Annals of Clinical Microbiology and

Background: Antimicrobial therapy is considered an important component in the medical management of most patients with acute exacerbation of chronic bronchitis (AECB). The three predominant bacterial species isolated are nontypeable Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Staphylococcus aureus is also frequently isolated while atypical bacteria are thought to cause up to 10% of exacerbations. Antibacterial resistance is increasing worldwide and little surveillance data exist concerning pathogens isolated from patients with AECB.


Introduction
The World Health Organization (WHO) estimates that chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide. In the year 2000, it was estimated that 2.74 million people died from COPD worldwide [1]. COPD is defined by the presence of irreversible or partially irreversible airway obstruction in patients with chronic bronchitis or emphysema [2,3]. The disease is characterized by recurrent (1-4 per year) acute exacerbations of chronic bronchitis (AECB), defined by a subjective increase from baseline of one or more symptoms including shortness of breath, cough, sputum production, and sputum purulence [4]. The precipitating factors for AECB have been extensively researched and determined to be heterogeneous with complex aetiology [5][6][7][8][9][10].
Results from a number of placebo-controlled clinical investigations have demonstrated that antibacterial agents are of significant clinical benefit in the treatment of AECB, particularly for those patients with at least two of the three cardinal symptoms of AECB (worsening dyspnoea, increased sputum volume, and increased sputum purulence) and/or severe airway obstruction [11][12][13]. Other clinical trials measuring non-traditional endpoints have shown that antibiotic therapy reduces the time to symptom resolution and has long-term benefits including greater intervals between episodes of exacerbation [14,15]. Consequently, antibiotic therapy is considered an important component in the medical management of patients with AECB.
Amoxycillin, ampicillin, sulfamethoxazole-trimethoprim (trimethoprim-sulphamethoxazole), tetracyclines, and erythromycin are considered first-line antimicrobial therapy for AECB [17]. The clinical utility of these agents is, however, being hampered by the increasing global spread of pathogens with resistance to one or more of these agents. Up to 40% of H. influenzae isolates and more than 90% of M. catarrhalis isolates produce β-lactamase and this limits the value of penicillins and some other βlactams [18]. Furthermore, resistance to penicillin and macrolides has spread rapidly among isolates of S. pneumoniae [19]. Other agents used include extended spectrum cephalosporins, amoxycillin/clavulanate, azithromycin, clarithromycin, and levofloxacin.
Telithromycin is the first ketolide available for clinical use. Derivatives of erythromycin-A, the ketolides, like the macrolides, exert their antimicrobial action by binding to the bacterial ribosome. Although both macrolides and ketolides bind strongly to a region of domain V in the 23S rRNA of the ribosome, telithromycin has additional strong binding to a region in domain II to which the macrolides bind weakly [20]. Ketolides are also poor substrates for the efflux pump (mefA) responsible for macrolide resistance in S. pneumoniae [21]. Consequently, telithromycin has been found to have potent activity against macrolide resistant S. pneumoniae with methylase, efflux or ribosomal mutations as the mechanisms of resistance [22,23].
There is a need for alterative therapeutic options for the treatment of AECB and surveillance data are needed to help determine the suitability of new agents. The PRO-TEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) study is an international, longitudinal, antibacterial resistance surveillance study, which was initiated in 1999 to monitor the spread of resistance among respiratory tract pathogens worldwide. Here we analyze the in vitro antimicrobial activity of bacterial isolates obtained from patients clinically diagnosed with AECB in 3 consecutive years of the PROTEKT study. Using these data, and previously published clinical data, the potential role of telithromycin in the treatment of AECB will be discussed.

Patients and bacterial isolates
Details of the study design, including the selection of patients and the methodology for the identification of isolates and their storage in the PROTEKT study has been described previously [24]. Isolates in this study were obtained from patients diagnosed with AECB from in 85 centres in 29 countries (Table 1). To be included in this analysis, an isolate was deemed pathogenic in AECB by clinical and laboratory findings. Isolates were only acceptable if the patient was ≥ 30 years old and the specimen was obtained from blood, bronchoalveolar lavage (BAL), or sputum. Isolates from patients diagnosed with AECB obtained from other sites (e.g., ear, throat, nasopharynx) and isolates obtained from patients <30 years of age were excluded from this analysis because AECB is more likely to be present in patients ≥ 30 years of age and the responsible bacterial pathogen is more likely to be correctly isolated from the blood, BAL, or sputum. In
Minimum inhibitory concentrations (MIC) of each antibacterial were determined using the National Committee for Clinical and Laboratory Standards (NCCLS) broth microdilution methodology and lyophilised microtitre plates (Sensititre, Trek Diagnostics) at a central laboratory (GR Micro Ltd., London, UK) [26]. NCCLS breakpoints [25,26] were used to interpret the MIC data and to determine susceptibility status. The NCCLS breakpoints for telithromycin for S. pneumoniae and for S. aureus are ≤ 1 mg/ l is susceptible, 2 mg/l is intermediate, and ≥ 4 mg/l is resistant, and for H. influenzae ≤ 4 mg/l is susceptible, 8 mg/l is intermediate, and ≥ 16 mg/l is resistant [27].

Results
A total of 3043 bacterial pathogens were isolated from patients in 29 countries around the world, with by far the largest number of specimens (1841, 60.5%) coming from Europe (  One hundred and three (9.6%) S. pneumoniae isolates (from 51 and 53 patients in the 30-64 and >64 year old age groups respectively)) were resistant to both penicillin (MIC ≥ 2 mg/L) and erythromycin (MIC ≥ 1 mg/L) and this was reflected in resistance to amoxycillin, cefuroxime, clarithromycin and azithromycin also (Table 4). These isolates were found in 35 centres in 16 countries. Sixty of these resistant isolates were also resistant to both trimethoprim-sulphamethoxazole and tetracycline. Both telithromycin and levofloxacin had good activity against these

Discussion
The primary cause of COPD is exposure to tobacco smoke, the major risk factor being cigarette smoking. The demography of the disease in this study and others reflects this, as the majority of patients in this analysis were male and half were elderly (>64 yrs of age) (2). S. pneumoniae is most frequently isolated in the least severe cases of AECB, whereas H. influenzae is more commonly isolated from moderate to severe cases, with P. aeruginosa occurring in severe hospitalised cases [28]. Telithromycin does not have good activity against Pseudomonas spp. (GR Micro Limited, data on file, internal report number 141-02-99) and hence may not be an appropriate empirical therapeutic option for AECB patients with severe underlying disease who are hospitalized for an acute exacerbation.
Whether the isolation of a pathogen during AECB represents an infection responsible for the exacerbation has been debated for many years [29][30][31]. Bacteria have been isolated almost as frequently from patients with stable COPD as those with an AECB, and clinical trials of antibiotic therapy in AECB show contradictory and sometimes unconvincing results [30]. The presence of bacteria in the lower airways is, however, regarded as abnormal since these airways are sterile in healthy adults, and it has been hypothesized that the presence of bacteria in stable COPD represents a low-grade smouldering infection. In addition, a recent study has shown that infection with different strains of pathogens that are new to the patient is associated with development of exacerbation [32,33].
Amoxycillin-clavulanate, azithromycin, and levofloxacin have been shown to be effective in the treatment of AECB, however, there is concern regarding their long-term usefulness, because of the development of resistance to these agents among the causative pathogens [34,35]. Telithromycin has a more focused spectrum of activity than the βlactams and the fluoroquinolones; it is specifically targeted against pathogens causing community-acquired respiratory disease, including those most commonly associated with AECB. In addition, it is active against penicillin-and macrolide-resistant strains of S. pneumoniae and hence offers a viable potential option for the empiric treatment of AECB in non-hospitalised patients [36].
The data in this study demonstrate that telithromycin has high in vitro activity against the commonest bacterial pathogens causing AECB. These data also show that telithromycin has the highest overall activity against bacterial isolates from patients with AECB, regardless of species. Almost 10% of S. pneumoniae isolated were resistant to penicillin, macrolides, and at least one of the other antibiotics tested, with only telithromycin and levofloxacin retaining high activity against these isolates (99.0% and 98.1%, respectively). The validity of this finding is strengthened as the isolates were obtained from a large number of patients over a wide geographical distribution.
Although atypical pathogens were not examined in the PROTEKT study, telithromycin has been shown to have superior activity in vitro against Chlamydophila pneumoniae to the other macrolides with the exception of clarithromycin and has similar activity to the fluoroquinolones [37]. In guinea pig models, telithromycin had better activity than erythromycin against Legionella pneumophila infections [38]. In vitro, the activity of telithromycin against L. pneumophila was similar to levofloxacin but better than erythromycin [38]. β-lactams and cephalosporins have no activity against Mycoplasma pneumoniae as this species lacks a typical bacterial cell wall, the site of activity for these drugs. Telithromycin has been found to have higher activity than doxycycline and levofloxacin against M. pneumoniae [39]. As the atypical pathogens can represent up to 10% of infections associated with AECB, the efficacy of telithromycin against these pathogens could be a consideration in the selection of empiric therapy for AECB.
Telithromycin has been shown to penetrate into respiratory tissues well [40]. The concentration of telithromycin in alveolar macrophages and epithelial lining fluid exceeds that of plasma markedly and remains at therapeutic levels for 24 hours after dosing. Bactericidal levels are also maintained in plasma. A good post-antibiotic effect has also been observed [41]. Telithromycin causes only moderate ecological disturbance to oral and intestinal flora comparable to that associated with clarithromycin and it does not significantly increase the development of resistance in the normal flora, although the MIC of oral streptococci can be slightly raised [42].
Telithromycin can be administered once a day for AECB. Clinical studies have demonstrated that 800 mg administered once daily for 5 days was as effective and well tolerated as a 10-day course of amoxycillin/clavulanate (500/ 125 mg 3 times daily for 10 days), cefuroxime axetil (500 mg twice daily for 10 days) or clarithromycin (500 mg twice daily for 10 days) [43]. Other clinical studies have also confirmed the safety and tolerability of telithromycin 800 mg administered for 5 -10 days [44]. Once a day dosing schedules and shorter courses may promote patient adherence to therapy, and this in turn could delay the development of resistance.
Although this study provides valuable information on the overall antimicrobial profile of bacteria causing AECB, care should be taken when interpreting data related to specific demographics. The prevalence of species could not be calculated in this study as a major limitation, inherent to most surveillance studies, is the requirement for collecting centres to fulfil a specified quota of isolates over a defined time period (1 year). If, for instance, a centre managed to fulfil the quota for S. pneumoniae isolates from patients with community-acquired pneumonia, it could then only send H. influenzae from patients with AECB to fulfil the quota for this organism. In addition, atypical pathogens were not sampled and they can represent up to 10% of the causative pathogens [28].
In summary, the data presented here demonstrate that telithromycin has good in vitro activity against H. influenzae, S. pneumoniae, and M. catarrhalis, respiratory pathogens commonly isolated in AECB. It is as active as or more active than agents that are currently used in this clinical setting. Additionally, although not shown here, telithromycin has better in vitro activity against atypical pathogens than other agents; an important advantage in this clinical setting as these pathogens may represent 10% of AECB associated infections.
The development of resistance will always be a threat to the usefulness of antibacterial compounds, however surveillance studies such as PROTEKT allow the rapid detection and characterization of resistance mechanisms and highlight the need for and examine the in vitro efficacy of newer antibacterial agents. Providing careful surveillance for the development of resistance is maintained, telithromycin currently offers a useful agent in the treatment of AECB.