Genomic Surveillance of Clinical Pseudomonas aeruginosa Isolates Reveals an Additive Effect of Carbapenemase Production on Carbapenem Resistance.
Genomic Surveillance of Clinical Pseudomonas aeruginosa Isolates Reveals an Additive Effect of Carbapenemase Production on Carbapenem Resistance.
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临床铜绿假单胞菌分离株的基因组监测揭示碳青霉烯酶产生对碳青霉烯耐药性的累加效应。
DOI：
10.1128/spectrum.00766-22
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发表时间：
2022-06-29
影响因子：
3.7
通讯作者：
Dantas, Gautam
中科院分区：
文献类型：
--
作者：
Diorio-Toth, Luke;Irum, Sidra;Potter, Robert F.;Wallace, Meghan A.;Arslan, Muhammad;Munir, Tehmina;Andleeb, Saadia;Burnham, Carey-Ann D.;Dantas, Gautam
关键词：
全球铜绿假单胞菌对碳青霉烯类抗生素的耐药性正在增加，对确定低收入和中等收入国家这种耐药性机制的监测有限。本研究通过对2016-2017年间从伊斯兰堡和巴基斯坦拉瓦尔品第三家医院分离的142株铜绿假单胞菌临床分离株的全基因组测序，建立了β-内酰胺类抗生素耐药的基因分型机制。用Kirby-Bauer纸片扩散法进行药敏试验(AST)，根据Illumina测序数据进行基因组拼接。β-内酰胺类耐药较高，46%的菌株对哌拉西林-他唑巴坦耐药，42%对头孢吡肟耐药，48%对头孢洛唑-他唑巴坦耐药，65%对至少一种碳青霉烯类耐药。22%的分离株对所有测试的β-内酰胺类药物都具有耐药性。研究发现，碳青霉烯类耐药与BLBS、BLAVIM和BLANDM家族中金属β-内酰胺酶(MBLS)或超广谱β-内酰胺酶(ESBL)的获得性以及porin基因oprD突变有关。这些抗性决定因素在全球分布的谱系中发现，包括ST235和ST664，以及在另一项调查中描述的多个新的ST。AST结果分析显示，在孔蛋白突变的基础上获得MBLS/ESBL s对亚胺培南耐药具有相加效应，这表明临床分离株编码同一药物的多个耐药决定因素具有选择性优势。这些耐药决定因素与系统发育背景的强烈关联表明了WGS在监测铜绿假单胞菌对碳青霉烯类抗生素耐药性方面的有效性，而这些决定因素在整个系统发育树中的存在表明，对当地流行病学的了解对于指导多重耐药铜绿假单胞菌感染的潜在治疗至关重要。重要性铜绿假单胞菌与严重感染有关，治疗可能具有挑战性。正因为如此，碳青霉烯类和β-内酰胺/β-内酰胺酶抑制剂组合已成为治疗多重耐药铜绿假单胞菌感染的关键工具，但不断增加的耐药性威胁着它们的疗效。在这里，我们使用WGS对来自巴基斯坦波托哈尔地区的142株铜绿假单胞菌的基因分型和系统发育模式进行了研究。我们对MDR和抗生素敏感菌株进行了测序，发现虽然耐药的基因型式和表型模式与系统学背景相关，但在所有主要的系统群中都发现了MDR铜绿假单胞菌的种群。我们还发现，与具有单一耐药机制的菌株相比，具有多种耐药机制的菌株对亚胺培南的耐药水平明显更高。这项研究证明了WGS在监测铜绿假单胞菌耐药模式方面的应用，并基于β-内酰胺酶基因的局部传播潜在地指导治疗选择。
Carbapenem resistance in Pseudomonas aeruginosa is increasing globally, and surveillance to define the mechanisms of such resistance in low- and middle-income countries is limited. This study establishes the genotypic mechanisms of β-lactam resistance by whole-genome sequencing (WGS) in 142 P. aeruginosa clinical isolates recovered from three hospitals in Islamabad and Rawalpindi, Pakistan between 2016 and 2017. Isolates were subjected to antimicrobial susceptibility testing (AST) by Kirby-Bauer disk diffusion, and their genomes were assembled from Illumina sequencing data. β-lactam resistance was high, with 46% of isolates resistant to piperacillin-tazobactam, 42% to cefepime, 48% to ceftolozane-tazobactam, and 65% to at least one carbapenem. Twenty-two percent of isolates were resistant to all β-lactams tested. WGS revealed that carbapenem resistance was associated with the acquisition of metallo-β-lactamases (MBLs) or extended-spectrum β-lactamases (ESBLs) in the blaGES, blaVIM, and blaNDM families, and mutations in the porin gene oprD. These resistance determinants were found in globally distributed lineages, including ST235 and ST664, as well as multiple novel STs which have been described in a separate investigation. Analysis of AST results revealed that acquisition of MBLs/ESBLs on top of porin mutations had an additive effect on imipenem resistance, suggesting that there is a selective benefit for clinical isolates to encode multiple resistance determinants to the same drugs. The strong association of these resistance determinants with phylogenetic background displays the utility of WGS for monitoring carbapenem resistance in P. aeruginosa, while the presence of these determinants throughout the phylogenetic tree shows that knowledge of the local epidemiology is crucial for guiding potential treatment of multidrug-resistant P. aeruginosa infections. IMPORTANCE Pseudomonas aeruginosa is associated with serious infections, and treatment can be challenging. Because of this, carbapenems and β-lactam/β-lactamase inhibitor combinations have become critical tools in treating multidrug-resistant (MDR) P. aeruginosa infections, but increasing resistance threatens their efficacy. Here, we used WGS to study the genotypic and phylogenomic patterns of 142 P. aeruginosa isolates from the Potohar region of Pakistan. We sequenced both MDR and antimicrobial susceptible isolates and found that while genotypic and phenotypic patterns of antibiotic resistance correlated with phylogenomic background, populations of MDR P. aeruginosa were found in all major phylogroups. We also found that isolates possessing multiple resistance mechanisms had significantly higher levels of imipenem resistance compared to the isolates with a single resistance mechanism. This study demonstrates the utility of WGS for monitoring patterns of antibiotic resistance in P. aeruginosa and potentially guiding treatment choices based on the local spread of β-lactamase genes.
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DOI：
10.3390/antibiotics10111386
发表时间：
2021-11-12
期刊：
Antibiotics (Basel, Switzerland)
影响因子：
--
作者：
Irum S;Naz K;Ullah N;Mustafa Z;Ali A;Arslan M;Khalid K;Andleeb S
通讯作者：
Andleeb S
开放式细菌种群基因组学：BIGSDB软件，pubmlst.org网站及其应用。
影响因子：
--
作者：
Jolley KA;Bray JE;Maiden MCJ
通讯作者：
Maiden MCJ
影响因子：
3.6
作者：
Cao, L;Srikumar, R;Poole, K
通讯作者：
Poole, K
影响因子：
4.9
作者：
Fiett, J;Baraniak, A;Gniadkowski, M
通讯作者：
Gniadkowski, M
影响因子：
13.8
作者：
Hopman, Joost;Meijer, Corianne;Wertheim, Heiman F. L.
通讯作者：
Wertheim, Heiman F. L.