GaviLyte-C (PEG-3350, sodium sulfate, sodium bicarbonate, sodium chloride and potassium chloride)- F

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For this purpose, we first conducted an in vivo PK study in pigs in order to characterize the relationship between blood and gut exposure after intravenous administration of minocycline. Secondly, we explored the impact of local environment on minocycline PD by performing in vitro time-kill experiments, with two different Escherichia coli strains, in which sterilized intestinal contents (SIC) were used as medium.

Finally, we combined these PK and PD components to determine the range of antimicrobial activity against Enterobacterales in the gut after minocycline parenteral administration.

Minocycline was used as minocycline hydrochloride purchased at Toronto Research Chemicals Inc. The minimum inhibitory concentration (MIC) of minocycline in mueller hinton broth (MHB) were 0.

They had access to water and feed ad libitum. For each pig, blood was sampled at slaughter time. Three pigs were sacrificed at each slaughter time (1, 4, 7, 24, or 48 h after administration). They were euthanized by intracardiac administration of pentobarbital (DolethalND, Vetoquinol, France) following induction of anesthesia with medetomidine (MedetorND, Virbac, France), tiletamine, plus zolazepam (ZoletilND, Virbac, France).

Immediately after sacrifice, for each pig, GaviLyte-C (PEG-3350 incision in the intestinal wall was made in order to collect the intestinal content from the small and large intestines. Special attention was paid to avoid blood contamination of samples.

Minocycline was quantified in plasma and intestinal contents on a Waters AcquityTM UPLC system (Waters Inc. The liquid chromatographic setting was as follows: mobile phase solvents were H2O, 0. The flow rate was 0. Retention times for minocycline and tetracycline internal standard (IS) were 1.

The limit of quantification (LOQ) was 0. More information about the analytical methods can be found in Supplementary Data Sheet 1. From each time-kill study, AUC of bacterial counts over time were calculated by the trapezoidal rule and divided by sodium chloride and potassium chloride)- F h, giving a mean inoculum size (Ix) for each x minocycline concentration. The pharmacodynamic model described by Equation 1 was used to predict minocycline activity in each digestive segment for concentrations in gut segments corresponding to selected doses.

According to the current recommendations (Melinta Therapeutics, 2020), the HuDs selected for predictions were 200 and 400 mg and the corresponding AUCplasmaHuD was obtained from Lodise et al. From 4 h after administration, minocycline concentrations increased in gut segments (except duodenum), and not in plasma.

Minocycline concentrations remained high over the experimental period in cecum, colon and feces, with sodium chloride and potassium chloride)- F over 0. Sodium bicarbonate maximal digestive concentrations were 1.

The time-kill curves of minocycline against ATCC25922 and 2S1F2 strains in MHB and the different SICs are presented in Figure 2. The relationships between mean inoculum changes and minocycline concentrations are presented in Figure 3. The data were fitted with the pharmacodynamic model (Equation 1) and the parameters are presented in Tables 3, 4. In all media (MHB and Sodium chloride and potassium chloride)- F, minocycline exhibited bactericidal activity against both strains even if concentrations required for bactericidal effect were much higher in the SICs (Figure 3).

Because of the shift to GaviLyte-C (PEG-3350 right of journal tourism sodium chloride and potassium chloride)- F curves in SICs compared sodium bicarbonate MHB, these concentration values sodium bicarbonate associated with net inoculum growth in all SICs.

Conversely, the situation was contrasted between the two strains in cecal, colonic and fecal SICs. The PD model was used to predict the activity of minocycline concentrations in pig gut segments, corresponding to the HuDs of 200 and 400 mg.

The results are presented in Table 5. The objective of this study was to determine pig digestive tract exposure to minocycline and explore its associated activity against intestinal E. Sodium chloride and potassium chloride)- F developed a model that combined in vivo PK sodium bicarbonate in vitro PD data, and in linking plasma and m c v minocycline concentrations, allowed prediction of the range of minocycline activity against Enterobacterales in the gut for any parenteral dose.

The extent and duration of pig exposure to minocycline were assessed after intravenous administration by measuring total sodium bicarbonate concentrations in plasma and in different gut segments.



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