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Ann Clin Microbiol AntimicrobAnnals of Clinical Microbiology and Antimicrobials1476-0711BioMed Central London 1476-0711-4-51575532610.1186/1476-0711-4-5ResearchAntibiotic activity of telithromycin and comparators against bacterial pathogens isolated from 3,043 patients with acute exacerbation of chronic bronchitis Sethi Sanjay 1ssethi@buffalo.eduAnzueto Antonio 2anzueto@uthscsa.eduFarrell David J 3d.farrell@grmicro.co.uk1 University at Buffalo SUNY, Buffalo NY, USA2 South Texas Veterans Health Care System, Audie L. Murphy Memorial Veterans Hospital Division, San Antonio, USA3 GR Micro Limited, London, UK2005 8 3 2005 4 5 5 8 2 2005 8 3 2005 Copyright © 2005 Sethi et al; licensee BioMed Central Ltd.2005Sethi et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.

Methods
This study examines the prevalence of antibacterial resistance in isolates obtained from patients with clinically diagnosed AECB. A total of 3043 isolates were obtained from 85 centres in 29 countries, between 1999–2003, and were tested against the new ketolide telithromycin and a panel of commonly used antibiotics.

Results and Discussion
Of the S. pneumoniae isolates, 99.9% were susceptible to telithromycin, but only 71% were susceptible to erythromycin and 75.3% to penicillin. Of the H. influenzae isolates, 99.6% were susceptible to telithromycin. 11.7% of these isolates produced β-lactamase. Almost 10% of S. pneumoniae were multidrug-resistant; 99.0% of these isolates were susceptible to telithromycin. Telithromycin also demonstrated good in vitro activity against M. catarrhalis (MIC90 = 0.12 mg/L) and was the most active compound against methicillin-susceptible S. aureus (98.9% susceptible).

Conclusion
Telithromycin demonstrated similar or better activity against the bacterial species investigated than the other agents, with the most complete coverage overall. These species are the predominant causative bacterial pathogens in AECB and thus the spectrum of activity of telithromycin makes it a potential alternative for the empirical treatment of AECB.
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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 [5-10].

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 [11-13]. 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.

Bacteria can be isolated from 40–60% of sputum samples of patients experiencing AECB [16]. The three predominant bacterial species isolated are non-typeable Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Other less frequently isolated potential pathogens are Gram-negative enterobacteria, Haemophilus parainfluenzae, Staphylococcus aureus, and Pseudomonas aeruginosa. Gram negative enterobacteria and Pseudomonas aeruginosa are more frequently isolated in patients with severe underlying disease [10]. Viral infections are present in approximately 30% of exacerbations, Mycoplasma pneumoniae in 1–10%, and Chlamydophila pneumoniae in 4–5% (serologically identified) [6-10].

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 β-lactams [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 PROTEKT (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.

Materials and Methods
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.

Table 1 Geographical distribution of isolates from AECB patients used in this study

Area	Countries	Centres	Isolates	
North America	2	4	319	
South America	6	14	427	
Europe	13	41	1847	
Australasia	6	19	437	
South Africa	1	6	13	
	
Totals	29	85	3043	
In Year 1 (1999–2000), each centre had a quota of 60 isolates of S. pneumoniae, 40 H. influenzae, 15 H. parainfluenzae, 20 M. catarrhalis, 25 Streptococcus pyogenes and 20 S. aureus to collect. In years 2 (2000–2001) and 3 (2001–2002), H. parainfluenzae were not collected and 15 extra isolates of S. pneumoniae were collected instead.

Antimicrobial testing
The comparator agents used were four β-lactams; penicillin (for S. pneumoniae and S. aureus), ampicillin (for H. influenzae, H. parainfluenzae and M. catarrhalis), amoxycillin/clavulanate, and cefuroxime, three macrolides/azalides; erythromycin, clarithromycin, and azithromycin, the folate synthesis inhibitor; trimethoprim-sulphamethoxazole, the tetracycline; tetracycline and a fluoroquinolone, levofloxacin.

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 (Table 1). Percentage of isolates by country were as follows: Argentina 8.0%, Australia 1.1%, Austria 0.6%, Brazil 4.0%, Canada 9.1%, China 1.7%, Colombia 0.1%, Ecuador 0.6%, Eire 0.03%, France 3.4%, Germany 14.3%, Hungary 1.2%, Indonesia 0.03%, Italy 18.9%, Japan 10.0%, Mexico 1.3%, Poland 10.2%, Portugal 2.8%, Russia 0.2%, South Africa 0.4%, South Korea 0.9%, Spain 5.3%, Sweden 0.4%, Switzerland 0.6%, Taiwan 0.7%, Turkey 0.3%, United Kingdom 2.4%, United States 1.4%, Venezuela 0.1%.

Of these isolates identified as causative pathogens for bacterial AECB, S. pneumoniae and H. influenzae formed the majority (1075 and 1037 respectively), followed by M. catarrhalis (536) (Table 2). Patients were predominantly male (63.5%), with 47.5% of patients belonging to the (30–64) year age group and 52.5% in the >64 year old age group. No difference in the distribution of pathogens by age group was observed (data not shown).

Table 2 Distribution of specimen types by species for the 3043 bacterial pathogens described in this study

Specimen	S. pneumoniae	H. influenzae	M. catarrhalis	S. aureus	H. parainfluenzae1	Total [n (%)]	
Sputum	832	895	492	219	43	2481 (81.5)	
BAL2	144	135	44	66	17	406 (13.4)	
Blood	99	7	0	50	0	156 (5.1)	
	
Total [n (%)]	1075 (35.3)	1037 (34.1)	536 (17.6)	335 (11.0)	60 (2.0)	3043 (100)	
1Only isolated in the first year of the study

2Bronchoalveolar lavage

Table 3 shows the range of MIC values, the MIC50 and MIC90 of the various agents against the five species. Where breakpoints were available the percentage of isolates to the various agents is also included. Telithromycin had similar or better in vitro susceptibility than the comparator agents against all of these species. Activity against S. pneumoniae was particularly good, with telithromycin being the most active agent; 99.9% of isolates were classified as susceptible and the MIC90 (0.12 mg/L) was substantially lower than all other compounds tested.

Table 3 In vitro activity of antibacterial agents against 3043 bacterial pathogens isolated from patients with AECB and % susceptibilities to antibacterial agents.

Organism	Antibacterial	MIC mg/l	% susceptible	
		range	50	90	total	MSSA	MRSA	
S. pneumoniae N = 1075	Telithromycin	0.004–2	0.015	0.12	99.9			
	Azithromycin	0.03->64	0.12	>64	71.2			
	Clarithromycin	0.015->32	0.03	>32	71			
	Erythromycin	0.03->64	0.06	>64	71			
	Penicillin	0.008–8	0.03	2	75.3			
	Amox/clavulanate1	0.015–8	0.03	2	96.1			
	Cefuroxime	0.015–16	0.03	2	82.2			
	Trimethoprim-sulphamethoxazole	0.12–32	0.25	8	62			
	Tetracycline	0.12–32	0.25	32	69.6			
	Levofloxacin	0.5->32	1	1	98.9			
								
H. influenzae N = 1037	Telithromycin	0.002–16	1	2	99.6			
	Azithromycin	0.06–32	1	2	99.7			
	Clarithromycin	0.25->64	8	16	82.4			
	Erythromycin	0.25->64	4	8	-2			
	Ampicillin	0.12–32	0.25	16	87.3			
	Amox/clavulanate1	0.12–4	0.5	1	100			
	Cefuroxime	0.12–16	1	2	99.5			
	Trimethoprim-sulphamethoxazole	0.03–32	0.06	4	80.7			
	Tetracycline	0.12–32	0.5	1	97.4			
	Levofloxacin	0.008–8	0.015	0.015	99.8			
								
M. catarrhalis N = 536	Telithromycin	0.004–0.5	0.06	0.12				
	Azithromycin	0.06–0.25	0.06	0.06				
	Clarithromycin	0.25–0.5	0.25	0.25				
	Erythromycin	0.25–1	0.25	0.25				
	Ampicillin	0.12–32	8	16				
	Amox/clavulanate1	0.12–0.5	0.12	0.25				
	Cefuroxime	0.12–16	1	2				
	Trimethoprim-sulphamethoxazole	0.06–4	0.25	0.5				
	Tetracycline	0.12–32	0.25	0.5				
	Levofloxacin	0.008–0.06	0.03	0.03				
								
S. aureus N = 335	Telithromycin	0.03->32	0.06	>32	85.1	98.9	24.2	
	Azithromycin	0.12->64	1	>64	70.4	84.2	9.7	
	Clarithromycin	0.03->32	0.25	>32	70.4	84.2	9.7	
	Erythromycin	0.12->64	0.25	>64	70.4	84.6	9.7	
	Penicillin	0.008–8	4	8	23.6	28.9	0	
	Amox/clavulanate1	0.06–8	0.5	8	83.1	100	0	
	Cefuroxime	0.12–16	1	16	81.2	100	0	
	Trimethoprim-sulphamethoxazole	0.12–32	0.12	0.25	94.9	97.4	83.9	
	Tetracycline	0.12–32	0.5	32	84.8	92.7	50	
	Levofloxacin	0.5–64	0.5	8	76.7	81.7	6.5	
								
H. parainfluenzae N = 60	Telithromycin	0.06–4	1	2	100			
	Azithromycin	0.06–2	0.5	1	100			
	Clarithromycin	0.25–16	4	8	93.3			
	Erythromycin	0.5–8	2	4	-2			
	Ampicillin	0.12–32	0.25	1	90			
	Amox/clavulanate1	0.12–2	0.5	1	100			
	Cefuroxime	0.12–4	0.25	0.5	100			
	Trimethoprim-sulphamethoxazole	0.03–32	0.03	1	88.3			
	Tetracycline	0.12–16	0.5	4	88.3			
	Levofloxacin	0.008–8	0.015	0.06	98.4			
1Amox/clavulanate = Amoxycillin/clavulanate

2No CLSI interpretive criteria for erythromycin and Haemophilus spp.

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 isolates, 99% susceptibility to telithromycin and 98.1% to levofloxacin. The MIC50 and MIC90 values for telithromycin in this population were 0.06 mg/L and 0.5 mg/L, respectively.

Table 4 Antibacterial activity against 103 Streptococcus pneumoniae isolates with combined macrolide and penicillin resistance

Antibacterial	% susceptible	% intermediate	% resistant	
Telithromycin	99.0	1.0	0.0	
Azithromycin	0	0	100	
Clarithromycin	0	0	100	
Erythromycin	0	0	100	
Penicillin	0	0	100	
Amoxycillin	0	0	100	
Amoxycillin-clavulanate	72.8	13.6	13.6	
Cefuroxime	1.0	1.0	98.0	
Trimethoprim-sulphamethoxazole	19.4	16.5	64.1	
Tetracycline	11.7	0.0	88.3	
Levofloxacin	98.1	0.0	1.9	
Over 99% of H. influenzae isolates were susceptible to amoxycillin-clavulanate, cefuroxime, telithromycin, azithromycin, and levofloxacin. Tetracycline also had good activity with 97.4% of isolates susceptible. Only 11.7% of H. influenzae isolates produced β-lactamase. There were only 60 isolates of H. parainfluenzae and 100% of these were susceptible to four of the eight compounds tested, telithromycin, amoxycillin/clavulanate, cefuroxime and azithromycin. Trimethoprim-sulphamethoxazole and tetracycline were the least active compounds. In terms of MICs, levofloxacin, azithromycin and telithromycin were the most potent compounds against M. catarrhalis with MIC90 values of 0.03 mg/l, 0.06 mg/l and 0.12 mg/l respectively.

There are currently no interpretative NCCLS guidelines available for M. catarrhalis to allow classification into susceptible or resistant categories.

The total number of isolates of S. aureus was 335 and of these only 62 were resistant to methicillin (MRSA). Trimethoprim-sulphamethoxazole was the most active compound overall, with 94.9% of all isolates being susceptible. Telithromycin and tetracycline were the next most active with 85.1% and 84.8% of all isolates susceptible. Telithromycin was the most active compound against the MSSA isolates, with 98.9% being susceptible. The susceptibility of MSSA to tetracycline and trimethoprim-sulphamethoxazole was 92.7% and 97.4% susceptible respectively. These three compounds were the only ones to have activity against the MRSA isolates (trimethoprim-sulphamethoxazole 83.9%, tetracycline 50% and telithromycin 24.2%). Less than 10% of the MRSA isolates were susceptible to the remainder of the compounds.

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 [29-31]. 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 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 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.

Acknowledgements
We are grateful to our colleagues worldwide for the supply of bacterial isolates as part of the PROTEKT study and the GR Micro PROTEKT team who performed the MIC testing. Aventis is acknowledged for their financial support of the PROTEKT study.

The data and discussion in the manuscript were presented in part at the European Respiratory Society Congress held in Glasgow in 2004 (Abstract P3902).
==== Refs
WHO  The World Health Report 2002. Reducing risks, promoting healthy life 2002 MDI.WHR.202.A Geneva , The World Health Organization 
Gross NJ  The GOLD standard for chronic obstructive pulmonary disease Am J Respir Crit Care Med 2001 163 1047 1048 11316631 
GOLD  Global Initiative for Chronic Obstructive Lung Disease http://wwwgoldcopdcom/ 2003 
ATS  Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Thoracic Society Am J Respir Crit Care Med 1995 152 S77 121 7582322 
Gump DW Phillips CA Forsyth BR McIntosh K Lamborn KR Stouch WH  Role of infection in chronic bronchitis Am Rev Respir Dis 1976 113 465 474 1267252 
Buscho RO Saxtan D Shultz PS Finch E Mufson MA  Infections with viruses and Mycoplasma pneumoniae during exacerbations of chronic bronchitis J Infect Dis 1978 137 377 383 206630 
Smith CB Golden CA Kanner RE Renzetti ADJ  Association of viral and Mycoplasma pneumoniae infections with acute respiratory illness in patients with chronic obstructive pulmonary diseases Am Rev Respir Dis 1980 121 225 232 6244766 
Blasi F Legnani D Lombardo VM Negretto GG Magliano E Pozzoli R Chiodo F Fasoli A Allegra L  Chlamydia pneumoniae infection in acute exacerbations of COPD Eur Respir J 1993 6 19 22 8425589 
Miyashita N Niki Y Nakajima M Kawane H Matsushima T  Chlamydia pneumoniae infection in patients with diffuse panbronchiolitis and COPD Chest 1998 114 969 971 9792563 
Sethi S  Infectious exacerbations of chronic bronchitis: diagnosis and management J Antimicrob Chemother 1999 43 Suppl A 97 105 10225579 10.1093/jac/43.suppl_1.97 
Saint S Bent S Vittinghoff E Grady D  Antibiotics in chronic obstructive pulmonary disease exacerbations. A meta-analysis Jama 1995 273 957 960 7884956 10.1001/jama.273.12.957 
Allegra L Blasi F de Bernardi B Cosentini R Tarsia P  Antibiotic treatment and baseline severity of disease in acute exacerbations of chronic bronchitis: a re-evaluation of previously published data of a placebo-controlled randomized study Pulm Pharmacol Ther 2001 14 149 155 11273797 10.1006/pupt.2001.0289 
Anthonisen NR Manfreda J Warren CPW Hershfield ES Harding GKM Nelson NA  Antibiotic Therapy in Exacerbations of Chronic Obstructive Pulmonary Disease Annals of Internal Medicine 1987 106 196 204 3492164 
Wilson R Schentag JJ Ball P Mandell L  A comparison of gemifloxacin and clarithromycin in acute exacerbations of chronic bronchitis and long-term clinical outcomes Clin Ther 2002 24 639 652 12017408 10.1016/S0149-2918(02)85139-6 
Spencer S Jones PW Group GLOBES  Time course of recovery of health status following an infective exacerbation of chronic bronchitis Thorax 2003 58 589 593 12832673 10.1136/thorax.58.7.589 
Sethi S Murphy TF  Bacterial infection in chronic obstructive pulmonary disease in 2000: a state-of-the-art review Clin Microbiol Rev 2001 14 336 363 11292642 10.1128/CMR.14.2.336-363.2001 
Destache CJ  Optimizing economic outcomes in acute exacerbations of chronic bronchitis Pharmacotherapy 2002 22 12S 17S; discussion 30S-32S 11791624 10.1592/phco.22.2.12S.33134 
Hoban D Felmingham D  The PROTEKT surveillance study: antimicrobial susceptibility of Haemophilus influenzae and Moraxella catarrhalis from community-acquired respiratory tract infections J Antimicrob Chemother 2002 50 Suppl S1 49 59 12239228 
Jacobs MR Felmingham D Appelbaum PC Gruneberg RN  The Alexander Project 1998-2000: susceptibility of pathogens isolated from community-acquired respiratory tract infection to commonly used antimicrobial agents J Antimicrob Chemother 2003 52 229 246 12865398 10.1093/jac/dkg321 
Douthwaite S Hansen LH Mauvais P  Macrolide-ketolide inhibition of MLS-resistant ribosomes is improved by alternative drug interaction with domain II of 23S rRNA Mol Microbiol 2000 36 183 193 10760175 10.1046/j.1365-2958.2000.01841.x 
Zhong P Shortridge VD  The role of efflux in macrolide resistance Drug Resist Updat 2000 3 325 329 11498400 10.1054/drup.2000.0175 
Farrell DJ Morrissey I Bakker S Felmingham D  Molecular characterization of macrolide resistance mechanisms among Streptococcus pneumoniae and Streptococcus pyogenes isolated from the PROTEKT 1999-2000 study J Antimicrob Chemother 2002 50 Suppl S1 39 47 12239227 
Farrell DJ Douthwaite S Morrissey I Bakker S Poehlsgaard J Jakobsen L Felmingham D  Macrolide Resistance by Ribosomal Mutation in Clinical Isolates of Streptococcus pneumoniae from the PROTEKT 1999-2000 Study Antimicrob Agents Chemother 2003 47 1777 1783 12760848 10.1128/AAC.47.6.1777-1783.2003 
Felmingham D  The need for antimicrobial resistance surveillance J Antimicrob Chemother 2002 50 1 7 12239224 
NCCLS  Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; Approved Standard - Fifth Edition.
NCCLS document M7 - A5 2000 Wayne, Pennsylvania 19087 - 1898, USA  
NCCLS  Performance standards antimicrobial susceptibility testing; Twelfth information supplement.  
NCCLS document M100 - 12 2002 Wayne, Pennsylvania 19807 - 1898, USA , NCCLS 
NCCLS  Performance standards antimicrobial susceptibility testing; Twelfth information supplement.NCCLS document M100-S14 2004 Wayne, Pennsylvania 19807 - 1898, USA , NCCLS 
Sethi S  Infectious etiology of acute exacerbations of chronic bronchitis Chest 2000 117 380S 5S 10843981 10.1378/chest.117.5_suppl_2.380S 
Tager I Speizer FE  Role of infection in chronic bronchitis N Engl J Med 1975 292 563 571 802896 
Murphy TF Sethi S  Bacterial infection in chronic obstructive pulmonary disease Am Rev Respir Dis 1992 146 1067 1083 1416398 
Isada CM  Pro: antibiotics for chronic bronchitis with exacerbations Semin Respir Infect 1993 8 243 253 7938921 
Sethi S  The Role of Antibiotics in Acute Exacerbations of Chronic Obstructive Pulmonary Disease Curr Infect Dis Rep 2003 5 9 15 12525285 
Sethi S Evans N Grant BJ Murphy TF  New strains of bacteria and exacerbations of chronic obstructive pulmonary disease N Engl J Med 2002 347 465 471 12181400 10.1056/NEJMoa012561 
Moellering RCJ  Meeting the challenges of beta-lactamases J Antimicrob Chemother 1993 31 Suppl A 1 8 8449834 
Scheld WM  Maintaining fluoroquinolone class efficacy: review of influencing factors Emerg Infect Dis 2003 9 1 9 12533274 
Nord CE Farrell DJ Leclercq R  Impact of ketolides on resistance selection and ecologic effects during treatment for respiratory tract infections Microb Drug Resist 2004 10 255 263 15383171 
Miyashita N Fukano H Niki Y Matsushima T  In vitro activity of telithromycin, a new ketolide, against Chlamydia pneumoniae J Antimicrob Chemother 2001 48 403 405 11533006 10.1093/jac/48.3.403 
Edelstein PH Edelstein MA  In vitro activity of the ketolide HMR 3647 (RU 6647) for Legionella spp., its pharmacokinetics in guinea pigs, and use of the drug to treat guinea pigs with Legionella pneumophila pneumonia Antimicrob Agents Chemother 1999 43 90 95 9869571 
Hammerschlag MR Roblin PM Bebear CM  Activity of telithromycin, a new ketolide antibacterial, against atypical and intracellular respiratory tract pathogens J Antimicrob Chemother 2001 48 Suppl T1 25 31 11566973 
Khair OA Andrews JM Honeybourne D Jevons G Vacheron F Wise R  Lung concentrations of telithromycin after oral dosing J Antimicrob Chemother 2001 47 837 840 11389116 10.1093/jac/47.6.837 
Nicolau DP  Predicting antibacterial response from pharmacodynamic and pharmacokinetic profiles Infection 2001 29 Suppl 2 11 15 11785851 
Edlund C Alvan G Barkholt L Vacheron F Nord CE  Pharmacokinetics and comparative effects of telithromycin (HMR 3647) and clarithromycin on the oropharyngeal and intestinal microflora J Antimicrob Chemother 2000 46 741 749 11062193 10.1093/jac/46.5.741 
Aubier M Aldons PM Leak A McKeith DD Leroy B Rangaraju M Bienfait-Beuzon C  Telithromycin is as effective as amoxicillin/clavulanate in acute exacerbations of chronic bronchitis Respir Med 2002 96 862 871 12418583 10.1053/rmed.2002.1382 
Zhanel GG Walters M Noreddin A Vercaigne LM Wierzbowski A Embil JM Gin AS Douthwaite S Hoban DJ  The ketolides: a critical review Drugs 2002 62 1771 1804 12149046

