Plectasin shows intracellular activity against staphylococcus aureus in human THP-1 monocytes and in the mouse peritonitis model

Brinch, Karoline Sidelmann Sandberg, Anne Baudoux, Pierre [UCL] Van Bambeke, Françoise [UCL] Tulkens, Paul M. [UCL] Frimodt-Møller, Niels Høiby, Niels Kristensen, Hans-Henrik et al.[show all]

Antimicrobial therapy of infections with Staphylococcus aureus can pose a challenge due to slow response to therapy and recurrence of infection. These treatment difficulties can partly be explained by intracellular survival of staphylococci, why the intracellular activity of anti-staphylococcal compounds has received increased attention within the recent years. The intracellular activity of plectasin, an antimicrobial peptide, against S. aureus was determined both in vitro and in vivo. In vitro studies in THP-1 monocytes showed that some intracellular antibacterial activity of plectasin was maintained (Emax of 1.0-1.3 log reduction in CFU) even though efficacy was inferior to the extracellular killing (>4.5 log CFU reduction). Animal studies included a novel use of the mouse peritonitis model exploiting an extra- and intracellular differentiation assay and assessment of the correlations between activity and PK-parameters. The intracellular activity of plectasin was in accordance with the in vitro studies with a relative efficacy of 1.1 log CFU reduction. The parameter most important for activity was fCpeak/MIC. These findings stress the importance of performing studies of extra- and intracellular activity since these features cannot be predicted from traditional MIC and killing kinetic studies. Application of both the THP-1 and the mouse peritonitis model showed that the in vitro results were similar to findings in the in vivo model with respect to demonstration of intracellular activity. Therefore the in vitro model was a good screening model for intracellular activity. However, animal models should be applied if further information on activity, PK/PD-parameters and optimal dosing regimens is required.