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

PLoS One. 2020 Jun 4;15(6):e0234211. doi: 10.1371/journal.pone.0234211. eCollection 2020.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drug Interactions
  • Fluoroquinolones / pharmacokinetics*
  • Fluoroquinolones / pharmacology*
  • Gallic Acid / analogs & derivatives*
  • Gallic Acid / pharmacokinetics
  • Gallic Acid / pharmacology
  • Male
  • Microbial Sensitivity Tests
  • Rats
  • Rats, Sprague-Dawley
  • Salmonella typhimurium / drug effects*

Substances

  • Fluoroquinolones
  • methyl gallate
  • Gallic Acid
  • marbofloxacin

Grants and funding

SCP received funds from National Research Foundation of Korea (NRF) funded by the Ministry of Education under Grant [No. 2016R1A2B4013507 and 2019R1A2C2006277]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.