Livermore David M, Mushtaq Shazad, Warner Marina, Woodford Neil
Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England, London, UK Norwich Medical School, University of East Anglia, Norwich, UK
Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England, London, UK.
J Antimicrob Chemother. 2015 Nov;70(11):3032-41. doi: 10.1093/jac/dkv239. Epub 2015 Aug 25.
OP0595 is a diazabicyclooctane that (i) acts as a PBP2-active antibacterial, (ii) inhibits Class A and C β-lactamases and (iii), like mecillinam, gives β-lactamase-independent potentiation of β-lactams targeting other PBPs. We tested its behaviour against β-lactam-resistant Enterobacteriaceae and non-fermenters.
Organisms were UK clinical isolates; MICs were determined by CLSI agar dilution for OP0595 alone or combined at 1-4 mg/L with aztreonam, biapenem, cefepime or piperacillin.
MICs of OP0595 for Escherichia coli, Enterobacter, Citrobacter and Klebsiella spp. were mostly 1-4 mg/L but values >4 mg/L were seen for minorities of isolates irrespective of other resistances, and for 50%-60% of those with ertapenem resistance involving porin loss plus ESBL or AmpC activity. OP0595 MICs for Serratia, Proteeae and non-fermenters mostly were >4 mg/L. When its MIC was ≤4 mg/L, OP0595's antibacterial activity dominated combination activity. For 'OP0595-resistant' (MIC >4 mg/L) isolates with Class A or C β-lactamases OP0595 achieved strong potentiation of substrate β-lactams, contingent on β-lactamase inhibition. β-Lactamase-independent potentiation was evident with aztreonam, cefepime and piperacillin-less so for biapenem-for many OP0595-resistant Enterobacteriaceae with Class B carbapenemases, which are not inhibited by OP0595. OP0595 acted solely as a β-lactamase inhibitor for non-fermenters.
OP0595 inhibited Enterobacteriaceae, not non-fermenters; its combinations had broad activity versus Enterobacteriaceae, largely contingent on OP0595's antibacterial activity but also on inhibition of Class A and C β-lactamases and on the β-lactam-enhancer effect, which allowed activity against many OP0595-resistant metallo-β-lactamase-producing Enterobacteriaceae. For non-fermenters OP0595 acted only as a β-lactamase inhibitor.
OP0595是一种二氮杂双环辛烷，（i）作为一种对青霉素结合蛋白2（PBP2）有活性的抗菌药物，（ii）抑制A类和C类β-内酰胺酶，（iii）与美西林一样，能对靶向其他PBPs的β-内酰胺类药物产生不依赖β-内酰胺酶的增效作用。我们测试了其对β-内酰胺耐药肠杆菌科细菌和非发酵菌的作用。
所用菌株为英国临床分离株；通过美国临床和实验室标准协会（CLSI）琼脂稀释法测定OP0595单独使用时的最低抑菌浓度（MIC），以及其与氨曲南、比阿培南、头孢吡肟或哌拉西林以1 - 4 mg/L的浓度联合使用时的MIC。
OP0595对大肠埃希菌、肠杆菌属、柠檬酸杆菌属和克雷伯菌属的MIC大多为1 - 4 mg/L，但少数分离株的值>4 mg/L，与其他耐药情况无关，而对于50% - 60%对厄他培南耐药且涉及孔蛋白缺失加超广谱β-内酰胺酶（ESBL）或AmpC活性的菌株也是如此。OP0595对沙雷菌属、变形杆菌属和非发酵菌的MIC大多>4 mg/L。当OP0595的MIC≤4 mg/L时，其抗菌活性主导联合用药的活性。对于具有A类或C类β-内酰胺酶的“OP0595耐药”（MIC>4 mg/L）分离株，OP0595能对底物β-内酰胺类药物产生强效增效作用，这取决于β-内酰胺酶的抑制作用。氨曲南、头孢吡肟和哌拉西林存在不依赖β-内酰胺酶的增效作用，比阿培南则不太明显——对于许多具有B类碳青霉烯酶的OP0595耐药肠杆菌科细菌，OP0595不能抑制此类酶。OP0595对非发酵菌仅起β-内酰胺酶抑制剂的作用。
OP0595可抑制肠杆菌科细菌，而非非发酵菌；其联合用药对肠杆菌科细菌具有广泛活性，很大程度上取决于OP0595的抗菌活性，但也依赖于对A类和C类β-内酰胺酶的抑制以及β-内酰胺增强效应，这使得其对许多产生金属β-内酰胺酶的OP0595耐药肠杆菌科细菌也有活性。对于非发酵菌，OP0595仅起β-内酰胺酶抑制剂的作用。
