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
目的:研究头孢他啶-阿维巴坦(CZA)在连续性肾脏替代治疗(CRRT)的严重感染患者中的药代动力学特征。方法:收集2024年3月-2025年4月因严重感染入院接受CZA和CRRT支持治疗的患者26例,每隔8 h分别于1、2和3 h内静脉匀速推注CZA 2.5 g,给药...目的:研究头孢他啶-阿维巴坦(CZA)在连续性肾脏替代治疗(CRRT)的严重感染患者中的药代动力学特征。方法:收集2024年3月-2025年4月因严重感染入院接受CZA和CRRT支持治疗的患者26例,每隔8 h分别于1、2和3 h内静脉匀速推注CZA 2.5 g,给药达稳态后在给药间隔的5~7个时间点进行血样采集,用LC-MS/MS法测定血药浓度,使用Phoenix Win⁃nonlin 8.1建立药代动力学房室模型,统计分析不同CRRT模式的药代动力学参数差异。依据纸片扩散法KB值对应最小抑菌浓度(MIC)折点对研究患者进行药动学/药效学(PK/PD)研究和治疗结局评价,使用蒙特卡罗模拟2.5 g q6 h、2.5 g q8 h、1.25 g q8 h和1.25 g q1 h 4种给药剂量下连续性静脉-静脉血液滤过(CVVH)和连续性静脉-静脉血液透析(CVVHD)患者的目标达成概率和累积反应分数,提供用药建议。结果:LC-MS/MS法标准曲线线性良好,头孢他啶线性范围1~200μg·mL^(-1);阿维巴坦线性范围0.5~100μg·mL^(-1),线性系数>0.999,准确度、精密度、提取回收率、基质效应和稳定性考察均符合分析方法验证指导原则。建立一房室药代动力学模型,26例患者的头孢他啶、阿维巴坦药代动力学参数:C_(ss,max)为(111.73±31.82)、(22.12±6.92)μg·mL^(-1),C_(ss,min)为(54.31±18.08)、(11.66±4.21)μg·mL^(-1),t1/2为(5.39±1.47)、(5.83±1.92)h,k_(10)为(0.14±0.05)、(0.13±0.05)h^(-1),AUC_(ss,0~8 h)为(626.37±206.29)、(126.58±47.33)h·μg·mL^(-1),Vss为(26.99±11.58)、(36.34±16.49)L,CL_(ss)为(3.49±1.03)、(4.46±1.59)L·h^(-1)。CZA的CL_(ss)在CVVHD患者较CVVH患者更大[(3.83±1.00)L vs(3.08±0.95)L,P=0.046;(5.16±1.62)L vs(3.63±1.11)L,P=0.005],对于头孢他啶、阿维巴坦的AUC_(ss,0~8 h)和阿维巴坦的C_(ss,max)、C_(ss,min),CVVH治疗患者和CVVHD治疗患者差异有统计学意义(P=0.046,P=0.005;P=0.046,P=0.001)。16例具有药敏试验结果患者中,10例患者为最优,6例准最优患者均为耐药菌感染。模拟给药2.5 g q6 h、2.5 g q8 h和1.25 g q8 h均完成靶标,1.25 g q12 h低剂量给药CVVH组为最优,CVVHD组为准最优。结论:本研究中,头孢他啶和阿维巴坦药代动力学参数的个体间变异较大。头孢他啶和阿维巴坦的CL_(ss)和AUC_(ss,0~8 h),阿维巴坦的C_(ss,max)和C_(ss,min)在不同CRRT模式下的差异有统计学意义,CVVHD模式CZA的CL_(ss)更高,接受CRRT治疗无需调整用药剂量,给予1.25 g q12 h或更低剂量时可选择CVVH模式。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.
文摘目的:研究头孢他啶-阿维巴坦(CZA)在连续性肾脏替代治疗(CRRT)的严重感染患者中的药代动力学特征。方法:收集2024年3月-2025年4月因严重感染入院接受CZA和CRRT支持治疗的患者26例,每隔8 h分别于1、2和3 h内静脉匀速推注CZA 2.5 g,给药达稳态后在给药间隔的5~7个时间点进行血样采集,用LC-MS/MS法测定血药浓度,使用Phoenix Win⁃nonlin 8.1建立药代动力学房室模型,统计分析不同CRRT模式的药代动力学参数差异。依据纸片扩散法KB值对应最小抑菌浓度(MIC)折点对研究患者进行药动学/药效学(PK/PD)研究和治疗结局评价,使用蒙特卡罗模拟2.5 g q6 h、2.5 g q8 h、1.25 g q8 h和1.25 g q1 h 4种给药剂量下连续性静脉-静脉血液滤过(CVVH)和连续性静脉-静脉血液透析(CVVHD)患者的目标达成概率和累积反应分数,提供用药建议。结果:LC-MS/MS法标准曲线线性良好,头孢他啶线性范围1~200μg·mL^(-1);阿维巴坦线性范围0.5~100μg·mL^(-1),线性系数>0.999,准确度、精密度、提取回收率、基质效应和稳定性考察均符合分析方法验证指导原则。建立一房室药代动力学模型,26例患者的头孢他啶、阿维巴坦药代动力学参数:C_(ss,max)为(111.73±31.82)、(22.12±6.92)μg·mL^(-1),C_(ss,min)为(54.31±18.08)、(11.66±4.21)μg·mL^(-1),t1/2为(5.39±1.47)、(5.83±1.92)h,k_(10)为(0.14±0.05)、(0.13±0.05)h^(-1),AUC_(ss,0~8 h)为(626.37±206.29)、(126.58±47.33)h·μg·mL^(-1),Vss为(26.99±11.58)、(36.34±16.49)L,CL_(ss)为(3.49±1.03)、(4.46±1.59)L·h^(-1)。CZA的CL_(ss)在CVVHD患者较CVVH患者更大[(3.83±1.00)L vs(3.08±0.95)L,P=0.046;(5.16±1.62)L vs(3.63±1.11)L,P=0.005],对于头孢他啶、阿维巴坦的AUC_(ss,0~8 h)和阿维巴坦的C_(ss,max)、C_(ss,min),CVVH治疗患者和CVVHD治疗患者差异有统计学意义(P=0.046,P=0.005;P=0.046,P=0.001)。16例具有药敏试验结果患者中,10例患者为最优,6例准最优患者均为耐药菌感染。模拟给药2.5 g q6 h、2.5 g q8 h和1.25 g q8 h均完成靶标,1.25 g q12 h低剂量给药CVVH组为最优,CVVHD组为准最优。结论:本研究中,头孢他啶和阿维巴坦药代动力学参数的个体间变异较大。头孢他啶和阿维巴坦的CL_(ss)和AUC_(ss,0~8 h),阿维巴坦的C_(ss,max)和C_(ss,min)在不同CRRT模式下的差异有统计学意义,CVVHD模式CZA的CL_(ss)更高,接受CRRT治疗无需调整用药剂量,给予1.25 g q12 h或更低剂量时可选择CVVH模式。
