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The inflammatory response induced by implant/macrophage interaction has been considered to be one of the vital factors in determining the success of implantation. In this study, TiCuN x O y coating with an immunomodulatory strategy was proposed for the first time, using nanostructured TiCuN x O y coating synthesized on Ti-Cu alloy by oxygen and nitrogen plasma-based surface modification. It was found that TiCuN x O y coating inhibited macrophage proliferation but stimulated macrophage preferential activation and presented an elongated morphology due to the surface nanostructure. The most encouraging discovery was that TiCuN x O y coating promoted the initial pro-inflammatory response of macrophages and then accelerated the M1-to-M2 transition of macrophages via a synergistic effect of fast-to-slow Cu 2+ release and surface nanostructure, which was considered to contribute to initial infection elimination and tissue healing. As expected, TiCuN x O y coating released desirable Cu 2+ and generated a favorable immune response that facilitated HUVEC recruitment to the coating, and accelerated proliferation, VEGF secretion and NO production of HUVECs. On the other hand, it is satisfying that TiCuN x O y coating maintained perfect long-term antibacterial activity (≥99.9%), mainly relying on Cu 2 O/CuO contact sterilization. These results indicated that TiCuN x O y coating might offer novel insights into the creation of a surface with immunomodulatory effects and long-term bactericidal potential for cardiovascular applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Contezolid is a novel oxazolidinone antibiotic with good antibacterial activity against gram-positive bacteria including methicillin-resistant Staphylococcus aureus. For the purpose to further characterize the pharmacokinetics of contezolid and its major metabolite M2, accurate and rapid ultra-performance liquid chromatography-tandem mass spectrometric assays (UPLC-MS/MS) were developed and validated for simultaneous quantification of contezolid and M2 in human plasma and urine. The plasma samples were pretreated by liquid-liquid extraction. The automated solid phase extraction method was used to preprocess urine samples. ACQUITY UPLC® BEH C8 (2.1 mm × 100 mm, 1.7 µm) column was used to separate the analytes with a gradient mobile phase of acetonitrile and water at a flow rate of 0.4 mL/min. The calibration curves showed good linearity over the concentration ranges of 0.0100-5.00 µg/mL for contezolid in plasma and urine, 0.00200-1.00 µg/mL in plasma and 0.0200-10.0 µg/mL in urine for M2, respectively. For both plasma and urine assays, the intra- and inter-batch accuracy and precision were within 15% for all quality control levels, including the lower limit of quantitation. The methods were fully validated and successfully applied to a pharmacokinetic study of contezolid tablets in subjects with moderate hepatic impairment., (Copyright © 2022. Published by Elsevier B.V.)

Polymyxin-based combination therapy is commonly used to treat carbapenem-resistant Acinetobacter baumannii (CRAB) infections. In the present study, the bactericidal effect of polymyxin B and minocycline combination was tested in three CRAB strains containing bla OXA-23 by the checkerboard assay and in vitro dynamic pharmacokinetics/pharmacodynamics (PK/PD) model. The combination showed synergistic or partial synergistic effect (fractional inhibitory concentration index ≤0.56) on the tested strains in checkboard assays. The antibacterial activity was enhanced in the combination group compared with either monotherapy in in vitro PK/PD model. The combination regimen (simultaneous infusion of 0.75 mg/kg polymyxin B and 100 mg minocycline via 2 h infusion) reduced bacterial colony counts by 0.9-3.5 log 10 colony forming units per milliliter (CFU/mL) compared with either drug alone at 24 h. In conclusion, 0.75 mg/kg polymyxin B combined with 100 mg minocycline via 2 h infusion could be a promising treatment option for CRAB bloodstream infections.

Objectives: Polymyxin B is a last-line antibiotic for multidrug-resistant gram-negative bacterial infections. However, limited safety and pharmacokinetic information is available. We investigated the safety and pharmacokinetics of intravenous polymyxin B in healthy subjects., Methods: An open-label, single-dose clinical trial was conducted in healthy Chinese subjects. Polymyxin B (sulphate) was administered intravenously at 0.75 or 1.5 mg/kg (n = 10 per dose, 5 males and 5 females) to examine the safety and pharmacokinetics., Results: One female subject in the 1.5-mg/kg group discontinued due to abdominal pain during administration. The most frequently reported adverse events were perioral paraesthesia, dizziness, and numbness of extremities (7/10 subjects in the 0.75-mg/kg group, all subjects in the 1.5-mg/kg group). All neurotoxicity-related events dissipated without treatment within a maximum of 23 h. Notably, abdominal pain (3/5) and vulvar pruritus (2/5), colpitis (2/5) or abnormal uterine bleeding (1/5) were reported in female subjects receiving the 1.5-mg/kg dose. In the 0.75-mg/kg group, the total clearance, volume of distribution and half-life of polymyxin B were 0.028±0.002 L/h/kg, 0.219±0.023 L/kg and 5.44±0.741 h, respectively; similar values were observed in the 1.5-mg/kg group. Urinary recovery was 3.7 ± 1.1% and 8.1 ± 1.3% in the 0.75- and 1.5-mg/kg groups, respectively. Population pharmacokinetics of polymyxin B was consistent with a three-compartment model. The clearance and distribution of the central compartment were 0.027 L/h/kg and 0.071 L/kg, respectively., Conclusions: This study is the first to examine the safety and pharmacokinetics of polymyxin B in healthy subjects. Our results highlight that acute toxicity is a dose-limiting factor for intravenous polymyxin B., Competing Interests: Declarations of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests, (Copyright © 2021 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

In order to improve antibacterial properties and cell biocompatibility of Ti-Cu alloy, an ultrasonic micro-arc oxidation (UMAO) has been applied to Ti-Cu alloy. The corrosion resistance, antibacterial activity and cell compatibility of Ti-Cu alloy before and after UMAO were studied in detail by means of electrochemical test, plate count method and CCK-8 test scanning electron microscopy (SEM) technology to evaluate the application possibilities of UMAO as a surface bio-modification method for Ti-Cu alloy. The surface microstructure characterisation showed that a typical porous coating with a pore diameter of 3-8 μm and a thickness of 5-15 μm was formed on the surface of the Ti-Cu alloy, which significantly improved the surface roughness and hydrophilicity. The plate count method demonstrated that UMAO coatings on Ti-Cu alloy showed strong antibacterial activity (≥99%) against Staphylococcus aureus (S. aureus) even after being immersed in a physiological saline for up to 20 days, indicating that UMAO-treated Ti-Cu alloy had very strong long-term antibacterial properties. It is believed that the strong long-term antimicrobial properties of Ti-Cu-UMAO samples were mainly due to the formation of Cu 2 O and CuO in UMAO coatings. The results of cell compatibility evaluation showed that UMAO treatment did not bring about cytotoxicity but improved the early adhesion of MC3T3 cell., Competing Interests: Declaration of competing interest No conflict of interest., (Copyright © 2020. Published by Elsevier B.V.)

Purpose: This study was designed to correlate the pharmacokinetic/pharmacodynamic (PK/PD) parameters with PD indices of levornidazole against Bacteroides fragilis and to calculate the PK/PD target value for levornidazole to attain its expected maximal bactericidal effect using an in vitro anaerobic dynamic PK/PD model., Methods: An anaerobic dynamic PK/PD model was developed in vitro. The scheme for PK modeling was designed according to the PK parameters of levornidazole in the human body. The device of 2-compartment PK/PD model was constructed by using digital control of flow rate to simulate 4 regimens of single-dose intravenous infusion of levornidazole to determine the bactericidal activity of levornidazole against the 3 strains of B fragilis within 72 hours. PD parameters such as reduction of colony count within 24 hours (∆Log 24h ), area under bactericidal curve (AUBC), and 2-hour initial killing rate (IKR) were calculated and correlated with PK/PD parameters. Sigmoid E max model of levornidazole was established to calculate PK/PD target values to attain corresponding PD effect., Findings: PK and PD validation proved the stability of the model in simulating levornidazole against B fragilis and the precision and accuracy in the results of PK modeling. C max and AUC 0-24h found only -1.46% and -6.72% differences from the values in vivo. Our study found that ∆Log 24h , AUBC, and IKR were more correlated with AUC 0-24h /MIC and C max /MIC than with %T>MIC. According to ∆Log 24h , the PK/PD target values of AUC 0-24h /MIC, C max /MIC, and %T>MIC of levornidazole against B fragilis were 157.6%, 14.1%, and 56.4%, respectively., Implications: Our findings are useful for optimizing the clinical dosing regimen of levornidazole sodium chloride injection to attain maximal bactericidal effect., (Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.)

This study evaluated the in vitro anti-anaerobic activity and spectrum of levornidazole, its metabolites and comparators against 375 clinical isolates of anaerobic bacteria, including Gram-negative bacilli (181 strains), Gram-negative cocci (11 strains), Gram-positive bacilli (139 strains) and Gram-positive cocci (44 strains), covering 34 species. Minimum inhibitory concentrations (MICs) of levornidazole, its five metabolites and three comparators against these anaerobic isolates were determined by the agar dilution method. Minimum bactericidal concentrations (MBCs) of levornidazole and metronidazole were measured against 22 strains of Bacteroides fragilis. Levornidazole showed good activity against B. fragilis, other Bacteroides spp., Clostridium difficile, Clostridium perfringens and Peptostreptococcus magnus, evidenced by MIC90 values of 0.5, 1, 0.25, 2 and 1mg/L, respectively. The activity of levornidazole and the comparators was poor for Veillonella spp. Generally, levornidazole displayed activity similar to or slightly higher than that of metronidazole, ornidazole and dextrornidazole against anaerobic Gram-negative bacilli, Gram-positive bacilli and Gram-positive cocci, especially B. fragilis. Favourable anti-anaerobic activity was also seen with levornidazole metabolites M1 and M4 but not M2, M3 or M5. For the 22 clinical B. fragilis strains, MBC50 and MBC90 values of levornidazole were 2mg/L and 4mg/L, respectively. Both MBC50/MIC50 and MBC90/MIC90 ratios of levornidazole were 4, similar to those of metronidazole. Levornidazole is an important anti-anaerobic option in clinical settings in terms of its potent and broad-spectrum in vitro activity, bactericidal property, and the anti-anaerobic activity of its metabolites M1 and M4., (Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)