Methods for determining carbapenem resistance.

BackgroundKlebsiella pneumoniae is the most common pathogen causing neonatal infections, leading to high mortality worldwide. Along with increasing antimicrobial use in neonates, carbapenem-resistant K. pneumoniae (CRKP) has emerged as a severe challenge for infection control and treatment. However, no comprehensive systematic review is available to describe the global epidemiology of neonatal CRKP infections. We therefore performed a systematic review of available data worldwide and combined a genome-based analysis to address the prevalence, clonal diversity, and carbapenem resistance genes of CRKP causing neonatal infections.Methods and findingsWe performed a systematic review of studies reporting population-based neonatal infections caused by CRKP in combination with a genome-based analysis of all publicly available CRKP genomes with neonatal origins. We searched multiple databases (PubMed, Web of Science, Embase, Ovid MEDLINE, Cochrane, bioRxiv, and medRxiv) to identify studies that have reported data of neonatal CRKP infections up to June 30, 2022. We included studies addressing the prevalence of CRKP infections and colonization in neonates but excluded studies lacking the numbers of neonates, the geographical location, or independent data on Klebsiella or CRKP isolates. We used narrative synthesis for pooling data with JMP statistical software. We identified 8,558 articles and excluding those that did not meet inclusion criteria. We included 128 studies, none of which were preprints, comprising 127,583 neonates in 30 countries including 21 low- and middle-income countries (LMICs) for analysis. We found that bloodstream infection is the most common infection type in reported data. We estimated that the pooled global prevalence of CRKP infections in hospitalized neonates was 0.3% (95% confidence interval [CI], 0.2% to 0.3%). Based on 21 studies reporting patient outcomes, we found that the pooled mortality of neonatal CRKP infections was 22.9% (95% CI, 13.0% to 32.9%). A total of 535 neonatal CRKP genomes were identified from GenBank including Sequence Read Archive, of which 204 were not linked to any publications. We incorporated the 204 genomes with a literature review for understanding the species distribution, clonal diversity, and carbapenemase types. We identified 146 sequence types (STs) for neonatal CRKP strains and found that ST17, ST11, and ST15 were the 3 most common lineages. In particular, ST17 CRKP has been seen in neonates in 8 countries across 4 continents. The vast majority (75.3%) of the 1,592 neonatal CRKP strains available for analyzing carbapenemase have genes encoding metallo-β-lactamases and NDM (New Delhi metallo-β-lactamase) appeared to be the most common carbapenemase (64.3%). The main limitation of this study is the absence or scarcity of data from North America, South America, and Oceania.ConclusionsCRKP contributes to a considerable number of neonatal infections and leads to significant neonatal mortality. Neonatal CRKP strains are highly diverse, while ST17 is globally prevalent and merits early detection for treatment and prevention. The dominance of blaNDM carbapenemase genes imposes challenges on therapeutic options in neonates and supports the continued inhibitor-related drug discovery.

【背景】肺炎克雷伯菌（Klebsiella pneumoniae）是引发新生儿感染的最常见病原菌，在全球范围内导致较高的病死率。随着新生儿抗菌药物使用量不断增加，耐碳青霉烯类肺炎克雷伯菌（carbapenem-resistant K. pneumoniae, CRKP）已成为感染防控与治疗的严峻挑战。然而，目前尚无全面的系统综述阐述新生儿CRKP感染的全球流行病学特征。为此，本研究对全球已发表的相关数据开展系统综述，并结合基因组分析，以明确引发新生儿感染的CRKP的流行率、克隆多样性及碳青霉烯类耐药基因特征。

【方法与结果】本研究针对报道基于人群的新生儿CRKP感染的研究开展系统综述，并对所有公开可获取的新生儿来源CRKP基因组进行基因组分析。我们检索了多个数据库（PubMed、Web of Science、Embase、Ovid MEDLINE、Cochrane、bioRxiv及medRxiv），以筛选截至2022年6月30日发表的新生儿CRKP感染相关研究。本研究纳入探讨新生儿CRKP感染及定植流行率的研究，排除未提供新生儿样本量、地理位置或克雷伯菌/CRKP分离株独立数据的研究。我们采用叙事合成法结合JMP统计软件对数据进行合并分析。本研究共检索到8558篇文献，剔除不符合纳入标准的文献后，最终纳入128项研究（均非预印本），涵盖30个国家的127583例新生儿，其中包括21个中低收入国家（low- and middle-income countries, LMICs）。分析结果显示，血流感染是报道中最常见的感染类型。我们估算得出，住院新生儿中CRKP感染的全球合并流行率为0.3%（95%置信区间[CI]：0.2%~0.3%）。基于21项报道患者转归的研究，我们发现新生儿CRKP感染的合并病死率为22.9%（95% CI：13.0%~32.9%）。从GenBank（包括Sequence Read Archive）中共检索到535株新生儿来源CRKP基因组，其中204株未关联任何已发表文献。我们将这204株基因组与文献综述相结合，以明确其菌种分布、克隆多样性及碳青霉烯酶类型。本研究共鉴定出146种新生儿CRKP菌株的序列型（sequence types, STs），其中ST17、ST11及ST15为最常见的3个克隆谱系。尤为值得注意的是，ST17型CRKP已在全球4大洲的8个国家的新生儿中被检出。在可用于碳青霉烯酶分析的1592株新生儿CRKP菌株中，绝大多数（75.3%）携带编码金属β-内酰胺酶的基因，其中New Delhi金属β-内酰胺酶（NDM）是最常见的碳青霉烯酶（占比64.3%）。本研究的主要局限性在于北美、南美及大洋洲地区的数据缺失或稀缺。

【结论】CRKP可引发大量新生儿感染，并导致显著的新生儿病死率。新生儿CRKP菌株具有高度的遗传多样性，而ST17型CRKP在全球范围内广泛流行，值得对其开展早期检测以用于治疗与防控。blaNDM型碳青霉烯酶基因的主导地位给新生儿的治疗方案选择带来了挑战，同时也提示需持续开展针对β-内酰胺酶抑制剂的药物研发。