key: cord-324810-92fosk3c
authors: Sharma, Sat; Anthonisen, Nicholas
title: Role of Antimicrobial Agents in the Management of Exacerbations of COPD
date: 2012-08-23
journal: Treat Respir Med
DOI: 10.2165/00151829-200504030-00001
sha: 
doc_id: 324810
cord_uid: 92fosk3c

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are a common occurrence and characterize the natural history of the disease. Over the past decade, new knowledge has substantially enhanced our understanding of the pathogenesis, outcome and natural history of AECOPD. The exacerbations not only greatly reduce the quality of life of these patients, but also result in hospitalization, respiratory failure, and death. The exacerbations are the major cost drivers in consumption of healthcare resources by COPD patients. Although bacterial infections are the most common etiologic agents, the role of viruses in COPD exacerbations is being increasingly recognized. The efficacy of antimicrobial therapy in acute exacerbations has established a causative role for bacterial infections. Recent molecular typing of sputum isolates further supports the role of bacteria in AECOPD. Isolation of a new strain of Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae was associated with a considerable risk of an exacerbation. Lower airway bacterial colonization in stable patients with COPD instigates airway inflammation, which leads to a protracted self-perpetuating vicious circle of progressive lung damage and disease progression. A significant proportion of patients treated for COPD exacerbation demonstrate incomplete recovery, and frequent exacerbations contribute to decline in lung function. The predictors of poor outcome include advanced age, significant impairment of lung function, poor performance status, comorbid conditions and history of previous frequent exacerbations requiring antibacterials or systemic corticosteroids. These high-risk patients, who are likely to harbor organisms resistant to commonly used antimicrobials, should be identified and treated with antimicrobials with a low potential for failure. An aggressive management approach in complicated exacerbations may reduce costs by reducing healthcare utilization and hospitalization.

First described by Badham in 1808 and then by Laennec in tial part of the natural history, is a common cause of medical visits, hospital admissions and death in COPD. [6] We reviewed published 1827, COPD is a devastating respiratory illness that affects a literature on the etiology, pathophysiology, treatment and outcome sizeable world population and is the fourth leading cause of death of acute exacerbations of COPD (AECOPD) by searching MEDin US after heart disease, cancer and stroke. [1, 2] Primarily a conse-LINE, EMBASE, and CINAHL ® databases. The following search quence of tobacco consumption in the developed world, COPD terms were used: acute exacerbation of COPD, COPD exacerbaaffects patient's quality of life, utilization of healthcare resources, tion, AECOPD, acute exacerbation of chronic bronchitis and and also has adverse economic impacts on the patient and society.

AECB. The search encompassed all publications from 1966 until At present, more than 16 million adults have COPD in the US and 31 December 2004. Additionally, consensus statements, review 52 million worldwide, and the disease accounts for approximately articles, and articles written by selected authorities were reviewed. 125 500 deaths in the US and 2.74 million globally annually. [3, 4] The prevalence of COPD has continued to increase internationally 1. Definition of Acute Exacerbation of Chronic because of rapidly increasing smoking rates in developing nations.

Obstructive Pulmonary Disease (AECOPD) By the year 2020, COPD is predicted to become the fifth leading cause of death and disability worldwide. [5] Acute deterioration of AECOPD lacks a uniform and widely accepted definition in the chronic symptoms frequently occurs and besides being an essen-published literature. Worsening of one or more chronic symptoms including dyspnea, cough, sputum production, or sputum purulence appears to be the most commonly accepted definition. [7] Currently, the clinical practice guidelines have incorporated Winnipeg criteria (increased dyspnea, increased sputum volumes and increased sputum purulence) to define and grade the severity of AECOPD (table I) . Anthonisen et al. [8] showed that the presence of two or more of these clinical features predicted benefit of antimicrobial therapy in AECOPD. An American-European working II Two of the above three symptoms present III One of the above symptoms present plus at least one of the following: upper respiratory tract infection in the last 5 days, fever, increased wheezing, and increased cough group proposed a widely accepted definition of AECOPD as follows: "A sustained worsening of the patients' condition, from were considered to be a consequence of infection with respiratory the stable state and beyond normal day-to-day variations, necessiviruses. [21] tating a change in regular medication in a patient with underlying COPD." [9] Atypical bacteria are difficult to isolate but the investigators have performed serologic testing to evaluate the role of chlamydia and mycoplasma in AECOPD. Although mycoplasma infection as 2. Role of Bacteria in AECOPD a cause of exacerbation is uncommon, Chlamydia pneumoniae infection is reported to account for 5-10% of exacerbations, although a concomitant bacterial pathogen may also be present. [15] 2.1 Pathogens in AECOPD

The predominant pathogens and their relative frequency in AECOPD are listed in table II. Approximately half of the exacer-At least 80% of AECOPD are caused by infections, although bations yield positive sputum cultures for aerobic bacteria. Fagon other causes including environmental factors (air pollution, cold et al. [16] performed bronchoscopy with protected specimen brush air, allergens) may be responsible. [10] The common etiologic orgabefore empiric antimicrobial therapy in 54 patients requiring nisms are bacteria (40-50%), viruses (30-50%) and atypical bacmechanical ventilation for respiratory failure due to AECOPD. teria (5-10%). Interestingly, more than one infectious agent is the The findings were similar to that of sputum culture and showed culprit in 10-20% of all exacerbations. [11] [12] [13] that Haemophilus parainfluenzae was the most common pathogen The role of viruses in AECOPD was previously examined with (11 of 44 organisms), followed by Streptococcus pneumoniae (7 of serial serology and viral cultures but more recent studies have 44), non-typeable H. influenzae (6 of 44), and Moraxella catarutilized polymerase chain reaction (PCR) techniques. The specific rhalis (3 of 44). A variety of other Gram-negative (8 of 44) and viruses and proportion of exacerbations caused by each of these Gram-positive (9 of 44) bacteria were also isolated. are detailed in table II. Soler et al. [11] analyzed serologic samples for viruses in 38 of 50 patients with exacerbations of COPD that Monso et al. [17] performed bronchoscopies and protected specirequired intensive care admission. Viruses were isolated in six men brush cultures in a group of 40 patients with moderately (15.8%) of the cases, influenza virus in five and respiratory severe stable COPD and in 29 patients who were experiencing an syncytial virus in one exacerbation. In three of the five influenza acute exacerbation. In the stable group, 25% of protected speciinfections, a concomitant bacterial pathogen was also present. men brush cultures isolated bacterial pathogens (>10 3 cfu/mL) More recent data have demonstrated the increasing role of respira-compared with 51.7% of culture-positive samples in the exacerbatory viruses in AECOPD. Seemungal et al. [20] observed that 64% tion group. Non-typeable H. influenzae was the most common of all exacerbations were preceded by a cold. In an East London bacterial pathogen in both groups. Soler et al. [11] also demonstrated COPD study, 83 patients developed 168 exacerbations. [20] Viruses positive cultures in bronchoscopic samples during an acute exacerwere detected by reverse transcriptase PCR, viral culture of nasal bation. Interestingly, a remarkably high incidence of Pseuaspirates and serology in 66 (39.2%) exacerbations. The role of domonas aeruginosa and other Gram-negative bacilli (14 of 50 viruses in COPD exacerbations is becoming clearer: viruses cause patients) was evident in this study. Colonization and infection with more severe exacerbations, increase airway obstruction, slow Gram-negative organisms including P. aeruginosa occurred in symptom resolution and induce systemic and airway inflamma-patients who had repeated courses of antimicrobial therapy, as is tion. [14, 20] Rhinoviruses were detected in 39.2% of 168 exacerba-often the case in bronchiectasis. [18] The consistent results of these tions; viral infections caused higher symptom scores and increased studies prove that the bacteria are recovered in the distal airways levels of inflammatory markers (plasma fibrinogen and in-of COPD patients during exacerbations and may be responsible for terleukin-6). In addition, more severe and frequent exacerbations the observed clinical symptoms.

In the literature there exists criticism of data incriminating ber of bacteria and neutrophils in the sputum during exacerbabacteria as causative agents of AECOPD. In support, Hirschtions. [18, 23, 24] Bacteria were thought not only to be the primary mann [19, 22] eloquently debated that current evidence does not subcause of the exacerbations but were also considered to be the stantiate the role of bacteria because: (i) bacterial colonization is secondary invaders following acute viral or mycoplasma infection. not prevalent during exacerbations, and available pathologic and Patel et al. [25] recently demonstrated that lower airway colonizaserologic data fail to demonstrate activation of host defense retion in the stable state was associated with increased exacerbation sponse; and (ii) antimicrobial trials in AECOPD do not validate frequency and colonization. Furthermore, non-typeable H. inadvantage, and symptomatic improvement does not coincide with fluenzae colonization led to higher total symptom score and sputhe eradication of bacteria. While more data are definitely needed tum purulence. However, evaluating the role of bacterial infection to further elucidate the pathogenesis of AECOPD, and the role of in AECOPD has been a difficult task for a variety of reasons. bacteria and antimicrobials, the evidence reviewed in this paper Because the airways of many stable patients with COPD are definitely establishes the importance of bacteria and the use of colonized by H. influenzae, S. pneumoniae and M. catarrhalis, antimicrobials in patients presenting with two or more symptoms evaluation of the expectorated sputum during exacerbations may of AECOPD.

be inconclusive. Serologic studies attempted to establish a causal relationship between bacterial infection and acute exacerbation by finding an acute antibody response in serum to these bacteria. [26] 

These studies had conflicting results and, in general, failed to establish a correlation between the antibody titers and exacerba-The role of infection in AECOPD has been controversial for a tions. [27] Most studies used the whole organism preparations of long time, although the antimicrobials are prescribed frequently to unrelated strains as the antigen for serologic studies, and therefore treat these patients. Early investigators identified increased nummeasured a mixture of antibodies to a combination of antigens. [26] [27] [28] Future studies may utilize antibody response to more specific surface antigens of bacteria to establish the importance of bacterial infection in COPD.

Positive sputum culture does not predict benefit of antimicrobial therapy in AECOPD. [17] Increased sputum purulence was previously thought to be associated with bacterial exacerbations. [29] Airway infection rather than colonization activate secondary host defenses and recruit neutrophils to the airways. [30] Therefore, an acute exacerbation will be associated with change of sputum color from mucoid to purulent (myeloperoxidase from neutrophil azurophil granules is green colored), which will reverse on resolution. [30] Stockley et al. [31] studied sputum characteristics in 121 COPD patients presenting with an acute exacerbation. A positive bacterial culture was obtained from 84% of patients who expectorated green, purulent sputum. White or clear sputum yielded a positive bacterial culture in only 38% of exacerbations. In contrast, on repeat sputum culture in stable state, the incidence of positive bacterial culture was similar (38% and 41%, respectively) with purulent and mucoid sputum. Furthermore, all exacerbations associated with mucoid sputum improved without antimicrobials. This study provides additional evidence that bacteria play an important role in causing acute exacerbations and that antimicrobial success can be predicted simply by recognizing sputum color. Table II . Pathogens associated with acute exacerbations of COPD [11] [12] [13] [14] [15] [16] [17] [18] [19] Frequency of Specific organism Proportion of pathogens exacerbations (%) (%)

Influenza Table III . Relative risk of an exacerbation according to whether a new bacterial pathogen or a strain of bacterial pathogen was isolated (reproduced from Sethi et al., [32] with permission)

Frequency of exacerbation 

Data published by Sethi [33] lend credence to their previously Sethi et al. [32] recently published data strongly supporting the advanced model of recurrent bacterial infections, where virulence bacterial etiology of some exacerbations (table III) . They cultured of the infecting organism and the strain-specific immune response sputum samples for pathogenic bacteria on a monthly basis in appear to be important determinants of acute exacerbation. Acqui-COPD patients during stable state as well as during exacerbations sition of a new strain of organism by a patient who possesses preand typed the strains of bacteria using molecular methods. About existing protective antibodies will lead to no increase in symptoms 48% of exacerbations were associated with positive sputum culand hence colonization. The absence of defending antibodies to tures. About 48% of exacerbations were associated with positive the newly acquired bacterial strain will cause an exacerbation. sputum cultures. A bacterial pathogen was isolated in 23.6% of Development of antibodies to the infecting bacteria will help clear exacerbations compared with 18% with no pathogen (p < 0.001).

the organism. Recurrent infections from antigenically different virulent strains in repetitive fashion are an attractive model of Interestingly, a new bacterial strain was isolated in 33% of exacerpathogenesis of AECOPD (figure 1). [32] bations compared with 15.4% of exacerbations in which no new strains were identified (p < 0.001). In particular, acquiring a new 3. Trials of Antimicrobial Therapy in AECOPD strain of H. influenzae, S. pneumoniae, and M. catarrhalis correlated with a significantly higher rate of acute exacerbations, there-

The role of bacterial infection in AECOPD can also be assessed fore providing credibility to the concept that bacteria play a by systematically evaluating the efficacy of antimicrobial therapy. causative role in AECOPD.

Anthonisen et al. [8] helped settle the controversy over the roles of bacterial infection and antimicrobials in AECOPD. Over a 3-year period, 173 patients with COPD developed 362 exacerbations; 180 exacerbations were treated with placebo and 182 with antimicrobial therapy. The exacerbations were classified according to the Winnipeg criteria based on symptoms of increased dyspnea, increased sputum volume, and increased sputum purulence. A type I exacerbation was defined when all three symptoms were present, type II when two symptoms were present and type III when there was only one symptom (table I) . Therapeutic success was defined as 'resolution' if all symptoms returned to baseline within 21 days, 'no resolution' if all symptoms did not resolve and 'failure with deterioration' when symptoms worsened. Considering all exacerbations, treatment with antimicrobials led to higher resolution (68.1%) compared with placebo (55%, p < 0.05) [ figure 2 ]. Deterioration occurred in 9.9% of those treated with antimicrobials, compared with 18.9% with placebo (figure 3). The rate of peak flow recovery was faster with antimicrobial treatment compared with placebo. Analysis according to the a priori subgroups showed that the exacerbations classified as type I achieved the greatest success with antimicrobial therapy (62.9% vs 43% with placebo, p < 0.05). In type II exacerbations, the antimicrobials were still associated with better outcome than placebo, whereas the success with antimicrobial therapy was not significantly better than placebo in type III exacerbations. Correspondingly, deterioration occurred less frequently on antimicrobial therapy in patients categorized as type I or type II exacerbations. Overall, the length of illness was 2 days shorter for the antimicrobial-treated group compared with the placebo-treated group.

A meta-analysis by Saint et al. [34] reviewed nine randomized controlled trials published from 1955 through to 1994. The outcome data were retrieved from each of the studies and transformed complex organisms such as Enterobacteriaceae and Pseudomonas into units of standard deviation, and the effect size was calculated.

spp. Similarly Miravitlles et al. [37] found that H. influenzae and P. The overall effect size was 0.22 (95% CI 0.10, 0.34), thus, estabaeruginosa were more common in patients with FEV1 values of lishing a benefit with antimicrobial therapy compared with place-<50% of predicted. These studies further corroborate that patients bo. The mean change in PEFR favored the antimicrobial-treated with poor lung function tended to have more frequent exacerbagroup by a difference of 10.75 L/min (95% CI 4.96, 16.54, tions, and received repeated antimicrobial therapy that likely led to p < 0.05). The meta-analysis also demonstrated that the studies alteration of the airway microbial flora. that included a large number of patients and also inpatients displayed a greater benefit from antimicrobial therapy, possibly be-4. AECOPD and Natural History of COPD cause these exacerbations were more severe. Discrepancies in outcome in these studies were possibly secondary to design flaws, small numbers of patients, unclear selection criteria, non-standard 4.1 Vicious Circle Hypothesis evaluation criteria and lack of patient stratification. [34] [35] [36] Patients

It has been suggested that the progressive deterioration of lung with different severities of COPD have exacerbations with diverse function in patients with COPD is produced by bacterial colonizaorganisms; therefore, further studies should be conducted to assess tion of the lower respiratory tract and recurrent infective exacerbadifferent classes of antimicrobials in specific clinical situations. In tions. Airway colonization in low numbers may not engender an patients with more severe air flow obstruction, the bacteriology inflammatory response. [29] As bacterial counts increase, neutroshifted from Pneumococcus spp. and Haemophilus spp. to more philic host response leads to release of pro-inflammatory cytokines, and activated proteinases. Wilkinson et al. [38] have recently shown that increase in airway bacterial load and change in the colonizing bacterial type contributed to greater airway inflammation and accelerated decline in FEV1. In 30 stable COPD patients, the relationship between absolute FEV1 and change in bacterial load was statistically significant (r = 0.593, p < 0.001).

Stockley et al. [39] recently confirmed that purulent sputum correlated directly with the myeloperoxidase content of sputum and with various other indicators of airway inflammation. Visual measurements of sputum color correlated strongly with myeloperoxidase, interleukin-8, leukocyte elastase (both activity and total quantity), sputum volume, protein leak, and secretory leukocyte proteinase inhibitor. This study provides a useful scientific tool for improving the monitoring of chronic airways diseases and response to treatment. Inflammatory cytokines along with bacterial products im- pair mucociliary function, mucus gland hyperplasia, mucus hyper-tained different results. Lung Health Study data were analyzed to secretion, and tissue damage, particularly of the small airways and assess the influence of respiratory illnesses on the rate of decline the alveoli, leading to airflow obstruction. Bacterial colonization is of FEV 1 , over the 5-year study duration. [46] Acute respiratory relatively common in stable COPD patients. Acquisition of a new illnesses were associated with an excessive decline in lung funcbacterial pathogen or a newer strain of the colonizing bacteria tion proportional to the exacerbation frequency among individuals allows proliferation of organisms and an increase in the bacterial who continued to smoke, as opposed to no deterioration in individload. The higher bacterial load facilitates neutrophilic influx and uals who ceased smoking. Kanner et al., [47] who demonstrated that inflammatory response ensues. [31, [38] [39] [40] frequent respiratory tract infections in patients with COPD led to a Therefore, a self-perpetuating vicious circle of host-and bactemore rapid decline in lung function, supported this hypothesis. ria-mediated respiratory tract damage sets in. Sustained by prod-Recently, Seemungal et al. [48] prospectively measured PEF in ucts of inflammation, this cycle impairs host defense response and COPD patients before, during, and after acute outpatient exacerbapredisposes to further bacterial colonization and infections. This tions. Incomplete recovery of lung function was noted in 25% of process has been termed the 'vicious circle hypothesis' and is patients at 35 days, and 7% of patients had not returned to baseline likely responsible for progressive deterioration of lung function lung function at 3 months. These studies support the hypothesis (figure 4). [41] that repeated acute exacerbations are a factor in progressive airways obstruction and likely affect the natural history of COPD. [46] [47] [48] [49] 

Whether the acute exacerbations lead to decline in lung func-

tion or contribute to the progression of COPD has been more clearly elucidated in recent studies. The early studies of Fletch-Acute exacerbations are a common cause of hospitalization and er, [43] Howard, [44] and Bates [45] demonstrated that acute respiratory death in patients with COPD. The previously reported mortality illnesses did not contribute to the progression of airway obstrucrates of 20-40% [50] have now decreased to 11%, as recently tion over the long-term. However, more recent studies have obreported by Connors et al. [51] However, these patients continue to have poor long-term prognosis, as a mortality rate of 43% at 1 year and 49% at 2 years was reported. The predictors of high long-term mortality have been identified as follows: severity of physiologic abnormalities during exacerbation, poor overall health status, comorbidities, poor nutrition as indicated by low body mass index, and low serum albumin.

In 1995, Ball et al. [52] found that the presence of cardiovascular comorbidity and more than four exacerbations in the previous year were associated with treatment failure. In a retrospective study of 232 exacerbations in 107 patients with COPD, Dewan et al. [53] identified patient host factors and not the antimicrobial choice as influencing treatment outcome. The use of home oxygen and frequency of exacerbation correctly classified treatment failure in 83% of the patients. The presence of cardiovascular comorbidity combined with greater than four exacerbations in the previous year has a sensitivity of 70% and specificity of 37% in predicting treatment failure. [52, 54] In other studies, advanced age, significant impairment of lung function, poor performance status, comorbid conditions and a history of previous frequent exacerbations requiring systemic corticosteroids characterized the high-risk group. [42, 55] Additionally, the risk factors for relapse are increasing number of previous exacerbations, severity of airflow obstruction, and increasing baseline dyspnea. [ 

Treatment failures in AECOPD lead to return physician or AECOPD are associated with a significant increase in healthclinic visits, require repeated courses of antimicrobial therapy, risk care utilization and are a frequent cause of hospital admishospitalization, and increase overall costs. [74] Furthermore, pasion. [57] [58] [59] [60] Therefore, exacerbations are the major cost drivers in tients with severe COPD have limited ventilatory reserve, and overall cost of COPD, which consumes significant healthcare acute exacerbations are a common cause of acute respiratory resources. [61, 62] Several investigators estimated the cost of acute failure requiring intubation and mechanical ventilation. [75] Stratifiexacerbation in patients above the age of 65 years to be $US1.2 cation of patients into risk categories may allow physicians to billion, and $US419 million for patients below this age. [61] The select appropriate antimicrobial therapy, so as to avoid treatment annual costs of AECOPD in England and Wales were estimated to failure and improve outcome in an era of increasing antimicrobial be £45 million by McGuire et al.; [63] this represents 0.1% and 0.2% resistance. [74] [75] [76] [77] [78] of the National Health Services budget, respectively. Data from France demonstrated that direct healthcare costs per acute exacer-

bation were about FF3289, of which 60% were hospital related. [64] Several risk stratification schemes have been proposed to im-In a recent Swedish study, the average healthcare costs per exacerprove initial microbial selection. Lode [75] in 1991 proposed that bation were SEK120, SEK354, SEK2111 and SEK21852 for mild, patients be divided into three groups based on severity of lung mild/moderate, moderate and severe exacerbations, respectivefunction, number of exacerbations each year, and presence of a ly. [65] These translated to SEK1.7 billion per year nationally where comorbidity. Treatment with oral amoxicillin, doxycycline, hospitalization was the key cost driver, accounting for 67% of the trimethoprim/sulfamethoxazole (co-trimoxazole) or a macrolide total cost. AECOPD is costly; the costs are variable but higher for was recommended for low-risk patients (first degree). Patients severe exacerbations and in patients requiring hospitalization. A with a longer history of COPD, several exacerbations each year, retrospective study by Destache et al. [66] reported reduced overall other comorbidity, impaired lung function and inpatients were healthcare costs with the use of newer agents compared with firstconsidered high-risk patients (second and third degree). line antimicrobials. Another such study by Torrance et al. [67] In 1994, Balter et al. [79] initially suggested a five-group classifidemonstrated benefit and lower total costs with fluoroquinolones cation of patients with AECOPD, and in a recent publication these in patients who had a history of moderate-to-severe bronchitis and patient are classified into four groups. [80] The patients with acute at least four exacerbations in the previous year.

simple bronchitis and no previous respiratory problems were Several recent studies have supported the use of different classified as Group 0, the Group I patients had simple chronic antimicrobials based on patient stratification. [68] [69] [70] [71] These studies bronchitis with minimal or no impairment of pulmonary function utilized either computerized modeling or a prospective study and without any risk factors. Group II patients were similar to design. The use of newer broad-spectrum antimicrobials was Group I but had one or more significant comorbid illnesses such as associated with better clinical outcomes and lower healthcare costs congestive heart failure, diabetes mellitus, chronic renal failure or in patients with AECOPD who had moderate-to-severe exacerbachronic liver disease. Group III patients were classified as having tions and comorbid conditions. Outpatient drug costs, an important chronic bronchial sepsis. This scheme is problematic and impracticomponent of total AECOPD expenditure, vary inversely with cal for various reasons, as Group 0 patients do not have COPD and severity of exacerbation. Van Barlingen et al. [71] reported lower Group III patients are those who have bronchiectasis or are fredrug utilization costs in severe (7%) compared with mild (17%) quently colonized by Gram-negative bacterial pathogens, which exacerbations.

may not be the causative pathogen. In the older classification, the Current antimicrobial trials in AECOPD are focusing on sympdivision between Group 3 and Group 4 was arbitrary and the tomatic improvement as the outcome measure. [8, 34, 35, 43, [50] [51] [52] 55] treatment recommendations were identical. [79] Since exacerbations frequently recur, a disease-free interval (DFI) may be more meaningful. DFI is defined as "the length of time in 6.2 A Practical Approach days between the end of therapy and the beginning of next episode". [72] An antimicrobial agent successful in eradicating bacteri-Modified from the publications of Wilson, [42] Grossman [81] and al colonization from the lower airways will delay the recur-Balter et al. [79, 80] we proposed a simpler risk scheme to stratify rence. [73] DFI is an outcome measure that should be evaluated AECOPD (table IV) . [82] It may be more practical to categorize all additionally in future clinical trials, to demonstrate clinical success patients with Anthonisen's type I and type II exacerbations into of antimicrobial therapy. either simple or complicated AECOPD. [83] Since antimicrobial

First-line antimicrobials demonstrated equivalent efficacy in the study by Anthonisen et al. [8] Since then an array of newer antimicrobial agents have become available. These agents have generally been as successful in treating AECOPD as previously approved antimicrobials. Whether one antimicrobial agent is superior to another is not known, because the trials have not been designed with this goal in mind. A retrospective study by Adams et al. [84] looked at the risk factors for treatment failure at 14 days after onset of AECOPD. A return visit within 14 days with persistent or worsening symptoms was defined as treatment failure. The failure Table IV . Risk stratification of patients with acute exacerbations of chronic obstructive pulmonary disease [82] Classification Characteristics

Patients with chronic bronchitis and two or more of the chronic following symptoms (Anthonisen's type I and II): bronchitis increased cough; increased sputum volume; increased dyspnea

Patients with chronic bronchitis and Anthonisen's type I chronic and II exacerbations and at least one of the following bronchitis risk factors: FEV1 <50% predicted; experience more than four exacerbations/year; comorbid medical illness (congestive heart failure, diabetes mellitus, chronic renal failure, or chronic liver disease)

rates were reported to be 54% with amoxicillin, 8% with amoxiciltherapy has not been shown to benefit type III exacerbation, lin/clavulanic acid, 11% with trimethoprim/sulfamethoxazole, and 21% with macrolides. Another retrospective study by Destache et therefore, symptomatic therapy suffices for these patients. Patients al. [66] analyzed 224 episodes of AECOPD requiring antimicrobials with simple AECOPD will have only mild-to-moderate impairin 60 outpatients. The antimicrobials were divided into three ment of lung function (FEV 1 >50% predicted), have fewer than groups: first-line (amoxicillin, trimethoprim/sulfamethoxazole, four exacerbations per year and are likely to be colonized with tetracycline, erythromycin), second-line (cefuroxime, cefaclor, usual strains of H. influenzae, S. pneumoniae, and M. catarrhalis, cefprozil), and third-line (amoxicillin/clavulanic acid, azithroalthough viral infections often precede bacterial superinfection. mycin, ciprofloxacin). Deterioration of symptoms requiring addi-Recommendations are to use any first-line antimicrobial agent, as tional antimicrobials within 2 weeks of initial therapy was defined the consequences of treatment failure are not likely to be grave. as treatment failure. The patients who received first-line agents The patients with complicated AECOPD have poorer underlying had significantly higher failure rates; the patients treated with lung function (FEV1 <50% predicted), significant medical third-line agents were hospitalized less frequently, and had a comorbidity (e.g. diabetes, congestive heart failure, chronic renal longer exacerbation-free interval. disease, chronic liver disease) and/or experience four or more

In 1974, <5% of isolates of H. influenzae were β-lactamase exacerbations per year. The predominant organisms may not be positive in the US. [23] Since then, resistance to the commonly used more likely to be resistant strains of H. influenzae, S. pneumoniae, antimicrobials among non-typeable H. influenzae, S. pneumoniae and M. catarrhalis, but since treatment failure may have major and M. catarrhalis has dramatically risen over the past 2 decades. implications, empiric antimicrobial therapy directed toward resis-In 1997, the prevalence of β-lactamase producing H. influenzae exceeded 33%, [85] and presently 30% of all H. influenzae strains tant organisms should be initiated. Second-line antimicrobial are estimated to be β-lactamase positive. [74, 85, 86] Furthermore, 35% agents such as quinolones, amoxicillin/clavulanic acid, second-or of H. influenzae strains are known to possess multiple mechanisms third-generation cephalosporins or second-generation macrolides of antimicrobial resistance, including production of β-lactamase are recommended in these patients. Occasional patients with repetand alterations in penicillin binding. Additionally, 15% or more H. itive exacerbations are likely to become colonized with P. aerugiinfluenzae are cefaclor-and cefprozil-resistant, and 3% are nosa; some of these individuals have underlying bronchiectasis azithromycin-resistant. [85] The prevalence of penicillin-resistant S. when studied by high-resolution imaging studies. Since many of pneumoniae isolates increased from 3-6% before 1991 to 43.8% these patients have received multiple courses of antimicrobials, the in 1997. [82] The current data on resistance are similar: [85] [86] [87] [88] a presence of P. aeruginosa represents colonization. In unusual survey of 33 medical centers from November 1999 to April 2000 circumstances when infection is documented, use of a quinolone showed that approximately 35% of S. pneumoniae are resistant to with antipseudomonal activity empirically and further tailoring the penicillin, with 60% of isolates exhibiting a high level of resistherapy based on sputum culture is appropriate. Although none of tance (minimum inhibitory concentration ≥2 μg/mL). [88] these proposed classification schemes have been prospectively Bronchopulmonary infections comprised 44.5% and 22.1% of tested for their utility and efficacy, they emphasize that potentially resistant infections with S. pneumoniae were from patients ≥65 resistant organisms should be targeted in patients at high risk of years of age. The current overall pneumococcal resistance prevaantimicrobial treatment failure. lence in the US is: macrolides 25.9%, clindamycin 8.8%, tetracy-cline 16.4%, chloramphenicol 8.4%, and trimethoprim/ The initial cure rates (93% vs 95%, p = 0.48) and 6-month exacersulfamethoxazole 30.3%. [87, 88] In another study, a total of 6515 bation-free period (34% vs 28%, p = 0.37) were similar in patients isolates of S. pneumoniae and 6726 H. influenzae strains revealed receiving older versus newer antimicrobials. [97] Therefore, large ampicillin resistance of approximately 25% among H. influenzae clinical trials are needed to establish the adequacy of current isolates and did not significantly differ between strains from empiric guidelines and to address the role of newer broad-speccommunity-acquired infections or hospitalized patients. [8] Further-trum antimicrobials. more, β-lactamase-negative ampicillin-resistant strains and fluoroquinolone-refractory strains were rare (0.3% and ≤0.2%, 8. Prescribing the Appropriate Antimicrobial respectively). Macrolide-resistance to H. influenzae was 24.4% (clarithromycin) in hospitalized patients with pneumonia. Another

There are several theoretical characteristics that would be desirrecent study from North America demonstrated nonsusceptibility able in selecting an antimicrobial for AECOPD: (i) activity against rates to penicillin at 21.0%, cefotaxime 7.3%, imipenem 3.8%, the most common and most likely etiologic organisms, including ciprofloxacin 11.2%, erythromycin 30.3%, and tetracycline H. influenzae, S. pneumoniae and M. catarrhalis; (ii) resistance to 38.5%. [89] destruction by β-lactamase; (iii) narrow spectrum of activity During 2000-01, Jones et al. [90] prospectively collected 1995 against the likely pathogen; (iv) good penetration into the sputum, isolates of H. influenzae, 1870 isolates of S. pneumoniae and 649 bronchial mucosa and epithelial lining fluid; (v) easy to take, with isolates of M. catarrhalis from hospital laboratories in France, few adverse effects; (vi) prolonged DFI or delay of the next Germany, Greece, Italy, Spain, and the UK. S. pneumoniae isoexacerbation; (vii) cost effectiveness, including the drug and hoslates were 99.6% susceptible to moxifloxacin, gatifloxacin and pital costs and the costs of treatment failure (table V) . [98] levofloxacin, and H. influenzae and M. catarrhalis were 100% susceptible. The incidence of penicillin non-susceptibility to S. pneumoniae remained similar to or higher than previously reported: France, 165 of 291 (56.7%); Germany, 46 of 506 (9.1%); Greece, 20 of 55 (36.4%); Italy, 45 of 364 (12.4%); Spain, 146 of 268 (54.5%); and the UK, 26 of 386 (6.7%). The β-lactamase production among H. influenzae isolates ranged from 6.2% to 33.1% per country. A higher resistance against Pneumococcus has been reported from Spain (53.4%) than in Italy (15.1%), whereas erythromycin resistance was higher in Italy (42.9%) than in Spain (28.6%). [91] Selective pressure from antimicrobial prescription appears to be the most important factor associated with drug-resistant S. pneumoniae. Resistance is encountered more commonly in patients who have identifiable risk factors, including age >65 years, prescription of β-lactam antimicrobials during the past 3 months, previous hospitalizations, and nursing home residence. [86, 92] However, the majority of studies have not classified the exacerbations in detail and have not demonstrated a difference in clinical outcomes with newer or the older antimicrobial agents. [93] [94] [95] Grossman et al. [96] assessed safety and efficacy of ciprofloxacin versus standard antimicrobial care in patients with moderate-tosevere bronchitis and at least four exacerbations in the previous year. A trend towards accelerated resolution with ciprofloxacin existed but the difference was not statistically significant in this open-label, uncontrolled study. A retrospective analysis performed by Madaras-Kelly et al. [97] concluded that the use of older versus newer antimicrobials did not independently predict either the outcome or the subsequent development of an exacerbation. 

Trimethoprim/sulfamethoxazole, combined in a ratio of 1 : 20, is a bactericidal combination which works synergistically against bacterial organisms. Both antimicrobials inhibit enzyme systems In 1948, chlortetracycline was the first tetracycline discovered.

involved in the bacterial synthesis of tetrahydrofolic acid by Since then, tetracycline, demeclocycline, doxycycline, and minodifferent mechanisms. Resistance occurs with development of a cycline have been synthesized for clinical use, although doxytarget enzyme with decreased bacterial affinity for the drugs and cycline and minocycline are the most frequently prescribed. The via dihydrofolic reductase gene mutations. Although very popular tetracyclines are broad-spectrum bacteriostatic antimicrobials.

in the 1970s and 1980s, the potential for resistance and increasing They either passively diffuse or are actively transported into the availability of safer agents has resulted in declining use of this bacterial cell. They inhibit ribosomal bacterial protein synthesis.

antimicrobial. In older studies, comparisons with oral The mechanism of resistance to tetracycline is to prevent accumucephalosporins have generally shown equivalent efficacy. [104] The lation of the drug inside the cell by decreasing influx or increasing SENTRY Antimicrobial Surveillance Program reported 15-20% efflux. Many of the original trials of antimicrobial therapy demontrimethoprim/sulfamethoxazole resistance to common respiratory strated that tetracycline therapy was more effective than placebo in pathogens in Europe and the US, and higher in Latin America and milder infections. Tetracyclines can be used in AECOPD because Asia-Pacific regions. [105] Penicillin-resistant pneumococci have they are active against H. influenzae and atypical pathogens, but 80-90% likelihood of cross-resistance to trimethoprim/ there have been reports of increasing resistance against sulfamethoxazole. [106] Consequently, local resistance patterns and pneumococci. [88] [89] [90] 99] severity of disease should be taken into account for appropriate use β-Lactam antimicrobials are generally bactericidal by virtue of of trimethoprim/sulfamethoxazole in AECOPD. inhibition of bacterial cell wall synthesis. Bacterial resistance to β-lactams may occur by any of three general mechanisms: (i) 10. Second-Line Antimicrobials decreased penetration of antimicrobial to the target binding protein in the bacterial plasma membrane; (ii) alterations in penicillin-

The mechanism of antimicrobial action of newer macrolides is binding proteins; and (iii) production of β-lactamase, which may similar to that of erythromycin. These agents bind to the 50S cleave the penicillins or cephalosporins. Production of βsubunit of bacterial ribosome and inhibit bacterial protein synthelactamase is the most important mechanism. The bacteria may sis. Compared with erythromycin, these agents are more acid either synthesize β-lactamase constitutively or initiate synthesis in stable, have improved oral absorption and tolerance, and have a the presence of antimicrobials; the β-lactamase positivity varies broader spectrum of antimicrobial activity. Macrolides and fluorobetween centers and countries. Amoxicillin has been widely used quinolones are active against C. pneumoniae. There has been for the management of AECOPD. [74] In countries and centers increasing resistance to macrolides among Gram-positive orgawhere resistance among H. influenzae and pneumococci remain at nisms. Up to 15% of S. pneumoniae may have resistance to low levels, β-lactam antimicrobials are drugs of choice in patients erythromycin and cross-resistance to other macrolides. Azithrowith purulent or type I and II exacerbations. Despite their relativemycin and clarithromycin have improved pharmacokinetics and ly poor activity and suboptimal respiratory pharmacokinetics, antimicrobial activity against H. influenzae compared with erythcephalexin and cefaclor have been extensively used for the manromycin. [84] The significant advantages of azithromycin are enagement of AECOPD. The newer cephalosporins, cefprozil and hanced potency against H. influenzae, once-daily administration, cefixime, may have some advantages such as activity against reduced rates of adverse effects (specifically gastrointestinal efresistant pneumococci, but have not been proven to be superior to fects), an abbreviated 3-to 5-day treatment course, and perhaps a amoxicillin [100, 101] when organisms are fully sensitive to both reduced frequency of relapse during extended follow-up. [107] [108] [109] [110] agents.

The efficacy and safety of a 3-day regimen of azithromycin and of The combination of amoxicillin/clavulanic acid is an improve-a 10-day regimen of amoxicillin/clavulanic acid were compared in ment over amoxicillin alone when prescribed for β-lactamasepatients with AECOPD. Major improvement or cure on day 14 producing organisms. Addition of clavulanic acid makes the com-occurred in 95% of patients in the azithromycin group compared bination therapy resistant to most but not all bacterial βwith 90% on amoxicillin/clavulanic acid. At 30 days, the success lactamases. Most studies of patients with lower respiratory tract was 77% and 66% in azithromycin-and amoxicillin/clavulanic infection have shown this agent to be equivalent to standard acid-treated patients, respectively. [108] Another recent randomized, comparators. [102] Comparison with cefixime and ciprofloxacin double-blind, multicenter trial compared the safety and efficacy of showed better clinical success in AECOPD but no significant oral azithromycin and levofloxacin in outpatients with difference in bacterial eradication rates. [103] AECOPD. [110] Both treatments were well tolerated, and favorable clinical outcomes were demonstrated in 89% of patients receiving than 300 primary care physicians compared the efficacy of azithromycin and 92% of patients receiving levofloxacin by day 4 ciprofloxacin and clarithromycin. Equivalent clinical success of therapy. At day 24, favorable responses were approximately (93% vs 90%) and bacteriologic eradication (98% vs 95%) were 82% and 86% and bacterial eradication rates were 96% and 85%, reported with ciprofloxacin compared with clarithromycin. Derespectively, for patients in the two treatment groups. Another spite a relatively high inhibitory concentration against S. study compared the clinical efficacy and tolerability of 5-day pneumoniae, ciprofloxacin has demonstrated clinical efficacy simcourses of dirithromycin and azithromycin given once daily for the ilar to amoxicillin, clarithromycin and cefuroxime. [119] Oral treatment of AECOPD. Comparable clinical efficacy was revealed levofloxacin 250 or 500mg daily was compared with oral cefuroxbetween 5-day courses of once-daily dirithromycin and azithroime axetil (250mg twice daily) in a randomized, double-blind, mycin in AECOPD. [111] multicenter study. [120] The cure rates in the intention-to-treat population were 70% for levofloxacin 250mg, 70% for levofloxacin Clarithromycin per se has only intermediate activity against 500mg and 61% for cefuroxime axetil. Another randomized, H. influenzae but synergy with one of its metabolites increases its double-blind study demonstrated equivalent clinical and bacterioactivity to satisfactory levels. [109, 112] Clinical studies of clarithrologic success with levofloxacin 500mg once daily for a 5-or 7-day mycin involving 7-to 14-day regimens in patients with mild-tocourse. [121] A shorter course of gatifloxacin for 5 days was commoderate infections have shown equivalence to ampicillin. [113] A phase III randomized, double-blind study in AECOPD patients pared with 7-day gatifloxacin therapy and 10-day clarithromycin demonstrated that extended release clarithromycin at 500mg once therapy for acute exacerbation of chronic bronchitis. [122] Similar daily compared favorably with immediate release clarithromycin clinical success rates of >88% were reported compared with 500mg twice daily: the clinical cure rates were 86% and 85%, comparator antimicrobials. Another open-label noncomparative respectively. [114] A recent study compared clarithromycin with post-marketing trial of gatifloxacin in the treatment of AECOPD amoxicillin/clavulanic acid in the treatment of AECOPD. Clinical in community-based practice settings was reported recently. [123] success was documented in 85% of patients receiving erythromy-Overall cure rates were 95.8% for H. influenzae, 98.6% for S. cin and was equivalent to amoxicillin/clavulanic acid, and the pneumoniae and 89.2% for M. catarrhalis; the most serious adinidence of adverse events was similar in the two treatment verse effects were nausea (1.5%), dizziness (1.5%), diarrhea groups. [115] (1.2%), and vomiting (0.9%). [123] Another respiratory fluoroquinolone, moxifloxacin, has been reported to be efficacious in pa-Fluoroquinolones, synthetic analogs of the original molecule tients with AECOPD. [124] [125] [126] These multicenter trials compared (nalidixic acid), exert their antimicrobial effect by direct inhibition oral moxifloxacin 400 mg/day for 5 days with oral clarithromycin of bacterial DNA synthesis. [116] [117] [118] Two bacterial enzymes -DNA 500 mg/day for 10 days or intramuscular ceftriaxone 2g once daily gyrase and topoisomerase IV -have essential roles in DNA for 7 days or oral amoxicillin/clavulanic acid (three 625mg tablets replication. Fluoroquinolones bind to each of these enzymes, thus interfering with DNA replication, leading to bacterial cell death. daily for 7 days). Similar clinical success rates, classified as Resistance to fluoroquinolones occurs via mutations in the genes resolution or improvement of symptoms, occurred with moxifloxby encoding the subunits of DNA gyrase and topoisomerase IV. acin. A multinational, double-blind study, MOSAIC (Moxiflox-Altered permeation mechanisms may contribute to resistance by acin Oral tablets to Standard oral antibiotic regimen given as firstenhancing cytoplasmic membrane efflux pumps. These agents line therapy in out-patients with Acute Infective exacerbations of penetrate well into the respiratory secretions and bronchial muco-Chronic Bronchitis), compared effectiveness of moxifloxacin sa, but the clinical relevance of this is uncertain. The respiratory (400mg once daily for 5 days) and standard therapy (amoxicillin fluoroquinolones are active against both typical and atypical bac-[500mg three times daily for 7 days], clarithromycin [500mg twice terial pathogens. The fluoroquinolones are highly active against βdaily for 7 days], or cefuroxime-axetil [25mg twice daily for 7 lactamase producing H. influenzae and M. catarrhalis. These days]). Patients were stratified according to oral and inhaled antimicrobial agents have 70-95% bioavailability after oral adcorticosteroid usage. The primary endpoint was clinical success ministration, a prolonged half-life (>8-12 hours), low protein (sufficient improvement, no alternative antimicrobial therapy rebinding and renal clearance. Fluoroquinolones are well tolerated, quired) 7-10 days after therapy. Secondary predefined endpoints and adverse effects are mild and transient, including rash, dizziwere clinical cure (return to pre-exacerbation status), further antiness, headache, gastrointestinal disturbance (nausea, vomiting, microbial use, time to next exacerbation and bacteriologic success. diarrhea, abdominal pain) and minor hematologic abnormalities.

In this parallel study, 354 patients received moxifloxacin and 376 The efficacy of fluoroquinolones has been established in sever-patients received standard therapy. In an intention-to-treat (ITT) al randomized trials. A community-based study involving more population, clinical success rates were similar (87.6% for mox-ifloxacin, 83% for standard therapy, p = 0.02) at 7-10 days after creased sputum volume, and increased sputum purulence), should therapy. Moxifloxacin showed superior clinical cure rates over be treated. The traditional antimicrobials termed as first-line therstandard therapy in both ITT patients (95% CI 1.4, 14.9) and per apy are appropriate; these include amoxicillin, tetracycline, doxyprotocol patients (95% CI 0.3, 15.6), and higher bacteriologic cycline and trimethoprim/sulfamethoxazole. Cure rates with these success in microbiologically valid patients (95% CI 0.4, 22.1).

antimicrobials approach 80-90% in mild-to-moderate exacerba-Time to next exacerbation was longer with moxifloxacin; median tions. In patients who have more severe underlying lung disease, time to new AECOPD was 132.8 days in moxifloxacin, and 118.0 frequent exacerbations, and comorbid conditions, failure of initial days in standard therapy, respectively (p = 0.03). The occurrence antimicrobial therapy may result in repeat visits, hospitalization, of failure, new exacerbation, or any further antibiotic use was less and increased morbidity and mortality. In these patients (complifrequent in moxifloxacin-treated patients for up to 5 months of cated AECOPD), second-line antimicrobials including macrolides follow-up (p = 0.03). [127] A recent randomized, double-blind trial and fluoroquinolones, and second-or third-generation macrolides of gemifloxacin 320mg once daily antibiotic therapy was used to should be considered. investigate its efficacy and the magnitude and time course of effect Clinical trials utilizing newer antimicrobials showed equivaof an AECOPD on health status. Clarithromycin 500mg twice lence but not superiority compared with the regimens already in daily for 7 days was used as comparator drug, patients were use. Future studies should attempt to identify patients with followed up for 26 weeks. Clinical success rates at the 2-3 week AECOPD most likely to benefit from antimicrobial therapy. Well follow-up visit were 85.4% for gemifloxacin and 84.6% for defined prospective analyses of cost, DFI, quality-of-life improveclarithromycin. Bacteriologic success rates were 86.7% for ment and recovery of lung function should be addressed in these gemifloxacin and 73.1% for clarithromycin. Significantly more studies to ascertain the utility of antimicrobial therapy in patients receiving gemifloxacin than clarithromycin remained free AECOPD. of AECB recurrences (71.0% vs 58.5%, respectively; p = 0.016). [128] The greatest improvement in St George's Respiratory

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Etiology, susceptibility, and treatment BG034, St Boniface General Hospital, 409 Tache Avenue

of acute bacterial exacerbations of complicated chronic bronchitis in the prima-2A6, Canada. ry care setting: ciprofloxacin 750mg b.i.d. versus clarithromycin 500mg b.i.d. E-mail: ssharma@sbgh

Questionnaire score occurred within the first 4 weeks (mean 8.9 units, 95% CI 6.5, 11.5; p < 0.0001). [128] Subsequently, scores This study demonstrated sustained effect on health status even after a single episode of AECOPD; recurrences unfavorably affect quality of life. Treatments that reduce exacerbation frequency References could have a significant impact on health status. Despite consider-