PK-PD Integration Modeling and Cutoff Value of Florfenicol against Streptococcus suis in Pigs

Abstract

The aims of the present study were to establish optimal doses and provide an alternate CO_PD for florfenicol against Streptococcus suis based on pharmacokinetic-pharmacodynamic integration modeling. The recommended dose (30 mg/kg b.w.) were administered in healthy pigs through intramuscular and intravenous routes for pharmacokinetic studies. The main pharmacokinetic parameters of C_max, AUC_0-24h, AUC, Ke, t_1/2ke, MRT, T_max, and Cl_b, were estimated as 4.44 μg/ml, 88.85 μg⋅h/ml, 158.56 μg⋅h/ml, 0.048 h^-1, 14.46 h, 26.11 h, 4 h and 0.185 L/h⋅kg, respectively. The bioavailability of florfenicol was calculated to be 99.14% after I.M administration. A total of 124 Streptococcus suis from most cities of China were isolated to determine the minimum inhibitory concentration (MIC) of florfenicol. The MIC₅₀ and MIC₉₀ were calculated as 1 and 2 μg/ml. A serotype 2 Streptococcus suis (WH-2), with MIC value similar to MIC₉₀, was selected as a representative for an in vitro and ex vivo pharmacodynamics study. The MIC values of WH-2 in TSB and plasma were 2 μg/ml, and the MBC/MIC ratios were 2 in TSB and plasma. The MPC was detected to be 3.2 μg/ml. According to inhibitory sigmoid E_max model, plasma AUC_0-24h/MIC values of florfenicol versus Streptococcus suis were 37.89, 44.02, and 46.42 h for the bactericidal, bacteriostatic, and elimination activity, respectively. Monte Carlo simulations the optimal doses for bactericidal, bacteriostatic, and elimination effects were calculated as 16.5, 19.17, and 20.14 mg/kg b.w. for 50% target attainment rates (TAR), and 21.55, 25.02, and 26.85 mg/kg b.w. for 90% TAR, respectively. The PK-PD cutoff value (CO_PD) analyzed from MCS for florfenicol against Streptococcus suis was 1 μg/ml which could provide a sensitivity cutoff value. These results contributed an optimized alternative to clinical veterinary medicine and showed that the dose of 25.02 mg/kg florfenicol for 24 h could have a bactericidal action against Streptococcus suis after I.M administration. However, it should be validated in clinical practice in the future investigations.

Keywords: Streptococcus suis; florfenicol; optimal dosages; pharmacodynamic; pharmacokinetic.

FIGURE 1

Minimum inhibitory concentration distribution of FF against SS (n = 124).

FIGURE 2

The growth-time curves of WH-2 in TSB (in vitro) and plasma (in vivo).

FIGURE 3

The killing-time curves of FF against WH-2 in TSB and plasma. (A) Represented the curve in TSB, (B) represented the curve in plasma.

FIGURE 4

The HPLC method for FF quantification in plasma. (A) Blank sample, (B) plasma sample at the LLOQ of 0.05 μg/ml, (C) plasma sample at the 2 h after I.M administration, (D) plasma sample at the 2 h after I.V administration, 1, the retention time of 5.5 min.

FIGURE 5

The curves of FF concentrations-time in plasma after I.V and I.M administrations (30 mg/kg) at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 h (n = 8). (A) The curve after I.V administration, (B) the curve after I.M administration.

FIGURE 6

Plots of ex vivo AUC/MIC ratios versus the amount difference of FF against SS within 24 (n = 8).

FIGURE 7

The predicted doses of FF curing SS for 50 and 90% TAR. (A₁) Presented the predicted population dose for bacteriostatic at 50% target, (A₂) presented the predicted population dose for bacteriostatic at 90% target, (B₁) presented the predicted population dose for bactericidal at 50% target, (B₂) presented the predicted population dose for bactericidal at 90% target, (C₁) presented the predicted population dose for elimination at 50% target, (C₂) presented the predicted population dose for elimination at 90% target.