Macrolides and Quinolones for AECOPD

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are responsible for more than 600,000 hospitalizations annually, resulting in direct costs of over $20 billion.1 Bacterial infections appear responsible for 50% of such exacerbations,25 and current COPD guidelines recommend treatment with antibiotics for patients with severe exacerbations or a change in sputum.1^,69 These recommendations are based on a number of small randomized trials, most of which were conducted more than 20 years ago using narrow spectrum antibiotics that are no longer commonly used.10 Only 4 studies, totaling 321 subjects, included hospitalized patients, and most studies excluded patients who required steroids. Because no clinical trials have compared different antibiotic regimens for AECOPD, existing guidelines offer a range of treatment options, including amoxicillin‐clavulonate, macrolides, quinolones, cephalosporins, aminopenicillins, and tetracyclines.

Among hospitalized patients, macrolides and quinolones appear to be the most frequently prescribed antibiotics.11 Both are available in oral formulations, have excellent bioavailability, and are administered once daily. In addition to their antimicrobial activity, macrolides are believed to have antiinflammatory effects, which could be especially advantageous in AECOPD.1214 In trials of chronic bronchitis, however, fluoroquinolones have been shown to reduce the risk of recurrent exacerbation when compared to macrolides.15 The wide variation that has been observed in antibiotic selection for patients hospitalized for AECOPD suggests a high degree of uncertainty among clinicians about the benefits of different treatment options.11 Given the limited evidence from randomized trials, we sought to evaluate the comparative effectiveness of macrolides and quinolones among a large, representative sample of patients hospitalized with AECOPD.

Subjects and Methods

Results

Of 26,248 AECOPD patients treated with antibiotics, 19,608 patients met the inclusion criteria; of these, 6139 (31%) were treated initially with a macrolide; the median age was 70 years; 60% were female; and 78% were white. A total of 86% of patients had a primary diagnosis of obstructive chronic bronchitis with acute exacerbation, and 6% had respiratory failure. The most common comorbidities were hypertension, diabetes, and congestive heart failure. Twenty‐two percent had been admitted at least once in the preceding 12 months. Treatment failure occurred in 7.7% of patients, and 1.3% died in the hospital. Mean length of stay was 4.8 days. Hospital prescribing rates for macrolides varied from 0% to 100%, with a mean of 33% and an interquartile range of 14% to 46% (Supporting Appendix Figure 1).

Compared to patients receiving macrolides, those receiving quinolones were older, more likely to have respiratory failure, to be cared for by a pulmonologist, and to have an admission in the previous year (Table 1). They were also more likely to be treated with bronchodilators, methylxanthines, steroids, diuretics, and noninvasive positive pressure ventilation, and to have an arterial blood gas, but less likely to receive concomitant treatment with a cephalosporin (11% vs. 57%). With the exception of cephalosporin treatment, these differences were small, but due to the large sample were statistically significant. Comorbidities were similar in both groups. Patients in the quinolone group were also more likely to experience treatment failure (8.1% vs. 6.8%), death (1.5% vs. 1.0%), and antibiotic‐associated diarrhea (1.1% vs. 0.5%).

In the unadjusted analysis, compared to patients receiving quinolones, those treated with macrolides were less likely to experience treatment failure (OR, 0.83; 95% CI, 0.740.94) (Table 2). Adjusting for all patient, hospital, and physician covariates, including the propensity for treatment with macrolides, increased the OR to 0.89 and the results were no longer significant (95% CI, 0.781.01). Propensity matching successfully balanced all measured covariates except for the use of short‐acting bronchodilators and additional antibiotics (Table 1). In the propensity‐matched sample (Figure 1), quinolone‐treated patients were more likely to experience antibiotic‐associated diarrhea (1.2% vs. 0.6%; P = 0.0003) and late mechanical ventilation (1.3% vs. 0.8%; P = 0.02). There were no differences in adjusted cost or length of stay between the 2 groups. The results of the grouped treatment analysis, substituting the hospital's specific rate of macrolide use in place of the actual treatment that each patient received suggested that the 2 antibiotics were associated with similar rates of treatment failure. The OR for a 100% hospital rate of macrolide treatment vs. a 0% rate was 1.01 (95% CI, 0.751.35).

Figure 1

Discussion

In this large observational study conducted at 375 hospitals, we took advantage of a natural experiment in which antibiotic prescribing patterns varied widely across hospitals to compare the effectiveness of 2 common antibiotic regimens for AECOPD. Treatment with macrolides and quinolones were associated with a similar risk of treatment failure, costs, and length of stay; however, patients treated with macrolides were less likely to experience late mechanical ventilation or treatment for antibiotic‐associated diarrhea.

Despite broad consensus in COPD guidelines that patients with severe acute exacerbations should receive antibiotics, there is little agreement about the preferred empiric agent. Controversy exists regarding antibiotics' comparative effectiveness, and even over which pathogens cause COPD exacerbations. Given the frequency of hospitalization for AECOPD, understanding the comparative effectiveness of treatments in this setting could have important implications for health outcomes and costs. Unfortunately, most antibiotic studies in AECOPD were conducted >20 years ago, using antibiotics that rarely appeared in our sample.26 Consequently, clinical practice guidelines offer conflicting recommendations. For example, the National Institute for Clinical Excellence recommends empirical treatment with an aminopenicillin, a macrolide, or a tetracycline,8 while the American Thoracic Society recommends amoxicillin‐clavulonate or a fluoroquinolone.9

As might be expected in light of so much uncertainty, we found wide variation in prescribing patterns across hospitals. Overall, approximately one‐third of patients received a macrolide and two‐thirds a quinolone. Both regimens provide adequate coverage of H. influenza, S. pneumoniae, and M. catarrhalis, and conform to at least 1 COPD guideline. Nevertheless, patients receiving macrolides often received a cephalosporin as well; this pattern of treatment suggests that antibiotic selection is likely to have been influenced more by guidelines for the treatment of community‐acquired pneumonia than COPD.

Previous studies comparing antibiotic effectiveness suffer from shortcomings that limit their application to patients hospitalized with AECOPD. First, they enrolled patients with chronic bronchitis, and included patients without obstructive lung disease, and most studies included patients as young as 18 years old. Second, many either did not include treatment with steroids or excluded patients receiving more than 10 mg of prednisone daily. Third, almost all enrolled only ambulatory patients.

While there are no studies comparing quinolones and macrolides in patients hospitalized for AECOPD, a meta‐analysis comparing quinolones, macrolides, and amoxicillin‐clavulonate identified 19 trials of ambulatory patients with chronic bronchitis. That study found that all 3 drugs had similar efficacy initially, but that quinolones resulted in the fewest relapses over a 26‐week period.27 Macrolides and quinolones had similar rates of adverse effects. In contrast, we did not find a difference in treatment failure, cost, or length of stay, but did find a higher rate of diarrhea associated with quinolones. Others have also documented an association between fluoroquinolones and C. difficile diarrhea.2830 This trend, first noted in 2001, is of particular concern because the fluoroquinolone‐resistant strains appear to be hypervirulent and have been associated with nosocomial epidemics.3134

Our study has several limitations. First, its observational design leaves open the possibility of selection bias. For this reason we analyzed our data in several ways, including using a grouped treatment approach, an adaptation of the instrumental variable technique, and accepted only those differences which were consistent across all models. Second, our study used claims data, and therefore we could not directly adjust for physiological measures of severity. However, the highly detailed nature of the data allowed us to adjust for numerous tests and treatments that reflected the clinician's assessment of the patient's severity, as well as the number of prior COPD admissions. Third, we cannot exclude the possibility that some patients may have had concurrent pneumonia without an ICD‐9 code. We think that the number would be small because reimbursement for pneumonia is generally higher than for COPD, so hospitals have an incentive to code pneumonia as the principal diagnosis when present. Finally, we compared initial antibiotics only. More than one‐quarter of our patients received an additional antibiotic before discharge. In particular, patients receiving macrolides were often prescribed a concomitant cephalosporin. We do not know to what extent these additional antibiotics may have affected the outcomes.

Despite the large number of patients hospitalized annually for AECOPD, there are no randomized trials comparing different antibiotics in this population. Studies comparing antibiotics in chronic bronchitis can offer little guidance, since they have primarily focused on proving equivalence between existing antibiotics and newer, more expensive formulations.35 Because many of the patients enrolled in such trials do not benefit from antibiotics at all, either because they do not have COPD or because their exacerbation is not caused by bacteria, it is relatively easy to prove equivalence. Given that AECOPD is one of the leading causes of hospitalization in the United States, large, randomized trials comparing the effectiveness of different antibiotics should be a high priority. In the meantime, macrolides (often given together with cephalosporins) and quinolones appear to be equally effective initial antibiotic choices; considering antibiotic‐associated diarrhea, macrolides appear to be the safer of the 2.

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are responsible for more than 600,000 hospitalizations annually, resulting in direct costs of over $20 billion.1 Bacterial infections appear responsible for 50% of such exacerbations,25 and current COPD guidelines recommend treatment with antibiotics for patients with severe exacerbations or a change in sputum.1^,69 These recommendations are based on a number of small randomized trials, most of which were conducted more than 20 years ago using narrow spectrum antibiotics that are no longer commonly used.10 Only 4 studies, totaling 321 subjects, included hospitalized patients, and most studies excluded patients who required steroids. Because no clinical trials have compared different antibiotic regimens for AECOPD, existing guidelines offer a range of treatment options, including amoxicillin‐clavulonate, macrolides, quinolones, cephalosporins, aminopenicillins, and tetracyclines.

Among hospitalized patients, macrolides and quinolones appear to be the most frequently prescribed antibiotics.11 Both are available in oral formulations, have excellent bioavailability, and are administered once daily. In addition to their antimicrobial activity, macrolides are believed to have antiinflammatory effects, which could be especially advantageous in AECOPD.1214 In trials of chronic bronchitis, however, fluoroquinolones have been shown to reduce the risk of recurrent exacerbation when compared to macrolides.15 The wide variation that has been observed in antibiotic selection for patients hospitalized for AECOPD suggests a high degree of uncertainty among clinicians about the benefits of different treatment options.11 Given the limited evidence from randomized trials, we sought to evaluate the comparative effectiveness of macrolides and quinolones among a large, representative sample of patients hospitalized with AECOPD.

Subjects and Methods

Results

Of 26,248 AECOPD patients treated with antibiotics, 19,608 patients met the inclusion criteria; of these, 6139 (31%) were treated initially with a macrolide; the median age was 70 years; 60% were female; and 78% were white. A total of 86% of patients had a primary diagnosis of obstructive chronic bronchitis with acute exacerbation, and 6% had respiratory failure. The most common comorbidities were hypertension, diabetes, and congestive heart failure. Twenty‐two percent had been admitted at least once in the preceding 12 months. Treatment failure occurred in 7.7% of patients, and 1.3% died in the hospital. Mean length of stay was 4.8 days. Hospital prescribing rates for macrolides varied from 0% to 100%, with a mean of 33% and an interquartile range of 14% to 46% (Supporting Appendix Figure 1).

Compared to patients receiving macrolides, those receiving quinolones were older, more likely to have respiratory failure, to be cared for by a pulmonologist, and to have an admission in the previous year (Table 1). They were also more likely to be treated with bronchodilators, methylxanthines, steroids, diuretics, and noninvasive positive pressure ventilation, and to have an arterial blood gas, but less likely to receive concomitant treatment with a cephalosporin (11% vs. 57%). With the exception of cephalosporin treatment, these differences were small, but due to the large sample were statistically significant. Comorbidities were similar in both groups. Patients in the quinolone group were also more likely to experience treatment failure (8.1% vs. 6.8%), death (1.5% vs. 1.0%), and antibiotic‐associated diarrhea (1.1% vs. 0.5%).

In the unadjusted analysis, compared to patients receiving quinolones, those treated with macrolides were less likely to experience treatment failure (OR, 0.83; 95% CI, 0.740.94) (Table 2). Adjusting for all patient, hospital, and physician covariates, including the propensity for treatment with macrolides, increased the OR to 0.89 and the results were no longer significant (95% CI, 0.781.01). Propensity matching successfully balanced all measured covariates except for the use of short‐acting bronchodilators and additional antibiotics (Table 1). In the propensity‐matched sample (Figure 1), quinolone‐treated patients were more likely to experience antibiotic‐associated diarrhea (1.2% vs. 0.6%; P = 0.0003) and late mechanical ventilation (1.3% vs. 0.8%; P = 0.02). There were no differences in adjusted cost or length of stay between the 2 groups. The results of the grouped treatment analysis, substituting the hospital's specific rate of macrolide use in place of the actual treatment that each patient received suggested that the 2 antibiotics were associated with similar rates of treatment failure. The OR for a 100% hospital rate of macrolide treatment vs. a 0% rate was 1.01 (95% CI, 0.751.35).

Figure 1

Discussion

In this large observational study conducted at 375 hospitals, we took advantage of a natural experiment in which antibiotic prescribing patterns varied widely across hospitals to compare the effectiveness of 2 common antibiotic regimens for AECOPD. Treatment with macrolides and quinolones were associated with a similar risk of treatment failure, costs, and length of stay; however, patients treated with macrolides were less likely to experience late mechanical ventilation or treatment for antibiotic‐associated diarrhea.

Despite broad consensus in COPD guidelines that patients with severe acute exacerbations should receive antibiotics, there is little agreement about the preferred empiric agent. Controversy exists regarding antibiotics' comparative effectiveness, and even over which pathogens cause COPD exacerbations. Given the frequency of hospitalization for AECOPD, understanding the comparative effectiveness of treatments in this setting could have important implications for health outcomes and costs. Unfortunately, most antibiotic studies in AECOPD were conducted >20 years ago, using antibiotics that rarely appeared in our sample.26 Consequently, clinical practice guidelines offer conflicting recommendations. For example, the National Institute for Clinical Excellence recommends empirical treatment with an aminopenicillin, a macrolide, or a tetracycline,8 while the American Thoracic Society recommends amoxicillin‐clavulonate or a fluoroquinolone.9

As might be expected in light of so much uncertainty, we found wide variation in prescribing patterns across hospitals. Overall, approximately one‐third of patients received a macrolide and two‐thirds a quinolone. Both regimens provide adequate coverage of H. influenza, S. pneumoniae, and M. catarrhalis, and conform to at least 1 COPD guideline. Nevertheless, patients receiving macrolides often received a cephalosporin as well; this pattern of treatment suggests that antibiotic selection is likely to have been influenced more by guidelines for the treatment of community‐acquired pneumonia than COPD.

Previous studies comparing antibiotic effectiveness suffer from shortcomings that limit their application to patients hospitalized with AECOPD. First, they enrolled patients with chronic bronchitis, and included patients without obstructive lung disease, and most studies included patients as young as 18 years old. Second, many either did not include treatment with steroids or excluded patients receiving more than 10 mg of prednisone daily. Third, almost all enrolled only ambulatory patients.

While there are no studies comparing quinolones and macrolides in patients hospitalized for AECOPD, a meta‐analysis comparing quinolones, macrolides, and amoxicillin‐clavulonate identified 19 trials of ambulatory patients with chronic bronchitis. That study found that all 3 drugs had similar efficacy initially, but that quinolones resulted in the fewest relapses over a 26‐week period.27 Macrolides and quinolones had similar rates of adverse effects. In contrast, we did not find a difference in treatment failure, cost, or length of stay, but did find a higher rate of diarrhea associated with quinolones. Others have also documented an association between fluoroquinolones and C. difficile diarrhea.2830 This trend, first noted in 2001, is of particular concern because the fluoroquinolone‐resistant strains appear to be hypervirulent and have been associated with nosocomial epidemics.3134

Our study has several limitations. First, its observational design leaves open the possibility of selection bias. For this reason we analyzed our data in several ways, including using a grouped treatment approach, an adaptation of the instrumental variable technique, and accepted only those differences which were consistent across all models. Second, our study used claims data, and therefore we could not directly adjust for physiological measures of severity. However, the highly detailed nature of the data allowed us to adjust for numerous tests and treatments that reflected the clinician's assessment of the patient's severity, as well as the number of prior COPD admissions. Third, we cannot exclude the possibility that some patients may have had concurrent pneumonia without an ICD‐9 code. We think that the number would be small because reimbursement for pneumonia is generally higher than for COPD, so hospitals have an incentive to code pneumonia as the principal diagnosis when present. Finally, we compared initial antibiotics only. More than one‐quarter of our patients received an additional antibiotic before discharge. In particular, patients receiving macrolides were often prescribed a concomitant cephalosporin. We do not know to what extent these additional antibiotics may have affected the outcomes.

Despite the large number of patients hospitalized annually for AECOPD, there are no randomized trials comparing different antibiotics in this population. Studies comparing antibiotics in chronic bronchitis can offer little guidance, since they have primarily focused on proving equivalence between existing antibiotics and newer, more expensive formulations.35 Because many of the patients enrolled in such trials do not benefit from antibiotics at all, either because they do not have COPD or because their exacerbation is not caused by bacteria, it is relatively easy to prove equivalence. Given that AECOPD is one of the leading causes of hospitalization in the United States, large, randomized trials comparing the effectiveness of different antibiotics should be a high priority. In the meantime, macrolides (often given together with cephalosporins) and quinolones appear to be equally effective initial antibiotic choices; considering antibiotic‐associated diarrhea, macrolides appear to be the safer of the 2.

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are responsible for more than 600,000 hospitalizations annually, resulting in direct costs of over $20 billion.1 Bacterial infections appear responsible for 50% of such exacerbations,25 and current COPD guidelines recommend treatment with antibiotics for patients with severe exacerbations or a change in sputum.1^,69 These recommendations are based on a number of small randomized trials, most of which were conducted more than 20 years ago using narrow spectrum antibiotics that are no longer commonly used.10 Only 4 studies, totaling 321 subjects, included hospitalized patients, and most studies excluded patients who required steroids. Because no clinical trials have compared different antibiotic regimens for AECOPD, existing guidelines offer a range of treatment options, including amoxicillin‐clavulonate, macrolides, quinolones, cephalosporins, aminopenicillins, and tetracyclines.

Among hospitalized patients, macrolides and quinolones appear to be the most frequently prescribed antibiotics.11 Both are available in oral formulations, have excellent bioavailability, and are administered once daily. In addition to their antimicrobial activity, macrolides are believed to have antiinflammatory effects, which could be especially advantageous in AECOPD.1214 In trials of chronic bronchitis, however, fluoroquinolones have been shown to reduce the risk of recurrent exacerbation when compared to macrolides.15 The wide variation that has been observed in antibiotic selection for patients hospitalized for AECOPD suggests a high degree of uncertainty among clinicians about the benefits of different treatment options.11 Given the limited evidence from randomized trials, we sought to evaluate the comparative effectiveness of macrolides and quinolones among a large, representative sample of patients hospitalized with AECOPD.

Subjects and Methods

Results

Of 26,248 AECOPD patients treated with antibiotics, 19,608 patients met the inclusion criteria; of these, 6139 (31%) were treated initially with a macrolide; the median age was 70 years; 60% were female; and 78% were white. A total of 86% of patients had a primary diagnosis of obstructive chronic bronchitis with acute exacerbation, and 6% had respiratory failure. The most common comorbidities were hypertension, diabetes, and congestive heart failure. Twenty‐two percent had been admitted at least once in the preceding 12 months. Treatment failure occurred in 7.7% of patients, and 1.3% died in the hospital. Mean length of stay was 4.8 days. Hospital prescribing rates for macrolides varied from 0% to 100%, with a mean of 33% and an interquartile range of 14% to 46% (Supporting Appendix Figure 1).

Compared to patients receiving macrolides, those receiving quinolones were older, more likely to have respiratory failure, to be cared for by a pulmonologist, and to have an admission in the previous year (Table 1). They were also more likely to be treated with bronchodilators, methylxanthines, steroids, diuretics, and noninvasive positive pressure ventilation, and to have an arterial blood gas, but less likely to receive concomitant treatment with a cephalosporin (11% vs. 57%). With the exception of cephalosporin treatment, these differences were small, but due to the large sample were statistically significant. Comorbidities were similar in both groups. Patients in the quinolone group were also more likely to experience treatment failure (8.1% vs. 6.8%), death (1.5% vs. 1.0%), and antibiotic‐associated diarrhea (1.1% vs. 0.5%).

In the unadjusted analysis, compared to patients receiving quinolones, those treated with macrolides were less likely to experience treatment failure (OR, 0.83; 95% CI, 0.740.94) (Table 2). Adjusting for all patient, hospital, and physician covariates, including the propensity for treatment with macrolides, increased the OR to 0.89 and the results were no longer significant (95% CI, 0.781.01). Propensity matching successfully balanced all measured covariates except for the use of short‐acting bronchodilators and additional antibiotics (Table 1). In the propensity‐matched sample (Figure 1), quinolone‐treated patients were more likely to experience antibiotic‐associated diarrhea (1.2% vs. 0.6%; P = 0.0003) and late mechanical ventilation (1.3% vs. 0.8%; P = 0.02). There were no differences in adjusted cost or length of stay between the 2 groups. The results of the grouped treatment analysis, substituting the hospital's specific rate of macrolide use in place of the actual treatment that each patient received suggested that the 2 antibiotics were associated with similar rates of treatment failure. The OR for a 100% hospital rate of macrolide treatment vs. a 0% rate was 1.01 (95% CI, 0.751.35).

Figure 1

Discussion

In this large observational study conducted at 375 hospitals, we took advantage of a natural experiment in which antibiotic prescribing patterns varied widely across hospitals to compare the effectiveness of 2 common antibiotic regimens for AECOPD. Treatment with macrolides and quinolones were associated with a similar risk of treatment failure, costs, and length of stay; however, patients treated with macrolides were less likely to experience late mechanical ventilation or treatment for antibiotic‐associated diarrhea.

Despite broad consensus in COPD guidelines that patients with severe acute exacerbations should receive antibiotics, there is little agreement about the preferred empiric agent. Controversy exists regarding antibiotics' comparative effectiveness, and even over which pathogens cause COPD exacerbations. Given the frequency of hospitalization for AECOPD, understanding the comparative effectiveness of treatments in this setting could have important implications for health outcomes and costs. Unfortunately, most antibiotic studies in AECOPD were conducted >20 years ago, using antibiotics that rarely appeared in our sample.26 Consequently, clinical practice guidelines offer conflicting recommendations. For example, the National Institute for Clinical Excellence recommends empirical treatment with an aminopenicillin, a macrolide, or a tetracycline,8 while the American Thoracic Society recommends amoxicillin‐clavulonate or a fluoroquinolone.9

As might be expected in light of so much uncertainty, we found wide variation in prescribing patterns across hospitals. Overall, approximately one‐third of patients received a macrolide and two‐thirds a quinolone. Both regimens provide adequate coverage of H. influenza, S. pneumoniae, and M. catarrhalis, and conform to at least 1 COPD guideline. Nevertheless, patients receiving macrolides often received a cephalosporin as well; this pattern of treatment suggests that antibiotic selection is likely to have been influenced more by guidelines for the treatment of community‐acquired pneumonia than COPD.

Previous studies comparing antibiotic effectiveness suffer from shortcomings that limit their application to patients hospitalized with AECOPD. First, they enrolled patients with chronic bronchitis, and included patients without obstructive lung disease, and most studies included patients as young as 18 years old. Second, many either did not include treatment with steroids or excluded patients receiving more than 10 mg of prednisone daily. Third, almost all enrolled only ambulatory patients.

While there are no studies comparing quinolones and macrolides in patients hospitalized for AECOPD, a meta‐analysis comparing quinolones, macrolides, and amoxicillin‐clavulonate identified 19 trials of ambulatory patients with chronic bronchitis. That study found that all 3 drugs had similar efficacy initially, but that quinolones resulted in the fewest relapses over a 26‐week period.27 Macrolides and quinolones had similar rates of adverse effects. In contrast, we did not find a difference in treatment failure, cost, or length of stay, but did find a higher rate of diarrhea associated with quinolones. Others have also documented an association between fluoroquinolones and C. difficile diarrhea.2830 This trend, first noted in 2001, is of particular concern because the fluoroquinolone‐resistant strains appear to be hypervirulent and have been associated with nosocomial epidemics.3134

Our study has several limitations. First, its observational design leaves open the possibility of selection bias. For this reason we analyzed our data in several ways, including using a grouped treatment approach, an adaptation of the instrumental variable technique, and accepted only those differences which were consistent across all models. Second, our study used claims data, and therefore we could not directly adjust for physiological measures of severity. However, the highly detailed nature of the data allowed us to adjust for numerous tests and treatments that reflected the clinician's assessment of the patient's severity, as well as the number of prior COPD admissions. Third, we cannot exclude the possibility that some patients may have had concurrent pneumonia without an ICD‐9 code. We think that the number would be small because reimbursement for pneumonia is generally higher than for COPD, so hospitals have an incentive to code pneumonia as the principal diagnosis when present. Finally, we compared initial antibiotics only. More than one‐quarter of our patients received an additional antibiotic before discharge. In particular, patients receiving macrolides were often prescribed a concomitant cephalosporin. We do not know to what extent these additional antibiotics may have affected the outcomes.

Despite the large number of patients hospitalized annually for AECOPD, there are no randomized trials comparing different antibiotics in this population. Studies comparing antibiotics in chronic bronchitis can offer little guidance, since they have primarily focused on proving equivalence between existing antibiotics and newer, more expensive formulations.35 Because many of the patients enrolled in such trials do not benefit from antibiotics at all, either because they do not have COPD or because their exacerbation is not caused by bacteria, it is relatively easy to prove equivalence. Given that AECOPD is one of the leading causes of hospitalization in the United States, large, randomized trials comparing the effectiveness of different antibiotics should be a high priority. In the meantime, macrolides (often given together with cephalosporins) and quinolones appear to be equally effective initial antibiotic choices; considering antibiotic‐associated diarrhea, macrolides appear to be the safer of the 2.