1. Antimicrob Agents Chemother. 2009 Nov;53(11):4801-8. Epub 2009 Sep 8.

Plectasin shows intracellular activity against Staphylococcus aureus in human
THP-1 monocytes and in a mouse peritonitis model.

Brinch KS, Sandberg A, Baudoux P, Van Bambeke F, Tulkens PM, Frimodt-Møller N,
Høiby N, Kristensen HH.

Novozymes A/S, Anti-Infective Discovery, Krogshøjvej 36, DK-2880 Bagsvaerd,
Denmark. kbri@novozymes.com

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 [E(max)], 1.0- to 1.3-log reduction in CFU) even though
efficacy was inferior to that of extracellular killing (E(max), >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 E(max) of a 1.1-log CFU reduction. The parameter most important for
activity was fC(peak)/MIC, where fC(peak) 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.

PMID: 19738011 [PubMed - in process]