Dynamic migration and risk of cephalosporin antibiotic resistance genes: Move from pharmaceutical plants through wastewater treatment plants to coastal tidal flats sediments.

The migration and dissemination of antibiotics and their corresponding antibiotic resistance genes (ARGs) from pharmaceutical plants through wastewater treatment to the environment introduce exogenous ARGs, increasing the risk of antibiotic resistance. Cephalosporin antibiotics (Ceps) are among the most widely used antibiotics with the largest market scale today, and the issue of resistance is becoming increasingly severe. In this study, a cephalosporin pharmaceutical plant was selected and metagenomic analysis was employed to investigate the dissemination patterns of cephalosporin antibiotics (Ceps) and their ARGs (CepARGs) from the pharmaceutical plant through the wastewater treatment plant to tidal flats sediments. The findings revealed a significant reduction in the total concentration of Ceps by 90.32 % from the pharmaceutical plant's Pioneer Bio Reactor (PBR) to the effluent of the wastewater treatment plant, and a notable surge of 172.13 % in the relative abundance of CepARGs. It was observed that CepARGs originating from the PBR could migrate along the dissemination chain, contributing to 60 % of the CepARGs composition in tidal flats sediments. Microorganisms play a crucial role in the migration of CepARGs, with efflux-mediated CepARGs, as an intrinsic resistance mechanism, exhibiting a higher prospensity for migration due to their presence in multiple hosts. While Class I risk CepARGs are present at the pharmaceutical and wastewater plant stages, Class I ina-CepARGs are completely removed during wastewater treatment and do not migrate to the environment. This study reveals the dynamic migration characteristics and potential risk changes regarding Ceps and CepARGs in real dissemination chains, providing new theoretical evidence for the mitigation, control, and risk prevention of CepARGs.

Development of Magnetic Molecularly Imprinted Polymer Coupled Nanospray Ion Source for Analysis of Cephalosporin Antibiotics in Food Samples.

A magnetic molecularly imprinted polymer (MMIP) coupled nanospray ion source was developed for analysis of cephalosporin antibiotics in food samples. MIP coated Fe3O4 nanospheres were prepared for magnetic solid-phase extraction (MSPE) of the antibiotics in the extract of samples and then integrated into the nanospray capillary for further desorption and mass spectrometry analysis. The developed device combines the advantages of high extraction efficiency of MSPE, unique selectivity of MIPs, and fast analysis speed of ambient ionization mass spectrometry (AIMS). Five cephalosporin antibiotics in milk, egg, and beef samples were analyzed using the developed methods. High sensitivities with limits of detection (LODs) from 0.3 to 0.5 µg kg-1 were achieved for cephalosporin antibiotics in milk, egg, and beef samples, respectively. Good linearity, determination coefficient values (R2 > 0.992), and precision (RSD < 15%) with recoveries ranging from 72.6% to 115.5% were obtained using the spiked milk, egg, and beef sample matrices.

Preparation of pH-responsive block copolymers for separation of cephalosporin antibiotics by open-tubular capillary electrochromatography.

Stimuli-responsive block copolymers have exhibited their feasibility for drug delivery and analysis of biomolecules. However, study of the electrophoretic behavior of antibiotics by open tubular capillary electrochromatography (OT-CEC) based on smart block copolymers coatings is still a substantial challenge. Herein, we reported an OT-CEC protocol for analysis of cephalosporin antibiotics with pH-responsive block copolymers as coatings. By using the reversible addition-fragmentation chain-transfers radical polymerisation technique, the smart poly(styrene-maleic anhydride-acrylic acid) (P(St-MAn-AA)) was synthesized and subsequently chemical bonded onto the inner walls of amino-grafted capillaries. The pH induced changes in the stretch/curl states of P(St-MAn-AA) chains were used to generate an adjustable hydrophobic/hydrophilic interaction and hydrogen bonds between the polymer coatings and the analytes. The OT-CEC performance was evaluated by varying the monomer ratios, polymer coating amounts and layers, buffer concentrations and pH values. Baseline separation of the three-test antibiotics was achieved at pH 8.0. The proposed OT-CEC technique was further applied to the determination of rat serum antibiotics in the metabolic processes. The present work demonstrates an enhancement in antibiotics separation efficiency, and shows a great potential for the preparation of stimuli-responsive block copolymers coatings and in OT-CEC analysis of real samples in living bio-systems.

Analytical Determination of Cephalosporin Antibiotics Using Coordination Polymer Based on Cobalt Terephthalate as a Sorbent.

In this work, a coordination polymer based on cobalt terephthalate was obtained and characterized by elemental analysis, infrared spectroscopy, X-ray diffraction analysis, and scanning electron microscopy. The coordination polymer was tested as a sorbent for the solid-phase extraction of cephalosporin antibiotics, including ceftriaxone, cefotaxime, and cefazolin, from aqueous solutions. The coordination polymer had a high adsorption capacity (520.0 mg/g). Antibiotics adsorption followed pseudo-second order kinetic model and the Freundlich isotherm model. The calculated thermodynamic parameters indicate a spontaneous process. The resulting coordination polymer has good stability and reusability. The possibility of separating the studied cephalosporins on a chromatographic column filled with a coordination polymer was shown. This work opens great prospects for the development and application of a coordination polymer based on cobalt terephthalate for the removal of cephalosporins from ambient water.

Combination of Cefotaxime and Cisplatin Specifically and Selectively Enhances Anticancer Efficacy in Nasopharyngeal Carcinoma.

BACKGROUND: HMOX1 has a dual role in cancers, especially involving chemoresistance. We demonstrate that cephalosporin antibiotics exert strong anticancer activity in nasopharyngeal carcinoma mainly via drastic upregulation of HMOX1. OBJECTIVES: Cephalosporin antibiotics are commonly used for the treatment or prophylaxis of bacterial infectious diseases in cancer patients. It is unknown whether they lead to chemoresistance in cancer patients, especially in nasopharyngeal carcinoma patients, who are being treated or required prophylaxis for an infectious syndrome with cephalosporin antibiotics. METHODS: MTT and clonogenic colony formation assays assessed the viability and proliferation of cultured cancer cells. Flow cytometry was used to detect apoptosis. Tumor growth was assessed using a xenograft model. Microarray and RT-qPCR expression analyses investigated differential gene expression. RESULTS: Cefotaxime enhanced anticancer efficacy of cisplatin in nasopharyngeal carcinoma without enhancing the toxic side effects both in vitro and in vivo. However, cefotaxime significantly reduced the cytotoxicity of cisplatin in other cancer cell lines. Cefotaxime and cisplatin co-regulated 5 differential genes in CNE2 cells in a direction supporting the enhancement of anticancer efficacy, of which, THBS1 and LAPTM5 were further upregulated, STAG1, NCOA5, and PPP3CB were further downregulated. Out of the 18 apoptotic pathways significantly enriched in the combination group, THBS1 and HMOX1 overlapped in 14 and 12 pathways, respectively. Extrinsic apoptotic signaling pathway (GO: 2001236) was the only apoptotic pathway commonly enriched in cefotaxime group, cisplatin group and combination group, and THBS1 and HMOX1 were the overlapped genes of this pathway. THBS1 also overlapped in P53 signaling pathway and ECM-receptor interaction signaling pathway enriched by KEGG. CONCLUSION: Cephalosporin antibiotics are chemosensitizers of conventional chemotherapeutic drugs in the chemotherapy of nasopharyngeal carcinoma, but they may lead to chemoresistance by cytoprotection in other cancers. Cefotaxime and cisplatin co-regulate THBS1, LAPTM5, STAG1, NCOA5 and PPP3CB suggesting their involvement in the enhancement of anticancer efficacy in nasopharyngeal carcinoma. Targeting of P53 signaling pathway and ECM-receptor interaction signaling pathway was correlated to the enhancement. With additional benefit for treatment or prophylaxis of an infectious syndrome, cephalosporin antibiotics can benefit the therapy of nasopharyngeal carcinoma either as anticancer agents or as chemosensitizers of chemotherapeutic drugs in combination chemotherapy.

Development and Validation for Quantification of Cephapirin and Ceftiofur by Ultraperformance Liquid Chromatography with Triple Quadrupole Mass Spectrometry.

Cross contamination of ß-lactams is one of the highest risks for patients using pharmaceutical products. Penicillin and some non-penicillin ß-lactams may cause potentially life-threatening allergic reactions. The trace detection of ß-lactam antibiotics in cleaning rinse solutions of common reactors and manufacturing aids in pharmaceutical facilities is very crucial. Therefore, the common facilities adopt sophisticated cleaning procedures and develop analytical methods to assess traces of these compounds in rinsed solutions. For this, a highly sensitive and reproducible ultra-performance liquid chromatography with triple quadrupole mass spectrometry (UHPLC-MS/MS) method was developed for the analysis of Cephapirin and Ceftiofur. As per the FDA guidelines described in FDA-2011-D-0104, the contamination of these ß-lactam antibiotics must be regulated. The analysis was performed on an XBridge C18 column with 100 mm length, 4.6 mm diameter, and 3.5 µm particle size at an oven temperature of about 40 °C. The mobile phase was composed of 0.15% formic acid in water and acetonitrile as mobile phases A and B, and a flow rate was set to 0.6 mL/min. The method was validated for Cephapirin and Ceftiofur. The quantification precision and accuracy were determined to be the lowest limit of detection 0.15 parts per billion (ppb) and the lowest limit of quantification 0.4 ppb. This method was linear in the range of 0.4 to 1.5 ppb with the determination of coefficient (R2 > 0.99). This sensitive and fast method was fit-for-purpose for detecting and quantifying trace amounts of ß-lactam contamination, monitoring cross contamination in facility surface cleaning, and determining the acceptable level of limits for regulatory purposes.

The binding characteristics of sediment-derived dissolved organic matter with ceftazidime: a microstructural and spectroscopic correlation study.

This research focused on the characterization of sediment-derived dissolved organic matter (SDOM) extracted from sediment of Yellow River and the binding behaviors of ceftazidime (CAZ) with the presence of SDOM. The morphology, surface composition and structure of SDOM and the complexation between SDOM and CAZ in terms of component features, binding capacity and sequence were studied by multiple approaches. Results showed that SDOM was in situ autochthonous-dominated with a low weight-average molecular weight and aromaticity (the value of SR was 2.523). The multiple morphological characteristics, high surface oxygen contents (53.49%) and more aliphatic (H/C = 1.91) of SDOM were further confirmed. Studies on SDOM-CAZ interaction suggested that the functional groups and chemical compositions of SDOM were susceptible to CAZ. In more detail, the aromatic protons and aliphatic protons of CAZ impacted significantly, and the binding between CAZ and SDOM might relate to noncovalent. The protein-like fractions were considered to be the primary participant with 49% fractions lost and the aromatics and amides as mainly active site interaction with CAZ. These findings have significant implications on the environmental fate of cephalosporin antibiotics and that of sediment-derived DOM.

Performance and bacterial community of bio-electrochemical system treating simulated domestic wastewater containing low concentration of cephalosporin antibiotics.

This study investigated the effects of five cephalosporin antibiotics (ceftazidime, ceftriaxone, cefdinir, cefixime and cefepime) on performance and bacterial community structure in bio-electrochemical systems (BES) and sequencing batch biofilm reactor (SBBR). The results showed that the external electric field had no significant effect on the removal of COD and ammonia nitrogen in water. The removal rates of five antibiotics in BES increased by 28.5%, 20.0%, 9.1%, 21.0%, and 11.5%, respectively. High-through sequencing showed that microbial membrane-growing process increased species diversity, and antibiotics had a significant inhibitory effect on the initial biofilm of the reactor. As time progressed, the inhibitory effect was weakened, and the microorganism were tolerated and re-enriched. The increase in the type and concentration of antibiotics and the applied electric field had a significant effect on the microorganisms in the reactor. The dominant microorganisms for antibiotic removal in the SBBR were Luteococcus, Cloacibacterium, Dysgonomonas, and Ottowia. The dominant bacteria in the BES were Ottowia and Tahibacte. The abundance of these strains increased significantly during antibiotic acclimation. The abundance of Ottowia, Tahibacter, and Nakamurella were significantly higher than SBBR. Thus the BES system had a good antibiotic degradation effect. The BES can effectively treat simulated domestic sewage containing multiple antibiotics, laying a theoretical foundation for the actual wastewater treatment.

Structure-dependent surface catalytic degradation of cephalosporin antibiotics on the aged polyvinyl chloride microplastics.

Microplastics (MPs) have been recognized as a global concern due to their potential health effect, as MPs could adsorb and carry various pollutants in aquatic environment. In the present study, a new environmental behavior related to polyvinyl chloride microplastics (PVC-MPs) and the underlying mechanism were described. Our results showed that the photo-aged PVC-MPs could affect the transformation of cephalosporin antibiotics. For instance, the presence of altered PVC-MPs significantly accelerated the hydrolysis of cefazolin (CFZ), but exhibited negligible effect on the degradation of cephalexin (CFX). As indicated by in situ Fourier transform infrared spectra and theoretical calculations, hydrogen bonds could be formed between ß-lactam carbonyl of CFZ and the oxygen-containing moieties on the aged PVC-MP surfaces. The hydrogen-bonding was able to significantly increase the positive atomic Mulliken charge on the ß-lactam carbonyl carbon, thus narrowing the energy gap of CFZ hydrolysis and subsequently enhancing the disruption of ß-lactam ring. While for CFX, instead of the ß-lactam carbonyl, the amide amino group was involved in the hydrogen-bonding due to the structural difference. Therefore, in addition to increasing the adsorption capacity, the aged PVC-MPs could act as the catalyst to mediate the transformation of antibiotics. Our study would help improve the understanding for interactions between contaminants and MPs in natural environments.

Cephalosporin antibiotics specifically and selectively target nasopharyngeal carcinoma through HMOX1-induced ferroptosis.

AIMS: Many antibiotics derived from mold metabolites have been found to possess anticarcinogenic properties. We aimed to investigate whether they may elicit anticancer activity, especially against nasopharyngeal carcinoma. MAIN METHODS: The response of nasopharyngeal and other carcinoma cell lines to cephalosporin antibiotics was evaluated in vitro and in vivo. MTT and clonogenic colony formation assays assessed the viability and proliferation of cultured cells. Flow cytometry was used to assess cell cycle parameters and apoptotic markers. Tumor growth was determined using a xenograft model in vivo. Microarray and RT-qPCR expression analyses investigate differential gene expression. Mechanistic assessment of HMOX1 in cefotaxime-mediated ferroptosis was tested with Protoporphyrin IX zinc. KEY FINDINGS: Cephalosporin antibiotics showed highly specific and selective anticancer activity on nasopharyngeal carcinoma CNE2 cells both in vitro and vivo with minimal toxicity. Cefotaxime sodium significantly regulated 11 anticancer relevant genes in CNE2 cells in a concentration-dependent manner. Pathway analyses indicate apoptotic and the ErbB-MAPK-p53 signaling pathways are significantly enriched. HMOX1 represents the top one ranked upregulated gene by COS and overlaps with 16 of 42 enriched apoptotic signaling pathways. Inhibition of HMOX1 significantly reduced the anticancer efficacy of cefotaxime in CNE2 cells. SIGNIFICANCE: Our discovery is the first to highlight the off-label potential of cephalosporin antibiotics as a specific and selective anticancer drug for nasopharyngeal carcinoma. We mechanistically show that induction of ferroptosis through HMOX1 induction mediates cefotaxime anticancer activity. Our findings provide an alternative treatment for nasopharyngeal carcinoma by showing that existing cephalosporin antibiotics are specific and selective anticancer drugs.

Development of a Broad-Specific Competitive ELISA for First-Generation Cephalosporin Antibiotics in Animal-Derived Foods Samples.

The abuse of antibiotics, such as the cephalosporins in livestock and aquaculture productions, usually causes the widespread antibiotic resistance due to their growth-promoting effects. In this study, cephalexin was chosen as the hapten molecule to prepare a broad-spectrum rabbit polyclonal antibody for cephalosporin antibiotics. The obtained antibody exhibited broad cross-reactivity ranging from 0.05% to 100% with 10 cephalosporins. Based on this antibody, we developed a broad-specific indirect competitive ELISA (ic-ELISA) for cefalexin, cefradine, cefadroxil and cefazolin with the half maximal inhibitory concentration (IC50) ranging from 0.72 to 2.99 ng/mL in working buffer. For animal-derived food samples with spiked cephalosporins, the ic-ELISA exhibited an excellent recovery ranging from 72.3% to 95.6%. To verify the accuracy of this proposed ic-ELISA, its detection performance was evaluated utilizing the high-performance liquid chromatography with satisfactory results. This study confirmed that: firstly, the prepared antibody can be used as a class-specific recognition element to develop immunoassays for cephalosporin antibiotics; and secondly, the developed ic-ELISA provided a new tool for broad-spectrum detection of first-generation cephalosporins in animal-derived foods.

Magnetic N-doped 3D graphene-like framework carbon for extraction of cephalexin monohydrate and ceftiofur hydrochloride.

Magnetic N-doped 3D graphene-like framework carbon (Fe3O4@N-3DFC) was prepared via direct pyrolysis of sodium citrate and further hydrothermal reaction, and employed in the extraction of two cephalosporin antibiotics including cephalexin monohydrate and ceftiofur hydrochloride. The scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectrometry, X-ray photoelectron spectroscopy and X-ray diffraction were employed to confirm the successful synthesis of 3DFC-based adsorbents (3DFCs) including 3DFC, Fe3O4@3DFC and Fe3O4@N-3DFC. Fe3O4@N-3DFC sorbent with 3D graphene-like honeycomb architecture combined magnetic and N doping shows the attractive features including graphene carbon sheets, hierarchical porous structure, good wettability and higher surface affinity for cephalosporin antibiotics. Furthermore, the comparison of extraction efficiency with raw 3DFC and Fe3O4@3DFC sorbent also confirmed the superiority of Fe3O4@N-3DFC sorbent. Under optimized conditions, good linearity lines were obtained with the determination coefficients from 0.9953 to 0.9995. The limit of detections were in the range of 0.20-0.45 µg L-1 and 0.03-0.10 µg L-1 for cephalexin and ceftiofur, respectively. The spiked extraction recoveries were between 81.59% and 98.35% with the relative standard deviation values less than 6.98%. Combined with high performance liquid chromatography, Fe3O4@N-3DFC based magnetic solid-phase extraction was successfully applied in river water and zebrafish samples analysis.

Highly efficient removal of ceftiofur sodium using a superior hydroxyl group functionalized ionic liquid-modified polymer.

The occurrence of cephalosporin antibiotics in water resources has caused increasing concerns about their potential effects on ecosystem and human health. However, reports on the efficient removal of these antibiotics are limited. In this work, a superior hydroxyl-functionalized ionic liquid based polymer (PS-[Hemim][Cl]) was prepared for highly efficient removal of ceftiofur sodium (CFS) antibiotic from aqueous solutions, and the effect of various factors on the adsorption was investigated. It was found that the PS-[Hemim][Cl] exhibited a super-high adsorption capacity of 1260.5 mg/g for CFS within 60 min and kept high removal efficiency in a wide range of antibiotic concentrations from 5 ppb level to 1000 mg/L. Even the concentration of common inorganic ions was 1000 times higher than that of CFS, the adsorption efficiency remained above 93%. At the same time, the PS-[Hemim][Cl] showed excellent adsorption performance for the antibiotics with similar structure to CFS. Compared with commercially available adsorbents, the adsorption capacity of PS-[Hemim][Cl] for CFS was 4-468 times higher under the same experimental conditions. The application of PS-[Hemim][Cl] to real wastewater containing different concentrations of CFS was investigated and promising results were reported. Additionally, preliminary mechanism studies suggested that electrostatic attraction, hydrogen bond and ion exchange synergistically contributed to the highly efficient adsorption of CFS.

Pharmacological significance of prostaglandin E2 and D2 transport at the brain barriers.

Prostaglandin (PG) E2 and PGD2, which are biosynthesized from arachidonic acid generated by enzymatic cleavage of membrane phospholipid in response to various stimuli, play key roles in multiple brain pathophysiological processes, including modulation of synaptic plasticity, neuroinflammation, and sleep promotion. Concentrations of PGE2 and PGD2 in brain interstitial fluid (ISF) and cerebrospinal fluid (CSF) are maintained at appropriate levels for normal brain function by regulatory systems. The blood-brain barrier (BBB) and the blood-CSF barrier (BCSFB) possess ISF/CSF-to-blood efflux transport systems that are the primary cerebral clearance pathways for PGE2 and PGD2. However, regulatory dysfunction at the brain barriers may seriously affect brain function. In a mouse inflammation model, significant reduction of PGE2 efflux transport at the BBB has been observed. Several kinds of cephalosporin antibiotics and nonsteroidal anti-inflammatory drugs inhibit the BBB- and BCSFB-mediated efflux transport of PGE2 and PGD2. Especially, drugs that inhibit multidrug resistance-associated protein 4 (MRP4)-mediated PGE2 transport are capable of reducing PGE2 efflux at the BBB. Thus, it might be important in the treatment of inflammatory and infectious diseases to use drugs that do not inhibit clearance of PGE2 at the brain barriers, in order to avoid unexpected adverse CNS effects. Further, considering that PGD2 in CSF is a natural sleep-promoting factor, changes in the activity of the PGD2 efflux transport system at the BCSFB may modify the PGD2 level in CSF, thus affecting physiological sleep. These findings indicate that the efflux transport systems at the brain barriers play key roles in the pathophysiology and pharmacology of PGE2 and PGD2.

Simultaneous Analysis of Seven Cephalosporin Antibiotics in Water by High Performance Liquid Chromatography / 环境与健康杂志

Objective To develop a satisfactory and reliable method for simultaneous determination of seven cephalosporin antibiotics (cefadroxil,cephalexin,cefoperazone,cefuroxime,cefradine,ceftazidime and cefotaxime) in water samples using solidphase extraction and high performance liquid chromatography.Methods The detection and reference wavelengths were 254 and 270 nm,respectively.The analytes were separated within 20 min by a gradient elution program.The optimized pretreatment of water samples was as following:using hydrophilic-lipophilic balance HLB as SPE cartridges,adjusting pH to 3 and adding 3.0 g NaCl per 500 ml water sample.Results The linear range of the method was 0.05-5.00 mg/L for ceftazidime,cefotaxime and cefuroxime,0.10-10.00 mg/L for cefadroxil,cephalexin and cefradine,and 0.20-20.00mg/L for cefoperazone.The coefficients for the analytes were above 0.99 and the limits of determination were 0.05-0.39 ?g/L.The recoveries of seven cephalosporin antibiotics in purified water were 86.64%-105.28%,and its relative standard deviation were 2.61%-11.64%.Conclusion The method was sensitive,accurate and repeatable,it is applicable to the determination of the cephalosporin antibiotics in waters.