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

IntroductionConservative 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.AimTo 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.MethodsThe 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.ResultsDespite 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.ConclusionConservative 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.

In vitro synergy of sertraline and tetracycline cannot be reproduced in pigs orally challenged with a tetracycline resistant Escherichia coli

“…Toleration of the clinical relevant concentrations of the helper-drugs by the animals (or humans) is probably underrated [13] e.g. in another recent published study evaluating in vivo helper-compound activity of thioridazine, also a neurotrophic active medical compound, the authors report that their study had to pre-terminate due to severe side-effects of thioridazine in pigs with the concentrations used [22].…”

Медикаментозне Інгібування Активності Бактеріальних Двокомпонентних Систем Регуляції

“…Активностью Продемонстрировано, что дериват фенотиазина -антипсихотический препарат тиоридазин (thioridazine) подавляет транскрипцию нескольких генов, принадлежащих регулону VraRS и участвующих в биосинтезе аминокислот, транспортеров, компонентов стенки бактерий Staphylococcus aureus [7,40]. Применение тиоридазина повышает восприимчивость бактерий MRSA к действию β-лактамных антибиотиков [34,38,39]. Mette Thorsing и соавт.…”

A Novel Promazine Derivative Shows High in vitro and in vivo Antimicrobial Activity Against Staphylococcus aureus

“…The concentration of phenothiazines must be relatively high to obtain the synergistic effects, and studies have revealed that these compounds did not perform well as helper compounds when tested in vivo . In some cases, the administrated dose needed to be reduced considerably due to severe side-effects observed in the phenothiazine-treated animals ( Stenger et al, 2015 , 2017 ). Since phenothiazines possess lipophilic properties, they can easily cross the blood-brain barrier (BBB) and cause effects on the central nervous systems (CNS) ( Seelig et al, 1994 ).…”