Guidance
Summary of the evidence
The recommendations in this guideline are based on the evidence identified, which was for antibiotics for managing an acute exacerbation of chronic obstructive pulmonary disease (COPD) in adults. Non-antimicrobial interventions, such as bronchodilators, corticosteroids and oxygen therapy are covered in the NICE guideline on COPD in over 16s.
Antibiotics
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A number of factors are known to trigger an acute exacerbation of COPD, including a viral respiratory tract infection and environmental factors, such as smoking (see the NICE guideline on COPD in over 16s). Only about half of exacerbations are thought to be caused by a bacterial infection (Vollenweider et al. 2012).
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The diagnosis of COPD or chronic bronchitis varied across included studies, and may have been confirmed by spirometry or by a clinician. It was not defined in some studies.
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Similarly, the diagnosis of an acute exacerbation varied, but was mainly based on the Anthonisen classification or a clinical evaluation of worsening symptoms and signs. In some studies, it was not defined.
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Studies often included people with varying severity of acute exacerbation (often based on the Anthonisen classification of type of exacerbation or not defined). Studies were conducted in various settings.
Back-up antibiotics
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No systematic reviews or randomised controlled trials (RCTs) were identified on back-up antibiotics for people with an acute exacerbation of COPD.
Efficacy of antibiotics
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The evidence review for the efficacy of antibiotics was based on a systematic review and meta-analysis of RCTs (Vollenweider et al. 2012). This systematic review conducted subgroup analyses by care setting, and a sensitivity analysis restricted to antibiotics, which the authors considered to be in current use.
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With antibiotics, significantly fewer people (age range 52 to 72 years) with an acute exacerbation of COPD had symptoms that didn't resolve or improve up to 1 month after treatment starting, compared with placebo (28.4% versus 37.4%, number needed to treat [NNT] 12 [range 8 to 23], very low quality evidence).
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However, this was a heterogeneous population receiving treatment in the community, in hospital or in intensive care, and the result was influenced by the large positive effect observed in 1 RCT in people in intensive care. When this study was removed from the analysis, the benefit of antibiotics compared with placebo was reduced (29.4% versus 36.1%, NNT 15 [range 9 to 50], moderate quality evidence).
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The diagnosis of an acute exacerbation was a worsening of previously stable COPD, with 1 or more symptoms such as increased breathlessness, increased cough, increased sputum volume or change in sputum colour. The care setting was used a marker of the severity of the acute exacerbation.
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A wide range of antibiotics were included across the studies and the antibiotic course length ranged from 5 to 17 days. Corticosteroid treatment was allowed in 2 of the 16 RCTs.
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Significantly fewer people who had antibiotics had symptoms that didn't resolve or improve compared with placebo. The effect of antibiotics appeared to be greater in people with increasing severity of exacerbation (based on care setting), as follows:
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in people receiving treatment in the community (classified as a mild to moderate exacerbation): 19.9% versus 27.5%, NNT 14 (range 8 to 46), moderate quality evidence
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in people receiving treatment in hospital (classified as a severe exacerbation): 41.8% versus 52.0%, NNT 10 (range 6 to 45), moderate quality evidence
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in people receiving treatment in intensive care (classified as a very severe exacerbation): 10.6% versus 56.5%, NNT 3 (range 2 to 4), high quality evidence.
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Vollenweider et al. (2012) also conducted a sensitivity analysis, which only included antibiotics that the authors considered to be in current use (including amoxicillin, co‑amoxiclav, co‑trimoxazole and doxycycline). Studies assessing oxytetracycline, tetracycline and chloramphenicol were excluded from this analysis. There remained a significant difference between antibiotics and placebo overall in this analysis (24.5% versus 34.5%; NNT 11 [range 7 to 21], low quality evidence), but there was no significant difference in a subgroup receiving treatment in the community (22.2% versus 29.1%, low quality evidence) or in people receiving treatment in hospital (excluding intensive care: 28.9% versus 45.9%, low quality evidence).
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Antibiotics were not significantly more effective than placebo in reducing the length of hospital stay in 3 RCTs that reported this outcome (11 days versus 17 days, very low quality evidence). Antibiotics significantly reduced the number of days off work during follow‑up in people receiving treatment in the community in 1 RCT, although this was based on small numbers of participants (n=88) and a short follow‑up (17 days; 4.3 days versus 9.4 days, high quality evidence, Vollenweider et al. 2012).
Safety of antibiotics
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Antibiotic-associated diarrhoea is estimated to occur in 2 to 25% of people taking antibiotics, depending on the antibiotic used (NICE clinical knowledge summary on diarrhoea – antibiotic associated).
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About 10% of the general population claim to have a penicillin allergy; this is often because of a skin rash that occurred while taking a course of penicillin as a child. Fewer than 10% of people who think they are allergic to penicillin are truly allergic. See the NICE guideline on drug allergy for more information.
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People with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF, October 2018).
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Macrolides should be used with caution in people with a predisposition to QT interval prolongation (BNF, October 2018).
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Tendon damage (including rupture) has been reported rarely in people receiving fluoroquinolones (BNF, October 2018), and the European Medicines Agency's Pharmacovigilance Risk Assessment Committee (press release October 2018) has recommended restricting the use of these antibiotics following a review of disabling and potentially long-lasting side effects mainly involving muscles, tendons and bones and the nervous system. This includes a recommendation to not use them for mild or moderately severe infections unless other antibiotics cannot be used.
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Co-trimoxazole is currently under restriction for use in the UK. It is advised that it only be considered for use in acute exacerbations of COPD when there is bacteriological evidence of sensitivity to co‑trimoxazole and good reason to prefer this combination to a single antibiotic (BNF, October 2018).
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From the systematic review and meta-analysis of RCTs (Vollenweider et al. 2012), adverse events were significantly increased with antibiotics compared with placebo between 5 and 28 days after treatment (10.6% versus 7.4%, low quality evidence), although there is considerable uncertainty in this result because the frequency of adverse events was low. Significantly more people reported diarrhoea with antibiotics compared with placebo (4.4% versus 1.8%, low quality evidence), although the incidence was low in both groups.
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See the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.
Committee discussion on antibiotics Limitations of the data:
Interpretation of the results
Rationale for decision-making
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Choice of antibiotics
First-line antibiotics compared with second-line antibiotics
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Evidence for the choice of first-line or second-line antibiotics was based on a systematic review and meta-analysis of RCTs (Dimopoulos et al. 2007).
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First-line antibiotics (amoxicillin, ampicillin, pivampicillin, co‑trimoxazole and doxycycline) were significantly less effective in resolving or improving exacerbation symptoms up to 7 days after the end of treatment, compared with second-line antibiotics (co‑amoxiclav, macrolides, fluoroquinolones and cefaclor) in people (age range 49 to 71 years) with an acute exacerbation of chronic bronchitis (81.8% versus 91.3%, NNT 11 [range 8 to 16], moderate quality evidence).
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Similar results were observed in a subgroup who received treatment in the community with first-line and second-line antibiotics respectively (90.3% versus 95.5%, moderate quality evidence), although most people in both groups had resolving or improving exacerbation symptoms up to 7 days after the end of treatment. In people receiving treatment in hospital, there was no significant difference between first-line and second-line antibiotics (74.0% versus 87.5%, low quality evidence), but some studies also included people receiving treatment in the community.
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Dimopoulos et al. (2007) included 4 RCTs in people receiving treatment in the community and 6 RCTs in people receiving treatment in hospital (4 of these RCTs had a mixed population who received treatment in the community or in hospital).
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The diagnosis of an acute exacerbation and the type of symptoms was based on the Anthonisen classification. The severity of exacerbation varied across studies and was not specified in 2 RCTs.
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Dosage varied by antibiotic and the course length ranged from 5 to 14 days. Corticosteroid treatment was permitted before an acute exacerbation in 3 RCTs.
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There were no significant differences between groups in antibiotic-related adverse events (14.6% versus 20.6%, very low quality evidence) or in all‑cause mortality (1.0% versus 1.6%, low quality evidence).
Other antibiotic comparisons
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There were no significant differences in clinical effectiveness between antibiotics or classes of antibiotics, including co‑amoxiclav, macrolides, fluoroquinolones, cephalosporins and trimethoprim (with or without a sulfonamide) in people with an acute exacerbation of COPD. This is based on 2 systematic reviews and meta-analyses of RCTs (Korbila et al. 2009 and Siempos et al. 2007), and 4 RCTs (Nouira et al. 2010, Petitpretz et al. 2007, Yoon et al. 2013 and Urueta-Robledo et al. 2006), which all cover different comparisons of antibiotic regimens for up to 6 months' (in 2 RCTs) follow‑up.
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One large systematic review and meta-analysis of 19 RCTs (Siempos et al. 2007; n=7,045) comparing commonly used broader-spectrum antibiotics (co‑amoxiclav, macrolides and fluoroquinolones) for 3 to 10 days found no significant difference in clinical effectiveness between groups (moderate to high quality evidence). Most people included in this review received treatment in the community. The available data did not allow subgroup analyses to be carried out in people considered to be at increased risk of poorer outcomes (such as older people, people with severe COPD and people with more frequent exacerbations).
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In Siempos et al. (2007), a subgroup analysis of people with moderate or severe acute exacerbations found no significant difference in the resolution or improvement in exacerbation symptoms between macrolides and fluoroquinolones (80.7% versus 80.1%, high quality of evidence).
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In 1 double-blinded RCT (Nouira et al. 2010; n=170), the effectiveness of co‑trimoxazole 160/800 mg twice a day for 10 days was compared with ciprofloxacin 750 mg twice a day for 10 days in people (mean age 67 years) with a severe acute exacerbation of COPD being admitted to an intensive care unit in hospital. No significant differences between antibiotic groups were found up to 6 months after treatment (low to moderate quality evidence).
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The antibiotic course length ranged from 3 to 14 days in the studies. One double-blinded RCT (Urueta-Robledo et al. 2006) found no significant difference in the resolution of exacerbation symptoms with levofloxacin for 7 days compared with moxifloxacin for 5 days (moderate quality evidence).
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Overall, there were no major differences in adverse effects between antibiotics or classes of antibiotics based on the included studies (low to high quality evidence).
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In the systematic review by Siempos et al. (2007), significantly more people reported adverse events with co‑amoxiclav compared with fluoroquinolones (16.6% versus 12.8%, NNH 27 [range 13 to 207], moderate quality evidence).
Committee discussion on choice of antibiotic
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Antibiotic course length
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Short-course antibiotics (for less than 6 days) were not significantly different from long-course antibiotics (for 7 days or more of the same antibiotic) in resolution of exacerbation symptoms after completing treatment, in people with an acute exacerbation of COPD (moderate quality evidence). This was based on a systematic review and meta-analysis (Stolbrink et al. 2017). This result was consistent regardless of the length of follow‑up (within 6 days, 7 to 14 days or more than 20 days) or the care setting (3 of the 10 RCTs were in hospital).
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The diagnosis of an acute exacerbation was based on clinical evaluation in all studies, except 1 RCT that used microscopically confirmed purulent sputum. The severity of exacerbation ranged from mild to severe, and 4 RCTs used the Anthonisen classification of type of exacerbation for assessing exacerbation severity.
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A range of antibiotics were included in Stolbrink et al. (2017) with fluoroquinolones being the most commonly studied antibiotics. In most studies, a 3‑day or 5‑day course was compared with a 7‑day or 10‑day course of the same antibiotic.
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There were significantly fewer adverse events with short-course antibiotics compared with long-course antibiotics (20.9% versus 24.9%, NNH 25 [range 14 to 100]; low quality evidence).
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No systematic reviews or RCTs were identified that compared the frequency of antibiotic dosing or the route of antibiotic administration.
Committee discussion on antibiotic course length
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See the full evidence review for more information.