Abstract
Salmonella typhimurium is a highly transmissible pathogen in rabbits that causes significant losses. Danofloxacin shows excellent efficacy against S. typhimurium infections. However, there are few reports of the pharmacokinetic/pharmacodynamic (PK/PD) modeling of danofloxacin against this pathogen. The aim of this study was to evaluate the in vivo PK/PD relationship of danofloxacin in rabbits infected with S. typhimurium. We used the reduction of bacterial burden in the blood, liver, spleen, and lung as the target PD endpoints, and determined the PK/PD indexes that best correlated with the efficacy and its corresponding magnitude. Danofloxacin was administrated orally to experimentally S. typhimurium-infected rabbits once daily for three successive days. The concentrations of danofloxacin in the serum and the bacterial burden in the blood, liver, spleen, and lung were determined. The PK/PD relationships of danofloxacin against S. typhimurium were evaluated using a Sigmoid Emax model. The results showed that the area under the concentration-time curve from 0 to 24 h/minimum inhibitory concentration (AUC24 h/MIC) ratio correlated well with the in vivo antibacterial effectiveness in different organs, with an r2 of 0.8971, 0.9186, 0.9581, and 0.8708 in the blood, liver, spleen, and lung, respectively. The AUC24 h/MIC ratios for the bactericidal effect (3 × Log10 colony forming units/mL reductions) were 121.30, 354.28, 216.64, and 228.66 in the blood, liver, spleen, and lung, respectively, indicating that the in vivo effectiveness of danofloxacin against S. typhimurium using bacterial reduction in different organs as PD endpoints was not identical. This study illustrated that the selection of the target organ for bacterial reduction determination had little effect on best PK/PD parameter determination, but is critical for parameter magnitude calculation in antimicrobial PK/PD modeling, and furthermore, has an impact on the rational dosage optimization process.
Highlights
MATERIALS AND METHODSSalmonella typhimurium is associated with 1 million human deaths annually (Preethi et al, 2017)
Maximal killing was observed at 2× the minimum inhibitory concentration (MIC) of danofloxacin (Figure 1)
The MIC and minimum bactericidal concentration (MBC) for danofloxacin against S. typhimurium in rabbit serum were twice those in artificial broth, which could be explained by the protein binding ratio of danofloxacin in serum (Qu et al, 2015) and the differences of matrix
Summary
Salmonella typhimurium is associated with 1 million human deaths annually (Preethi et al, 2017). It is the most important serotype of Salmonella that is transmitted from animals to humans, causing a marked threat to public health (Preethi et al, 2017). Danofloxacin, the third generation of fluoroquinolones, is applied solely for veterinary use and displays excellent antimicrobial activity against both gram-negative and gram-positive bacteria (Shojaee Aliabadi and Lees, 2003). The ex vivo PK/PD model of danofloxacin has been studied for several pathogens such as Escherichia coli, Mannheimia haemolytica, and Staphylococcus aureus in calves, sheep, goats, camels, chickens, and turkeys (Aliabadi et al, 2003a,b; Shojaee Aliabadi and Lees, 2003; Haritova et al, 2006; SerranoRodriguez et al, 2017). Neither ex vivo nor in vivo PK/PD modeling of danofloxacin against S. typhimurium has been established
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