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

Karoline Sidelmann Brinch; Anne Sandberg; Pierre Baudoux; Françoise Van Bambeke; Paul M Tulkens; Niels Frimodt-Møller; Niels Hoiby; Hans-Henrik Kristensen

doi:10.1128/AAC.00685-09

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

Karoline Sidelmann Brinch, Anne Sandberg, Pierre Baudoux, Françoise Van Bambeke, Paul M Tulkens, Niels Frimodt-Møller, Niels Hoiby, Hans-Henrik Kristensen

Department of Immunology and Microbiology

48 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Antimicrobial Agents and Chemotherapy
Volume	53
Issue number	11
Pages (from-to)	4801-8
Number of pages	7
ISSN	0066-4804
DOIs	https://doi.org/10.1128/AAC.00685-09
Publication status	Published - 2009

Access to Document

10.1128/AAC.00685-09

Cite this

@article{fe5df490aabf11df928f000ea68e967b,

title = "Plectasin shows intracellular activity against Staphylococcus aureus in human THP-1 monocytes and in a mouse peritonitis model",

abstract = "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.",

author = "Brinch, {Karoline Sidelmann} and Anne Sandberg and Pierre Baudoux and {Van Bambeke}, Fran{\c c}oise and Tulkens, {Paul M} and Niels Frimodt-M{\o}ller and Niels Hoiby and Hans-Henrik Kristensen",

note = "Keywords: Amino Acid Sequence; Animals; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Mice; Microbial Sensitivity Tests; Molecular Sequence Data; Monocytes; Peptides; Peritonitis; Staphylococcus aureus",

year = "2009",

doi = "10.1128/AAC.00685-09",

language = "English",

volume = "53",

pages = "4801--8",

journal = "Antimicrobial Agents and Chemotherapy",

issn = "0066-4804",

publisher = "American Society for Microbiology",

number = "11",

}

TY - JOUR

T1 - Plectasin shows intracellular activity against Staphylococcus aureus in human THP-1 monocytes and in a mouse peritonitis model

AU - Brinch, Karoline Sidelmann

AU - Sandberg, Anne

AU - Baudoux, Pierre

AU - Van Bambeke, Françoise

AU - Tulkens, Paul M

AU - Frimodt-Møller, Niels

AU - Hoiby, Niels

AU - Kristensen, Hans-Henrik

N1 - Keywords: Amino Acid Sequence; Animals; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Mice; Microbial Sensitivity Tests; Molecular Sequence Data; Monocytes; Peptides; Peritonitis; Staphylococcus aureus

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

U2 - 10.1128/AAC.00685-09

DO - 10.1128/AAC.00685-09

M3 - Journal article

C2 - 19738011

SN - 0066-4804

VL - 53

SP - 4801

EP - 4808

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

IS - 11

ER -

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

Abstract

Access to Document

Fingerprint

Cite this