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Antimicrobial Agents and Chemotherapy, November 2009, p. 4801-4808, Vol. 53, No. 11
0066-4804/09/$08.00+0 doi:10.1128/AAC.00685-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Plectasin Shows Intracellular Activity against Staphylococcus aureus in Human THP-1 Monocytes and in a Mouse Peritonitis Model
Karoline Sidelmann Brinch,1*
Anne Sandberg,2
Pierre Baudoux,4
Françoise Van Bambeke,4
Paul M. Tulkens,4
Niels Frimodt-Møller,2
Niels Høiby,3 and
Hans-Henrik Kristensen1
Novozymes A/S, Anti-Infective Discovery, Krogshøjvej 36, DK-2880 Bagsværd, Denmark,1 National Center for Antimicrobials and Infection Control, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark,2 Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, Juliane Maries Vej 22, DK-2100 Copenhagen Ø, Denmark,3 Unité de pharmacologie cellulaire et moléculaire and Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium4
Received 19 May 2009/ Returned for modification 7 July 2009/ Accepted 28 August 2009
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, which is why the intracellular activity of antistaphylococcal compounds has received increased attention within recent years. The intracellular activity of plectasin, an antimicrobial peptide, against S. aureus was determined both in vitro and in vivo. In vitro studies using THP-1 monocytes showed that some intracellular antibacterial activity of plectasin was maintained (maximal relative efficacy [Emax], 1.0- to 1.3-log reduction in CFU) even though efficacy was inferior to that of extracellular killing (Emax, >4.5-log CFU reduction). Animal studies included a novel use of the mouse peritonitis model, exploiting extra- and intracellular differentiation assays, and assessment of the correlations between activity and pharmacokinetic (PK) parameters. The intracellular activity of plectasin was in accordance with the in vitro studies, with an Emax of a 1.1-log CFU reduction. The parameter most important for activity was fCpeak/MIC, where fCpeak is the free peak concentration. 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 models 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/pharmacodynamic parameters, and optimal dosing regimens is required.
* Corresponding author. Mailing address: Novozymes A/S, Anti-Infective Discovery, Krogshøjvej 36, DK-2880 Bagsværd, Denmark. Phone: 45 4446 4787. Fax: 45 4446 3233. E-mail: kbri{at}novozymes.com
Published ahead of print on 8 September 2009.
Antimicrobial Agents and Chemotherapy, November 2009, p. 4801-4808, Vol. 53, No. 11
0066-4804/09/$08.00+0 doi:10.1128/AAC.00685-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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