Meropenem and Vaborbactam: Stepping up the Battle against Carbapenem‐resistant Enterobacteriaceae

Vaborbactam (VAB; formerly RPX7009) is a novel beta‐lactamase inhibitor based on a cyclic boronic acid pharmacophore with potent inhibitory activity against Ambler class A and C beta‐lactamases. It has been co‐formulated with meropenem to restore its activity against Klebsiella pneumoniae carbapenemases (KPC). VAB does not inhibit class B or D carbapenemases, nor does it improve the activity of meropenem against multidrug‐resistant nonfermenting gram‐negative bacilli, notably Acinetobacter spp. and Pseudomonas aeruginosa. The purpose of this article is to review existing data pertaining to the biochemistry, mechanism of action, pharmacokinetics/pharmacodynamics, in vitro activity, and current progress in clinical trials of meropenem and VAB (MV). Phase 1 studies have demonstrated single and multiple doses of VAB up to 2000 mg, alone or in combination with meropenem 2000 mg administered as a prolonged infusion over 3 hours, are well tolerated with an adverse effect profile similar to that of meropenem monotherapy. The available data suggest preexisting resistance among KPC‐producing isolates is rare. Strains with elevated MICs have been characterized by multiple resistance determinants including porin defects, increased drug efflux, and increased blaKPC expression. It remains uncertain whether multifactorial resistance will emerge during MV treatment and with more widespread use. Early data are positive for complicated urinary tract infections and MV compared with best available therapy in patients with serious carbapenem‐resistant Enterobacteriaciae (CRE) infections. As clinicians contemplate how to incorporate MV into CRE treatment strategies, it will be important to track and understand resistance, discern the role, if any, of combination therapy in enhancing efficacy and/or preserving activity, and define the specific therapeutic niche of MV among the expanding anti‐CRE armamentarium.     

不同底物在CIM试验检测革兰阴性杆菌碳青霉烯酶中的应用评价

目的评价不同碳青霉烯类抗生素作为指示底物对碳青霉烯类抗生素不活跃检测方法(CIM)结果的影响。方法分别用美罗培南、亚胺培南和厄他培南作为指示药物,对90株肠杆菌科细菌和105株非发酵菌进行CIM试验来检测碳青霉烯酶,并用PCR方法检测碳青霉烯酶基因。结果肠杆菌科细菌中碳青霉烯酶基因阳性菌株用美罗培南检出率为91.0%(71/78),亚胺培南检出率为92.3%(72/78),厄他培南检出率为85.9%(67/78),3种药物检出率差异无统计学意义(χ2=1.95,P=0.377);肠杆菌科细菌中碳青霉烯酶基因阴性菌株CIM试验用美罗培南、亚胺培南和厄他培南检测均阴性。非发酵菌碳青霉烯酶基因阳性菌株用美罗培南检出率为94.0%(63/67),亚胺培南检出率为74.6%(50/67),厄他培南检出率为70.1%(47/67),美罗培南检出率均高于厄他培南和亚胺培南的检出率,差异有统计学意义(P0.05)。32株碳青霉烯酶基因阴性鲍曼不动杆菌菌株中有2株美罗培南CIM试验阳性,而亚胺培南和厄他培南检测均阴性。结论应用美罗培南作为反应底物进行CIM试验与基因检测的一致性最高。此方法操作简单,成本低廉,结果易判断,适合在临床实验室开展。     

产KPC型碳青霉烯类耐药肠杆菌对头孢他啶-阿维巴坦的体外敏感性变化的机制分析

目的检测未接受过头孢他啶-阿维巴坦(ceftazidime-avibactam,CAZ-AVI)治疗的产KPC型碳青霉烯类耐药肠杆菌(KPC-producing carbapenem-resistant Enterobacteriacea,KPC-CRE)对CAZ-AVI的体外敏感性;研究产KPC型肺炎克雷伯菌(KPC-producing Klebsiella pneumoniae,KPC-KP)对CAZ-AVI敏感性降低机制。方法收集2016年10月—2018年6月苏州大学附属第二医院非重复CRE临床菌株70株;全自动微生物分析仪进行菌种鉴定,并用16S rRNA PCR扩增及测序进行验证;革兰阴性菌药敏板及微量肉汤稀释法进行药敏分析;改良碳青霉烯酶灭活试验(mCIM)对CRE菌株进行产碳青霉烯酶表型检测;PCR结合Sanger测序检测耐药相关基因;多位点序列分型分析KPC-CRE的序列分型(ST);以CAZ-AVI最低抑菌浓度(MIC)≤2/4 mg/L的KPC-KP为对照组,以CAZ-AVI MIC为4/4 mg/L的KPC-KP为实验组,采用qRT-PCR检测bla_(KPC)相对拷贝数及表达量。结果 70株CRE菌株中49株(70.0%)为产碳青霉烯酶阳性,其中26株携带bla_(KPC);25株KPC-KP中23株为ST11;26株KPC-CRE对CAZ-AVI敏感率为100%,其中1株CAZ-AVI敏感性降低KPC-KP,MIC为4/4 mg/L;CAZ-AVI敏感性降低KPC-KP携带野生型bla_(KPC-2)以及2种ESBLs基因bla_(CTX-M-65)和bla_(TEM-1),外膜蛋白OmpK35缺失,OmpK36功能缺陷;其bla_(KPC)相对拷贝数及表达量均高于对照组。结论 CAZ-AVI对未接受过CAZ-AVI治疗的KPC-CRE具有很强的体外抑制作用;bla_(KPC)拷贝数和/或表达量增加合并ESBLs以及外膜蛋白缺失和功能缺陷可能会导致KPC-KP对CAZ-AVI敏感性降低。     

Pathogens resistant to antibacterial agents

Resistance to antimicrobial drugs is increasing at an alarming rate among both gram-positive and gram-negative bacteria. Traditionally, bacteria resistant to multiple antimicrobial agents have been restricted to the nosocomial environment. A disturbing trend has been the recent emergence and spread of resistant pathogens in nursing homes, in the community, and in the hospital. This article reviews the epidemiology, molecular mechanisms of resistance, and treatment options for pathogens resistant to antimicrobial drugs.     

Australian infection control in endoscopy consensus statements on carbapenemase‐producing Enterobacteriaceae

Outbreaks of carbapenemase‐producing Enterobacteriaceae clinical infections related to endoscopic transmission are well documented. The high morbidity and mortality associated with these infections emphasizes the need to reassess endoscopic reprocessing protocols. The Gastroenterological Society of Australia established a multi‐society committee to formulate evidence‐based consensus statements on the prevention and management of endoscopic transmission of carbapenemase‐producing Enterobacteriaceae. A literature search was undertaken utilizing the MEDLINE database. Further references were sourced from published paper bibliographies. Nine statements were formulated. Using the Delphi methodology, the statements were initially reviewed electronically by the committee members and subsequently at a face‐to‐face meeting in Melbourne, Australia. After further discussion, four additional sub‐statements were added resulting in a total of 13 statements. Each statement was assessed for level of evidence, recommendation grade and the voting on recommendation was recorded. For a statement to be accepted, five out of six committee members had to “accept completely” or “accept with some reservation.” All 13 statements achieved consensus agreement. Eleven statements achieved 100% “accepted completely.” Two statements were 83% “accepted completely” and 17% “accepted with some reservation.” Of particular significance, automated flexible endoscope reprocessors were mandated for high‐level disinfection, and the use of forced‐air drying cabinets was mandated for endoscope storage. These evidence‐based statements encourage preventative strategies with the aim of ensuring the highest possible standards in flexible endoscope reprocessing thereby optimizing patient safety. They must be considered in addition to the broader published guidelines on infection control in endoscopy.     

“Double carbapenem” and oral fosfomycin for the treatment of complicated urinary tract infections caused by blaNDM‐harboring Enterobacteriaceae in kidney transplantation

Infections with carbapenemase‐producing carbapenem‐resistant Enterobacteriaceae represent an emergent problem worldwide. Treatment of infections caused by New Delhi metallo‐beta‐lactamase (NDM)‐harboring Enterobacteriaceae is particularly challenging as it frequently involves the use of nephrotoxic agents, which is problematic in kidney transplant recipients and non‐renal transplant patients with marginal kidney function. We present two cases of urinary tract infections caused by NDM‐harboring Enterobacteriaceae successfully treated with a combination of “double carbapenem” and oral fosfomycin.     

imCIM检测B类碳青霉烯酶的效果评价

目的评价抑制剂增强改良碳青霉烯失活法(im CIM)在B类碳青霉烯酶检测中的应用价值,并与EDTA纸片增效试验(EDPT)进行比较分析。方法收集碳青霉烯类抗生素不敏感菌株181株,其中肺炎克雷伯菌44株、大肠埃希菌44株、鲍曼不动杆菌43株、铜绿假单胞菌50株;碳青霉烯类抗生素敏感菌株83株,其中肺炎克雷伯菌25株、大肠埃希菌16株、鲍曼不动杆菌25株、铜绿假单胞菌17株。采用im CIM和EDPT对上述264株菌株进行B类碳青霉烯酶的筛查,以PCR结果作为金标准。应用一致性检验、Wilcoxon符号秩和检验、独立样本Kruskal-Wallis H检验及ROC曲线进行统计学分析。结果 181株碳青霉烯类抗生素不敏感菌株中144株PCR扩增耐药基因阳性,A、B、D类碳青霉烯酶分别为39株、77株、28株;im CIM检测70株阳性,111株阴性,其中166株与PCR结果一致;EDPT检测72株阳性,109株阴性,其中134株与PCR结果一致。碳青霉烯类抗生素敏感菌株83株,PCR扩增耐药基因、im CIM及EDPT检测结果均为阴性。im CIM敏感性和特异性分别为85.71%(66/77)和97.86%(183/187),与PCR结果一致性Kappa值为0.859;EDPT敏感性和特异性分别为66.23%(51/77)和88.77%(166/187),Kappa值为0.561。im CIM抑菌圈差值(Δdim CIM)与EDPT抑菌圈差值(ΔdEDPT)有差别,差异有统计学意义(Z=-6.941,P0.05)。采用im CIM检测B类碳青霉烯酶的Δdim CIM水平与A、D类酶Δdim CIM总体分布位置不同,差异有统计学意义(χ2=108.887,P0.05)。im CIM与EDPT的ROC曲线下面积分别为0.988(95%CI:0.977~0.999)和0.936(95%CI:0.909~0.963)。结论 im CIM是一种准确、高效、便捷的碳青霉烯酶表型筛选方法,敏感性、特异性较高,适合用于流行病学监测。     

Meropenem/vaborbactam: a next generation β-lactam β-lactamase inhibitor combination

ABSTRACT

Introduction

infections due to carbapenem-resistant Enterobacterales (CRE) constitute a worldwide threat and are associated with significant mortality, especially in fragile patients, and costs. Meropenem-vaborbactam (M/V) is a combination of a group 2 carbapenem with a novel cyclic boronic acid-based β-lactamase inhibitor which has shown good efficacy against KPC carbapenemase-producing Klebsiella pneumoniae, which are amongst the most prevalent types of CRE.