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
]. 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
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
]. Telithromycin has a more focused spectrum of activity than the β-lactams 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
]. 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
]. 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.