1. Stephanie Manning, Pharm.D. Candidate OUHSC College of Pharmacy
When to Use Antibiotics in Acute Exacerbation of Chronic Obstructive Pulmonary Disease
Stephanie Manning, Pharm.D. Candidate
OUHSC College of Pharmacy
Seminar – PHAR 7970
March 10, 2011

2. Summary of Topics COPD overview Current research Current guidelines
Epidemiology, definition, and pathogenesis
Current research
Current guidelines
Application of research data
Future directions

3. Objectives
Identify 3 symptoms which change acutely during a COPD exacerbation.
Outline the 5 components of the proposed model of pathogenesis of bacterial exacerbations.
Assess the need for antibiotic therapy in a patient experiencing a COPD exacerbation according to current guidelines.

4. Overview of COPD

5. Question The fourth leading cause of death in the United States is:
Heart disease
Cancer
Chronic obstructive pulmonary disease (COPD)
Cerebrovascular accidents
It is the only leading cause of death to increase over the last 30 years and is projected to be the third leading cause by 2020.

6. Epidemiology Prevalence Morbidity and Mortality
2001: million over age 25 in the U.S.
> 40 years of age
Men > Women
Morbidity and Mortality
8 million office/hospital outpatient visits and 1.5 million ER visits in the U.S. in the year 2000
Men: deaths per 100,000
Women: deaths per 100,000
Prevalence:
The true prevalence of COPD is likely underreported. Data from the National Health Interview Survey in 2001 indicate that 12.1 million people older than 25 years in the United States have COPD.
Mortality: data from the CDC in the United States.
Centers for Disease Control and Prevention Chronic Obstructive Pulmonary Disease (COPD) page. CDC website:
Global Strategy for the Diagnosis, Management and Prevention of COPD, Available from:
Williams DM, et al. Chronic Obstructive Pulmonary Disease. In: DiPiro JT, et al, eds. Pharmacotherapy: a pathophysiologic approach. 7th ed, 2008.

7. Stable COPD Chronic disease Loss of lung function
Airflow limitation and abnormal inflammatory response
Diagnosis based on:
Symptoms
History of exposure: tobacco smoke, occupational dusts and chemicals
COPD is characterized by chronic inflammatory changes that lead to destructive changes and the development of chronic airflow limitation.
3. Airflow limitation is not fully reversible and is associated with an abnormal inflammatory response to noxious particles or gases
The diagnosis of COPD is made based on the patient’s symptoms and a history of exposure to risk factors such as tobacco smoke and occupational exposures, such as dusts and chemicals. Patients may have these symptoms for several years before dyspnea develops and often will not seek medical attention until dyspnea is significant. A diagnosis should be considered in any patient who presents with chronic cough, sputum production, or dyspnea and who has risk factors for the disease.
Williams DM, Bourdet SV. Chronic Obstructive Pulmonary Disease. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: a pathophysiologic approach. 7th ed. McGraw-Hill Companies, Inc; 2008:

8. Exacerbation of COPD Acute change in baseline symptoms: Consequences:
Dyspnea, cough, and/or sputum production
Consequences:
Decreased quality of life
Accelerated lung function decline
Increased mortality
Increased resource utilization and costs
An exacerbation of COPD is an event in the natural course of the disease characterized by a change in the patient’s baseline dyspnea, cough, and/or sputum production that is beyond normal day to day variations, is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD.
Each exacerbation leaves a permanent decrement of lung function and accelerates the rate of subsequent decline in 1-second forced expiratory volume (or FEV1). Frequent exacerbations are particularly deleterious to long-term well-being, especially when they occur at intervals of 6 months or less. Patients with 3 or more exacerbations yearly have faster lung function decline, worse health-related quality of life and greater mortality risk than those without exacerbations. Severe exacerbations requiring emergency care or hospitalization increase mortality rates both acutely, especially if respiratory failure occurs, and 1 to 2 years afterward.
Hospitalization and emergency care requirements in COPD are driven largely by exacerbations. Direct costs of COPD care in the United States have been estimated at $4,120 per patient per year. And hospitalization, emergency, and unplanned outpatient costs represent some 78% of this, incurred primarily in acute exacerbation care.
Williams DM, Bourdet SV. Chronic Obstructive Pulmonary Disease. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: a pathophysiologic approach. 7th ed. McGraw-Hill Companies, Inc; 2008:
Can Respir J 2008;15 (Suppl A):1A-8A.

9. Exacerbation: Goals of Therapy
Prevention of hospitalization or reduction in hospital stay
Prevention of acute respiratory failure and death
Resolution of symptoms
Return to baseline
Goals of therapy:
1. Prevention of hospitalization or reduction in hospital stay: factors favoring hospitalization for treatment include presence of high risk comorbidity, including pneumonia, CHF, and diabetes, worsening of dyspnea, and worsening hypoxemia.
4. Return to baseline clinical status and quality of life
Williams DM, Bourdet SV. Chronic Obstructive Pulmonary Disease. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: a pathophysiologic approach. 7th ed. McGraw-Hill Companies, Inc; 2008:

10. Pathogenesis and Infection

11. Etiology of COPD Exacerbations
~20% Mucoid Sputum
Infectious
Noninfectious
Purulent Sputum
Allergies, smoking, pollution, stress; undertreatment or nonadherence in established COPD
Bacterial
Viral
Exacerbations may result from noninfectious environmental causes, totaling approximately 20% of all exacerbations. Or they may result from bacterial or viral infections, totaling approximately 80% of all exacerbations.
Mucoid = white, milky, or opaque.
Purulent sputum = off-white, yellow, or green.
~40-50%
~40-50%
Atypical
~5-10%
Bacterial-viral co-infection may occur
Anzueto A. Primary care management of chronic obstructive pulmonary disease to reduce exacerbations and their consequences. Am J Med Sci. 2010;340(4):

12. Bacteria as a Cause of Exacerbation
Common bacteria:
Haemophilus influenzae
Streptococcus pneumoniae
Moraxella catarrhalis
Pseudomonas aeruginosa
Indicators of bacterial infection
Bronchoscopic sampling in pooled analysis of studies
Purulent sputum
As stated previously, approximately 50% of COPD exacerbations are bacterial. These are the 4 most common bacteria, with H. influenzae accounting for 20-30% of exacerbations, 10-15% from strep. Pneumo, and 10-15% from M. catarrhalis. Pseudomonas is prevalent in advanced disease and is likely to appear in a severe case of exacerbation. It accounts for approximately 5-10% of exacerbations.
Bronchoscopic sampling with the use of a protected specimen brush yields reliable specimens from the lower airways. A pooled analysis of studies relying on this technique revealed that bacteria were present in clinically significant concentrations in the airways of 4% of healthy adults, 29% of adults with stable COPD, and 54% of adults with exacerbated COPD.
Purulent sputum during an exacerbation is highly correlated with the presence of bacteria in the lower respiratory tract, providing an additional line of evidence for the pathogenic role of bacteria. Purulent sputum is that containing, or consisting of, pus.
Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med. 2008;359:22.

13. Proposed Model of Pathogenesis
Acquire new bacterial strain
Change in airway/systemic inflammation
Increased respiratory symptoms
Pathogen virulence
Host lung defense
The first step in the proposed model of pathogenesis of a bacterial COPD exacerbation is acquisition of a new bacterial strain, and this appears to be the predominant initiating event for an exacerbation. In the absence of COPD, infection with the previous mentioned bacteria is colonization of the UPPER respiratory tract. However, in patients with an ABNORMAL tracheobronchial tree, such as those with COPD, these bacteria infect both the upper AND LOWER respiratory tracts.
So, after acquisition of a new strain, pathogen virulence and host factors are going to determine the outcome of this new acquisition, as not all are going to result in an exacerbation.
Elimination of infecting strain
Strain-specific immune response,
+/- Antibiotics
Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med. 2008;359:22.

14. Innate Lung Defense Disruption of innate lung defense
Impaired mucociliary clearance
Impaired phagocytosis of alveolar macrophage
Epithelial cells as physical barrier and orchestrators of host defense
A failure of the host’s innate lung defense allows bacteria to proliferate and persist in the airways. Probably most important is impairment of mucociliary clearance. Cilia in the lung help maintain sterility of the lower respiratory tract by transporting bacteria trapped in mucus toward the pharynx. So, disruption of this can contribute to bacterial proliferation.
Also, macrophages found in the lower airways show impaired phagocytosis for H. influenzae and don’t respond as well to H. flu’s antigens.
Lastly, airway epithelial cells serve as both a physical barrier and orchestrators of host defense. Bacteria and their products can cause damage to these cells that line the airway, and this injury would contribute to bacterial persistence.
Adapted from Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med ;359:22.

15. Proposed Model of Pathogenesis
Acquire new bacterial strain
Change in airway/systemic inflammation
Increased respiratory symptoms
Pathogen virulence
Host lung defense
So, after acquisition of this new bacterial strain, this results in increased airway and systemic inflammation, because bacteria slough highly inflammatory cell wall-antigens, including endotoxin and peptidoglycan fragments.
Large increases in airway inflammation would lead to symptoms intense enough to be called exacerbation.
A strain-specific immune response develops, which leaves the host susceptible to infection by other pathogenic bacterial strains, which may account for the recurrent pattern of exacerbations.
The strain is eliminated with or without antibiotics, and the whole process starts over with acquisition of a new bacterial strain.
Elimination of infecting strain
Strain-specific immune response,
+/- Antibiotics
Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med. 2008;359:22.

16. COPD Exacerbation Treatment: Role of Antibiotics

17. Exacerbation Treatment
Oxygen therapy
 Dose/frequency of bronchodilators
Glucocorticosteroids
Mechanical ventilation
General approach to exacerbation therapy includes oxygen therapy, increasing dose or frequency of the patient’s bronchodilator, glucocorticosteroids for inflammation, mechanical ventilation if respiratory failure occurs, and antibiotics. In order to answer my topic’s question, I am going to be focusing on antibiotics for exacerbation treatment.
Antibiotics
Global Strategy for the Diagnosis, Management and Prevention of COPD, Available from:

18. Controversy Over Antibiotic Use
Overuse can lead to resistance
20% of exacerbations are noninfectious
Mixed results from studies
COPD exacerbations have a serious impact on patients in terms of disease progression, morbidity and mortality, and poor quality of life. It also involves enormous economic costs. Thus, it is important to treat with antibiotics only when necessary to try to avoid contributing to growing antibiotic resistance and cost utilization, as well as to avoid any adverse reactions that may result from unnecessary use of antibiotics.

19. Current Research

20. Ofloxacin vs. Placebo
Study design: Prospective randomized controlled trial
Objective
Therapy: ofloxacin vs. placebo
Primary outcome measures
This was a randomized controlled trial, and their objective was to assess the effects of ofloxacin in patients with COPD exacerbations who required mechanical ventilation. So, these were ICU patients who were randomized to receive either 400mg of ofloxacin once daily or placebo for 10 consecutive days. Their primary outcome was ICU and hospital death, the need for additional antibiotics, and these events combined.
Nouira S, et al. Once daily oral ofloxacin in chronic obstructive pulmonary disease exacerbation requiring mechanical ventilation; a randomised placebo-controlled trial. Lancet. 2001;358:

21. Results Outcome Measure ICU death Hospital death
Ofloxacin (n=47)
Placebo
(n=46)
Absolute Risk Reduction
(95% CI)
P Value
ICU death
2(4%)
8(17%)
13.2(0.8 to 25.6)
0.05
Hospital death
10(22%)
17.5(4.3 to 30.7)
0.01
Need for additional antibiotics
3(6%)
16(35%)
28.4(12.9 to 43.9)
0.0006
Combined events
5(11%)
26(57%)
45.9(29.1 to 62.7)
<0.0001
The results of this study show 5 times more hospital deaths and 4 times more ICU deaths in the placebo group than the ofloxacin group, and the combined events was lower by 5-fold in the ofloxacin group than the placebo group. This was shown to be statistically significant, as the p value is less than
The results may suggest that patients with severe acute exacerbation requiring mechanical ventilation benefit from antibiotic therapy. However, one potential imitation of this study is that these patients did not receive corticosteroids to treat their exacerbation, which leads me to my next study.
Nouira S, et al. Once daily oral ofloxacin in chronic obstructive pulmonary disease exacerbation requiring mechanical ventilation; a randomised placebo-controlled trial. Lancet. 2001;358:

22. Doxycycline vs. Placebo
Study design: Prospective randomized controlled trial
Objective
Therapy: doxycycline vs. placebo
Primary and secondary outcome measures
This is another randomized controlled trial, and their objective was to determine the effects of doxycycline in addition to corticosteroids on clinical outcome in patients hospitalized with an acute COPD exacerbation.
Patients were randomly assigned within 24 hours of admission to receive a 7-day course of 200mg of doxycycline or placebo. All patients received concomitant IV prednisolone.
Their primary endpoints were clinical success and clinical cure on day 30. A secondary endpoint was clinical success and cure on day 10. Success was defined as a resolution or reduction of the symptoms and signs without new symptoms or signs associated with the infection. Cure was defined as a complete resolution of signs and symptoms associated with the exacerbation.
Daniels, et al. Antibiotics in addition to systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;181:

23. Results Outcome Measure Doxycycline (n=128) Placebo (n=137)
Odds Ratio or Mean Difference
(95% CI)
P Value
Clinical success on Day 10,
no. (%)
103(80)
94(69)
1.9(1.1 to 3.2)
0.03
Clinical cure on Day 10,
86(67)
69(51)
1.9(1.2 to 3.2)
0.01
Clinical success on Day 30,
78(61)
72(53)
1.3(0.8 to 2.0)
0.32
Clinical cure on Day 30,
65(51)
56(41)
1.4(0.9 to 2.3)
0.15
There was a significant difference in success and cure on day 10, but not on day 30, as indicated by the high p values. One explanation for this may be due to the patient population being treated. This study included patients with moderate to severe exacerbations that required hospitalization. The severe nature of these exacerbations might have caused a large proportion to relapse early. Another reason could be insufficient antibacterial activity of doxycycline. Also, doxycycline is recommended in uncomplicated exacerbations, which are those involving patients under 65 years of age, an FEV1 greater than 50%, and patients with less than 3 exacerbations per year with no cardiac disease. Patient characteristics would indicate that the average patient in this study had complicated cases of exacerbation, as the average patient was 71 years of age and had an average FEV1 of around 25%.
Daniels, et al. Antibiotics in addition to systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;181:

24. Early Antibiotic Administration
Study design: Retrospective cohort
Objective
Primary and secondary outcome measures
This next study was a retrospective cohort which compared the outcomes of patients 40 years or older treated with antibiotics in the first 2 hospital days with those treated later or not at all.
The primary outcome measure was a composite measure of treatment failure, defined as the initiation of mechanical ventilation after the second hospital day, in-hospital mortality, or readmission for acute exacerbations within 30 days of discharge. Secondary outcome measure included hospital costs and length of stay.
Rothberg MB, et al. Antibiotic therapy and treatment failure in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease. JAMA. May 2010;303(20):

25. People without exposure
Cohort Study Design
Treatment Failure
Antibiotics x 2 days
No Treatment Failure
Population
People without exposure
Treatment Failure
Population: Patients hospitalized for acute exacerbations of COPD at acute care facilities in the United States
People without exposure: Patients 40 years or older hospitalized for exacerbation of COPD
Exposed: Those who received at least 2 consecutive days of antibiotics
Not exposed: Those who did not receive antibiotic treatment or whose treatment started later than hospital day 2
Disease: treatment failure
No disease: no treatment failure
Limitations of cohort design:
not possible to randomize study groups
Strengths of cohort design:
ethically safe
subjects can be matched – this was done in this study: nontreated patients were matched to treated patients of similar propensity
Late/No Antibiotics
No Treatment Failure
Study design. Duke University Medical Center Library.
last modified (Accessed ).

26. Results Treatment Failure Length of Stay & Cost Model Odds Ratio
(95% CI)
Unadjusted
0.82
( )
Adjusted
0.87
( )
Outcome Measure
Adjusted Ratio
(95% CI)
Length of stay
1.03
( )
Cost
Results: After multivariable adjustment, the risk of treatment failure was lower in antibiotic-treated patients, as noted by the adjusted odds ratio, which is less than one, indicating that those who had received antibiotics were less likely to result in treatment failure than those who did not receive antibiotics.
The authors also included length of hospital stay and hospital costs as secondary outcomes, and the antibiotic group had higher costs and a longer length of stay than the nonantibiotic group.
Limitations: Observational design makes it vulnerable to selection bias, however, the authors did attempt to overcome this with rigorous multivariable adjustment.
Conclusions: Early antibiotic administration was associated with improved outcomes among patients hospitalized for acute exacerbations of COPD.
Rothberg MB, et al. Antibiotic therapy and treatment failure in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease. JAMA. May 2010;303(20):

27. Non-Hospitalized Exacerbation Patients
Study design: Systematic review
Objective
Study subjects
The last study that I want to cover is a systematic review of randomized controlled trials using antibiotics to treat an exacerbation vs. a placebo group. Their objective was to estimate the value of antibiotic therapy in patients treated for COPD exacerbations, and the types of participants included were those with an exacerbation of COPD both in the hospital and community setting. They included 11 studies, two of which were conducted in the community, eight in hospital inpatient medical wards, and one in a medical intensive care unit.
Ram FSF, et al. Antibiotics for exacerbations of chronic obstructive pulmonary disease (Review). Cochrane Database Sys. Rev. (2): CD004403, 2006.

28. Results Outcome Measure Relative Risk Reduction Relative Risk (95% CI)
Mortality
77%
0.23( )
Sputum purulence
48%
0.52( )
Treatment failure (Hospital-based trials)
53%
0.47( )
Treatment failure (Community-based trials) -
0.91( )
This study included several outcomes in their review, including mortality during the study intervention period, reduction in sputum purulence, and treatment failure, which was defined as no resolution or deterioration of symptoms after trial medication of any duration, or death. Treatment failure was included as an outcome in 4 of the 8 hospital-based trials and the two community based trials as well. The authors of this review analyzed this outcome for hospital and community-based trials separately.
The results of the study showed that mortality, sputum purulence, and treatment failure in the hospital-based trials showed a difference between the antibiotic group and the placebo group. However, treatment failure in the community-based trials did not show a difference between the two treatment groups.
Ram FSF, et al. Antibiotics for exacerbations of chronic obstructive pulmonary disease (Review). Cochrane Database Sys. Rev. (2): CD004403, 2006.

29. Current Guidelines

30. GOLD Guidelines Antibiotics should be given to patients with:
All 3 cardinal symptoms:
 dyspnea
 sputum volume
 sputum purulence
2 of the cardinal symptoms if  sputum purulence included
Severe exacerbation requiring mechanical ventilation
According to the GOLD guidelines, which were updated in 2010, antibiotics, in an acute exacerbation setting, should be given to patients with all 3 cardinal symptoms of a bacterial exacerbation, which include increased dyspnea, sputum volume, and sputum purulence. OR, if the patient has only 2 of the cardinal symptoms, but one of those symptoms is increased sputum purulence. OR if the exacerbation is severe and requires mechanical ventilation.
A randomized controlled trial published in 1987 has provided evidence for a significant beneficial effect of antibiotics in COPD patients who presented with an increase in all three symptoms listed. There was also some benefit in those patients with an increase in only two of these cardinal symptoms.
A study on nonhospitalized patients with exacerbations of COPD published in 2000 in the journal CHEST showed a relationship between the purulence of the sputum and the presence of bacteria, suggesting that these patients should be treated with antibiotics if they also have at least one of the other two cardinal symptoms (dyspnea or sputum volume). However, these criteria for antibiotic treatment of exacerbations of COPD have not been validated in other studies.
A study in COPD patients with exacerbations requiring mechanical ventilation (invasive or noninvasive) published in 2001 in the Lancet indicated that not giving antibiotics was associated with increased mortality and a greater incidence of secondary nosocomial pneumonia.
So, these studies are what the current GOLD guidelines are based upon. I will be discussing one of these studies in further detail.
Global Strategy for the Diagnosis, Management and Prevention of COPD, Available from:

31. Application of Research Data
Continue to use antibiotics in severe exacerbations requiring mechanical ventilation
Limit antibiotic use to those patients requiring hospitalization for their exacerbation
Administer antibiotics early, if necessary, within first 2 days of hospital admission

32. Future Directions: Serum C-Reactive Protein (CRP) Guidance
Subgroup Analysis in Doxycycline Study
Outcome Measure
N (%)
P Value
Serum CRP of >50 mg/L on Day 10
109 (41%)
0.01
Serum CRP of >50 mg/L on Day 30
109 (41%))
0.04
Serum CRP of <50 mg/L on Day 10
156 (59%)
0.53
Serum CRP of <50 mg/L on Day 30
0.75
The authors of this study constructed subgroups according to serum CRP levels, and hypothesized that infection with a new strain, as opposed to colonization, results in more pronounced systemic inflammation. Whereas, they observed that doxycycline was superior on day 10 in patients with a CRP value equal to or exceeding 50 mg/L, it was equivalent in patients with a CRP value less than 50 mg/L. Although they were unable to prove interaction between serum CRP levels and treatment effect, this might suggest that only patients with marked systemic inflammation harbor a bacterial infection that requires antimicrobial therapy. This is the first RCT that indicates CRP’s possible value in selecting patients for antibiotic therapy. Because the authors of this study observed only a trend, additional studies are needed to further investigate the role of CRP in the management of acute exacerbation of COPD.
Daniels, et al. Antibiotics in addition to systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;181:

33. Future Directions: Procalcitonin Guidance
Outcome Measure
Relative Risk
(95% CI)
P Value
Antibiotic exposure
0.56 ( )
<0.0001
Randomized controlled trial
Standard therapy group vs. procalcitonin group
Equivalent clinical success rate (p = 0.853)
Procalcitonin is a small protein that is normally undetectable in plasma. It increases markedly in bacterial infections, especially those associated with sepsis, but is not increased by inflammation that is autoimmune or due solely to viral infection.
There is already evidence from other RCTs that procalcitonin-guided therapy can safely reduce antibiotic use in patients with lower respiratory infection at a low likelihood of bacterial infection. This study extends this technique. They randomized patients to usual care or to a procalcitonin group for whom antibiotic use was based on the procalcitonin level at the time of hospital admission. A procalcitonin level at the time of admission of <0.1 micrograms/L was considered to be nonbacterial and antimicrobial use was discouraged. In those with a procalcitonin level of >0.25 micrograms/L, the AECOPD were believed to be bacterial and antimicrobial therapy was encouraged. For patients with procalcitonin levels between 0.1 micrograms/L and 0.25 micrograms/L, the use of antimicrobial agents was based on the stability of the clinical condition. The primary endpoint was total antimicrobial use during the index hospitalization and was significantly lower in the procalcitonin-guided group. (40% vs. 72%). No difference was noted in clinical success rate during the index hospitalization, antimicrobial use during the subsequent months, or time to the next exacerbation.
The question remains whether these results can be replicated in centers less familiar with procalcitonin-guided decision making. Nevertheless, the authors should be commended for using a novel biomarker to reduce unnecessary antimicrobial use without adverse outcome. Further, they provide vital preliminary data for the conduct of multicenter trials using similar methodologies that may provide clear guidance on optimal use of antimicrobial agents in AECOPD.
Stolz D, et al. Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy. Chest 2007;131:9-19.

34. Review of Topics COPD overview Current research Current guidelines
Epidemiology, definition, and pathogenesis
Current research
Current guidelines
Recommendations
Future directions

35. Questions?