Mr. S is a 68-year old man with longstanding COPD and a 40-pack-year smoking history. He presents to clinic with three days of increasing shortness of breath, and complains that he has been coughing up “more junk” than usual. As I watch him spit a wad of chartreuse sputum into his tissue, I reach for the prescription pad and tell him he’ll need a week of antibiotics. He wants to know why he can’t just go up on his inhaled medications instead of taking more pills.
The use of antibiotics in treating COPD exacerbations is common practice, but what is the evidence behind their use?
The search for proof of a bacterial etiology of COPD exacerbations has been on for decades, but imperfect techniques led to inconclusive results. In fact, a major review published in the NEJM in 1975 concluded that the available data was not sufficient to support a bacterial role in COPD . Current techniques using bronchoscopy and the protected specimen brush (PSB) method provide lower airway samples without the upper airway contaminants found in sputum samples, and newer technology allows reliable assessment of acute immune response to new bacterial exposures. Analysis of newer data found that about 50% of COPD exacerbations are caused by bacterial infections, with the remainder caused by either viral infections or environmental factors such as pollution , but it can be difficult to determine the etiology of a specific exacerbation in practice.
Pooled data from six studies using the PSB method found significant bacterial colonization in 54% of patients with a COPD exacerbation, 29% of those with stable COPD, and in only 4% of healthy controls . Haemophilus influenzae and Streptococcus pneumoniae were the most commonly encountered bacteria in stable COPD airways, while H. influenzae and Pseudomonas aeruginosa were most strongly associated with exacerbations. Multiple studies using immunologic analysis have shown that exacerbations are associated with colonization by new strains of bacteria, specifically H. influenzae, S. pneumoniae, Moraxella catarrhalis, or Pseudomonas .
The Global Initiative for Chronic Obstructive Lung Disease (GOLD)  guidelines recommend the use of antibiotics in exacerbations with the three cardinal symptoms of increased dyspnea, increased sputum volume, and increased sputum purulence, exacerbations involving only two of the cardinal symptoms as long as one of them is increased purulence, and in exacerbations requiring mechanical ventilation. While it’s always nice to have guidelines, it’s also important to know the evidence behind them.
A landmark study in 1987 of 362 acute exacerbations in 173 patients treated with either placebo or antibiotic demonstrated a benefit for antibiotic use in exacerbations classified as moderate or severe (two or three cardinal symptoms), but not in mild cases (only one symptom) . The antibiotics used were TMP-SMX, amoxicillin, or doxycycline, which were considered to be equally effective based on multiple published studies. Though none of those cover Psuedomonas, and amoxicillin does not cover non-typeable H. influenzae, it is likely that in the 25 years since the study’s publication the most common pathogens as well as resistance profiles have changed, and the antibiotic regimens were suitable for the bacterial milieu of the time. The study evaluated the success rate, defined as complete resolution within 21 days, as well as the rate of failures with deterioration, defined as patients worsening to the point of needing to be hospitalized or removed from blinding to be treated. While there was no major clinical difference in success rate between the two groups, failures with deterioration were twice as common in the placebo group (30.5%) than in the treatment group (14.3%) in patients with severe exacerbations. Peak flow data from 64 patients who had experienced two or more exacerbations during the course of the study and were treated with both placebo and antibiotic was analyzed as paired controls. The peak flow in these patients declined from an average of 215 L/min at baseline to 190 L/min at the onset of the exacerbation. Both groups recovered to their baseline peak flow, but the rate of increase was greater in the antibiotic treated group. Though the difference was statistically significant, it is unclear whether it is clinically significant, as the greatest difference between groups was 10 L/min at day 6 and by day 12 the groups were equivalent.
A 1995 meta-analysis  has provided the most evidence favoring antibiotic use in COPD exacerbations, based on pooled results of 9 RCTs. A caveat in interpreting the results of the meta-analysis is that the nine studies used different antibiotics and different outcome measures, including overall score by physician, days of illness, change in PEFR, and overall symptom score. The authors calculated an overall effect size of 0.22, which is considered “small,” and signifies that the two groups have about 85% overlap . So, though the pooled results suggest a slight benefit, there is no way to translate the effect size into clinical improvement.
Interestingly, six of the nine studies reported change in peak expiratory flow rate (PEFR) as one of the main outcomes, with an overall effect size of 0.19 . The average change in PEFR across studies was 10.75 L/min with antibiotic therapy. How clinically significant is that difference?
Based on available data, it appears that both of these papers suffer from relying on an endpoint that may not be clinically significant. The baseline PEFR in the 173 patients in the 1987 study in Annals was 227.5 L/min, with a standard deviation (SD) of 96.1 . Another study of 73 COPD patients reported a baseline of 235 L/min with a SD of 89 . Overall, the 10.75 L/min difference in PEFR with antibiotic use represents less than 5% of baseline values and less than 12% of the standard deviation reported in multiple studies, which makes one question the clinical effect of such a small increase. Moreover, patients may experience daily variation in their baseline PEFR which exceeds 10.75 L/min: Donohue et al  reported baseline values of 623 patients taken daily for six months and found they averaged 233 L/min in the morning and 246 L/min in the evening. In other words, though the results achieved statistical significance, the clinical difference from a PEFR standpoint is negligible.
A more recent review and meta-analysis from 2008  included only 3 papers published since 1987, but did not rely on PEFR as an endpoint. Instead, it used treatment failure, defined as requiring additional antibiotics with the first week or unchanged or worsening symptoms within 3 weeks, and in-hospital mortality as the two main endpoints. The authors concluded that for antibiotics, “although the combined analysis showed a survival benefit, each individual study was relatively small in size and was underpowered to answer this critical question.” When the studies were reviewed based on inpatient versus outpatient setting, a reduction in treatment failures was found only among inpatients, and the in-hospital mortality was also decreased. The authors postulate that this could be a result of the more severe exacerbations found in hospitalized patients or that the antibiotics may help to prevent nosocomial infections, though others believe that the use of broad-spectrum antibiotics in this setting may contribute to resistance and lead to dangerous superinfections.
Though antibiotics appear to have a solid place in inpatient treatment guidelines, among outpatients, some evidence shows that sputum purulence may be the most important factor in driving antibiotic treatment. Stockley et al  found that sputum purulence correlates with positive bacterial culture, with a sensitivity of 94.4% and a specificity of 77.0% for a high bacterial load. In their study, COPD patients presenting with an acute exacerbation were assigned to treatment based on the color of their sputum. The results found 84% of the purulent sputum samples to be culture-positive, compared to only 38% of the mucoid samples; which was comparable to the baseline positive culture rate of 38-41%. Perhaps most relevant to the current discussion is that 32 out of 34 patients with mucoid exacerbations recovered without antibiotics; the two who did not recover subsequently developed purulent sputum and required antibiotic treatment.
In short, the evidence supporting antibiotic use in this select population is less robust than many clinicians may presuppose given their wide use in clinical practice. In hospitalized patients, the use of antibiotics seems to confer a real benefit, though how much of that is due to the increased risk of bacterial infection associated with inpatient treatment is impossible to say. Macrolides may play an increasingly important role in treating COPD exacerbations, as they have demonstrated anti-inflammatory and immunomodulatory potential on top of their antibacterial effects. Moving forward, we may see a paradigm shift for dealing with outpatient exacerbations, with a focus on only the more colorful of the cardinal symptoms. 
Aviva Regev is a 4th year medical student at NYU Langone School of Medicine
Peer Reviewed by: Robert Smith, MD, Associate Professor of Medicine (Pulmonary/Critical Care)
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