Evaluation of the pharmacokinetic-pharmacodynamic integration of marbofloxacin in combination with methyl gallate against Salmonella Typhimurium in rats.

Biruk Tesfaye Birhanu,Seung-Chun Park,Eon-Bee Lee,Praveen Rishi

doi:10.1371/journal.pone.0234211

Abstract

Fluoroquinolone resistance in Salmonella Typhimurium is becoming a major concern. Hence, an intervention to limit the growth in resistance is inevitable. One way to combat this challenge is through combination therapy. The combination of antibiotics with phytochemicals has become an ideal means of preventing antimicrobial resistance. Recently, in an in vitro study, the combination of methyl gallate (MG) with marbofloxacin (MAR) has shown to prevent Salmonella Typhimurium invasion. It is also worth to study the effects of plant extracts on the pharmacokinetics of antibiotics. Hence, the objective of this study was to determine the effect of MG on the pharmacokinetics of MAR and pharmacokinetics/pharmacodynamics integration of MG and MAR. The micro-broth dilution method was used to obtain the minimum inhibitory concentration (MIC), and fractional inhibitory concentration (FIC) of MAR and MG. Whereas, the pharmacokinetic was conducted in rats by administering either MAR alone or combined with MG through oral and/or intravenous routes. The results indicated that the MIC of MAR and MG against standard strain Salmonella Typhimurium (ATCC 14028) was 0.031 and 500 μg/mL, respectively. The FICindex of the combination of MAR and MG was 0.5. For orally administered drugs, the Cmax and AUC24h of MAR were 1.04 and 0.78 μg/mL and 5.98 and 6.11 h.μg/mL when MAR was given alone and in combination with MG, respectively. The intravenous administration of MAR showed a half-life of 3.8 and 3.9 h; a clearance rate of 1.1 and 0.73 L/h/kg and a volume of distribution of 5.98 and 4.13 L/kg for MAR alone and in combination with MG, respectively. The AUC24/MIC for MAR alone and in combination with MG was 192.8 and 381.9 h, respectively. In conclusion, MG has shown to increase the antimicrobial activity of MAR in vitro and ex vivo experiments without affecting the pharmacokinetics of MAR in rats.

Highlights

The broad-spectrum efficacy of fluoroquinolones against a wide range of pathogenic bacterial species has led to its extensive use globally with strict safety measures
In this study, we investigated the effect of methyl gallate (MG) on the PK of MAR, and its PK/ PD integration with MAR for the first time using in vitro, ex vivo and in vivo rat experiments
The in vitro experiments showed a synergistic activity of MAR and MG

Summary

Introduction

The broad-spectrum efficacy of fluoroquinolones against a wide range of pathogenic bacterial species has led to its extensive use globally with strict safety measures. A combination might affect the pharmacokinetics (PK) and pharmacodynamic (PD) of an antimicrobial agent [4,5]. Their effectiveness relies on the association between the PK and PD properties of the drugs [6]. The AUC/MIC ratio is much preferable to determine the efficacy and potency of marbofloxacin (MAR), which is a widely used antibiotic in veterinary medicine [12]

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Discussion

Conclusion