Clinical Corner: Acute Exacerbation of Chronic Obstructive Pulmonary Disease and Antibiotic Therapy: Are Antibiotics Beneficial or Potentially Harmful? 

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Originally published November 2023. Written by Adam R. Olsen, DMSc, M.S., PA-C, CCDS.

Introduction

Chronic obstructive pulmonary disease (COPD) is an airway disease characterized by persistent respiratory symptoms and airflow limitation due to chronic inflammation, destruction of lung parenchyma and alveolar abnormalities.1 COPD is the fourth-ranked leading cause of death in the United States and the third leading cause of death globally.2,3 Tobacco smoking is the main risk factor for COPD but other factors like environmental exposures or genetic abnormalities may contribute. An exacerbation of COPD is defined by the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) as “an acute worsening of respiratory symptoms that result in additional therapy.”1 

The most common causes of acute exacerbations include viral and/or bacterial respiratory infections and environmental insults like air pollution. It has been reported that 43% of exacerbations are due to viral infections and that bacterial pathogens are detectable in 20-50% of exacerbations.1,4 As part of the management of these acute exacerbations, it has become standard practice to treat with a cocktail of medications to include corticosteroids, short-acting bronchodilators and antibiotics. However, not all acute exacerbations of chronic obstructive pulmonary disease (AECOPD) will benefit from antibiotic treatment and current practice may lead to overuse of antibiotics, drug resistance and side effects. 

The purpose of this article is to review the current literature to determine the role of antibiotic therapy in the treatment of AECOPD and whether antibiotic therapy is beneficial for patient outcomes or simply over-prescribed with an increased risk of adverse effects. 

Rationale for current use

Exacerbations of COPD typically result in patients seeking medical attention by healthcare professionals and commonly results in medical hospital admission when patients meet specific criteria based on the GOLD guidelines.1 Typical symptoms associated with an exacerbation can include increased dyspnea, increased sputum production, increased cough and/or wheezing. A history of exacerbation is the strongest independent risk factor for an acute exacerbation.5 

Assessment of patients with AECOPD involves a systematic approach to determine the need for hospitalization based on the severity of exacerbation. Exacerbations are classified as mild, moderate, or severe.1 Management of all exacerbations involves both non-pharmacologic and pharmacologic therapy to include influenza and pneumococcal vaccination, smoking cessation, supplemental oxygen when hypoxemia is present, inhaled short-acting beta2-agonists, with or without inhaled short-acting anticholinergics, systemic corticosteroids, and non-invasive mechanical ventilation as the first mode of ventilation in hospitalized patients with acute respiratory failure. Antibiotic therapy is commonly administered when a bacterial infection is suspected, but using antibiotics for all AECOPD is controversial.1 Bacterial colonization with pathogenic bacteria has been found in nearly 50% of patients with COPD due to the inability to eradicate and control these respiratory pathogens. Additionally, viral infections can lead to secondary bacterial infections.5 Current international guidelines recommend antibiotic therapy for patients that have cardinal signs for bacterial infection which includes increased sputum volume, sputum purulence and dyspnea, or if patients need invasive or noninvasive mechanical ventilation.4,5 These signs and symptoms, however, tend to overlap with a bacterial or nonbacterial cause in clinical practice and may lead to overuse of antibiotics.4 It is a challenge for clinicians to be able to identify patients with AECOPD who would benefit from antibiotics. The current strategy of antibiotic treatment may lead to overuse of antibiotics, increasing the potential for antibiotic side effects and drug resistance. 

There were two main studies found in the literature that support the use of antibiotic therapy in most patients with AECOPD for reduction in treatment failure.

Literature review

 The first study by Long and April6 was an updated systematic review and meta-analysis on the use of antibiotics in patients with AECOPD. Investigators reviewed 19 randomized controlled trials of adults with AECOPD who were followed between 7 days and 1 month and underwent randomization to either antibiotic therapy or placebo, and included a total of 2,663 patients. The primary outcome was treatment failure between 7 days and 1 month, defined as no improvement or worsening symptoms after completion of the prescribed medication, death caused by exacerbation, or the need for additional course of antibiotics, or another medication. Secondary outcomes included mortality, adverse events, intensive care unit (ICU) or hospital admission, length of stay, and time to next exacerbation. Results of this review suggested that for patients with mild to moderate exacerbation who were treated as outpatients, antibiotic use reduced risk of treatment failure (absolute reduction 8.3%). For inpatients, antibiotics did not display statistically significant results, but trends suggested benefit in treatment failure (absolute reduction 11%). There was a reduced risk of treatment failure, improved mortality, and decreased hospital stay in ICU patients who received antibiotics (absolute reduction 17.2%). Evidence suggested no effect on overall incidence of adverse effects due to antibiotic therapy. In summary, this systematic review and meta-analysis demonstrated a positive effect of antibiotic therapy for patients with AECOPD on treatment failure reduction in outpatients and patients admitted to ICU with no significant increase in adverse effects.

The second study by Vermeersch et al7 aimed to determine whether the 3-month administration of a macrolide antibiotic, azithromycin, initiated at hospital admission for patients with AECOPD, in addition to standard therapy, could decrease treatment failure. This study was a multi-center, randomized, double-blind, placebo-controlled trial that included patients hospitalized for AECOPD between August 2014 and April 2017. The study drug, azithromycin, was administered at a specified dose for 3 months, in addition to standardized acute treatment. Patients were followed for 6 months thereafter. The primary endpoint was the evaluation of treatment failure rate within 3 months, defined as a step-up in hospital care or readmission for respiratory-related reasons, or all-cause mortality. A total of 301 patients were randomized to azithromycin (n = 147) or placebo (n = 154). The treatment failure rate within 3 months was 49% in the azithromycin group and 60% in the placebo group (hazard ratio, 0.73; 95% confidence interval, 0.53–1.01; P = 0.0526). Treatment intensification, step-up in hospital care, and mortality rates within 3 months were 47% versus 60% (P = 0.0272), 13% versus 28% (P = 0.0024), and 2% versus 4% (P = 0.5075) in the azithromycin and placebo groups, respectively. Results of this study show that the addition of azithromycin upon admission and for 3 months may safely reduce treatment failure in patients hospitalized for AECOPD.7

Analysis 

There were several limitations to the Long and April6 systematic review and meta-analysis that included a lack of consideration on the severity of underlying COPD across trials due to inadequate reporting from the included studies. The definition of treatment failure varied across trials. Significant heterogenicity was present for both outpatient and admitted patients. Therefore, the evidence to suggest a reduction of treatment failure for outpatients with mild to moderate exacerbation treated with antibiotics is of low quality. The meta-analysis included patients with suspected bacterial infection and patients with other potential causes of exacerbation. Although the results may differ with the inclusion of suspected bacterial infection patients only, results still favored improvement in treatment failure, regardless of bacterial infection as the underlying trigger.

The second study by Vermeersch et al7 also has some limitations. The trial was underpowered as a result of slow recruitment resulting in early termination. The overall results of the primary endpoint were not statistically significant, but favored a reduction in treatment failure for patients treated with 3 months of azithromycin. AECOPD patients included in this study were those with both viral and bacterial etiologies. However, patients with radiographic evidence of lobar pneumonia were excluded.7   

Discussion

For patients with AECOPD, the initial trigger is commonly viral or bacterial infectious agents. Current evidence supports the use of antibiotics in patients who have the cardinal signs of a bacterial infection.1 In AECOPD patients, regardless of the infectious trigger, the studies favor antibiotic therapy for treatment of mild to moderate exacerbations as an outpatient. The greatest risk deduction, to include mortality, was shown in patients with severe exacerbation and ICU admission. A reduced benefit was observed for inpatients not admitted to ICU. Additionally, adding the low dose macrolide antibiotic, azithromycin, to patients hospitalized for AECOPD for a treatment period of 3 months may show a reduction in treatment failure. Importantly, the use of antibiotic therapy did not lead to a statistically significant increase in adverse effects, such a diarrhea.  

Current clinical practice includes antibiotic therapy as the primary approach for COPD patients with exacerbation. These studies support this practice without a significant increase in patient risk, despite the perception that antibiotics may be overused. Antibiotic stewardship remains an important part of patient management. Additional research is being done to determine the benefit of biomarkers, such as Procalcitonin and C-reactive protein, to guide antibiotic prescribing in these patients.3,4 

Conclusion

Antibiotics have been shown to reduce the risk of treatment failure and the risk of short-term mortality in patients with AECOPD.1 They should be given to patients with exacerbations of COPD that present with cardinal symptoms. The greatest benefit is seen in patients with severe exacerbations and ICU admission. Additional benefit may be seen in patients regardless of the infectious trigger. 

References

1Global initiative for chronic obstructive lung disease (GOLD). Global strategy for the prevention, diagnosis, and management of COPD: 2021 Report. http://www.goldcopd.org. Accessed on October 23, 2023.

2Centers for disease control and prevention, national center for health statistics. Underlying cause of death 1999-2019 on CDC wonder online database, released in 2020. Data are from the multiple cause of death files, 1999-2019, as compiled from data provided by the 57 vital statistics jurisdictions through the vital statistics cooperative program. http://wonder.cdc.gov/ucd-icd10.html. Accessed on Oct 23, 2023.

3Gillespie D, Butler CC, Bates J, et al. Associations with antibiotic prescribing for acute exacerbation of COPD in primary care: secondary analysis of a randomised controlled trial. Br J Gen Pract. 2021;71(705):e266-e272. Published 2021 Mar 26. doi:10.3399/BJGP.2020.0823.

4Li Z, Yuan X, Yu L, Wang B, Gao F, Ma J. Procalcitonin-guided antibiotic therapy in acute exacerbation of chronic obstructive pulmonary disease: An updated meta-analysis. Medicine (Baltimore). 2019;98(32):e16775. 

5Whittaker Brown SA, Braman S. Recent Advances in the management of acute exacerbations of chronic obstructive pulmonary disease. Med Clin North Am. 2020;104(4):615-630. doi:10.1016/j.mcna.2020.02.003

6Long B, April MD. Do antibiotics improve patient outcomes in acute exacerbations of chronic obstructive pulmonary disease?. Ann Emerg Med. 2019;74(5):e79-e81. doi:10.1016/j.annemergmed.2019.01.004.

7Vermeersch K, Gabrovska M, Aumann J, et al. Azithromycin during acute chronic obstructive pulmonary disease exacerbations requiring hospitalization (BACE). A multicenter, randomized, double-blind, placebo-controlled trial. Am J Respir Crit Care Med. 2019;200(7):857-868. doi:10.1164/rccm.201901-0094OC.

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