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Liver sinusoidal endothelial cells (LSECs) have a unique morphological structure known as "fenestra" that plays a crucial role in liver substance exchange and homeostasis maintenance. In this study, we demonstrate that ADAMTS18 protease is primarily secreted by fetal liver endothelial cells. ADAMTS18 deficiency leads to enlarged fenestrae and increased porosity of LSECs, microthrombus formation in liver vessels, and an imbalance of liver oxidative stress. These defects worsen carbon tetrachloride (CCl4)-induced liver fibrosis and diethylnitrosamine (DEN)/high-fat-induced hepatocellular carcinoma (HCC) in adult Adamts18-deficient mice. Mechanically, ADAMTS18 functions as a modifier of fibronectin (FN) to regulate the morphological acquisition of LSECs via the vascular endothelial growth factor A (VEGFA) signaling pathways. Collectively, a mechanism is proposed for LSEC morphogenesis and liver homeostasis maintenance via ADAMTS18-FN-VEGFA niches.
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Aiming at the existing high-temperature liquid metal flow online accurate measurement by the metal melt characteristics, installation space, and high-temperature environment adaptability limitations, this paper innovatively puts forward a soft measurement method based on the impact force generated in the fluid flow process as an observational variable series. Fluid mechanics theory and simulation software are used to analyze and verify the feasibility of the impact force as an observable variable to measure the flow rate, followed by the construction of the CNN-LSTM-CNN-Double (CLCD) flow measurement model of impact force and flow rate based on the parameters of the learning rate and the number of training times, and finally the construction of a test platform for the flow measurement, and the validity of the method is verified through actual operation.
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Developing effective electrochemiluminescence (ECL) platforms is always an essential concern in highly sensitive bioanalysis. In this work, a low-triggering-potential ECL sensor was designed for detecting synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV) based on a dual-signal amplification strategy. Initially, a probe was created by integrating Ruthenium into the hollow porphyrin-based MOF (PCN-222) structure to decrease the excitation potential and enhance ECL performance without external co-reaction accelerators. Additionally, for the first time, photonic crystals (PCs) assembled from covalent organic frameworks (COFs) were employed to amplify the ECL signal, thereby increasing the photon flux and the loading capacity of the ECL emitter to enhance sensitivity of the sensor. In the presence of the target MDPV, the aptamer labeled with Ferrocene (Fc) experienced conformational changes, causing Fc to approach the luminophore and resulting in ECL quenching. This effect was attributed to aptamer's conformational changes induced by the target, directly correlating with the target concentration. The constructed sensor showed good linearity with the target MDPV concentration, covering a dynamic range from 1.0 × 10-14 to 1.0 × 10-6 g/L and achieved an ultra-low detection limit of 4.79 × 10-15 g/L. This work employed dual amplification strategies to enhance ECL signals effectively, providing a novel method for developing highly responsive and bioactive sensors.
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Técnicas Eletroquímicas , Medições Luminescentes , Estruturas Metalorgânicas , Fótons , Pirrolidinas , Rutênio , Estruturas Metalorgânicas/química , Técnicas Eletroquímicas/métodos , Rutênio/química , Pirrolidinas/química , Alcaloides/química , Alcaloides/análise , Limite de DetecçãoRESUMO
AIMS: This study aims to establish a population pharmacokinetic (PK) model of teicoplanin in Chinese adult patients to evaluate the dosing regimen in the label sheet and optimize it. METHODS: Nonlinear mixed-effects modelling was used to estimate PK parameters. Monte Carlo simulations were used to evaluate the attainment of various dosing regimens in achieving the target trough concentrations in patients with normal or decreased renal function. RESULTS: A total of 115 patients were enrolled in this retrospective study. Creatinine clearance (CrCL) and albumin (ALB) were identified as covariates on the clearance of teicoplanin. For the treatment of non-complicated methicillin-resistant Staphylococcus aureus (MRSA) infections in patients with normal renal function and serum ALB concentration, the recommended dosing regimen was 600 mg q12h with five administrations as the loading dose followed by 600 mg qd as the maintenance dose; for the treatment of serious and/or complicated MRSA infections, the recommended dosing regimen was 800 mg q12h with five administrations as the loading dose followed by 800 mg qd as the maintenance dose. It is worth noting that both the loading and maintenance doses ought to be modified based on the patient's renal function and serum ALB concentration. In addition, trough concentrations of teicoplanin were significantly increased every other week. CONCLUSIONS: Both loading dosing and maintenance dosing regimens were recommended to be adjusted according to patient's renal function and serum ALB concentration. In addition, it is necessary to perform follow-up therapeutic drug monitoring of teicoplanin at least once every week.
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Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Adulto , Humanos , Teicoplanina/uso terapêutico , Antibacterianos , Estudos Retrospectivos , Monitoramento de Medicamentos , Albumina Sérica , Infecções Estafilocócicas/tratamento farmacológicoRESUMO
Signal amplification is a powerful approach to increasing the detection sensitivity of electrochemiluminescence (ECL). Here, we developed synergistic multieffect catalytic strategies based on CuCo2O4 nanorod combination of Ag NPs as coreaction accelerators to fabricate an efficient covalent organic framework (PTCA-COF)-based ternary ECL biosensor. Concretely, the high redox reversibility of Co3+/Co2+ and Cu2+/Cu+ would constantly promote the decomposition of S2O82- for ECL emission. Meanwhile, the introduction of Ag NPs with excellent electrocatalytic activity further realized multiple amplification of the ECL signal. Furthermore, the good hydrogen evolution reaction (HER) ability of Ag@CuCo2O4 nanorods could accelerate the proton transmission rate of the system to amplify ECL behavior. In the presence of the target synthetic cathinone 4-chloroethcathinone (4-CEC) as the quenching ECL signal-response probe, the Ferrocene (Fc)-labeled aptamer folded into the conformationally limited stem-loop structure, bringing Fc near the ECL luminophore and resulting in quenched ECL emission. The quenching effect was connected with target-induced aptamer conformational changes and consequently reflected the target concentration. Under optimum conditions, the proposed biosensor realized a highly sensitive assay for 4-CEC with a large dynamic range from 1.0 × 10-12 to 1.0 × 10-6 g/L and a detection limit as low as 2.5 × 10-13 g/L. This study integrated multiple amplification strategies for efficient ECL enhancement, which provided a novel approach to constructing highly bioactive and sensitive sensors.
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Aptâmeros de Nucleotídeos , Técnicas Biossensoriais , Catinona Sintética , Técnicas Eletroquímicas/métodos , Medições Luminescentes/métodos , Técnicas Biossensoriais/métodos , Aptâmeros de Nucleotídeos/química , Limite de DetecçãoRESUMO
As is common knowledge, a strong electrochemiluminescence (ECL) signal is required to ensure the high sensitivity of trace target detection. Here, a dual signal amplification strategy by integrating of perovskite and photonic crystal was fabricated for quantitative synthetic cannabinoids (AB-PINACA) detection based on Zr-connected PTCA and TCPP (PTCA-TCPP) with excellent ECL performance as luminophores. On the one hand, the co-reaction accelerator perovskite (LaCoO3) improved the effective electroactive area of the electrode and promoted the decomposition of K2S2O8, resulting in a stronger ECL signal value. On the other hand, polystyrene inverse opal (PIOPCs) formed after the swelling of PS microspheres not only taken advantage of the light scattering effect and excellent catalytic property of photonic crystals to amplify the ECL signal, but also could be used as a binder to fix LaCoO3 and PTCA-TCPP on the electrode surface to generate unprecedented ECL response and stable ECL signals. Subsequently, the detection substance AB-PINACA was loaded on the electrode surface via the amide bond with the luminophores PTCA-TCPP, thus quenching the ECL signal, so as to realize the sensitive detection of synthetic cannabinoids. Under the optimal conditions, the proposed sensor achieved highly sensitive AB-PINACA detection with a dynamic range from 1.0 × 10-12 to 1.0 × 10-3 g/L and the detection limit was 1.1 × 10-13 g/L, which had great application potential in the detection of synthetic cannabinoids.
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Recently, up-conversion luminescent (UCL) materials have caught extensive sight on account of their excellent biocompatibility and weak automatic fluorescence background, but the low optical signal makes researchers shy away. Organic dye-sensitized UCL materials can improve the low optical signal drawback of UCL and rejuvenate it with adjustable optical properties and unique antenna effects. In this work, an efficient, simple and selective electrochemiluminescence (ECL) sensing platform was developed for determination of enrofloxacin (ENR). 3,4,9,10-perylene tetracarboxylic acid (PTCA) was successfully used as an "antenna" to improve the ECL performance of the UCL nanoparticles (PEI-NaYF4: Yb, Er) due to its appropriate excitation spectrum position and superior electron transfer rate. The specific recognition function of the aptamer enabled the sensor to eliminate the interference from conspecific impurity. In the presence of ENR, the specific combination of ENR with aptamer made the aptamer fall from surface of the electrode, thus we could see a considerable enhancement of signal. Under the most favourable conditions, the aptasensor based on antenna effect displayed a wide detection range (1.0 × 10-14â¼1.0 × 10-6 M), low limit of detection (LOD = 3.0 × 10-15 M) and receivable recoveries (96.0%-102.4%) during water samples analysis. At this point, antenna effect provides a powerful strategy to expand the application of UCL in the field of ECL biosensing.
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Aptâmeros de Nucleotídeos , Técnicas Biossensoriais , Nanopartículas Metálicas , Perileno , Enrofloxacina , Medições Luminescentes , Técnicas Eletroquímicas , Limite de DetecçãoRESUMO
Currently, studies on electrochemiluminescence (ECL) mainly focused on the single emission of luminophores while those on multi-color ECL were rarely reported. Here, a bi-mesoporous composite of the metal-organic framework (MOF)/covalent-organic framework (COF) with strong and stable dual-color ECL was prepared to construct a novel ECL sensor for sensitive detecting targets. A PTCA-COF with excellent ECL performance was loaded with a great amount of another ECL emitter Cu3(HHTP)2. Remarkably, the integrated composite had both ECL properties of PTCA-COF at 520 nm and Cu3(HHTP)2 at 600 nm wavelengths. Furthermore, Cu3(HHTP)2 with good electron transfer ability can greatly enhance the electrical conductivity and promote electrochemical activation. Thus, the simultaneous enhanced two-color ECL intensity and the catalytic properties of the conductive MOF exerted a dual enhancement effect on the ECL signal of the composite. Significantly, diclazepam can not only be adsorbed well on the multi-stage porous structure MOF/COF composite by π-π interactions but also selectively quench the ECL signal of the PTCA-COF, realizing the sensitive detection. The ECL sensor showed a wide detection range from 1.0 × 10-13 to 1.0 × 10-8 g/L, and the limit of detection (LOD) was as low as 2.6 × 10-14 g/L (S/N = 3). The proposed ECL sensor preparation method was simple and sensitive, providing a new perspective for the potential application of multi-color ECL in the sensing field.
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Estruturas Metalorgânicas , Estruturas Metalorgânicas/química , Limite de Detecção , Diazepam , CatáliseRESUMO
Multiple clinical studies have treated mesothelin (MSLN)-positive solid tumors by administering MSLN-directed chimeric antigen receptor (CAR) T cells. Although these products are generally safe, efficacy is limited. Therefore, we generated and characterized a potent, fully human anti-MSLN CAR. In a phase 1 dose-escalation study of patients with solid tumors, we observed two cases of severe pulmonary toxicity following intravenous infusion of this product in the high-dose cohort (1-3 × 108 T cells per m2). Both patients demonstrated progressive hypoxemia within 48 h of infusion with clinical and laboratory findings consistent with cytokine release syndrome. One patient ultimately progressed to grade 5 respiratory failure. An autopsy revealed acute lung injury, extensive T cell infiltration, and accumulation of CAR T cells in the lungs. RNA and protein detection techniques confirmed low levels of MSLN expression by benign pulmonary epithelial cells in affected lung and lung samples obtained from other inflammatory or fibrotic conditions, indicating that pulmonary pneumocyte and not pleural expression of mesothelin may lead to dose-limiting toxicity. We suggest patient enrollment criteria and dosing regimens of MSLN-directed therapies consider the possibility of dynamic expression of mesothelin in benign lung with a special concern for patients with underlying inflammatory or fibrotic conditions.
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Mesotelina , Neoplasias , Humanos , Proteínas Ligadas por GPI/genética , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Linfócitos TRESUMO
Device-to-device (D2D) communication is a promising wireless communication technology which can effectively reduce the traffic load of the base station and improve the spectral efficiency. The application of intelligent reflective surfaces (IRS) in D2D communication systems can further improve the throughput, but the problem of interference suppression becomes more complex and challenging due to the introduction of new links. Therefore, how to perform effective and low-complexity optimal radio resource allocation is still a problem to be solved in IRS-assisted D2D communication systems. To this end, a low-complexity power and phase shift joint optimization algorithm based on particle swarm optimization is proposed in this paper. First, a multivariable joint optimization problem for the uplink cellular network with IRS-assisted D2D communication is established, where multiple DUEs are allowed to share a CUE's sub-channel. However, the proposed problem considering the joint optimization of power and phase shift, with the objective of maximizing the system sum rate and the constraints of the minimum user signal-to-interference-plus-noise ratio (SINR), is a non-convex non-linear model and is hard to solve. Different from the existing work, instead of decomposing this optimization problem into two sub-problems and optimizing the two variables separately, we jointly optimize them based on Particle Swarm Optimization (PSO). Then, a fitness function with a penalty term is established, and a penalty value priority update scheme is designed for discrete phase shift optimization variables and continuous power optimization variables. Finally, the performance analysis and simulation results show that the proposed algorithm is close to the iterative algorithm in terms of sum rate, but lower in power consumption. In particular, when the number of D2D users is four, the power consumption is reduced by 20%. In addition, compared with PSO and distributed PSO, the sum rate of the proposed algorithm increases by about 10.2% and 38.3%, respectively, when the number of D2D users is four.
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Algoritmos , Comunicação , Simulação por Computador , Exercício Físico , InteligênciaRESUMO
Current single signal electrochemiluminescence (ECL) sensors are susceptible to false positive or false negative phenomena due to experimental conditions. Therefore, sensors with "self-checking" function are attracting democratic attention. In quick succession, a highly sensitive single-cathode dual ECL signal aptasensor with self-checking function to improve the shortcomings mentioned above was designed. This aptasensor used In-based metal-organic framework (MIL-68) as load and stabilizer to effectively attenuate the aggregation-induced quenching (ACQ) effect of porphyrin derivatives (Sn-TCPP) while improve ECL stability. The introduction of cooperative-binding split-aptamers" (CBSAs) aptamers increased the specificity of the aptasensor and its unique double-binding domains detection accelerated the detection efficiency. When analyzing 3,4-methylenedioxypyrovalerone (MDPV), we could calculate two concentrations based on the strength of ECL 1 and ECL 2. If the concentrations are the same, the result would be obtained; if not, it should be retested. Depending on the above operation, the results achieve self-check. It was found that the designed aptasensor could quantify the concentration of MDPV between 1.0 × 10-12 g/L and 1.0 × 10-6 g/L with the limit of detection (LOD) of 1.4 × 10-13 g/L and 2.0 × 10-13 g/L, respectively (3 σ/slope). This study not only improves the detection technology of MDPV, but also explores the dual-signal detection of porphyrin for the first time and enriches the definition of self-checking sensor.
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Aptâmeros de Nucleotídeos , Técnicas Biossensoriais , Sistemas Eletrônicos de Liberação de Nicotina , Nanopartículas Metálicas , Nanopartículas Metálicas/química , Catinona Sintética , Medições Luminescentes/métodos , Aptâmeros de Nucleotídeos/química , Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/métodos , Limite de DetecçãoRESUMO
PURPOSE: The purpose of the current study was to evaluate an analytical characterization of a novel synthetic cannabinoid ethyl-2-(1-(5-fluoropentyl)-1H-indole-3-carboxamido)-3,3-dimethylbutanoate (5F-EDMB-PICA), which has a similar chemical structure to the controlled synthetic cannabinoid 5F-MDMB-PICA. METHODS: The compound was analyzed by gas chromatography-mass spectrometry (GC-MS), supercritical fluid chromatography-quadrupole time-of-flight-mass spectrometry (SFC-QTOF-MS) and spectroscopic methods, such as attenuated total reflection (ATR)-Fourier transform infrared (FTIR), ultraviolet-visible (UV-VIS) and nuclear magnetic resonance (NMR) spectroscopies. RESULTS: In this study, we reported a comprehensive analytical data of 5F-EDMB-PICA. The data of analytical characterization for the 5F-EDMB-PICA were obtained by GC-MS, SFC-QTOF-MS, ATR-FTIR spectroscopy, UV-VIS spectroscopy, and 1H and 13C NMR spectroscopy. CONCLUSIONS: In this study, we presented a comprehensive analytical characterization of 5F-EDMB-PICA obtained by 1H NMR, 13C NMR, GC-MS, SFC-QTOF-MS, ATR-FTIR spectroscopy and UV-VIS spectroscopy. The analytical data of 5F-EDMB-PICA are very useful for forensic, toxicological, and clinical diagnosis.
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Canabinoides , Cromatografia com Fluido Supercrítico , Indóis , Cromatografia Gasosa-Espectrometria de Massas , Toxicologia ForenseRESUMO
Objectives: Sabatolimab is a humanized monoclonal antibody (hIgG4, S228P) directed against human T-cell immunoglobulin domain and mucin domain-3 (TIM-3). Herein, we describe the development and characterization of sabatolimab. Methods: Sabatolimab was tested for binding to its target TIM-3 and blocking properties. The functional effects of sabatolimab were tested in T-cell killing and myeloid cell cytokine assays. Antibody-mediated cell phagocytosis (ADCP) by sabatolimab was also assessed. Results: Sabatolimab was shown to (i) enhance T-cell killing and inflammatory cytokine production by dendritic cells (DCs); (ii) facilitate the phagocytic uptake of TIM-3-expressing target cells; and (iii) block the interaction between TIM-3 and its ligands PtdSer/galectin-9. Conclusion: Taken together, our results support both direct anti-leukemic effects and immune-mediated modulation by sabatolimab, reinforcing the notion that sabatolimab represents a novel immunotherapy with immuno-myeloid activity, holding promise for the treatment of myeloid cell neoplasms.
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A ternary composite material with Au, Co-based organic frameworks (ZIF-67) and perylene derivatives (PTCD-cys) has been synthesized for identification of synthetic cannabinoids. Through contact with Au-S, Au-ZIF-67 increased electrochemiluminescence (ECL) sensitivity and stability and efficiently catalyzed the ECL of PTCD-cys. Compared with the ECL response of PTCD-cys monomer, the ECL signal value of the composite material was significantly increased, and the onset potential of Au-ZIF-67/PTCD-cys favorably shifted more than that of PTCD-cys/GCE. When the target cannabinoid molecule RCS-4 appeared, Au-ZIF-67 captured and immobilized it on the sensor surface by adsorption to achieve target-induced self-enrichment of RCS-4. Under optimal conditions, the ECL sensor was found to be linearly related to the logarithm of the RCS-4 concentration ranging from 3.1 × 10-15 to 3.1 × 10-9 mol/L with a detection limit (LOD) of 6.0 × 10-16 mol/L (S/N = 3). The approach had the advantages of being simple to use, having a high sensitivity, a wide detection range, and good stability, making it a novel platform for RSC-4 detection in public health safety monitoring.
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Canabinoides , Nanopartículas Metálicas , Catálise , Técnicas Eletroquímicas , Ouro , Medições LuminescentesRESUMO
Background: Presently, colistin is commercially available in two different forms, namely, colistin sulfate and its sulphomethylated derivative, colistimethate sodium (CMS). However, in the currently reported studies, most of the clinical studies on colistin for parenteral use are referred to as CMS. Data on the pharmacokinetics (PK), clinical efficacy, and side effects of colistin sulfate in clinical use have not been reported. Methods: This retrospective study was performed on carbapenem-resistant organism (CRO)-infected patients treated with colistin sulfate for more than 72 h. The population pharmacokinetic model was developed using the NONMEM program. The clinical outcomes including clinical treatment efficacy, microbiological eradication, and nephrotoxicity were assessed. Monte Carlo simulation was utilized to calculate the probability of target attainment (PTA) in patients with normal or decreased renal function. Results: A total of 42 patients were enrolled, of which 25 (59.52%) patients were considered clinical treatment success and 29 (69.06%) patients had successful bacteria elimination at the end of treatment. Remarkably, no patient developed colistin sulfate-related nephrotoxicity. A total of 112 colistin concentrations with a range of 0.28-6.20 mg/L were included for PK modeling. The PK characteristic of colistin was well illustrated by a one-compartment model with linear elimination, and creatinine clearance (CrCL) was identified as a covariate on the clearance of colistin sulfate that significantly explained inter-individual variability. Monte Carlo simulations showed that the recommended dose regimen of colistin sulfate, according to the label sheet, of a daily dose of 1-1.5 million IU/day, given in 2-3 doses, could attain PTA > 90% for MICs ≤ 0.5 µg/mL, and that a daily dose of 1 million IU/day could pose a risk of subtherapeutic exposure for MIC ≥1 µg/ml in renal healthy patients. Conclusion: Renal function significantly affects the clearance of colistin sulfate. A dose of 750,000 U every 12 h was recommended for pathogens with MIC ≤1 µg/ml. The dosage recommended by the label inserts had a risk of subtherapeutic exposure for pathogens with MIC ≥2 µg/ml. Despite higher exposure to colistin in patients with acute renal insufficiency, dose reduction was not recommended.
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Patterning high-resolution microstructures on thermoplastic substrates is of fundamental importance for the commercialization of microfluidics, advanced functional surfaces, and optical elements. Though many methods are developed to fabricate micropatterned plastic devices with 100 µm resolution, they suffer substantially higher cost or lower productivity when the resolution of the micropatterns is to be further improved. Here, we develop low-cost molds consisting of thin ceramic-filled-epoxy composite coatings on steel substrates. By virtue of the loaded ZrO2 nanoparticle fillers, the enhanced mechanical and thermal properties of the composite molds enable the epoxy microstructures to survive harsh conditions in conventional thermoplastic processing methods including hot embossing, imprinting, and mold injection. With the ceramic-filled-epoxy coated molds, we are able to improve the fabrication resolution of microstructures on plastics to 10 µm with unprecedented low-cost and excellent durability.
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Background: Linezolid is associated with myelosuppression, which may cause failure in optimally treating bacterial infections. The study aimed to define the pharmacokinetic/toxicodynamic (PK/TD) threshold for critically ill patients and to identify a dosing strategy for critically ill patients with renal insufficiency. Methods: The population pharmacokinetic (PK) model was developed using the NONMEM program. Logistic regression modeling was conducted to determine the toxicodynamic (TD) threshold of linezolid-induced myelosuppression. The dosing regimen was optimized based on the Monte Carlo simulation of the final model. Results: PK analysis included 127 linezolid concentrations from 83 critically ill patients at a range of 0.25-21.61 mg/L. Creatinine clearance (CrCL) was identified as the only covariate of linezolid clearance that significantly explained interindividual variability. Thirty-four (40.97%) of the 83 patients developed linezolid-associated myelosuppression. Logistic regression analysis showed that the trough concentration (Cmin) was a significant predictor of myelosuppression in critically patients, and the threshold for Cmin in predicting myelosuppression with 50% probability was 7.8 mg/L. The Kaplan-Meier plot revealed that the overall median time from the initiation of therapy to the development of myelosuppression was 12 days. Monte Carlo simulation indicated an empirical dose reduction to 600 mg every 24 h was optimal to balance the safety and efficacy in critically ill patients with CrCL of 30-60 ml/min, 450 mg every 24 h was the alternative for patients with CrCL <30 ml/min, and 600 mg every 12 h was recommended for patients with CrCL ≥60 ml/min. Conclusion: Renal function plays a significant role in linezolid PKs for critically ill patients. A dose of 600 mg every 24 h was recommended for patients with CrCL <60 ml/min to minimize linezolid-induced myelosuppression.
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Limited data are available for ceftazidime-avibactam (CZA) dosing in patients receiving renal replacement therapy, especially the data on the dosing in patients receiving intermittent hemodialysis (IHD). In this report, we firstly described a case in which CZA was administered as 2.5 g after each time of IHD, and a dose of 1.25 g was added on the 48th-hour for the 72-h interdialytic interval. Plasma concentrations of CZA measured at different time indicated that > 50% of administered ceftazidime and avibactam were removed during the 4-h hemodialysis. In addition, we described another case on continuous venovenous hemodialysis (CVVHD), in which CZA was administered as 2.5 g q12h in 2-h infusions. The dose regimen for these two cases could achieve trough concentration of ceftazidime higher than fourfold of the MIC and trough concentration of avibactam higher than the threshold of 1 µg/mL during the treatment, and exert efficient antimicrobial effect.
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AIMS: Data regarding clinical pharmacokinetic/toxicodynamic (PK/TD) of polymyxin B is short of direct quantitative data. This study aims to investigate the risk factors of polymyxin B associated acute kidney injury (AKI) and to assess the relationship between polymyxin B plasma levels and its nephrotoxicity. METHODS: A retrospective study was performed in adult patients treated with polymyxin B. Risk factors associated with AKI and plasma trough concentrations of polymyxin B were identified via medical record review. A multivariate logistic regression model was established and the risk of polymyxin B-associated AKI were predicted by a receiver operating characteristic curve, with maximal Youden index used to identify safety thresholds among the study population. RESULTS: Fifty-four adult patients were included in the study. AKI was detected in 14 patients during polymyxin B treatment (25.9%, 14 out of 54). Cmin (odds ratio [OR] 2.071; 95% confidence interval [CI] 1.235-3.472) and baseline serum creatinine (OR 1.024; 95% CI 1.005-1.043) were significant independent risk factors for developing AKI. The area under the ROC curve of the combined predictor was larger based on the above factors. When the Youden index was at maximum, the optimal cut-off point was 6.678 of the ROC curve. When Cmin ≥ 3.13 mg/L, the probability of AKI was more than 50%. CONCLUSION: In this study, when the calculated combined predictor value was >6.678, there was an increased risk of AKI. Maintaining a polymyxin B Cmin level below 3.13 mg/L may be helpful in reducing the incidence of polymyxin B associated nephrotoxicity.