X2.2.3 Antibiotics for treatment of exacerbations

Exacerbations with clinical features of infection (increased volume and change in colour of sputum and/or fever) benefit from antibiotic therapy [evidence level II, strong recommendation]

Bacterial infection may have either a primary or secondary role in about 50% of exacerbations of COPD (Macfarlane 1993Wilson 1998Miravitlles 1999Patel 2002). Haemophilus influenzae, Streptococcous pneumoniae and Moraxella catarrhalis are most commonly involved (Macfarlane 1993Soler 1998Murphy 1999). Mycoplasma pneumoniae and Chlamydia pneumoniae have also been reported (Macfarlane 1993Mogulkoc 1999). As lung function deteriorates (FEV1 < 35%), Pseudomonas aeruginosa and Staphylococcus aureus may be encountered (Macfarlane 1993, Soler 1998Miravitlles 1999). Multi drug resistant Ps. aeruginosa is associated with 6 fold increased risk of death (Montero 2009) [evidence level III-2].

A 2018 Cochrane systematic review (Vollenweider 2018) found a reduction in treatment failure in patients with severe exacerbations who were treated with antibiotics (RR 0.77; 95% CI 0.65 to 0.91; I2 = 47%). Treatment failure was defined as lack of improvement in symptoms, deterioration, need for further antibiotics or death due to exacerbation. A reduction in mortality (data from one trial only) and a reduced length of stay was only seen in patients admitted to ICU. Patients treated with antibiotics experienced higher rates of diarrhoea (OR 2.62; 95% CI 1.11 to 6.17). No significant benefit for treatment failure in outpatients was found when analysis was restricted to currently available antibiotics (RR 0.80; 95% CI 0.63 to 1.01; I2 = 33%). A re-examination of data from the placebo arm of a Spanish antibiotic trial that recruited patients with mild to moderate COPD from primary care confirmed that sputum purulence increased the likelihood of treatment failure 6-fold.  A CRP elevated greater than 40 mg/L was also independently associated with a 13 fold increase in the risk of treatment failure.(Miravitlles 2013) [evidence level III-2].

A study of 220 patients hospitalised with exacerbations of COPD with clinical features of infection, randomised to CRP-guided antibiotic therapy (antibiotics if CRP ≥ 50mg/L) or GOLD criteria based antibiotic treatment found a significant reduction in antibiotic use in the CRP guided group, with an absolute reduction in antibiotic use of 14.5% (Prins 2019) [evidence level II]. An open label RCT (n=653) of patients in the UK showed that in patients with COPD exacerbations treated in primary care, use of point-of-care CRP testing to guide prescribing of antibiotics lowered patient-reported antibiotic use (OR 0.31, 95% CI 0.20 to 0.47) (Butler 2019) [evidence level II]. The judicious use of CRP testing in primary or tertiary care may assist in determining the need for antibiotics for exacerbation management.

El Moussaoui et al (El Moussaoui 2008) conducted a systematic review of 21 randomised controlled trials of antibiotics in exacerbations of chronic bronchitis and COPD. There were similar rates of clinical or bacteriological cure with short courses (≤ 5 days) and longer courses of antibiotics [evidence level I]. A related systematic review (Falagas 2008) found that patients receiving short courses experienced fewer adverse effects than those receiving longer courses. It would be necessary to treat 26 (95% CI 15 to 134) patients with short course antibiotics to prevent one adverse effect. However, the antibiotics evaluated were late generation cephalosporins, macrolides and fluoroquinolones, which are not those recommended in Australia.

Procalcitonin is an acute phase reactant. Procalcitonin levels increase in bacterial infections but do not increase in viral infections or auto-immune inflammation (Gilbert 2011). Procalcitonin has been proposed as a measure to determine if patients with an exacerbation of COPD require oral antibiotics.  In most clinical trials, use of antibiotics was discouraged if procalcitonin was 0.1ng/ml or lower and encouraged if procalcitonin was above 0.25ng/ml.

A meta-analysis of eight randomised or quasi-randomised trials, evaluating 1,062 patients, compared procalcitonin-based protocols to initiate or discontinue antibiotics, versus standard care in COPD exacerbation (Mathioudakis 2017). Procalcitonin-based protocols decreased antibiotic prescription (relative risk (RR) 0.56, 95% CI 0.43–0.73) without affecting clinical outcomes such as rate of treatment failure, length of hospitalisation, exacerbation recurrence rate or mortality (low to moderate quality evidence). Since the publication of this meta-analysis, a further trial has also reported that procalcitonin-based protocols reduce antibiotic use without increasing complications (Wang 2016a).

A meta-analysis of RCTs and observational studies investigating the impact of a procalcitonin-based protocol on antibiotic prescription and clinical outcomes in patients with COPD exacerbations, found that the use of procalcitonin-based protocols significantly reduced the length of antibiotic treatment in COPD exacerbation (MD = -2.01 days, 95% CI -3.89 to -0.14 days, p=0.04, moderate quality, and MD = -1.64 days, 95% CI -2.91 to -0.36 days, p=0.01, very low quality for RCTs and observational study, respectively), while no apparent effects were found on length of hospital stay, treatment failure and all-cause mortality. The effect of procalcitonin on antibiotic duration was no longer significant (MD = -1.88 days, 95% CI -3.95 to 0.19 days, p=0.08, and MD = -1.72 days, 95% CI -4.28 to 0.83 days, p=0.19, respectively), when studies with high risk of bias were excluded.

Procalcitonin has limited value in guiding antibiotic use in COPD exacerbation (Chen 2020) [evidence level I].

It is important to note that patients with pneumonia were excluded from these trials. Based on the evidence from these trials, it may be possible to withhold antibiotic therapy in patients presenting to the emergency department with an exacerbation of COPD, who are afebrile, have no pneumonia on chest imaging, and have a serum procalcitonin level of <0.1ng/ml. This test is not currently funded by Medicare in Australia and is only available in some centres.  Despite promising data from multiple clinical trials, cross-sectional and longitudinal analysis of over 200,000 COPD admissions from 505 US hospitals did not show a change in antibiotic prescribing rates or duration of use in hospitals that had begun using procalcitonin testing (Lindenauer 2017). The authors conclude that further implementation research is required.

Therapeutic guidelines: antibiotic (Therapeutic Guidelines Limited 2014) recommend the use of oral agents such as amoxycillin or doxycycline.

If patients do not respond to the above antibiotics, or if resistant organisms are suspected, amoxycillin–clavu­lanate could be prescribed. If pneumonia, Pseudomonas or staphylococci are suspected, appropriate antibiotics should be used.

Typically, a course of treatment should be at least five days. A response is usually seen within three to five days, and a change of antibiotic should be considered if the response is unsatisfactory. If parenteral administration was commenced, oral treatment should be substituted within 72 hours. An historical population-based cohort study (Roede 2008) [evidence level III-2] found that co-treatment of an exacerbation with oral corticosteroids and oral antibiotics significantly increased the time to subsequent exacerbations (median 312 versus 418 days, p<0.001 to next compared to oral corticosteroids alone).

Two Australian retrospective case series of hospitalised COPD patients have found that antibiotic treatment was guideline concordant in less than 15% of cases (Brownridge 2017, Fanning 2014). This was due to over-use of intravenous antibiotics and prescription of dual antibiotics. Further efforts are needed to increase adherence to the use of oral antibiotics in patients hospitalised with exacerbations of COPD, where appropriate.

An Australian retrospective case series of 84 hospitalised COPD patients found that antibiotic treatment was non-concordant with guideline recommendations in the majority of patients (86%), mainly due to over-use of intravenous antibiotics (Fanning 2014). Further efforts are needed to increase adherence to use of oral antibiotics in patients hospitalised with exacerbations of COPD, where appropriate.

Radiologically proven pneumonia in patients with COPD, especially in those who have been frequently hospitalised, may not be restricted to the above organisms. Gram-negative organisms, Legionella and even anaerobic organisms may be responsible. Initial empiric antibiotic therapy should be tailored according to clinical and radio­graphic criteria.