Prevalence and clonal diversity of carbapenem-resistant Klebsiella pneumoniae causing neonatal infections: A systematic review of 128 articles across 30 countries

Abstract

Background Klebsiella 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 findings We 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. Conclusions CRKP 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. In an updated systematic review, Zhiyong Zong and colleagues report the prevalence and clonal diversity of carbapenem-resistant Klebsiella pneumoniae responsible for neonatal infections across 30 different countries. Author summary Why was this study done? Klebsiella pneumoniae is a leading cause of neonatal infections with high mortality, representing a severe global problem. Carbapenem-resistant K. pneumoniae (CRKP) has emerged as a particularly severe challenge for infection control and treatment. Understanding the global burden of neonatal infections caused by CRKP and their clonal background could provide critical insights for guiding countermeasures, but no systematic review has been accomplished to address this gap. What did the researchers do and find? We systematically reviewed all published articles addressing CRKP in neonates and included a total of 128 studies comprising 127,583 neonates in 30 countries and 2,057 neonatal CRKP isolates. We estimated a 0.3% pooled prevalence of CRKP infections in hospitalized neonates with a 22.9% pooled mortality. We found that neonatal CRKP strains were diverse in clonal background and most lineages did not exhibit intercountry dissemination. We utilized publicly available CRKP genomes with neonatal origins in GenBank to complement the literature for data about species, strain types, and carbapenemase types. However, we observed intercontinental distribution of ST17, representing a particular widespread CRKP lineage associated with neonates, and most neonatal CRKP strains encode a metallo-β-lactamase, particularly NDM (New Delhi metallo-β-lactamase). What do these findings mean? CRKP is a severe threat to this vulnerable population worldwide, in particular for those in LMICs. Most CRKP lineages in neonates appeared to emerge locally. Individualized approaches that are informed by local data may be needed for designing countermeasures. The dominance of carbapenemase genes impose challenges to effective treatment of neonatal infection. Our findings support the need for ongoing research into effective therapeutics.