Epidemiological and PK/PD cutoff values determination and PK/PD-based dose assessment of gamithromycin against Haemophilus parasuis in piglets

Abstract

Background: Gamithromycin is a macrolide approved for the treatment of bovine and swine respiratory diseases. Our study aims to establish the clinical breakpoint and optimum dose regimen for gamithromycin against Haemophilus parasuis in piglets. Results: Gamithromycin was well absorbed and fully bioavailable (87.2-101%) after intramuscular and subcutaneous administrations. The MICs of gamithromycin for 192 clinical H. parasuis isolates ranged from 0.008 to 128 mg/L and the epidemiological cutoff (ECOFF) was calculated as 1.0 mg/L. A large potentiation effect of serum on in vitro susceptibility of gamithromycin was observed for H. parasuis, with broth/serum ratios of 8.93 for MICs and 4.46 for MBCs, respectively. The postantibiotic effects were 1.5 h (1 × MIC) and 2.4 h (4 × MIC), and the postantibiotic sub-MIC effects ranged from 2.7 to 4.3 h. Gamithromycin had rapid and concentration-dependent killing against H. parasuis, and the AUC 24h /MIC ratio correlated well with ex vivo efficacy (R 2 = 0.97). The AUC 24h /MIC targets in serum associated with bacteriostatic, bactericidal and eradication activities were 15.8, 30.3 and 41.2, respectively. The PK/PD-based population dose prediction indicated a probability of target attainment (PTA) for the current marketed dose (6 mg/kg) of 88.9% against H. parasuis. The calculated gamithromycin dose for a PTA ≥ 90% was 6.55 mg/kg. Based on Monte Carlo simulations, the PK/PD cutoff (CO PD) was determined to be 0.25 mg/L. Conclusion: The determined cutoffs and PK/PD-based dose prediction will be of great importance in gamithromycin resistance surveillance and serve as an important step in the establishment of optimum dose regimen and clinical breakpoints.

Determination of Susceptibility Breakpoint for Cefquinome against Streptococcus suis in Pigs

“…From the manuscript, the ECOFF, CO PD and CO CL were determined as 1 μg/mL, 0.06 μg/mL and 0.5 μg/mL, respectively. Compared with CO PD and ECOFF, CO PD is less than ECOFF which indicates the recommended dose regimen is a little bit too low to treat the wild-type population infected by S. suis [ 22 ]. From the clinical experiment, for the pathogens associated with high MIC values, the cure rate is less than 67% at a dose of 2 mg/kg, indicating the dose of cefquinome against S. suis needs to be optimized.…”

Pharmacokinetics and bioavailability of tildipirosin in rabbits following single‐dose intravenous and intramuscular administration

“…However, for newer macrolides such as azithromycin and clarithromycin, the plasma AUC/MIC ratio seems to strongly correlated with successful results (Lees, Concordet, Aliabadi, & Toutain, 2006). In addition, recent studies have demonstrated that the use of AUC/MIC as a PK/PD predictor of efficacy is feasible for previously approved veterinary macrolides such as tulathromycin and gamithromycin (Toutain et al, 2017;Zhou et al, 2020). At present, the minimum inhibitory concentration (MIC) of TD against P. multocida isolated from rabbits has not been determined.…”

Pharmacokinetics and pharmacodynamics of enrofloxacin treatment of Escherichia coli in a murine thigh infection modeling

“…The model can establish the relationship between drug concentration, antimicrobial effect, and time. Based on the scientific calculation, the model can provide the optimal dose regimen and dose interval [ 6 ]. Certain PK parameters (i.e., AUC and C max ) and PD parameters (i.e., minimal inhibitory concentration (MIC) and time-kill curve) are commonly considered to integrate the PK-PD model.…”