Assessments of Thioridazine as a Helper Compound to Dicloxacillin against Methicillin-Resistant Staphylococcus aureus: In Vivo Trials in a Mouse Peritonitis Model.
BACKGROUND
The rise in antimicrobial resistance is a major global concern and requires new treatment strategies. The use of helper compounds, such as thioridazine (TDZ), an antipsychotic drug, in combination with traditional antibiotics must be investigated.


OBJECTIVE
The aim of this study was to investigate the efficacy of TDZ as a helper compound for dicloxacillin (DCX) against methicillin-resistant Staphylococcus aureus (MRSA) in vivo, and compare the combination treatment of DCX+TDZ with vancomycin (VAN).


METHODS
Mice were inoculated with an intraperitoneal (IP) injection of MRSA (108 CFU) and treated in a 12-hour cycle for 48 hours. By termination, bacterial quantities in a peritoneal flush, spleen and kidneys were obtained. In the main trial the drugs were administered subcutaneously in five treatment groups: 1) DCX, 2) TDZ, 3) DCX+TDZ, 4) VAN, 5) SALINE. Additional smaller studies with IP administration and higher subcutaneous dosages (×1.5 and ×4) of the drugs were subsequently performed.


RESULTS
In the main trial no significant differences were found between DCX+TDZ and DCX or TDZ alone (p≥0.121-0.999). VAN performed significantly better than DCX+TDZ on all bacteriological endpoints (p<0.001). Higher subcutaneous dosages of DCX and TDZ improved the antibacterial efficacy, but the combination treatment was still not significantly better than monotherapy. IP drug administration of DCX+TDZ revealed a significantly better antibacterial effect than DCX or TDZ alone (p<0.001) but not significantly different from VAN (p>0.999).


CONCLUSIONS
In conclusion, TDZ did not prove to be a viable helper compound for dicloxacillin against MRSA in subcutaneous systemic treatment. However, IP-administration of DCX+TDZ, directly at the infection site resulted in a synergetic effect, with efficacy comparable to that of VAN.
Research Unit of Clinical Microbiology, University of Southern Denmark, Odense, Denmark; Department of Cardiothoracic Surgery, Odense University Hospital, Odense, Denmark.
Michael
M
Stenger
Research Unit of Clinical Microbiology, University of Southern Denmark, Odense, Denmark.
Kristoffer
K
Hendel
Biomedical Laboratory, University of Southern Denmark, Odense, Denmark.
Peter
P
Bollen
Department of Cardiothoracic Surgery, Odense University Hospital, Odense, Denmark.
Peter B
PB
Licht
Research Unit of Clinical Microbiology, University of Southern Denmark, Odense, Denmark.
Hans Jørn
HJ
Kolmos
Research Unit of Clinical Microbiology, University of Southern Denmark, Odense, Denmark; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
Janne K
JK
Klitgaard
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D004009:Dicloxacillin / Q000494:pharmacology*; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D005260:Female; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000472:pathogenicity*; D051379:Mice; D010538:Peritonitis / Q000188:drug therapy*; D013203:Staphylococcal Infections / Q000188:drug therapy; D013881:Thioridazine / Q000494:pharmacology
D000900:Anti-Bacterial Agents; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D004009:Dicloxacillin; D013881:Thioridazine