title: Systemic thioridazine in combination with dicloxacillin against early aortic graft infections caused by Staphylococcus aureus in a porcine model: In vivo results do not reproduce the in vitro synergistic activity.
abstract: BACKGROUND
  Conservative treatment solutions against aortic prosthetic vascular graft infection (APVGI) for inoperable patients are limited. The combination of antibiotics with antibacterial helper compounds, such as the neuroleptic drug thioridazine (TDZ), should be explored.
  
  
  OBJECTIVE
  To investigate the efficacy of conservative systemic treatment with dicloxacillin (DCX) in combination with TDZ (DCX+TDZ), compared to DCX alone, against early APVGI caused by methicillin-sensitive Staphylococcus aureus (MSSA) in a porcine model.
  
  
  METHODS
  The synergism of DCX+TDZ against MSSA was initially assessed in vitro by viability assay. Thereafter, thirty-two pigs had polyester grafts implanted in the infrarenal aorta, followed by inoculation with 106 CFU of MSSA, and were randomly administered oral systemic treatment with either 1) DCX or 2) DCX+TDZ. Treatment was initiated one week postoperatively and continued for a further 21 days. Weight, temperature, and blood samples were collected at predefined intervals. By termination, bacterial quantities from the graft surface, graft material, and perigraft tissue were obtained.
  
  
  RESULTS
  Despite in vitro synergism, the porcine experiment revealed no statistical differences for bacteriological endpoints between the two treatment groups, and none of the treatments eradicated the APVGI. Accordingly, the mixed model analyses of weight, temperature, and blood samples revealed no statistical differences.
  
  
  CONCLUSIONS
  Conservative systemic treatment with DCX+TDZ did not reproduce in vitro results against APVGI caused by MSSA in this porcine model. However, unexpected severe adverse effects related to the planned dose of TDZ required a considerable reduction to the administered dose of TDZ, which may have compromised the results.
authors.affiliation: Research Unit of Clinical Microbiology, University of Southern Denmark, Odense, Denmark.|Department of Cardiothoracic and Vascular Surgery, Odense University Hospital, Odense, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Stenger
authors.affiliation: Department of Vascular Surgery, Viborg Hospital, Viborg, Denmark.
authors.forename: Carsten
authors.initials: C
authors.lastname: Behr-Rasmussen
authors.affiliation: Research Unit of Clinical Microbiology, University of Southern Denmark, Odense, Denmark.
authors.forename: Kasper
authors.initials: K
authors.lastname: Klein
authors.affiliation: Research Unit of Clinical Microbiology, University of Southern Denmark, Odense, Denmark.
authors.forename: Rasmus B
authors.initials: RB
authors.lastname: Grønnemose
authors.affiliation: Research Unit of Clinical Microbiology, University of Southern Denmark, Odense, Denmark.
authors.forename: Thomas Emil
authors.initials: TE
authors.lastname: Andersen
authors.affiliation: Research Unit of Clinical Microbiology, University of Southern Denmark, Odense, Denmark.|Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
authors.forename: Janne K
authors.initials: JK
authors.lastname: Klitgaard
authors.affiliation: Research Unit of Clinical Microbiology, University of Southern Denmark, Odense, Denmark.
authors.forename: Hans Jørn
authors.initials: HJ
authors.lastname: Kolmos
authors.affiliation: Department of Cardiothoracic and Vascular Surgery, Odense University Hospital, Odense, Denmark.
authors.forename: Jes S
authors.initials: JS
authors.lastname: Lindholt
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004009:Dicloxacillin / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006242:Haptoglobins / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D007958:Leukocyte Count; D013203:Staphylococcal Infections / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects / Q000502:physiology*; D013552:Swine; D013881:Thioridazine / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D058017:Vascular Grafting / Q000009:adverse effects*
chemical_list: D006242:Haptoglobins; D006454:Hemoglobins; D004009:Dicloxacillin; D013881:Thioridazine