Treatment research in endotoxemia: Comparison of the efficacy of marbofloxacin, flunixin meglumine, pentoxifylline and methotrexate

Endotoxemia is a significant clinical condition in farm animals, characterized by high morbidity and mortality, leading to substantial economic losses. Although the combined use of fluid-electrolyte support, antimicrobial, and anti-inflammatory agents has been reported to enhance treatment success in routine practice, a standardized treatment protocol has yet to be established. In this study, the effects of flunixin meglumine (FM), pentoxifylline (PTX), and methotrexate (METO) on the therapeutic efficacy were evaluated in a lipopolysaccharide (LPS)-induced endotoxemia model in sheep, in addition to fluid-electrolyte and marbofloxacin therapy. Furthermore, changes in hematological, biochemical, acute phase, oxidative stress, and blood gas parameters in response to different treatment protocols were investigated, and the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of marbofloxacin were measured to compare the effects of these combinations. In the study, thirty Romanov breed sheep aged between 2 and 4 years were randomly assigned to five equal groups (n=6): endotoxemia control, marbofloxacin, flunixin, pentoxifylline, and methotrexate groups. All groups received an intravenous infusion of LPS at a dose of 20 µg/kg, followed by intravenous administration of marbofloxacin (10 mg/kg), FM (2,2 mg/kg), PTX (40 mg/kg), METO (5 mg/kg), and fluid-electrolyte therapy at a dose of 20 mL/kg. To evaluate the efficacy of the treatment options, clinical symptoms, hematological and biochemical parameters, oxidative stress markers, acute phase proteins, cytokines, and blood gas parameters were thoroughly assessed. The alterations in the pharmacokinetics of marbofloxacin caused by different treatment regimens were analyzed using high-performance liquid chromatography (HPLC). The results demonstrated that FM and PTX administration significantly increased total antioxidant capacity and reduced proinflammatory markers. METO, on the other hand, suppressed the early inflammatory response but appeared to adversely affect the antioxidant system. Moreover, these agents were found to induce significant changes in the PK and PK/PD relationships of marbofloxacin. Marbofloxacin was shown to have a high plasma protein binding rate, resulting in a low free drug fraction; hence, its efficacy is evaluated based on the area under the curve/minimum inhibitory concentration (AUC/MIC) and maximum concentration/minimum inhibitory concentration (Cmax/MIC) ratios. According to Monte Carlo simulations, while the MARBO group was found to be effective up to an MIC of 0,125 µg/mL, the FM, PTX, and METO groups were effective at MIC values as low as 0,0625 µg/mL. This finding suggests that a 10 mg/kg dose may not always be sufficient and dose escalation might be necessary. However, to confirm the clinical relevance and reliability of these findings, further clinical trials involving larger populations are warranted.