Assessments of Thioridazine as a Helper Compound to Dicloxacillin against Methicillin-Resistant Staphylococcus aureus: In Vivo Trials in a Mouse Peritonitis Model

• Published in: PloS one Vol. 10; no. 8; p. e0135571
• Main Authors: Stenger, Michael, Hendel, Kristoffer, Bollen, Peter, Licht, Peter B, Kolmos, Hans Jørn, Klitgaard, Janne K
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.08.2015; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Anti-Bacterial Agents - pharmacology; Antibiotics; Antiinfectives and antibacterials; Antimicrobial agents; Antimicrobial resistance; Antipsychotics; Chemotherapy; Dicloxacillin; Dicloxacillin - pharmacology; Disease Models, Animal; Doublecortin protein; Drug dosages; Drug resistance; Drugs; Effectiveness; Female; Gene expression; Heart surgery; Kidneys; Laboratory animals; Methicillin; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - pathogenicity; Mice; Microbial drug resistance; Penicillin; Peritoneum; Peritonitis; Peritonitis - drug therapy; Pharmacology; Phenothiazines; Psychotropic drugs; Spleen; Staphylococcal Infections - drug therapy; Staphylococcus aureus; Staphylococcus aureus infections; Staphylococcus infections; Studies; Thioridazine; Thioridazine - pharmacology; Tuberculosis; Vancomycin; Denmark
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0135571

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. 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). 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. 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). 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.