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 COPD 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 Cmax, AUC0-24h, AUC, Ke, t1/2ke, MRT, Tmax, and Clb, 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 Emax model, plasma AUC0-24h/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 (COPD) 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.

Comparative Pharmacokinetics and Preliminary Pharmacodynamics Evaluation of Piscidin 1 Against PRV and PEDV in Rats

“…Since the difficulty in measuring the antibiotic concentrations at the infected site, the PK data were mostly determined from the serum of the animals in the most previous reports. However, the drug concentrations in plasma are significantly different to target sites which have been reported in the previously published reports such as the marbofloxacin and cyadox concentrations in ileum and plasma (Lei et al, 2017a , b , d , 2018 ; Yan et al, 2017 ). Thus, as a kind of intestinal tract infection virus, it is essential to investigate the PK profiles with an appropriate route in ileum content for Piscidin 1 against PEDV.…”

“…PK evaluation plays a key role in new animal drugs development. Moreover, it could support a supplemental application for modification of administration routes, dosage forms, scheme, and manufacturing process which may make a significant effect for usage (Lei et al, 2017b , c , 2018 ; Zaid et al, 2017 ). As a newly developed antibiotic substitute, Piscidin 1 has barely been investigated for PK with different administrations and dosages.…”

Optimal Regimens and Cutoff Evaluation of Tildipirosin Against Pasteurella multocida

“…Based on the killing-time curve profiles of tildipirosin against PM04 ( Figure 3 ) in vitro and ex vivo , it was obvious that tildipirosin presented the concentration-dependent action and the parameter “AUC 24 h /MIC” was generally regarded as the threshold for the successful therapeutic outcome of macrolides ( Lei et al, 2017b , 2018b , c ). In the previously published studies ( Sang et al, 2016 ; Wang et al, 2016 ; Zhang et al, 2016 ; Lei et al, 2017a , 2018a ), the AUC 24 h /MIC > 30 h, and AUC 24 h /MIC > 125 h were used frequently for macrolides and fluoroquinolones against Gram-negative bacteria; these thresholds might be different for different drugs, against different kinds of bacteria due to the differences in the immune status of target animals and pathogens ( Toutain et al, 2002 ; Ahmad et al, 2015 ).…”

“…In the previously published studies ( Sang et al, 2016 ; Wang et al, 2016 ; Zhang et al, 2016 ; Lei et al, 2017a , 2018a ), the AUC 24 h /MIC > 30 h, and AUC 24 h /MIC > 125 h were used frequently for macrolides and fluoroquinolones against Gram-negative bacteria; these thresholds might be different for different drugs, against different kinds of bacteria due to the differences in the immune status of target animals and pathogens ( Toutain et al, 2002 ; Ahmad et al, 2015 ). Therefore, it is essential to obtain the exclusive PK/PD target for tildipirosin against PM ( Lei et al, 2018c ). In this study, the PK/PD target (AUC 24 h /MIC) for tildipirosin against PM was 29.13 h when it acted on the bactericidal activity ( E = -3) using PK/PD integration modeling ( Table 4 ).…”

Effects of anemoside B4 on pharmacokinetics of florfenicol and mRNA expression of CXR, MDR1, CYP3A37 and UGT1E in broilers

“…The reported minimum inhibitory concentrations (MICs) of florfenicol for bacteria isolated from poultry, fish, swine and calves are approximately 0.4 to 8 μg/ml [8,14,15,23,28], and the bacterium is reported sensitive to antibiotics at average concentration in blood 2-4 times their MIC [18]. Therefore, 1-16 µg/ml may be the effective blood concentration of florfenicol against various pathogenic bacteria in vivo.…”