerbations and reduce the risk of adverse effects [36]. Although theoretical, the evidence for thrice weekly azithromycin is marginal and it is unknown whether this strategy would maintain a favorable benefit to risk ratio compared with daily therapy [35]. Therefore, this strategy should be reserved for patients who are intolerant to daily therapy. Additionally, whether the benefit of azithromycin prophylaxis is maintained beyond 12 months is unknown. At a minimum, patients should be evaluated at the end of 12 months to ascertain the success of therapy and the emergence of macrolide-resistant bacteria, to determine whether continued prophylactic therapy is likely to be beneficial. &
SYSTEMIC CORTICOSTEROID THERAPY Systemic corticosteroids are a cornerstone of treatment for patients with severe AECOPD. A recent evaluation of nine studies (n ¼ 917) by the Cochrane group determined that, in comparison with placebo, the use of corticosteroids was associated with a more than 50% reduction in treatment failure (OR 0.48; 95% CI 0.35–0.67), making it only necessary to treat nine people to avoid a treatment failure [37 ]. &&
Reductions in 30-day relapse rates were also observed (hazard ratio 0.78; 95% CI 0.63–0.97). Hospitalized patients treated with corticosteroids had shorter hospital lengths of stay (1.22 days; 95% CI 2.26 to 0.18), but corticosteroids were not associated with a reduction in 30-day mortality. Corticosteroids were not without risk, and one adverse event occurred for every six people treated (OR 2.33; 95% CI 1.59–3.43) [37 ]. The choice of systemic corticosteroid for severe AECOPD includes medications with predominant glucocorticoid effects (e.g. prednisone, prednisolone, or methylprednisolone). These options are the most studied for AECOPD and are considered preferred to other systemic corticosteroid therapies that have more mineralocorticoid effects (e.g., hydrocortisone) [38]. Several clinical studies have evaluated corticosteroids for severe AECOPD (Table 2) [12,13 ,39,40 ,41 ]. However, owing to the variety of corticosteroid dosing regimens utilized in these studies, considerable debate still exists regarding the most appropriate dose, route, and duration of corticosteroids in severe AECOPD. In patients that can tolerate oral therapy, the use of oral treatment results in similar rates of treatment failure, relapse rates, and mortality when compared with parenteral corticosteroid therapy [37 ,42]. However, given the severity of exacerbations in patients admitted to the hospital or intensive care unit, many physicians still choose to initiate parenteral corticosteroid therapy and transition to oral therapy later in the hospitalization [13 ,41 ,42]. Initial corticosteroid dosages in patients with severe AECOPD have ranged from prednisone 40 mg daily [41 ] to methylprednisolone 500 mg daily (125 mg every 6 h) [39]. An evaluation of patients admitted to the intensive care unit for AECOPD from 2003 to 2008 demonstrated that in US hospitals, there is an almost universal preference for initiating parenteral therapy with two-thirds of patients receiving greater than 240 mg of methylprednisolone daily [13 ]. The use of high-dose methylprednisolone is frequently justified by the severity of exacerbation and the resulting morbidity and mortality. Corticosteroid resistance and reduced clinical response in these patients are additional concerns [23]. It is also likely that the results of the Department of Veteran’s Affairs Cooperative Study published in 1999 (methylprednisolone 125 mg intravenous every 6 h) drove the dosing practices over much of the last decade [39]. However, studies published after 2008 have questioned the need to use such high doses because despite the wide range of corticosteroid dosages utilized, the major clinical outcome results are not substantially different among most recent studies [12,39,41 ]. &&
&
&
&&
&&
&
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&&
&&
&
&&
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Design
Treatment groups
Outcomes
Results
Niewoehner et al. [39] RCT 3 Groups N ¼ 271 Inclusion: AECOPD Exclusion: ventilation
Group 1: Methylprednisolone 125 mg IV q6h on days 1–3 Prednisone taper on days 4–14 Group 2: Methylprednisolone 125 mg IV q6h on days 1–3 Prednisone taper on days 4–56 Group 3: Placebo
1o Outcome Treatment failure: Death Intubation COPD readmission Intensified therapy 2o Outcomes Hospital LOS Hyperglycemia
1o Outcome Both steroid regimens decreased treatment failure 2o Outcomes Steroids decreased hospital LOS Steroids increased hyperglycemia
Alia et al. [12]
RCT 2 Groups N ¼ 83 Inclusion: AECOPD, ventilation
Group 1: Methylprednisolone 0.5 mg/kg IV q6h on days 1–3 Methylprednisolone taper on days 4–10 Group 2: Placebo
1o Outcome Ventilation time ICU LOS Noninvasive ventilation failure 2o Outcomes Hospital LOS Hospital mortality Hyperglycemia
1o Outcome Steroids decreased ventilation time Steroids decreased noninvasive ventilation failure 2o Outcomes Steroids did not alter: Hospital LOS Hospital mortality Steroids increased hyperglycemia
Leuppi et al. [41 ]
RCT 2 Groups Noninferiority N ¼ 256 Inclusion: AECOPD
Group 1: Prednisone 40 mg daily 5 days Group 2: Prednisone 40 mg daily 14 days
1o Outcome Time to next AECOPD within 6 months 2o Outcomes Mortality Hospital LOS Need for ventilation Open-label steroids Hyperglycemia
1o Outcome No effect on time to next AECOPD 2o Outcomes No effect on Mortality Ventilation Open-label steroids Hyperglycemia Short-course steroids decreased hospital LOS
Abroug et al. [40 ]
RCT 2 Groups N ¼ 217 Inclusion: AECOPD, ventilation
Group 1: Prednisone 1 mg/kg/ day until discharge or 10 days Group 2: Usual care/no steroids
1o Outcome ICU mortality 2o Outcomes Ventilation time ICU LOS Noninvasive ventilation failure Hyperglycemia
1o Outcome Steroids did not alter ICU mortality 2o Outcomes Steroids did not alter Ventilation time ICU LOS Noninvasive failure Steroids increased hyperglycemia
Kiser et al. [13 ]
Observational 2 Groups N ¼ 17 239 Inclusion: AECOPD, ICU
Group 1: High dose: >240 mg/ day in methylprednisolone equivalent within first 48 h Group 2: Lower dose: 240 mg/ day in methylprednisolone equivalent within first 48 h
1o Outcome Hospital mortality 2o Outcomes Hospital LOS ICU LOS Total cost Hyperglycemia
1o Outcome Lower-dose steroids were not associated with decreased mortality 2o Outcomes Lower-dose steroids associated with: Lower hospital LOS Lower ICU LOS Lower total cost Increased hyperglycemia
&&
&
&
AECOPD, acute exacerbation of chronic obstructive pulmonary disease; LOS, length of stay; RCT, randomized controlled trial.
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Corticosteroids and antibiotics in severe AECOPD Kiser and Vandivier
A recent meta-analysis of 12 studies involving 1172 patients with AECOPD was unable to demonstrate any clinical benefit to initiating systemic corticosteroids at a dose 80 mg/day or higher of prednisone equivalents [43]. In the most critically ill patients requiring ventilator support, initial methylprednisolone dosages of 0.5 mg/kg every 6 h were sufficient for achieving improved clinical outcomes (decreased length of stay, decreased length of ventilation, and lower failure rates for noninvasive ventilation) [12]. In addition to efficacy endpoints, adverse effects of systemic corticosteroids in patients with AECOPD can be significant and are dose-related and durationrelated. The predominant adverse effect is hyperglycemia, but other potentially significant effects include skeletal muscle weakness or myopathy, neurological effects (e.g., anxiety, delirium), infection, hypertension, and gastrointestinal bleed. The mechanisms behind corticosteroid function make it difficult to optimize beneficial effects while minimizing adverse events in patients with AECOPD. There appears to be dissociation between repression of inflammatory genes and activation of off-target genes, which could ultimately result in amplified risk of adverse effects without additional clinical benefits as steroid doses are increased [44,45]. A recent evaluation of high-dose versus lower-dose corticosteroids in severe AECOPD found associations with increased rates of hyperglycemia, need for insulin therapy, and increased rates of invasive fungal infections in patients treated with more than 240 mg/day of methylprednisolone [13 ]. Similarly, an open-label placebo-controlled prospective study of AECOPD patients requiring ventilatory support highlights the increased risk of hyperglycemia that requires initiation or alteration of insulin therapy, and questions whether the risks of steroids outweigh the potential beneficial effects on patient outcomes [40 ]. Taking into account the efficacy and safety conclusions from the available studies, the majority of patients with severe AECOPD should be managed with systemic corticosteroid dosages of 40–80 mg/ day (prednisone equivalents). Dosages greater than 2 mg/kg/day do not appear to be clinically indicated, even in patients requiring mechanical ventilation. The duration of corticosteroid treatment in clinical trials has ranged from 5 days to 8 weeks [39,41 ]. Similar to the trends with corticosteroid dosage, more recent evidence has suggested that a change in clinical practice patterns regarding the duration of corticosteroid therapy utilized for severe AECOPD should be considered. A Cochrane review evaluating studies of 7 days or less compared with greater than 7 days of therapy was unable to demonstrate any difference in treatment failure rates &
&
&&
based upon duration of corticosteroid therapy (OR 0.82; 95% CI 0.24–2.79) [46]. The REDUCE trial, which evaluated prednisone 40 mg/day for 5 days versus 14 days, demonstrated that short-term therapy was noninferior to a longer duration (OR 0.95; 90% CI 0.68–1.26) [41 ]. There were no differences in time to death, re-exacerbations, or recovery of lung function based upon treatment duration. Patients receiving only 5 days of therapy had shorter hospital length of stay (median 8 versus 9 days, P ¼ 0.04) [41 ]. This evidence clearly suggests that there is no additional benefit to treating patients for greater than 5–7 days of systemic corticosteroid therapy during an AECOPD. &&
&&
CONCLUSION Severe AECOPD is an especially concerning event that results in significant morbidity and mortality. Antibiotic therapy is an important intervention for patients with severe AECOPD and increased sputum production or purulence, as they reduce treatment failure rates. Macrolides, fluoroquinolones, and beta-lactams are all reasonable treatment choices and the decision to use one over the other should be based upon patient characteristics and institutional or regional antimicrobial susceptibility patterns. Macrolides should be considered the antibiotic of choice for prevention of AECOPD in patients that qualify for therapy. Recent data also suggest that macrolide-based treatment regimens for AECOPD may have beneficial effects on morbidity, readmission rates, and adverse events compared with other antibiotics; however, more rigorous prospective studies are needed before definitive conclusions can be made. The best available evidence now suggests that higher-dose corticosteroids are not superior to treatment with lower-dose corticosteroids in patients with severe AECOPD. Additionally, longer durations of systemic corticosteroid therapy do not improve clinical outcomes. Based upon the current available evidence, a corticosteroid dose of 40–80 mg/day (prednisone equivalents) for 5–7 days may provide the best approach to managing severe AECOPD in the majority of patients. Acknowledgements None. Financial support and sponsorship This work is unfunded. Conflicts of interest The authors report no conflicts of interest related to this manuscript.
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Volume 21 Number 2 March 2015
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