Managing Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease: Considering the Appropriate Patient for Antimicrobial Therapy

At an industry-sponsored symposium held in conjunction with CHEST 2003, the annual meeting of the American College of Chest Physicians in Orlando, Florida, three leaders in antimicrobial therapy discussed the role of antibiotic treatment for the management of acute exacerbations in chronic obstructive pulmonary disease (AECOPD).

This program was supported by an educational grant from Abbott Laboratories.

Introduction

Ronald F. Grossman, MD, FCCP, Professor of Medicine at the University of Toronto and Chief of Medicine at Credit Valley Hospital in Toronto, Ontario, Canada, introduced the topic of the symposium by stating that chronic obstructive pulmonary disease (COPD) has been one of those disorders which has been given ‘very little respect’. The major cause of COPD is tobacco smoke. Dr. Grossman stated, “up to 40 percent of individuals who smoke will develop an accelerated loss of lung function and develop COPD. In the United States and in Canada, up to 90% of COPD is clearly related to tobacco smoke.” While the number of people who smoke has declined in recent years, 20-25% of U.S. adults still smoke. Given the population of the U.S at 300 million, it appears that “we will always have to be looking after patients with this disorder,” acknowledged Dr. Grossman.

“We’ve learned, over the years, that acute exacerbations (AECOPD) are the single most important driver of quality of life in these individuals and interventions that alter the frequency of exacerbations or reduce their severity or shorten these exacerbations have a huge impact on patient care,” said Dr. Grossman.

The Role of Bacteria in COPD and AECOPD

Sanjay Sethi, MD, Associate Professor of Medicine at the University of Buffalo and the State University of New York at Buffalo, NY began his presentation by stating, “bacteria have a role in COPD and they definitely have a role in exacerbations.” In regard to COPD, bacteria do appear to enhance the development of COPD and/or its symptoms. This is based on the observations summarized by Drs. Sethi and Murphy (Clin Microbiol Rev. 2001; 14:336) which include:

• Childhood lower respiratory tract infections are associated with decreased lung function in adults
• Bacteria cause acute exacerbations (AECOPD)
• Chronic colonization by bacteria is an inflammatory stimulus
• Bacterial antigens induce hypersensitivity

Bacteria also play an important role in AECOPD. Infectious exacerbations account for 80% of AECOPD and of these, 40-50% are bacterial, 30-40% are viral, and the remaining 5-10% involve atypical bacteria (mostly chlamydia) (Chest. 2000; 117:380S). The major bacterial patho-gens are Haemophilus influenzae (31%), Moraxella catarrhalis (14%), and Streptococcus pneumoniae (14%). Other pathogens that may be involved include Haemophilus parainfluenzae, Pseudo-monas aeruginosa, Staphylococcus aureus, and enterobacteria (Drugs Aging. 2001;18:1)

In a brief review of the earlier antibiotic clinical trials, Dr. Sethi explained that many were difficult to interpret for a variety of reasons, including no pre-sera antibody levels measured, use of acute exacerbation antibody levels instead of pre-sera antibody levels, and use of assays not specific for surface-exposed epitopes (Am Rev Respir Dis. 1992; 146:1057). In the past 10 years, how-ever, laboratory techniques have greatly improved. First among the improvements is the use of bronchoscopy.

Bronchoscopy
“If you sample the distal areas with bronchoscopy, you can get uncontaminated cultures from the airways,” said Dr. Sethi, adding, “you find a certain threshold or concentration of bacteria in the airways that’s highly correlated with having tissue infection.” Dr. Sethi discussed 4 studies that applied this technique and found that bacteria are of significant concentrations about 50% of the time (Am Rev Respir Dis. 1990;142:1004; Am J Respir Crit Care Med. 1995;152:1316; Am J Respir Crit Care Med. 1998; 157:1498; Monaldi Arch Chest Dis. 1998;53:262). “It’s not just bacteria sitting in the upper airway or even in the trachea, they are there in the distal areas at the time of exacerbation in a substantial number of patients,” said Dr. Sethi.

Molecular Epidemiology
Dr. Sethi’s group has a cohort of 50 COPD patients seen every month or whenever they are having an exacerbation. “At each visit, we do a clinical evaluation, a serum sample and a sputum sample for quantitative bacteriology,” said Dr. Sethi, adding, “we do spirometry about two or three times a year.”

Quantifying these results showed that acquisition of new strains of bacteria is associated with an increased risk of exacerbation. Generally, these are moderate to severe COPD patients and the mean number of exacerbations per year (2-3) is similar to that observed in the general COPD population. An examination of the pathogens associated with exacerbations led to the finding that there is somewhat higher incidence of exacerbation with a pathogen.

On the surface, this is very similar to results published 37 years ago (Am Rev Respir Dis. 1976;113:465) but Dr. Sethi’s group characterized all the Haemophilus influenza, Moraxella, and Pneumococcus and Pseudomonas in their study as new or old strains. What they found was a very dynamic process in the patients. To illustrate, Dr. Sethi described one patient with exacerbations on the fifth, the eighth and tenth visit. “If you look at it on the surface, it seems that there are three visits when he was colonized with Haemophilus, two visits with exacerbations and it seems like a very static phenomena,” stated Dr. Sethi, adding, “if you take those five Haemophilus strains and you characterize them, what you find is it’s a very dynamic phenomena in these patients: on the fifth visit, he had a strain of Haemophilus, which persisted until the sixth, and on the seventh, a week later, he acquires a new strain, and on the eighth, he acquires another new strain, which persists until the ninth.” Overall, patients have a two-fold increased risk of exacerbation if a new strain is present. “That applies for Haemophilus, for Moraxella and for the Pneumococcus,” said Dr. Sethi.

Airway Inflammation
To further discuss the important role bacteria plays in AECOPD, Dr. Sethi described a study in which they compared inflammation in the sputum during both bacterial and non-bacterial exacerbations. Dr. Sethi’s group examined chemoattractants and neutrophil elastase as markers of neutrophilic inflammation. They found that more inter- leukin-8, the major neutrophil chemoattractant, and more free neutrophil elastase were in the sputum when patients had pathogens. “if you have all those free elastase floating around, there’s a good chance that that free elastase could contribute to the progression of disease because that’s one of the major mediators of disease development in these patients,” stated Dr. Sethi.

Immunology
Dr. Sethi informed the audience of studies in his lab examining bactericidal activity in patients with new strains of Haemophilus. What they found was many patients develop new bactericidal antibodies following exacerbation. “What was more interesting was, if they develop antibodies, the second part of our hypothesis was, these antibodies are strain- specific,” said Dr. Sethi, adding, “that is, they are very good at killing the infecting strain, but they are not able to kill the next strain that comes along and that would explain why these patients develop exacerbations when they get new strains.” Essentially, Dr. Sethi feels that it is time to replace the model of bacterial load going up and down to describe bacterial infection in COPD, and realize that it is much more complicated and a ‘vicious cycle hypothesis’ of COPD pathogenesis should be thought of as a possible theory about this disease (Am Rev Respir Dis. 1992: 146:1067; Clin Microbiol Rev. 2001;14:336).

Concluding Remarks
“ I hope in the last few minutes I have convinced you that bacteria are not innocent bystanders in this disease or epiphenomena and that they do cause acute exacerbations, and they do cause airway inflammation,” said Dr. Sethi, adding, “the question is, whether they contribute to the progression of lung disease?”

The Impact of Antimicrobial Therapy on Patient Outcomes in AECOPD

COPD is not a steady state disease but a progressive one and its progression is associated with the number of exacerbations. “We used to accept that we tell our patients, you have COPD, just ride with it and there’s not much we can do for you,” said Antonio Anzueto, MD, Associate Professor of Medicine at the University of Texas Health Science Center and Chief of the Pulmonary Section at the South Texas Veterans Health Care System in San Antonio, TX, adding, “but now we have effective therapies that can impact the national history of this disease.” Data from Dr. Pechere has shown the association between clinical failure and the presence of bacteria in the airway (Infect Med. 1998;15:46). “The more bacteria there is present in the airway, the least likely your patients are going to get better,” said Dr. Anzueto.

Treatment options of AECOPD include removal of irritants (i.e., cigarettes, dust), bronchodilators, corticosteroids, antibiotics, and possibly oxygen. Dr. Anzueto said treatment should employ a combination of these options but focused the remainder of his presentation on antibiotic treatment.

Antibiotics
The choice of antibiotic is very important in treating AECOPD. Adams et al. found treatment with amaxicillin led to a higher failure rate (55%) than if the patient received placebo (32%) (Chest. 2000;117:1345). Dr. Anzueto said, “next time you get a patient with an exacerbation of COPD, there are several questions that we have to answer: has this patient been seen recently, did he/she receive an antibiotic over the last 3 months,” said Dr. Anzueto, adding, “you’re going to find out that a large number of these patients have been treated with amoxicillin or trimethoprim sulfa, and these treatments resulted in clinical failure.”

Recently the Canadian Thoracic Society (Can Respir J. 2003;10 [(suppl B]): 3B) published their treatment recommendations based on the patient
following clinical characteristics:

Simple, uncomplicated AECOPD
• Any age
• < 4 exacerbations per year
• No comorbid illness
• FEV1 > 50%
• Treatment: Macrolide (azithromycin, clarithromycin) or new cephalosporin (cefdinir), doxycycline

Complicated AECOPD
• > 64 years
• > 4 exacerbations per year
• serious comorbid illness
• FEV1 < 50%
• Treatment: Newer fluoroquinolones (e.g., moxifloxacin or amoxicillin/ clavulanate)

Complicated AECOPD at risk for P. aeruginosa
• Patients with chronic bronchial sepsis
• Need for chronic corticosteroid therapy and frequent (>4 per year) courses of antibiotics
• Treatment: fluoroquinolines with antipseudomonal activity (e.g., cipro-floxacin)

While Dr. Anzueto states that clinicians have to realize that not all exacerbations are produced by bacteria and many may have a viral process, for those that are bacterial, the benefits of antibiotics are numerous (Table 1).

Concluding Remarks
Dr. Anzueto ended his presentation by stating that AECOPD continues to be an important cause of morbidity, mortality and has a huge economic impact. Therapy must be tailored to patients’ disease severity and specific risk factors. If practice guidelines for treatment are properly followed, Dr. Anzueto believes that outcomes will improve and antimicrobial resistance attenuated.

Health Economics of AECOPD

“The global impact of COPD is pretty straightforward: it’s the second most common chronic, non-communicable disease in the world with some 600 million cases worldwide and associated with about 3 million deaths per year,” said Dr. Grossman, who returned to the podium for the final presentation. In 1990, COPD was the 12th largest burden of disability globally and the 6th leading cause of death, globally. With the increased population of aging smokers, it is now projected that by the year 2020, COPD will be the 5th leading reason for disability and the 3rd leading cause of death (Science. 1996;174:740; Lancet .1997;349:1498). In the United States, 117,522 deaths were attributed to COPD in 2000, equally among men and women. Previously this was thought to be a ‘man’s disease”, but we are starting to learn that women are more susceptible to tobacco smoke and Dr. Grossman said that over the next few years we will see more women than men actually dying from COPD.

Cost of COPD
Estimates of direct and indirect costs of lung diseases in the United States are shown in Table 1.

As shown, the total cost of COPD in 2000 was $30.4 billion and highest among the common lung diseases (asthma, pneumonia, tuberculosis). The high direct costs ($14.7 billion) of COPD are mostly due to the hospitalization and management of patients who have exacerbations. “The major driver of costs in this disease is that of treatment failure, leading to hospitalizations where the costs are 10- to 100-fold higher than the treatment in the outpatient setting,” stated Dr. Grossman. In a study by Hillman et al. examining the annual cost of COPD treatment in mild, moderate, and severe COPD, the costs were found to be $1681, $5037, and $10,812, respectively, with the majority of the costs in moderate and severe cases due to hospital costs (Chest. 2000;118:1278).

Interventions that can prevent exacerbations or stretch out the time between exacerbations can improve the patient’s health and lower medical costs. Miravitlles and colleagues looked at the distribution of COPD costs and attributed 63% of costs to treatment failure (Chest. 2002;121:1449). “When you look at the piece that drives the costs, it’s the cost of hospitalization and any intervention, including antibiotics, that will prevent hospitalization, will save the system money,” said Dr. Grossman. To illustrate this point, Dr. Grossman mentioned a study by Destache et al. (J Antimicrob Chemother. 1999;43{suppl A}:107). In patients who received first- line antibiotic therapy (amoxicillin or tetracycline) the average cost of treatment was $10.30 and 18% of the patients required hospitalization due to AECOPD relapse at an average cost of $942 per hospitalization. In contrast, patients who received 3rd line treatment (co-amoxiclav, azithromycin, or ciprofloxacin) at an average cost of $45 had a failure rate of only about 6% with each hospitalization averaging only $542. In patients receiving 2nd line treatment (cephradine, cefuroxime, cefaclor, or cefprozil), the average drug cost was $24 and 16% of the patients required hospitalization at an average cost of $563.

The net result is that choosing the right antibiotic can reduce exacerbations, relapse rates, and costs. “In outpatient studies, the treatment failure rate is up to one in three if the wrong antibiotic is chosen for the wrong patient,” stated Dr. Grossman (JAMA. 1995;274: 1852; Ann Emerg Med.1991;20:125; Chest. 2000;117:1345).

Concluding remarks
COPD continues to be a major cause of mortality and morbidity and the main precipitating factor is acute exacerbations. Frequent exacerbations are associated with a worsening quality of life and more rapid loss of lung function. “Finally, patient’s therapy needs to be tailored to their disease severity, previous antibiotic history, the risk of treatment failure and their ability to tolerate treatment failure,” concluded Dr. Grossman, adding, “choose an appropriate therapy for that individual patient.”