title: Rifampicin-containing combinations are superior to combinations of vancomycin, linezolid and daptomycin against Staphylococcus aureus biofilm infection in vivo and in vitro.
abstract: Susceptibility to antibiotics is dramatically reduced when bacteria form biofilms. In clinical settings this has a profound impact on treatment of implant-associated infections, as these are characterized by biofilm formation. Current routine susceptibility testing of microorganisms from infected implants does not reflect the actual susceptibility, and the optimal antibiotic strategy for treating implant-associated infections is not established. In this study of biofilm formation in implant-associated osteomyelitis, we compared thein vitroandin vivoefficacy of selected antibiotics alone and in combination againstStaphylococcus aureus.We tested vancomycin, linezolid, daptomycin and tigecycline alone and in combination with rifampicin, vancomycin, linezolid and daptomycin againstS. aureusIn vitro, biofilm formation dramatically reduced susceptibility by a factor of 500-2000.In vivo, antibiotic combinations were tested in a murine model of implant-associated osteomyelitis. Mice were infected by inserting implants colonized withS. aureustrough their tibia. After 11 days, the animals were divided into different groups (five animals/group) and given 14 days of antibiotic therapy. All antibiotics resulted in a reduced bacterial load in the infected bone surrounding the implant. Overall, the most effective antibiotic combinations contained rifampicin. Combinations containing two non-rifampicin antibiotics were not more active than single drugs.
authors.affiliation: Department of Infectious Diseases, Institute of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens bvld 99, 8200 Aarhus, Denmark Department of Clinical Microbiology, Institute of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens bvld 99, 8200 Aarhus, Denmark nisjoe@rm.dk.
authors.forename: Nis Pedersen
authors.initials: NP
authors.lastname: Jørgensen
authors.affiliation: Department of Infectious Diseases, Institute of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens bvld 99, 8200 Aarhus, Denmark Department of Clinical Microbiology, Institute of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens bvld 99, 8200 Aarhus, Denmark.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Skovdal
authors.affiliation: Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds vej 14, 8000 Aarhus, Denmark Department of Bioscience, Aarhus University, Vennelyst Boulevard 4, 8000 Aarhus, Denmark.
authors.forename: Rikke L
authors.initials: RL
authors.lastname: Meyer
authors.affiliation: Department of Biomedicine, Faculty of Health Sciences, Aarhus University, Vennelyst Boulevard 4, 8000 Aarhus, Denmark.
authors.forename: Frederik
authors.initials: F
authors.lastname: Dagnæs-Hansen
authors.affiliation: Microbiology and Infection Control, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen, Denmark.
authors.forename: Kurt
authors.initials: K
authors.lastname: Fuursted
authors.affiliation: Department of Infectious Diseases, Institute of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens bvld 99, 8200 Aarhus, Denmark.
authors.forename: Eskild
authors.initials: E
authors.lastname: Petersen
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D017576:Daptomycin / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D000069349:Linezolid / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D010019:Osteomyelitis / Q000188:drug therapy / Q000382:microbiology; D019736:Prostheses and Implants / Q000382:microbiology; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000502:physiology*; D016896:Treatment Outcome; D014640:Vancomycin / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D014640:Vancomycin; D000069349:Linezolid; D017576:Daptomycin; D012293:Rifampin
keywords: Staphylococcus aureus; antibiotic combination therapy; biofilm; murine model