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Integrated pharmacokinetics/pharmacodynamics parameters-based dosing guidelines of enrofloxacin in grass carp Ctenopharyngodon idella to minimize selection of drug resistance.

Xu L, Wang H, Yang X, Lu L - BMC Vet. Res. (2013)

Bottom Line: The pathogenic A. hydrophila strain (AH10) in grass carp was identified and found to be sensitive to enrofloxacin.Dosing of 30 μg/g resulted in serum maximum concentration (Cmax) of 7.151 μg/mL, and concentration in serum was above MPC till 24 h post the single dose.Based on integrated PK/PD parameters (AUC/MIC, Cmax/MIC, and T>MPC), the results of this study established a principle, for the first time, on drawing accurate dosing guideline for pharmacotherapy against A. hydrophila strain (AH10) for prevention of drug-resistant mutants.

View Article: PubMed Central - HTML - PubMed

Affiliation: Key Laboratory of Freshwater Fishery Germplasm Resources, Ministry of Agriculture, Shanghai Ocean University, Shanghai 201306, People's Republic of China.

ABSTRACT

Background: Antibiotic resistance has become a serious global problem and is steadily increasing worldwide in almost every bacterial species treated with antibiotics. In aquaculture, the therapeutic options for the treatment of A. hydrophila infection were only limited to several antibiotics, which contributed for the fast-speed emergence of drug tolerance. Accordingly, the aim of this study was to establish a medication regimen to prevent drug resistant bacteria. To determine a rational therapeutic guideline, integrated pharmacodynamics and pharmacokinetics parameters were based to predict dose and dosage interval of enrofloxacin in grass carp Ctenopharyngodon idella infected by a field-isolated A. hydrophila strain.

Results: The pathogenic A. hydrophila strain (AH10) in grass carp was identified and found to be sensitive to enrofloxacin. The mutant selection window (MSW) of enrofloxacin on isolate AH10 was determined to be 0.5-3 μg/mL based on the mutant prevention concentration (MPC) and minimum inhibitory concentration (MIC) value. By using high-performance liquid chromatography (HPLC) system, the Pharmacokinetic (PK) parameters of enrofloxacin and its metabolite ciprofloxacin in grass carp were monitored after a single oral gavage of 10, 20, 30 μg enrofloxacin per g body weight. Dosing of 30 μg/g resulted in serum maximum concentration (Cmax) of 7.151 μg/mL, and concentration in serum was above MPC till 24 h post the single dose. Once-daily dosing of 30 μg/g was determined to be the rational choice for controlling AH10 infection and preventing mutant selection in grass carp. Data of mean residue time (MRT) and body clearance (CLz) indicated that both enrofloxacin and its metabolite ciprofloxacin present similar eliminating rate and pattern in serum, muscle and liver. A withdraw time of more than 32 d was suggested based on the drug eliminating rate and pharmacokinetic model described by a polyexponential equation.

Conclusions: Based on integrated PK/PD parameters (AUC/MIC, Cmax/MIC, and T>MPC), the results of this study established a principle, for the first time, on drawing accurate dosing guideline for pharmacotherapy against A. hydrophila strain (AH10) for prevention of drug-resistant mutants. Our approach in combining PK data with PD parameters (including MPC and MSW) was the new effort in aquaculture to face the challenge of drug resistance by drawing a specific dosage guideline of antibiotics.

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Replication of isolate AH10 after 1 h exposure to enrofloxacin at indicated concentration. Control groups (C1 and C2) referred to bacterial without drug treatment. (n = 3,The mean ± SD). After 1 h exposure to enrofloxacin with a concentration as indicated in the figure, the concentration of isolate AH10 was determined to be 8.71 × 103 CFU/mL (C1), 8.51 × 103 CFU/mL (C2), 8.71 × 102 CFU/mL (2 MIC), 5.50 × 102 CFU/mL (4 MIC) and 3.63 × 102 CFU/mL (8MIC), respectively.
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Figure 1: Replication of isolate AH10 after 1 h exposure to enrofloxacin at indicated concentration. Control groups (C1 and C2) referred to bacterial without drug treatment. (n = 3,The mean ± SD). After 1 h exposure to enrofloxacin with a concentration as indicated in the figure, the concentration of isolate AH10 was determined to be 8.71 × 103 CFU/mL (C1), 8.51 × 103 CFU/mL (C2), 8.71 × 102 CFU/mL (2 MIC), 5.50 × 102 CFU/mL (4 MIC) and 3.63 × 102 CFU/mL (8MIC), respectively.

Mentions: The post antibiotic effect (PAE) may contribute to the in vivo efficacy of enrofloxacin [16]. It was well known that enrofloxacin prevented the synthesis of bacterial DNA by gyrase, the PAE might represent the time for it to dissociate from the receptor binding sites and to diffuse out of the bacterium. It was generally believed that PAE was concentration dependent and directly related to the exposure time [17]. In this study, PAE of enrofloxacin was evaluated by exposure of isolate AH10 to it at 2, 4, and 8 times MIC for 1 h (Figure. 1). The PAE of enrofloxacin was 1.44 ± 0.36h, 1.57 ± 0.09h, 1.83 ± 0.21h, respectively. The data predicted that the dosing interval deduced from the time-concentration PK curve could be 1 – 2 h longer due to the existence of PAE. Although the in vivo PAE of enrofloxacin was still awaiting further investigation, our data at least suggested that the T>MPC seemed to be the dominant factor in drawing dose intervals since PAE of enrofloxacin was comparably short.


Integrated pharmacokinetics/pharmacodynamics parameters-based dosing guidelines of enrofloxacin in grass carp Ctenopharyngodon idella to minimize selection of drug resistance.

Xu L, Wang H, Yang X, Lu L - BMC Vet. Res. (2013)

Replication of isolate AH10 after 1 h exposure to enrofloxacin at indicated concentration. Control groups (C1 and C2) referred to bacterial without drug treatment. (n = 3,The mean ± SD). After 1 h exposure to enrofloxacin with a concentration as indicated in the figure, the concentration of isolate AH10 was determined to be 8.71 × 103 CFU/mL (C1), 8.51 × 103 CFU/mL (C2), 8.71 × 102 CFU/mL (2 MIC), 5.50 × 102 CFU/mL (4 MIC) and 3.63 × 102 CFU/mL (8MIC), respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3717066&req=5

Figure 1: Replication of isolate AH10 after 1 h exposure to enrofloxacin at indicated concentration. Control groups (C1 and C2) referred to bacterial without drug treatment. (n = 3,The mean ± SD). After 1 h exposure to enrofloxacin with a concentration as indicated in the figure, the concentration of isolate AH10 was determined to be 8.71 × 103 CFU/mL (C1), 8.51 × 103 CFU/mL (C2), 8.71 × 102 CFU/mL (2 MIC), 5.50 × 102 CFU/mL (4 MIC) and 3.63 × 102 CFU/mL (8MIC), respectively.
Mentions: The post antibiotic effect (PAE) may contribute to the in vivo efficacy of enrofloxacin [16]. It was well known that enrofloxacin prevented the synthesis of bacterial DNA by gyrase, the PAE might represent the time for it to dissociate from the receptor binding sites and to diffuse out of the bacterium. It was generally believed that PAE was concentration dependent and directly related to the exposure time [17]. In this study, PAE of enrofloxacin was evaluated by exposure of isolate AH10 to it at 2, 4, and 8 times MIC for 1 h (Figure. 1). The PAE of enrofloxacin was 1.44 ± 0.36h, 1.57 ± 0.09h, 1.83 ± 0.21h, respectively. The data predicted that the dosing interval deduced from the time-concentration PK curve could be 1 – 2 h longer due to the existence of PAE. Although the in vivo PAE of enrofloxacin was still awaiting further investigation, our data at least suggested that the T>MPC seemed to be the dominant factor in drawing dose intervals since PAE of enrofloxacin was comparably short.

Bottom Line: The pathogenic A. hydrophila strain (AH10) in grass carp was identified and found to be sensitive to enrofloxacin.Dosing of 30 μg/g resulted in serum maximum concentration (Cmax) of 7.151 μg/mL, and concentration in serum was above MPC till 24 h post the single dose.Based on integrated PK/PD parameters (AUC/MIC, Cmax/MIC, and T>MPC), the results of this study established a principle, for the first time, on drawing accurate dosing guideline for pharmacotherapy against A. hydrophila strain (AH10) for prevention of drug-resistant mutants.

View Article: PubMed Central - HTML - PubMed

Affiliation: Key Laboratory of Freshwater Fishery Germplasm Resources, Ministry of Agriculture, Shanghai Ocean University, Shanghai 201306, People's Republic of China.

ABSTRACT

Background: Antibiotic resistance has become a serious global problem and is steadily increasing worldwide in almost every bacterial species treated with antibiotics. In aquaculture, the therapeutic options for the treatment of A. hydrophila infection were only limited to several antibiotics, which contributed for the fast-speed emergence of drug tolerance. Accordingly, the aim of this study was to establish a medication regimen to prevent drug resistant bacteria. To determine a rational therapeutic guideline, integrated pharmacodynamics and pharmacokinetics parameters were based to predict dose and dosage interval of enrofloxacin in grass carp Ctenopharyngodon idella infected by a field-isolated A. hydrophila strain.

Results: The pathogenic A. hydrophila strain (AH10) in grass carp was identified and found to be sensitive to enrofloxacin. The mutant selection window (MSW) of enrofloxacin on isolate AH10 was determined to be 0.5-3 μg/mL based on the mutant prevention concentration (MPC) and minimum inhibitory concentration (MIC) value. By using high-performance liquid chromatography (HPLC) system, the Pharmacokinetic (PK) parameters of enrofloxacin and its metabolite ciprofloxacin in grass carp were monitored after a single oral gavage of 10, 20, 30 μg enrofloxacin per g body weight. Dosing of 30 μg/g resulted in serum maximum concentration (Cmax) of 7.151 μg/mL, and concentration in serum was above MPC till 24 h post the single dose. Once-daily dosing of 30 μg/g was determined to be the rational choice for controlling AH10 infection and preventing mutant selection in grass carp. Data of mean residue time (MRT) and body clearance (CLz) indicated that both enrofloxacin and its metabolite ciprofloxacin present similar eliminating rate and pattern in serum, muscle and liver. A withdraw time of more than 32 d was suggested based on the drug eliminating rate and pharmacokinetic model described by a polyexponential equation.

Conclusions: Based on integrated PK/PD parameters (AUC/MIC, Cmax/MIC, and T>MPC), the results of this study established a principle, for the first time, on drawing accurate dosing guideline for pharmacotherapy against A. hydrophila strain (AH10) for prevention of drug-resistant mutants. Our approach in combining PK data with PD parameters (including MPC and MSW) was the new effort in aquaculture to face the challenge of drug resistance by drawing a specific dosage guideline of antibiotics.

Show MeSH
Related in: MedlinePlus