JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2019
·
IF 2.983
Fábio de Souza Barbosa,Leonardo Capra Pezzi,Marisa Tsao,Sandra Manoela Dias Macedo,Tiago Franco de Oliveira,Elfrides E.S. Schapoval,Andreas S.L. Mendez
An ESI-MS/MS method through direct infusion was validated for quantitative analysis of meropenem powder for injection. The validation parameters were established in a rapid analysis of 30 s. Drug stability was studied through the submission to stress testing, resulting on four degradation products. Under hydrolytic conditions, in acid, neutral and alkaline media, the major degradation product was formed through the cleavage of the β-lactam ring. Oxidation of the drug using H 2 O 2 (3%) showed the formation of two degradation products from a decarboxylation reaction and N-oxide formation. Under high humidity conditions, there was detected a dimer product. The stability of meropenem after reconstitution was studied in conditions that simulate its clinical use. In samples reconstituted and diluted in infusion fluids, an extensive degradation was observed. At room temperature meropenem maintained its content > 90% for up to 4 h when prepared in 5% glucose and for up to 12 h when prepared in 0.9% NaCl. Through ESI-MS/MS analyzes it was observed a degradation product formed by β-lactam ring cleavage, detected in all conditions studied. It was also identified a degradation product formed only in 5% glucose, generated by the hydrolysis of β-lactam followed by the attachment of a glucose molecule to the nitrogen of the pyrrolidine ring. In general, all the results obtained in the stability studies contribute to the knowledge about this antibiotic and future candidates of this class.
研究领域:
药学
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分析化学
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药物代谢
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DOI
PubMed
高影响因子
Antibiotics-Basel
·
2022
·Vol. 11
·期 11
·1660
·
IF 5.222
Yan Wang,Lanyu Liu,Qiping Wu,Qiufen Yin,Feifan Xie
Background: The pharmacokinetic/pharmacodynamic (PK/PD) index of carbapenems that best correlates with in vivo antimicrobial activity is percent time of dosing interval in which free drug concentration remains above MIC (%fT > MIC), while the magnitudes of the PK/PD index of carbapenems remains undefined in critically ill sepsis patients.Methods: A sepsis rat model was first developed by comparing the survival outcomes after intraperitoneal injection of different inoculum size (1–10 × 107CFU) ofPseudomonas aeruginosaATCC9027 (MIC = 0.125 mg/L) in neutropenic rats. The PK characteristics of the model drug meropenem in the developed sepsis rat model was then evaluated, and PK modeling and simulation was applied to design meropenem dosing regimens attaining various PD targets (40%fT > MIC, 100%fT > MIC, and 100%fT > 4 × MIC). The microbiological response and survival outcomes for different meropenem treatment regimens were investigated in the rat sepsis model (n= 12 for each group).Results: The optimal inoculum for the rat sepsis model was 1 × 107CFU ofPseudomonas aeruginosaATCC9027. A one-compartment model with first-order absorption best described the PK of meropenem in sepsis rats. Pronounced survival prolongation and lower hazard risk were observed in the treatment groups of 50 or 75 mg/kg/q2.4h (100%fT > MIC) and 75 mg/kg/q2h (100%fT > 4 × MIC) compared to the 75 mg/kg/q6h (40%fT > MIC) group, while meropenem groups with PD targets of 100%fT > MIC and 100%fT > 4 × MIC showed comparable survival curves. Microbiological response for different PD targets is inconclusive due to irregular bacterial counts in blood samples.Conclusions: The PD target of 40%fT > MIC is suboptimal for sepsis rats, and the aggressive 100%fT > 4 × MIC target does not provide a survival benefit against the target of 100%fT > MIC.Keywords:pharmacokinetics;PK/PD;survival;meropenem;sepsis rat model
研究领域:
药理学
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感染病学
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产品关联
DOI
PubMed
高影响因子
RSC Advances
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2022
·Vol. 12
·期 48
·31497-31505
·
IF 4.036
M. R. Ali,M. S. Bacchu,D. D. Ridoy,P. L. Mozumder,M. N. Hasan,S. Das,M. F. H. Palash,S. Akter,N. Sakib,A. Khaleque,D. Chakrobortty,M. Z. H. Khan
In this study, hematite nanotube (HNT) and tyramine-based advanced nano-drug carriers were developed for inhibiting the growth of Klebsiella pneumoniae (K. pneumoniae). The HNT was synthesized by following the Teflon line autoclaved assisted hydrothermal process and tyramine was incorporated on the surface of the HNT to fabricate the formulated nano-drug. The nano-drug was prepared by conjugating meropenem (MP) on the surface of Tyramine-HNT and characterized using different techniques, such as scanning electron microscopy (SEM), attenuated total reflection Fourier transform infrared (ATR-FTIR), etc. Furthermore, the drug-loading efficiency and loading capacity were measured using a UV-vis spectrometer. The pH, amount of Tyr, and HNT required for drug loading were optimized. A controlled and gradual manner of pH-sensitive release profiles was found after investigating the release profile of MP from the carrier drug. The antibacterial activity of MP@Tyramine-HNT and MP was compared through the agar disc diffusion method which indicates that antibacterial properties of antibiotics are enhanced after conjugating. Surprisingly, the MP@Tyramine-HNT exhibits a minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of K. pneumoniae lower than MP itself. These results indicate the nanocarrier can reduce the amount of MP dosed to eradicate K. pneumoniae.
研究领域:
材料科学
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微生物学
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药学
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产品关联
DOI
PubMed
高影响因子
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
·
2024
·Vol. 68
·期 3
·
IF 4.1
Xiaonan Zhang,Yan Wang,Sanwang Li,Feifan Xie,Hanxi Yi
Bacterial infections, including those caused by Pseudomonas aeruginosa, often lead to sepsis, necessitating effective antibiotic treatment like carbapenems. The key pharmacokinetic/pharmacodynamic (PK/PD) index correlated to carbapenem efficacy is the fraction time of unbound plasma concentration above the minimum inhibitory concentration (MIC) of the pathogen (%fT > MIC). While multiple targets exist, determining the most effective one for critically ill patients remains a matter of debate. This study evaluated meropenem’s bactericidal potency and its ability to combat drug resistance in Pseudomonas aeruginosa under three representative PK/PD targets: 40% fT > MIC, 100% fT > MIC, and 100% fT > 4× MIC. The hollow fiber infection model (HFIM) was constructed, validated, and subsequently inoculated with a substantial Pseudomonas aeruginosa load (1 × 108 CFU/mL). Different meropenem regimens were administered to achieve the specified PK/PD targets. At specified intervals, samples were collected from the HFIM system and subjected to centrifugation. The resulting supernatant was utilized to determine drug concentrations, while the precipitates were used to track changes in both total and drug-resistant bacterial populations over time by the spread plate method. The HFIM accurately reproduced meropenem’s pharmacokinetics in critically ill patients. All three PK/PD target groups exhibited a rapid bactericidal response within 6 h of the initial treatment. However, the 40% fT > MIC and 100% fT > MIC groups subsequently showed bacterial resurgence and resistance, whereas the 100% fT > 4× MIC group displayed sustained bactericidal activity with no evidence of drug resistance. The HFIM system revealed that maintaining 100% fT > 4× MIC offers a desirable microbiological response for critically ill patients, demonstrating strong bactericidal capacity and effective prevention of drug resistance.
研究领域:
药理学
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感染病学
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临床医学
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产品关联
DOI
PubMed
高影响因子
ANALYTICAL LETTERS
·
2017
·
IF 1.15
Yuan Liu,Jianye Liu,Xiaowei Li,Kunxia Zhao,Pengchun Zhang,Shuangyang Ding
A simple and sensitive method was developed and validated by high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS) for the determination of meropenem and ertapenem in environmental materials from dairy farms. The limits of quantification were between 1 and 20 ng/mL for the analytes in lagoon water, bedding soil, and silage. The recoveries for meropenem and ertapenem exceeded 80%. The intraday and interday precision values were less than 15% in all samples. The validated method was employed to determine the meropenem and ertapenem in environment samples obtained from dairy farms.
研究领域:
分析化学
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环境科学
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产品关联
DOI
高影响因子
TALANTA
·
2023
·
IF 6.1
Xuan Ma,Yue Wang,Wenting Wang,Jake Heinlein,Lisa D. Pfefferle,Xuemeng Tian
In this study, a facile method has been developed to synthesize a novel type of porous magnetic molecularly imprinted polymers (Fe 3 O 4 -MER-MMIPs) for the selective adsorption and removal of meropenem. The Fe 3 O 4 -MER-MMIPs, with abundant functional groups and sufficient magnetism for easy separation, are prepared in aqueous solutions. The porous carriers reduce the overall mass of the MMIPs, greatly improving their adsorption capacity per unit mass and optimizing the overall value of the adsorbents. The green preparation conditions, adsorption performance, and physical and chemical properties of Fe 3 O 4 -MER-MMIPs have been carefully studied. The developed submicron materials exhibit a homogeneous morphology, satisfactory superparamagnetism (60 emu g −1 ), large adsorption capacity (11.49 mg g −1 ), quick adsorption kinetics (40 min), and good practical implementation in human serum and environmental water. Finally, the protocol developed in this work delivers a green and feasible method for synthesizing highly efficient adsorbents for the specific adsorption and removal of other antibiotics as well.
研究领域:
环境科学
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材料科学
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药物化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF INORGANIC BIOCHEMISTRY
·
2021
·
IF 4.155
Dongmei Zhao,Hongru Li,Chengcheng Yue,Kaili Sun,Yuanyuan Dai,Hui Zhang,Yanyan Liu,Yufeng Gao,Jiabin Li
This study investigated whether captopril can reverse drug resistance in metallo-β-lactamase (MBL)-producing carbapenem-resistant Klebsiella pneumoniae (CRKP) and increase their sensitivity to antimicrobial agents. And also aimed to further characterize the affinity of captopril for imipenemase 4 (IMP-4) to explore the drug resistance treatment of MBL-producing bacteria. Five clinically isolated MBL-producing strains of CRKP were screened and the combined effects of captopril and meropenem were examined in vitro and in vivo to analyze whether captopril can reverse antimicrobial resistance in drug-resistant bacteria. Additionally, enzyme inhibition kinetics was analyzed to characterize the affinity of captopril for IMP-4. In MBL-producing Klebsiella pneumoniae , combined treatment with captopril significantly reduced the minimum inhibitory concentration (MIC) of carbapenems to 1 μg/mL at least, and captopril inhibited New-Delhi metallo-β-lactamase 1 (NDM-1) and IMP-4 in a concentration-dependent manner in vitro . Following the infection of Galleria mellonella by IMP-expressing bacteria, the survival rates were significantly higher in the combination treatment group than in the monotherapy groups. And the bacterial load in the combination treatment group was significantly lower than those in the monotherapy groups and IMP-4–producing bacteria were more sensitive to the combination treatment than NDM-1–producing bacteria. Additionally, enzyme inhibition kinetics firstly illustrated that the half-maximal inhibitory concentration of captopril for IMP-4 was 26.34 μM, and the dissociation constant was 37.14 μM. In brief, captopril potentiated meropenem activity and restored its efficacy against MBL-producing CRKP. Additionally, analysis of enzyme inhibition kinetics confirmed that captopril has good inhibitory effects on IMP-4 activity. Therefore, captopril or its derivatives may have clinical utility for overcoming antibiotic resistance.
研究领域:
微生物学
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药理学
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感染病学
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产品关联
DOI
PubMed
高影响因子
Current Research in Microbial Sciences
·
2024
·
IF 4.8
Sirui Zhang,Jingdan Wang,Rong Yu,Haiping Liu,Shuyan Liu,Kai Luo,Jin'e Lei,Bei Han,Yanjiong Chen,Shaoshan Han,E Yang,Meng Xun,Lei Han
Although various mechanisms of carbapenem-resistance have been identified in the nosocomial pathogen Acinetobacter baumannii , the critical process of resistance evolution and the factors involved in are not well understood. Herein, we identified a universal stress protein Usp1413 which played an important role in adaptive resistance of A. baumannii to meropenem (MEM). Based on RNA-Seq and genome sequencing, Usp1413 was not only one of the most downregulated USPs, but also the bare one having mutation of tyrosine and glycine inserted at the site of 229-230 (YG229-230) under the stimulation of MEM. Deletion of Usp1413 resulted in increased MEM resistance. In addition, Usp1413 affected the bacterial abilities of biofilm formation and swarm motility, as well as helped A. baumannii response to various environmental stresses. These effects of Usp1413 were achieved by regulating its interaction proteins, within the functions of YigZ family protein, acetyltransferase, and SulP family inorganic anion transporter. The insertion mutation of YG229-230 influenced both the expression of interaction proteins and the phenotypes of bacteria. Finally, the promotor region of Usp1413 was convinced by point mutations. Overall, our findings identified the universal stress protein Usp1413 as a contributor involved in MEM adaptive resistance and responded to numerous environmental stresses. This study provides novel insights into the mechanism of universal stress proteins in participating antibiotic resistance, and affords a potential target for controlling drug resistance development in A. baumannii .
研究领域:
微生物学
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抗药性研究
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Science & Engineering C-Materials for Biological Applications
·
2019
·
IF 4.959
Mohamed I. Gadallah,Hassan Refat H. Ali,Hassan F. Askal,Gamal A. Saleh
A square wave voltammetric method for selective determination of meropenem (MRP) and ertapenem (ERP) was developed using pencil graphite electrode modified with poly (bromocresol green) (PGE/PBCG). The modified electrode film was characterized by scanning electron microscopy and electro-chemical impedance spectroscopy. Under the optimized conditions, the prepared electrode has good linearity over concentration range 1.0–60.0 and 0.3.0–75.0 μM for MRP and ERP, respectively. The developed method was validated according to ICH guidelines. In addition, the diffusion co-efficients of MRP and ERP were estimated to be 1.24 × 10 −6 and 9.09 × 10 −6 cm 2 s −1 , respectively using chronoamperometric technique. The developed method was highly sensitive and selective for the determination of MRP or ERP in the presence of their corresponding open beta-lactam ring degradation products. Consequently, it was successfully utilized for in-vitro and in-vivo applications in spiked and real plasma samples of healthy rabbits for their pharmacokinetic studies. Furthermore, the method was applied for the assay of the available dosage forms of both drugs.
研究领域:
分析化学
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医学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
Heliyon
·
2024
·
IF 3.4
Ying Jin,Hongtu Ma,Lisha Fu,Xiaohui Qi,Mengyu Zhang,Xiangjie Di,Li Zheng,Cuiyao He,Zhenlei Wang
Meropenem is an ultrabroad-spectrum antimicrobial agent that is often recommended for the treatment of bacterial meningitis (BM) in children. However, a subtherapeutic phenomenon occurred in BM children complicated with augmented renal clearance (ARC) at the recommended dose of meropenem. To support its pharmacokinetics, a sensitive, fast and robust ultra-liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) method was developed to measure meropenem concentrations in serum and cerebrospinal fluid (CSF). The method involved protein precipitation, and samples were diluted with a large proportion of water to eliminate solvent effects. The separation of samples was performed on a Waters Acquity™ BEH C 18 column (2.1 × 50 mm i.d., 1.7 μm) with a gradient profile. The mobile phases were formic acid–water (1:1000, v/v) and acetonitrile. The linear range was good, with a concentration range of 0.100–100 μg/mL for serum and 0.0400–20.0 μg/mL for CSF. The intra-day and inter-day precisions were less than 8.0%, and the intra-day and inter-day accuracies varied −6.6% from 6.5% for the both serum and CSF. The selectivity, carry-over, dilution integrity, matrix effect, recovery and stability were validated according to international guidelines. The developed UPLC–MS/MS method successfully determined the meropenem concentrations in the serum and CSF of children with BM complicated with ARC. The results indicated that under the recommended dosing regimen (40 mg/kg every 8 h), the time to reach the effective treatment target of 50%T > MIC was only approximately 3 h and lower CSF concentrations of meropenem were observed in children with BM with ARC.
研究领域:
药代动力学
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临床药学
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分析化学
·
儿科
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2017
·
IF 3.255
Katerina Grigori,Yannis L. Loukas,Anđelija Malenović,Vicky Samara,Anastasia Kalaskani,Efi Dimovasili,Magda Kalovidouri,Yannis Dotsikas
A sensitive Liquid Chromatography tandem mass spectrometry (LC–MS/MS) method was developed and validated for the quantitative analysis of three potential genotoxic impurities (318BP, M9, S5) in meropenem Active Pharmaceutical Ingredient (API). Due to the requirement for LOD values in ppb range, a high concentration of meropenem API (30 mg/mL) had to be injected. Therefore, efficient determination of meropenem from its impurities became a critical aim of this study, in order to divert meropenem to waste, via a switching valve. After the selection of the important factors affecting analytes’ elution, a Box-Behnken design was utilized to set the plan of experiments conducted with UV detector. As responses, the separation factor s between the last eluting impurity and meropenem, as well as meropenem retention factor k were used. Grid point search methodology was implemented aiming to obtain the optimal conditions that simultaneously comply to the conflicted criteria. Optimal mobile phase consisted of ACN, methanol and 0.09% HCOOH at a ratio 71/3.5/15.5 v/v. All impurities and internal standard omeprazole were eluted before 7.5 min and at 8.0 min the eluents were directed to waste. The protocol was transferred to LC–MS/MS and validated according to ICH guidelines.
研究领域:
分析化学
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药物分析
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药学
✓ 已验证
DOI
PubMed
高影响因子
Antibiotics-Basel
·
2019
·Vol. 8
·期 4
·181
·
IF 2.921
Taniya Bardhan,Madhurima Chakraborty,Bornali Bhattacharjee
Carbapenem resistantKlebsiella pneumoniaehas been highlighted to be a critical pathogen by the World Health Organization. The objectives of this study were to assess the efficacy of lactic acid (LA) against planktonic cells and biofilms formed by carbapenem-hydrolyzingK. pneumoniaeisolates obtained from the nares of preterm neonates. Time-kill assays with graded percentages of (v/v) LA in water were initially carried out against planktonic cells of a meropenem (MRP)-resistantK. pneumoniaeisolate, JNM11.C4. The efficacy parameters such as optimal incubation time and minimum inhibitory concentration were determined by comparing colony-forming unit counts (log(10)CFU). Scanning electron microscopy was used to visualize cell damage. Likewise, JNM11.C4 biofilms were treated with graded series of (v/v) LA. Six carbapenem-hydrolyzing isolates were next used to validate the results. A reduction of 3.6 ± 0.6 log(10)CFU/mL in JNM11.C4 planktonic cells and >3 ± 0.03log(10)CFU/mL in biofilm-forming cells were observed using 0.225% and 2% LA, respectively, after three hours. Similar decreases in viable cell-counts were observed both in the case of planktonic (˃3.6 ± 0.3log(10)CFU/mL) and biofilm-forming cells (3.8 ± 0.3log(10)CFU/mL) across all the six clinical isolates. These results indicate that LA is an effective antimicrobial against planktonic carbapenem-hydrolyzingK. pneumoniaecells and biofilms.Keywords:Klebsiella pneumoniae;carbapenem-hydrolyzing;lactic acid;meropenem;planktonic;biofilm-forming;bactericidal
研究领域:
微生物学
·
传染病学
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药理学
✓ 已验证
DOI
PubMed
高影响因子
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