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

Date Published: May 13, 2019

Publisher: Public Library of Science

Author(s): Betty San Martín, Marcela Fresno, Javiera Cornejo, Marcos Godoy, Rolando Ibarra, Roberto Vidal, Marcelo Araneda, Arturo Anadón, Lisette Lapierre, Yung-Fu Chang.


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.

Partial Text

Resistance to antimicrobials is a common problem in human and veterinary medicine, therefore the World Organization for Animal Health [1], jointly with FAO/WHO, points out that preventative measures should be carried out under the “One Health” approach; thus promoting the responsible and prudent use of antimicrobials in the human population as well as in terrestrial and aquatic animals.

It has been recently observed that the doses of florfenicol indicated in veterinary recommendations for the treatment of P. salmonis range from 20 to 40 mg/Kg l.w. [5], even though the Veterinary Medical Registry recommends a dose of 10 mg/kg l.w. for the different salmonid species. These doses have no scientific basis, considering that there is neither a clinical cut-off value nor an epidemiological cut-off point indicated by international organizations, such as EUCAST, VETCAST or CLSI, or national agencies responsible for monitoring bacterial resistance programs.




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