International Journal of Chronic Obstructive Pulmonary Disease Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Nebulized Colistin And Continuous Cyclic International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ on 22-Mar-2022 Azithromycin In Severe COPD Patients With Chronic Bronchial Infection Due To Pseudomonas aeruginosa: A Retrospective Cohort Study This article was published in the following Dove Press journal: International Journal of Chronic Obstructive Pulmonary Disease Concepción Montón 1,2 Introduction: Long-term use of nebulized or oral antibiotics is common in the treatment of Elena Prina 1 cystic fibrosis and non-cystic fibrosis bronchiectasis. To date, however, few studies have For personal use only. Xavier Pomares 1,3 focused on the use of nebulized antibiotics in COPD patients. The aims of this study are: to Jose R Cugat 4 establish whether a combination of nebulized colistin plus continuous cyclic azithromycin in severe COPD patients with chronic bronchial infection due to Pseudomonas aeruginosa Antonio Casabella 5 reduces the frequency of exacerbations, and to assess the effect of this treatment on micro- Joan Carles Oliva 6 biological sputum isolates. Miguel Gallego 1,3 Material and methods: A retrospective cohort was created for the analysis of patients with Eduard Monsó 1,3 severe COPD and chronic bronchial infection due to P. aeruginosa treated with nebulized 1 Department of Respiratory Medicine, colistin at the Respiratory Day Care Unit between 2005 and 2015. The number and Hospital De Sabadell, Institut Universitari characteristics of COPD exacerbations (ECOPD) before and up to two years after the Parc Taulí-UAB, Sabadell, Spain; 2Health Services Research on Chronic Diseases introduction of nebulized colistin treatment were recorded. Network-REDISSEC, Galdakao, Spain; Results: We analyzed 32 severe COPD patients who received nebulized colistin for at least 3 CIBER de Enfermedades Respiratorias, CIBERES, Madrid, Spain; 4Department of three months (median 17 months [IQR 7–24]). All patients but one received combination Respiratory Medicine, Fundació Althaia, therapy with continuous cyclic azithromycin (median 24 months [IQR 11–30]). A significant Manresa, Spain; 5Laboratory of reduction in the number of ECOPD from baseline of 38.3% at two years of follow-up was Microbiology-UDIAT, Institut Universitari Parc Taulí-UAB, Sabadell, Spain; observed, with a clear decrease in P. aeruginosa ECOPD (from 59.5% to 24.6%) and a 6 Epidemiology and Assessment Unit, P. aeruginosa eradication rate of 28% over the two-year follow-up. Fundació Parc Taulí, Universitat Conclusion: In patients with severe COPD and chronic bronchial infection due to Autònoma de Barcelona, Sabadell, Spain P. aeruginosa, combination therapy with nebulized colistin and continuous cyclic azithro- mycin significantly reduced the number of ECOPD, with a marked decrease in P. aeruginosa sputum isolates. Keywords: COPD, exacerbation, azithromycin, colistin, Pseudomonas aeruginosa Introduction In patients with severe chronic obstructive pulmonary disease (COPD), infectious exacerbations (ECOPD) are associated with poor prognosis.1,2 Some interventions in this disease aim to prevent exacerbations, in order to improve the course of Correspondence: Concepción Montón COPD. Department of Respiratory Medicine, Pseudomonas aeruginosa is responsible for 5–10% of COPD exacerbations.3 Hospital de Sabadell, Institut Universitari Parc Tauli-UAB, Parc Taulí 1, Sabadell, Patients with severe and very severe COPD have a higher risk of suffering exacer- Barcelona 08208, Spain bations due to this potentially pathogenic microorganism (PPM) than patients with Tel +34 93 7458262 Email cmonton@tauli.cat mild or moderate COPD.4,5 In a recent 3-year follow-up study conducted in a submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 2365–2373 2365 DovePress © 2019 Montón et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. http://doi.org/10.2147/COPD.S209513 php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Montón et al Dovepress cohort of severe COPD patients, P. aeruginosa was iso- The patients were enrolled in the cohort when starting lated in nearly 35%. Moreover, 12% of patients with nebulized colistin and were followed for a period of up to P. aeruginosa isolates developed chronic bronchial colo- two years from their inclusion. Annual events occurring nization by this PPM, which also presented clonal one year before and two years after enrolment were persistence.6 Recovery of P. aeruginosa has also been assessed, including the number of ECOPD and sputum associated with increased mortality.3,7 cultures with isolates of PPMs, in order to evaluate the Inhaled antibiotics are approved by the US Food and Drug efficacy of the chronic antibiotic therapy. Only patients administration and the European Medicines Agency for the who had used inhaled colistin for a minimum of three treatment of chronic bronchial infection by P. aeruginosa in consecutive months in the study period were included in cystic fibrosis (CF). In these patients, Saiman et al8 also the present analysis. All patients underwent the same demonstrated that continuous cyclic azithromycin signifi- scheduled clinical assessments at the Respiratory Day cantly improved lung function and reduced exacerbations Care Unit conducted by the same team of pulmonologists when added to standard therapy, which included a nebulized before and after starting nebulized therapy.16 Data were antibiotic in more than half of the patients. Since then, chronic collected at each 3-month control visit while the patient antibiotic treatment with inhaled antibiotics and oral macro- was stable, and when exacerbations appeared. The study lides has been used to treat chronic bronchial infection by was approved by the Ethics Committee of the ParcTaulí P. aeruginosa in CF, and the extension of these treatments to University Hospital (CEIC number 2017/555) and was non CF-bronchiectasis has been recommended in recent conducted in accordance with the Declaration of guidelines.9–11 The last update of the GOLD guidelines for Helsinki. All patients provided written informed consent. COPD recommends the use of oral azithromycin treatment in COPD patients with frequent ECOPD despite triple inhaled Nebulized Colistin And Continuous therapy, and the use of nebulized antibiotics in cases with Cyclic Azithromycin associated bronchiectasis.12 However, these recommendations All patients received nebulized colistin in two possible are mainly based on consensus; the scientific evidence is forms of administration: 1) Generic nebulized colistin scarce and only a few small studies have focused on the use with Jet nebulizer (PARI-LC-PLUS®, PARI): 1,000,000– of nebulized antibiotics in COPD patients.13–15 2,000,000 UI/12 hrs; or 2) Colistin Promixin® with I-neb The aim of our study is to evaluate the efficacy of adaptive aerosol delivery device (Philips Respironics): combination therapy with nebulized colistin and continu- 500,000–1,000,000 UI/12 hrs. The treatment regimen ous cyclic azithromycin on the frequency of exacerbations was administered according to current national guidelines in severe COPD patients with chronic bronchial infection on bronchiectasis.9,17 due to P. aeruginosa, when these antibiotics are added to The first doses were administered at the hospital for the baseline treatment. We also aim to assess the eradicat- tolerance assessment, and the treatment was discontinued ing effect of this antibiotic combination on the chronic in patients with bronchospasm on the first administration of presence of this PPM in the bronchial tree. nebulized colistin. A forced spirometry was performed before and after the first dose of nebulized antibiotic for Materials And Methods closer monitoring of adverse events, and any FEV1 reduc- tion of more than 200 mL and 12% was also considered as a Design And Patients contraindication for continuing the treatment. Continuous A retrospective cohort was created including all patients cyclic azithromycin (500 mg three times for week orally) with severe COPD and chronic bronchial infection due to was introduced at the same time as nebulized colistin, or P. aeruginosa attending the Respiratory Day Care Unit at during the previous months, in the patients enrolled. Sabadell Hospital, Barcelona, who initiated a treatment with nebulized colistin between 2005 and 2015, in combination with long-term oral azithromycin. Patients with bronchiec- Definition And Treatment Of tasis as a main diagnosis were excluded. Chronic bronchial Exacerbations infection due to P. aeruginosa was defined as the presence ECOPD was defined as a sustained worsening of the of three or more positive sputum samples, collected at one- patient’s condition from the stable state and beyond nor- month intervals, over at least six months.9 mal day-to-day variations, of acute onset, requiring a submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 2366 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Montón et al change in regular treatment (antibiotics with or without exacerbations per year was adjusted according to the corticosteroids, with or without hospital admission) in a length of follow-up. patient with underlying COPD.18 ECOPD were attended A random intercept linear mixed model for repeated from Monday to Friday (8 am to 5 pm) at the Respiratory measures with fixed effects of follow-up time was used to Day Care Unit, always by the same team of estimate the population mean of exacerbations, number of pulmonologists;16 outside these hours, exacerbations hospitalizations, and length of hospital stay at different were attended at the emergency department. A chest radio- time-points. These estimations allowed the calculation of graph was performed for each ECOPD to exclude acute the percentage changes over time from baseline. All sta- pneumonia. ECOPD attended at primary care were also tistical analyses were performed in R (The R Foundation recorded. Antibiotics were prescribed during ECOPD for Statistical Computing Platform, version 3.5.0) and according to Anthonisen’s criteria19 and were adjusted lme4 package for R. according to sputum culture antibiograms. Decisions regarding hospital admission were made in accordance Results with clinical practice guidelines.20 Nebulized colistin was Fifty-three patients with severe COPD and chronic bron- stopped during hospital admissions. chial infection due to P. aeruginosa started treatment with nebulized colistin at Respiratory Care Day Unit at some Bacteriological Assessments point between 2005 and 2015. The main reason for dis- Sputum samples were collected from all patients for each continuation of nebulized colistin during the first three ECOPD and during stable phases, in accordance with rou- months was intolerance due to respiratory symptoms, tine clinical practice, and were processed locally by Gram mainly cough, breathlessness or bronchospasm, which stain and bacteriological culture. All bacterial isolates were was observed in 11 patients (20.8%). Of these patients identified and antibiograms were performed following stan- with colistin intolerance, two presented bronchospasm at dardized microbiological protocols.21 Microorganisms iso- the first administration, while the remaining nine presented lated during ECOPD were classified into four groups: respiratory symptoms at home which obliged treatment Group 1, common respiratory PPMs (Haemophilus influen- withdrawal during the first three months. Ten additional zae, Streptococcus pneumoniae, Moraxella catarrhalis and patients who initiated nebulized colistin were excluded methicillin-susceptible Staphylococcus aureus MSSA); from the study due to death or other causes. Overall, 32 Group 2, methicillin-resistant Staphylococcus aureus of the 53 patients who had initiated nebulized colistin had (MRSA); Group 3, Pseudomonas aeruginosa; and Group followed this treatment during at least three months, and 4, other Gram-negative bacteria (Stenotrophomonas malto- were included in the study (Figure 1). philia, Achromobacter xylosoxidans, Serratia marcescens, A good quality forced spirometry before and after Escherichia coli and Proteus mirabilis). the colistin nebulization trial (not showing significant To evaluate the microbiological efficacy of the combi- changes) was obtained in 19 of these 32 partici- nation therapy of nebulized colistin and continuous cyclic pants (59.4%). azithromycin, eradication was defined as the absence of Baseline characteristics of the 32 participating patients P. aeruginosa after the introduction of the treatment and are shown in Table 1. Bronchiectasis was identified in 25 during the first and second years of follow up. patients in the computed tomography scan (78%) and most Multidrug resistant P. aeruginosa was defined as resis- patients were treated with inhaled triple therapy (78%).The tance to at least one agent in three or more antibiotic median (IQR) duration of treatment with nebulized colistin groups, including beta-lactams (penicillins plus β-lactamase was 17 (7–24) months. Only 9% of patients (3/32) pre- inhibitor, cephalosporins and carbapenems), quinolones, sented bronchospasm as a late adverse event (after the first aminoglycosides, monobactam and polymyxins.22 3-month period of treatment). Continuous cyclic azithro- mycin was used during colistin therapy by all patients but Statistical Analysis one (due to pharmacological interactions). The median Means and standard deviations (SD) or medians and inter- duration of azithromycin therapy was 24 (IQR 11–30) quartile ranges (IQR) were used to summarize continuous months. Azithromycin was started before nebulized colis- variables, as appropriate. Absolute and relative frequencies tin in 17 patients (55%) and simultaneously in the remain- were used for categorical variables. The number of ing 14 (45%). submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 2367 DovePress Powered by TCPDF (www.tcpdf.org) Montón et al Dovepress Table 1 Baseline Characteristics Of COPD Patients Chronically Colonized By P. Aeruginosa Characteristics (n = 32) Results Age(years), mean (SD) 74 (7) Male, n (%) 32 (100) Current smoker, n (%) 1 (3) Pack-year, mean (SD) 60.6 (30.8) BMI (Kg/m2), mean (SD) 24.1 (4) Bronchiectasis, CT scan, n (%) 25 (78) Lung function, mean (SD) FEV1, liters 0.98 (0.4) FEV1, % predicted 34.4 (13.7) FVC, liters 2.5 (0.6) FVC, % predicted 61.4 (15.6) FEV1/FVC % 39.4 (10.7) pO2 (mmHg) 62.4 (10.4) pCO2 (mmHg) 43.8 (6.4) BODE index 4.6 (1.6) Figure 1 Flow chart. Flow-chart illustrating the patients treated with nebulized colistin at Respiratory Care Day Unit during a 10-year period (2005–2015) and the COPD treatment, n (%) patients who received nebulized colistin for at least three months and were finally Inhaled triple therapy (LAMA+LABA+ICs) 25 (78) included in the study. Roflumilast 1 (3) Theophylline 2 (6) Chronic oxygen therapy 13 (41) Respiratory Exacerbations In the 12 months prior to the start of nebulized colistin, the Abbreviations: COPD, chronic obstructive pulmonary disease; SD, standard deviation; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; 32 study participants presented a total of 126 ECOPD, BMI, body mass index; BODE index, body mass index, airflow obstruction, Dyspnea and exercise capacity index; LAMA, Long-acting anti-muscarinic; LABA, long-acting with a median of four ECOPD per patient [IQR 3–5]. β-Agonist; ICs, inhaled corticosteroids; CT, computed tomography. Eighty-five (67%) were severe enough to require hospita- lization (median of three admissions per patient [IQR during the first and second year of follow-up. ECOPD 1–4]), representing a total hospital stay of 1625 days caused by common PPMs showed only small variations, (median 49 days per patient [IQR 14.5–70]). Data regard- with a slight decrease during the first year of follow-up ing respiratory exacerbations during the first and second years of follow-up are detailed in Table 2, which shows a and a slight increase during the second year. ECOPD clear reduction in ECOPD, hospitalizations and length of caused by MRSA and other Gram-negative bacteria also hospital stay. The mixed model applied showed that com- showed a slight increase during the two years of follow-up bination therapy with nebulized colistin and continuous (Table 6, Figure 5). cyclic azithromycin attained an estimated mean reduction P. aeruginosa sputum isolates (related to the number of in ECOPD of 38.3% with respect to baseline after 24 sputum samples obtained) clearly decreased during follow- months (Figure 2), and parallel reductions in hospitaliza- up, not only in exacerbations but also in the regular stable tions and hospital stays of up to 41.5% and 41.9% respec- phase sampling (Figure 6). Eradication of P. aeruginosa in tively (Figures 3 and 4).The data of the fixed effects of the the first year of follow-up was observed in 15 patients model applied for ECOPD, hospitalizations and days of (47%), and in nine patients cultures remained negative hospital stay are detailed in Tables 3–5; they reached for this PPM after two years (28%). Therefore, 6/15 statistical significance for ECOPD frequency, and border- (40%) patients presented a recurrence of P. aeruginosa line significance for hospitalizations due to respiratory isolation during the second year. disease. P. aeruginosa sputum isolates were multidrug resistant to antibiotics in 14 patients at baseline (43.7%), and this Microbiology percentage did not increase throughout follow-up (11 After nebulized colistin plus azithromycin therapy, patients, 34.3%). No resistance to colistin was observed ECOPD caused by P. aeruginosa decreased markedly during follow-up. submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 2368 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Montón et al Table 2 Respiratory Exacerbations Before And After Combination Therapy With Nebulized Colistin And Continuous Cyclic Azithromycin. For Differences Between Periods, See Table 3–5 Variable No Nebulized Colistin (Baseline) Long-Term Nebulized Colistin Plus Azithromycin Prior 12 Months (n:32) 0-12 Months (n:32) 12-24 Months (n:24) Exacerbation - Total (n) 126 76 57 - Median per year [IQR] 4 [3-5] 2 [1-3.2] 2 [1-4] - Median per month [IQR] 0.33 [0.25-0.42] 0.17 [0.08-0.35] 0.17 [0.14-0.33)] Hospitalization - Total (n) 85 46 35 - Median per year [IQR] 3 [1-4] 1 [0-2] 1 [0-3] - Median per month [IQR] 0.25 [0.08-0.33] 0.08 [0-0.17] 0.08 [0-0.25] Hospital stay (days) - Total (n) 1625 1108 595 - Median per year [IQR] 49 [14.5-70] 9 [0-49.2] 20.5 [0-45.2] - Median per month [IQR] 0.13 [0.04-0.19] 0.05 [0-0.13] 0.06 [0-0.13] Abbreviation: IQR, interquartile range. Discussion due to P. aeruginosa and frequent exacerbations. This To our knowledge, this is the first study to examine the combination therapy achieved a significant reduction in long-term clinical and microbiological effectiveness of the the number of ECOPD during the 2-year follow-up, with introduction of nebulized colistin in combination with a marked decrease in P. aeruginosa sputum isolates not continuous cyclic azithromycin for the treatment of only in exacerbations but also in stable periods, and with patients with severe COPD, chronic bronchial infection good tolerance in most of the patients. Figure 3 Hospitalizations (rate per month). Number of hospitalizations due to Figure 2 Exacerbations (rate per month). Number of ECOPD per patient before respiratory disease per patient before (time 0) and after nebulized colistin, in the (time 0) and after nebulized colistin, at first and second year. Each patient is first and second years. Each patient is represented by a thin unbroken coloured line. represented by a thin unbroken coloured line. The thick black line represents the The thick black line represents the estimated average decrease of the whole group estimated average decrease in the whole group based upon the applied mixed based upon the applied mixed model for repeated measures with fixed effects of model for repeated measures with fixed effects of follow-up time. follow-up time. submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 2369 DovePress Powered by TCPDF (www.tcpdf.org) Montón et al Dovepress Table 5 Random Intercept Linear Mixed Model For Repeated Measures With Fixed Effects Of Follow-Up Time Used To Estimate The Population Mean Of Days Of Hospital Stay Due To Respiratory Disease Fixed Estimate Standard t value p value Effects Error (Intercept) 0.1484 0.0241 6.1633 <0.0000 Time −0.0311 0.0197 −1.5770 0.1205 exacerbations.8 Treatment with inhaled antibiotics and oral macrolides has been extended to chronic bronchial infection by P. aeruginosa in non CF-bronchiectasis, and has been included in different guidelines as a consensus recommendation,9–11 in spite of the limited evidence avail- able in non-CF patients. Althoughit is well known that P. aeruginosa fre- quently causes exacerbations in severe COPD, which Figure 4 Days of hospital stay (rate per month). Number of days of hospital stay due to respiratory disease per patient before (time 0) and after nebulized colistin, at evolves to chronic bronchial colonization in over 10% first and second year. Each patient is represented by a thin unbroken coloured line. of patients,6 so far the experience with inhaled antibiotics The thick black line represents the estimated average decrease in the whole group based upon the applied mixed model for repeated measures with fixed effects of in COPD patients is very limited. Steinfort et al15 follow-up time. included four severe COPD in a group of 18 patients with chronic respiratory disease (non-CF bronchiectasis) Inhaled antibiotics are approved by the US Food and and chronically infected by Gram-negative bacteria, who Drug administration and the European Medicines Agency were treated with nebulized colistin for at least six for treatment of chronic bronchial infection due to P. months. These authors reported a slower decline in lung aeruginosa in CF. In these patients, Saiman et al have function with this treatment and an improvement in qual- also demonstrated that continuous cyclic azithromycin sig- ity of life. Later, Dal Negro et al13 used nebulized tobra- nificantly improves lung function and reduces mycin for 14 days in 13 patients with severe COPD colonized by multiresistant P. aeruginosa, finding a Table 3 Random Intercept Linear Mixed Model For Repeated short-term reduction in local inflammation and a long- Measures With Fixed Effects Of Follow-Up Time Used To term reduction in bacterial load and severe exacerbations Estimate The Population Mean Of ECOPD during a 6-month follow-up. More recently, Bruguera- Fixed Estimate Standard t value p value Avila et al14 reported a prospective study of 36 COPD Effects Error patients with chronic or intermittent bronchial coloniza- (Intercept) 0.3258 0.0302 10.7873 < 0.0000 tion by P. aeruginosa treated with long-term nebulized Time −0.0624 0.0250 −2.4920 0.0157 colistin (at least three months of treatment and 1-year follow-up), in which they found reductions in the number and length of admissions after treatment initiation. Similarly, our data confirmed a decrease in the number Table 4 Random Intercept Linear Mixed Model For Repeated of hospitalizations due to ECOPD in severe COPD Measures With Fixed Effects Of Follow-Up Time Used To patients colonized by P. aeruginosa, and demonstrated Estimate The Population Mean Of Hospitalizations Due To Respiratory Disease an additional effect on moderate exacerbations, with a significant reduction in the total number of ECOPD over Fixed Estimate Standard t value p value the two years of treatment. This reduction, previously Effects Error suggested in studies with a shorter follow-up,13,14 high- (Intercept) 0.2211 0.0291 7.5991 <0.0000 lights the long-term beneficial effect of inhaled colistin in Time −0.0458 0.0241 −1.9008 0.0626 this clinical setting, when added to oral macrolides. submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 2370 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Montón et al Table 6 Number Of Microbiological Isolates And Percentages Adjusted Per Total Number Of ECOPD Before And After Combination Therapy With Nebulized Colistin And Continuous Cyclic Azithromycin Microbiological Isolates Number (%ECOPD) No Nebulized Colistin Long-Term Nebulized Colistin Plus Azithromycin Number Of Isolates Number Of Isolates Number Of Isolates Prior 12 Months 0-12 Months 12-24 Months (n:32) (n:32) (n:24) ECOPD n:126 ECOPD n: 76 ECOPD n: 57 Group 1: Common potentially pathogenic microorganisms 18 (14.2) 9 (11.8) 10 (17.5) H.influenzae 4 (3.2) 1 (1.3) 1 (1.7) S. pneumoniae 5 (3.4) 5 (6.6) 7 (12.3) M. catarrhalis 9 (7.1) 2 (2.6) 0 (0) MSSA 0 (0) 1 (1.3) 2 (3.5) Group 2: MRSA 0 (0) 1 (1.3) 2 (3.5) Group 3: P.aeruginosa 75 (59.5) 21 (27.6) 14 (24.6) Group 4: Other Gram-negative bacteria 7 (5.5) 9 (11.8) 5 (8.7) S.maltophilia 1 (0.7) 0 (0) 3 (5.2) A.xylosoxidans 6 (4.7) 8 (10.5) 1 (1.7) S.marcescens 0 (0) 0 (0) 0 (0) E. coli 0 (0) 1 (1.3) 1 (1.7) P. mirabilis 0 (0) 0 (0) 0 (0) Abbreviation: ECOPD, chronic obstructive pulmonary disease exacerbation. The beneficial effects of macrolides in COPD patients azithromycin therapy in reducing exacerbation frequency, are mediated by the inhibition of quorum sensing and a small subgroup of patients with chronic P. aeruginosa biofilm formation, mechanisms which have been proven colonization also treated with nebulized colistin was particularly useful in reducing the virulence of P. aerugi- included, and presented a statistically significant reduction nosa and in facilitating the activity of antipseudomonal in ECOPD of 43%. These preliminary results suggest that antibiotics.23 In a previous study conducted by our group24 the combination of long-term cyclic azithromycin therapy to evaluate the usefulness of long-term cyclic and nebulized antibiotics may be useful in this group of patients. Our group has previously confirmed that contin- uous cyclic azithromycin therapy as a single antimicrobial therapy, for more than one year, reduces the number of ECOPD due to common PPMs, albeit associated with a relative increase in ECOPD due to P. aeruginosa.25 Therefore, considering that patients treated with long- term cyclic azithromycin are susceptible to developing chronic bronchial infection by P. aeruginosa, the addition of nebulized antibiotics active against this PPM seems justifiable. Figure 5 Long-term nebulized colistin and ECOPD microbiology. ECOPD micro- The fall in exacerbations in COPD patients colonized by biology in the 12 months prior to starting nebulized colistin (baseline) with respect to the first and second year afterwards. Common PPMs, common potential patho- P. aeruginosa in our study is paralleled by a marked decrease genic microorganisms; MRSA, methicillin-resistant Staphylococcus aureus; P. aerugi- in P. aeruginosa sputum isolates, not only in exacerbations nosa, Pseudomonas aeruginosa and Other GNB,other Gram-negative bacteria; COLI, nebulized colistin. but also in stable phase. This may be considered as the main submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 2371 DovePress Powered by TCPDF (www.tcpdf.org) Montón et al Dovepress Figure 6 P. aeruginosa sputum isolates before and after nebulized colistin. P. aeruginosa sputum isolates (related to the number of sputum samples obtained) in the 12 months prior to starting nebulized colistin (baseline) with respect to the first and second year afterwards. COLI, nebulized colistin; Total PA-isolates, Total P. aeruginosa isolates in exacerbations and in stable phase; ECOPD PA-isolates, P. aeruginosa isolates in exacerbations; Control PA-isolates, P. aeruginosa isolates in stable phase. explanation of the fall in the number of ECOPD, while the This study has several limitations: its retrospective design, number of ECOPD due to other microorganisms did not the limited sample size (with only men included), and the change significantly. These microbiological effects have not absence of a control group (either untreatred or treated only been reported in previous studies conducted in severe COPD with azithromycin). However, among its strengths are the fact patients,14 but are particularly relevant for the identification that it reflects the situation in real life and describes practices of the mechanisms underlying the observed improvement in that are now recommended in clinical guidelines but are not the evolution of severe COPD patients when using the com- backed as yet up by a large body of evidence. bined therapy. On this issue, we can only say that our eradi- In conclusion, this study shows that the use of nebulized cation rate of P. aeruginosa at 1-year follow-up is slightly colistin added to continuous cyclic azithromycin as a combina- higher than that observed by Bruguera-Avila et al14 (47% tion therapy in severe COPD patients with chronic bronchial versus 39%), probably due to the addition of cyclic azithro- infection by P. aeruginosa achieves a significant reduction in mycin to the treatment and its indirect antimicrobial effects. the number of ECOPD over a 2-year period, with a marked Although nebulized colistin was generally well tolerated in decrease in P. aeruginosa sputum isolates, not only in exacer- our study, adverse events such as bronchospasm were more bations but also in the stable phase, and relatively good toler- frequent than in previous reports. Episodes of bronchospasm ance. Further studies with prospective designs and with a larger were not reported by Dal Negro et al13 and accounted for only number of patients are now needed to elucidate the role of each 11% in the study conducted by Bruguera-Avila et al.14 chronic antibiotic treatment (inhaled antibiotics and oral However, the differences between these publications may be macrolides) and their interactions. These studies should also related to differences in study design, which means that com- help to establish the most appropriate treatments for severe parison is difficult. The results of the present study point to the COPD patients with chronic bronchial infection by P. aerugi- need for careful monitoring of COPD patients when initiating nosa, and the timings of their introduction – a particularly inhaled colistin, previous to their maintenance on long-term important issue, given that this situation is often difficult to inhaled therapy. handle in clinical practice. submit your manuscript | www.dovepress.com International Journal of Chronic Obstructive Pulmonary Disease 2019:14 2372 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Montón et al Acknowledgments 10. Martínez-García MÁ, Máiz L, Olveira C, et al. Normativa sobre el tratamiento de las bronquiectasias en el adulto. Arch Bronconeumol. The authors thank Adela García, nurse at the Department 2018;54(2):88–98. of Respiratory Medicine, for her clinical assistance, and 11. Polverino E, Goeminne PC, McDonnell MJ, et al. European respiratory society guidelines for the management of adult bronchiectasis. Eur Michael Maudsley of the University of Barcelona’s Respir J. 2017;50(3):1700629. doi:10.1183/13993003.00711-2017 Language Service for checking the English. 12. Global Initiative for Chronic Obstructive Lung Disease; 2019. Available from: www.goldcopd.org. Accessed March 1, 2019. 13. Dal Negro R, Micheletto C, Tognella S, Visconti M, Turati C. Author Contributions Tobramycin Nebulizer Solution in severe COPD patients colonized All authors contributed to data analysis, drafting or revising the with Pseudomonas aeruginosa: effects on bronchial inflammation. Adv Ther. 2008;25(10):1019–1030. doi:10.1007/s12325-008-0105-2 article, gave final approval of the version to be published, and 14. Bruguera-Avila N, Marín A, Garcia-Olive I, et al. Effectiveness of treat- agree to be accountable for all aspects of the work. ment with nebulized colistin in patients with COPD. 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