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
目的探讨耐碳青霉烯类肺炎克雷伯菌(CRKP)对头孢他啶/阿维巴坦(ceftazidime/avibactam,CZA)的耐药情况及危险因素。方法选取2019年10月至2022年5月在西安国际医学中心重症监护病房(intensive care unit,ICU)住院治疗的CRKP病人156例,根...目的探讨耐碳青霉烯类肺炎克雷伯菌(CRKP)对头孢他啶/阿维巴坦(ceftazidime/avibactam,CZA)的耐药情况及危险因素。方法选取2019年10月至2022年5月在西安国际医学中心重症监护病房(intensive care unit,ICU)住院治疗的CRKP病人156例,根据CRKP病人是否对CZA耐药分为CZA敏感组(n=111)和耐药组(n=45)。采用微量肉汤稀释法检测CRKP对CZA的药敏情况。分析比较CRKP对CZA敏感病人和耐药病人的一般资料,多因素logistic回归分析CRKP对CZA耐药的危险因素。比较两组病人住院期间的死亡率。结果156株CRKP中111株(71.15%)对CZA敏感,45株(28.85%)对CZA耐药。两组病人在年龄、性别、身体质量指数、标本来源和基础疾病上差异无统计学意义(P>0.05)。在侵入性操作中,CZA耐药组机械通气(77.78%比55.86%)、透析(46.67%比18.02%)和手术的病人(77.78%比54.05%)比例明显高于CZA敏感组(P<0.05)。同时,CZA耐药组既往接受CZA治疗的病人比例明显高于CZA敏感组(24.44%比9.01%),差异有统计学意义(P<0.05)。多因素logistic回归分析显示CRKP对CZA耐药的危险因素包括透析、机械通气和既往接受CZA治疗(P<0.05)。CZA耐药组中病人住院期间死亡率(28.89%)明显高于CZA敏感组(10.81%),差异有统计学意义(χ^(2)=7.78,P=0.005)。结论部分CRKP对CZA耐药,耐药病人住院期间死亡率高。透析、机械通气和既往接受CZA治疗是CRKP对CZA耐药的危险因素。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.
文摘目的探讨耐碳青霉烯类肺炎克雷伯菌(CRKP)对头孢他啶/阿维巴坦(ceftazidime/avibactam,CZA)的耐药情况及危险因素。方法选取2019年10月至2022年5月在西安国际医学中心重症监护病房(intensive care unit,ICU)住院治疗的CRKP病人156例,根据CRKP病人是否对CZA耐药分为CZA敏感组(n=111)和耐药组(n=45)。采用微量肉汤稀释法检测CRKP对CZA的药敏情况。分析比较CRKP对CZA敏感病人和耐药病人的一般资料,多因素logistic回归分析CRKP对CZA耐药的危险因素。比较两组病人住院期间的死亡率。结果156株CRKP中111株(71.15%)对CZA敏感,45株(28.85%)对CZA耐药。两组病人在年龄、性别、身体质量指数、标本来源和基础疾病上差异无统计学意义(P>0.05)。在侵入性操作中,CZA耐药组机械通气(77.78%比55.86%)、透析(46.67%比18.02%)和手术的病人(77.78%比54.05%)比例明显高于CZA敏感组(P<0.05)。同时,CZA耐药组既往接受CZA治疗的病人比例明显高于CZA敏感组(24.44%比9.01%),差异有统计学意义(P<0.05)。多因素logistic回归分析显示CRKP对CZA耐药的危险因素包括透析、机械通气和既往接受CZA治疗(P<0.05)。CZA耐药组中病人住院期间死亡率(28.89%)明显高于CZA敏感组(10.81%),差异有统计学意义(χ^(2)=7.78,P=0.005)。结论部分CRKP对CZA耐药,耐药病人住院期间死亡率高。透析、机械通气和既往接受CZA治疗是CRKP对CZA耐药的危险因素。
