Pharmacokinetic-pharmacodynamic modeling of tylosin against Streptococcus suis in pigs

Abstract

Background: The aim of this study was to optimize the dosage regimen of tylosin against S.suis in Pigs using pharmacokinetic-pharmacodynamic (PK-PD) modeling. The antibacterial activity of tylosin against S.suis CVCC606 was investigated in Mueller Hinton (MH) broth and serum. The objectives of this investigation were to study the PD data of tylosin against S.suis CVCC606 and the PK data of tylosin in healthy and diseased model of pigs and formulate a rational dosage regimen for the treatment of pig streptococcosis.

Results: The minimum inhibitory concentrations (MIC) were 0.25 μg/mL, and the minimal bactericidal concentrations (MBC) were 1 μg/mL in MH broth and serum. The killing curve showed time-dependent activity and weak concentration-dependent antibacterial activity. A pig pneumoniae model of S. suis infection was built by inoculating subcutaneously with S. suis CVCC606. Tylosin was (10 mg/kg b.w) administered intramuscularly (IM) to the healthy and S.suis infected pigs, The pharmacokinetic properties, including area under the curve(AUC), peak concentration (C_max) and time to reach C_max (T_max), were determined in plasma using UV-HPLC method. The AUC, C_max and T_max in plasma of healthy and infected pigs were 10.80 ± 2.20 and 10.30 ± 3.46 μg.h/mL, 2.06 ± 0.43 and 2.37 ± 0.38 μg/mL, 1.95 ± 0.22 and 1.58 ± 0.49 h, respectively.

Conclusions: The in vivo PK and in vitro PD data were integrated to determine the surrogate marker of antibacterial activity, C_max/MIC, AUC/MIC and T_>MICwere 8.90, 43.21, 8.86 for healthy pigs, and 9.76, 41.18, 7.56 for infected pigs, respectively. Ex vivo AUC/MIC data were integrated with ex vivo bacterial count to calculate the values for bacteriostatic and bactericidal action, which were 10.67 h and 49.66 h for healthy pigs, 11.73 h and 43.03 h for pigs infected with S.suis. A dosage regimen of 5.32-19.50 mg/kg b.w. every 24 h should be sufficient for tylosin against S.suis.

Keywords: Dosage regimen; PK/PD modeling; Pig; Streptococcus suis; Tylosin.

Fig. 1

Killing curve of tylosin against S. suis in broth (a) and serum (b) measured at pre-determined time. The x-axis was the 0–24 h incubation time point; y-axis was the count numbers exposed to a series of concentrations of tylosin

Fig. 2

The ex vivo antibacterial curve of tylosin against CVCC606 in serum from healthy pigs (a) and diseased pigs (b). The ex vivo antibacterial activity in serum was determined in samples harvested at pre-determined times (0.17, 0.33, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 h after tylosin IM dosing)

Fig. 3

Semi-logarithmic plot of serum concentrations of tylosin after IM administration at a dose rate of 10 mg/kg b.w. (n = 8)

Fig. 4

Sigmoid Emax relationship for bacterial count vs. ex vivo AUC/MIC in serum from healthy pigs(a) and diseased pigs(b)