Kill Rate and Evaluation of Ex Vivo PK/PD Integration of Cefquinome Against Actinobacillus pleuropneumoniae

We wished to study the detailed and precise antibacterial activity of cefquinome against Actinobacillus pleuropneumoniae (APP) in vitro and ex vivo. We analyzed the relationships between kill rate and cefquinome concentration in broth and between pharmacokinetic/pharmacodynamic (PK/PD) parameters and antibacterial effect in serum and tissue cage fluid (TCF) of piglets. Cefquinome exhibited time-dependent antibacterial activity against APP according to the kill rate. The maximum kill rate was 0.48 log10 CFU/mL/h at the 0-9-h period in broth. In the ex vivo PK/PD study, the maximum concentration (Cmax), time to reach the maximum concentration (Tmax), terminal half-life (T1/2β), and area under the concentration time curve (AUCinfinity) were 5.65 μg/ml, 0.58 h, 2.24 h, and 18.48 μg·h/ml in serum and 1.13 μg/ml, 2.60 h, 12.22 h, and 20.83 μg·h/ml in TCF, respectively. The values of area under the curve during 24 h/minimum inhibitory concentration (AUC24h/MIC) for bacteriostatic, bactericidal, and bacterial eradication effects were 18.94, 246.8, and 1013.23 h in serum and 4.20, 65.81, and 391.35 h in TCF, respectively. Our findings will provide a valuable basis for optimization of dosage regimens when applying cefquinome to treat APP infection.

Case Report: Monitoring Vancomycin Concentrations and Pharmacokinetic Parameters in Continuous Veno-Venous Hemofiltration Patients to Guide Individualized Dosage Regimens: A Case Analysis

There are limited pharmacokinetic (PK) studies on vancomycin in patients treated with continuous renal replacement therapy (CRRT), and the results have been inconsistent. Because of individual differences, proposing a definite recommendation for the clinical regimen is not possible. Rapidly reaching target vancomycin concentrations will facilitate effective treatment for critically ill patients treated with CRRT. In this study, to understand the dynamic change in drug clearance rates in vivo, analyze the effect of PK changes on drug concentrations, and recommend loading and maintenance dosage regimens, we monitored the blood concentrations of vancomycin and calculated the area under the curve in two critically ill patients treated with vancomycin and continuous veno-venous hemofiltration (CVVH). On the basis of real-time therapeutic drug monitoring results and PK parameters, an individualized vancomycin regimen was developed for patients with CVVH. Good clinical efficacy was achieved, which provided support and reference for empirical vancomycin therapy in these patients.

Machine Learning Predicts Drug Metabolism and Bioaccumulation by Intestinal Microbiota

Over 150 drugs are currently recognised as being susceptible to metabolism or bioaccumulation (together described as depletion) by gastrointestinal microorganisms; however, the true number is likely higher. Microbial drug depletion is often variable between and within individuals, depending on their unique composition of gut microbiota. Such variability can lead to significant differences in pharmacokinetics, which may be associated with dosing difficulties and lack of medication response. In this study, literature mining and unsupervised learning were used to curate a dataset of 455 drug–microbiota interactions. From this, 11 supervised learning models were developed that could predict drugs’ susceptibility to depletion by gut microbiota. The best model, a tuned extremely randomised trees classifier, achieved performance metrics of AUROC: 75.1% ± 6.8; weighted recall: 79.2% ± 3.9; balanced accuracy: 69.0% ± 4.6; and weighted precision: 80.2% ± 3.7 when validated on 91 drugs. This machine learning model is the first of its kind and provides a rapid, reliable, and resource-friendly tool for researchers and industry professionals to screen drugs for susceptibility to depletion by gut microbiota. The recognition of drug–microbiome interactions can support successful drug development and promote better formulations and dosage regimens for patients.

Dose Optimization of Vancomycin for Critically Ill Patients Undergoing CVVH: A Prospective Population PK/PD Analysis

The optimal dose of vancomycin in critically ill patients receiving continuous venovenous hemofiltration (CVVH) remains unclear. The objective of this study was to identify factors that significantly affect pharmacokinetic profiles and to further investigate the optimal dosage regimens for critically ill patients undergoing CVVH based on population pharmacokinetics and pharmacodynamic analysis. A prospective population pharmacokinetic analysis was performed at the surgical intensive care unit in a level A tertiary hospital. We included 11 critically ill patients undergoing CVVH and receiving intravenous vancomycin. Serial blood samples were collected from each patient, with a total of 131 vancomycin concentrations analyzed. Nonlinear mixed effects models were developed using NONMEM software. Monte Carlo Simulation was used to optimize vancomycin dosage regimens. A two-compartment model with first-order elimination was sufficient to characterize vancomycin pharmacokinetics for CVVH patients. The population typical vancomycin clearance (CL) was 1.15 L/h and the central volume of distribution was 16.9 L. CL was significantly correlated with ultrafiltration rate (UFR) and albumin level. For patients with normal albumin and UFR between 20 and 35 mL/kg/h, the recommended dosage regimen was 10 mg/kg qd. When UFR was between 35 and 40 mL/kg/h, the recommended dosage regimen was 5 mg/kg q8h. For patients with hypoalbuminemia and UFR between 20 and 25 mL/kg/h, the recommended dosage regimen was 5 mg/kg q8h. When UFR was between 25 and 40 mL/kg/h, the recommended dosage regimen was 10 mg/kg q12h. We recommend clinicians choosing the optimal initial vancomycin dosage regimens for critically ill patients undergoing CVVH based on these two covariates.

Comparison between two dosage regimens of enrofloxacin given in drinking water for treatment of induced air sacculitis in chicks

Response to treatment of induced air sacculitis by a pathogenic strain of E coli with enrofloxacin when it was given by the recommended therapeutic concentration (50 mg/ml) for 3 days in drinking water was compared with the method of giving the same drug at double the above concentration for one time after a period of thirstiness . Athird group of infected bird was left without treatment while a non – infected group was left as a negative control . Parameters of mortality , clinical symptoms, feed consumption , weight gain and feed conversion were measured to evaluate the effectiveness of either method of treatment. Also, after sacrifying of some birds one week and 3 weeks after infection, pathological lesions and air sacculitis index were considered. The results showed significant differences in most parameters between infected and non – infected groups while either of the two infected treated groups were intermediate between them. This result encourages the use of the suggested single method of treatment especially when cost of drug, full dosing and stability of drug are taken in consideration

Pharmacokinetics and Monte Carlo Simulation of Meropenem in Critically Ill Adult Patients Receiving Extracorporeal Membrane Oxygenation

Objectives: There have been few clinical studies of ECMO-related alterations of the PK of meropenem and conflicting results were reported. This study investigated the pharmacokinetics (PK) of meropenem in critically ill adult patients receiving extracorporeal membrane oxygenation (ECMO) and used Monte Carlo simulations to determine appropriate dosage regimens.Methods: After a single 0.5 or 1 g dose of meropenem, 7 blood samples were drawn. A population PK model was developed using nonlinear mixed-effects modeling. The probability of target attainment was evaluated using Monte Carlo simulation. The following treatment targets were evaluated: the cumulative percentage of time during which the free drug concentration exceeds the minimum inhibitory concentration of at least 40% (40% fT>MIC), 100% fT>MIC, and 100% fT>4xMIC.Results: Meropenem PK were adequately described by a two-compartment model, in which creatinine clearance and ECMO flow rate were significant covariates of total clearance and central volume of distribution, respectively. The Monte Carlo simulation predicted appropriate meropenem dosage regimens. For a patient with a creatinine clearance of 50–130 ml/min, standard regimen of 1 g q8h by i. v. infusion over 0.5 h was optimal when a MIC was 4 mg/L and a target was 40% fT>MIC. However, the standard regimen did not attain more aggressive target of 100% fT>MIC or 100% fT>4xMIC.Conclusion: The population PK model of meropenem for patients on ECMO was successfully developed with a two-compartment model. ECMO patients exhibit similar PK with patients without ECMO. If more aggressive targets than 40% fT>MIC are adopted, dose increase may be needed.

Folium Sennae Increased the Bioavailability of Methotrexate through Modulation on MRP 2 and BCRP

Folium Sennae (FS), a popular laxative (Senna), contains polyphenolic anthranoids, whose conjugation metabolites are probable modulators of multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP). We suspected that the combined use of FS might alter the pharmacokinetics of various medicines transported by MRPs or BCRP. This study investigated the effect of FS on the pharmacokinetics of methotrexate (MTX), an anticancer drug and a probe substrate of MRPs/BCRP. Rats were orally administered MTX alone and with two dosage regimens of FS in a parallel design. The results show that 5.0 g/kg of FS significantly increased the AUC0–2880, AUC720–2880 and MRT of MTX by 45%, 102% and 42%, and the seventh dose of 2.5 g/kg of FS significantly enhanced the AUC720–2880 and MRT by 78% and 42%, respectively. Mechanism studies indicated that the metabolites of FS (FSM) inhibited MRP 2 and BCRP. In conclusion, the combined use of FS increased the systemic exposure and MRT of MTX through inhibition on MRP 2 and BCRP.

A Review on Neurotoxins from Clostridium botulinum against Neuro-muscular Disorders

Neuro-muscular disorders cause a series of serious complications in the human body, where some lead to considerable morbidity and mortality ocassionally. Neurological diseases result in dystrophy, inhibited growth, etc. This present review aimed to emphasize the employment of neurotoxins against neuro degenerative disorders. The source of neurotoxins includes botulinum (Clostridium botulinum), snakes like Vespa orientalis and some medically important arthropods like hornets and spiders. The review not only describes the potential of the neurotoxins in the treatment but also elucidates the mechanism of action of lethal toxins like botulinum. Safety and dosage regimens of various toxins with the help of proven study data would aid in endorsing researchers for further research on toxins making them more superior targeted drugs.

Treatment of Kawasaki Disease: A Network Meta-Analysis of Four Dosage Regimens of Aspirin Combined With Recommended Intravenous Immunoglobulin

Aspirin was once believed to reduce the mortality of Kawasaki disease (KD) due to its effect on the thrombotic occlusion of coronary arteries. However, conflicting evidence has been found regarding aspirin treatment and its benefit in patients with acute KD. We compared the efficacy of different aspirin doses in acute KD. A literature search of PubMed, EMBASE, and Cochrane databases was conducted to identify studies comparing different doses of aspirin for acute KD. The primary outcome of interest was coronary artery lesions (CAL). We used random-effects network meta-analysis. Six retrospective studies, including 1944 patients receiving aspirin in doses of 0, 3–5, 30–50, or 80–100 mg/kg/day, were selected. The risks of CAL were not significantly different for the various doses of aspirin compared to the placebo: odds ratio (OR) was 1.10 [95% confidence interval (CI): 0.70–1.71] for patients with aspirin 3–5 mg/kg/day; OR = 1.23 (95% CI: 0.67–2.26) for aspirin 30–50 mg/kg/day, and OR = 1.59 (95% CI: 0.74, 3.421) for 80–100 mg/kg/day. The P-score ranged from 0.76 for placebo to 0.19 for aspirin 80–100 mg/kg/day. The different doses of aspirin exhibited no significant difference with regard to the efficacy of CAL or with the secondary outcomes of intravenous immunoglobulin resistance or hospital stays for acute KD. Therefore, we found that treatment without any aspirin is not inferior to other doses of aspirin and can also slightly reduce the risk of CAL.