The role of the plasmid-mediated fluoroquinolone resistance genes as resistance mechanisms in pediatric infections due to Enterobacterales.
The role of the plasmid-mediated fluoroquinolone resistance genes as resistance mechanisms in pediatric infections due to Enterobacterales.
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DOI：
10.3389/fcimb.2023.1249505
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发表时间：
2023
影响因子：
5.7
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中科院分区：
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氟喹诺酮类药物（FQs）不常用于儿童，但该人群中多重耐药（MDR）肠道菌（Ent）感染的发生率增加通常表明FQ耐药性。我们试图确定氟喹诺酮类药物耐药在儿童多药肠球菌流行病学中的作用，总体目标是制定治疗和预防策略。对芝加哥三家医院的儿童（0-18岁）进行了病例对照研究。例患者感染了对β-内酰胺酶敏感的产β-内酰胺酶（bla）Ent，但PMFQR基因无表达或低表达（PMFQS Ent）。对照组由于具有表达的PMFQR基因的bla Ent（PMFQR Ent）而具有FQR感染。我们通过PCR或DNA（BD Max Check-Points assay®）寻找bla基因，并通过PCR寻找PMFQR基因。我们进行了rep-PCR、MLST和E.大肠杆菌系统发育分类。另外对PMFQS Ent阳性分离株进行全基因组测序。评价了人口统计学、合并症以及器械、抗生素和医疗保健暴露。评估了感染的预测因素。在170株产β-内酰胺酶Ent分离株中，85株（50%）为FQS; 23株（27%）具有PMFQR基因（PMFQS病例）。85例（50%）为FQR; 53例（62%）有PMFQR基因（PMFQR对照）。PMFQS Ent和PMFQR Ent儿童的中位年龄分别为4.3岁和6.2岁（p = NS）。在23例PMFQS Ent中，56%为克雷伯菌属，PMFQR Ent 53只，其中E.杆菌在PMFQS Ent中检出的最常见的bla和PMFQR基因是bla SHV ESBL（44%）和oqxAB（57%），而在PMFQR Ent中检出的相应基因是bla CTX-M-1-group ESBL（79%）和aac（6 '）-Ib-cr（83%）。PMFQS Ent的全基因组测序显示，在47%的分离株中还存在mcr-9（一种可转移的多粘菌素耐药基因），沿着传播耐药性的多种质粒和移动的遗传元件。多变量回归分析显示，PMFQS Ent感染的儿童更可能发生医院感染（OR 5.7，95%CI 1.6-22）和含有多种bla基因的分离株（OR 3.8，95%CI 1.1-14.5）。在最终模型中，侵入性器械的存在介导了医疗环境的影响。在人口统计学、合并症或抗生素使用方面没有发现差异。奇怪的是，PMFQS Ent感染通常是医院发病，而PMFQR Ent感染是社区发病。PMFQS Ent通常共携带多种bla和PMFQR基因，以及额外的沉默但可转移的抗生素耐药基因，如mcr-9，影响治疗选择，并表明需要解决感染预防策略以控制传播。PMFQS Ent感染的控制需要验证社区和医疗保健来源以及与收购相关的风险因素。
Fluoroquinolones (FQs) are not commonly prescribed in children, yet the increasing incidence of multidrug-resistant (MDR) Enterobacterales (Ent) infections in this population often reveals FQ resistance. We sought to define the role of FQ resistance in the epidemiology of MDR Ent in children, with an overall goal to devise treatment and prevention strategies. A case–control study of children (0–18 years) at three Chicago hospitals was performed. Cases had infections by FQ-susceptible, β-lactamase-producing (bla) Ent harboring a non- or low-level expression of PMFQR genes (PMFQS Ent). Controls had FQR infections due to bla Ent with expressed PMFQR genes (PMFQR Ent). We sought bla genes by PCR or DNA (BD Max Check-Points assay®) and PMFQR genes by PCR. We performed rep-PCR, MLST, and E. coli phylogenetic grouping. Whole genome sequencing was additionally performed on PMFQS Ent positive isolates. Demographics, comorbidities, and device, antibiotic, and healthcare exposures were evaluated. Predictors of infection were assessed. Of 170 β-lactamase-producing Ent isolates, 85 (50%) were FQS; 23 (27%) had PMFQR genes (PMFQS cases). Eighty-five (50%) were FQR; 53 (62%) had PMFQR genes (PMFQR controls). The median age for children with PMFQS Ent and PMFQR Ent was 4.3 and 6.2 years, respectively (p = NS). Of 23 PMFQS Ent, 56% were Klebsiella spp., and of 53 PMFQR Ent, 76% were E. coli. The most common bla and PMFQR genes detected in PMFQS Ent were bla SHV ESBL (44%) and oqxAB (57%), and the corresponding genes detected in PMFQR Ent were bla CTX-M-1-group ESBL (79%) and aac(6’)-Ib-cr (83%). Whole genome sequencing of PMFQS Ent revealed the additional presence of mcr-9, a transferable polymyxin resistance gene, in 47% of isolates, along with multiple plasmids and mobile genetic elements propagating drug resistance. Multivariable regression analysis showed that children with PMFQS Ent infections were more likely to have hospital onset infection (OR 5.7, 95% CI 1.6–22) and isolates containing multiple bla genes (OR 3.8, 95% CI 1.1–14.5). The presence of invasive devices mediated the effects of healthcare setting in the final model. Differences in demographics, comorbidities, or antibiotic use were not found. Paradoxically, PMFQS Ent infections were often hospital onset and PMFQR Ent infections were community onset. PMFQS Ent commonly co-harbored multiple bla and PMFQR genes, and additional silent, yet transferrable antibiotic resistance genes such as mcr-9, affecting therapeutic options and suggesting the need to address infection prevention strategies to control spread. Control of PMFQS Ent infections will require validating community and healthcare-based sources and risk factors associated with acquisition.