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 MIC(90 )well below achievable concentrations at the site of infection.
Ong
C T
CT
Center for Anti-Infective Research and Development, Hartford Hospital, CT 06102, USA.
Dandekar
P K
PK
Sutherland
C
C
Nightingale
C H
CH
Nicolau
D P
DP
D000368:Aged; D000704:Analysis of Variance; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001682:Biological Availability; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D005260:Female; D006801:Humans; D048628:Ketolides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008168:Lung / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D011008:Pneumococcal Infections / Q000188:drug therapy*; D011446:Prospective Studies; D012141:Respiratory Tract Infections / Q000188:drug therapy*; D018709:Statistics, Nonparametric
D000900:Anti-Bacterial Agents; D048628:Ketolides; C106791:telithromycin