Optimization of florfenicol dose against Piscirickettsia salmonis in Salmo salar through PK/PD studies

PLoS One. 2019 May 13;14(5):e0215174. doi: 10.1371/journal.pone.0215174. eCollection 2019.

Abstract

Salmonid Rickettsial Septicemia (SRS) is the disease of greatest economic importance in the Chilean salmon farming industry, causing high mortality in fish during the final stage of their productive cycle at sea. Since current, commercially available vaccines have not demonstrated the expected efficacy levels, antimicrobials, most commonly florfenicol, are still the main resource for the treatment and control of this pathogen. The aim of this study was to determine the most appropriate single dose of florfenicol, administered through medicated feed, for the treatment of Piscirickettsia salmonis (P. salmonis), using pharmacokinetic/pharmacodynamic (PK/PD) models. Previously, Minimum Inhibitory Concentrations (MICs) of florfenicol were determined for 87 P. salmonis isolates in order to define the epidemiological cut-off point (COWT). The most commonly observed MIC was 0.125 μg mL-1 (83.7%). The COWT value was 0.25 μg mL-1 with a standard deviation of 0.47 log2 μg mL-1 and 0.36 log2 μg mL-1, for Normalized resistance interpretation (NRI) method and ECOFFinder method, respectively. A MIC of 1 μg mL-1 was considered the pharmacodynamic value (PD) to define PK/PD indices. Three doses of florfenicol were evaluated in fish farmed under controlled conditions. For each dose, 150 fish were used and blood plasma samples were collected at different time points (0-48 hours). PK parameters were obtained from curves representing plasma concentrations as a function of time. The results of Monte Carlo simulation indicate that at a dose of 20 mg/Kg l.w. of florfenicol, administered orally as medicated feed, there is 100% probability (PTA) of achieving the desired efficacy (AUC0-24h/MIC>125). According to these results, we suggest that at the indicated dose, the PK/PD cut-off point for florfenicol versus P. salmonis could be 2 μg mL-1 (PTA = 99%). In order to assess the indicated dose in Atlantic salmon, fish were inoculated with P. salmonis LF-89 strain and then treated with the optimized dose of florfenicol, 20 mg/Kg bw for 15 days.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Bacterial Agents / pharmacokinetics
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use*
  • Area Under Curve
  • Drug Resistance, Bacterial
  • Fish Diseases / drug therapy*
  • Fish Diseases / microbiology
  • Fisheries
  • Half-Life
  • Microbial Sensitivity Tests
  • Monte Carlo Method
  • Piscirickettsia / drug effects
  • Piscirickettsia / isolation & purification
  • Piscirickettsiaceae Infections / drug therapy*
  • Piscirickettsiaceae Infections / microbiology
  • ROC Curve
  • Salmo salar
  • Thiamphenicol / analogs & derivatives*
  • Thiamphenicol / pharmacokinetics
  • Thiamphenicol / pharmacology
  • Thiamphenicol / therapeutic use

Substances

  • Anti-Bacterial Agents
  • florfenicol
  • Thiamphenicol

Grants and funding

This research received financial support from the "Program for Health Management Aquaculture" which has public and private financing, by the Ministry of Economy, Development and Tourism and the Association of the Chilean Salmon Industry AG (SalmonChile), implemented by the National Fisheries and Aquaculture (SERNAPESCA). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The author Marcelo Araneda did only the Montecarlo Analysis for the determination of the optimal dose. The commercial company Benchmark Genetics Chile provided support in the form of a salary for author Marcelo Araneda but played no role in the study design, data collection and analysis, decision to publish and preparation of the manuscript. The specific roles of all authors are articulated in the ‘author contributions’ section.