TY - JOUR

T1 - Assessments of thioridazine as a helper compound to dicloxacillin against methicillin-resistant Staphylococcus aureus

T2 - In vivo trials in a mouse peritonitis model

AU - Stenger, Michael

AU - Hendel, Kristoffer

AU - Bollen, Peter

AU - Licht, Peter B.

AU - Kolmos, Hans Jørn

AU - Klitgaard, Janne K.

N1 - Publisher Copyright: © 2015 Stenger et al.

PY - 2015

Y1 - 2015

N2 - Introduction 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. Objectives 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). Conclusion 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.

AB - Introduction 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. Objectives 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). Conclusion 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.

U2 - 10.1371/journal.pone.0135571

DO - 10.1371/journal.pone.0135571

M3 - Journal article

C2 - 26267376

AN - SCOPUS:84942930754

VL - 10

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 8

M1 - e0135571

ER -