TY - JOUR
AU - Eelko, Hak,
AB - Abstract Background As bacterial infections provoke exacerbations, COPD patients may benefit from prophylactic antibiotics. However, evidence regarding their overall benefit–risk profile is conflicting. Objectives To update previous evidence and systematically evaluate the beneficial effects and side effects of prophylactic antibiotics in stable COPD patients. Methods Several databases were searched up to 26 April 2017 for randomized controlled trials (RCTs) on prophylactic antibiotics in stable COPD patients. The primary outcomes were exacerbations and quality of life. Duration and schedule of antibiotics were considered in subgroup analyses. Results Twelve RCTs involving 3683 patients were included. Prophylactic antibiotics significantly reduced the frequency of exacerbations [risk ratio (RR) 0.74, 95% CI 0.60–0.92] and the number of patients with one or more exacerbations (RR 0.82, 95% CI 0.74–0.90). Erythromycin and azithromycin appeared the most effective, with the number needed to treat ranging from four to seven. Quality of life was also significantly improved by prophylactic antibiotics (mean difference −1.55, 95% CI −2.59 to −0.51). Time to first exacerbation was prolonged in six studies, with one conflicting result. Neither the rate of hospitalization nor the rate of adverse events was significantly changed. Furthermore, no significant changes were observed in lung function, bacterial load and airway inflammation. However, antibiotic-resistant isolates were significantly increased (OR 4.49, 95% CI 2.48–8.12). Conclusions Prophylactic antibiotics were effective in preventing COPD exacerbations and improving quality of life among stable patients with moderate to severe COPD. The choice of prophylactic antibiotics should be analysed and considered case by case, especially for long and continuous use. Introduction COPD is an inflammatory disease that is characterized by persistent respiratory symptoms and airflow limitation.1 At present, COPD is one of the leading causes of chronic morbidity and mortality worldwide, and its burden is predicted to increase in the coming decades due to continuous exposure to risk factors and ageing of the population globally.2 In the course of COPD, exacerbation as an acute worsening of respiratory symptoms has a profound negative impact on health oucomes.3 A vicious circle of infection and inflammation is thought to be a key trigger of exacerbations of COPD; ∼40%–50% of exacerbations are caused by bacteria.4 The use of prophylactic antibiotics has been suggested to prevent exacerbations in COPD patients for a long time. However, a Cochrane review in 2003 concluded that antibiotics only contribute to a small (9%) reduction in exacerbations and should not be part of routine treatment, considering the risk of antibiotic resistance and adverse effects.5 Ten years later, in 2013, the review by Herath and Poole6 concluded that there was a clinically significant benefit in reducing COPD exacerbations from continuous use of prophylactic antibiotics, but not from intermittent use. In that review, due to the fact that only one randomized controlled trial (RCT) was included in the subgroup of intermittant use, more studies are needed to further confirm the effects of intermittant antibiotics. The influence of different durations of antibiotic intervention was not explored in that study. The most recent review, by Ni et al.7 in 2015, focused on macrolides only and did not evaluate meaningful outcomes including the time to first exacerbation, change in lung function, bacterial load and airway inflammation. The last two outcomes are important in supporting the hypothetical mechanism behind the reduction in exacerbations by antibiotics.8 The current recommendation from guidelines about prophylactic antibiotic use in the management of COPD exacerbations is conditional and unspecific.1,9 At present, the optimal regimen of prophylactic antibiotics for exacerbations has not been well established and there is no advice regarding an appropriate schedule and duration of specific antibiotic intervention. To further enhance information on the public health benefit–risk profile associated with this intervention, we aimed to provide a comprehensive overview of the positive and negative effects of prophylactic antibiotics on COPD patients. Methods Search strategy We performed an update of the previous review by Herath and Poole6 in 2013 according to the PRISMA guidelines. The Cochrane Central Register of Controlled Trials (CENTRAL), Medline, EMBASE, Web of Science, CINAHL, AMED and PsycINFO databases were systematically searched for relevant RCTs published from 29 August 2013 (when the review by Herath and Poole6 ended) until 26 April 2017 using the key elements of ‘COPD’, ‘RCT’ and ‘antibiotics’ (details are presented in Table S1, available as Supplementary data at JAC Online). References from identified studies and relevant review articles were also checked manually. No language restrictions were applied. For the final analysis, we included both the new studies from this searching strategy and previous studies from the review by Herath and Poole.6 Table 1. Characteristics of included studies Study (first author, year) Study design Country Patients (T:P) Age (years) (T:P) FEV1/FVC ratio (%) (T:P) Prophylactic antibiotic, dose Duration of treatment and follow-up (months) Maintenance medication Previous included studies  Albert, 201119 RCT USA 570:572 65:66 42:43 azithromycin, 250 mg daily 12 and 12 ICS, LABA, LAMA  He, 201012 RCT UK 18:18 68.8:69.3 46.9:48.6 erythromycin, 125 mg, 3 times a day; 6 and 6 ICS,  Mygind, 201013 RCT Denmark 287:288 71 (median) NA azithromycin, 500 mg daily, 3 days a month 36 and 36 ICS, theophylline, inhaled anticholinergic agents, inhaled β-adrenergic agents  Sethi, 201021 RCT USA 569:580 66.1:66.6 45.0:46.3 moxifloxacin, 400 mg daily, 5 days every 8 weeks 12 and 18 LABA, LAMA, SABA, SAMA, ICS, theophylline  Seemungal, 200820 RCT UK 53:56 66.6:67.8 48.9:50.9 erythromycin, 250 mg twice daily 12 and 12 LABA, LAMA, theophylline  Banerjee, 200515 RCT UK 31:36 65.1:68.1 43.8:45.5 clarithromycin, 500 mg once daily 3 and 3 ICS  Suzuki, 200114 RCT Japan 55:54 69.1:71.7 NA erythromycin, 200–400 mg daily 12 and 12 inhaled anticholinergic agents, theophylline Newly included studies  Brill, 2015,a,16 RCT UK (25:25:25):24 (70.9:70.4:67.9):68.7 (51:51:45):51 T1: moxifloxacin, 400 mg, 5 times every 4 weeks T2: doxycycline, 100 mg daily T3: azithromycin, 250 mg, 3 times a week 3.25 and 3.25 ICS  Shafuddin, 2015b,22 RCT New Zealand 97:94 67.6:66.7 41.5:43.7 roxithromycin, 300 mg daily 3 and 12 NA  Simpson, 201411 RCT Australia 15:15 71.7:69.9 52.3:51.3 azithromycin, 250 mg daily 3 and 6 ICS  Uzun, 201417 RCT the Netherlands 47:45 64.7:64.9 38.0:40.3 azithromycin, 500 mg, 3 times a week 12 and 12 LABA, LAMA, SABA, ICS, prednisolone  Berkhof, 201318 RCT the Netherlands 42:42 67:68 42.2:43.2 azithromycin, 250 mg, 3 times a week 3 and 4.5 LABA, LAMA, ICS Study (first author, year) Study design Country Patients (T:P) Age (years) (T:P) FEV1/FVC ratio (%) (T:P) Prophylactic antibiotic, dose Duration of treatment and follow-up (months) Maintenance medication Previous included studies  Albert, 201119 RCT USA 570:572 65:66 42:43 azithromycin, 250 mg daily 12 and 12 ICS, LABA, LAMA  He, 201012 RCT UK 18:18 68.8:69.3 46.9:48.6 erythromycin, 125 mg, 3 times a day; 6 and 6 ICS,  Mygind, 201013 RCT Denmark 287:288 71 (median) NA azithromycin, 500 mg daily, 3 days a month 36 and 36 ICS, theophylline, inhaled anticholinergic agents, inhaled β-adrenergic agents  Sethi, 201021 RCT USA 569:580 66.1:66.6 45.0:46.3 moxifloxacin, 400 mg daily, 5 days every 8 weeks 12 and 18 LABA, LAMA, SABA, SAMA, ICS, theophylline  Seemungal, 200820 RCT UK 53:56 66.6:67.8 48.9:50.9 erythromycin, 250 mg twice daily 12 and 12 LABA, LAMA, theophylline  Banerjee, 200515 RCT UK 31:36 65.1:68.1 43.8:45.5 clarithromycin, 500 mg once daily 3 and 3 ICS  Suzuki, 200114 RCT Japan 55:54 69.1:71.7 NA erythromycin, 200–400 mg daily 12 and 12 inhaled anticholinergic agents, theophylline Newly included studies  Brill, 2015,a,16 RCT UK (25:25:25):24 (70.9:70.4:67.9):68.7 (51:51:45):51 T1: moxifloxacin, 400 mg, 5 times every 4 weeks T2: doxycycline, 100 mg daily T3: azithromycin, 250 mg, 3 times a week 3.25 and 3.25 ICS  Shafuddin, 2015b,22 RCT New Zealand 97:94 67.6:66.7 41.5:43.7 roxithromycin, 300 mg daily 3 and 12 NA  Simpson, 201411 RCT Australia 15:15 71.7:69.9 52.3:51.3 azithromycin, 250 mg daily 3 and 6 ICS  Uzun, 201417 RCT the Netherlands 47:45 64.7:64.9 38.0:40.3 azithromycin, 500 mg, 3 times a week 12 and 12 LABA, LAMA, SABA, ICS, prednisolone  Berkhof, 201318 RCT the Netherlands 42:42 67:68 42.2:43.2 azithromycin, 250 mg, 3 times a week 3 and 4.5 LABA, LAMA, ICS T:P, treatment group versus placebo group; ICS, inhaled corticosteroid; LABA, long-acting β-2 agonist; LAMA, long-acting muscarinic antagonist; SABA, short-acting β-2 agonist; SAMA, short-acting muscarinic antagonist; NA, not available. a This study included three different treatment arms with one common placebo arm. b This study included two treatment arms; according to preset criteria, we have only included the arm regarding single antibiotic use (the other arm in this study, regarding combined antibiotic treatment, has been excluded). Table 1. Characteristics of included studies Study (first author, year) Study design Country Patients (T:P) Age (years) (T:P) FEV1/FVC ratio (%) (T:P) Prophylactic antibiotic, dose Duration of treatment and follow-up (months) Maintenance medication Previous included studies  Albert, 201119 RCT USA 570:572 65:66 42:43 azithromycin, 250 mg daily 12 and 12 ICS, LABA, LAMA  He, 201012 RCT UK 18:18 68.8:69.3 46.9:48.6 erythromycin, 125 mg, 3 times a day; 6 and 6 ICS,  Mygind, 201013 RCT Denmark 287:288 71 (median) NA azithromycin, 500 mg daily, 3 days a month 36 and 36 ICS, theophylline, inhaled anticholinergic agents, inhaled β-adrenergic agents  Sethi, 201021 RCT USA 569:580 66.1:66.6 45.0:46.3 moxifloxacin, 400 mg daily, 5 days every 8 weeks 12 and 18 LABA, LAMA, SABA, SAMA, ICS, theophylline  Seemungal, 200820 RCT UK 53:56 66.6:67.8 48.9:50.9 erythromycin, 250 mg twice daily 12 and 12 LABA, LAMA, theophylline  Banerjee, 200515 RCT UK 31:36 65.1:68.1 43.8:45.5 clarithromycin, 500 mg once daily 3 and 3 ICS  Suzuki, 200114 RCT Japan 55:54 69.1:71.7 NA erythromycin, 200–400 mg daily 12 and 12 inhaled anticholinergic agents, theophylline Newly included studies  Brill, 2015,a,16 RCT UK (25:25:25):24 (70.9:70.4:67.9):68.7 (51:51:45):51 T1: moxifloxacin, 400 mg, 5 times every 4 weeks T2: doxycycline, 100 mg daily T3: azithromycin, 250 mg, 3 times a week 3.25 and 3.25 ICS  Shafuddin, 2015b,22 RCT New Zealand 97:94 67.6:66.7 41.5:43.7 roxithromycin, 300 mg daily 3 and 12 NA  Simpson, 201411 RCT Australia 15:15 71.7:69.9 52.3:51.3 azithromycin, 250 mg daily 3 and 6 ICS  Uzun, 201417 RCT the Netherlands 47:45 64.7:64.9 38.0:40.3 azithromycin, 500 mg, 3 times a week 12 and 12 LABA, LAMA, SABA, ICS, prednisolone  Berkhof, 201318 RCT the Netherlands 42:42 67:68 42.2:43.2 azithromycin, 250 mg, 3 times a week 3 and 4.5 LABA, LAMA, ICS Study (first author, year) Study design Country Patients (T:P) Age (years) (T:P) FEV1/FVC ratio (%) (T:P) Prophylactic antibiotic, dose Duration of treatment and follow-up (months) Maintenance medication Previous included studies  Albert, 201119 RCT USA 570:572 65:66 42:43 azithromycin, 250 mg daily 12 and 12 ICS, LABA, LAMA  He, 201012 RCT UK 18:18 68.8:69.3 46.9:48.6 erythromycin, 125 mg, 3 times a day; 6 and 6 ICS,  Mygind, 201013 RCT Denmark 287:288 71 (median) NA azithromycin, 500 mg daily, 3 days a month 36 and 36 ICS, theophylline, inhaled anticholinergic agents, inhaled β-adrenergic agents  Sethi, 201021 RCT USA 569:580 66.1:66.6 45.0:46.3 moxifloxacin, 400 mg daily, 5 days every 8 weeks 12 and 18 LABA, LAMA, SABA, SAMA, ICS, theophylline  Seemungal, 200820 RCT UK 53:56 66.6:67.8 48.9:50.9 erythromycin, 250 mg twice daily 12 and 12 LABA, LAMA, theophylline  Banerjee, 200515 RCT UK 31:36 65.1:68.1 43.8:45.5 clarithromycin, 500 mg once daily 3 and 3 ICS  Suzuki, 200114 RCT Japan 55:54 69.1:71.7 NA erythromycin, 200–400 mg daily 12 and 12 inhaled anticholinergic agents, theophylline Newly included studies  Brill, 2015,a,16 RCT UK (25:25:25):24 (70.9:70.4:67.9):68.7 (51:51:45):51 T1: moxifloxacin, 400 mg, 5 times every 4 weeks T2: doxycycline, 100 mg daily T3: azithromycin, 250 mg, 3 times a week 3.25 and 3.25 ICS  Shafuddin, 2015b,22 RCT New Zealand 97:94 67.6:66.7 41.5:43.7 roxithromycin, 300 mg daily 3 and 12 NA  Simpson, 201411 RCT Australia 15:15 71.7:69.9 52.3:51.3 azithromycin, 250 mg daily 3 and 6 ICS  Uzun, 201417 RCT the Netherlands 47:45 64.7:64.9 38.0:40.3 azithromycin, 500 mg, 3 times a week 12 and 12 LABA, LAMA, SABA, ICS, prednisolone  Berkhof, 201318 RCT the Netherlands 42:42 67:68 42.2:43.2 azithromycin, 250 mg, 3 times a week 3 and 4.5 LABA, LAMA, ICS T:P, treatment group versus placebo group; ICS, inhaled corticosteroid; LABA, long-acting β-2 agonist; LAMA, long-acting muscarinic antagonist; SABA, short-acting β-2 agonist; SAMA, short-acting muscarinic antagonist; NA, not available. a This study included three different treatment arms with one common placebo arm. b This study included two treatment arms; according to preset criteria, we have only included the arm regarding single antibiotic use (the other arm in this study, regarding combined antibiotic treatment, has been excluded). Selection criteria Studies included in this review met the following criteria: (i) focus on the effects of prophylactic antibiotics in COPD patients; (ii) study designs must be RCTs with placebo group; (iii) COPD patients should be aged >18 years and have a well-defined diagnosis of COPD and confirmed evidence of persistent airflow limitation [the presence of post-bronchodilator FEV1/FVC (forced expiratory volume in 1 s/forced vital capacity) ratio <0.7]; (iv) prophylactic antibiotics must be given for a minimum period of 12 weeks; and (v) patients must be clinically stable without exacerbation for at least 3 weeks before enrolment. Studies that focused on combined antibiotics (two or more) and studies of patients with other respiratory diseases (e.g. bronchiectasis, asthma) or related genetic diseases, such as cystic fibrosis and primary ciliary dyskinesia, were excluded. Outcomes and data analysis The primary outcomes were as follows: number of patients with exacerbations; frequency of exacerbation; and health-related quality of life assessed by the St George’s Respiratory Questionnaire (SGRQ).10 The secondary outcomes were as follows: median time to first exacerbation; frequency of hospitalization; all-cause mortality; adverse events; antibiotic resistance; and change in lung functions, bacterial load and airway inflammation. The influences of different schedules and durations of prophylactic antibiotic use on exacerbations and quality of life in COPD patients were explored. Because the standard deviation of the SGRQ score change was missing in two studies,11,12 we calculated it according to the Cochrane guideline (see Supplementary Methods). All analyses were done in accordance with the ITT principle using Review Manager Version 5.3. Risk ratio (RR) or OR was calculated for binary outcomes, while mean difference (MD) was calculated for continuous outcomes. Generic inverse variance (GIV) methods were used for non-standard types of both dichotomous and continuous data. Summary measures were pooled using random-effects models. If data could not be combined, we performed a descriptive analysis. Statistical heterogeneity among studies was assessed using the conventional χ2 test and the I2 statistic of inconsistency. Sensitivity analysis was performed by removing studies with a high risk of bias or deviation. A funnel plot was used to assess publication bias. Results Search results From the 667 records generated by new search strategy, 5 new RCT studies were eligible and included (Figure 1). Together with the previous 7 studies from the review by Herath and Poole,6 a total of 12 RCTs were included in this systematic review. However, among all 12 studies, 1 was a conference abstract,13 1 was not blinded14 and 1 did not report effect measures.15 In total, nine studies were qualified for the meta-analysis. Figure 1. View largeDownload slide Flow diagram of literature search and study selection. Figure 1. View largeDownload slide Flow diagram of literature search and study selection. Characteristics of included studies The characteristics of the 12 included studies are shown in Table 1; other specific baseline characteristics about COPD severity and exacerbation history are summarized in Table S2. All these studies were conducted over the last 17 years and involved 3683 stable COPD patients, with 2932 patients involved in the meta-analysis. All included studies focused on one antibiotic arm with one placebo arm except the study by Brill et al.,16 which compared three antibiotics with one common placebo, and we treated this study as three independent RCTs (T1, T2 and T3). In all, six antibiotics were investigated in this review: azithromycin,11,13,16–19 erythromycin,12,14,20 moxifloxacin,16,21 clarithromycin,15 roxithromycin22 and doxycycline.16 The duration of treatment ranged from 3 to 36 months with study size ranging from 30 to 1149 patients. Quality assessment The review authors’ judgement about each risk of bias item in each study can be seen in Figure S1(a). The risk of bias items presented as percentage across all included studies are presented in Figure S1(b). There was no reporting bias in all included studies; only two studies14,16 had potential high risk in the blinding process. For the remaining of bias items, only a small proportion of unclear bias existed. Overall, low risk of bias dominated in all domains of bias. Primary outcomes Seven studies involving 2642 participants11,12,17–21 reported the number of patients with exacerbations (Figure 2), which was significantly reduced (RR 0.82, 95% CI 0.74–0.90) by prophylactic antibiotics, and there was no difference between continuous and intermittent subgroups. However, the difference between other subgroups, with a distinct trend towards significance (P = 0.07), suggested that using antibiotics for ≤6 months may achieve better treatment effects (RR 0.59, 95% CI 0.40–0.86) than longer times (RR 0.84, 95% CI 0.77–0.93), which requires further confirmation. The risk difference (RD) between antibiotic and placebo groups is presented in Figure 3. For erythromycin the RD was substantial (−0.24, 95% CI −0.39 to −0.08) and the corresponding number needed to treat (NNT) was 4, for azithromycin the RD was moderate (−0.14, 95% CI −0.20 to −0.08) and the NNT was 7, and there was no statistically significant effect for moxifloxacin intervention. Figure 2. View largeDownload slide Forest plot of RR (antibiotics versus placebo) for total number of patients with one or more exacerbations stratified by (a) schedule of prophylactic antibiotics and (b) duration of prophylactic antibiotics. M-H, Mantel–Haenszel test. *Studies reviewed by Herath and Poole6 in 2013. Figure 2. View largeDownload slide Forest plot of RR (antibiotics versus placebo) for total number of patients with one or more exacerbations stratified by (a) schedule of prophylactic antibiotics and (b) duration of prophylactic antibiotics. M-H, Mantel–Haenszel test. *Studies reviewed by Herath and Poole6 in 2013. Figure 3. View largeDownload slide Forest plot of RD (antibiotics versus placebo) for total number of patients with one or more exacerbations stratified by types of antibiotics. M-H, Mantel–Haenszel test. *Studies reviewed by Herath and Poole6 in 2013. Figure 3. View largeDownload slide Forest plot of RD (antibiotics versus placebo) for total number of patients with one or more exacerbations stratified by types of antibiotics. M-H, Mantel–Haenszel test. *Studies reviewed by Herath and Poole6 in 2013. Use of prophylactic antibiotic was also associated with a significant reduction in the frequency of exacerbations (RR 0.74, 95% CI 0.60–0.92; Figure 4). As the study by Brill et al.16 has a potential risk of bias in the blinding process, a sensitivity analysis was done with the other six studies, which resulted in a 31% RR reduction in exacerbations among patients taking prophylactic antibiotics (RR 0.69, 95% CI 0.58–0.82). In the subgroup analysis shown in Figure 4, macrolides (azithromycin, erythromycin and roxithromycin) showed beneficial effects on frequency reduction of exacerbations; the benefits from both azithromycin and erythromycin were of clinical significance. However, this beneficial effect was not seen in the use of moxifloxacin and doxycycline. These subgroup differences for frequency of exacerbations were of statistical significance (P = 0.02). Figure 4. View largeDownload slide Forest plot of RR (antibiotics versus placebo) for frequency of exacerbations stratified by types of antibiotic. IV, inverse variance; T1–3, three independent RCTs in study by Brill et al.16 *Studies reviewed by Herath and Poole6 in 2013. Figure 4. View largeDownload slide Forest plot of RR (antibiotics versus placebo) for frequency of exacerbations stratified by types of antibiotic. IV, inverse variance; T1–3, three independent RCTs in study by Brill et al.16 *Studies reviewed by Herath and Poole6 in 2013. Health-related quality of life using the SGRQ was measured in seven studies.11,12,16–19,21 When we performed a sensitivity analysis by removing the study by Berkhof et al.,18 which was very different from the other data, the heterogeneity reduced sharply (I2 changed from 92% to 0%). Hence, only the remaining six studies were included in the final meta-analysis. The pooled result indicated that prophylactic antibiotics led to a significant improvement in the total SGRQ score (MD −1.55, 95% CI −2.59 to −0.51; Figure 5). In subgroup analysis, the improvement in SGRQ score was not seen in either continuous or intermittent antibiotics. However, another subgroup result indicated that the total SGRQ score was significantly changed by long-term intervention (MD −1.70, 95% CI% −2.81 to −0.60), although it was not changed by short-term (≤6 months) intervention (MD −0.34, 95% CI −3.43 to 2.75). Figure 5. View largeDownload slide Forest plot of MD (antibiotics versus placebo) of quality of life by SGRQ stratified by (a) schedule of prophylactic antibiotics and (b) duration of prophylactic antibiotics. IV, inverse variance; T1–3, three independent RCTs in study by Brill et al.16 *Studies reviewed by Herath and Poole6 in 2013. Figure 5. View largeDownload slide Forest plot of MD (antibiotics versus placebo) of quality of life by SGRQ stratified by (a) schedule of prophylactic antibiotics and (b) duration of prophylactic antibiotics. IV, inverse variance; T1–3, three independent RCTs in study by Brill et al.16 *Studies reviewed by Herath and Poole6 in 2013. Four studies12,17,19,21 also reported the component scores of the SGRQ (Figure S2). Both the symptom (MD −3.89, 95% CI −5.48 to −2.31) and impact (MD −1.32, 95% CI −2.61 to −0.03) scores were improved with prophylactic antibiotics. However, the activity score did not show any significant improvement. Of note, none of the improvements in SGRQ score mentioned above reached the hypothesized clinically beneficial level (>4 unit reduction).10 Secondary outcomes Seven studies involving 2803 patients reported the median time to first exacerbation (Table S3). Four studies indicated that using prophylactic antibiotics lengthened the median time to first exacerbation signficantly.12,17,19,20 Two other studies found a similar trend, but without statistical significance.18,21 Only one study showed the opposite result in antibiotic and placebo arms.22 The frequency of hospitalization related to COPD was pooled from five studies with 2576 participants.17–21 No significant difference was observed between antibiotic and placebo groups (RR 0.94, 95% CI 0.83–1.06; Figure 6). Also, no difference in the rate of all-cause mortality was found between the two arms (Figure S3). Figure 6. View largeDownload slide Forest plot of RR (antibiotics versus placebo) for frequency of hospitalization. M-H, Mantel–Haenszel test. *Studies reviewed by Herath and Poole6 in 2013. Figure 6. View largeDownload slide Forest plot of RR (antibiotics versus placebo) for frequency of hospitalization. M-H, Mantel–Haenszel test. *Studies reviewed by Herath and Poole6 in 2013. Eight studies involving 2833 participants reported adverse events related to antibiotic use.11,12,17–22 Overall, there was no significant difference between two comparison arms in the rate of adverse events (RR 1.09, 95% CI 0.84–1.42; Figure 7). As there was a lack of uniform definition about adverse events, the heterogeneity was substantial (I2 = 73%). Considering that the rate of adverse events reported by Shafuddin et al.22 was deviant from the other seven studies, a sensitivity analysis was performed after removal of this study. The homogeneous result (RR 0.93, 95% CI 0.83–1.05, I2=2%) also did not show a significant difference between two arms. In subgroups, gastrointestinal disorders were more frequent in the intervention group than in the control group (RR 1.87, 95% CI 0.98–3.59; Figure S4), with a borderline statistical significance (P = 0.06). However, no statistically significant differences for respiratory and cardiovascular disorders were found. Figure 7. View largeDownload slide Forest plot of RR (antibiotics versus placebo) for adverse events. M-H, Mantel–Haenszel test; *Studies reviewed by Herath and Poole6 in 2013. Figure 7. View largeDownload slide Forest plot of RR (antibiotics versus placebo) for adverse events. M-H, Mantel–Haenszel test; *Studies reviewed by Herath and Poole6 in 2013. Eight studies had bacteriological assessments (Table S4);12,15–21 however, only three studies with five RCTs reported quantitative results for antibiotic resistance.16,17,19 Due to the different definition regarding bacterial resistance outcome in the study by Uzun et al.,17 only the other homogeneous studies involving four RCTs were included for pooled results (OR 4.49, 95% CI 2.48–8.12; Figure 8); long-term (versus short-term) and continuous (versus intermittent) antibiotic intervention seemed to cause more antibiotic resistance, although these subgroup differences did not reach a statistically significant level. Antibiotic resistance appeared for all types of antibiotics involved (Figure 9), although the result for moxifloxacin did not reach statistical significance. No subgroup differences about this outcome were seen among azithromycin, moxifloxacin and doxycycline (P = 0.63). Figure 8. View largeDownload slide Forest plot of OR (antibiotics versus placebo) for antibiotic resistance stratified by (a) schedule of prophylactic antibiotics and (b) duration of prophylactic antibiotics. IV, inverse variance; T1–3, three independent RCTs in study by Brill et al.16 *Study reviewed by Herath and Poole6 in 2013. Figure 8. View largeDownload slide Forest plot of OR (antibiotics versus placebo) for antibiotic resistance stratified by (a) schedule of prophylactic antibiotics and (b) duration of prophylactic antibiotics. IV, inverse variance; T1–3, three independent RCTs in study by Brill et al.16 *Study reviewed by Herath and Poole6 in 2013. Figure 9. View largeDownload slide Forest plot of OR (antibiotics versus placebo) for antibiotic resistance stratified by type of antibiotic. IV, inverse variance; T1–3, three independent RCTs in study by Brill et al.16 *Study reviewed by Herath and Poole6 in 2013. Figure 9. View largeDownload slide Forest plot of OR (antibiotics versus placebo) for antibiotic resistance stratified by type of antibiotic. IV, inverse variance; T1–3, three independent RCTs in study by Brill et al.16 *Study reviewed by Herath and Poole6 in 2013. Eight studies11,13,16–18,20–22 provided the data on changes in lung function (Table S5). However, no study found a significant increase by antibiotic intervention compared with placebo. Mygind et al.13 did not compare the lung function change directly, but measured and compared the lung function in both groups at enrolment and endpoint separately; they also did not find any significant difference. Three studies reported the change in bacterial load.11,15,16 Although both Brill et al.16 and Simpson et al.11 found a greater reduction in bacterial load by prophylactic antibiotic use compared with placebo, the results did not reach statistical significance, even though both quantitative culture and 16S qPCR methods were used by Brill et al.16 Banerjee et al.15 also did not find a significant difference between pre- and post-sputum in terms of the ratio of cfu numbers/bacterial (PPM, potential pathogenic microorganisms) isolates in two arms. The change in airway inflammation was only reported in two studies.11,16 The study by Brill et al.16 showed that no significant changes were seen in cytokines IL-6, IL-8 and IL-1β in any of three antibiotic arms compared with placebo. Similarly, Simpson et al.11 also did not report a significant reduction in sputum neutrophil proportion level or IL-8 in those who received azithromycin compared with placebo group. Discussion This update of previous systematic reviews demonstrates that prophylactic antibiotic use could significantly lower the risk of exacerbations and reduce the number of stable COPD patients experiencing one or more exacerbations, which is consistent with the result by Herath and Poole,6 but the difference is that our review, with more RCTs, suggests that intermittent antibiotics may also be effective in preventing exacerbations, although the result is of borderline significance. Moreover, in contrast with the results of Ni et al.,7 we found that both short-term (≤6 months) and long-term (>6 months) treatments can reduce the number of patients with exacerbations significantly. A short-term treatment had better prevention effects than long-term treatment. Considering that all included patients are clinically stable without exacerbation before enrolment, the above benefit from short therapy is likely due to the benefits of less resistance and adverse events or shorter follow-up time to detect related exacerbations compared with long therapy. Besides duration and schedule of antibiotics, the type of antibiotic also has a profound influence on preventing exacerbations of COPD. In our pre-specified subgroup analysis, we did not find a significant effect of moxifloxacin and doxycycline intervention in the prevention of exacerbations, although a previous study showed that moxifloxacin is equivalent and bacteriologically superior to other antibiotic regimens routinely used.23 However, our results confirmed the superiority of macrolides (azithromycin, erythromycin) in preventing exacerbations of COPD. This benefit of macrolides has also been confirmed previously in patients with cystic fibrosis and non-cystic fibrosis bronchiectasis.24,25 Although the optimal treatment using macrolides for preventing exacerbation has already been conditionally recommended by related guidelines,1,9 the underlying mechanisms are not totally clear.8 Many studies have confirmed that macrolides with 14- and 15-membered macrocyclic lactone rings have properties such as anti-inflammatory, antiviral and potential immune-modulation effects,26 which were proved to be beneficial for COPD patients.27 Therefore, some researchers hypothesized that prevention of exacerbation by macrolides may be due to its antimicrobial effects or anti-inflammatory effects or both. However, neither of the above mechanisms could be supported by evidence in our review.11,15,16,20 More studies are needed in future to explore the answers to this question. Regarding health-related quality of life, our review showed a significant reduction in the total SGRQ score with no heterogeneity. This is consistent with the association study by Martin et al.28 From our study, duration of antibiotic intervention of >6 months can significantly improve the total SGRQ score. As health-related quality of life is influenced largely by the frequency of exacerbations in COPD patients,29 it will be an ideal therapy if both exacerbations and quality of life change in the same positive direction. Our subgroup analysis of both exacerbation and quality of life showed positive results for longer duration (above 6 months) of prophylactic antibiotics. However, as the improvements in total SGRQ score did not reach a clinically significant level, further research is needed to explore the influence of prophylactic antibiotic use on quality of life in the real world. The benefits achieved by prophylactic antibiotics always came at the expense of a variety of adverse events according to the earlier reviewers.30 However, we did not find significant differences in the overall rate of adverse events between antibiotic and placebo arms. It is worth noting that the heterogeneity was substantial due to the variety of definition and measurement methods, and therefore more consistent definition is needed in future studies. Furthermore, much attention should be paid to gastrointestinal disorder with antibiotic use as this disorder was also observed in patients with cystic fibrosis.24 Although not established as an endpoint in our review, hearing loss caused by azithromycin also needs much attention.19 Along with the use of prophylactic antibiotics, there is another growing concern regarding the development of antibiotic resistance. In this review, increases in resistant isolates were seen during intervention with prophylactic antibiotics, which involved macrolides (azithromycin), tetracyclines (doxycycline) and quinolones (moxifloxacin).16,19 As many conflicting reports exist with heterogeneous definitions,15,17,18,20,21 much related evidence from studies with uniform criteria is needed for further exploration. However, based on present evidence, clinicians should pay particular attention to the long and continuous use of antibiotics, considering the potential risk of bacterial resistance for future treatment of infections.4 Furthermore, although the use of macrolides in preventing exacerbations was considered to be a cost-effective strategy,31 the rather rapid induction of bacterial resistance by macrolides should not be ignored.32 Their use should at best be limited to high-risk populations based on considerations of age, exacerbation frequency in the previous year, COPD severity and comorbidities. The choice of antibiotics should be based on the community resistance pattern and their benefits and potential risks must be weighed up by analysing the specific situation case by case. Despite the obvious benefits of antibiotics in prevention of exacerbations, we did not find any reduction in the rate of hospital admission by antibiotic intervention, which is in contrast with the results of Donath et al.33 Moreover, as hospitalization for exacerbation is always associated with poor prognosis and increased mortality in COPD patients,34 there was also no difference in the rate of all-cause mortality between antibiotic and placebo groups. Besides, lung function was not improved in any of the included studies after the antibiotic intervention. There is still no conclusive clinical trial evidence to show that any existing medication for COPD could modify the long-term decline in lung function.1 Study limitations and future perspectives There were several limitations in this review. Firstly, there was some notable heterogeneity in the results between studies. On the one hand, due to limited information available, we could not completely analyse and exclude the influence on outcomes of potential differences in the distribution of baseline characteristics, especially COPD severity, exacerbation history and bacterial colonization, although all included patients were relative stable and had similar COPD severity (GOLD 2–4). On the other hand, heterogeneity also existed between antibiotic therapies, as regimens, dosages, durations and follow-up times of antibiotic interventions were different. Secondly, the included patients may have been concomitantly taking other therapies, such as influenza vaccines, bronchodilators or inhaled corticosteroids, which could also have a potential impact on related outcomes if these factors are not comparable between antibiotic and placebo groups. For example, the LABA/LAMA (long-acting β-2 agonist/long-acting muscarinic antagonist) combination as a maintenance therapy of COPD could reduce the rate of exacerbation.35,36 Thirdly, the definitions and measurements of some outcomes were different, such as the varying definitions of adverse events and varying methods for identifying antibiotic resistance. Finally, due to the limited number of studies included, we could not evaluate the effects of the different doses of a specific antibiotic in COPD patients. In the future, more RCTs of high quality are needed to explore more personalized therapy by studying the optimal dose, duration and schedule of use of specific antibiotics, preferably macrolides, with therapeutic drug monitoring for more homogeneous COPD patients. Besides, uniform standards for evaluating the effects of antibiotic use should be established. Considering the safety of antibiotics, how to avoid or reduce side effects such as gastrointestinal events and bacterial resistance during long-term use of antibiotic is still a problem that needs to be tackled. Conclusions This updated systematic review confirms the benefit of prophylactic antibiotics in preventing exacerbations in stable patients with moderate to severe COPD. This benefit existed in all subgroups, ignoring the different durations and schedules of antibiotic intervention. Overall quality of life was also significantly increased by prophylactic antibiotics. However, this benefit was only observed in the subgroup with long-term (>6 months) use of antibiotics. At the same time, considering the possible risk of bacterial resistance, long-term and continuous prophylactic antibiotics are at best limited to high-risk populations with severe COPD and a history of frequent exacerbations, and the choice of antibiotic should be based on the local bacterial resistance pattern. Furthermore, much attention should be paid to some adverse effects, such as gastrointestinal disorders and hearing loss. Funding This study was supported by internal funding. Y. W. received a scholarship (file number: 201506010259) from the China Scholarship Council (CSC) for her PhD at the University of Groningen, Groningen, The Netherlands. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Transparency declarations None to declare. Author contributions Y. W., T. R. Z. and E. H. contributed to the study design and statistical analysis of the data. Y. W., T. R. Z. and M. A. B. contributed to the data collection. J. W. H. K., B. W. and E. H. contributed to the interpretation of the data for the work. Y. W. drafted the initial manuscript. All authors critically revised the manuscript for important intellectual content and approved the final version of this manuscript. 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TI - Effects of prophylactic antibiotics on patients with stable COPD: a systematic review and meta-analysis of randomized controlled trials
JO - Journal of Antimicrobial Chemotherapy
DO - 10.1093/jac/dky326
DA - 2018-12-01
UR - https://www.deepdyve.com/lp/oxford-university-press/effects-of-prophylactic-antibiotics-on-patients-with-stable-copd-a-0afjEDaLjY
SP - 3231
VL - 73
IS - 12
DP - DeepDyve
ER -