Are antibiotics beneficial for flare-ups of chronic obstructive pulmonary disease?

Review question

We conducted this systematic review to find out if the benefits of taking antibiotics for flare-ups of COPD outweigh potential harms (e.g. risks of multi-resistant bacteria for this population).

Background

Chronic obstructive pulmonary disease (COPD) is a chronic condition (most often caused by smoking or environmental exposure) that affects the passage of air into and out of the lungs. As a consequence, patients experience shortness of breath and coughing. Flare-ups of COPD are a hallmark of more advanced stages of the disease. Flare-ups are defined as sustained worsening of symptoms from the patient's usual stable state. Commonly reported symptoms include worsening breathlessness, cough, increased sputum production, and change in sputum colour. Clinicians frequently prescribe antibiotics for flare-ups in patients with COPD, although the cause of flare-ups is often difficult to determine (viral, bacterial, environmental).

Study characteristics

Evidence gathered for this review is current to September 2018. We found 19 randomised studies that compared antibiotics versus placebo in a total of 2663 COPD patients with a wide range of flare-up severity.

Key results

Analyses show that currently used antibiotics reduced treatment failures (no improvement in symptoms, despite treatment, within 7 to 28 days, depending on the study) compared with placebo in outpatients with mild to moderate flare-ups, as well as in patients admitted to an intensive care unit for very severe flare-ups with respiratory failure. However, antibiotics did not reduce treatment failures among hospitalised patients with severe flare-ups, although we are less certain about this result because the effect estimate also suggested findings similar to those seen in outpatients, but the confidence interval crossed 1.0. Use of antibiotics led to reduced mortality only in patients admitted to an intensive care unit, but not in patients with mild to moderate (outpatients) or severe (inpatients) flare-ups, although deaths were rare in these latter groups. Antibiotics did not reduce length of hospital stay for hospitalised patients. Patients treated with antibiotics experienced diarrhoea more often than those given placebo, but the difference was not statistically significant. Reviewers could not compare the severity of underlying COPD across trials because trial authors inconsistently reported lung function and other parameters.

Quality of the evidence

The quality of evidence for review outcomes was low to moderate.

Conclusion

Although trial results show that antibiotics were effective across outcomes for patients with very severe flare-ups and respiratory failure who needed treatment in an intensive care unit, researchers report inconsistent effects in patients with mild to severe flare-ups. Future high-quality studies should examine clinical signs or blood tests at the time of presentation that are useful for identifying patients who can benefit from antibiotic therapy.

Authors' conclusions: 

Researchers have found that antibiotics have some effect on inpatients and outpatients, but these effects are small, and they are inconsistent for some outcomes (treatment failure) and absent for other outcomes (mortality, length of hospital stay). Analyses show a strong beneficial effect of antibiotics among ICU patients. Few data are available on the effects of antibiotics on health-related quality of life or on other patient-reported symptoms, and data show no statistically significant increase in the risk of adverse events with antibiotics compared to placebo. These inconsistent effects call for research into clinical signs and biomarkers that can help identify patients who would benefit from antibiotics, while sparing antibiotics for patients who are unlikely to experience benefit and for whom downsides of antibiotics (side effects, costs, and multi-resistance) should be avoided.

Read the full abstract...
Background: 

Many patients with an exacerbation of chronic obstructive pulmonary disease (COPD) are treated with antibiotics. However, the value of antibiotics remains uncertain, as systematic reviews and clinical trials have shown conflicting results.

Objectives: 

To assess effects of antibiotics on treatment failure as observed between seven days and one month after treatment initiation (primary outcome) for management of acute COPD exacerbations, as well as their effects on other patient-important outcomes (mortality, adverse events, length of hospital stay, time to next exacerbation).

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library, MEDLINE, Embase, and other electronically available databases up to 26 September 2018.

Selection criteria: 

We sought to find randomised controlled trials (RCTs) including people with acute COPD exacerbations comparing antibiotic therapy and placebo and providing follow-up of at least seven days.

Data collection and analysis: 

Two review authors independently screened references and extracted data from trial reports. We kept the three groups of outpatients, inpatients, and patients admitted to the intensive care unit (ICU) separate for benefit outcomes and mortality because we considered them to be clinically too different to be summarised as a single group. We considered outpatients to have a mild to moderate exacerbation, inpatients to have a severe exacerbation, and ICU patients to have a very severe exacerbation. When authors of primary studies did not report outcomes or study details, we contacted them to request missing data. We calculated pooled risk ratios (RRs) for treatment failure, Peto odds ratios (ORs) for rare events (mortality and adverse events), and mean differences (MDs) for continuous outcomes using random-effects models. We used GRADE to assess the quality of the evidence. The primary outcome was treatment failure as observed between seven days and one month after treatment initiation.

Main results: 

We included 19 trials with 2663 participants (11 with outpatients, seven with inpatients, and one with ICU patients).

For outpatients (with mild to moderate exacerbations), evidence of low quality suggests that currently available antibiotics statistically significantly reduced the risk for treatment failure between seven days and one month after treatment initiation (RR 0.72, 95% confidence interval (CI) 0.56 to 0.94; I² = 31%; in absolute terms, reduction in treatment failures from 295 to 212 per 1000 treated participants, 95% CI 165 to 277). Studies providing older antibiotics not in use anymore yielded an RR of 0.69 (95% CI 0.53 to 0.90; I² = 31%). Evidence of low quality from one trial in outpatients suggested no effects of antibiotics on mortality (Peto OR 1.27, 95% CI 0.49 to 3.30). One trial reported no effects of antibiotics on re-exacerbations between two and six weeks after treatment initiation. Only one trial (N = 35) reported health-related quality of life but did not show a statistically significant difference between treatment and control groups.

Evidence of moderate quality does not show that currently used antibiotics statistically significantly reduced the risk of treatment failure among inpatients with severe exacerbations (i.e. for inpatients excluding ICU patients) (RR 0.65, 95% CI 0.38 to 1.12; I² = 50%), but trial results remain uncertain. In turn, the effect was statistically significant when trials included older antibiotics no longer in clinical use (RR 0.76, 95% CI 0.58 to 1.00; I² = 39%). Evidence of moderate quality from two trials including inpatients shows no beneficial effects of antibiotics on mortality (Peto OR 2.48, 95% CI 0.94 to 6.55). Length of hospital stay (in days) was similar in antibiotic and placebo groups.

The only trial with 93 patients admitted to the ICU showed a large and statistically significant effect on treatment failure (RR 0.19, 95% CI 0.08 to 0.45; moderate-quality evidence; in absolute terms, reduction in treatment failures from 565 to 107 per 1000 treated participants, 95% CI 45 to 254). Results of this trial show a statistically significant effect on mortality (Peto OR 0.21, 95% CI 0.06 to 0.72; moderate-quality evidence) and on length of hospital stay (MD -9.60 days, 95% CI -12.84 to -6.36; low-quality evidence).

Evidence of moderate quality gathered from trials conducted in all settings shows no statistically significant effect on overall incidence of adverse events (Peto OR 1.20, 95% CI 0.89 to 1.63; moderate-quality evidence) nor on diarrhoea (Peto OR 1.68, 95% CI 0.92 to 3.07; moderate-quality evidence).

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