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Antimicrobial Agents and Chemotherapy, January 2001, p. 170-175, Vol. 45, No. 1
Aventis Pharma, Hoechst Marion
Roussel/Romaineville, 93235 Romainville Cedex, France
Received 27 April 2000/Returned for modification 31 July
2000/Accepted 17 October 2000
Telithromycin (HMR 3647) is a novel ketolide antimicrobial with
good activity against both common and atypical respiratory pathogens,
including many resistant strains. This randomized, three-period
crossover study determined the dose proportionality of telithromycin
pharmacokinetics after single and multiple dosing in healthy subjects.
In each treatment period, subjects received a single oral dose of 400, 800 or 1,600 mg of telithromycin followed 4 days later by the same dose
once daily for 7 days. Blood and urine samples were taken throughout
the study for determination of pharmacokinetic parameters for
telithromycin and RU 76363, its main metabolite. Telithromycin and RU
76363 achieved steady state within 2 to 3 days of once-daily dosing. A
slight accumulation of telithromycin was observed after 7 days of
therapy, with values of the area under the concentration-time curve
from 0 to 24 h approximately 1.5 times higher than those achieved
with the single dose. The pharmacokinetics of telithromycin and RU
76363 deviated moderately from dose proportionality. At a dose of 800 mg/day, telithromycin attained mean maximal and trough plasma
concentrations of 2.27 and 0.070 mg/liter respectively. Elimination was
biphasic; initial and terminal half-lives were 2.87 and 9.81 h for
the 800-mg dose. Study medication was well tolerated, although adverse
events tended to be more frequent at the 1,600-mg dose. This study
showed that telithromycin was generally well tolerated and suggests
that a once-daily 800-mg oral dose of telithromycin maintains an
effective concentration in plasma for the treatment of respiratory
tract infections involving the key respiratory pathogens.
Telithromycin (HMR 3647) is
the first of a novel family of antimicrobials, the ketolides,
developed specifically for the treatment of community-acquired
respiratory tract infections. The ketolides are a new addition to
the macrolide-lincosamide-streptogramin B (MLS) group of
antimicrobials. These agents inhibit bacterial protein synthesis via
two mechanisms: first by directly blocking translation of mRNA
and second by interfering with the assembly of new ribosomal
units (7). Ketolides are characterized by a ketone group,
which replaces the cladinose sugar at position 3 of the macrolactone
ring. This ketone group not only confers excellent acid
stability but also accounts for the fact that, unlike
macrolides, telithromycin does not induce MLS resistance in vitro
(4, 6, 14). Furthermore, the C11-12
carbamate side chain of telithromycin enhances binding to
MLS-resistant ribosomes, and this may explain the activity of
telithromycin against MLS-resistant organisms (11).
The global spread of resistance among respiratory tract pathogens is a
matter of serious concern. Indeed, a U.S. analysis of
Streptococcus pneumoniae isolates from the 1998-1999
respiratory season reported resistance rates of 14, 25, and 22% for
penicillin (high-level resistance), cefuroxime, and
clarithromycin-azithromycin, respectively (C. Thornsberry, I. A. Critchley, Y. Mauriz, J. Khan, G. Piazza, and D. F. Sahm, Abstr.
39th Intersci. Conf. Antimicrob. Agents Chemother. abstr. 820, p. 109, 1999). Telithromycin has a spectrum of activity covering most common
and atypical respiratory tract pathogens, irrespective of their
susceptibilities to In vitro, telithromycin exhibits concentration-dependent
killing and has a significant postantibiotic effect (D. Felmingham, S. Clark, M. J. Robbins, C. Dencer, and A. Bryskier, Abstr.
38th Intersci. Conf. Antimicrob. Agents, Chemother., abstr. E-133, p.
207, 1998). These properties are generally characteristic of antimicrobials for which, in relation to MIC, the amount of drug delivered rather than the time for which plasma levels are
maintained above the MIC is a better predictor of outcome
(9). This suggests that a once-daily dosage regimen of
telithromycin may be suitable for further evaluation in
humans. The present study was conducted to evaluate the single- and
multiple-dose pharmacokinetics and dose proportionality of
telithromycin given once daily over the dose range of 400 to 1,600 mg/day in healthy human subjects.
This single-center, randomized, open-label, single- and
multiple-dose, three-way crossover study was conducted between August 1998 and November 1998 in Bloemfontein, South Africa. The study was
performed in accordance with the European Community Good Clinical Practice and International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals guidelines, and all
subjects were required to provide written, informed consent.
Subjects.
This study recruited male subjects aged 18 to 45 years who were judged to be healthy by medical history, physical
examination, routine laboratory tests, blood pressure, heart rate, and
12-lead electrocardiogram (ECG).
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.1.170-175.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Pharmacokinetics of the New Ketolide Telithromycin (HMR 3647)
Administered in Ascending Single and Multiple Doses
ABSTRACT
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
-lactams or macrolides (1, 2, 3, 5, 10,
12, 13).
MATERIALS AND METHODS
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
Study design and procedures. Each of the three treatment periods consisted of a single oral dose of telithromycin at either 400, 800, or 1,600 mg (day 1), followed 4 days later by the same oral dose of telithromycin given once daily for 7 days (days 5 to 11). Each treatment period was separated by a washout period of at least 7 days. The sequence in which subjects received the different dosages of telithromycin was determined by a Williams randomization plan (8). Study medication was administered with 240 ml of water after an overnight fast, and administration was followed by a light breakfast. Telithromycin (400-mg) tablets for oral administration were provided by Hoechst Marion Roussel (Romainville, France).
Subjects were housed for 24 h on the first day (day 1) and the last day (day 11) of each of the three treatment periods and reported to the clinic before breakfast to receive study medication on the other dosing days. Subjects were to abstain from strenuous physical exercise and consumption of tobacco, alcohol, and xanthine derivatives from 48 h before the first dose of telithromycin until 24 h after the last dosing of each treatment period. In addition, grapefruit juice was not permitted from 48 h before the first dose of telithromycin until 96 h after the last dosing of each treatment period.Sample collection.
Blood samples (3.5 ml) for
pharmacokinetic analysis were taken at the screening visit (2 weeks
before study entry), before dosing on all days, and at the following
times after dosing on days 1 and 11 of each treatment period: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 h. Urine for
determination of telithromycin concentrations was collected
at screening and for three consecutive 24-h periods, starting at the
time of the last dose on days 1 and 11 of each treatment period. For
safety evaluations, blood (30 ml at screening and 20 ml thereafter) was
collected at screening, before the first dose of the first treatment
period, 24 h after the last dose of each treatment period, and 96 h after the last dose of the third treatment period. Urine was
collected at screening, before the first dose of the first treatment
period, and 96 h after the last dose of the third treatment
period. Plasma and urine samples were stored frozen at 
20°C until analysis.
Analytical methodology. (i) Telithromycin. Telithromycin was assayed in plasma using a validated liquid chromatography/mass spectrometry (LC/MS) method following precipitation of plasma proteins by acetonitrile in a 96-well format. The method has a standard curve range of 0.005 to 3 mg/liter using 100 µl of plasma and a limit of quantification of 0.005 mg/liter. Each run included calibration and quality controls over the standard range. The interbatch percent coefficient of variation (CV) for the quality control samples was between 2.8 and 8%. Telithromycin concentration in urine was assayed using a validated reverse-phase high-performance liquid chromatography method. The column eluent was monitored by fluorimetry (excitation at 263 nm and emission at 460 nm), and the detector signal was integrated to produce peak heights. The method has a standard curve range of 0.5 to 100 mg/liter using 50 µl of urine and a limit of quantification of 0.5 mg/liter. Each run included calibration (0.5 to 100 mg/liter) and quality controls (0.5 to 75 mg/liter). The interbatch percent CV for the quality control samples was between 0.8 and 2.9%.
(ii) RU 76363. RU 76363, the main metabolite of telithromycin, was assayed in plasma by liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry using the full-scan MS mode. Samples were deproteinated with acetonitrile, evaporated to dryness, and reconstituted in the analytical mobile phase prior to injection for reversed-phase chromatography. The validated method has a standard curve range of 0.0025 to 0.25 mg of RU 76363/liter (using 100 µl plasma) and a limit of quantification of 0.0025 mg/liter. Each run included calibration (0.0025 to 0.25 mg/liter) and quality controls (0.006 to 0.25 mg/liter). The interbatch percent CV for the quality control samples was between 4.2 and 9.6%.
Safety. Safety was evaluated on the basis of ECG, blood pressure, heart rate, and laboratory variables (hematology, blood chemistry, and urinalysis) at screening, before dosing on day 1, 24 h after the last dose of each treatment period, and 96 h after the last dose of the third treatment period. Adverse events were recorded throughout the study. An adverse event, which could be nonserious or serious, was defined as any sign, symptom, syndrome, or illness that appeared or worsened in a subject during the observation period and that could impair the well-being of the subject.
Pharmacokinetic and statistical analysis. A sample size of six subjects was calculated to provide 80% power to observe a difference of at least 1 mg · h/liter in the area under the concentration-time curve (AUC) standardized to the dose, with a risk of 5% and a mean square error of 0.5, based on observations from previous studies. However, since it is common to use 18 subjects for such a pivotal study, this was the number used.
Pharmacokinetic parameters were calculated using WinNonLin software (version 2.0), and descriptive statistics were performed using SAS software (version 6.12). Concentrations of telithromycin and its major metabolite, RU 76363, in plasma were determined for all sampling times throughout the study. The following pharmacokinetic parameters were calculated for telithromycin and RU 76363 after a single dose (day 1) and multiple doses (day 11): maximal plasma concentration (Cmax), time to reach maximal plasma concentration (tmax), trough plasma concentration 24 h after dosing (C24) AUC over 24 h (AUC0-24), AUC until the last quantifiable measurement (AUC0-z), AUC until infinity (AUC0-
), (when the terminal half-life was available),
amount of telithromycin excreted in urine over
24 h (Ae0-24), renal clearance of telithromycin [CLR(0-24)],
accumulation ratio (Rac),
Cmax and C24 standardized
to the 800-mg dose (Cmax/dose and
C24/dose, respectively), and the AUC
standardized to the 800-mg dose (AUC0-24/dose and
AUC0-z/dose). In addition, the ratio of
AUC0-24 for RU 76363/AUC0-24 for
telithromycin (R) was calculated for days 1 and
11, and C24 hs for
telithromycin and RU 76363 were determined for each
treatment period from days 6 to 11. The primary and terminal half-lives
(t1/2
1 and
t1/2z, respectively)
were calculated using a one- or two-compartment model, depending on the
profile. In most cases,
t1/2z could not be
assessed for RU 76363, so this was not tabulated.
Dose proportionality for telithromycin and RU 76363 was
tested for after oral administration of single and multiple doses of
telithromycin using analyses of variance (ANOVA) of
log-transformed data with subject, dose, and treatment period as the
main effects for the following parameters:
Cmax/dose, AUC0-24/dose,
AUC0-z/dose; C24/dose;
t1/21, and, for
telithromycin only,
t1/2z, CLR(0-24),
and R. Comparisons between doses were performed using
Tukey's test. The dose effect on tmax was
assessed using the Kruskal-Wallis nonparametric test. The effect of
dose on Rac was assessed using ANOVA with
subject, dose, and treatment period as the main effects. Trough
concentrations of telithromycin and RU 76363 in plasma
determined for days 5 to 11 were compared for each dose to determine
the day at which steady states were achieved. ANOVA were applied to the
log-transformed data with subject and day as the main effects, followed
by Tukey's test. Mean trough plasma concentrations on the last dosing
day (day 11) were taken as the mean trough plasma concentrations at
steady state.
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RESULTS |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Subjects. Eighteen Caucasian, healthy male subjects of mean age 21.3 years (range, 18 to 29 years), mean height 183.2 cm (ranges, 170 to 195 cm) and mean weight 79.2 kg (ranges, 67.8 to 98.4 kg) were recruited. No subjects had concomitant illness, and none were receiving concomitant treatments at the time of inclusion. However, six subjects received concomitant medications for acute minor illnesses during the study, none of which are likely to interfere with the pharmacokinetics or safety of telithromycin. One subject withdrew because of an adverse event during dosing at 1,600 mg/day.
Telithromycin and RU 76363 assays.
The mean accuracy and
precision of the plasma telithromycin assay were 95.7 to
100.7% (percent recovery relative to the theoretical concentration)
and 7.5 to 11.7% (percent CV), respectively. For the urine
telithromycin assay, the mean accuracy was 2.0 to +2.0% (percent relative error) and the precision was 5.5 to 8.8% (percent CV). The mean accuracy of the plasma RU 76363 assay was 98.8 to 103.3%
(percent recovery relative to the theoretical concentration), and the
precision was 4.6 to 7.1% (percent CV).
Pharmacokinetics. Pharmacokinetic analysis was performed on data from 18 subjects for the 400- and 800-mg doses but from only 16 subjects for the 1,600-mg dose: one subject withdrew due to a severe adverse event, and in another subject the trough concentrations suddenly decreased by a factor of 2 between the third and fourth administrations. In the latter subject, the results could be due to a decrease in bioavailability, although no explanation for a potential decrease in bioavailability could be found, e.g. vomiting, concomitant medication, or compliance. Hence, the data from this subject were rejected from the 1,600-mg multiple-dose pharmacokinetic analysis of telithromycin and RU 76363.
(i) Telithromycin.
The pharmacokinetics and dose
proportionality of single and multiple
doses of telithromycin are shown in Tables 1 and
2, respectively. Following a single oral
dose of 400, 800, or 1,600 mg, telithromycin was
quantifiable in the plasma from the first time point (0.5 h) and
reached tmax after a median of 1 h,
irrespective of dose (Fig. 1).
Telithromycin was no longer quantifiable in plasma 48, 72, and 96 h after dosing for the 400-, 800-, and 1,600-mg single doses,
respectively, and 72 and 96 h after the final dose in the 7-day
multiple-dose phase (400- and 800-mg groups). Telithromycin was still
quantifiable in 14 out of 16 subjects after the final dose in the 7-day
multiple-dose phase in the 1,600-mg group.
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1 followed
by a longer t1/2z. In
the multiple-dose phase, t1/21
increased significantly by 1.5-fold between the 800- and 1,600-mg
doses, while
t1/2
z increased
by a factor of 1.8 over the 800- to 1,600-mg dose interval. CLR(0-24) for telithromycin was constant
over the dose range after both single and multiple doses.
In the 72-h period following administration of a single dose of
telithromycin of 400, 800, or 1,600 mg, 7.64, 13.0, and
19.0%, respectively, of the dose was eliminated unchanged in the
urine. Corresponding values for the 72-h period following the final
dose of the 7-day treatment period were 9.93, 18.4, and 25.8%.
Approximately 96% of urinary excretion took place within 24 h of
the final dose.
(ii) RU 76363. RU 76363, an alcohol resulting from loss of aryl rings, is the major hepatic metabolite of telithromycin. Following single doses of telithromycin at 400, 800, or 1,600 mg, RU 76363 was quantifiable in plasma at the same time points as telithromycin. The levels of RU 76363 peaked after those of the parent compound. The AUC0-24 of this metabolite was 10 to 12% that of the parent compound, a figure that was constant across the dose range.
The pharmacokinetics and dose proportionality for single and multiple doses of RU 76363 are shown in Tables 3 and 4. RU 76363 deviated moderately from dose proportionality in a manner similar to that for telithromycin, with a doubling of dose resulting in a 2.5- to 3.7-fold increase in AUC. For both Cmax and C24, RU 76363 deviated significantly from dose proportionality within the 400- to 800-mg subinterval, although dose proportionality was shown over the entire 400- to 1,600-mg dose range. In the single- and multiple-dose phases, t1/2z increased by
means of 17 and 26%, respectively, between 400 and 800 mg, and by
means of 16 and 30%, respectively, between 800 and 1,600 mg.
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Safety. No deaths or other serious adverse events were reported during the study. The incidence of possibly drug-related adverse events increased with the dose of telithromycin, being 5.6, 27.8, and 77.8% for 400, 800, and 1,600 mg, respectively. A total of 29 possibly drug-related adverse events were reported, of which most (24) occurred during multiple-dose administration. Adverse events most commonly affected the digestive tract and were manifest as diarrhea, nausea, and gastrointestinal pain and disorder. All were mild or moderate in intensity, except for one case of vomiting and diarrhea, which was of severe intensity and which occurred during the multiple-dose 1,600-mg phase. This patient was withdrawn from the study.
Telithromycin had no clinically significant effect on clinical laboratory assessments, vital signs (blood pressure, heart rate, and ECG), or physical examination. In addition, no QTc values above 450 ms were observed throughout the study.| |
DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Telithromycin (HMR 3647) is an innovative new ketolide antimicrobial, which has been specifically designed for the treatment of community-acquired respiratory tract infections. The pharmacokinetic profile and dose proportionality of telithromycin and its main circulating metabolite, RU 76363, have been established when the drugs are given as single and as multiple once-daily doses to healthy subjects. RU 76363, an alcohol formed from loss of aryl rings during hepatic metabolism, is 4- to 16-fold less active than telithromycin in vitro.
Following oral administration telithromycin was rapidly absorbed, reaching Cmax within 1 h of dosing. Steady state plasma concentrations of both telithromycin and its major metabolite, RU 76363, were reached within 2 to 3 days of multiple dosing, regardless of the dose. After 7 days of dosing, there was moderate accumulation of both telithromycin and RU 76363, with AUC values approximately 1.5-fold higher than those attained following a single dose. Rac was relatively constant over the dosage range. This moderate accumulation might be explained by a slight decrease in nonrenal clearance with multiple dosing, since the main (initial) elimination half-life increased by 20 to 30% while CLR(0-24) remained unchanged.
The pharmacokinetics of telithromycin deviated moderately
from dose proportionality after single and multiple oral
administration: a doubling of the dose resulted in an increase of
approximately threefold in AUC. Cmax deviated
only slightly from dose proportionality. t1/21 and
t1/2z also increased
significantly with dose in the multiple-dose phase: over the 800- to
1,600-mg dosage interval
t1/21 increased by a factor of
1.5, while t1/2z
increased 1.8-fold. CLR(0-24) remained constant
over the 400- to 1,600-mg dose range. Consequently, the percentage of
telithromycin eliminated unchanged in the urine increased
with dose with a magnitude similar to that of the AUC.
The moderate deviation from dose proportionality observed in this study
may reflect a decrease in the metabolic clearance of the drug and a
slight increase in the bioavailability of telithromycin with increasing dose. As the amount of telithromycin
eliminated in the initial phase represents the major fraction, it may
be assumed that the 30% increase in the
t1/21 for a doubling of dose
corresponds to a 30% decrease in plasma clearance. As CLR(0-24) was unchanged in this study, this suggests
that nonrenal clearance (i.e., hepatic metabolic clearance) decreases with increasing dose.
RU 76363, the main circulating metabolite of telithromycin, is formed by hydrolysis of the aryl rings of the carbamate side chain of telithromycin; its AUC represents about 10 to 12% that of telithromycin. The decrease of telithromycin clearance cannot be attributed to a decrease in the formation of the RU 76363 metabolite, since the pharmacokinetics of this metabolite also deviated from dose proportionality in a manner similar to that observed for telithromycin. The dose proportionality of other circulating metabolites of telithromycin was not assessed since their AUC values represent only 1 to 2% of that of telithromycin (15).
In the present study, the Cmax and
C24 values after 7 days of dosing with 800 mg
telithromycin were 2.27 and 0.070 mg/liter, respectively.
The telithromycin MICs at which 90% of the isolates are
inhibited values for S. pneumoniae (including MLS-resistant strains) and Haemophilus influenzae are 
0.06 and 2 mg/liter, respectively (1, 5). These data therefore
suggest that telithromycin given at a daily dose of 800 mg
will provide adequate plasma levels to maintain activity against
respiratory pathogens, irrespective of macrolide susceptibility.
Telithromycin was generally well tolerated at all doses, though the incidence of adverse events tended to be higher at the 1,600-mg dose. These data, taken together with the pharmacokinetic profile of the compound, suggest that a once-daily 800-mg oral dose of telithromycin maintains an effective concentration in plasma and is suitable for evaluation in further pharmacokinetic and clinical trials for the treatment of community-acquired respiratory tract infections.
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ACKNOWLEDGMENT |
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Funding for this study was provided by Hoechst Marion Roussel.
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FOOTNOTES |
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* Corresponding author. Mailing address: Aventis Pharma, Hoechst Marion Roussel/Romaineville, 102 route de Noisy, 93235 Romainville Cedex, France. Phone: 33 1 4991 5807. Fax: 33 1 4991 4842. E-mail: florence.namour{at}aventis.com.
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Abstract
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Results
Discussion
References
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Antimicrobial Agents and Chemotherapy, January 2001, p. 170-175, Vol. 45, No. 1
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.1.170-175.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Kuehnel, T. S., Schurr, C., Lotter, K., Kees, F.
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Gattringer, R., Urbauer, E., Traunmuller, F., Zeitlinger, M., Dehghanyar, P., Zeleny, P., Graninger, W., Muller, M., Joukhadar, C.
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Tellier, G., Niederman, M. S., Nusrat, R., Patel, M., Lavin, B.
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Reinert, R. R.
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Shi, J., Montay, G., Chapel, S., Hardy, P., Barrett, J. S., Sack, M., Marbury, T., Swan, S. K., Vargas, R., Leclerc, V., Leroy, B., Bhargava, V. O.
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Muller-Serieys, C., Andrews, J., Vacheron, F., Cantalloube, C.
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Schentag, J. J, Meagher, A. K, Forrest, A.
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Clark, J. P., Langston, E.
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Seral, C., Van Bambeke, F., Tulkens, P. M.
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Bingen, E., Doit, C., Loukil, C., Brahimi, N., Bidet, P., Deforche, D., Geslin, P.
(2003). Activity of Telithromycin against Penicillin-Resistant Streptococcus pneumoniae Isolates Recovered from French Children with Invasive and Noninvasive Infections. Antimicrob. Agents Chemother.
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Ackermann, G., Rodloff, A. C.
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Araujo, F. G., Slifer, T. L., Remington, J. S.
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Lascols, C., Bryskier, A., Soussy, C.-J., Tankovic, J.
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