Given the poor sensitivity of sputum culture results and the limited microbiological monitoring that is usually carried out, it is difficult to prove the microbiological status of the COPD patient. No validated definitions are available for the presence of PPMs in the airway in these individuals, so the following definitions were agreed upon:

• •

  Primary infection: The first isolation of a given PPM in a respiratory sample culture from a patient in a clinically stable disease stage.

• •

  Chronic bronchial infection (CBI): Growth of the same PPM in at least 3 cultures in a period of 1 year, performed at least 1 month apart.

• •

  Eradication: When the PPM causing the CBI is not isolated in at least 3 consecutive cultures in a 1-year period, performed at least 1 month apart.

• •

  If a PPM is isolated again after eradication, it will be considered as another primary infection, provided the patient is not receiving chronic antibiotic therapy.

• •

  For patients who do not exactly meet these definitions, the case should be classified as the closest in clinical terms.

Fig. 1 shows a summary of the management of COPD patients with exceptional or persistent PPM isolates.

Fig. 1.

Summary of management of COPD patients in whom potentially pathogenic microorganisms are isolated.

GNB: gram-negative bacilli; COPD: chronic obstructive pulmonary disease; CBI: chronic bronchial infection; PPM: potentially pathogenic microorganisms.

(0.41MB).

Despite their limitations, standard culture techniques are still used for the isolation of PPMs in respiratory samples,25 since molecular techniques, albeit useful in the determination and study of the pulmonary microbiota,26,27 are costly.28,29

A special case is that of Pseudomonas aeruginosa, present in 3% to 20% of stable patients with certain risk factors: FEV1 < 50%, more than 3 exacerbations in the previous year, chronic use of oral corticosteroids, bronchiectasis, admission to intensive care, and a high BODE index.5,30–33 It confers a more severe COPD phenotype than other PPMs, with more inflammation,34 exacerbations, and mortality.19,35–37

In the case of other microorganisms, isolation of Aspergillus is common in patients with certain risk factors, and is associated with more symptoms.38,39 Detection rates of non-tuberculous mycobacteria have increased in the past 10 years40: these microorganisms are associated with more frequent COPD exacerbations and accelerated functional decline.41

Agreement was reached on the following recommendations for the microbiological diagnosis and follow-up of COPD patients:

• •

  Perform sputum culture as part of the initial study in high-risk COPD23 and/or in the case of persistent mucopurulent expectoration.

• •

  Samples with > 25 leukocytes and < 25 epithelial cells per field (Murray-Washington grades 4−5) are valid.42 In case of non-valid samples, sampling should be repeated (especially if there is high suspicion of CBI or if P. aeruginosa has been isolated).

• •

  Perform microbiological follow-up on all patients with previous PPM isolated in a clinically stable phase or with 1 of the criteria listed in Table 2.18,43–45

  Table 2.

  Clinical criteria for deciding on the treatment of primary PPM infection other than P. aeruginosa in clinically stable patients with COPD (at least one must be met)a.

  Persistent mucopurulent/purulent (Murray scale 3−8) or hemoptoic expectoration
  Poor disease control132,133: increased dyspnea, increased need for rescue medication, decreased physical activity, increased sputum purulence, CAT score decline
  Progressive worsening of lung function
  Frequent infectious exacerbations (≥ 2 exacerbations requiring oral antibiotic treatment or ≥ 1 requiring hospitalization or intravenous antibiotic treatment)

  CBI: chronic bronchial infection; COPD: chronic obstructive pulmonary disease; PPM: potentially pathogenic microorganisms.

  a

  To be evaluable, all these criteria must be present in a patient receiving optimal treatment at the discretion of the treating physician, including drug prescription, verification of the inhalation technique, and compliance.
• •

  Monitor sputum color, as this is associated with the presence of PPM in stable COPD46,47 (Fig. 2).

  
  

  Fig. 2.

  Murray scale to assess sputum color from lowest to highest purulence. M: mucoid; MP: mucopurulent; P: purulent.

  (0.37MB).

  Source: Reproduced with permission from Murray et al.47
• •

  Cultures for fungi and/or non-tuberculous mycobacteria should be performed at least once a year, even if the patient is stable. This should also be performed in patients with: ≥ 2 exacerbations requiring systemic steroids and/or antibiotics in the last year; treatment with high-dose ICS; bronchiectasis; if radiological images are compatible with mycobacterial infection; before and during chronic macrolide treatment (for mycobacteria); and if there is no clinical improvement despite proper treatment of isolated PPMs.38–41,48–50

• •

  In cases where a microorganism considered not potentially pathogenic (“mixed oropharyngeal flora” or “normal flora”) is isolated, no further action is necessary, unless there is a high suspicion of CBI.

• •

  Time between collection, transport and processing of the samples must be less than 6 h. In any case, samples should not remain more than 24 h at room temperature, and should preferably be stored at 4°C rather than −20°C.51

CBI may contribute to the appearance and/or progression of bronchiectasis in COPD patients.52 Bronchiectasis is associated with more severe and symptomatic forms of COPD: increased sputum production and purulence, more comorbidities, greater dyspnea, greater bronchial obstruction, more frequent and severe exacerbations, increased bacterial burden, increased risk of CBI (particularly due to P aeruginosa) and increased risk of mortality.44,45,53–59 Therefore, detection of bronchiectasis is important, since the patient may benefit from specific treatments.60 In these patients, antibiotic treatment is essential, because while eradication is virtually impossible, it reduces bacterial counts, decreases exacerbations, and improves lung function.61 There is no evidence that the presence of bronchiectasis increases the likelihood of isolating microorganisms that are resistant to standard antibiotics.62

Agreement was reached on the following statements on the relationship between COPD, CBI, and bronchiectasis:

• •

  A high-resolution computed tomography scan of the chest should be performed to assess the presence of bronchiectasis in patients with certain clinical characteristics (Table 3).51

  Table 3.

  Clinical criteria that warrant a high-resolution computed tomography scan of the chest in patients with COPD to assess the presence of bronchiectasis.

  High-risk COPD23
  Frequent infectious exacerbations (≥ 2 exacerbations requiring oral antibiotic treatment or ≥ 1 requiring hospitalization or intravenous antibiotic treatment)
  Persistent mucopurulent or purulent expectoration
  Hemoptoic expectoration
  X-ray changes suggestive of bronchiectasis
  Repeated isolation of PPM (or a single isolation of P. aeruginosa)
  Progressive functional decline
  Presence of comorbidities associated with the development of bronchiectasis51

  PPM: Potentially pathogenic microorganisms.
• •

  If COPD and bronchiectasis co-exist in the patient, follow the definitions and therapeutic regimens proposed by the bronchiectasis guidelines with regard to the isolation of PPMs in cultures of respiratory samples.51

• •

  These patients should be managed according to the treatment guidelines for both COPD23,24 and bronchiectasis.63–65

In COPD patients without bronchiectasis, there is no evidence to indicate the best eradication strategy or whether primary infection should be treated. However, P. aeruginosa, particularly mucoid strains,66 is liable to persist and, like Haemophilus influenzae, it has a tendency to form biofilms that hinder the action of antimicrobials and promote the persistence of the microorganism.67–70

Agreement was reached on the following recommendations for the treatment of primary infection (Fig. 1):

• •

  In primary infection with P. aeruginosa, eradication treatment is always advisable.

• •

  For other PPMs, consider eradication therapy in stable patients with bronchiectasis or at least 1 of the criteria listed in Table 2.

• •

  Table 4 shows the most common PPM eradication treatment regimens.

• •

  It is advisable to verify eradication with sputum cultures at least 15 days after the end of treatment. If eradication is not achieved after 2 cycles, consider treating as CBI (Table 4).

  Table 4.

  Recommendations for antibiotic treatment in COPD patients without bronchiectasis, with PPM isolated from respiratory samples.

  	P. aeruginosa	H. influenzae	S. aureus	MRSA	Non-fermenting GNB other than P. aeruginosa
  Treatment of primary infection	First option: Ciprofloxacin 750 mg/12 h p.o.Alternative: Levofloxacin 500 mg/12 h p.o. or 750 mg/24 h p.o.Duration 2−3 weeks (based on clinical improvement and tolerance)	First option: Amoxicillin/clavulanic acid 875/125 mg/8 p.o.Alternatives:Amoxicillin 1−2 g/8 h p.o.Ciprofloxacin 750 mg/12 h p.o.Azithromycin 500 mg/24 h p.o.Cefditoren 400 mg/12 h p.o.Duration 10−14 days except azithromycin (6 days) and cefditoren (10 days)	First option: Cloxacillin 500−1,000 mg/6 h p.o.Alternatives: Amoxicillin/clavulanic acid 875 mg/8 h p.o..Cotrimoxazole 160/800 mg/12 h p.o.Duration 2 weeks	First option: Linezolid 600 mg/12 h p.o.Alternatives:Cotrimoxazole 160/800 mg/12 h p.o.Clindamycin 300−450 mg/ 6−8 h p.o.Duration 2 weeks	S. maltophilia:First option: Cotrimoxazole 800/160 mg/12 h p.o.Alternative: Levofloxacin 500 mg/12 h p.o.A. baumani Imipenem 0.5−1 g/6−8 h i.v.Duration 2 weeks
  If not eradicated after a first treatment cycle	Repeat the regimenAssess i.v. treatmentAssess inhaled antibiotic therapy	Repeat the regimen or switch to another antibiotic (p.o. or i.v.)	Repeat the regimen or switch to another antibiotic (p.o. or i.v.)	Repeat the regimen or switch to another antibiotic (p.o. or i.v.)	S. maltophilia: Minocycline 200 mg loading dose, 100 mg/12 h p.o. or i.v. Colistin: 2−3 MU/8 h or 4.5 MU/12 h i.v.A. baumani Tigecycline: 100 mg loading dose, 50 mg/12 h i.v. Colistin 2−3 MU/8 h or 4.5 MU/12 h i.v.
  Treatment of severe exacerbation (or first isolation detected during severe exacerbation)	First option: Ceftazidime 2 g/8 h p.o. + Tobramycin 5−10 mg/kg/24 h i.v.Alternatives: Imipenem 1 g/8 h i.v. orPiperacillin/tazobactam 4 g/6−8 h i.v. orAztreonam 2 g/8 h i.v. orCefepime 1−2 g/8 h i.v. orMeropenem 2 g/8 h i.v. orCiprofloxacin 400 mg/12 h i.v. orCeftolozane/tazobactam 1−2 g/8 h i.v. or Ceftazidime-avibactam 3 g/8 h i.v. + Amikacin 15−20 mg/kg/24 h i.v. orGentamicin 5−7 mg/kg/24 h i.v.Duration 14−21 days (based on clinical improvement)	First option: Amoxicillin/clavulanic acid 1−2 g/8 h i.v.Alternative: Ceftriaxone 2 g/24 h i.v.Duration 10−14 days (start antibiotic treatment i.v. and switch to p.o. when permitted by the patient’s clinical situation)	First option: Cloxacillin 1−2 g/4−6 h i.v.Alternatives: Amoxicillin/clavulanic acid 1−2 g/8 h i.v.Vancomycin (dose adjusted for weight and renal function)Duration 2 weeks	First option: Linezolid 600 mg/12 h i.v.Alternatives: Vancomycin (dose adjusted for weight and renal function)Ceftaroline 600 mg/8 h i.v.Ceftobiprole medocaril 500 mg/8 h i.v.Duration 2 weeks	S. maltophilia:First option: Cotrimoxazole 800/160 mg/12 h i.v.Alternative: Levofloxacin 500 mg/12 h i.v.A. baumani Imipenem 0.5−1 g/6−8 h i.v.Duration 2 weeks
  Treatment of CBI	Start inhaled antibiotic therapy with (in alphabetical order): Aztreonam lysine (inhalation solution) Gentamycin (i.v. formulation administered by inhaled route) Sodium cholistimethate (dry powder or inhalation solution) Tobramycin (dry powder or inhalation solution)Combine with long-term macrolides	1. Long-term macrolide treatment2. If not effective, start long-term (or cyclic) oral antibiotic treatment, according to susceptibility testing3. If not effective, start inhaled antibiotics with gentamicin (80 mg, twice a day, continuous treatment) or any of the specific inhalation antibiotics used in CBI caused by P. aeruginosa	1. Long-term macrolide treatment2. If not effective, start long-term (or cyclic) oral antibiotic treatment, according to susceptibility testing3. If not effective, start inhaled antibiotics with gentamicin (80 mg, twice a day, continuous treatment) or any of the specific inhalation antibiotics used in CBI caused by P. aeruginosa	1. Long-term macrolide treatment2. If not effective, start long-term (or cyclic) oral antibiotic treatment, according to susceptibility testing3. If not effective, start vancomycin inhaled antibiotic therapy (IV formulation administered by inhaled route), continuous treatment, 250 mg, twice a day	Start inhaled antibiotic therapy with sodium cholistimethate (dry powder or inhalation solution)Combine with long-term macrolides

  CBI: Chronic bronchial infection; IV: intravenous; v.o.: oral route; MRSA: methicillin-resistant S. aureus.

The use of inhaled antibiotic (IA) therapy has increased remarkably due to its good results in the treatment of CBI in cystic fibrosis71 and bronchiectasis.72 IAs achieve high concentrations in the bronchial tree and produce few systemic adverse effects.73,74 There are no published clinical trials in COPD, but some small studies with colistin, tobramycin, and amoxicillin-clavulanic acid have reported good outcomes and few adverse effects.75–79

Agreement was reached on the following recommendations for IA treatment in patients with COPD and CBI (Fig. 1 and Table 4). In all cases, it should be confirmed that the patient is receiving correct treatment for COPD (including correct prescription, inhalation technique, and adherence).

• • •

    If COPD and bronchiectasis co-exist, follow bronchiectasis guidelines on the treatment of CBI with IA.63

  • •

    Prescribe IAs in patients with CBI caused by P. aeruginosa or other particularly virulent non-fermenting gram-negative bacilli (Table 1).

  • •

    Treat patients with CBI caused by other PPMs, with clinical and functional deterioration or frequent infectious exacerbations, with long-term macrolides.23,80 If positive cultures and poor disease control persist, start IA.

  • •

    The decision to prescribe a specific IA depends on the PPMs rather than on the susceptibility testing results, since IAs reach far higher levels in bronchial mucosa than the mean inhibitory concentration. An IA to which the PPM family is known to be susceptible must be selected.

  • •

    The dosage is the same as that used in bronchiectasis (Table 5).

    Table 5.

    Antibiotics specifically designed for inhalation available on the marketa.

    	Dosis, regimen	Administration time	Inhalation system
    Aztreonam lysine, inhalation solution	75 mg, 3 times daily, on/offb	2−3 min	E-Flow® nebulizer system (Altera)
    Colistimethate, dry powder for inhalation	1,662,500 IU, twice daily, continuous treatment	1−2 min	Turbospin®
    Colistimethate, solution for inhalation	1−2 million IU, twice daily, continuous treatment	Variable, depending on the nebulizer	E-Flow® nebulizer system, Pari LC plus®
    	0.5−1 million IU, twice daily, continuous treatment	3−6 min	I-neb AAD®
    Tobramycin, dry powder for inhalation	112 mg, 2 times daily, on/offb	∼ 6 min	T-326 inhaler
    Tobramycin, solution for inhalation	300 mg/5 mL, twice a day on/offb	Variable, depending on the nebulizer	E-Flow® nebulizer system, Pari LC plus®
    	300 mg/4 mL, twice a day on/offb	Variable, depending on the nebulizer

    a

    In exceptional cases, depending on the type of potentially pathogenic microorganism or its susceptibility to antibiotics, parenteral formulations of some antibiotics may be administered by the nebulized route: gentamycin (80 mg/12 h continuously), vancomycin (250 mg/12 h continuously) or ceftazidime (1 g/12 h continuously).

    b

    On/off cycles are 28 days.
  • •

    Maintain IA treatment as long as a clinical benefit is observed, i.e., the least purulent sputum possible according to the sputum color scale in Fig. 2 and reduction of exacerbations. Assess withdrawal after 6 months in case of clinical stability and negative cultures. In this case, continue with close microbiological monitoring, and if CBI reappears, give long-term treatment.

  • •

    Given the possible risk of allergy, bronchospasm, dyspnea, cough or hemoptysis,81–83 take certain precautions when using IAs, especially in patients with more severe COPD:

• none-

  Education on the use and maintenance of devices.

• none-

  Pre-inhalation of fast-acting bronchodilators.

• none-

  Administer the first dose in the hospital setting, either in a day hospital (with observation for 2−3 hours) or during a short hospital stay (in the most severe patients).

• none-

  In severe COPD, consider the risk of IA-induced bronchoconstriction. Assess the possibility of performing spirometry before and after the first dose (reduction of FEV1 ≥ 15%).84 If bronchoconstriction is observed, consider changing the type of IA, the diluent or the volume of nebulization.

  • •

    Assess the risk of nephrotoxicity and ototoxicity due to aminoglycosides: avoid their use in severe chronic renal insufficiency; perform 6-monthly analytical testing during the first year (then annual); evaluate hearing loss during treatment.85

  • •

    If the patient performs bronchial drainage techniques or receives nebulized hypertonic saline therapy, these should precede IA.

Macrolides (the most widely studied is azithromycin) modulate neutrophilic bronchial inflammation, interfere with biofilm formation, reduce bacterial load, and reduce exacerbations.86–89 Although the emergence of resistance is a possible long-term risk,90,91 the benefits of this treatment are currently thought to outweigh the risks.23,24,90,92

Agreement was reached on the following recommendations for macrolide treatment in patients with COPD and CBI (Fig. 1):

• •

  Start macrolide treatment in stable patients with 3 or more exacerbations/year (moderate or severe, requiring antibiotic treatment), despite the correct core treatment.

• •

  In the case of CBI due to P. aeruginosa, monotherapy with macrolides is inadvisable; instead, these compounds should be combined with IA.

• •

  The regimens supported by the most evidence are: azithromycin 500 mg/day, 3 days/week, or azithromycin 250 mg daily, for 1 year. Treatment will subsequently be individualized according to clinical response (reduction of exacerbations and expectoration) and the appearance of side effects.

• •

  Due to the seasonal distribution of exacerbations,93 a treatment holiday may be considered during the warm months, if there has been a long period of stability without exacerbations and little mucous secretion. Consider restarting in autumn (or before, if exacerbations reappear).

• •

  Electrocardiogram, liver function tests, mycobacterial culture, and hearing evaluation should be performed before starting treatment. Assess whether to repeat these tests at least annually in prolonged treatments. Appendix B Online Supplement 2 details the requirements and precautions to be taken when initiating long-term macrolide treatment.

ICS therapy reduces exacerbations and improves symptoms and quality of life in patients with advanced COPD.94 ICS in patients with COPD, frequent bacterial exacerbations, CBI, and/or low blood eosinophils are associated with adverse effects: these compounds alter the antiviral immune response,95 modify the composition of the microbiome,96 and increase the bacterial load97 and the risk of upper airway infections, pneumonia98–100 and non-tuberculous mycobacteria.101,102

Agreement was reached on the following recommendations for ICS treatment in patients with COPD and CBI:

• •

  Special precautions must be taken with the use of ICS in patients with CBI63.

• •

  If they are prescribed, consider using the lowest possible dose.

• •

  Re-evaluate the risk/benefit ratio of ICS use in patients who do not present: eosinophilia (persistently < 100 eosinophils/mm3) or features consistent with concomitant asthma.23

Respiratory rehabilitation and physiotherapy programs are underutilized, despite showing improvement in various health outcomes, including bronchial symptoms, respiratory function, quality of life, and risk of hospital readmission.103,104 Physical activity programs should be an integral and complementary part of respiratory rehabilitation, as they improve physical fitness and promote a healthier lifestyle in COPD patients.105

Prolonged use of mucolytics in COPD may have clinical benefits in exacerbators, especially N-acetyl cysteine and carbocysteine.93,106–109

Given the increased risk of malnutrition and increased energy requirement of COPD patients, adequate nutritional assessment, diet and nutrition are essential.110–112

The use of probiotics appears to reduce the rate of upper respiratory tract infections,113 and their potential effect also seems promising in lung infections.114 They can also help prevent diarrhea and antibiotic-induced dysbiosis.115–117

Agreement was reached on the following recommendations for other treatments in patients with COPD and CBI:

• •

  A respiratory rehabilitation program (including health education, respiratory physiotherapy, muscle training, and physical activity programs) should be prescribed for patients with persistent expectoration, dyspnea grade ≥ 2, or low physical activity levels.

• •

  Prolonged treatment with N-acetyl cysteine or carbocysteine may be considered in COPD patients with frequent exacerbations23,24.

• •

  A nutritional assessment should be made in patients with COPD and CBI, including at least: body mass index, nutritional intake, and a longitudinal evaluation of progressive weight loss.

• •

  Assess, according to the physician’s criteria, the possible benefit of the use of probiotics in patients who require several antibiotic cycles per year, coinciding with each cycle, in order to avoid diarrhea and intestinal dysbiosis.

COPD exacerbations have a very varied etiology. Bacterial etiology is usually mediated by an increase in the bronchial bacterial load,118 the acquisition of new strains of a specific bacterium,119,120 or changes in the bronchial microbiome.121 However, evidence suggests that PPMs colonizing the lower airway during the stable phase are associated with PPMs isolated during exacerbations.122

Agreement was reached on the following recommendations for the management of exacerbations in patients with COPD and CBI:

• •

  A sputum sample for culture should always be collected at the beginning of the exacerbation before starting antibiotic treatment.

• •

  A previous CBI should guide the choice of antibiotic according to the results of the last susceptibility testing (anticipated treatment) and the antibiotic susceptibility data of the hospital (Table 4).

• •

  Adjust treatment if the result of the new culture is different from the previous one or if the clinical course of the exacerbation is unfavorable.

• •

  If during an exacerbation a different PPM is isolated from that which is causing the CBI, administer antibiotic treatment covering both PPMs (Table 4)9,15,121–128

• •

  In general, any exacerbation of COPD should assess risk factors for P. aeruginosa being involved.

• •

  After an exacerbation involving a PPM, a follow-up culture should be performed at least 15 days after the end of antibiotic treatment whenever possible.

Agreement was reached on the following recommendations for the follow-up of patients with COPD and CBI (Table 6):

• •

  The initial follow-up after primary infection is determined by the need for microbiological monitoring (to assess eradication, reduction of bacterial load, or new PPMs) and clinical monitoring (reduction of symptoms and exacerbations).

• •

  Schedule follow-up visits scheduled depending on COPD severity, the frequency of exacerbations, and functional progress. In severe patients (GOLD D, FEV1 < 50% and/or chronic respiratory failure), monitoring may be required at least every 3 months; in milder or more stable patients, visits may be performed every 4−6 months.

• •

  During the first 2 years after the primary infection, consider monitoring the patient's microbiological status at each visit; schedule visits at longer intervals if the patient remains stable.

• •

  At least 3 sputum samples/year should be obtained, and whenever an exacerbation associated with an increase in the amount or purulence of the sputum occurs, before starting antibiotic treatment.

• •

  Perform at least 1 spirometry a year to detect patients with rapid decline.24 In patients who start IA, perform a spirometry every 3−6 months during the first year, and also after severe exacerbation or a change in maintenance treatment.