The study protocols were reviewed and approved by the Hai Phong International Hospital Institutional Review Board, Vietnam. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on the Harmonization of the Technical Requirements for the Registration of Pharmaceuticals for Human Use - Good Clinical Practice guidelines. All subjects gave written informed consent before study initiation.
The participants consisted of patients aged over 45 years, diagnosed with COPD stages I-IV as stated by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 13, with acute exacerbations (onset of signs under 14 days as defined by Anthonisen et al. 14: type 1 \[increased dyspnea, increased sputum volume, and sputum purulence\] or type 2 \[involved two or three symptoms that needed hospitalization\]), the incompetence to use medication by mouth, fever (temperature over 38.5°C), antibiotic usage for longer than 1 day, treatment with systemic administration of corticosteroids (dosage equivalent to more than 30 mg of prednisolon over four days), signs of pneumonia on radiographs, history of mechanical ventilation during acute exacerbations of COPD in the past, recently detected or unresolved pulmonary malignancy, other infectious diseases requiring antibiotic treatment, and kidney failure.
Randomization and Intervention This was an open-label, randomized study using two types of treatments. Participants were divided into two groups using a randomization procedure. Within 24 hours of admission, patients were assigned randomly to two groups, one to receive a course of single-antibiotic therapy with only beta-lactam antibiotics and the other to get concomitant antibiotic treatment, defined as the use of two antibiotics, including one beta-lactam antibiotic and one fluoroquinolone. The beta-lactam antibiotics with activity against gram-negative bacilli in this study included piperacillin-tazobactam, ticarcillin-clavulanate, imipenem-cilastin, meropenem, ertapenem, ceftazidime, ceftriaxone, cefotaxime, and cefixime. The fluoroquinolone antibiotics included ciprofloxacin, levofloxacin, and moxifloxacin. The other COPD medications were continued. When antibiotic therapy failed, the attending physician had the right to reevaluate the clinical status and to replace the antibiotic therapy in the study with a more appropriate treatment. Safety was recorded daily with the support of a clinical pharmacist to report adverse events. Patient data is stored in electronic medical records.
Outcomes and Follow-Up On days 1, 10, and 20, patients were evaluated clinically, and blood was drawn, collected and the levels of C-reactive protein (CRP, Beckman Coulter Inc., Fullerton, CA) measured. Pulmonary function testing was done and expectorated sputum samples were collected. The symptoms were scored by using the visual analogue scale (VAS) for shortness of breath, tiredness, cough, and sputum color. The specific scores for each symptom ranged from 1 to 10 15. Separate and total scores were calculated.
The primary endpoint was a clinical outcome on day 20, as stated by Chow et al. 16. Successful treatment was defined as a cure (completely resolved signs and symptoms related to exacerbations) or improvement (resolved or decreased symptoms and signs without new symptoms or signs related to infection). Treatment failure was defined as the failure to address symptoms and signs, worsening of symptoms and signs, the appearance of new symptoms and signs related to the primary or a new infection, or death.
Secondary endpoints included clinical outcome on day 10 and clinical success on days 10 and 20, based on lung function (forced expiratory volume in one second \[FEV1\]), serum CRP, symptoms, and microbiological responses.
