Livermore David M, Mushtaq Shazad, Warner Marina, Miossec Christine, Woodford Neil
Health Protection Agency Centre for Infections, London, UK.
J Antimicrob Chemother. 2008 Nov;62(5):1053-6. doi: 10.1093/jac/dkn320. Epub 2008 Aug 9.
The beta-lactamase landscape is changing radically, with CTX-M types now the most prevalent extended-spectrum beta-lactamases (ESBLs) worldwide, except maybe in the USA. In addition, there are growing numbers of Enterobacteriaceae with KPC and metallo-carbapenemases. We examined whether combinations of oxyimino-cephalosporins with NXL104, a novel non-beta-lactam beta-lactamase inhibitor, overcame these resistances.
NXL104 was tested at 4 mg/L in combination with cefotaxime and ceftazidime versus: (i) Escherichia coli transconjugants and wild-type Enterobacteriaceae with CTX-M ESBLs; (ii) Enterobacteriaceae with ertapenem resistance contingent on combinations of impermeability and ESBLs or AmpC; and (iii) Enterobacteriaceae with KPC, SME, metallo- or OXA-48 carbapenemases.
MICs of cefotaxime + NXL104 were < or = 1 mg/L for most Enterobacteriaceae with CTX-M, KPC or OXA-48 enzymes and were < or = 2 mg/L for those that also had ertapenem resistance contingent on combinations of beta-lactamase and impermeability. MICs of the ceftazidime + NXL104 combination were < or = 4 mg/L, except for a single Enterobacter aerogenes with KPC and AmpC enzymes together with porin loss, which required an MIC of 32 mg/L. The major gap was that NXL104 could not potentiate cephalosporins against Enterobacteriaceae with IMP or VIM metallo-enzymes.
Oxyimino-cephalosporin + NXL104 combinations have potential against strains with the prevalent ESBLs and non-metallo-carbapenemases.
β-内酰胺酶格局正在发生根本性变化,目前CTX-M型是全球最普遍的超广谱β-内酰胺酶(ESBLs),美国可能除外。此外,产KPC和金属碳青霉烯酶的肠杆菌科细菌数量不断增加。我们研究了氧亚氨基头孢菌素与新型非β-内酰胺β-内酰胺酶抑制剂NXL104的联合使用是否能克服这些耐药性。
将NXL104以4mg/L的浓度与头孢噻肟和头孢他啶联合进行测试,对比:(i)携带CTX-M ESBLs的大肠杆菌转接合子和野生型肠杆菌科细菌;(ii)因通透性和ESBLs或AmpC联合作用而对厄他培南耐药的肠杆菌科细菌;(iii)产KPC、SME、金属或OXA-48碳青霉烯酶的肠杆菌科细菌。
对于大多数携带CTX-M、KPC或OXA-48酶的肠杆菌科细菌,头孢噻肟+NXL104的MIC≤1mg/L,对于那些因β-内酰胺酶和通透性联合作用而对厄他培南耐药的细菌,MIC≤2mg/L。头孢他啶+NXLl04联合用药的MIC≤4mg/L,但有一株同时产KPC和AmpC酶且孔蛋白缺失的产气肠杆菌除外,其MIC为32mg/L。主要差距在于NXL104不能增强头孢菌素对携带IMP或VIM金属酶的肠杆菌科细菌的作用。
氧亚氨基头孢菌素+NXL104联合用药对携带常见ESBLs和非金属碳青霉烯酶的菌株具有潜在作用。