Journal of Antimicrobial Chemotherapy (2001) 47, 837-840
© 2001 The British Society for Antimicrobial Chemotherapy
Lung concentrations of telithromycin after oral dosing
a Departments of Medical Microbiology and Thoracic Medicine, City Hospital NHS Trust, Birmingham B18 7QH; b Department of Thoracic Medicine, Heartlands Hospital, Birmingham, UK; c Clinical Pharmacology, Aventis Pharma, Romainville, France
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Abstract |
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Concentrations of telithromycin were measured in plasma, bronchial mucosa (BM), epithelial lining fluid (ELF) and alveolar macrophages (AM) following multiple oral doses. Concentrations were determined using a microbiological assay. There were 20 subjects in the study, allocated to three nominal time periods: 2, 12 and 24 h. Mean concentrations in plasma, BM, ELF and AM for 2, 12 and 24 h were as follows: 2 h, 1.86 mg/L, 3.88 mg/kg, 14.89 mg/L and 69.32 mg/L; 12 h, 0.23 mg/L, 1.41 mg/kg, 3.27 mg/L and 318.1 mg/L; and 24 h, 0.08 mg/L, 0.78 mg/kg, 0.97 mg/L and 161.57 mg/L. These concentrations of telithromycin in BM and ELF exceeded for 24 h the mean MIC90s of the common respiratory pathogens Streptococcus pneumoniae (0.12 mg/L) and Moraxella catarrhalis (0.03 mg/L), as well as the atypical microorganism Mycoplasma pneumoniae (0.001 mg/L), and suggest that telithromycin may be effective for the treatment of community-acquired pneumonia and chronic obstructive pulmonary disease.
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Telithromycin (HMR 3647) belongs to the family of ketolides representing a new class of 14-membered ring macrolides.1 Ketolides are characterized by a keto function in position 3 of the erythronolide A ring, which replaces the cladinose moiety. Telithromycin is a C11–C12 carbamate ketolide. On the carbamate residue, imidazolyl and pyridinyl rings are linked by a butyl chain. Telithromycin inhibits protein synthesis, acting mainly on the 50S ribosomal subunit.
Telithromycin possesses a well-balanced activity against all the relevant pathogens associated with respiratory tract infections, including pneumococci resistant to penicillin and erythromycin, as well as Haemophilus influenzae and Moraxella catarrhalis, atypical bacteria (Mycoplasma pneumoniae) or intracellular bacteria (Chlamydia pneumoniae and Legionella pneumophila).1
The aim of this study was to measure concentrations of telithromycin in bronchial mucosa (BM), epithelial lining fluid (ELF), alveolar macrophages (AM) and plasma following multiple once daily oral dosing of 800 mg for 5 days before bronchoscopy in patients.
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Patients and methods |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Patients
Twenty-seven patients (11 female and 16 male) undergoing elective fibre-optic bronchoscopy were enrolled. Subjects were recruited from a respiratory outpatient clinic. Patients were divided into three nominal time windows of 2, 12 and 24 h after the last dose. All of the patients were over 18 years of age and all females were post-menopausal. The study was approved by the hospital ethics committee and all subjects gave written informed consent. Patients were excluded from the study if they had active lung infection, were receiving another antibiotic, had any unstable medical condition, any significant renal or hepatic disease, a history of allergy to macrolide antibiotics or were receiving theophyllines.
All subjects were screened within 14 days before bronchoscopy; screening included a detailed medical history, physical examination and blood samples for haematological, biochemical analysis and pre-dose microbiological assay.
Bronchoscopy and sample collection
Bronchoscopy and sample collection was as described previously.2 Briefly, at bronchoscopy BM samples were taken and broncho-alveolar lavage (BAL) was performed. A standard BAL was performed using 200 mL of pre-warmed 0.9% saline divided into four aliquots of 50 mL. The aspirate from the first lavage was discarded to avoid contamination with proximal airway fluids and cells, the remaining aliquots were pooled for analysis.
Microbiological assay
Assay plates (Mast Laboratories, Bootle, UK) containing a base layer of Antibiotic Medium No. 1 adjusted to pH 8 with NaOH, were overlaid with the same medium seeded with Bacillius subtilis ATCC 6633/NCTC 10400 spore suspension (spore suspension adjusted to 80% light transmission at 54 nm). Calibrators, internal controls and quality assurance samples were prepared from known potency standard telithromycin powder (Aventis Pharma, Romainville, France) in human serum (E&O Laboratories, Bonnybridge, UK), pH 8 phosphate buffer and 9% NaCl for the assay of plasma, AM and BM and ELF, respectively. Calibrator ranges in serum, pH 8 buffer and 9% NaCl were 0.05–0.8 mg/L, 0.03–0.04 mg/L and 0.05–0.8 mg/L, respectively. Six millimetre diameter wells were punched into the agar and samples (calibrators, internal controls, quality assurance samples and tests) were applied in triplicate in a random pattern. Plates were incubated at 32°C for 18–20 h and zones of inhibition were measured using an Image Analyser (Imaging Associates, Teme, UK) pre-programmed with Bennet's calculation to obtain a line of best fit.3 The lower limit of quantification of the assay was 0.03 mg/L. The assay was validated externally by Aventis Pharma before commencement of the bronchial study (30 serum samples correlation of assigned concentration and assayed concentration r2 = 0.9894).
Calculation of telithromycin concentration in ELF, BM and AM
Concentrations of telithromycin in ELF, BM and AM were calculated as described previously.2 Briefly, the concentration of antibiotic in each of the sites was calculated as follows:
Bronchial biopsies.
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where AC = assayed concentration (mg/L), VB = volume of buffer added to homogenize sample (µL) and WS = weight of tissue (mg).
ELF. The concentration of urea in the BAL was determined using a modified Sigma Diagnostic kit (UV-66, Sigma Chemicals, Poole, UK).
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where ACL = assayed concentration (mg/L), UL = urea concentration in lavage (mmol/L), and BL = blood urea concentration (mmol/L).
Alveolar macrophages. Antibiotic concentration was determined using a mean cell volume of an alveolar macrophage of 2.48 µL/106 cells.
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Results |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Between-assay coefficients of variation for serum (0.6 and 0.8 mg/L), 9% NaCl (0.6 mg/L and 0.8 mg/L) and pH 8 buffer (0.3 mg/L and 0.04 mg/L) were 5.7, 9.9 and 12%, respectively. Correlation of the assayed concentration with the assigned concentration for the quality assurance samples (within-assay variation) for serum (range 0.06–0.74 mg/L), 9% NaCl (range 0.06–0.76 mg/L) and pH 8 buffer (range 0.035–0.75 mg/L) gave r2 values of 0.9782, 0.9774 and 0.9690, respectively.
Seven patients were withdrawn from the study, one who withdrew consent before taking the medication; one with moderate diarrhoea; one with a creatinine clearance of <50 mL/min; one for administrative reasons because a spillage of disinfectant in theatre prevented the collection of samples; one with a minor adverse event (vomited the last tablet); and three patients who did not take all of the prescribed tablets. Individual patient results for each of the nominal time windows and ratios of site to plasma concentration are shown in the Table.
Mean concentrations in plasma, BM, AM and ELF for the three nominal time windows (hours after the last dose) were: 2 h, 1.86 mg/L, 3.88 mg/kg, 69.32 mg/L, 14.89 mg/L; 12 h, 0.23 mg/L, 1.41 mg/kg, 318.1 mg/L, 3.27 mg/L; and 24 h, 0.08 mg/L, 0.78 mg/kg, 161.57 mg/L, 0.97 mg/L. There were no clinically relevant changes in clinical laboratory parameters and no drug-related adverse reactions in any patient.
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Discussion |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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The findings of this study show that there was good penetration of telithromycin into respiratory tissues after administration of multiple oral doses of 800 mg to patients undergoing diagnostic fibre-optic bronchoscopy. The mean site to serum ratios at c. 2 h for telithromycin in BM were slightly lower than those for clarithromycin,4 but similar to those for erythromycin.5 In ELF, telithromycin ratios were similar to those for clarithromycin yet higher than those seen for erythromycin. In the first time window there was considerable inter-subject variation. A possible reason for this is that the drug had not equilibrated between the various compartments at this early time post dosing. The greatest difference in ratios was noted with AMs where ratios of 94.1 and 40.8 for clarithromycin and telithromycin, respectively, were observed. Concentrations of telithromycin in BM and ELF exceeded for 24 h the mean MIC90s of the common respiratory pathogens Streptococcus pneumoniae (0.12 mg/L)1 and M. catarrhalis (0.03 mg/L),1 as well as the atypical microorganism M. pneumoniae (0.001 mg/L).1 For H. influenzae (MIC90 2 mg/L)1 concentrations in ELF and BM were exceeded for 12 h. High AM concentrations suggest that telithromycin may have good activity against intracellular pathogens C. pneumoniae and L. pneumophila. These data suggest that telithromycin may be effective for the treatment of respiratory infections and is worthy of further investigation.
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Acknowledgments |
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We would like to thank Aventis Pharma for their financial support.
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Notes |
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* Corresponding author. Tel: +44-121-507-5693; Fax: +44-121-551-7763.
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References |
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1 . Bryskier, A., Agouridas, C. & Chantot, J. F. (1997). Ketolides: semisynthetic 14-membered-ring macrolides. In Expanding Indications for the New Macrolides, Azolides and Streptogramins, (Zinner, S. H., Young, L. S., Acar, J. F. & Neu, H. C., Eds), pp. 39–49. Marcel Dekker, New York.
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Andrews, J. M., Honeybourne, D., Brenwald, N. P., Bannergee, D., Iredale, M., Cunningham, B. et al. (1997). Concentrations of trovafloxacin in bronchial mucosa, epithelial lining fluid, alveolar macrophages and serum after administration of single or multiple oral doses to patients undergoing fibre-optic bronchoscopy. Journal of Antimicrobial Chemotherapy 39, 797–802.
3 . Bennett, J. V., Brodie, J. L., Benner, E. J. & Kirby, W. M. (1966). Simplified, accurate method for antibiotic assay of clinical specimens. Applied Microbiology 14, 170–7.[Web of Science][Medline]
4 . Honeybourne, D., Kees, F., Andrews, J. M., Baldwin, D. & Wise, R. (1994). The levels of clarithromycin and its 14-hydroxy metabolite in the lung. European Respiratory Journal 7, 1275–80.[Abstract]
5 . Matera, M. G., Tufano, M. A., Polverino, M., Rossi, F. & Cazzola, M. (1997). Pulmonary concentrations of dirithromycin and erythromycin during acute exacerbation of mild chronic obstructive pulmonary disease. European Respiratory Journal 10, 98–103.[Abstract]
Received 15 November 2000; returned 1 February 2000; revised 23 February 2001; accepted 7 March 2001
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