Concentrations Of Telithromycin Research Articles

Aerosol-based efficient delivery of telithromycin, a ketolide antimicrobial agent, to lung epithelial lining fluid and alveolar macrophages for treatment of respiratory infections

Purpose: The efficacy of aerosol-based delivery of telithromycin (TEL), as a model antimicrobial agent, for the treatment of respiratory infections was evaluated by comparison with oral administration. Method: The aerosol formulation (0.2 mg/kg) was administered to rat lungs using a Liquid MicroSprayer®. Results and discussion: The time courses of the concentration of TEL in lung epithelial lining fluid (ELF) and alveolar macrophages (AMs) following administration of an aerosol formulation to rat lungs were markedly higher than that following the administration of an oral formulation (50 mg/kg). The time course of the concentrations of TEL in plasma following administration of the aerosol formulation was markedly lower than that in ELF and AMs. These results indicate that the aerosol formulation is more effective in delivering TEL to ELF and AMs, compared to the oral formulation, despite a low dose and it avoids distribution of TEL to the blood. In addition, the antibacterial effects of TEL in ELF and AMs following administration of the aerosol formulation were estimated by pharmacokinetics/pharmacodynamics analysis. The concentrations of TEL in ELF and the AMs time curve/minimum inhibitory concentration of TEL ratio were markedly higher than the effective values. Conclusion: This study indicates that an antibiotic aerosol formulation may be an effective pulmonary drug delivery system for the treatment of respiratory infections.

Multiple-dose pharmacokinetics of telithromycin in peripheral soft tissues

Based on clinicians’ expectations of high concentrations of telithromycin (TEL) in tissues, combined with its excellent in vitro antimicrobial characteristics, TEL is casually considered as a potential therapeutic option for the therapy of minor cases of soft tissue or bite-wound infections. To clarify this clinically important issue, the present investigation was carried out to measure the pharmacokinetic profile of TEL in the interstitial space fluid (ISF) of skeletal muscle and subcutaneous adipose tissue by means of the microdialysis technique in 10 healthy subjects following repetitive daily doses of 800 mg TEL. These data were compared with free concentrations of TEL determined in plasma. External controls for the present examination were the use of historic, single-dose data collected by our study group utilising identical methods and the same trial subjects. Despite an increase in the median half-life from ca. 3 h after a single dose to ca. 10 h at steady-state conditions in all compartments, accumulation of TEL in ISF of soft tissues and plasma was clinically non-relevant. Median free peak concentrations in plasma, skeletal muscle and subcutis were 0.52, 0.13 and 0.19 mg/L, respectively. The median ratios of the tissue to plasma free areas under the concentration–time curves from 0 to 24 h ( fAUC 0–24 tissue/ fAUC 0–24 plasma) were 0.27 and 0.58 for muscle and subcutis, respectively ( P > 0.05). The present multiple-dose investigation of TEL is in line with a previous single-dose study confirming that TEL 800 mg/day may not be optimally effective in the therapy of soft tissue infections.

Distribution Characteristics of Telithromycin, a Novel Ketolide Antimicrobial Agent Applied for Treatment of Respiratory Infection, in Lung Epithelial Lining Fluid and Alveolar Macrophages

The distribution characteristics of telithromycin (TEL), a novel ketolide antimicrobial agent, in lung epithelial fluid (ELF) and alveolar macrophages (AMs) were evaluated. In vivo animal experiments, the time-courses of the concentrations of TEL in ELF and AMs following oral administration of TEL solution (50 mg/4 mL/kg) to rats were markedly higher than in plasma, and areas under drug concentration-time curve (AUC) ratios of ELF/plasma and AMs/plasma were 2.4 and 65.3, respectively. In vitro transport experiments, the basolateral-to-apical transport of TEL through model lung epithelial cell (Calu-3) monolayers was greater than apical-to-basolateral transport. Rhodamine123 and verapamil, MDR1 substrates, reduced the basolateral-to-apical transport of TEL. In vitro uptake experiments, the intracellular equilibrated concentration of TEL in cultured AMs (NR8383) was approximately 40 times the extracellular concentration. The uptake of TEL by NR8383 was inhibited by rotenone and FCCP, ATP depletors and was temperature-dependent. These data suggest that the high distribution of TEL to AMs is due to the sustained distribution to ELF via MDR1 as well as the high uptake by AMs themselves via active transport mechanisms.

The Intracellular Accumulation of Phagocytic and Epithelial Cells and the Inhibitory Effect on Chlamydophila (Chlamydia) pneumoniae of Telithromycin and Comparator Antimicrobials

The intracellular accumulation of telithromycin was measured and compared with ciprofloxacin, clarithromycin, minocycline and erythromycin. The activities of telithromycin, clarithromycin and minocycline against Chlamydophila (Chlamydia) pneumoniae were compared in an intracellular killing assay. Maximal telithromycin accumulation (mean intracellular/extracellular concentration ratio) ranged from 6.7 (A549 lung epithelial cells) to 11.8 (THP-1 monocytic cells). This ratio was similar to that of clarithromycin, but less than for minocycline. Minimum inhibitory and minimum lethal telithromycin concentrations against six clinical strains of C. pneumoniae were <0.015-0.03 mg/L and 0.03-0.06 mg/L, respectively, which were lower than those found for minocycline. These results show that telithromycin accumulates rapidly into epithelial cells, similar to previously reported results for phagocytic cells. Intracellular accumulation of telithromycin was lower than that observed for minocycline, but telithromycin demonstrated substantially more potent antichlamydial activity.

Subinhibitory concentrations of telithromycin, clarithromycin and azithromycin reduce methicillin-resistant Staphylococcus aureus coagulase in vitro and in vivo

Subinhibitory levels of clarithromycin and azithromycin have been shown to reduce the activity of bacterial virulence factors, but few studies have examined the effects of subinhibitory levels of telithromycin. Here, we examined the effects of telithromycin, clarithromycin and azithromycin on methicillin-resistant Staphylococcus aureus (MRSA) coagulase in vitro. We also examined the effects of these antibiotics on bacterial survival in a murine model of pulmonary infection, in which the number of bacteria in the lung correlates with the coagulase titre. The coagulase titre in MRSA strain NUMR101, a clinical isolate, was measured after a 16 h treatment with telithromycin, clarithromycin or azithromycin at the MIC (512 mg/L) and 1/2, 1/4, 1/8 and 1/16 of the MIC. In addition, we examined the effect of these drugs in a murine model of pulmonary infection induced by the intravenous injection of S. aureus enmeshed in agar beads. Treatment was started 1 day before infection and mice were treated once a day for 7 days by oral administration of 10 or 100 mg/kg telithromycin, clarithromycin or azithromycin, and the number of viable bacteria in the lungs was counted 24 h after the injection of the bacteria. The coagulase titres in mice treated with 1/8 of the MIC of telithromycin, clarithromycin and azithromycin and in the control were 8, 4, 8 and 32, respectively. In the mouse model of infection, the log cfu/lung (mean +/- SEM; n = 5 or 6) were 6.62 +/- 0.81, 4.79 +/- 0.41, 6.15 +/- 0.38 and 8.41 +/- 0.30 for mice treated with 100 mg/kg/day of telithromycin, clarithromycin and azithromycin and for controls, respectively (P < 0.05 for all groups versus control). Subinhibitory concentrations of telithromycin inhibit MRSA coagulase in vitro. In addition, the in vivo results indicate that pre-treatment with telithromycin, clarithromycin or azithromycin can reduce the bacterial load in a murine model of pulmonary infection.

Pharmacokinetics of telithromycin using bronchoscopic microsampling after single and multiple oral doses

Objectives Bronchoscopic microsampling (BMS) is a new technique for repeated sampling of bronchial epithelial lining fluid (ELF) to obtain the pharmacokinetic profile of drugs. We analyzed the time versus concentration profiles of telithromycin in bronchial ELF obtained by BMS and compared these finding to those in plasma and alveolar ELF obtained by bronchoalveolar lavage (BAL). Methods Bronchial ELF samples were obtained from five healthy subjects using BMS probe at 0, 2, 3, 4, 6, 10 and 24 h after single or multiple oral doses of 600 mg of telithromycin. Alveolar ELF was also obtained by BAL 3 h after single or multiple oral doses of 600 mg of telithromycin. Results The areas under the concentration–time curve from 0 to 24 h (AUC0-24) of telithromycin in plasma and bronchial ELF were 2.86±0.60 and 19.5±10.4 mg h/l after single treatment and 3.60±0.49 and 42.2±22.7 mg h/l after multiple treatments, respectively. Single and multiple oral doses of telithromycin produced significantly ( p<0.05) higher AUC0-24 in bronchial ELF compared to those in plasma. While concentrations in bronchial ELF obtained by BMS were significantly lower than those in alveolar ELF obtained by BAL, they tended to be higher than those in plasma after multiple administration. The telithromycin concentrations obtained by BMS method were very consistent in bronchial ELF at different bronchi at one time point and at the same bronchus at different time points. Conclusions Using the BMS technique, we could describe the pharmacokinetics of telithromycin in bronchial ELF. Furthermore, BMS was reasonably validated and reconfirmed to be a feasible and reliable method for measuring antimicrobial concentrations in bronchial ELF.

Methyltransferase Erm(37) Slips on rRNA to Confer Atypical Resistance in Mycobacterium tuberculosis

Members of the Mycobacterium tuberculosis complex possess a resistance determinant, erm(37) (also termed ermMT), which is a truncated homologue of the erm genes found in a diverse range of drug-producing and pathogenic bacteria. All erm genes examined thus far encode N(6)-monomethyltransferases or N(6),N(6)-dimethyltransferases that show absolute specificity for nucleotide A2058 in 23 S rRNA. Monomethylation at A2058 confers resistance to a subset of the macrolide, lincosamide, and streptogramin B (MLS(B)) group of antibiotics and no resistance to the latest macrolide derivatives, the ketolides. Dimethylation at A2058 confers high resistance to all MLS(B) and ketolide drugs. The erm(37) phenotype fits into neither category. We show here by tandem mass spectrometry that Erm(37) initially adds a single methyl group to its primary target at A2058 but then proceeds to attach additional methyl groups to the neighboring nucleotides A2057 and A2059. Other methyltransferases, Erm(E) and Erm(O), maintain their specificity for A2058 on mycobacterial rRNA. Erm(E) and Erm(O) have a full-length C-terminal domain, which appears to be important for stabilizing the methyltransferases at their rRNA target, and this domain is truncated in Erm(37). The lax interaction of the M. tuberculosis Erm(37) with its rRNA produces a unique methylation pattern and confers resistance to the ketolide telithromycin.

Intrapulmonary Concentrations of Telithromycin: Clinical Implications for Respiratory Tract Infections due to Streptococcus pneumoniae

Background: Antimicrobial efficacy is dependent on the ability of the agent to reach the site of infection. To assess the bronchopulmonary drug disposition of a novel ketolide, telithromycin (TEL), the epithelial lining fluid (ELF) and alveolar macrophage (AM) concentrations were utilized as a surrogate marker for lung penetration. Methods: Adult subjects scheduled for diagnostic bronchoscopy received oral TEL 800 mg once daily for 5 days. Plasma and bronchoalveolar lavage (BAL) samples were collected 2, 8, 12, or 24 h after the last TEL dose. TEL concentrations in the ELF and AM were determined using a validated HPLC assay. ELF drug concentrations were calculated using the urea dilution method. Results: Seventeen subjects with a mean age 65 ± 13 years and a mean weight of 81 ± 25 kg completed this open-label study. The median (range) TEL concentrations in plasma and ELF, respectively, were 1.09 mg/l (1.00–4.81) and 3.91 mg/l (2.64–9.59) at 2 h (n = 6), 0.48 and 1.09 mg/l at 8 h (n = 1), 0.65 mg/l (0.18–1.55) and 1.81 mg/l (0.61–10.0) at 12 h (n = 5), and 0.11 mg/l (0.09–0.24) and 0.69 mg/l (0.15–1.58) at 24 h (n = 5). The median AM concentrations obtained from these subjects were 53.35 mg/l at 2 h, 32.55 mg/l at 8 h, 65.96 mg/l at 12 h, and 26.43 mg/l at 24 h. Overall TEL was well tolerated. No discontinuation was required due to an adverse event. Conclusions: TEL displayed high intrapulmonary penetration with ELF concentrations exceeding that of plasma at all time points. AM intracellular concentrations were multiple times higher than in the ELF and plasma. These data support the clinical efficacy of TEL against intracellular and extracellular pathogens, particularly with Streptococcus pneumoniae having an MIC₉₀well below achievable concentrations at the site of infection.

The Bioequivalence of Telithromycin Administered Orally as Crushed Tablets Versus Tablets Swallowed Whole

This open-label, randomized, crossover study was conducted to demonstrate bioequivalence for telithromycin administered as crushed or whole tablets. Single 800-mg telithromycin doses (2x400-mg tablets) were administered as crushed tablets mixed in 240 mL nutritional supplement drink followed by 120 mL water or as whole tablets swallowed with 240 mL water. Plasma telithromycin concentrations were measured by liquid chromatography/mass spectrometry; pharmacokinetic parameters were determined using noncompartmental methods. Average bioequivalence criteria were applied. Thirty-two subjects received telithromycin by both methods. The 90% confidence intervals for the geometric mean ratios of maximum plasma concentration and area under the plasma concentration-time curve to 24 hours were within the 0.80 to 1.25 range. Median tmax was 3.00 hours for both treatments. Both methods of administration were well tolerated. Crushing telithromycin tablets and administering them with a nutritional supplement drink is bioequivalent to ingesting whole tablets and could be a viable method of administration for patients unable to swallow tablets whole.

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

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. 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. 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. Telithromycin achieved tissue concentrations that were generally above the MIC(90) 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.

Clinical Pharmacokinetics of Telithromycin, the First Ketolide Antibacterial

Telithromycin is the first ketolide, which is a new class of antibacterial agents related to the macrolides that have structural modifications permitting dual binding to bacterial ribosomal RNA so that activity is retained against Streptococcus pneumoniae with macrolide-lincosamide-streptogramin(B) resistance. Clinical experience in infectious patients has shown that oral telithromycin 800mg once daily for 5-10 days is effective for the treatment of community-acquired upper and lower respiratory tract infections. Absorption of telithromycin in humans is estimated to be > or = 90%. Prior to entering the systemic circulation, telithromycin undergoes first-pass metabolism (mainly by the liver). Its absolute bioavailability is 57% and is unaffected by food. The volume of distribution of telithromycin after intravenous infusion is 2.9 L/kg. Telithromycin is 60-70% bound to serum proteins and has extensive diffusion into a range of target biological tissues, achieving concentrations above its minimum inhibitory concentration (MIC) against key respiratory pathogens throughout the dosing interval. After entering the systemic circulation, telithromycin is eliminated by multiple pathways (7% by biliary and/or intestinal excretion, 13% by renal excretion and 37% by hepatic metabolism). Telithromycin is metabolised via cytochrome P450 (CYP) 3A4 and non-CYP pathways. The identified metabolites show minimal antibacterial activity compared with the parent drug. In healthy subjects receiving telithromycin 800 mg once daily, the peak plasma concentration achieved is 2.27 microg/mL. Plasma concentrations of telithromycin show a biphasic decrease over time, with an initial disposition half-life of 2.9 hours and a terminal elimination half-life of approximately 10 hours after multiple dose administration. Steady-state plasma concentrations are achieved within 2-3 days of once-daily administration. Owing to elimination by multiple pathways there is a small increase in exposure when one of these elimination pathways is impaired, as indicated by the results of studies in special patient populations (e.g. those with hepatic or renal impairment). Dosage reductions may be recommended in patients with severe renal impairment. Inhibition of CYP3A4 by potent inhibitors such as itraconazole and ketoconazole results in a 54% and 95% increase in telithromycin area under the plasma concentration-time curve, respectively. The potential for telithromycin to inhibit the CYP3A4 pathway is similar to that of clarithromycin. The once-daily administration of telithromycin is likely to limit the potential for drug interactions and clinically significant increases in exposure. In phase III clinical trials, the telithromycin 800 mg once-daily dose has been shown to provide close to the maximum antimicrobial activity against S. pneumoniae, Haemophilus influenzae and Staphylococcus aureus in patients with community-acquired pneumonia. In conclusion, telithromycin has a well characterised and reproducible pharmacokinetic profile, with pharmacokinetic/pharmacodynamic relationships supporting an oral dosage regimen of 800 mg once daily.

Pharmacodynamic Profile of Telithromycin against Macrolide- and Fluoroquinolone-Resistant Streptococcus pneumoniae in a Neutropenic Mouse Thigh Model

The new ketolide telithromycin has potent in vitro activity against Streptococcus pneumoniae, including strains resistant to penicillin, macrolides, and fluoroquinolones. The aim of the present study was to define the pharmacodynamic profile of telithromycin against S. pneumoniae strains with various resistance profiles in an in vivo system. Ten S. pneumoniae strains were studied; seven exhibited penicillin resistance, six demonstrated macrolide resistance, and two exhibited gatifloxacin resistance. The telithromycin MICs for all isolates were < or =0.5 microg/ml. Using the murine thigh infection model, CD-1/ICR mice were rendered neutropenic and were then inoculated with 10(5) to 10(6) CFU of S. pneumoniae per thigh. Telithromycin was administered orally at doses ranging from 25 to 800 mg/kg of body weight/day, with the doses administered one, two, three, or four times a day. The activity of telithromycin was assessed by determination of the change in the bacterial density in thigh tissue after 24 h of treatment for each treatment group and the untreated controls. Pharmacokinetic studies of telithromycin were conducted in infected, neutropenic animals. The levels of protein binding by telithromycin in mice ranged from 70 to 95% over the observed range of pharmacokinetic concentrations. By using either the total or the free concentrations of telithromycin, the area under the concentration-time curve (AUC)/MIC ratio was a strong determinant of the response against S. pneumoniae, regardless of the phenotypic resistance profile. The maximal efficacy (the 95% effective dose) against this cohort of S. pneumoniae strains and bacterial inhibition (stasis) of telithromycin were predicted by ratios of the AUC for the free drug concentration/MIC of approximately 1,000 and 200, respectively.

Pharmacodynamic activity of telithromycin against macrolide-susceptible and macrolide-resistant Streptococcus pneumoniae simulating clinically achievable free serum and epithelial lining fluid concentrations

The association between macrolide resistance mechanisms and ketolide bacteriological eradication of Streptococcus pneumoniae remains poorly studied. The present study, using an in vitro model, assessed telithromycin pharmacodynamic activity against macrolide-susceptible and macrolide-resistant S. pneumoniae simulating clinically achievable free serum and epithelial lining fluid (ELF) concentrations. Two macrolide-susceptible [PCR-negative for both mef(A) and erm(B)] and six macrolide-resistant [five mef(A)-positive/erm(B)-negative displaying various degrees of macrolide resistance and one mef(A)-negative/erm(B)-positive] S. pneumoniae were tested. Telithromycin was modelled simulating a dosage of 800 mg by mouth once daily [free serum: maximum concentration (C(max)) 0.7 mg/L, t(1/2) 10 h; and free ELF: C(max) 6.0 mg/L, t(1/2) 10 h]. Starting inocula were 1 x 10(6) cfu/mL in Mueller-Hinton broth with 2% lysed horse blood. Sampling at 0, 2, 4, 6, 12, 24 and 48 h assessed the extent of bacterial killing (decrease in log(10) cfu/mL versus initial inoculum). Telithromycin free serum concentrations achieved in the model were: C(max) 0.9+/-0.08 mg/L, AUC(0-24) 6.4+/-1.5 mg.h/L and t(1/2) of 10.6+/-1.6 h. Telithromycin free ELF concentrations achieved in the model were: C(max) 6.6+/-0.8 mg/L, AUC(0-24) 45.5+/-5.5 mg.h/L and t(1/2) of 10.5+/-1.7 h. At 2 h, free serum telithromycin concentrations achieved a 1.0-1.9 log(10) reduction in inoculum compared with a 3.0-3.3 log(10) reduction with free ELF versus macrolide-susceptible and macrolide-resistant S. pneumoniae. Free telithromycin serum and ELF concentrations simulating C(max)/MIC > or =14.1 and area under the curve to MIC (AUC(0-24)/MIC) > or =100 [time above the MIC (t > MIC) of 100%], were bactericidal (> or =3 log(10) killing) at 4, 6, 12, 24 and 48 h versus macrolide-susceptible and macrolide-resistant S. pneumoniae. Telithromycin serum and ELF concentrations rapidly eradicated macrolide-susceptible and macrolide-resistant S. pneumoniae regardless of resistance phenotype. Achieving C(max)/MIC > or =14.1 and AUC(0-24)/MIC > or =100 resulted in bactericidal activity at 4 h with no regrowth over 48 h.

Pharmacokinetics of Telithromycin in Plasma and Soft Tissues after Single-Dose Administration to Healthy Volunteers

By use of microdialysis we assessed the concentrations of telithromycin in muscle and adipose tissue to test its ability to penetrate soft tissues. The ratios of the area under the concentration-versus-time curve from 0 to 24 h to the MIC indicated that free concentrations of telithromycin in tissue and plasma might be effective against Streptococcus pyogenes but not against staphylococci and human and animal bite pathogens.

In vitro and in vivo Antibacterial Activities of Telithromycin

Background: Telithromycin is one of the ketolides, characterised by a 3-keto group instead of L-cladinose and a C₁₁–C₁₂ carbamate link by an alkyl chain to a pyridinum and imidazolium ring side chain. We evaluated in vitro and in vivo antibacterial activities of telithromycin against gynaecological pathogens. Methods: In the vitro study, the antibacterial activity of telithromycin against 180 isolates (isolated in the year 2000) of Streptococcus agalactiae (n = 33), Enterococcus faecalis (n = 22), Neisseria gonorrhoeae (n = 30), Peptostreptococcus anaerobius (n = 20), Finegoldia magna (n = 20), Bacteroides fragilis (n = 25) and Prevotella bivia (n = 30) was compared with that of erythromycin A, clarithromycin, azithromycin, ampicillin and levofloxacin. In the in vivo study, the efficacy of telithromycin was evaluated using experimental intra-abdominal abscesses in mice caused by B. fragilis (minimum inhibitory concentration of telithromycin 0.5 mg/l). Results: In the in vitro study, telithromycin inhibited more than 50% of clinical isolates of S. agalactiae, E. faecalis, N. gonorrhoeae, P. anaerobius, F. magna, B. fragilis and P. bivia at concentrations of 0.016, 0.063, 0.063, 0.032, 0.032, 0.5 and 0.25 mg/l, respectively. Telithromycin inhibited more than 90% of these clinical isolates at concentrations of 0.016, 4, 0.125, 0.063, 0.063, 4 and 1 mg/l, respectively. In the in vivo study, telithromycin inhibited abscess formation and significantly decreased viable cell counts in abscesses in comparison with the untreated group. Conclusions: These in vitro and in vivo antibacterial activities suggest that telithromycin could be a potential candidate for the treatment of bacterial infections complicated by chlamydial infection.

Studies on measuring methods of the concentration of telithromycin in body fluids

Studies on measuring methods of the concentration of telithromycin in body fluids

Penetration of telithromycin (HMR 3647), a new ketolide antimicrobial, into inflammatory blister fluid following oral administration.

The penetration of telithromycin (HMR 3647), a novel ketolide antimicrobial, has been assessed in an open, single-dose study in eight healthy male subjects. Following a single, oral, 600 mg dose the mean ratio of the concentration of telithromycin in blister fluid over plasma was 1.38. Significant blister fluid concentrations were maintained up to 24 h post-dose. These results indicate that telithromycin penetrates well into inflammatory extracellular fluid, achieving high and sustained concentrations in this medium.

Intrapulmonary Pharmacokinetics of Telithromycin, a New Ketolide, in Healthy Japanese Volunteers

The concentrations of telithromycin, a new ketolide antimicrobial agent, in alveolar macrophages (AMs) and bronchoalveolar epithelial lining fluid (ELF) were determined in order to investigate the transfer of the drug into target tissue, relative to plasma, following multiple oral doses of telithromycin. Twenty-four healthy male Japanese volunteers were randomly allocated to four groups. Each subject was given 600 or 800 mg of telithromycin once daily for 5 days, followed by bronchoalveolar lavage (BAL) 2 or 8 h after the last dose (group A and B: 600 mg, 2 and 8 h BAL time point; group C and D: 800 mg, 2 and 8 h BAL time point). The mean concentrations of the drug in AMs and ELF were 34.54 and 4.92 mg/liter in group A, 50.97 and 2.26 mg/liter in group B, 25.47 and 4.24 mg/liter in group C, and 108.22 and 4.31 mg/liter in group D, respectively, which markedly exceeded concentrations in plasma. These results demonstrated good transfer of telithromycin into AMs and ELF, suggesting good efficacy against common respiratory pathogens, including intracellular pathogens and atypical microorganisms.

Effect of pH on the susceptibility ofHelicobacter pylori to the ketolide telithromycin (HMR 3647) and clarithromycin

Sir, Clarithromycin is the most active macrolide against Helicobacter pylori, but pH reduction markedly decreases its activity. This is a cause of concern because H. pylori is found on the gastric mucosa, where the pH is low, c. 5.5. In addition, clarithromycin resistance is increasing in H. pylori, with prevalences attaining at least 10% in several countries. Telithromycin is a new ketolide antibiotic that has been found to be highly active against a variety of microorganisms. We determined its activity, at pH 7.4, 6.5 and 5.9, against 30 macrolide-susceptible and 15 -resistant clinical strains of H. pylori isolated from gastric biopsies in Henri-Mondor hospital between 1997 and 1999. H. pylori ATCC 43504 was used as a control strain. MICs of clarithromycin and telithromycin were determined by the agar dilution technique using Mueller–Hinton agar (Oxoid, Lyon, France) supplemented with 10% fresh horse blood. A Steers inoculating device was used to place 10–10 cfu per spot (2 L per spot) on to the plates (52 spots per plate), which were examined for growth after 72 h of incubation at 37 C under microaerophilic conditions. Strains were considered resistant to clarithromycin if the MIC was 1 mg/L. At pH 7.4, telithromycin was four-fold less active than clarithromycin against clarithromycin-susceptible strains, the MIC50 of telithromycin being 0.125 mg/L (Table). In agreement with previous findings, pH reduction caused a marked increase in the MICs of clarithromycin for clarithromycin-susceptible strains: at pH 6.5, the MIC50 and MIC90 increased twoand eight-fold, respectively; at pH 5.9, eightand 16-fold increases were observed (Table). The activity of telithromycin against clarithromycinsusceptible strains was similarly affected by pH reduction (Table). None the less, the MICs of telithromycin at pH 5.9 for most strains remained below the maximum achievable serum concentration of telithromycin: 2.27 mg/L after 800 mg od for 7 days. The A2142G and A2143G mutations in the 23S rRNA gene that are implicated in clarithromycin resistance of H. pylori were detected by restriction fragment length polymorphism analysis of PCR-amplified DNA, using MboII and BsaI restriction enzymes (New England Biolabs, Beverly, MA, USA), as described previously. All clarithromycin-resistant strains carried either a A2142G (five strains) or A2143G mutation (10 strains). H. pylori possesses two 23S rRNA genes and both were mutated in all strains. In agreement with previous findings, MICs of clarithromycin at pH 7.4 were significantly higher for A2142G mutants (64–128 mg/L) than for A2143G mutants (8–32 mg/L) (Table). Telithromycin was not spared by resistance but the two mutations, and especially the A2142G mutation, were associated with a lower increase in the MICs of telithromycin, MICs for A2142G and A2143G mutants being 8–32 and 4–32 mg/L, respectively (Table). Macrolides and ketolides interact with bacterial 23S rRNA making contacts with the peptidyl transferase loop in domain V but also with the hairpin 35 in domain II. A2142 and A2143 are included in this loop and mutations such as those observed in H. pylori, as well as methylation of A2142 (the principal resistance mechanism in Grampositive bacteria but which has not been described in H. pylori) markedly decrease the affinity of both classes of drugs for the loop. However, while interactions of macrolides and ketolides with domain V are similar, their interactions with domain II differ. The stronger interaction of ketolides with hairpin 35 could explain their good activity against strains that contain ribosomes with methylated rRNA. This could also explain why ketolides are less affected by rRNA gene mutations in H. pylori. In the future, it may be possible to discover new ketolides whose interaction with hairpin 35 is sufficient for the binding of the antibiotic, so that these drugs could remain active against macrolide-resistant rRNA mutants of H. pylori. Correspondence Journal of Antimicrobial Chemotherapy (2001) 48, 735–748

Antibacterial activity of telithromycin (HMR 3647) in relation to in vitro simulated human plasma kinetics.

Telithromycin (HMR 3647) is a ketolide suitable for the treatment of respiratory infections. The aim of this study was to demonstrate its antibacterial efficacy against an erythromycin-susceptible Staphylococcus aureus, an erythromycin-resistant Streptococcus pneumoniae and Haemophilus influenzae. The free serum concentrations of telithromycin, produced by repeated oral administration of 800 mg to adults for 10 days, was simulated in an in vitro system. The ketolide displayed bacteriostatic activity against all three strains tested. This study supported the observation that an 800 mg po dose of telithromycin demonstrated antibacterial efficacy against respiratory tract pathogens.