Using In Vitro Dynamic Models To Evaluate Fluoroquinolone Activity against Emergence of Resistant Salmonella enterica Serovar Typhimurium

The objectives of this study were to determine pharmacokinetic/pharmacodynamic (PK/PD) indices of fluoroquinolones that minimize the emergence of resistant Salmonella enterica serovar Typhimurium (S. Typhimurium) using in vitro dynamic models and to establish mechanisms of resistance. Three fluoroquinolones, difloxacin (DIF), enrofloxacin (ENR), and marbofloxacin (MAR), at five dose levels and 3 days of treatment were simulated. Bacterial killing-regrowth kinetics and emergence of resistant bacteria after antibacterial drug exposure were quantified. PK/PD indices associated with different levels of antibacterial activity were computed. Mechanisms of fluoroquinolone resistance were determined by analyzing target mutations in the quinolone resistance-determining regions (QRDRs) and by analyzing overexpression of efflux pumps. Maximum losses in susceptibility of fluoroquinolone-exposed S. Typhimurium occurred at a simulated AUC/MIC ratio (area under the concentration-time curve over 24 h in the steady state divided by the MIC) of 47 to 71. Target mutations in gyrA (S83F) and overexpression of acrAB-tolC contributed to decreased susceptibility in fluoroquinolone-exposed S. Typhimurium. The current data suggest AUC/MIC (AUC/mutant prevention concentration [MPC])-dependent selection of resistant mutants of S. Typhimurium, with AUC/MPC ratios of 69 (DIF), 62 (ENR), and 39 (MAR) being protective against selection of resistant mutants. These values could not be achieved in veterinary clinical areas under the current recommended therapeutic doses of the fluoroquinolones, suggesting the need to reassess the current dosing regimen to include both clinical efficacy and minimization of emergence of resistant bacteria

Optimizing tylosin dosage for co-infection of Actinobacillus pleuropneumoniae and Pasteurella multocida in pigs using pharmacokinetic/pharmacodynamic modeling

Formulating a therapeutic strategy that can effectively combat concurrent infections of Actinobacillus pleuropneumoniae (A. pleuropneumoniae) and Pasteurella multocida (P. multocida) can be challenging. This study aimed to 1) establish minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), time kill curve, and post-antibiotic effect (PAE) of tylosin against A. pleuropneumoniae and P. multocida pig isolates and employ the MIC data for the development of epidemiological cutoff (ECOFF) values; 2) estimate the pharmacokinetics (PKs) of tylosin following its intramuscular (IM) administration (20 mg/kg) in healthy and infected pigs; and 3) establish a PK–pharmacodynamic (PD) integrated model and predict optimal dosing regimens and PK/PD cutoff values for tylosin in healthy and infected pigs. The MIC of tylosin against both 89 and 363 isolates of A. pleuropneumoniae and P. multocida strains spread widely, ranging from 1 to 256 μg/mL and from 0.5 to 128 μg/mL, respectively. According to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) ECOFFinder analysis ECOFF value (≤64 µg/mL), 97.75% (87 strains) of the A. pleuropnumoniae isolates were wild-type, whereas with the same ECOFF value (≤64 µg/mL), 99.72% (363 strains) of the P. multicoda isolates were considered wild-type to tylosin. Area under the concentration time curve (AUC), T1/2, and Cmax values were significantly greater in healthy pigs than those in infected pigs (13.33 h × μg/mL, 1.99 h, and 5.79 μg/mL vs. 10.46 h × μg/mL, 1.83 h, and 3.59 μg/mL, respectively) (p < 0.05). In healthy pigs, AUC24 h/MIC values for the bacteriostatic activity were 0.98 and 1.10 h; for the bactericidal activity, AUC24 h/MIC values were 1.97 and 1.99 h for A. pleuropneumoniae and P. multocida, respectively. In infected pigs, AUC24 h/MIC values for the bacteriostatic activity were 1.03 and 1.12 h; for bactericidal activity, AUC24 h/MIC values were 2.54 and 2.36 h for A. pleuropneumoniae and P. multocida, respectively. Monte Carlo simulation lead to a 2 μg/mL calculated PK/PD cutoff. Managing co-infections can present challenges, as it often demands the administration of multiple antibiotics to address diverse pathogens. However, using tylosin, which effectively targets both A. pleuropneumoniae and P. multocida in pigs, may enhance the control of bacterial burden. By employing an optimized dosage of 11.94–15.37 mg/kg and 25.17–27.79 mg/kg of tylosin can result in achieving bacteriostatic and bactericidal effects in 90% of co-infected pigs

Effects of a radiation dose reduction strategy for computed tomography in severely injured trauma patients in the emergency department: an observational study

<p>Abstract</p> <p>Background</p> <p>Severely injured trauma patients are exposed to clinically significant radiation doses from computed tomography (CT) imaging in the emergency department. Moreover, this radiation exposure is associated with an increased risk of cancer. The purpose of this study was to determine some effects of a radiation dose reduction strategy for CT in severely injured trauma patients in the emergency department.</p> <p>Methods</p> <p>We implemented the radiation dose reduction strategy in May 2009. A prospective observational study design was used to collect data from patients who met the inclusion criteria during this one year study (intervention group) from May 2009 to April 2010. The prospective data were compared with data collected retrospectively for one year prior to the implementation of the radiation dose reduction strategy (control group). By comparison of the cumulative effective dose and the number of CT examinations in the two groups, we evaluated effects of a radiation dose reduction strategy. All the patients met the institutional adult trauma team activation criteria. The radiation doses calculated by the CT scanner were converted to effective doses by multiplication by a conversion coefficient.</p> <p>Results</p> <p>A total of 118 patients were included in this study. Among them, 33 were admitted before May 2009 (control group), and 85 were admitted after May 2009 (intervention group). There were no significant differences between the two groups regarding baseline characteristics, such as injury severity and mortality. Additionally, there was no difference between the two groups in the mean number of total CT examinations per patient (4.8 vs. 4.5, respectively; p = 0.227). However, the mean effective dose of the total CT examinations per patient significantly decreased from 78.71 mSv to 29.50 mSv (p < 0.001).</p> <p>Conclusions</p> <p>The radiation dose reduction strategy for CT in severely injured trauma patients effectively decreased the cumulative effective dose of the total CT examinations in the emergency department. But not effectively decreased the number of CT examinations.</p

Development of Gait Rehabilitation System Capable of Assisting Pelvic Movement of Normal Walking

Gait rehabilitation training with robotic exoskeleton is drawing attention as a method for more advanced gait rehabilitation training. However, most of the rehabilitation robots are mainly focused on locomotion training in the sagittal plane. This study introduces a novel gait rehabilitation system with actuated pelvic motion to generate natural gait motion. The rehabilitation robot developed in this study, COWALK, is a lower-body exoskeleton system with 15 degrees of freedom (DoFs). The COWALK can generate multi-DoF pelvic movement along with leg movements. To produce natural gait patterns, the actuation of pelvic movement is essential. In the COWALK, the pelvic movement mechanism is designed to help hemiplegic patients regain gait balance during gait training. To verify the effectiveness of the developed system, the gait patterns with and without pelvic movement were compared to the normal gait on a treadmill. The experimental results show that the active control of pelvic movement combined with the active control of leg movement can make the gait pattern much more natural

Comparative Pharmacokinetics of Orbifloxacin Following a Single Intravenous or Oral Administration to Healthy and Diabetic Rats

The single-dose disposition kinetics of orbifloxacin was determined in clinically healthy and diabetic rats  after intravenous or oral administration of 5 mg/kg body weight. Orbifloxacin concentrations were determined  by HPLC with fluorescence detection. The HPLC method was sensitive, specific and repeatable. A  systemic bioavailability of 99.1% and 108 %, and a Cmax of 6.55 } 1.09 μg /mL and 8.63 } 1.09 μg /mL were  observed in healthy and diabetic rats, respectively. The terminal half-life after intravenous and oral administration  was 4.17 } 0.38 h and 4.03 } 0.41 h for healthy and 2.31 } 0.34 h and 3.03 } 0.28 h for diabetic  rats. Orbifloxacin was cleared more rapidly in diabetic rats (0.15 } 0.01 L/kg.h) than healthy group (0.11 }  0.01 L/kg.h), with longer mean resident time (MRT) values observed in the latter. Other kinetic parameters  were almost the same between the healthy and diabetic groups. This investigation revealed that a dose of 5  mg/kg orbifloxacin can be safely and effectively used to combat infections in rats of either group associated  with susceptible bacteria.

Probiotic properties and adsorption of Enterococcus faecalis PSCT3-7 to vermiculite

The probiotic properties of Enterococcus (E.) faecalis PSCT3-7, a new strain isolated from the intestines of pigs fed dietary fiber containing 50% sawdust, were investigated. E. faecalis PSCT3-7 tolerated a pH range of 3 to 8 and 0.3% bile salts, and it inhibited the growth of Salmonella Typhimurium in a concentration-dependent manner. In addition, E. faecalis showed resistance to several antibacterial agents. Vermiculite, a nutrient and microbial carrier, increased the bile tolerance of the strain. Scanning electron microscope images revealed good adsorption of E. faecalis PSCT3-7 onto vermiculite. E. faecalis PSCT3-7 represents a potential probiotic candidate to administer with vermiculite to swine

Anti-Inflammatory Activity of the Methanol Extract of Moutan Cortex in LPS-Activated Raw264.7 Cells

Moutan Cortex (MCE) has been used in traditional medicine to remove heat from the blood, promote blood circulation and alleviate blood stasis. This study was conducted to evaluate the effects of MCE on regulatory mechanisms of cytokines and nitric oxide (NO) involved in immunological activity of Raw264.7 cells. Cells were pretreated with methanolic extracts of MCE, and further cultured for an appropriate time after lipopolyssacharide (LPS) addition. During the entire experimental period, 0.1 and 0.3 mg ml−1 of MCE had no cytotoxicity. In these concentrations, MCE inhibited the production of NO and prostaglandin E2 (PGE2), the expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2) and phosphorylated inhibitor of κBα (p-IκBα), and the activation of nuclear factor κB (NF-κB). MCE also reduced the concentration of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in the Raw264.7 cells that were activated by LPS. These results demonstrate that MCE has anti-inflammatory effects through the inhibition of iNOS and COX-2 expression by suppressing the phosphorylation of I-κBα and the activation of NF-κB