Substrate and functional characterization of the lysine acetyltransferase MsKat and deacetylase MsCobB in Mycobacterium smegmatis.

Tuberculosis (TB) is a serious cause of infectious death worldwide. Recent studies have reported that about 30% of the Mtb proteome was modified post-translationally, indicating that their functions are essential for drug resistance, mycobacterial survival, and pathogenicity. Among them, lysine acetylation, reversibly regulated by acetyltransferase and deacetylase, has important roles involved in energy metabolism, cellular adaptation, and protein interactions. However, the substrate and biological functions of these two important regulatory enzymes remain unclear. Herein, we utilized the non-pathogenic M. smegmatis strain as a model and systematically investigated the dynamic proteome changes in response to the overexpressing of MsKat/MsCobB in mycobacteria. A total of 4179 proteins and 1236 acetylated sites were identified in our data. Further analysis of the dynamic changes involved in proteome and acetylome showed that MsKat/MsCobB played a regulatory role in various metabolic pathways and nucleic acid processes. After that, the quantitative mass spectrometric method was utilized and proved that the AMP-dependent synthetase, Citrate synthase, ATP-dependent specificity component of the Clp protease, and ATP-dependent DNA/RNA helicases were identified to be the substrates of MsKat. Overall, our study provided an important resource underlying the substrates and functions of the acetylation regulatory enzymes in mycobacteria. SIGNIFICANCE: In this study, we systematically analyzed the dynamic molecular changes in response to the MsKat/MsCobB overexpression in mycobacteria at proteome and lysine acetylation level by using a TMT-based quantitative proteomic approach. Pathways related with glycolysis, degradation of branched chain amino acids, phosphotransferase system were affected after disturbance of the two regulates enzymes involved in lysine acetylation. We also proved that AMP-dependent synthetase Clp protease, ATP-dependent DNA/RNA helicases and citrate synthase was the substrate of MsKat according to our proteomic data and biological validation. Together, our study underlined the substrates and functions of the acetylation regulatory enzymes in mycobacteria.

Basic concepts, recent advances, and future perspectives in the diagnosis of bovine mastitis.

Mastitis is one of the most widespread infectious diseases that adversely affects the profitability of the dairy industry worldwide. Accurate diagnosis and identification of pathogens early to cull infected animals and minimize the spread of infection in herds is critical for improving treatment effects and dairy farm welfare. The major pathogens causing mastitis and pathogenesis are assessed first. The most recent and advanced strategies for detecting mastitis, including genomics and proteomics approaches, are then evaluated . Finally, the advantages and disadvantages of each technique, potential research directions, and future perspectives are reported. This review provides a theoretical basis to help veterinarians select the most sensitive, specific, and cost-effective approach for detecting bovine mastitis early.

A proteomic landscape of pharmacologic perturbations for functional relevance.

Pharmacological perturbation studies based on protein-level signatures are fundamental for drug discovery. In the present study, we used a mass spectrometry (MS)-based proteomic platform to profile the whole proteome of the breast cancer MCF7 cell line under stress induced by 78 bioactive compounds. The integrated analysis of perturbed signal abundance revealed the connectivity between phenotypic behaviors and molecular features in cancer cells. Our data showed functional relevance in exploring the novel pharmacological activity of phenolic xanthohumol, as well as the noncanonical targets of clinically approved tamoxifen, lovastatin, and their derivatives. Furthermore, the rational design of synergistic inhibition using a combination of histone methyltransferase and topoisomerase was identified based on their complementary drug fingerprints. This study provides rich resources for the proteomic landscape of drug responses for precision therapeutic medicine.

Progress of stimulus responsive nanosystems for targeting treatment of bacterial infectious diseases.

In recent decades, due to insufficient concentration at the lesion site, low bioavailability and increasingly serious resistance, antibiotics have become less and less dominant in the treatment of bacterial infectious diseases. It promotes the development of efficient drug delivery systems, and is expected to achieve high absorption, targeted drug release and satisfactory therapy effects. A variety of endogenous stimulation-responsive nanosystems have been constructed by using special infection microenvironments (pH, enzymes, temperature, etc.). In this review, we firstly provide an extensive review of the current research progress in antibiotic treatment dilemmas and drug delivery systems. Then, the mechanism of microenvironment characteristics of bacterial infected lesions was elucidated to provide a strong theoretical basis for bacteria-targeting nanosystems design. In particular, the discussion focuses on the design principles of single-stimulus and dual-stimulus responsive nanosystems, as well as the use of endogenous stimulus-responsive nanosystems to deliver antimicrobial agents to target locations for combating bacterial infectious diseases. Finally, the challenges and prospects of endogenous stimulus-responsive nanosystems were summarized.

Micro- and nanoplastics interact with conventional pollutants on microalgae: Synthesis through meta-analysis.

Micro- and nanoplastics (MNPs) have been found to occur intensively in aquatic environments, along with other conventional pollutants (Po) such as heavy metals, pesticides, pharmaceuticals, etc. However, our understanding of how MNPs and Po interact on aquatic primary producers is fragmented. We performed a quantitative meta-analysis based on 933 published experimental assessments from 44 studies to examine the coupled effects of MNPs and Po on microalgae. Although the results based on interaction type frequency (the proportion of each interaction type in all results) revealed dominantly additive interactions (56%) for overall physiological performance, an overall antagonistic effect was observed based on the mean interaction effect sizes. A higher proportion of antagonistic interaction type frequency was found in marine species compared to fresh species. The antagonistic effects were particularly significant for growth, oxidative responses, and photosynthesis, which could be attributed to the adsorption effect of MNPs on Po and thus the decreasing concentrations of pollutants in the medium. Larger-sized, negatively charged or uncharged and aged MNPs had higher proportions of antagonistic effects compared to smaller-sized, positively charged and virgin MNPs, due to their stronger adsorption capacity to Po. This study provides a comprehensive insight into the interactive effects of MNPs and Po on microalgae.

Endovascular therapy versus medical management for acute ischemic stroke with large infarct core: Systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To compare the efficacy and safety of endovascular therapy (EVT) versus best medical management (BMM) in patients with acute ischemic stroke (AIS) with large infarct core. METHODS: We searched Pubmed, Embase and Cochrane Central Register of Controlled Trials for published randomized clinical trials (RCTs) from inception to February 18, 2023. We defined patients with large core infarcts as having an Alberta Stroke Program early computed tomography score (ASPECTS) of 3-5. The primary outcome was functional independence, defined as a score of 0-2 on the modified Rankin scale (mRS) at 90 days. Secondary outcome was independent ambulation defined as mRS 0-3 at 90 days. Safety outcomes were mortality at 90 days, symptomatic intracranial hemorrhage (sICH) and any intracranial hemorrhage (ICH). RESULTS: The overall treatment effect was more favourable to EVT group. EVT was significantly correlated with improvement of functional independence at 90 days (mRS 0-2) (RR = 2.40; 95 % CI, 1.82-3.16; P < 0.01; I2 = 0 %) and independent ambulation (mRS 0-3) (RR = 1,78; 95 % CI, 1.28-2.48; P < 0.01; I2 = 58 %) at 90 days. 90-day mortality was not significantly different between the two groups(RR = 0.95; 95 % CI, 0.78-1.16; P > 0.05; I2 = 0 %). The risk of sICH and any ICH was higher in EVT group than in BMM group. CONCLUSION: Compared with BMM, EVT may improve functional outcomes in patients with ASPECTS 3-5, despite being associated with an increased risk of sICH and any ICH.

Targeting and arginine-driven synergizing photodynamic therapy with nutritional immunotherapy nanosystems for combating MRSA biofilms.

The resistance and immune escape of methicillin-resistant Staphylococcus aureus (MRSA) biofilms cause recalcitrant infections. Here, we design a targeting and synergizing cascade PDT with nutritional immunotherapy nanosystems (Arg-PCN@Gel) containing PCN-224 as PDT platform for providing reactive oxygen species (ROS), incorporating arginine (Arg) as nitric oxide (NO) donor to cascade with ROS to produce more lethal ONOO- and promote immune response, and coating with gelatin as targeting agent and persistent Arg provider. The nanosystems adhered to the autolysin of MRSA and inhibited Arg metabolism by down-regulating icdA and icaA. It suppressed polysaccharide intercellular adhesin and extracellular DNA synthesis to prevent biofilm formation. The NO broke mature biofilms and helped ROS and ONOO- penetrate into biofilms to inactivate internal MRSA. Arg-PCN@Gel drove Arg to enhance immunity via inducible NO synthase/NO axis and arginase/polyamine axis and achieve efficient target treatment in MRSA biofilm infections. The targeting and cascading PDT synergized with nutritional immunotherapy provide an effective promising strategy for biofilm-associated infections.

Recent progress of emitting long-wavelength carbon dots and their merits for visualization tracking, target delivery and theranostics.

As a novel strategy for in vivo visualization tracking and monitoring, carbon dots (CDs) emitting long wavelengths (LW, 600-950 nm) have received tremendous attention due to their deep tissue penetration, low photon scattering, satisfactory contrast resolution and high signal-to-background ratios. Although, the mechanism of CDs emitting LW remains controversial and what properties are best for in vivo visualization have not been specifically elucidated, it is more conducive to the in vivo application of LW-CDs through rational design and ingenious synthesis based on the appreciation of the luminescence mechanism. Therefore, this review analyzes the current tracer technologies applied in vivo and their advantages and disadvantages, with emphasis on the physical mechanism of emitting LW fluorescence for in vivo imaging. Subsequently, the general properties and merits of LW-CDs for tracking and imaging are summarized. More importantly, the factors affecting the synthesis of LW-CDs and its luminescence mechanism are highlighted. Simultaneously, the application of LW-CDs for disease diagnosis, integration of diagnosis and therapy are summarized. Finally, the bottlenecks and possible future directions of LW-CDs in visualization tracking and imaging in vivo are detailly discussed.

Guar gum modified tilmicosin-loaded sodium alginate/gelatin composite nanogels for effective therapy of porcine proliferative enteritis caused by Lawsonia intracellularis.

In order to overcome the treatment difficulty of Lawsonia intracellularis (L.intracellularis) using antibiotics, the tilmicosin (TIL)-loaded sodium alginate (SA)/gelatin composite nanogels modified with bioadhesive substances were designed. The optimized nanogels were prepared by electrostatic interaction between SA and gelatin at a mass ratio of 1:1 and CaCl2 as an ionic crosslinker and further modified with guar gum (GG). The optimized TIL-nanogels modified with GG had a uniform spherical shape with a diameter of 18.2 ± 0.3 nm, LC of 29.4 ± 0.2 %, EE of 70.4 ± 1.6 %, PDI of 0.30 ± 0.04, and ZP of -32.2 ± 0.5 mv. The FTIR, DSC, and PXRD showed that GG was covered on the surface of TIL-nanogels in a pattern of staggered arrangements. The TIL-nanogels modified with GG had the strongest adhesive strength amongst those with I-carrageenan and locust bean gum and the plain nanogels, and thus significantly enhanced the cellular uptake and accumulation of TIL via clathrin-mediated endocytosis. It exhibited an increased therapeutic effect against L.intracellularis in vitro and in vivo. This study will provide guidance for developing nanogels for intracellular bacterial infection treatment.

Ultraversatile Fluorescent Sensors Based on Two CoII/NiII Coordination Polymers for Identifying Various Antibiotics via the Turn-On/Off Effect and Detecting pH.

Because the accurate and rapid detection of antibiotics and pH plays an important role in biological systems and environmental fields, developing suitable and efficient sensors that can simultaneously detect antibiotics and pH has become important. In this work, we successfully designed and synthesized two new one-dimensional coordination polymers based on the mixed ligands L [N,N'-bis(4-methylpyridin-4-yl)-2,6-naphthalene dicarboxylamide] and H2CPG [3-(4-chlorophenyl)glutaric acid], [M(L)(HCPG)2(H2O)2] (M = Co for CP 1, and M = Ni for CP 2), which were structurally characterized by single-crystal X-ray diffraction, infrared spectroscopy, powder X-ray diffraction, and thermogravimetric analysis. CP 1 and CP 2 can be used as ultraversatile fluorescent sensors, which can sense erythromycin (ERY) and oxacillin (OXC) by turn-on fluorescent enhancement and detect furaltadone (FTD) via the turn-off fluorescent quenching effect, separately. The concentration ranges of different analytes sensed by CPs 1 and 2 were 0-0.046 and 0-0.069 mM for ERY, 0-0.04 and 0-0.028 mM for OXC, and 0-0.155 and 0-0.019 mM for FTD, respectively. Moreover, CP 2 can effectively sense pH, in both a wide pH range and the fine physiological range. The sensors have a rapid luminescence response, good recyclability, and excellent fluorescence stability. More importantly, they not only represent the first example of detecting ERY or OXC based on fluorescent CPs but also are the very rare ultraversatile fluorescent sensors. The fluorescent sensing mechanism for antibiotics and pH was discussed in detail.

ABC Transporters and CYP3A4 Mediate Drug Interactions between Enrofloxacin and Salinomycin Leading to Increased Risk of Drug Residues and Resistance.

Enrofloxacin (ENR) is one of the most common drugs used in poultry production to treat bacterial diseases, and there is a high risk of drug interactions (DDIs) between polyether anticoccidial drugs added to poultry feed over time. This may affect the efficacy of antibiotics or lead to toxicity, posing a potential risk to the environment and food safety. This study aimed to investigate the DDI of ENR and salinomycin (SAL) in broilers and the mechanism of their DDI. We found that SAL increased the area under the curve and elimination half-life of ENR and ciprofloxacin (CIP) by 1.3 and 2.4 times, 1.2 and 2.5 times, respectively. Cytochrome 3A4 (CYP3A4), p-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) were important factors for the DDI between ENR and SAL in broilers. ENR and SAL are substrates of CYP3A4, P-gp and BCRP in broilers; ENR and SAL inhibited the expression of CYP3A4 activity in a time- and concentration-dependent. Meanwhile, ENR downregulated the expression of P-gp and BCRP in a time- and concentration-dependent manner. A single oral administration of SAL inhibited CYP3A4, P-gp, and BCRP, but long-term mixed feeding upregulated the expression of CYP3A4, P-gp, and BCRP. Molecular docking revealed that ENR and SAL compete with each other for CYP3A4 to affect hepatic metabolism, and compete with ATP for P-gp and BCRP binding sites to inhibit efflux. ENR and SAL in broilers can lead to severe DDI. Drug residues and resistance following co-administration of ENR and SAL and other SAL-based drug-feed interactions warrant further study.

Core-shell nanosystems designed for effective oral delivery of polypeptide drugs.

The stomach acid degradation, mucus clearance and intestinal epithelial impermeability severely limit the oral delivery of polypeptide drugs. To simultaneously address the three major barriers, novel self-assembled core-shell nanosystems (CA-NPs) were designed. The fabricated shell of citric acid cross-linked carboxymethyl cellulose (CA-CMC) wrapped on core nanoparticles (HA-NPs) maintained the integrity of CA-NPs in the stomach. When CA-NPs passed through the stomach, the CA-CMC shell was gradually degraded to release the core HA-NPs in the intestine. HA-NPs with numerous hydrophilic groups and mannose side chains rapidly penetrated through the mucus layer and efficiently transcellular transported via the glucose transporter (GLUT)-mediated and paracellular transport through reversible opening of tight junctions (TJs) by CA-CMC. The oral bioavailability and therapeutic effects of CA-NPs-loaded polypeptide colistin against Escherichia coli (E. coli) bacteremia in mice were significantly increased compared with the native colistin, respectively. Good safety was observed following oral daily delivery for 14 consecutive days. Thus, CA-NPs may offer a promising strategy for the oral delivery of polypeptide drugs.

Intelligent-Responsive Enrofloxacin-Loaded Chitosan Oligosaccharide-Sodium Alginate Composite Core-Shell Nanogels for On-Demand Release in the Intestine.

Enrofloxacin has a poor palatability and causes strong gastric irritation; the oral formulation of enrofloxacin is unavailable, which limits the treatment of Escherichia coli (E. coli) infections via oral administration. To overcome the difficulty in treating intestinal E. coli infections, an oral intelligent-responsive chitosan-oligosaccharide (COS)-sodium alginate (SA) composite core-shell nanogel loaded with enrofloxacin was explored. The formulation screening, characteristics, pH-responsive performance in gastric juice and the intestinal tract, antibacterial effects, therapeutic effects, and biosafety level of the enrofloxacin composite nanogels were investigated. The optimized concentrations of COS, SA, CaCl2, and enrofloxacin were 8, 8, 0.2, and 5 mg/mL, respectively. The encapsulation efficiency, size, loading capacity, zeta potential, and polydispersity index of the optimized formulation were 72.4 ± 0.8%, 143.5 ± 2.6 nm, 26.6 ± 0.5%, -37.5 ± 1.5 mV, and 0.12 ± 0.07, respectively. Scanning electron microscopy images revealed that enrofloxacin-loaded nanogels were incorporated into the nano-sized cross-linked networks. Fourier transform infrared spectroscopy showed that the nanogels were prepared by the electrostatic interaction of the differently charged groups (positive amino groups (-NH3+) of COS and the negative phenolic hydroxyl groups (-COO-) of SA). In vitro, pH-responsive release performances revealed effective pH-responsive performances, which can help facilitate targeted "on-demand" release at the target site and ensure that the enrofloxacin has an ideal stability in the stomach and a responsive release in the intestinal tract. The antibacterial activity study demonstrated that more effective bactericidal activity against E. coli could have a better treatment effect than the enrofloxacin solution. Furthermore, the enrofloxacin composite nanogels had great biocompatibility. Thus, the enrofloxacin composite core-shell nanogels might be an oral intelligent-responsive preparation to overcome the difficulty in treating intestinal bacterial infections.

Nanocrystal Suspensions for Enhancing the Oral Absorption of Albendazole.

Albendazole (ABZ), an effective benzimidazole antiparasitic drug is limited by its poor solubility and oral bioavailability. In order to overcome its disadvantages, ABZ nanocrystals were prepared using a novel bottom-up method based on acid-base neutralization recrystallization with high-speed mixing and dispersing. The cosolvent, stabilizer and preparation temperature were optimized using single factor tests. The physicochemical properties, solubility and pharmacokinetics of the optimal ABZ nanocrystals were evaluated. The high-performance liquid chromatography (HPLC), differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD) showed that ABZ had no structural and crystal phase change after nanocrystallization. The saturated solubility of ABZ nanocrystals in different solvents was increased by 2.2-118 fold. The oral bioavailability of the total active ingredients (ABZ and its metabolites of albendazole sulfoxide (ABZSO) and albendazole sulfone (ABZSO2)) of the nanocrystals in rats was enhanced by 1.40 times compared to the native ABZ. These results suggest that nanocrystals might be a promising way to enhance the solubility and oral bioavailability of ABZ and other insoluble drugs.

Progress and prospects of nanomaterials against resistant bacteria.

Drug-resistant bacterial infections are increasingly heightening, which lead to more severe illness, higher cost of treatment and increased risk of death. Nanomaterials-based therapy, an "outrider", serving as a kind of innovative antimicrobial therapeutics, showing promise in replacing antimicrobial agents and enhancing the activity of antibiotics, generally bases on the various inorganic and/or organic materials. When the size of those materials is below to a certain nano-level and the content of nanomaterials is above a certain amount, they are lethal to the resistant bacteria, which bypass the traditional bacterial resistance mechanisms. This review highlights the effect of nanomaterials in combating extracellular/intracellular bacteria and eradicating biofilms. Based on the studies searched on the Web of Science through relevant keywords, this review article starts with analyzing the current situation, resistance mechanisms, and treatment difficulties of bacteria resistance. Then, the efficacy of nanomaterials against resistant bacteria and their mechanisms (e.g., physical impairment, biofilm lysis, regulating bacterial metabolism, protein and DNA replication as well as enhancing the antibiotics concentration in infected cells) are collected. Lastly, the factors affecting the antibacterial efficacy are argued from the side of nanomatrials and bacterium, which followed by the emerging challenges and recent perspectives of achieving higher targeting released nanomaterials as antibacterial therapeutics.

Preparation of Aditoprim Injection against Streptococcus suis in Pigs and a Dose Regimen Based on Pharmacokinetic-Pharmacodynamic Modeling.

In order to effectively treat the infection of Streptococcus suis and reduce the emergence of drug-resistant bacteria, an aditoprim (ADP) injection was developed in this study. The pharmaceutical property investigation results demonstrated that ADP injection was a clear yellow liquid with 10 g ADP distributing in every 100 mL solution uniformly. Its pH value and drug content were around 6.20 and 99.35~100.40%, respectively. And quality assessment preliminarily indicated its reliable quality and stability. Additionally, the bronchoalveolar lavage fluid method was first applied to evaluate accurate ADP concentration at infection site in this study. Through pharmacodynamic assay, the MIC, MBC and MPC of ADP against Streptococcus suis CVCC 607 was 2 µg/mL, 4 µg/mL and 12.8 µg/mL, respectively. The bacteria growth inhibition curves showed that ADP was a concentration-dependent antibacterial drug, and the PK-PD model parameter of AUC/MIC was selected. The pharmacokinetic parameters of alveolar fluid evaluated by WinNonlin software revealed similar pharmacokinetic process of ADP in healthy pigs and infected pigs. Combined with pharmacokinetics-pharmacodynamics (PK-PD) modeling, the dosage regimen of 3~5 days with an interval of 12 h at 4.10 mg/kg or 5.91 mg/kg could be adopted to treat the infection of Streptococcus suis. Consequently, this ADP injection with a multi-dose protocol would be a promising antimicrobial product for efficient treatment of S. suis infection of pigs.

Optimal Regimens and Clinical Breakpoint of Avilamycin Against Clostridium perfringens in Swine Based on PK-PD Study.

Clostridium perfringens causes significant morbidity and mortality in swine worldwide. Avilamycin showed no cross resistance and good activity for treatment of C. perfringens. The aim of this study was to formulate optimal regimens of avilamycin treatment for C. perfringens infection based on the clinical breakpoint (CBP). The wild-type cutoff value (COWT) was defined as 0.25 µg/ml, which was developed based on the minimum inhibitory concentration (MIC) distributions of 120 C. perfringens isolates and calculated using ECOFFinder. Pharmacokinetics-pharmacodynamics (PK-PD) of avilamycin in ileal content were analyzed based on the high-performance liquid chromatography method and WinNonlin software to set up the target of PK/PD index (AUC0-24h/MIC)ex based on sigmoid Emax modeling. The PK parameters of AUC0-24h, Cmax, and Tmax in the intestinal tract were 428.62 ± 14.23 h µg/mL, 146.30 ± 13.41 µg/ml,, and 4 h, respectively. The target of (AUC0-24h/MIC)ex for bactericidal activity in intestinal content was 36.15 h. The PK-PD cutoff value (COPD) was defined as 8 µg/ml and calculated by Monte Carlo simulation. The dose regimen designed from the PK-PD study was 5.2 mg/kg mixed feeding and administrated for the treatment of C. perfringens infection. Five respective strains with different MICs were selected as the infection pathogens, and the clinical cutoff value was defined as 0.125 µg/ml based on the relationship between MIC and the possibility of cure (POC) following nonlinear regression analysis, CART, and "Window" approach. The CBP was set to be 0.25 µg/ml and selected by the integrated decision tree recommended by the Clinical Laboratory of Standard Institute. The formulation of the optimal regimens and CBP is good for clinical treatment and to control drug resistance.

PK-PD Modeling and Optimal Dosing Regimen of Acetylkitasamycin against Streptococcus suis in Piglets.

Streptococcus suis (S. suis) causes severe respiratory diseases in pigs and is also an important pathogen causing hidden dangers to public health and safety. Acetylkitasamycin is a new macrolide agent that has shown good activity to Gram-positive cocci such as Streptococcus. The purpose of this study was to perform pharmacokinetic-pharmacodynamic (PK-PD) modeling to formulate a dosing regimen of acetylkitasamycin for treatment of S. suis and to decrease the emergence of acetylkitasamycin-resistant S. suis. The minimal inhibitory concentration (MIC) of 110 S. suis isolates was determined by broth micro dilution method. The MIC50 of the 55 sensitive S. suis isolates was 1.21 µg/mL. The strain HB1607 with MIC close to MIC50 and high pathogenicity was used for the PK-PD experiments. The MIC and MBC of HB1607 in both MH broth and pulmonary epithelial lining fluid (PELF) was 1 and 2 µg/mL, respectively. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used to determine the concentration change of acetylkitasamycin in piglet plasma and PELF after intragastric administration of a single dose of 50 mg/kg b.w. acetylkitasamycin. The PK parameters were calculated by WinNolin software. The PK data showed that the maximum concentration (Cmax), peak time (Tmax), and area under the concentration-time curve (AUC) were 9.84 ± 0.39 µg/mL, 4.27 ± 0.19 h and 248.58 ± 21.17 h·µg/mL, respectively. Integration of the in vivo PK data and ex vivo PD data, an inhibition sigmoid Emax equation was established. The dosing regimen of acetylkitasamycin for the treatment S. suis infection established as 33.12 mg/kg b.w. every 12 h for 3 days. This study provided a reasonable dosing regimen for a new drug used in clinical treatment, which can effectively be used to treat S. suis infection and slow down the generation of drug resistance.

Antibacterial activity of combined aditoprim and sulfamethoxazole against Escherichia coli from swine and a dose regimen based on pharmacokinetic-pharmacodynamic modeling.

The mortality of livestock caused by pathogenic Escherichia coli (E. coli) still accounts for a large proportion of deaths in large-scale production and reproduction, which causes devastating economic losses to the pig breeding industry. The aims of this study were to investigate the antibacterial activity of combined aditoprim (ADP) and sulfamethoxazole (SMZ) against clinical isolates of E. coli from pigs and to develop a pharmacokinetic-pharmacodynamic (PK-PD) model to formulate the optimal dose of ADP/SMZ for the treatment of pig colibacillosis. Blood and ileum fluid samples were collected at different times after single intramuscular injection of ADP/SMZ (5/25 mg/kg b.w.) to healthy pigs and E. coli-infected pigs. Concentrations of ADP and SMZ in plasma and ileum fluid were analyzed by HPLC. The peak concentration (Cmax ) and the area under the concentration-time curve (AUC0-24h ) in ileum fluid of healthy pigs were 1.76 ± 0.27 µg/ml and 18.92 ± 2.87 µg·h/ml for ADP and 19.15 ± 2.63 µg/ml and 125.70 ± 11.86 µg·h/ml for SMZ, respectively. Cmax and AUC0-24h in ileum fluid of infected pigs were 1.88 ± 0.13 µg/ml and 15.12 ± 0.75 µg·h/ml for ADP and 19.71 ± 3.68 µg/ml and 133.92 ± 17.14 µg·h/ml for SMZ, respectively. The minimum inhibitory concentrations (MICs) of combined ADP and SMZ (ADP/SMZ) against 185 strains of E. coli from pigs were determined. The MIC50 and MIC90 of ADP/SMZ were 0.5/2.5 and 4/20 µg/ml, respectively. The MIC of the selected pathogenic E. coli SHC28 was 0.5/2.5 µg/ml in Mueller-Hinton broth and 0.25/1.25 µg/ml in ileum fluid, respectively. In vitro, the mutant prevention concentration, the post-antibiotic effect, growth, and time-killing curves in vitro and ex vivo of ADP/SMZ against the isolate SHC28 were assayed for PD studies. The results showed that ADP/SMZ exhibited strong concentration-dependent antimicrobial activity against E. coli. After integrating the in vivo pharmacokinetic parameters of infected pigs and ex vivo PD data using the sigmoid Emax (Hill) equation, the AUC24h /MIC values in ileum fluid for bacteriostatic, bactericidal, and bacterial eradication were 18.84, 65.39, and 110.68 h, respectively. In conclusion, a dosage of 3.45/17.25 mg/kg ADP/SMZ by intramuscular injection daily for 3 consecutive days may be sufficient to treat swine colibacillosis due to E. coli with a MIC of 0.5/2.5 µg/ml.

Preparation and Evaluation of Valnemulin Hydrochloride Taste-Masking Granules.

BACKGROUND: The bitter taste and strong irritation of valnemulin hydrochloride limit its wide clinical application in pigs by oral. METHOD: In order to improve its palatability and residence time in the body, the valnemulin hydrochloride taste-masking granules with sustained-release were prepared by combining solid dispersion based on fatty acid with wet granulation. The formulation was screened by orthogonal test with content, yield, grain size and angle of repose as evaluation indexes. RESULT: The results showed that the optimal granules were composed of corn starch, sucrose, citric acid, valnemulin hydrochloride and myristic acid at a ratio of 40: 20: 20: 11: 19. The daily feed intake of pigs in the optimum taste-masking granule groups was similar to that of its self-control, and significantly higher than that in the valnemulin hydrochloride active ingredient group, suggesting that the optimum granules have satisfactory palatability. The prepared granules improved the oral bioavailability of valnemulin hydrochloride by 3.04 folds and extended its mean residence time (MRT) by 2.33 folds. CONCLUSION: The granules developed in this study could obviously improve the palatability and sustained release of valnemulin hydrochloride. The producing method of granules by combining solid dispersion powder with wet granulation can provide ideas for other drugs with poor palatability and a short half-life.