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

Biofilm. 2024 Feb 29:7:100189. doi: 10.1016/j.bioflm.2024.100189. eCollection 2024 Jun.

Authors

Affiliations

¹ Department of Clinical Medicine, Infectious Diseases, Aarhus University, Palle Juul-Jensens Blvd. 82, Aarhus N, Denmark.
² Department of Infectious Diseases, Aarhus University Hospital, Palle Juul-Jensens Blvd. 99, Aarhus N, Denmark.
³ Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds Vej 14, Aarhus C, Denmark.
⁴ Department of Biology, Aarhus University, Ny Munkegade 114, Aarhus C, Denmark.

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; VGEI; Vascular graft or endograft infections.