Abstract
Improper use of antibiotics results in poor treatment and severe bacterial resistance. In this study, ultrafiltration probes were successfully placed in the ileum of piglets with the aid of anesthetic. After the fluoroquinolone antimicrobial drug danofloxacin (DAN) was intramuscularly administered, blood and ileum ultrafiltrate were collected at different time points and then determined by High Performance Liquid Chromatography (HPLC). Pharmacokinetics (PK) parameters for plasma and ileum ultrafiltrate were calculated by WinNonlin software. The DAN concentration in ileum ultrafiltrate was much higher than that in plasma during the period 1.2–48 h. The DAN concentration in plasma reached its maximum at 1.10 ± 0.03 h, but reached at 6.00 ± 0.00 h in the ileum ultrafiltrate. The mean Cmax of the ileum is 13.59 times that of plasma. The elimination half-life (T1/2β) in the ileum ultrafiltrate (6.84 ± 1.49 h) was shorter than those in plasma (7.58 ± 3.20 h). The MIC, MBC and MPC of DAN in MH broth against Escherichia coli (O158) were 0.5 µg/mL, 0.5 µg/mL and 4 µg/mL, respectively. Both in vitro and ex vivo kill curves indicated that the killing mechanism of DAN against E. coli is concentration-dependent. The AUC/MPC ratio is 21.33 ± 2.14. Mean PK/PD index (AUC24h/MIC) for ileum ultrafiltrate that achieved bacteriostatic, bactericidal, and eradication were 99.85, 155.57, and 218.02 h, respectively. Three different dosages (1.49 mg/kg, 2.42 mg/kg, and 3.24 mg/kg) were calculated respectively based on AUC24h/MIC ratio above, which might provide a novel approach to the rational design of dosage schedules.
Highlights
Improper use of antibiotics results in poor treatment and severe bacterial resistance
Escherichia coli (E. coli), a prominent commensal bacterium in gastrointestinal tract of animals and humans, acts as an important human pathogen associated with intestinal diseases and a causative agent resulting in diarrhoea in a nimals[1,2]
The MIC is the lowest concentration of antimicrobial agent that inhibits growth of the organism in the microdilution wells as detected by the unaided eye; the minimal bactericidal concentration (MBC) is the minimal concentration of drug needed to kill most (≥ 99.9%) of the viable organisms after incubation for a fixed length of time; the mutant prevention concentration (MPC) is defined as the concentration preventing growth at a high (˃ 109 CFU/mL) inoculum using agar dilution m ethodology[4]
Summary
Improper use of antibiotics results in poor treatment and severe bacterial resistance. The DAN concentration in plasma reached its maximum at 1.10 ± 0.03 h, but reached at 6.00 ± 0.00 h in the ileum ultrafiltrate. The MIC, MBC and MPC of DAN in MH broth against Escherichia coli (O158) were 0.5 μg/mL, 0.5 μg/mL and 4 μg/mL, respectively. Three different dosages (1.49 mg/kg, 2.42 mg/kg, and 3.24 mg/kg) were calculated respectively based on AUC24h/MIC ratio above, which might provide a novel approach to the rational design of dosage schedules. In the prevention and control of drug resistance, the most important is to develop new antibiotics and to design effective dosage schedules. The design of rational dosage schedule is dependent on (i) the linkage of Pharmacokinetics (PK) data to ex vivo or in vivo pharmacodynamic (PD) data generated in animal models or in clinical trials and (ii) The killing mechanism of the drug against bacteria. The integrated PK-PD parameters the area under curve (AUC24h)/MIC and maximum concentration of drug (Cmax)/MIC are closely related to a successful treatment o utcome[3]
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