Chronic obstructive pulmonary disease (acute exacerbation): antimicrobial prescribing

The committee discussed the evidence from a large systematic review and meta-analysis of double-blind, placebo-controlled RCTs for the use of antibiotics in people with an acute exacerbation of COPD (Vollenweider et al. 2012).

The committee noted the variations in diagnosis of COPD (or chronic bronchitis) and acute exacerbations of COPD across the included studies (particularly in older studies). The included studies covered a heterogeneous population ranging from people with mild exacerbations receiving treatment in the community to people with very severe exacerbations requiring ventilation in intensive care. There was no definition for the severity of exacerbation that was used in the studies.

The committee questioned the appropriateness of using the care setting as a proxy for the severity of exacerbation (many included studies were from the USA where hospital admission systems differ from UK practice).

Evidence that is available from RCTs in the systematic review does not help to identify people who have a bacterial infection and may be more likely to benefit from an antibiotic. The committee noted, and agreed with the authors' conclusions, that in the analysis there was a lack of power to determine clinical effectiveness by the presence or absence of particular symptoms or signs (for example, sputum colour changes). The committee also noted that the systematic review included people who presented with 1 or more exacerbation symptom, and the analysis did not stratify people by symptoms when assessing the effectiveness of antibiotics.

The committee agreed that microbiological eradication outcomes were difficult to interpret and that clinical outcome measures should be prioritised, although they recognised that the definition of treatment failure (no improvement) varied across the studies.

The committee also noted the analysis based on antibiotics in current use, and agreed that these results should be prioritised for decision-making.

Overall, the committee noted reasonably high NNTs for antibiotics compared with placebo. In people who received treatment in the community, about 14 people would need antibiotics to prevent 1 person from having treatment failure (no improvement in symptoms). In people who received treatment in hospital, about 10 people would need antibiotics to prevent 1 person from having treatment failure.

When antibiotics not currently used in practice were excluded from the analysis, the differences between antibiotics and placebo were not statistically significant in the subgroup analyses by care setting (community and hospital). However, the committee agreed that this may be because of a lack of power when fewer studies were included in the analysis. Also not all the antibiotics considered to be in current use by the authors are in current use in the UK.

Overall, there was uncertain evidence about which groups of people may benefit most from antibiotics, although the committee noted that the NNT for symptoms that didn't resolve or improve was 3 in people receiving treatment in intensive care.

The committee agreed that the limited benefit was likely to be because many acute exacerbations are not caused by bacterial infections, but may be caused by viral infections or environmental factors, such as smoking.

No evidence was identified on back‑up antibiotics and the committee was not able to make a recommendation for people with an acute exacerbation of COPD.

The committee acknowledged the recommendations in the NICE guideline on COPD in over 16s, which cover managing acute exacerbations, including self-management. They recognised that some people at risk of exacerbations may have antibiotics to keep at home as part of their exacerbation action plan. This guideline focuses on optimising the use of antibiotics for an acute exacerbation of COPD and minimising the risk of antimicrobial resistance.

Based on experience, the committee agreed that many health professionals may not be aware of the limited benefit of antibiotics, and that many exacerbations are not caused by a bacterial infection.

The committee recognised that COPD is a complex condition and people often have multiple exacerbations and receive multiple courses of antibiotics, which may not always be appropriate. They were concerned that repeated use of antibiotics means that they will not continue to be effective in the future.

The committee agreed that the evidence suggested that antibiotics had some clinical benefit in a heterogeneous population with acute exacerbations of COPD, in the context of increased harms with antibiotics and antimicrobial resistance. The committee recognised that there isn't a clear distinction between severity of exacerbation and presence of a bacterial infection.

From the evidence identified, the committee agreed that it was not possible to identify which people with an acute exacerbation are more likely to benefit from antibiotics. However, from their experience, and based on existing expert consensus, the presence of sputum colour changes and increases in volume or thickness beyond the person's normal day-to-day variation appear to be important factors.

From experience, the evidence identified and the need to minimise the risk of antimicrobial resistance, the committee agreed that an antibiotic for an acute exacerbation of COPD should be considered on an individual patient basis. This should take into account the uncertain benefit of antibiotics, increased risk of harms and the risk of antimicrobial resistance with repeated courses, balanced against severity of their symptoms (particularly sputum colour changes and increases in volume or thickness beyond the person's normal day-to-day variation), their need for hospital treatment, their exacerbation and hospitalisation history, their risk of complications, and previous sputum culture results.

From experience, the committee recognised that a person's condition may change rapidly during an acute exacerbation. They agreed that health professionals should give the person individualised advice about seeking medical help without delay if symptoms worsen rapidly or significantly, do not start to improve within 2 to 3 days (or other agreed time), or they become systemically very unwell.

The committee was aware of recommendations from the NICE guideline on COPD in over 16s and NICE guideline on sepsis that cover when to refer people to hospital.

Although there was some evidence to suggest that second-line antibiotics were more effective than first-line antibiotics, the absolute difference between groups was small and this analysis was limited by the classification of first- and second-line antibiotics, which was not consistent with current UK practice.

Based on evidence of no major differences in clinical effectiveness between antibiotics or classes of antibiotics, the committee agreed that the choice of antibiotic should largely be driven by minimising the risk of resistance.

If an antibiotic is given, the committee agreed that this should be started empirically or based on the most recent sputum culture (if available). The committee was aware that the NICE guideline on COPD in over 16s makes recommendations about when to send sputum for culture.

The committee agreed that if a sputum sample has been sent for culture and susceptibility testing, when results are available, if they suggest the bacteria are not susceptible, the person should be contacted to assess symptoms. However, the antibiotic should only be changed according to susceptibility results if symptoms are not already improving. In line with good antimicrobial stewardship, narrow-spectrum antibiotics should be used wherever possible, and antibiotics switched from intravenous to oral where applicable.

Based on experience, common pathogens in acute exacerbations of COPD, the susceptibility of these to various classes of antibiotics, the risks of resistance, and good antimicrobial stewardship, the committee agreed antibiotic choices as described below. Several oral and intravenous antibiotics were recommended because people with acute exacerbations of COPD may have repeated courses of antibiotics and may be at an increased risk of resistance. It also enables antibiotics to be selected based on the severity of illness and antibiotic susceptibilities from culture results (if available).

The first-line oral antibiotics are amoxicillin (a penicillin), doxycycline (a tetracycline) and clarithromycin (a macrolide), used at the usual doses for an acute exacerbation of COPD, although the dosage may be increased in severe infections. These antibiotics have good activity against common pathogens, such as Streptococcus pneumoniae and Haemophilus influenzae. Where a person is receiving prophylactic antibiotics, antibiotic treatment for an acute exacerbation should be with an antibiotic from a different class.

The second-line oral antibiotics for people whose symptoms worsen on a first-choice antibiotic taken for at least 2 to 3 days are an alternative first-choice from a different antibiotic class (a different antibiotic may be used for a subsequent exacerbation). This allows broader-spectrum antibiotics (some of which also have additional safety warnings) to be reserved for people who may be at a higher risk of treatment failure (for example, people who have had repeated courses of antibiotics, previous or current sputum culture with resistant bacteria, or people at higher risk of developing complications).

The alternative oral antibiotics for people who may be at a higher risk of treatment failure (guided by susceptibilities when available) are:

The committee was aware of the EMA's Pharmacovigilance Risk Assessment Committee recommendation to restrict the use of fluoroquinolone antibiotics following a review of disabling and potentially long-lasting side effects mainly involving muscles, tendons and bones and the nervous system. However, they discussed that fluoroquinolones are appropriate as an alternative option for people who may be at a higher risk of treatment failure. The committee was keen to point out, however, that fluoroquinolone safety concerns should be taken into account on an individual patient basis.

First-choice intravenous antibiotics at usual doses for treating acute exacerbations in people who are unable to take oral antibiotics, or the severity of their exacerbation means than intravenous treatment is required, are:

Second-choice intravenous antibiotics may be needed for some people after specialist advice, based on the severity of illness, likely pathogens or antibiotic susceptibilities from culture results when available, and local resistance patterns.

The committee agreed that a sputum sample should be sent for culture and susceptibility testing if symptoms have not resolved following antibiotic treatment and this has not been done already. Specific organisms, such as Pseudomonas aeruginosa may need to be looked for if people have prolonged recurrent exacerbations. They discussed that some people with resistant bacteria may need intravenous antibiotics, particularly if their symptoms are not responding to several courses of oral antibiotics for the same episode, or if several sputum samples show resistance to oral antibiotics.

The committee discussed that specialist advice should be sought for people needing intravenous antibiotics, to discuss local options for giving intravenous antibiotics at home or in the community, rather than in hospital.