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Antimicrobial Agents and Chemotherapy, November 2001, p. 3104-3108, Vol. 45, No. 11
Unité de Microbiologie, Hôpital
Bichat-Claude Bernard, 75877 Paris,1
INSERM U-408, UFR Xavier Bichat, 75018 Paris,2 and Aventis Pharma, 93235 Romainville Cedex,3 France
Received 18 September 2000/Returned for modification 27 February
2001/Accepted 26 July 2001
Telithromycin (HMR 3647) is the first member of a new family
of antimicrobials, the ketolides, developed specifically for the
treatment of community-acquired respiratory tract infections. Telithromycin has proven in vitro activity against both common and
atypical respiratory tract pathogens. The penetration of
telithromycin into bronchopulmonary tissues and subsequent elimination
from these sites were evaluated in four groups (groups A, B, C, and D)
of six healthy male subjects who received telithromycin at 800 mg once
daily for 5 days. Subjects in groups A, B, C, and D underwent
fiberoptic bronchoscopy and bronchoalveolar lavage 2, 8, 24, and 48 h
after receipt of the last dose, respectively. The concentration of
telithromycin in the alveolar macrophages, epithelial lining
fluid (ELF), and plasma was determined by the agar diffusion method
with Bacillus subtilis ATCC 6633 as the test organism. The
concentration of telithromycin in alveolar macrophages markedly
exceeded that in plasma, reaching up to 146 times the concentration in
plasma 8 h after dosing (median concentration, 81 mg/liter).
Telithromycin was retained in alveolar macrophages 24 h
after dosing (median concentration, 23 mg/liter), and it was
still quantifiable 48 h after dosing (median concentration, 2.15 mg/liter). Telithromycin median concentrations in ELF also markedly
exceeded concentrations in plasma (median concentration in ELF,
3.7 mg/liter 8 h after dosing). Telithromycin achieves high and
sustained concentrations in ELF and in alveolar macrophages, while it maintains adequate levels in plasma, providing an ideal pharmacokinetic profile for effective treatment of community-acquired respiratory tract infections caused by either common or atypical, including intracellular, respiratory tract pathogens.
The global spread of antimicrobial
resistance among respiratory tract pathogens has created a need for new
agents that can demonstrate activity against isolates resistant to
existing antimicrobials but that do not readily induce resistance to
themselves or exhibit cross-resistance to other agents.
Telithromycin (HMR 3647) is the first member of a new family of
antimicrobial agents, the ketolides, specifically designed for the
treatment of community-acquired respiratory tract infections. Ketolides
are a novel addition to the macrolide-lincosamide-streptogramin B group
and are specifically characterized by a keto group at position 3 of the
macrolactone ring in place of the cladinose moiety present in the
macrolides. In vitro induction experiments with Staphylococcus
aureus and Streptococcus pneumoniae indicate that it is
this novel keto function which accounts for the fact that telithromycin
does not induce macrolide-lincosamide-streptogramin B resistance
(3). In addition, a large aromatic N-substituted carbamate
extension at position 11 and 12 confers enhanced antimicrobial activity
compared with those of the macrolides (8).
In vitro, telithromycin has potent, well-balanced antibacterial
activity against all common gram-positive and gram-negative respiratory tract pathogens, irrespective of their susceptibilities to
In humans, a once-daily oral dose of telithromycin at 800 mg has been
shown to provide concentrations in plasma adequate for maintenance of good activity against respiratory tract pathogens, including The objective of the present study was to determine the pulmonary
disposition of telithromycin relative to the concentrations in plasma
at steady state and selected times after the cessation of therapy
following the oral administration of telithromycin at 800 mg once daily
to healthy subjects for 5 days.
(Some of the data presented here have been presented previously in
abstract form [C. Muller-Serieys, C. Cantalloube, P. Soler, F. Lemaître, H. Pham Gia, F. Brunner, and A. Andremont,
Program abstr. 21st Int. Cong. Chemother., abstr. P 78, p. 57, 1999].)
Subjects.
Nonsmoking (for at least 6 months), white, healthy
male subjects between the ages of 18 and 40 years and with normal body weights ( Study design and procedures.
This was a single-center,
open-label study with four parallel groups. The study was approved by
the local ethics committee and was carried out in accordance with
European Good Clinical Practice guidelines.
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.11.3104-3108.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Bronchopulmonary Disposition of the Ketolide
Telithromycin (HMR 3647)
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
-lactams and macrolides (1, 16, 17). It is also
effective against atypical pathogens such as Chlamydia
pneumoniae, Legionella spp., and Mycoplasma
pneumoniae (2, 19, 21).
-lactam- and macrolide-resistant strains. (B. Lenfant, E. Sultan, C. Wable, M. H. Pascual, B. H. Meyer, and
H. E. Scholtz, Abstr. 38th Intersci. Conf. Antimicrob.
Agents Chemother., abstr. A-49, 1998). Furthermore, telithromycin
concentrates in white blood cells, facilitating delivery of this agent
to the site(s) of infection (H. Pham Gia, V. Roeder, F. Namour, E. Sultan, and B. Lenfant, Program abstr. 21st Int. Congr. Chemother.,
abstr. P79, p. 57, 1999).
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
15 to +10% according to the Broca formula [normal weight = height, in centimeters, 100]) were eligible for inclusion in the
study. All subjects provided written informed consent prior to
screening. Subjects were excluded from the study if they were receiving
regular medication or had been exposed to an investigational drug or
any drug with a well-defined potential for toxicity to a major organ in
the previous 3 months, a macrolide during the previous month, or any
other antimicrobial agent within the previous 7 days. Subjects with any
condition known to interfere with the absorption, distribution,
metabolism, or excretion of drugs or who had experienced symptoms of a
clinically significant illness in the previous 3 months or any kind of
infection within the previous 7 days were also ineligible.
Hypersensitivity to local anesthetics was also an exclusion criterion,
as lidocaine was used during bronchoscopy.
Sample analysis and handling.
Blood samples were centrifuged
(1,500 × g for 15 min at 4°C), and the plasma was
stored at 80°C until it was assayed for telithromycin and urea concentrations.
80°C until they were assayed. An aliquot of the BAL fluid was retained for determination of the total cell count
with a hemocytometer. A differential count of BAL cells was performed
with a stained cytocentrifuged sample of BAL fluid to determine the
percentage of alveolar macrophages. At least 300 to 500 cells
were counted (random-field counting method). It was assumed that all
cells in BAL fluid were alveolar macrophages and that
the volume of 106 alveolar macrophages was 2.5 µl
(6).
To estimate the volume of epithelial lining fluid (ELF) obtained by BAL
and to overcome the problem of the unknown dilution factor, introduced
by the instillation of saline during the BAL procedure, the urea
concentration in plasma and BAL fluid was determined and was used in
the following calculation (14): volume of ELF (in
milliliters) = (BAL fluid volume [in milliliters] × UBAL)/UP1, where
UBAL and UP1 are the urea
concentrations (in milligrams per milliliter) in BAL fluid and plasma, respectively.
Urea concentrations in plasma and BAL fluid were measured by a
colorimetric enzymatic test (Combination Urea S test [reference no. 7775/10; Boehringer]; assay sensitivity, 0.015 mmol/liter for both
plasma and BAL fluid).
Prior to analysis, alveolar macrophage pellets were lysed by
sonication and were resuspended in 1 ml of phosphate buffer (pH 8.0) by
shaking in ice for 4 h. The volume of BAL fluid supernatant was
measured; the samples were then freeze-dried and resuspended in 3 ml of
phosphate buffer (pH 8.0) by shaking in ice for 4 h.
Telithromycin assay. Telithromycin concentrations in ELF, alveolar macrophages, and plasma were determined in triplicate by a validated agar diffusion method with Bacillus subtilis ATCC 6633 as the test organism. Antibiotic medium 11 (Difco Laboratories) adjusted to pH 9 was used for the plates, which were incubated in air at 35°C. The limit of quantification was 0.03 mg/liter for plasma, ELF, and alveolar macrophages. All samples from the same subject were analyzed in a single batch to minimize assay variability. All samples were analyzed within 3 months of collection.
Spiked samples were included for quality control and to provide a standard curve. Standards for plasma samples were diluted in pooled antibiotic-free human plasma, while standards for ELF and alveolar macrophage samples were diluted in phosphate buffer (pH 8). Standard curves were prepared with telithromycin concentrations ranging between 0.03 and 8 mg/liter. Best-fit standard curves for the telithromycin assays were obtained by linear regression analysis. The intra- and interassay precisions were determined, and the results were considered acceptable when both the inter- and intra-assay differences were less than 20%.Calculation of telithromycin concentrations in alveolar
macrophages, ELF, and BAL fluid.
The concentration of
telithromycin in alveolar macrophages (milligram per liter of
cells) was calculated from the concentration of telithromycin in the
resuspended cell pellet and the total volume of cells. The volume
of alveolar macrophage cells was estimated from the
following equation: volume of cells (in milliliters) = (total cell
number [106 cells]) × (2.5 × 10
3 [in milliliters]). The total cell number
was calculated from the concentration of cells in the unconcentrated
BAL fluid (in numbers of cells per milliliter) and the BAL fluid volume
(in milliliters).
Safety. A clinical examination was performed, and standard laboratory parameters (hematology parameters, blood chemistry analysis, and urinalysis) and vital signs (including electrocardiographic findings) were monitored at screening, before the administration of telithromycin on days 1 and 5, and on day 7 (i.e., 48 h after administration of the last dose). Chest X rays were also performed at screening and within 4 h of the fiberoptic bronchoscopy procedure. Adverse events were assessed through questioning and spontaneous reporting from the time that informed consent was given until 15 days after the last dose of telithromycin was taken.
Statistical considerations. On the basis of previous studies with other antimicrobials, it was estimated that six subjects per group (a total of 24 subjects) would be sufficient to assess the concentrations of telithromycin in target tissues.
Descriptive statistics and statistical analysis were performed with SAS (version 6.11) software. The four groups (groups A, B, C, and D) were compared with respect to the demographic parameters (age, weight, and height) and with respect to the characteristic parameters for BAL fluid (BAL fluid volume, ELF volume, total and differential counts [macrophages, lymphocytes, neutrophils]) by an analysis of variance after logarithmic transformation of the parameters. The effect of the site sampled (for alveolar macrophages, ELF, and plasma) and the effect of the sampling time (2, 8, 24, and 48 h) on the telithromycin concentration were assessed by analysis of variance after logarithmic transformation of the telithromycin concentration. In the event that the effect was statistically significant, a t test was performed for pairwise comparisons. These analyses were performed with all subjects included in the pharmacokinetic analysis. For all tests performed, a P value of <0.05 was considered significant.| |
RESULTS |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Demography.
Twenty-four healthy, white males (mean age,
26.8 ± 4.4 years) were recruited and completed the study, with
six subjects included in each group. One subject in group A was
excluded from the pharmacokinetic analyses because he took only 400 mg
instead of 800 mg of telithromycin on days 2 to 4. All other subjects
were fully compliant. There were no significant differences among the
subjects in groups A, B, C, and D with regard to age, weight, or height
(P > 0.05) (Table 1).
|
Recovery of cells from BAL fluid and volumes of BAL fluid and
ELF.
The total and differential counts of cells recovered from BAL
fluid and the BAL fluid and ELF volumes are given in Table
2. The total cell count, the percentage
of each cell type, and the volumes of BAL fluid and ELF were compared
among the groups; none were significantly different (P > 0.05). These results are in agreement with data from previous
studies performed with healthy subjects (4, 5).
|
Pharmacokinetic results.
The mean accuracy of the
telithromycin assay for plasma quality control samples was between 8
and +3%, and the precision (coefficient of variation) was between 0.9 and 20%. For alveolar macrophage and ELF samples, the accuracy
of the telithromycin concentrations was between 10 and +7% and the
precision was between 1.2 and 10.9%.
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Safety results. All 24 subjects were included in the safety analysis. Of these, 11 (46%) subjects reported a total of 17 treatment-related emergent adverse events, usually of mild intensity and involving the gastrointestinal tract (abdominal pain and diarrhea). Alveolar opacity of the right middle lobe was observed on the chest X ray of one subject obtained within 4 h after fiberoptic bronchoscopy. It was reported as an adverse event and was related to the BAL procedure. The chest X ray for this subject was normal a few days later. No severe or serious adverse events were reported. There were no clinically significant changes in electrocardiographic parameters, vital signs, or laboratory safety data except for a transient, unexplained increase in the bilirubin level in one subject which may have been a result of borderline Gilbert's syndrome.
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DISCUSSION |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Telithromycin is the first clinical candidate of a new family of antimicrobials, the ketolides. Its spectrum of activity covers both common (1, 16, 17) and atypical (2, 19, 21) respiratory tract pathogens. The efficacy of any drug is dependent upon its delivery (i.e., transport and penetration) to the target organ and its stability in situ; a high bronchopulmonary antimicrobial concentration has been shown to be an important predictor of good clinical outcome for respiratory tract infections (12). This study used BAL to determine bronchopulmonary telithromycin concentrations (18), a technique that allows differentiation between ELF and alveolar macrophages and avoids contamination with sputum or saliva.
ELF represents a major site of infection in pneumonia caused by common
(extracellular) pathogens (15). In this study, elevated concentrations of telithromycin were sustained in ELF; median telithromycin concentrations in ELF exceeded those in plasma by 6.4-fold at 8 h and were still 0.82 mg/liter 24 h after dosing (which is 12.7-fold higher than those in plasma). Such concentrations are more than adequate to maintain good activity against common respiratory pathogens, including -lactam- and macrolide-resistant S. pneumoniae and -lactam-resistant Haemophilus
influenzae (C. Agouridas, A. Bonnefoy, and J. F. Chantot,
Program abstr. 4th Int. Conf. Macrolides, Azalides, Streptogramins
Ketolides, p. 10, 1998); individual concentrations in ELF were above
the MIC at which 90% of strains are inhibited for H. influenzae and S. pneumoniae for up to 8 and
24 h, respectively, after administration of the last dose.
Telithromycin was rapidly concentrated by alveolar macrophages, resulting in median intracellular concentrations of up to 81 mg/liter followed by a slow decline over 48 h, ensuring that excellent coverage against intracellular infections was maintained well beyond the cessation of therapy. These findings support the results of an in vitro study, which found that telithromycin was rapidly taken up by human neutrophils with cellular concentration:extracellular concentration ratios of 30 at 5 min and up to 348 at 180 min (22); the rate of efflux of telithromycin from neutrophils into a drug-free medium in this experiment was found to be sufficiently high and the efflux was sufficiently prolonged to suggest good delivery to target tissues in humans. Since alveolar macrophages are the primary reservoir of infection in pneumonia caused by atypical pathogens such as Legionella and Chlamydia spp. (15), telithromycin would be expected to perform well against infections caused by these pathogens. Indeed, telithromycin has shown excellent activity against these organisms both in vitro and in vivo (9, 19, 21) and has been shown to have potent bactericidal activity in a guinea pig model of Legionella pneumophila pneumonia (9).
The persistence of high telithromycin concentration in cells of the lower respiratory tract is also a characteristic of the macrolide antimicrobials, which allows short treatment regimens (13, 15). Previous studies conducted with healthy subjects have demonstrated that clarithromycin and azithromycin concentrate in alveolar macrophages (4, 20).
In addition, telithromycin also reaches high concentrations in plasma. This is critically important in the treatment of respiratory tract infections accompanied by bacteremia, which are associated with a greater risk of mortality (10, 11).
The penetration of telithromycin into ELF and cells is probably a
reflection of its amphipathic structure. In contrast, the hydrophilic
-lactams penetrate poorly into tissues, with concentrations reaching
only 20 to 40% of the levels in plasma (7).
The data presented here concern noninfected subjects. Nevertheless, it is unlikely that infection would reduce the concentration of telithromycin in alveolar macrophages and ELF. On the contrary, it is anticipated that the combination of increased blood flow, higher capillary permeability, and chemotaxis of white blood cells resulting from inflammation will actually increase the rate of penetration of telithromycin into the lungs.
The sustained penetration of telithromycin in ELF, and particularly
into alveolar macrophages, together with its spectrum of
activity
covering both common and atypical (intracellular) respiratory
pathogenssuggests that telithromycin is a promising new agent
for the empiric treatment of community-acquired respiratory tract infections.
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FOOTNOTES |
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* Corresponding author. Mailing address: Unité de Microbiologie, Hôpital Bichat-Claude Bernard, 46 rue Henri Huchard, 75877 Paris, France. Phone: 33 (1) 40 25 80 80. Fax: 33 (1) 40 25 88 52. E-mail: claudette.muller{at}bch.ap-hop-paris.fr.
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Antimicrobial Agents and Chemotherapy, November 2001, p. 3104-3108, Vol. 45, No. 11
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.11.3104-3108.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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