Concentrations in plasma, epithelial lining fluid, alveolar macrophages and bronchial mucosa after a single intravenous dose of 1.6 mg/kg of iclaprim (AR-100) in healthy men

• Published in: Journal of antimicrobial chemotherapy 2007-09, Vol.60 (3), p.677-680
• Main Authors: Andrews, J., Honeybourne, D., Ashby, J., Jevons, G., Fraise, A., Fry, P., Warrington, S., Hawser, S., Wise, R.
• Format: Article
• Language: English
• Subjects: Adult; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - blood; Anti-Bacterial Agents - pharmacokinetics; Antibiotics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacillus - drug effects; Biological and medical sciences; Bronchi - metabolism; Bronchoscopy; Chlamydophila pneumoniae; Clinical trials; concentration; Diagnostic tests; diaminopyrimidine; Epithelium - metabolism; Folic Acid Antagonists - administration & dosage; Folic Acid Antagonists - blood; Folic Acid Antagonists - pharmacokinetics; Haemophilus influenzae; Humans; Infusions, Intravenous; Macrophages, Alveolar - metabolism; Male; Medical sciences; Men; Microbial Sensitivity Tests; Microbiology; Moraxella catarrhalis; Pharmacology; Pharmacology. Drug treatments; Pyrimidines - administration & dosage; Pyrimidines - blood; Pyrimidines - pharmacokinetics; Respiratory Mucosa - metabolism; respiratory tree; Staphylococcus aureus; Streptococcus pneumoniae
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkm242

Objectives A validated microbiological assay was used to measure concentrations of iclaprim (AR-100) in plasma, bronchial mucosa (BM), alveolar macrophages (AM) and epithelial lining fluid (ELF) after a single 1.6 mg/kg intravenous 60 min iv infusion of iclaprim. Methods Male volunteers were randomly allocated to three nominal sampling time intervals 1–2 h (Group A), 3–4 h (Group B) and 5.5–7.0 h (Group C) after the start of the drug infusion. Results Mean iclaprim concentrations in plasma, BM, AM and ELF, respectively, were for Group A 0.59 mg/L (SD 0.18), 0.51 mg/kg (SD 0.17), 24.51 mg/L (SD 21.22) and 12.61 mg/L (SD 7.33); Group B 0.24 mg/L (SD 0.05), 0.35 mg/kg (SD 0.17), 7.16 mg/L (SD 1.91) and 6.38 mg/L (SD 5.17); and Group C 0.14 mg/L (SD 0.05), no detectable level in BM, 5.28 mg/L (SD 2.30) and 2.66 mg/L (SD 2.08). Conclusions Iclaprim concentrations in ELF and AM exceeded the MIC90 for penicillin-susceptible Streptococcus pneumoniae (MIC90 0.06 mg/L), penicillin-intermediate S. pneumoniae (MIC90 2 mg/L), penicillin-resistant S. pneumoniae (MIC90 4 mg/L) for 7, 7 and 4 h, respectively, and Chlamydia pneumoniae (MIC90 0.5 mg/L) for 7 h. Mean iclaprim concentrations in ELF exceeded the MIC90 for Haemophilus influenzae (MIC90 4 mg/L) and Moraxella catarrhalis (MIC90 8 mg/L) for up to 4 and 2 h, respectively; in AM the MIC90 was exceeded for up to 7 h. Furthermore, the MIC90 for methicillin-resistant Staphylococcus aureus of 0.12 mg/L was exceeded at all sites for up to 7 h. These data suggest that iclaprim reaches lung concentrations that should be effective in the treatment of community-acquired pneumonia.