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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. 10h 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.

In previous studies, tetracyclines have been shown to decrease the release of cytokines in experimental settings of endotoxaemia. Tigecycline is the first member of the closely related glycylglycines and, due to its broad antimicrobial spectrum, it is considered useful in the treatment of sepsis. We therefore tested its ability to influence the concentrations of the proinflammatory cytokines interleukin (IL)-1beta, tumour necrosis factor-alpha (TNFalpha) and IL-6 in an established ex vivo model of human endotoxaemia. Whole blood from ten healthy volunteers was incubated with either saline (negative control), tigecycline (1 microg/mL [therapeutic concentration] or 100 microg/mL [supratherapeutic concentration]), lipopolysaccharide (LPS; 50 pg/mL, control) or a combination of tigecycline plus LPS (test group). Concentrations of IL-1beta, TNFalpha and IL-6 in the supernatant were measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits. As expected, incubation with LPS significantly increased the cytokine concentrations in whole blood compared with baseline (P<0.05). The combination of tigecycline plus LPS did not exert any significant effect on the concentrations of IL-1beta, IL-6 and TNFalpha after 2h and 4h of incubation compared with LPS alone. These results indicate that proinflammatory cytokines remained unaffected by tigecycline in an established ex vivo model of systemic inflammatory response.