This work explores the potential of a triple combination of meropenem(MEM),a novel metallo-blactamase(MBL)inhibitor(indole-2-carboxylate 58(InC58)),and a serine-b-lactamase(SBL)inhibitor(avibactam(AVI))for broad-spect...This work explores the potential of a triple combination of meropenem(MEM),a novel metallo-blactamase(MBL)inhibitor(indole-2-carboxylate 58(InC58)),and a serine-b-lactamase(SBL)inhibitor(avibactam(AVI))for broad-spectrum activity against carbapenemase-producing bacteria.A diverse panel comprising MBL-and SBL-producing strains was used for susceptibility testing of the triple combination using the agar dilution method.The frequency of resistance(FoR)to MEM combined with InC58 was investigated.Mutants were sequenced and tested for cross resistance,fitness,and the stability of the resistance phenotype.Compared with the double combinations of MEM plus an SBL or MBL inhibitor,the triple combination extended the spectrum of activity to most of the isolates bearing SBLs(oxacillinase-48(OXA-48)and Klebsiella pneumoniae carbapenemase-2(KPC-2))and MBLs(New Delhi metallo-blactamases(NDMs)),although it was not effective against Verona integron-encoded metallo-blactamase(VIM)-carrying Pseudomonas aeruginosa(P.aeruginosa)and OXA-23-carrying Acinetobacter baumannii(A.baumannii).The FoR to MEM plus InC58 ranged from 2.22×10^(-7)to 1.13×10^(-6).The resistance correlated with mutations to ompC and comR,affecting porin C and copper permeability,respectively.The mutants manifested a fitness cost,a decreased level of resistance during passage without antibiotic pressure,and cross resistance to another carbapenem(imipenem)and a b-lactamase inhibitor(taniborbactam).In conclusion,compared with the dual combinations,the triple combination of MEM with InC58 and AVI showed a much wider spectrum of activity against different carbapenemaseproducing bacteria,revealing a new strategy to combat b-lactamase-mediated antimicrobial resistance.展开更多
A surveillance study was undertaken to identify prominent β-lactamase encoding genes in 131 carbapenem non-susceptible gram-negative clinical isolates at a New York City community hospital. KPC carbapenemases were de...A surveillance study was undertaken to identify prominent β-lactamase encoding genes in 131 carbapenem non-susceptible gram-negative clinical isolates at a New York City community hospital. KPC carbapenemases were detected in 89% of Enterobacteriaceae as well as additional TEM, SHV, and CTX-M class A enzymes. OXA-23 and OXA-24 were the prevalent class D carbapenemases identified in Acinetobacter species. One OXA-23 in M. morganii and one OXA-48 in K. pneumoniae were also identified. Among class C β-lactamases CMY, ACT/MIR, DHA, and FOX were detected. The in vitro activity of ceftazidime-avibactam by E-test methodology was tested with minimal inhibitory concentrations (MIC) of ≤3 μg/ml for 97.8% of all Enterobacteriaceae, MIC<sub>50/90</sub> of 16/>256 μg/ml for carbapenem non-susceptible Acinetobacter, and 3/6 μg/ml for carbapenem non-susceptible Pseudomonas aeruginosa. Periodic surveillance of isolates to characterize current and emerging β-lactamase genotypes present in local isolates may help identify outbreak situations, provide assistance to infection control and antibiotic stewardship programs, and potentially improve patient outcomes.展开更多
Background:The purpose of this study was to analyze and classify adverse drug events(ADEs)related to ceftazidime/avibactam reported in the Food and Drug Administration Adverse Event Reporting System(FAERS)database and...Background:The purpose of this study was to analyze and classify adverse drug events(ADEs)related to ceftazidime/avibactam reported in the Food and Drug Administration Adverse Event Reporting System(FAERS)database and to evaluate their potential safety signals since the drug’s market introduction.Methods:This analysis systematically extracted and filtered FAERS data for ceftazidime/avibactam from its market launch in 2015 to the last quarter of 2024,utilizing the Medical Dictionary for Regulatory Activities(MedDRA)terminology for ADE recoding.The analysis employed the reporting odds ratio(ROR)method to assess the strength of ADE signals and to identify significant diseases associated with infections,the hepatobiliary system,the urinary system,and the nervous system.Results:A review of 540 adverse reaction reports revealed significant signals of adverse effects related to infections,hepatobiliary disorders,urinary system issues,and neurological impairments,including pathogen resistance,liver and kidney function impairment,encephalopathy,thrombocytopenia,and toxic epidermal necrolysis.However,these issues require further clinical attention.Conclusion:Ceftazidime/avibactam is associated with a range of adverse reactions,necessitating enhanced clinical monitoring,particularly in patients with underlying liver or kidney dysfunction.Continuous risk assessment and vigilant monitoring are critical for its clinical use.However,this study is limited by inherent reporting biases and confounders associated with the spontaneous reporting database(FAERS).Future research should validate these signals through prospective cohort and mechanistic studies and explore personalized risk management strategies for high-risk populations.展开更多
目的:建立头孢他啶(ceftazidime,CAZ)-阿维巴坦(avibactam,AVI)的生理药动学(physiologically based pharmacoki‐netic,PBPK)模型,并利用该模型探索CAZ-AVI在慢性肾脏疾病(chronic kidney disease,CKD)患者中的临床最优给药方案。方法...目的:建立头孢他啶(ceftazidime,CAZ)-阿维巴坦(avibactam,AVI)的生理药动学(physiologically based pharmacoki‐netic,PBPK)模型,并利用该模型探索CAZ-AVI在慢性肾脏疾病(chronic kidney disease,CKD)患者中的临床最优给药方案。方法:收集CAZ-AVI物理化学参数、药动学(PK)参数、组织-血液分配参数以及CKD患者生理参数等数据,利用PK-Sim软件构建CAZ-AVI的PBPK模型。结果:PBPK模型预测的肾功能正常人群和CKD患者的药动学参数(包括血浆AUC、Cmax以及尿液中累积排泄量)与实测值的倍数误差均在1.5倍以内。对于轻微肾损伤患者,PBPK模型推荐给药方案为0.94 g q8 h或1.25 g q8 h;对于中等肾损伤患者,推荐给药方案为1.25 g q8 h;对于严重肾损伤患者,推荐给药方案为0.625 g q8 h、0.94 g q12 h或1.25 g q12 h。轻微肾损伤患者的推荐剂量与临床现有给药剂量的建议有所不同,而中等和严重肾损伤患者的推荐剂量与临床现有给药方案基本一致。结论:该研究建立的PBPK模型能够同时准确预测CAZ和AVI在人体内的药物浓度,可为CKD患者提供最优给药方案指导。展开更多
基金supported by the Ineos Oxford Institute for Antimicrobial Research,the Biotechnology and Biological Sciences Research Council(BB/V003291/1)the WellcomeTrust(106244/Z/14/Z).
文摘This work explores the potential of a triple combination of meropenem(MEM),a novel metallo-blactamase(MBL)inhibitor(indole-2-carboxylate 58(InC58)),and a serine-b-lactamase(SBL)inhibitor(avibactam(AVI))for broad-spectrum activity against carbapenemase-producing bacteria.A diverse panel comprising MBL-and SBL-producing strains was used for susceptibility testing of the triple combination using the agar dilution method.The frequency of resistance(FoR)to MEM combined with InC58 was investigated.Mutants were sequenced and tested for cross resistance,fitness,and the stability of the resistance phenotype.Compared with the double combinations of MEM plus an SBL or MBL inhibitor,the triple combination extended the spectrum of activity to most of the isolates bearing SBLs(oxacillinase-48(OXA-48)and Klebsiella pneumoniae carbapenemase-2(KPC-2))and MBLs(New Delhi metallo-blactamases(NDMs)),although it was not effective against Verona integron-encoded metallo-blactamase(VIM)-carrying Pseudomonas aeruginosa(P.aeruginosa)and OXA-23-carrying Acinetobacter baumannii(A.baumannii).The FoR to MEM plus InC58 ranged from 2.22×10^(-7)to 1.13×10^(-6).The resistance correlated with mutations to ompC and comR,affecting porin C and copper permeability,respectively.The mutants manifested a fitness cost,a decreased level of resistance during passage without antibiotic pressure,and cross resistance to another carbapenem(imipenem)and a b-lactamase inhibitor(taniborbactam).In conclusion,compared with the dual combinations,the triple combination of MEM with InC58 and AVI showed a much wider spectrum of activity against different carbapenemaseproducing bacteria,revealing a new strategy to combat b-lactamase-mediated antimicrobial resistance.
文摘A surveillance study was undertaken to identify prominent β-lactamase encoding genes in 131 carbapenem non-susceptible gram-negative clinical isolates at a New York City community hospital. KPC carbapenemases were detected in 89% of Enterobacteriaceae as well as additional TEM, SHV, and CTX-M class A enzymes. OXA-23 and OXA-24 were the prevalent class D carbapenemases identified in Acinetobacter species. One OXA-23 in M. morganii and one OXA-48 in K. pneumoniae were also identified. Among class C β-lactamases CMY, ACT/MIR, DHA, and FOX were detected. The in vitro activity of ceftazidime-avibactam by E-test methodology was tested with minimal inhibitory concentrations (MIC) of ≤3 μg/ml for 97.8% of all Enterobacteriaceae, MIC<sub>50/90</sub> of 16/>256 μg/ml for carbapenem non-susceptible Acinetobacter, and 3/6 μg/ml for carbapenem non-susceptible Pseudomonas aeruginosa. Periodic surveillance of isolates to characterize current and emerging β-lactamase genotypes present in local isolates may help identify outbreak situations, provide assistance to infection control and antibiotic stewardship programs, and potentially improve patient outcomes.
基金Intramural Project of The First Affiliated Hospital of Guangxi University of Chinese Medicine(2018QN008).
文摘Background:The purpose of this study was to analyze and classify adverse drug events(ADEs)related to ceftazidime/avibactam reported in the Food and Drug Administration Adverse Event Reporting System(FAERS)database and to evaluate their potential safety signals since the drug’s market introduction.Methods:This analysis systematically extracted and filtered FAERS data for ceftazidime/avibactam from its market launch in 2015 to the last quarter of 2024,utilizing the Medical Dictionary for Regulatory Activities(MedDRA)terminology for ADE recoding.The analysis employed the reporting odds ratio(ROR)method to assess the strength of ADE signals and to identify significant diseases associated with infections,the hepatobiliary system,the urinary system,and the nervous system.Results:A review of 540 adverse reaction reports revealed significant signals of adverse effects related to infections,hepatobiliary disorders,urinary system issues,and neurological impairments,including pathogen resistance,liver and kidney function impairment,encephalopathy,thrombocytopenia,and toxic epidermal necrolysis.However,these issues require further clinical attention.Conclusion:Ceftazidime/avibactam is associated with a range of adverse reactions,necessitating enhanced clinical monitoring,particularly in patients with underlying liver or kidney dysfunction.Continuous risk assessment and vigilant monitoring are critical for its clinical use.However,this study is limited by inherent reporting biases and confounders associated with the spontaneous reporting database(FAERS).Future research should validate these signals through prospective cohort and mechanistic studies and explore personalized risk management strategies for high-risk populations.
文摘目的:建立头孢他啶(ceftazidime,CAZ)-阿维巴坦(avibactam,AVI)的生理药动学(physiologically based pharmacoki‐netic,PBPK)模型,并利用该模型探索CAZ-AVI在慢性肾脏疾病(chronic kidney disease,CKD)患者中的临床最优给药方案。方法:收集CAZ-AVI物理化学参数、药动学(PK)参数、组织-血液分配参数以及CKD患者生理参数等数据,利用PK-Sim软件构建CAZ-AVI的PBPK模型。结果:PBPK模型预测的肾功能正常人群和CKD患者的药动学参数(包括血浆AUC、Cmax以及尿液中累积排泄量)与实测值的倍数误差均在1.5倍以内。对于轻微肾损伤患者,PBPK模型推荐给药方案为0.94 g q8 h或1.25 g q8 h;对于中等肾损伤患者,推荐给药方案为1.25 g q8 h;对于严重肾损伤患者,推荐给药方案为0.625 g q8 h、0.94 g q12 h或1.25 g q12 h。轻微肾损伤患者的推荐剂量与临床现有给药剂量的建议有所不同,而中等和严重肾损伤患者的推荐剂量与临床现有给药方案基本一致。结论:该研究建立的PBPK模型能够同时准确预测CAZ和AVI在人体内的药物浓度,可为CKD患者提供最优给药方案指导。
