Penetration of telithromycin into the nasal mucosa and ethmoid bone of patients undergoing rhinosurgery for chronic sinusitis

T. S. Kuehnel1,*, C. Schurr1, K. Lotter2 and F. Kees2

Departments of 1 Otolaryngology, Head and Neck Surgery and 2 Department of Pharmacology, University of Regensburg, D-93053 Regensburg, Germany


* Correspondence address. Department of Otolaryngology, Head and Neck Surgery, University Hospital of Regensburg, Franz-Josef-Strauß-Allee 11, D-93042 Regensburg, Germany. Tel: +49-941-944-9440; Fax: +49-941-944-9441; Email: thomas.kuehnel{at}klinik.uni-regensburg.de

Received 20 September 2004; returned 28 October 2004; revised 24 November 2004; accepted 27 December 2004


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objectives: Telithromycin has a broad spectrum of activity against respiratory tract pathogens including penicillin- and macrolide-resistant streptococci. The aim of the study was to investigate the penetration of telithromycin into nasal tissue following a single oral dose of 800 mg.

Patients and methods: A total of 29 patients undergoing rhinosurgery for chronic sinusitis were evaluated. Samples of blood, nasal mucus, nasal mucosa and ethmoid bone were collected during surgery in groups of 5–6 patients after 3, 6, 9, 15 and 24 h following a single oral dose of 800 mg telithromycin. Drug concentrations were determined by HPLC with fluorimetric detection.

Results: The highest telithromycin concentrations were observed after 3 h in plasma as well as in all tissues sampled. The mean plasma concentrations were 0.73 mg/L in the 3 h group and 0.02 mg/L in the 24 h group. The concomitant tissue concentrations were higher. The tissue penetration, expressed by the ratio of the area under the concentration–time curve in tissue versus plasma, was 1.0 for nasal mucus, 5.9 for nasal mucosa and 1.6 for ethmoid bone.

Conclusions: Telithromycin achieved tissue concentrations that were generally above the MIC90 for common pathogens in upper respiratory tract infections. These results indicate that telithromycin diffuses rapidly into the nasal tissues and achieves high and prolonged concentrations in nasal mucosa and ethmoid bone.

Keywords: ketolides , pharmacokinetics , nasal tissue


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Telithromycin, the first ketolide, has a broad spectrum of activity against respiratory tract pathogens including Streptococcus pneumoniae (including penicillin- and macrolide-resistant isolates), Haemophilus influenzae, Moraxella catarrhalis, Group A ß-haemolytic streptococci as well as intracellular and atypical bacteria.13 Oral telithromycin 800 mg once-daily for one or more days has been shown to provide a high value for the ratio of AUC to the MIC against major respiratory pathogens,4,5 and is well tolerated in both young and elderly subjects.6

The aim of the present study was to investigate the penetration of telithromycin into the nasal mucosa and ethmoid bone of patients, to provide kinetic data supporting the use of telithromycin in upper respiratory tract infections, as well as data on the penetration of telithromycin in rarely investigated tissues such as bone.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study design and procedure

This was a single-centre, parallel-group, open-label trial in patients undergoing functional endoscopic sinus surgery, and in some cases additional septoplasty, for chronic sinusitis. Exclusion criteria included significant hepatic and renal disorder, therapy with enzyme inductors within 2 weeks prior to telithromycin administration or concomitant medication with CYP3A4 substrates such as cisapride, ergot alkaloids, terfenadine or statins. Subjects were divided into five groups based on sampling times at 3, 6, 9, 15 and 24 h after a single oral dose of telithromycin 800 mg. The study was approved by the ethics committee of the University Hospital of Regensburg, and all subjects gave written informed consent. Samples of blood, nasal mucus, nasal mucosa and ethmoid bone were collected during the surgical procedure. Blood was collected into tubes containing EDTA as anticoagulant (EDTA Monovette; Sarstedt, Nümbrecht, Germany) and centrifuged to obtain plasma. Nasal mucus was obtained by suction; contamination with differing volumes of rinsing saline was not always avoidable. The mucus was absorbed onto a cellulose tampon (Salivette; Sarstedt, Nümbrecht, Germany), and a clear liquid was obtained by centrifugation. The ethmoid bone was rinsed briefly with saline to remove blood, and swabbed. Loosely adherent mucosa was carefully removed with a scalpel. All specimens were stored frozen at –25 °C until assay.

Drugs and chemicals

Telithromycin tablets (400 mg, batch no. 1 A009; expiry date 05/2005; Aventis Pharma Germany, Bad Soden) were obtained from the pharmacy of the University Hospital of Regensburg, Germany. Telithromycin (HMR 3647) and HMR 3004 were obtained from Aventis Pharma, Romainville, France. Acetonitrile and methanol (ultra gradient HPLC grade) were purchased from Baker, Groß-Gerau, Germany, and the other chemicals (analytical grade) were from E. Merck, Darmstadt, Germany. Water was purified with a Milli-Q water purification system (Millipore, Eschborn, Germany).

Drug assay

Drug concentrations were determined by HPLC with fluorimetric detection adapting a published method.7,8 Plasma or nasal mucus (200 µL) was mixed with 25 µL of internal standard solution (HMR 3004 100 µg/mL in methanol/water 50:50, v/v) and 400 µL of acetonitrile, for precipitation of proteins. Following centrifugation, the clear supernatant was injected onto the column. Mucosa (200–300 mg) was homogenized with Ultraturrax (IKA, Breisgau, Germany) in eight volumes (w/v) of water/acetonitrile 30:70 (v/v) containing 5 µg/mL HMR 3004, followed by 30 min mixing using a horizontal shaker (SM30C, J. Otto, Tübingen, Germany). Bone (50–150 mg) was deep frozen in liquid nitrogen and pulverized in a homemade, chilled, stainless steel mortar with pestle (type: Bessman Tissue Pulverizer, Spectrum Europe, Breda, The Netherlands). The bonemeal was then extracted using the horizontal shaker for 30 min in five volumes (w/v) of the tissue homogenization solution.

For chromatography, an LC-10A series HPLC system was used with Class10 software and an SPD-10A photometric detector (for HMR 3004) set at 300 nm, followed by an RF-10AXL fluorimetric detector (for telithromycin) set at excitation and emission wavelengths of 263 nm and 460 nm (Shimadzu, Duisburg, Germany). Separation was performed at 30 °C using a Nucleodur CN analytical column (internal diameter 150 x 4.6 mm; Macherey and Nagel, Düren, Germany) and an eluent consisting of 400 mL of 20 mM ammonium acetate, 0.20 mL of glacial acetic acid and 600 mL of acetonitrile. Telithromycin eluted after 4.5 min and the internal standard HMR 3004 after 5.1 min at a flow rate of 1.0 mL/min. The retention times of the analytes were about 10% shorter when the concentration of ammonium acetate was increased to 30 mM for the analysis of tissue. The recovery of telithromycin and HMR 3004 was quantitative from plasma and mucus, and 80%–95% from tissue. However, the endogenous water content of the tissues was not taken into account for the calculation. Telithromycin adsorption at the cellulose tampon has been excluded by analysing spiked saline samples. The limit of quantification was 10 ng/mL in plasma and mucus and 30 ng/g in tissue, respectively. Accuracy and precision were better than 10% as determined by co-analysing appropriate quality control samples in spiked matrix.

Pharmacokinetic and statistical analysis

The area under the concentration–time curve in plasma and tissue from 0–24 h (AUC0–24) was calculated using the linear trapezoidal rule. Descriptive statistics (mean ± S.D.) are reported for telithromycin.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Thirty-five patients were enrolled into the study and a total of 29 patients were evaluated. Five patients were excluded for non-compliance with the scheduled time of surgery and tissue sampling, and one patient was considered as an outlier (the 24 h plasma and tissue concentrations of this patient were well above the concentrations of the other patients of that time window). The ages of the remaining fully evaluable 29 patients (24 males/five females) were 22–79 years (median 38 years), the height 162–196 cm (median 173 cm) and the weight 52–120 kg (median 78 kg).

The mean (± S.D.) telithromycin concentrations are listed in Table 1. The highest plasma and tissue concentrations were observed at the first sampling time 3 h after administration. Whereas the concentrations fell at comparable rates in plasma, mucosa and bone, the concentrations in nasal mucus showed a more variable concentration–time course. The concentrations in mucosa and bone were higher compared with the concomitant plasma concentration throughout the sampling period. The mean tissue-to-plasma ratio was 5.2 for mucosa and 1.5 for bone after 3 h and increased to 14.5 and 2.6, respectively, after 24 h. Accordingly, the AUCs were higher in tissue compared with plasma (mucosa 24900 ng/mL·h, bone 6730 ng/mL·h, plasma 4230 ng/mL·h). The AUC in mucus (4280 ng/mL·h) was comparable with that in plasma. The ratio of the tissue versus plasma AUCs, a more robust parameter assessing tissue penetration, was 1.0 for mucus, 1.6 for bone and 5.9 for mucosa.


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Table 1. Concentrations (mean ± S.D., n=6 or n24h=5) of telithromycin in plasma, nasal mucus, nasal mucosa and ethmoid bone of patients after a single oral dose of telithromycin 800 mg, and tissue to plasma ratio (T/P)

 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Peak plasma concentrations and AUCs seem to indicate a lower bioavailability of telithromycin in our patients compared with healthy volunteers. The concentrations of the 3 and 24 h groups were 0.73 and 0.02 µg/mL respectively, compared with 1.6–1.9 µg/mL at 1–3 h and 0.03 µg/mL at 24 h in healthy volunteers. The AUC0–24 was 4.2 in our patients versus 8.2–10.7 µg/mL·h in volunteers.6,7 However, one has to take into account several variables: the late first sampling point (which was presumably after the time of peak concentration), the small number of sampling time-points, the wide range of age and body-mass index in our patients, and additional perioperative conditions such as telithromycin intake with a minimum of water and pre-medication or general anaesthesia-altered gastric motility.

The results of this study show that telithromycin rapidly penetrated and achieved high concentrations in nasal tissue of surgical patients after a single oral dose of 800 mg. The relative systemic exposure, expressed by the ratio of the area under the concentration–time curve in tissue versus plasma, was 5.9 for nasal mucosa and 1.6 for ethmoid bone, respectively. The tissue concentrations were higher than in plasma throughout the whole measuring period except for nasal mucus, where some specimens were potentially contaminated with rinsing saline, resulting in underestimated telithromycin concentrations. A moderate increase in the tissue-to-plasma concentration ratio was observed from 3 to 24 h, similar to that in tonsils,9 indicating prolonged tissue concentrations of telithromycin compared with plasma after a single dose. The tissue-to-plasma ratio was comparable with previous results in mucosa of paranasal sinuses or bronchial mucosa.1,10 The concentrations in nasal mucosa at 3 h were lower than those of clarithromycin after 250 mg twice a day,11 but the telithromycin tissue concentrations were more sustained, supporting the once-daily dosage regimen for telithromycin compared with twice-daily for clarithromycin.

To our knowledge, this is the first report of data on the penetration of telithromycin into human bone, and compared with the vast literature on the penetration of antibiotics into other various tissues, only a few studies describe the penetration of antibiotics into human bone.12 In general, fluoroquinolones and macrolides are considered antibiotics with good diffusion into bone tissue.13,14 In terms of the tissue-to-plasma concentration ratio, the best tissue penetration of all macrolides is shown for azithromycin, which provides bone concentrations exceeding the concomitant plasma concentrations several-fold, and is detectable in bone even 1 week after the last dose.1517 When considering absolute tissue concentrations, the highest concentrations in bone following therapeutic doses were described for roxithromycin with 5.1 µg/g.18 In our patients, the concentration of telithromycin in bone at 3 h was 1.1 µg/g. The tissue-to-plasma ratio was 1.5 in the 3 h group and 2.5 in the 24 h group, indicating that bone behaves as a deep compartment with delayed elimination.

In summary, the achieved concentrations of telithromycin in mucosa as well as in bone were generally above the MIC90 of common pathogens in upper respiratory tract infections (S. pneumoniae 0.12 mg/L, methicillin-susceptible Staphylococcus aureus 0.06 mg/L, M. catarrhalis 0.12 mg/L; data from the PROTEKT surveillance study).

We conclude that telithromycin diffuses rapidly into the nasal tissues and achieves high and prolonged concentrations in nasal mucosa and ethmoid bone that are maintained throughout the dosing period above the MIC90 of susceptible strains.


    Acknowledgements
 
The study was supported by a grant from Aventis Pharma, Germany.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Balfour, J. A. & Figgitt, D. P. (2001). Telithromycin. Drugs 61, 815–29.

2 . Zhanel, G. G., Noreddin, W. M., Vercaigne, L. M. et al. (2002). The ketolides: a critical review. Drugs 62, 1771–804.[ISI][Medline]

3 . Muller-Serieys, C., Andrews, J., Vacheron, F. et al. (2004). Tissue kinetics of telithromycin, the first ketolide antibacterial. Journal of Antimicrobial Chemotherapy 53, 149–57.[Abstract/Free Full Text]

4 . Drusano, G. (2001). Pharmacodynamic and pharmacokinetic considerations in antimicrobial selection: focus on telithromycin. Clinical Microbiology and Infection 7, Suppl. 3, 24–9.[CrossRef][Medline]

5 . Nicolau, D. P. (2003). Optimizing outcomes with antimicrobial therapy through pharmacodynamic profiling. Journal of Infection and Chemotherapy 9, 292–6.[CrossRef][Medline]

6 . Perret, C., Lenfant, B., Weinling, E. et al. (2002). Pharmacokinetics and absolute oral bioavailability of an 800 mg oral dose of telithromycin in healthy young and elderly volunteers. Chemotherapy 48, 217–23.[CrossRef][ISI][Medline]

7 . Namour, F., Wessels, D. H., Pascual, M. H. et al. (2001). Pharmacokinetics of the new ketolide telithromycin (HMR 3647) administered in ascending single and multiple doses. Antimicrobial Agents and Chemotherapy 45, 170–5.[Abstract/Free Full Text]

8 . Namour, F., Sultan, E., Pascual, M. H. et al. (2002). Penetration of telithromycin (HMR 3647), a new ketolide antimicrobial, into inflammatory blister fluid following oral administration. Journal of Antimicrobial Chemotherapy 49, 1035–8.[Abstract/Free Full Text]

9 . Gehanno, P., Sultan, E., Passot, V. et al. (2003). Telithromycin (HMR 3647) achieves high and sustained concentrations in tonsils of patients undergoing tonsillectomy. International Journal of Antimicrobial Agents 21, 441–5.[CrossRef][ISI][Medline]

10 . Khair, O. A., Andrews, J. M., Honeybourne, D. et al. (2001). Lung concentrations of telithromycin after oral dosing. Journal of Antimicrobial Chemotherapy 47, 837–40.[Abstract/Free Full Text]

11 . Fraschini, F., Scaglione, F., Pintucci, G. et al. (1991). The diffusion of clarithromycin and roxithromycin into nasal mucosa, tonsil and lung in humans. Journal of Antimicrobial Chemotherapy 27, Suppl. A, 61–5.

12 . Darley, E. S. & MacGowan, A. P. (2004). Antibiotic treatment of gram-positive bone and joint infections. Journal of Antimicrobial Chemotherapy 53, 928–35.[Abstract/Free Full Text]

13 . Boselli, E. & Allaouchiche, B. (1999). Diffusion in bone tissue of antibiotics. Presse Medicale 28, 2265–76.[ISI][Medline]

14 . Periti, P., Mazzei, T., Mini, E. et al. (1989). Clinical pharmacokinetic properties of the macrolide antibiotics. Effects of age and various pathophysiological states (Part I). Clinical Pharmacokinetics 16, 193–214.[ISI][Medline]

15 . Malizia, T., Batoni, G., Ghelardi, E. et al. (2001). Interaction between piroxicam and azithromycin during distribution to human periodontal tissues. Journal of Periodontology 72, 1151–6.[ISI][Medline]

16 . Malizia, T., Tejada, M. R., Ghelardi, E. et al. (1997). Periodontal tissue disposition of azithromycin. Journal of Periodontology 68, 1206–9.[ISI][Medline]

17 . O'Reilly, T., Kunz, S., Sande, E. et al. (1992). Relationship between antibiotic concentration in bone and efficacy of treatment of staphylococcal osteomyelitis in rats: azithromycin compared with clindamycin and rifampin. Antimicrobial Agents and Chemotherapy 36, 2693–7.[Abstract]

18 . Del Tacca, M., Danesi, R., Bernardini, N. et al. (1990). Roxithromycin penetration into gingiva and alveolar bone of odontoiatric patients. Chemotherapy 36, 332–6.[ISI][Medline]





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