Pharmacokinetic-Pharmacodynamic modeling of enrofloxacin against Escherichia coli in broilers

The purpose of the present study was to establish a pharmacokinetic/pharmacodynamic (PK/PD) modeling approach for the dosage schedule design and decreasing the emergence of drug-resistant bacteria. The minimal inhibitory concentration (MIC) of 929 E. coli isolates from broilers to enrofloxacin and ciprofloxacin were determined following CLSI guidance. The MIC50 was calculated as the populational PD parameter for enrofloxacin against E. coli in broilers. The 101 E. coli strains with MIC closest to the MIC50 (0.05µg/mL) were submitted for serotype identification. The 13 E. coli strains with O and K serotype were further utilitzed for determining pathogencity in mice. Of all the strains tested, the E. coli designated strain Anhui 112 was selected for establishing the disease model and PK/PD study. The pharmacokinetics (PKs) of enrofloxacin after oral administration at the dose of 10mg/kg body weights (BW) in healthy and infected broilers was evaluated with high-performance liquid chromatography (HPLC) method. For intestinal contents after oral administration, the peak concentration (Cmax), the time when the maximum concentration reached (Tmax), and the area under the concentration-time curve (AUC) were 21.69~31.69μg/mL, 1.13~1.23h, and 228.97~444.86μg.hr/mL, respectively. The MIC and minimal bactericidal concentration (MBC) of enrofloxacin against E. coli (Anhui 112) in Mueller-Hinton (MH) broth and intestinal contents were determined to be similar, 0.25μg/mL and 0.5μg/mL respectively. In this study, the sum of concentrations of enrofloxacin and its metabolite (ciprofloxacin) was used for the PK/PD integration and modeling. The ex vivo growth inhibition data were fitted to the sigmoid Emax (Hill) equation to provide values for intestinal contents of 24h area under concentration–time curve/MIC ratios (AUC0~24h/MIC) producing, bacteriostasis (624.94h), bactericidal activity (1065.93h) and bacterial eradication (1343.81h). PK/PD modeling was established to simulate the efficacy of enrofloxacin for different dosage regimens. By model validation, the protection rate was 83.3%, demonstrating that the dosage regimen of 11.9mg/kg BW every 24h during 3 days provided great therapeutic significance. In summary, the purpose of the present study was to first design a dosage regimen for the treatment E. coli in broilers by enrofloxacin using PK/PD integrate model and confirm that this dosage regimen presents less risk for emergence of floroquinolone

Pharmacokinetic and pharmacodynamic integration and modeling of enrofloxacin in swine for Escherichia coli

The aim of this study was tooptimize the dose regimens of enrofloxacin to reduce the development of fluoroquinolone resistance in Escherichia coli (E.coli) using pharmacokinetic/pharmacodynamic (PK/PD) modeling approach. The single dose (2.5 mg/kg body weight) of enrofloxacin was administered intramuscularly (IM) to the healthy pigs. Using cannulation, the pharmacokinetic properties, including peak concentration (Cmax), time to reach Cmax (Tmax) and area under the curve (AUC), were determined in plasma and ileum content. The Cmax, Tmax, and AUC in the plasma were 1.09 ± 0.11 μg/mL, 1.27 ± 0.35 h and 12.70 ± 2.72 µg•h/mL, respectively. While in ileum content, the Cmax, Tmax and AUC were 7.07 ± 0.26 μg/mL, 5.54 ± 0.42 h and 136.18 ± 12.50 µg•h/mL, respectively. Based on the minimum inhibitory concentration (MIC) data of 918 E.coli isolates, an E.coli O101/K99 strain (enrofloxacin MIC = 0.25 μg/mL) was selected for pharmacodynamic studies. The in vitro minimum bactericidal concentration (MBC), mutant prevention concentration (MPC) and ex vivo time-killing curves for enrofloxacin in ileum content were established against the selected E.coli O101/K99 strain. Integrating the in vivo pharmacokinetic data and ex vivo pharmacodynamic data, a sigmoid Emax (Hill) equation was established to provide values for ileum content of AUC24h/MIC producing, bactericidal activity (52.65 h) and virtual eradication of bacteria (78.06 h). A dosage regimen of 1.96 mg/kg every 12 h for 3 days should be sufficient in the treatment of E.coli

The Epidemiologic and Pharmacodynamic Cutoff Values of Tilmicosin against Haemophilus parasuis

The aim of this study was to establish antimicrobial susceptibility breakpoints for tilmicosin against Haemophilus parasuis, which is an important pathogen of respiratory tract infections. The minimum inhibitory concentrations (MICs) of 103 H. parasuis isolates were determined by the agar dilution method. The wild-type (WT) distribution and epidemiologic cutoff value (ECV) were evaluated by statistical analysis. The new bronchoaveolar lavage (BAL) was used to establish intrapulmonary pharmacokinetic (PK) model in swine. The pharmacokinetic (PK) parameters of tilmicosin, both in pulmonary epithelial lining fluid (PELF) and in plasma, were determined using high performance liquid chromatography (HPLC) method and WinNonlin software. The pharmacodynamic cutoff (COPD) was calculated using Monte Carlo simulation. Our results showed that 100% of WT isolates were covered when the ECV was set at 16μg/mL. The tilmicosin had concentration-dependent activity against H. parasuis. The PK data indicated that tilmicosin concentrations in PELF was rapidly increased to high levels at 4 hours and kept stable until 48 hours after drug administration, while the tilmicosin concentration in plasma reached maximum levels at 4 hours and continued to decrease during 4-72 hours. Using Monte Carlo simulation, COPD was defined as 1 μg/mL. Conclusively, the ECV and COPD of tilmicosin against H. parasuis were established for the first time based on the MIC distribution and PK-PD analysis in the target tissue, respectively. These values are of great importance for detection of tilmicosin-resistant H. parasuis and for effective treatment of clinical intrapulmonary infection caused by H. parasuis

Antimicrobial Drugs in Fighting against Antimicrobial Resistance

The outbreak of antimicrobial resistance, together with the lack of newly developed antimicrobial drugs, represents an alarming signal for both human and animal healthcare worldwide. Selection of rational dosage regimens for traditional antimicrobial drugs based on pharmacokinetic/pharmacodynamic principles as well as development of novel antimicrobials targeting new bacterial targets or resistance mechanisms are key approaches in tackling AMR. In addition to the cellular level resistance (i.e., mutation and horizontal gene transfer of resistance determinants), the community level resistance (i.e., bilofilms and persisters) is also an issue causing antimicrobial therapy difficulties. Therefore, anti-resistance and antibiofilm strategies have currently become research hotspot to combat antimicrobial resistance. Although metallic nanoparticles can both kill bacteria and inhibit biofilm formation, the toxicity is still a big challenge for their clinical applications. In conclusion, rational use of the existing antimicrobials and combinational use of new strategies fighting against antimicrobial resistance are powerful warranties to preserve potent antimicrobial drugs for both humans and animals

Benefits and Risks of Antimicrobial Use in Food-Producing animals

Benefits and risks of antimicrobial drugs, used in food-producing animals, continue to be complex and controversial issues. This review comprehensively presents the benefits of antimicrobials drugs regarding control of animal diseases, protection of public health, enhancement of animal production, improvement of environment, and effects of the drugs on biogas production and public health associated with antimicrobial resistance. The positive and negative impact, due to ban issue of antimicrobial agents used in food-producing animals, is also included in discussion. As a double-edged sword, use of these drugs in food-animals persists as a great challenge