Table 5.

Main publications on the use of inhaled antibiotics in patients with stable COPD.

Study Type	Study Population	Antibiotic Studied and Doses	n/Treatment Duration	Main Results	Other Results	Antibiotic Resistance
Dal Negro (2008) [100] Single arm prospective intervention study	Severe COPD patients chronically colonized with P. aeruginosa resistant to oral/intravenous specific antibiotics. Exclusions: asthma; bronchiectasis; pregnancy or lactation; pneumonia; lung malignancy; immunosuppression; liver or renal insufficiency; cardiac failure; use of antibiotics in the previous 4 weeks; other infections.	Tobramycin Nebulizer Solution (TNS) TNS 300 mg/12 h	13 patients, 14 days further 6 months follow-up	TNS induced a significant reduction in sputum IL-1β, IL-8, ECP concentrations, and eosinophil count. At 6 months, P. aeruginosa eradication in two patients and density reduction in four. The incidence of exacerbations decreased by 42%.	TNS was well tolerated. Episodes of bronchospasm or other adverse effects were not reported. All patients completed the treatment with 100% compliance.	Atypical organisms were not detected during the study period in any of the patients. Respiratory viruses detected in the same period were influenza A/B (6), parainfluenza 1/2/3 (4), and RSV (2).
Nijdam (2016) [101] Two phase 1 single-arm prospective intervention studies	COPD patients, able to produce sputum. STONAC 1: stable COPD outpatients; STONAC 2: patients hospitalized for exacerbation. Exclusions: allergy to penicillin, amoxicillin or clavulanic acid, current pneumonia, and FEV1 post bronchodilator < 1.2 L (STONAC 1 only), systemic use of amoxicillin (STONAC 2 only).	Amoxicillin/clavulanic acid 1000 mg/200 mg powder for solution for injection (registered for intravenous administration) STONAC 1: ascending doses, up to 300:60 mg of amoxicillin-clavulanic acid. STONAC 2: amoxicillin clavulanic acid 200:40 mg, twice daily during hospitalization (with a maximum of 7 days).	STONAC 1: 8 patients. Each patient received 4 doses with at least 7 days between each dose. STONAC 2: 8 patients.	No clinically relevant deteriorations in FEV1 were observed. Minor side effects were reported in 30% of patients (cough, shortness of breath, bitter taste). One patient in STONAC 2 presented bronchospasm.	All plasma levels showed amoxicillin concentrations < 1.0 mg/L, indicating that systemic exposure is low. In both studies, sputum amoxicillin levels resulted well above MIC90.	Not available
Bruguera (2017) [102] Retrospective study	Severe COPD patients (FEV1 ≤ 50%) with chronic or intermittent colonization by P. aeruginosa who initiated treatment with nebulized colistin between 2010 and 2014. Exclusions: asthma, malignancy, unstable heart disease, main diagnosis of bronchiectasis.	Colistimethate sodium Colistimethate sodium 1 million IU/12 h administered through the I-neb adaptive aerosol delivery device.	36 patients, 5-year review. Comparison between the year prior to and the year after starting the treatment.	Significant reduction in the number and length of hospitalizations. No reduction in the number of ambulatory exacerbations. Eradication of P. Aeruginosa in 38.9% of patients.	The effects of treatment did not depend on COPD severity, or on the presence/extension of bronchiectasis.	Resistance to colistin only in bacteria known as constitutively resistant.
Montón (2019) [103] Retrospective study	Severe COPD patients with chronic bronchial infection by P. aeruginosa who initiated a treatment with nebulized colistin between 2005 and 2015, in combination with long-term oral azithromycin. Exclusions: main diagnosis of bronchiectasis.	Colistimethate sodium + azithromycin -Colistimethate sodium with jet nebulizer (1–2 million IU/12 h) OR with I-neb adaptive aerosol delivery device (0.5–1 million IU/12 h). -Azithromycin 500 mg three times/week.	53 patients (32 in final analysis)10-year review. Comparison between the two years prior to and the two years after starting the treatment.	Significant reduction in the number of exacerbations (38.3%). Decrease in exacerbations due to P. aeruginosa (from 59.5% to 24.6%). P. aeruginosa eradication rate of 47% and 28% at 12 and 24 months.	Intolerance due to respiratory symptoms in 11 (20.8%) of the initial 53 patients.	No increase in percentage of multi-resistant P. aeruginosa. No resistance to colistin was observed during follow-up.

ITT: intention to treat; ECP: eosinophilic cationic protein; COPD: chronic obstructive pulmonary disease; STONAC: Safety and Tolerability of Nebulized Amoxicillin-Clavulanic Acid in Patients with COPD; FEV1: Forced expiratory volume in 1 s.