1 Hôpital Bichat Claude Bernard, 75877 Paris Cedex 18; 3 Aventis, Romainville Cedex, France; 2 City Hospital Birmingham, Birmingham, UK
Received 22 July 2003; returned 9 September 2003; revised 3 November 2003; accepted 13 November 2003
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Abstract |
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Keywords: antibacterial, ketolide, telithromycin, tissue kinetics
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Introduction |
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Antibacterial therapy of RTIs is usually empirical, either because of the nature of the disease or because of the difficulty in establishing the microbiological aetiology. Treatment is generally a course of a ß-lactam or a macrolide.9 However, the effectiveness of this therapeutic approach is threatened by the increasing prevalence of resistance to these agents among common respiratory pathogens.6,10 As a result, there is a need for new antibacterials that retain activity against resistant organisms and have a low potential to select for resistance or induce cross-resistance to other antibacterial agents.11
Telithromycinthe first ketolide antibacterial to be developed for clinical usehas a targeted antibacterial spectrum of activity for community-acquired RTIs. In vitro studies have shown that telithromycin is active against common and atypical/intracellular respiratory tract pathogens, including pneumococcal strains resistant to ß-lactams or macrolides1217 (including those with very high erythromycin MICs).18 Importantly, telithromycin has a low potential to select for resistant strains and does not induce resistance to macrolide, lincosamide or group B streptogramin antibacterials.19,20 Telithromycin is well absorbed with Cmax (2.27 mg/L) reached within 13 h post-dose (800 mg once daily for 7 days), and has an elimination half-life of around 12 h allowing a convenient once-daily dosing regimen.21,22 Steady-state is reached within 23 days of treatment. Between 60% and 70% of telithromycin is bound to plasma protein (predominantly albumin). Telithromycin displays potent in vitro activity (including bactericidal activity against S. pneumoniae) and has a significant post-antibiotic effect (1.28.2 h) against major respiratory pathogens including S. pneumoniae, H. influenzae and M. catarrhalis, irrespective of their susceptibility to ß-lactams or macrolides.15,2226
In most RTIs, the bacteria are localized in the interstitial fluid of the infected tissue or multiply in alveolar macrophages (AM). Thus, the antibacterial concentration achieved at these sites is recognized as an important determinant of clinical efficacy and may vary with each drug.27 Tissue penetration studies have, therefore, become an essential part of the assessment of the potential efficacy of new antibacterial agents. The disposition/penetration of telithromycin into target tissues, fluids and cells after single and repeated doses (at steady-state), and the implication of these data for the use of telithromycin in treating RTIs, are reviewed here. Preliminary studies assessed drug penetration into white blood cells (WBCs) and into interstitial fluid and were carried out following a single or repeated 600 mg dose, while further tissue and fluid penetration studies were carried out at the recommended dose, 800 mg once daily for 5 days.
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Description of studies |
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In all studies, blood and tissue/fluid samples were collected at predefined timepoints following telithromycin administration, telithromycin concentrations were determined by HPLC or a validated agar diffusion method (Table 1), and pharmacokinetic parameters were determined. The collection of tissue/fluid samples at a single timepoint in studies involving bronchoscopy or tonsillectomy precluded calculation of telithromycin AUC024 values; therefore, comparison of telithromycin tissue/fluid penetration versus plasma levels was based on ratios of mean concentrations at specified timepoints.
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Statistics |
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Results from the studies |
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Single-dose study. Telithromycin concentrated rapidly in WBCs, achieving mean concentrations of 25.2 mg/L (range 10.5849.35 mg/L) 1 h and 52.8 mg/L (range 39.2673.29 mg/L) 6 h after dosing (Figure 1a). Levels declined thereafter, but were still quantifiable 48 h after a single dose. Telithromycin was quantifiable in plasma in all subjects 30 min after dosing [Cmax of 0.90 mg/L (range 0.59 1.29 mg/L) at Tmax of 1.50 h (range 1.003.00 h)], but was no longer quantifiable in plasma in any subjects 48 h after dosing. The geometric mean WBC to plasma concentration ratio was 44 (25.2:0.61 mg/L) 1 h after a single dose of telithromycin and increased to 217 (52.8:0.257 mg/L) and 705 (10.2:0.015 mg/L) 6 and 24 h after dosing, respectively.
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As in the single-dose study, telithromycin was detectable in plasma 30 min after repeat dosing. The Cmax was 0.98 mg/L (range 0.741.46 mg/L) and 1.31 mg/L (range 0.992.04 mg/L) at Tmax of 1.25 h (range 1.003.00 h) and 1.50 h (range 0.502.00 h) on Days 1 and 10 of dosing, respectively. On Day 10 of dosing, the mean WBC to plasma concentration ratio was 101 (83:0.856 mg/L) at 2 h, increasing at each timepoint to 2201 (8.9:0.003 mg/L) at 48 h. The ratio of geometric means of AUC024 for WBCs to plasma was 241 (on Day 10).
These data indicate that telithromycin accumulates rapidly in WBCs, reaching levels 44-fold greater than in plasma 1 h after administration of a single dose. Moreover, telithromycin is retained within WBCs so that the concentration 48 h after repeated once-daily dosing (8.9 mg/L) exceeds the MIC90 values for the majority of key respiratory pathogens (Table 2).3438
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Macrolide antibacterials also accumulate in WBCs, whereas the non-lipophilic ß-lactams do not.39 In vitro and in vivo studies indicate relatively poor penetration of erythromycin into WBCs, whereas roxithromycin, clarithromycin and particularly azithromycin give high site-to-serum ratios.4042 Azithromycin, a weak base, is thought to concentrate in the lysosomes of phagocytes and fibroblasts,41,43 with accumulation of the protonated drug leading to a slower efflux from the cells.44 The peak WBC-to-serum ratios observed for telithromycin are of the same magnitude as those for azithromycin.45,46 In contrast to azithromycin, however, which can be detected at levels of 18 mg/L in WBCs 10 days after administration of a single dose,47 telithromycin is rapidly cleared from WBC after treatment discontinuation, with a mean level of 2.93 mg/L 48 h after a single dose.
Inflammatory fluid
Although antibacterial sequestration into WBCs is important for efficacy against intracellular pathogens, many respiratory tract pathogens are located at extracellular sites within the airways. In particular, the concentration of an antibacterial in interstitial fluid is of import-ance when considering RTIs involving S. pneumoniae, H. influenzae and M. catarrhalis.48
Telithromycin was quantifiable in blister fluid at the first timepoint (2 h after dosing) in seven of the eight volunteers, and the mean maximum concentration in blister fluid, reached 6 h after dosing, was 0.373 mg/L (range 0.1540.741 mg/L), compared with a mean plasma concentration of 0.261 mg/L (range 0.1070.462 mg/L) at this timepoint. Concentrations of telithromycin plateaued up to 16 h after dosing and declined thereafter, but were still quantifiable in the blister fluid of all subjects 24 h after dosing (Figure 2). At this time, the mean concentration in blister fluid (0.08 mg/L, range 0.0420.155 mg/L) remained seven-times higher than in plasma (0.012 mg/L, range 0.0070.023 mg/L). The geometric mean of the AUC024 ratio of telithromycin in blister fluid over plasma was 1.38, indicating that telithromycin was well distributed in blister fluid. The mean residence time (from 0 to 24 h) in blister fluid was more than twice that in plasma (11.06 h versus 4.85 h).
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Bronchopulmonary tissues and fluids
Healthy volunteers. In the study involving healthy volunteers, four parallel groups underwent bronchoscopy and bronchoalveolar lavage 2, 8, 24 and 48 h, respectively, after administration of the last dose of telithromycin on Day 5.30 The mean concentration of telithromycin in AM was 65 mg/L (range 16168 mg/L) 2 h after dosing, and peaked at 100 mg/L (range 56166 mg/L) 8 h after the last dose. At the last timepoint (48 h), the telithromycin level in AM was 2.15 mg/L (range 1.952.35 mg/L) (Figure 3a and b). Mean telithromycin concentrations in epithelial lining fluid (ELF) peaked 2 h after dosing (5.4 mg/L, range 0.711.7 mg/L) and declined smoothly there- after. At the last timepoint (48 h), telithromycin was still quantifiable at a mean concentration of 0.30 mg/L (range 0.170.55 mg/L) (Figure 3a and b). Telithromycin levels in AM and ELF remained above the MIC90 values for key respiratory pathogens for up to 24 and 8 h, respectively.
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Patients undergoing bronchoscopy for diagnostic purposes
A second study assessed the penetration of telithromycin into AM, ELF and bronchial mucosa (BM) in patients requiring diagnostic fibre-optic bronchoscopy.31 Patients received telithromycin 800 mg once daily for 5 days and then underwent bronchoalveolar lavage and bronchial biopsy either 2, 12 or 24 h after the last dose of telithromycin. High telithromycin concentrations in AM (69.32 mg/L, range 21.7125.7 mg/L), ELF (14.89 mg/L, range 5.236.5 mg/L) and BM (3.88 mg/kg, range 1.86.9 mg/kg) were achieved 2 h after the last dose (Figure 4a and b). Mean plasma concentrations of telithromycin reached 1.86 mg/L (range 0.883.73 mg/L) at this sampling time. However, mean telithromycin concentrations in AM, ELF and BM were 2159.6-fold, 14.4-fold and 12.1-fold higher, respectively, than those in plasma 24 h after the last dose (Figure 4a and b), and concentrations of telithromycin in AM and ELF were above the MIC90 values for most key respiratory pathogens for 24 and 12 h after dosing, respectively.
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Macrolide antibacterials have also been shown to penetrate and accumulate in tissues, cells and fluids of the lower respiratory tract,51,52 whereas ß-lactam antibacterial penetration is poor, with concentrations reaching only 2040% of those achieved in plasma.53 Site-to-serum ratios at 24 and 48 h indicate that telithromycin penetration into lung tissue is far superior to that of erythromycin and comparable to that of clarithromycin.54,55 Although site-to-serum ratios of telithromycin are somewhat lower than those of azithromycin (determined in patients undergoing bronchoscopy for diagnostic purposes),56 this is because azithromycin achieves very low serum concentrations: the peak concentrations of telithromycin achieved in AM and ELF were in fact higher than those of azithromycin in this study. Whereas peak azithromycin concentrations in AM and ELF were achieved more than 48 h after dose administration, maximum levels of telithromycin in AM and ELF were achieved by 12 and 2 h post-dose, respectively. Telithromycin was also more rapidly cleared from AM following treatment discontinuation (levels had begun declining by 24 h), whereas high levels of azithromycin persisted in AM up to 96 h after the final dose.56
Tonsillar tissue and saliva
Of the Group A ß-haemolytic streptococci (GABHS), S. pyogenes is the primary bacterial cause of tonsillitis/pharyngitis. Penicillin is the current antibacterial of choice, although macrolides are prescribed to patients who are intolerant of ß-lactams. However, macrolide-resistant strains of GABHS are becoming prevalent in some countries.57
Telithromycin rapidly penetrated tonsillar tissue, achieving a mean concentration in tonsillar homogenates of 3.95 mg/kg (range 3.374.60 mg/kg) within 3 h of dosing (Figure 5). This was 3.38-times greater than the corresponding plasma concentration. Telithromycin was also eliminated more slowly from tonsils than plasma. This was reflected in the tonsil-to-plasma concentration ratio, which increased to 7.1 and 13.1 at 12 and 24 h after dosing, respectively. Telithromycin levels in both tonsils and plasma were maintained above the MIC90 for GABHS (0.015 mg/L) at all timepoints examined throughout the 24 h dosing period (Figure 5; Table 2). Indeed, up to 24 h, the average tonsillar concentrations of telithromycin (0.72 mg/kg) were 48-fold higher than the MIC90 of GABHS. The sustained high concentrations of telithromycin in tonsillar tissue suggest that this antibacterial agent will be effective in the treatment of GABHS tonsillitis/pharyngitis. It should be noted that the study design precluded assessment of telithromycin concentrations based on degree of tonsillar inflammation, therefore these results are only suggestive of the levels that may be achieved in patients with tonsillitis/pharyngitis.
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It should also be noted that all studies of drug penetration in tonsillar tissue used homogenized tissue for analysis, thus preventing the differentiation of intracellular and extracellular drug concentrations in study samples. Therefore, data may not accurately reflect the actual concentration of drug to which the pathogen is exposed in the tissue.
In a further study involving 10 healthy subjects who received telithromycin 800 mg once daily for 10 days, telithromycin achieved high concentrations in saliva (Cmax 3.06 mg/L, range 1.475.17).33 These concentrations were on average higher than those in plasma (2.03 mg/L, range 1.013.56 mg/L). The geometric mean of the AUC024 saliva/AUC024 plasma ratio was 1.6 at steady-state. The salivary concentrations of telithromycin exceeded its MIC90 for GABHS for up to 24 h after dosing, further supporting the use of this antibacterial agent in the treatment of tonsillitis/pharyngitis.
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Conclusions |
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The distribution, penetration and retention profile of telithromycin in lung and tonsillar tissues suggest that it can be taken reliably in a convenient once-daily dosing regimen. Importantly, this has the potential to improve patient adherence to antibacterial therapy and reduce the likelihood of development of resistance resulting from missed doses. Similarly, achieving high and maintained concentrations of telithromycin in respiratory tissues above the MICs of key pathogens may facilitate eradication of the infecting organism and prevent the selection and emergence of resistance. Telithromycin has a well-balanced intracellular/extracellular concentration ratio that results in bactericidal quantities necessary to eliminate the extracellular as well as the intracellular organisms. The tissue penetration of telithromycin is superior to that of ß-lactams and compares very favourably to that of macrolides. Telithromycin also reaches high concentrations in plasma (Cmax up to 2.03 mg/L). This has important implications for the successful treatment of RTIs accompanied by bacteraemia and thus associated with a greater risk of mortality.9,67
Pharmacokineticpharmacodynamic modelling suggests that the parameter predictive of clinical outcome for ß-lactams, erythromycin and clarithromycinwhich display time-dependent activityis the time above the MIC, whereas the parameter predictive of efficacy for fluoroquinolones, aminoglycosides and telithromycinwhich display concentration-dependent activityis the AUC or Cmax to MIC ratio.25,68,69 The high and sustained levels of telithromycin in WBCs and respiratory tissues and fluids, together with its MIC values for key respiratory pathogens, should ensure adequate efficacy at the site of infection.
In summary, telithromycin achieves high concentrations in respiratory and inflammatory tissues and fluids that are maintained throughout the dosing period. Together with its excellent microbiological profile against common and atypical/intracellular pathogensincluding resistant strainsand low potential to induce resistance, this makes telithromycin a promising new antibacterial for the treatment of community-acquired RTIs of the upper and lower respiratory tract.
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Acknowledgements |
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Footnotes |
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