Combination Antibiotic Therapy Compared to Monotherapy in the Treatment of Acute COPD (COPD)

Is Combination Antibiotic Therapy Superior to Monotherapy in the Treatment of Acute Exacerbations of Chronic Obstructive Pulmonary Disease

The investigators hypothesized that the empirical use of fluoroquinolones together with beta-lactam antibiotics will change their therapeutic success in patients with acute exacerbations of COPD compared to that in patients in whom a single beta-lactam treatment was used. The main goal of this study was to compare the clinical and bacterial success from the use of a combination of beta-lactam and fluoroquinolone antibiotics with that of a single beta-lactam treatment, in adult patients with COPD exacerbations.

Study Overview

• Status: Completed
• Conditions: COPD Exacerbation Acute
• Intervention / Treatment: Drug: Beta-Lactams; Drug: Fluoroquinolone

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 170
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Vietnam
  • Hải Phòng, Vietnam, 18000
    • Haiphong International Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• diagnosed with COPD stages I-IV with acute exacerbations
• incompetence to use medication by mouth
• fever
• antibiotic usage for longer than 1 day
• treatment with systemic administration of corticosteroids
• signs of pneumonia on radiographs
• history of mechanical ventilation during acute exacerbations of COPD in the past

Exclusion Criteria:

• recently detected or unresolved pulmonary malignancy
• other infectious diseases requiring antibiotic treatment
• kidney failure

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: beta-lactam monotherapy; only beta-lactam antibiotics	Drug: Beta-Lactams; The patient was randomized to use beta-lactams antibiotic; Other Names: piperacillin-tazobactam, ticarcillin-clavulanate, imipenem-cilastin, meropenem, ertapenem, ceftazidime, ceftriaxone, cefotaxime, and cefixime
Experimental: beta-lactam and fluoroquinolone combination therapy; one beta-lactam antibiotic and one fluoroquinolone	Drug: Beta-Lactams; The patient was randomized to use beta-lactams antibiotic; Other Names: piperacillin-tazobactam, ticarcillin-clavulanate, imipenem-cilastin, meropenem, ertapenem, ceftazidime, ceftriaxone, cefotaxime, and cefixime; Drug: Fluoroquinolone; The patient was indicated to use a combination of beta-lactams and fluoroquinolones; Other Names: ciprofloxacin, levofloxacin, and moxifloxacin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
clinical success on day 20	Proportion of patients were clinically successful on day 20 (%)	on day 20
FEV1 on day 20	Percent Predicted forced expiratory volume in one second on day 20 [FEV1] (%)	on day 20
FVC on day 20	Percent Predicted forced vital capacity (FVC) on day 20 (%)	on day 20
serum CRP on day 20	Concentration of serum CRP on day 20 (mg/L)	on day 20
WBC on day 20	white blood cell count on day 20 (10x109/L)	on day 20
microbiological success on day 20	The number of patients with success on microbiological outcomes on day 20	on day 20
VAS on day 20	the visual analogue scale (VAS) (Units on scale)	on day 20
PaO2 on day 20	pressure of oxygen (PaO2) on day 20 (mm Hg)	on day 20
PaCO2 on day 20	partial pressure of carbon dioxide (PaCO2) (mm Hg)	on day 20

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
clinical success on day 10	Proportion of patients were clinically successful on day 10 (%)	on day 10
FEV1 on day 10	Percent Predicted forced expiratory volume in one second [FEV1] on day 10 (%)	on day 10
FVC on day 10	Percent Predicted forced vital capacity (FVC) on day 10 (%)	on day 10
serum CRP on day 10	Concentration of serum CRP on day 10 on day 10 (mg/L)	on day 10
WBC on day 10	white blood cell count on day 10 (10x109/L)	on day 10
VAS on day 10	the visual analogue scale (VAS) on day 10 (Units on scale)	on day 10
PaO2 on day 10	pressure of oxygen (PaO2) on day 10 (mm Hg)	on day 10
PaCO2 on day 10	partial pressure of carbon dioxide (PaCO2) on day 10 (mm Hg)	on day 10

Collaborators and Investigators

• Sponsor: Haiphong University of Medicine and Pharmacy
• Investigators: Principal Investigator: Phuong TT Nguyen, PhD MD, Haiphong University of Medicine and Pharmacy

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2020
• Primary Completion (Actual): August 30, 2020
• Study Completion (Actual): December 30, 2020

Study Registration Dates

• First Submitted: April 27, 2021
• First Submitted That Met QC Criteria: May 4, 2021
• First Posted (Actual): May 10, 2021

Study Record Updates

• Last Update Posted (Actual): May 10, 2021
• Last Update Submitted That Met QC Criteria: May 4, 2021
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Antibiotic Therapy; fluoroquinolones; COPD exacerbation; beta-lactam antibiotics
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; beta-Lactamase Inhibitors; Anti-Infective Agents, Urinary; Renal Agents; Moxifloxacin; Ceftriaxone; Ciprofloxacin; Imipenem; Meropenem; Levofloxacin; Fluoroquinolones; Ertapenem; Clavulanic Acid; Piperacillin; Ceftazidime; Cefotaxime; Tazobactam; Piperacillin, Tazobactam Drug Combination; Cefixime; Lactams; beta-Lactams; Ticarcillin
• Other Study ID Numbers: HPMU.01.04.21

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No