Efficacy of rifampicin combination therapy against MRSA prosthetic vascular graft infections in a rat model

Mikkel Illemann Johansen; Maiken Engelbrecht Petersen; Emma Faddy; Anders Marthinsen Seefeldt; Alexander Alexandrovich Mitkin; Lars Østergaard; Rikke Louise Meyer; Nis Pedersen Jørgensen

doi:10.1016/j.bioflm.2024.100189

Efficacy of rifampicin combination therapy against MRSA prosthetic vascular graft infections in a rat model

Mikkel Illemann Johansen, Maiken Engelbrecht Petersen, Emma Faddy, Anders Marthinsen Seefeldt, Alexander Alexandrovich Mitkin, Lars Østergaard, Rikke Louise Meyer^*, Nis Pedersen Jørgensen^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

1 Citationer (Scopus)

Abstract

Staphylococcus aureus is a major cause of prosthetic vascular graft or endograft infections (VGEIs) and the optimal choice of antibiotics is unclear. We investigated various antibiotic choices as either monotherapy or combination therapy with rifampicin against MRSA in vitro and in vivo. Fosfomycin, daptomycin and vancomycin alone or in combination with rifampicin was used against MRSA USA300 FPR3757. Each antibiotic was tested for synergism or antagonism with rifampicin in vitro, and all antibiotic regimens were tested against actively growing bacteria in media and non-growing bacteria in buffer, both as planktonic cells and in biofilms. A rat model of VGEI was used to quantify the therapeutic efficacy of antibiotics in vivo by measuring bacterial load on grafts and in spleen, liver and kidneys. In vitro, rifampicin combinations did not reveal any synergism or antagonism in relation to growth inhibition. However, quantification of bactericidal activity revealed a strong antagonistic effect, both on biofilms and planktonic cells. This effect was only observed when treating active bacteria, as all antibiotics had little or no effect on inactive cells. Only daptomycin showed some biocidal activity against inactive cells. In vivo evaluation of therapy against VGEI contrasted the in vitro results. Rifampicin significantly increased the efficacy of both daptomycin and vancomycin. The combination of daptomycin and rifampicin was by far the most effective, curing 8 of 13 infected animals. Our study demonstrates that daptomycin in combination with rifampicin shows promising potential against VGEI caused by MRSA. Furthermore, we show how in vitro evaluation of antibiotic combinations in laboratory media does not predict their therapeutic effect against VGEI in vivo, presumably due to a difference in the metabolic state of the bacteria.

Originalsprog	Engelsk
Artikelnummer	100189
Tidsskrift	Biofilm
Vol/bind	7
DOI	https://doi.org/10.1016/j.bioflm.2024.100189
Status	Udgivet - jun. 2024

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10.1016/j.bioflm.2024.100189Licens: CC BY-NC

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title = "Efficacy of rifampicin combination therapy against MRSA prosthetic vascular graft infections in a rat model",

abstract = "Staphylococcus aureus is a major cause of prosthetic vascular graft or endograft infections (VGEIs) and the optimal choice of antibiotics is unclear. We investigated various antibiotic choices as either monotherapy or combination therapy with rifampicin against MRSA in vitro and in vivo. Fosfomycin, daptomycin and vancomycin alone or in combination with rifampicin was used against MRSA USA300 FPR3757. Each antibiotic was tested for synergism or antagonism with rifampicin in vitro, and all antibiotic regimens were tested against actively growing bacteria in media and non-growing bacteria in buffer, both as planktonic cells and in biofilms. A rat model of VGEI was used to quantify the therapeutic efficacy of antibiotics in vivo by measuring bacterial load on grafts and in spleen, liver and kidneys. In vitro, rifampicin combinations did not reveal any synergism or antagonism in relation to growth inhibition. However, quantification of bactericidal activity revealed a strong antagonistic effect, both on biofilms and planktonic cells. This effect was only observed when treating active bacteria, as all antibiotics had little or no effect on inactive cells. Only daptomycin showed some biocidal activity against inactive cells. In vivo evaluation of therapy against VGEI contrasted the in vitro results. Rifampicin significantly increased the efficacy of both daptomycin and vancomycin. The combination of daptomycin and rifampicin was by far the most effective, curing 8 of 13 infected animals. Our study demonstrates that daptomycin in combination with rifampicin shows promising potential against VGEI caused by MRSA. Furthermore, we show how in vitro evaluation of antibiotic combinations in laboratory media does not predict their therapeutic effect against VGEI in vivo, presumably due to a difference in the metabolic state of the bacteria.",

keywords = "Biofilm, Infections, MRSA, Persister cells, Prosthesis, Rat model, Rifampicin, Staphylococcus aureus, Vascular graft or endograft infections, VGEI",

author = "Johansen, {Mikkel Illemann} and Petersen, {Maiken Engelbrecht} and Emma Faddy and Seefeldt, {Anders Marthinsen} and Mitkin, {Alexander Alexandrovich} and Lars {\O}stergaard and Meyer, {Rikke Louise} and J{\o}rgensen, {Nis Pedersen}",

note = "Publisher Copyright: {\textcopyright} 2024",

year = "2024",

month = jun,

doi = "10.1016/j.bioflm.2024.100189",

language = "English",

volume = "7",

journal = "Biofilm",

publisher = "Elsevier BV",

}

TY - JOUR

T1 - Efficacy of rifampicin combination therapy against MRSA prosthetic vascular graft infections in a rat model

AU - Johansen, Mikkel Illemann

AU - Petersen, Maiken Engelbrecht

AU - Faddy, Emma

AU - Seefeldt, Anders Marthinsen

AU - Mitkin, Alexander Alexandrovich

AU - Østergaard, Lars

AU - Meyer, Rikke Louise

AU - Jørgensen, Nis Pedersen

PY - 2024/6

Y1 - 2024/6

N2 - Staphylococcus aureus is a major cause of prosthetic vascular graft or endograft infections (VGEIs) and the optimal choice of antibiotics is unclear. We investigated various antibiotic choices as either monotherapy or combination therapy with rifampicin against MRSA in vitro and in vivo. Fosfomycin, daptomycin and vancomycin alone or in combination with rifampicin was used against MRSA USA300 FPR3757. Each antibiotic was tested for synergism or antagonism with rifampicin in vitro, and all antibiotic regimens were tested against actively growing bacteria in media and non-growing bacteria in buffer, both as planktonic cells and in biofilms. A rat model of VGEI was used to quantify the therapeutic efficacy of antibiotics in vivo by measuring bacterial load on grafts and in spleen, liver and kidneys. In vitro, rifampicin combinations did not reveal any synergism or antagonism in relation to growth inhibition. However, quantification of bactericidal activity revealed a strong antagonistic effect, both on biofilms and planktonic cells. This effect was only observed when treating active bacteria, as all antibiotics had little or no effect on inactive cells. Only daptomycin showed some biocidal activity against inactive cells. In vivo evaluation of therapy against VGEI contrasted the in vitro results. Rifampicin significantly increased the efficacy of both daptomycin and vancomycin. The combination of daptomycin and rifampicin was by far the most effective, curing 8 of 13 infected animals. Our study demonstrates that daptomycin in combination with rifampicin shows promising potential against VGEI caused by MRSA. Furthermore, we show how in vitro evaluation of antibiotic combinations in laboratory media does not predict their therapeutic effect against VGEI in vivo, presumably due to a difference in the metabolic state of the bacteria.

AB - Staphylococcus aureus is a major cause of prosthetic vascular graft or endograft infections (VGEIs) and the optimal choice of antibiotics is unclear. We investigated various antibiotic choices as either monotherapy or combination therapy with rifampicin against MRSA in vitro and in vivo. Fosfomycin, daptomycin and vancomycin alone or in combination with rifampicin was used against MRSA USA300 FPR3757. Each antibiotic was tested for synergism or antagonism with rifampicin in vitro, and all antibiotic regimens were tested against actively growing bacteria in media and non-growing bacteria in buffer, both as planktonic cells and in biofilms. A rat model of VGEI was used to quantify the therapeutic efficacy of antibiotics in vivo by measuring bacterial load on grafts and in spleen, liver and kidneys. In vitro, rifampicin combinations did not reveal any synergism or antagonism in relation to growth inhibition. However, quantification of bactericidal activity revealed a strong antagonistic effect, both on biofilms and planktonic cells. This effect was only observed when treating active bacteria, as all antibiotics had little or no effect on inactive cells. Only daptomycin showed some biocidal activity against inactive cells. In vivo evaluation of therapy against VGEI contrasted the in vitro results. Rifampicin significantly increased the efficacy of both daptomycin and vancomycin. The combination of daptomycin and rifampicin was by far the most effective, curing 8 of 13 infected animals. Our study demonstrates that daptomycin in combination with rifampicin shows promising potential against VGEI caused by MRSA. Furthermore, we show how in vitro evaluation of antibiotic combinations in laboratory media does not predict their therapeutic effect against VGEI in vivo, presumably due to a difference in the metabolic state of the bacteria.

KW - Biofilm

KW - Infections

KW - MRSA

KW - Persister cells

KW - Prosthesis

KW - Rat model

KW - Rifampicin

KW - Staphylococcus aureus

KW - Vascular graft or endograft infections

KW - VGEI

U2 - 10.1016/j.bioflm.2024.100189

DO - 10.1016/j.bioflm.2024.100189

M3 - Journal article

C2 - 38481761

AN - SCOPUS:85186691764

VL - 7

JO - Biofilm

JF - Biofilm

M1 - 100189

ER -

Efficacy of rifampicin combination therapy against MRSA prosthetic vascular graft infections in a rat model

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