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Open Access

Peer-reviewed

Research Article

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

  • Ya Hu ,

    Contributed equally to this work with: Ya Hu, Yongqiang Yang, Yu Feng

    Roles Data curation, Investigation, Writing – original draft

    Affiliations Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China, Division of Infectious Diseases, State Key Laboratory of Biotherapy, Chengdu, China

    ⨯
  • Yongqiang Yang ,

    Contributed equally to this work with: Ya Hu, Yongqiang Yang, Yu Feng

    Roles Investigation, Project administration, Validation, Writing – original draft

    Affiliations Division of Infectious Diseases, State Key Laboratory of Biotherapy, Chengdu, China, Center for Pathogen Research, West China Hospital, Sichuan University, Chengdu, China

    ⨯
  • Yu Feng ,

    Contributed equally to this work with: Ya Hu, Yongqiang Yang, Yu Feng

    Roles Investigation, Methodology, Resources, Software, Validation

    Affiliations Division of Infectious Diseases, State Key Laboratory of Biotherapy, Chengdu, China, Center for Pathogen Research, West China Hospital, Sichuan University, Chengdu, China

    ⨯
  • Qingqing Fang,

    Roles Data curation, Formal analysis, Investigation

    Affiliations Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China, Division of Infectious Diseases, State Key Laboratory of Biotherapy, Chengdu, China

    ⨯
  • Chengcheng Wang,

    Roles Data curation, Formal analysis, Investigation

    Affiliations Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China, Division of Infectious Diseases, State Key Laboratory of Biotherapy, Chengdu, China

    ⨯
  • Feifei Zhao,

    Roles Data curation, Formal analysis, Investigation

    Affiliations Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China, Division of Infectious Diseases, State Key Laboratory of Biotherapy, Chengdu, China

    ⨯
  • Alan McNally,

    Roles Conceptualization, Formal analysis, Funding acquisition, Writing – review & editing

    Affiliation Institute of Microbiology and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

    ⨯
  • Zhiyong Zong

    Roles Conceptualization, Formal analysis, Funding acquisition, Project administration, Supervision, Writing – review & editing

    zongzhiy@scu.edu.cn

    Affiliations Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China, Division of Infectious Diseases, State Key Laboratory of Biotherapy, Chengdu, China, Center for Pathogen Research, West China Hospital, Sichuan University, Chengdu, China

    ⨯

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.

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.

Citation: Hu Y, Yang Y, Feng Y, Fang Q, Wang C, Zhao F, et al. (2023) Prevalence and clonal diversity of carbapenem-resistant Klebsiella pneumoniae causing neonatal infections: A systematic review of 128 articles across 30 countries. PLoS Med 20(6): e1004233. https://doi.org/10.1371/journal.pmed.1004233

Received: July 13, 2022; Accepted: April 4, 2023; Published: June 20, 2023

Copyright: © 2023 Hu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: The work was supported by a joint grant from the National Natural Science Foundation of China (81861138055 to ZZ) and the Medical Research Council (MR/S013660/1 to AM) and grants from West China Hospital of Sichuan University (ZYYC08006 and ZYGD22001 to ZZ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: ANI, average nucleotide identity; CI, confidence interval; CRE, carbapenem-resistant Enterobacterales; CRKP, carbapenem-resistant K. pneumoniae; ESBL, extended-spectrum β-lactamase; IQR, interquartile range; LMIC, low- and middle-income country; MALDI-TOF MS, matrix-assisted laser desorption ionization-time of flight mass spectrometry; MBL, metallo-β-lactamase; NDM, New Delhi metallo-β-lactamase; NICU, neonatal intensive care unit; NOS, Newcastle–Ottawa Scale; SRA, Sequence Read Archive; ST, sequence type

Introduction

Neonatal mortality is a major concern for public health [1], especially in low- and middle-income countries (LMICs) where optimized use of antimicrobial agents is problematic for many neonates [2]. The Every Newborn Action Plan aims for countries to have ≤12 neonatal deaths per 1,000 livebirths by 2030 or ≤10 by 2035 [3]. However, neonatal mortality rates vary significantly across countries, with a substantial proportion of deaths occurring in LMICs. In 2020, an estimated 2.4 million neonates died worldwide at an average global rate of 17 deaths per 1,000 live births (https://data.unicef.org/topic/child-survival/neonatal-mortality/). More than half of neonatal deaths are associated with infections [4]. In particular, neonates in LMICs have infection rates 3 to 20 times higher than those in high-income countries [5].

Klebsiella pneumoniae is a leading pathogen for neonatal infections [6] and is actually a complex comprising 5 closely related species including Klebsiella pneumoniae (sensu stricto), Klebsiella quasipneumoniae, Klebsiella variicola, Klebsiella quasivariicola, and Klebsiella africana [7]. Phenotype-based identification kits or systems such as API 20E, Vitek II, and BD Phoenix are widely used in clinical microbiology laboratories but provide limited performance for differentiating K. pneumoniae complex at the species level [8,9]. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) is also widely used for species identification, but misidentification of Klebsiella species occurs [10]. Even 16S ribosomal RNA (a constituent of the small subunit of prokaryotic ribosomes) gene sequencing, a common method of the molecular genetic approaches for species identification, does not reliably identify species within the K. pneumoniae complex [11,12]. Precise species identification relies on whole-genome sequencing and phylogenetic analysis. As such, K. pneumoniae reported in many studies may actually represent the complex rather than K. pneumoniae (sensu stricto).

In LMICs, the incidence of neonatal K. pneumoniae infection varies between 4.1 and 6.3 per 1,000 livebirths with a case fatality rate of 18% to 68% [5]. K. pneumoniae is also responsible for 16% to 28% of neonatal blood culture–confirmed sepsis in different countries [5]. A systematic review has estimated that the pooled proportion of neonatal sepsis caused by gram-negative organisms was 60% and that Klebsiella species accounted for 38% of sepsis caused by gram-negatives [13]. Another systematic review has identified that among 84,534 neonates from 26 countries in sub-Saharan Africa, Klebsiella spp. accounted for 15% to 21% of culture-positive sepsis [14]. Although the 2 systematic reviews did not specify the species [13,14], it appears that most Klebsiella strains causing sepsis were K. pneumoniae by examining the included studies.

Among bacterial pathogens in neonates, K. pneumoniae is notorious for the high prevalence of resistance towards most antimicrobial agents [15]. In particular, carbapenem-resistant K. pneumoniae (CRKP) is associated with increased mortality of patients [16], represents a serious public health threat, and has become the dominant pathogen disseminated in healthcare settings [17]. However, surveillance in many LMICs is often problematic in completeness and fidelity largely due to insufficient local data, inconsistent laboratory quality, and scarce microbiological facilities [18]. To date, the global burden of neonatal infections caused by CRKP has not yet been assessed.

Accordingly, we performed a systematic review of studies reporting population-based neonatal infections caused by CRKP to evaluate the availability of data worldwide and then attempted to provide an estimated prevalence of CRKP in neonatal infection globally. In addition, we utilized publicly available CRKP genomes with neonatal origins to complement the literature for information about species, strain types, and carbapenemases.

Methods

Search strategy and selection criteria

This study was designed and is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA; S1 Text) and registered in PROSPERO (ID: CRD42022346445). The full protocol for this study is available in the supporting information (S2 Text). We searched PubMed, Web of Science, Embase, Ovid MEDLINE, Cochrane, bioRxiv, and medRxiv to identify studies up to June 30, 2022, that reported neonatal infections caused by CRKP. The search strings were “Klebsiella” and “neonate,” “Klebsiella” and “neonatal,” “Klebsiella” and “newborn,” “Klebsiella” and “NICU,” “CRKP” and “neonate,” “CRKP” and “neonatal,” “CRKP” and “newborn,” and “CRKP” and “NICU.” We also examined articles in the reference lists of retrieved articles. We included all studies in English or non-English languages. For studies in a language other than English and Chinese, we used Google translate for translation.

We assessed studies addressing the prevalence of CRKP infections and colonization in neonates. We examined all study populations regardless of age, presence of symptoms, or study location. We considered surveillance, cohort, nested cohort, case-control, or cross-sectional, and randomized studies for estimating the prevalence. We also investigated case reports and microbiological and genomic studies for species, strain types, and carbapenemases of CRKP strains in neonates.

We excluded studies where the numbers of neonates in the study or the geographical location are not available, from estimating the prevalence. We also excluded studies lacking independent data on Klebsiella or CRKP isolates. For data that were from the same study population but were reported in multiple articles, we extracted those from the most comprehensive report. LMICs were defined using the list of World Bank (https://datahelpdesk.worldbank.org/knowledgebase/articles/906519-world-bank-country-and-lending-groups).

Data extraction

Two groups (4 investigators, 2 per group) independently reviewed the identified studies to determine eligibility. Disagreement over inclusion was resolved by arbitration by an additional, fifth, investigator.

Using a standardized data abstraction sheet, the following variables were recorded from articles that met our inclusion criteria: study design, country, study setting, study participants, year, population, age, sex, CRKP numbers and/or proportions, source of infection, antimicrobial susceptibility profiles, genomes and data availability, sequence types (STs), antimicrobial resistance genes, and primary outcomes.

Quality assessment

The quality of each included article (S1 Dataset) was assessed independently by 2 investigators using either the Newcastle–Ottawa Scale (NOS) quality assessment tool for case-control, cross-sectional, and cohort studies or Cochrane risk of bias tool for randomized controlled trials. A consensus was reached by a panel discussion among 5 investigators. The results of quality assessment are summarized in S2 Dataset for cross-sectional studies, S3 Dataset for cohort studies, and S4 Dataset for case-control studies.

Statistical analysis

We extracted raw data from the included studies and recalculated estimates wherever possible based on the extracted data. Descriptive analyses were used to describe the population. Pooled prevalence, mortality, and colonization rate were calculated and were presented with 95% confidence intervals (CIs). Rates and proportions were compared across groups using the chi-squared test. Analyses were performed using JMP Pro 14 statistical software (JMP; Cary, NC, USA) and Review Manager (RevMan) version 5.4.1 (The Cochrane Collaboration, 2020). Considering the limited number of eligible studies and the heterogeneity of the studies, we employed narrative synthesis to estimate the pooled prevalence, mortality, and colonization rate without measuring the biases with RevMan using the “Generic Inverse Variance” type and “Random” mode. Continuous variables were presented as median and interquartile range (IQR). Categorical variables were presented as numbers and percentages. All p-values of <0.05 were considered statistically significant.

Construction of dataset used for de novo genomic analysis

First, all BioProjects (n = 2,761) mentioning neonates or neonatal ICUs in their titles or descriptions were retrieved from NCBI by searching strategy “neonatal[All Fields] OR neonate[All Fields] OR neonates[All Fields] OR newborn[All Fields] OR newborns[All Fields] OR nicu[All Fields]” up to June 30, 2022. By applying filter “Bacteria” and manual curation for K. pneumoniae complex in neonates, 37 BioProjects with short reads in Sequence Read Archive (SRA) or assembly remained. Second, all BioSamples (n = 86,635) under the genus Klebsiella were retrieved, and those with the presence of keywords neonatal, neonate, newborn, or NICU (neonatal intensive care unit) were included for further curation. Third, genomes with accession numbers mentioned in all included publications (n = 21) regarding neonate-associated K. pneumoniae complex were also included in the dataset. Of note, local assemblies from SRA data were preferred over NCBI-retrieved ones. BioSample duplications, SRA with sequencing depth lower than 30 × and reads obtained from Nanopore sequencing only were discarded.

Genomic profiling and analysis

All included genomes (n = 2,093), each with a unique BioSample number, were subjected to a series of quality control and genome profiling measures. All bioinformatic settings and thresholds were set to the default unless otherwise specified. Among the 2,093 genomes, 264 were assembled and 1,829 had only short reads without assembly available. Therefore, short reads of the 1,829 genomes were retrieved from SRA of NCBI and were trimmed to remove adapters and reads shorter than 30 bp using Trimmomatic v.0.39 [19]. For each of the 1,829 genomes, maximum coverage of 150 × sequencing depth was subsampled using SeqKit v2.2.0 [20] and assembled into a draft genome using SPAdes v3.15.3 [21] under the isolate mode.

The precise species identification for each genome was performed using FastANI v1.33 [22] by comparing genomes with type strain of each species from the genus Klebsiella. The completeness and heterogeneity of genomes were assessed using CheckM v1.1.10 [23]. STs and virulence factors were identified using Kleborate v2.2.0 [24]. Antimicrobial resistance genes were detected using AMRFinderPlus v3.10.23 [25]. Plasmid replicons were typed using PlasmidFinder v2.1 [26].

Results

There were 128 articles reporting neonatal CRKP infection or colonization in 30 countries of 4 continents

A total of 16,246 articles were identified from various literature sources (Fig 1). After removing duplicates, 8,558 articles were assessed for eligibility by screening the title and the abstract. There were 382 articles eligible for full-text review, among which 254 were excluded (Fig 1). Finally, 128 articles at the time of writing, none of which were preprints, were analyzed (S1 Dataset). The 128 articles comprised a total study population of 127,583 neonates in 30 countries of Africa (n = 10; Algeria [27], Egypt [28,29], Ghana [30], Guinea [31], Morocco [32,33], Nigeria [34–37], South Africa [38–45], Tanzania [46], Tunisia [47], and Zambia [48]), Asia (n = 10; Bangladesh [34,49], China [50–92], India [34,93–113], Iran [114], Israel [115], Japan [116], Nepal [117], Pakistan [34,118–122], Saudi Arabia [123,124], and Vietnam [125–128]), Europe (n = 8; France [129], Greece [130], Hungary [131], Italy [132–142], Portugal [143], Russia [144], Turkey [145–147], and the United Kingdom [148]), and South America (Colombia [149–152] and Venezuela [153]) (Fig 2). Among the 30 countries, 21 were LMICs.

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Fig 1. Flow chart of inclusion and exclusion of studies for the systematic reviews.

aFor Ovid MEDLINE, we defined the limit at age group as “Newborn infant (birth to 1 month).” CRE, carbapenem-resistant Enterobacterales; CRKP, carbapenem-resistant Klebsiella pneumoniae; KP, Klebsiella pneumoniae.

https://doi.org/10.1371/journal.pmed.1004233.g001

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Fig 2. The worldwide distribution of CRKP in neonates.

The base layer of the map was downloaded and adapted from the website https://mapsvg.com/maps/world under the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/). Countries with the identification of CRKP in neonates are filled with brown. The CRKP infection prevalence in neonates are indicated by percentage (%) followed by the reference number. The pie charts illustrate the proportions of the 5 most common STs seen in the corresponding countries. Carbapenemase types and variants found in neonatal CRKP strains are indicated. CRKP, carbapenem-resistant Klebsiella pneumoniae; IMP, imipenemase; KPC, Klebsiella pneumoniae carbapenemase; MBL, metallo-β-lactamase; NDM, New Delhi metallo-β-lactamase; OXA, oxacillinase; SME, Serratia marcescens enzyme; ST, sequence type; VIM, Verona integron-encoded metallo-β-lactamase; -nd, not determined.

https://doi.org/10.1371/journal.pmed.1004233.g002

Most (n = 112, 87.5%) of the 128 studies were retrospective, while 15 (11.7%) were prospective and one contained both retrospective and prospective data. The study design comprises cross-sectional (n = 87, 68.0%), case report or series (n = 31, 24.2%), case-control (n = 8, 6.3%), and cohort (n = 3, 2.3%). Only cross-sectional, cohort, and case-control studies were used to estimate the prevalence of neonatal CRKP infections. The overall quality of included studies varied significantly. For cross-sectional studies, the median of NOS scores was 3 (IQR, 2 to 4) with 3 to 5 seen in most studies (65%, 56/86). Lower scores were mainly present in the selection of CRKP-negative groups for comparability, assessment of the outcome, and appropriately statistical tests (S2 Dataset). The 3 cohort studies were all scored 4 with lacking description of non-CRKP cohort and follow-up for outcomes (S3 Dataset). Six of the 8 case-control studies received a score of 6, one scored 7, and the remaining one scored 8, most of which lacked comparability between CRKP-positive cases and controls (S4 Dataset).

Susceptibilities to 1 carbapenem (any of ertapenem, imipenem, and meropenem) or 2 to 4 carbapenems (any 2 or all of the aforementioned 3 with or without doripenem) were reported in 113 out of the 128 included studies to demonstrate carbapenem resistance of studied CRKP strains. Among the remaining studies, 5, 2, and 1 study used whole genome sequencing, modified Hodge test, and PCR to detect carbapenemase genes or the production of carbapenemases, respectively, while 7 did not specify the methodology to define carbapenem resistance (S5 Dataset).

Bloodstream infection is the main type of neonatal CRKP infections

The 128 included studies documented 2,057 CRKP isolates from infected neonates or from colonized sites between 2005 and 2020. Of which, 1,504 isolates had clearly documented information of the sample type. Blood (n = 561, 37.3%) is the most common sample type of the 1,504 clinical CRKP isolates from infected neonates, followed by sputum (n = 262, 17.4%), and urine (n = 64, 4.3%) (S1 Table). The findings suggest that bloodstream infection, which often leads to sepsis, is likely the main type of neonatal CRKP infections.

The pooled prevalence of CRKP infection was 0.3% for hospitalized neonates

Prevalence of neonatal CRKP infections was reported in 23 studies, all of which contained hospitalized neonates only. Unfortunately, we were unable to find a study addressing the prevalence of CRKP infections for nonhospitalized neonates. The 23 studies comprised a total of 123,842 hospitalized neonates in 11 countries, all of which are LMICs (Bangladesh, China, Egypt, India, Nigeria, Pakistan, South Africa, Tanzania, Turkey, Vietnam, and Zambia) (Table 1 and Fig 2). The median number of neonates in the 23 studies was 1,704 (IQR, 409 to 3,836; range 218 to 36,285). The pooled prevalence of CRKP infection in hospitalized neonates was 0.3% (95% CI, 0.2% to 0.3%; range 0.0% to 5.7%). After excluding the BAR-RDS network study, in which data of Asian and African countries could not be separated for analysis, the remaining 22 studies were included for comparison. The prevalence (0.7% [95% CI, 0.4% to 1.0%]) in Asian countries was significantly higher than that (0.3% [95% CI, 0.1% to 0.4%]) in African countries (p = 0.006). Among the 23 studies, 15 reported data from NICU. Prevalence of CRKP neonatal infection in NICU was significantly higher than that in non-ICU neonatal care units (0.7% [95% CI, 0.5% to 0.9%] versus 0.0% [95% CI, 0.0% to 0.0%]; p < 0.001).

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Table 1. Prevalence of neonatal infections caused by CRKPa.

https://doi.org/10.1371/journal.pmed.1004233.t001

Patient outcomes of neonatal CRKP infections were reported in 21 studies comprising 302 CRKP neonatal infections and 79 neonatal deaths (S2 Table). The pooled mortality of infected neonates was 22.9% (95% CI, 13.0% to 32.9%), ranging from 0% to 100%.

Eleven studies comprising 9,938 neonates also had data about the prevalence of CRKP colonization (S3 Table). Six studies reported the colonization rate of CRKP in neonates via screening of rectal swabs but did not specify the timing of screening [27,140,143,145,147,152]. The pooled CRKP colonization of these studies was 6.2% (95% CI 4.0% to 8.4%; range 0.1% to 31.0%). One additional study based on rectal swabs of neonates (n = 326) in Vietnam specified the colonization rates at admission and at discharge, of 1.8% (6/326) and 3.7% (12/326), respectively [126]. The study exhibited an increasing colonization rate following admission, indicating the nosocomial acquisition of CRKP.

Most neonatal CRKP strains were K. pneumoniae (sensu stricto)

In the 128 included studies, 103 specified the methods used for species identification (S1 Fig). Most studies (n = 83) relied on phenotype-based methods and systems for species identification, while 34 studies employed whole genome sequencing allowing precise identification. However, among the 34 studies, only 9 specified the methods for species identification with 3 using the well-recognized average nucleotide identity (ANI) (S4 Table). The 9 studies comprised 191 neonatal CRKP strains with 178 (93.2%) belonging to K. pneumoniae (sensu stricto) and the remaining 13 (6.8%) to K. quasipneumoniae (S4 Table).

To complement the understanding of species, STs, and carbapenem genes, we also included all genomes of neonatal CRKP available in public databases. A total of 2,093 genomes of K. pneumoniae complex, each with a unique BioSample number, from neonates were identified. After quality control, 101 genomes were discarded from further analysis for completeness less than 95% (n = 37), contamination greater than 5% (n = 31), heterogeneity greater than 30% (n = 27), or genomes derived from species other than K. pneumoniae complex (n = 6). Therefore, 1,992 genomes of K. pneumoniae complex were included for analysis. Carbapenemase-encoding genes were identified in 535 (26.9%) genomes (S6 Dataset), of which 331 could be linked to publications (21 studies) and 204 were newly identified here, providing complementary data for strain distribution and carbapenem resistance of neonatal CRKP.

Among the 535 neonatal CRKP strains, 498 (93.1%) belonged to K. pneumoniae (sensu stricto), 33 (6.2%) to K. quasipneumoniae and 4 (0.7%) to K. variicola. By combing the results in literature and the genome-based analysis, it becomes evident that most neonatal CRKP strains were indeed K. pneumoniae (sensu stricto) but could also belong to other species within the complex.

Neonatal CRKP strains exhibited diverse clonal backgrounds with sequence type 17 (ST17), a globally disseminated lineage

Identifying epidemic lineages of CRKP seen in neonates is crucial for informing both treatment and prevention. We collected data on the ST of neonatal CRKP strains from all included studies, among which 69 reported data about STs of 1,145 CRKP strains. We additionally included the 204 neonatal CRKP genomes not linked to any publications. We therefore analyzed a total of 1,349 strains, which were recovered from 20 countries (Africa: Algeria, Ghana, Kenya, Nigeria, and South Africa; Asia: Bangladesh, China, India, Iran, Israel, Japan, Nepal, Pakistan, and Vietnam; Europe: Greece, Hungary, Italy, and Russia; South America: Colombia and Venezuela) (S5 Table). The 1,349 strains could be assigned to a total of 146 STs (S5 Table for all ST and Table 2 for those seen in at least 2 countries), indicating the high diversity of neonatal CRKP. Of note, among the 146 STs, 8 were newly identified here and are unnamed at present (S6 Table). ST15 (n = 183), ST17 (n = 136), and ST11 (n = 123) were the 3 most common types of neonatal CRKP. In particular, neonatal CRKP of ST17 was found in 8 countries across 4 continents (Africa, Asia, Europe, and South America), suggesting that it is a widespread lineage associated with neonatal infections. ST11 was found in 8 countries of 3 continents (Africa, Asia, and Europe). Other STs seen in 3 continents were ST54 (n = 45) and ST101 (n = 11), but these 2 STs were only found in 3 countries, i.e., 1 country per continent. ST15 (n = 183) was present in 6 countries of Asia and Europe, while ST307 (n = 42) were seen in 4 countries of Asia and Europe. ST14 (n = 34) and ST147 (n = 25) were both found in 4 countries of 1 continent. The remaining 138 STs were found in 1 to 3 countries of 1 or 2 continents.

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Table 2. ST of neonatal CRKP seen in at least 2 countriesa.

https://doi.org/10.1371/journal.pmed.1004233.t002

Most neonatal CRKP strains had genes encoding metallo-β-lactamases, and NDM (New Delhi metallo-β-lactamase) was particularly common

We next investigated the carbapenemase-encoding genes in neonatal CRKP strains. We first examined all included studies and identified 100 studies comprising 1,776 CRKP strains with data on carbapenemases. Carbapenemase genes were reported in 1,388 (78.1%) of the 1,776 strains. We then included 204 genomes not linked to any publications to make up a total of 1,592 strains for analysis of carbapenemases.

Genes encoding 7 known types of carbapenemases, either serine-based (KPC, OXA-23, OXA-48, and SME) or metallo-β-lactamases (MBLs; NDM, IMP, and VIM), and their 26 variants, e.g., KPC-2, NDM-1, and NDM-5, were identified (Table 3). Among the 1,592 neonatal CRKP strains for analysis of carbapenemases, most (n = 1,200, 75.3%) encode MBLs. NDM was the most common carbapenemase type, and its encoding gene was identified in 1,024 (64.3%, 1,024/1,592) neonatal CRKP strains, which were recovered in 14 countries (Fig 2). NDM-1 was seen in 643 strains as the most common NDM variant, followed by NDM-5 in 179 strains. KPC (KPC-2, KPC-3, and unspecified variants) and OXA-48-like (OXA-48, OXA-162, OXA-181, and OXA-232) were identified in 327 (20.5%) and 256 (16.1%) strains, representing the second and third most common carbapenemase type in neonatal CRKP, respectively. Of note, 210 strains had genes encoding 2 (n = 187) or 3 (n = 23) carbapenemases (S7 Table).

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Table 3. Carbapenemases of CRKP complex in neonates.

https://doi.org/10.1371/journal.pmed.1004233.t003

In addition, there are 3 studies that reported CRKP without known carbapenemases [61,63,88]. Two studies have described 23 neonatal CRKP strains, all of which belonged to ST37, but did not specify the mechanisms for carbapenem resistance [61,88]. The other study has reported a single CRKP strain of ST65, in which carbapenem resistance was due to production of the extended-spectrum β-lactamase (ESBL) TEM-53 in combination with decreased expression of outer membrane porins OmpK35 and OmpK36 [63].

We also examined the carbapenemase-encoding plasmids by reviewing literature and examining genomes. Unfortunately, there are no large-scale studies exploring the association of plasmid replicon types and carbapenemase genes for neonatal CRKP. Nonetheless, we found a few common associations (seen in ≥10 strains) of certain carbapenemases with certain plasmid replicon types including KPC-2 with IncN [154], IMP-38 with IncHI5 [155], NDM-1 with IncC [156], IncFI [85], IncFIIK [103], IncHI1B/IncFIB [117], or IncX3 [57,157], NDM-5 with IncX3 [67,76,158], OXA-48 with IncL/M [27,156], OXA-232 with ColKP3 [30,96,159,160], and VIM-1 with IncC [132] (S8 Table). All of these carbapenemase-encoding plasmids except IMP-38-encoding IncHI5, NDM-1-encoding IncHI1B/IncFIB, and VIM-1-encoding IncC were present in neonatal CRKP strains of multiple STs (S8 Table).

Few neonatal CRKP strains carried hypervirulent determinants

Only 2 studies have reported hypervirulent CRKP with a single strain from each study [63,96]. The 2 strains belonged to either K1 or K2 capsular type, the classical types of hypervirulent K. pneumoniae [161], had aerobactin-encoding gene iuc and the mucoid regulator rmpA, and caused bloodstream infection [63,96]. The presence of iuc with rmpA and/or rmpA2 (another mucoid regulator) could be used to predict the hypervirulence phenotype [161], and, therefore, we screened their presence for the 535 genomes (results shown in S6 Dataset). We identified 35 (6.5%) possible hypervirulent CRKP strains carrying iuc with rmpA (n = 4), rmpA2 (n = 21), or both (n = 10) (S9 Table). These strains were mainly of ST11 with KPC-2 in China, ST15 with KPC-2 in Vietnam, and several STs (ST11, ST15, ST23, and ST231) with NDM-1 or OXA-232 in India (S9 Table). However, the virulence of these strains remains to be determined.

Discussion

In this study, we found that neonatal CRKP infection has been reported from many countries, in particular LMICs, highlighting a global problem. Importantly, we estimated that the pooled global prevalence of CRKP infections in hospitalized neonates is 0.3% with a 22.9% mortality based on the pooled data. We also found that neonatal CRKP strains are diverse in clonal background, but few had determinants for hypervirulence. Furthermore, we demonstrated that most neonatal CRKP strains have genes encoding MBLs, in particular NDM.

To the best of our knowledge, this is the first comprehensive systematic review to assess neonatal infections caused by CRKP globally to date. About 135 million babies are born annually in the world [162], among which over 15 million new births are early or premature (https://www.gminsights.com/industry-analysis/neonatal-infant-care-market) and therefore are likely to be admitted to hospitals. Global data on neonatal admissions are not available but when considering these early or premature neonates only, there could be at least 60,000 estimated cases of neonatal CRKP infections with at least 5,880 estimated deaths worldwide.

For CRKP in neonates, most (120/146, 82.2%) STs were only seen in a single country (S5 Table). This is likely to be due to the fact that only limited data were available but could also suggest that CRKP seen in neonates have emerged multiple times in many different places, many countries may have their own specific lineages of CRKP in neonates, and most CRKP lineages in neonates are not globally disseminated. Nonetheless, we identified several particularly widespread lineages. ST17 CRKP is of a particular concern as it was identified in neonates in 8 countries of 4 continents and has also caused outbreaks of neonatal infections [81,82]. ST17 CRKP has also been sporadically reported in nonneonatal patients [163,164], animals [165,166], and wastewater [167]. Non-carbapenem-resistant ST17 K. pneumoniae has been found to commonly carry genes encoding ESBLs [168–173]. The vast majority of neonatal ST17 CRKP strains also carry ESBL genes [30,128], and there were 48 neonatal ST17 CRKP strains with genome sequences available, among which ESBL gene blaCTX-M was found in 43 (89.6%; S7 Dataset). This suggests that the ST17 CRKP may emerge as a result of acquisition of carbapenemase genes by ESBL-producing progenitors. Among other commonly identified STs for neonatal CRKP, ST11, ST15, and ST307 have also been frequently seen in adult patients. ST11 is particularly prevalent in Asia and South America and is typically associated with KPC-2 [174,175]. In contrast, neonatal CRKP of ST11 appears to have NDM more commonly than KPC (S6 Dataset). ST15 is an international high-risk lineage associated with a variety of carbapenemases including KPC, NDM, IMP, and OXA-48-like [176–178]. In neonates, ST15 appears to be particularly common in South and Southeast Asia such as Nepal (with NDM-1) [117], Pakistan (with both NDM-1 and OXA-181) [34], and Vietnam (with KPC-2; [128]) but has different carbapenemases. ST307 is another international high-risk lineage, endemic in Colombia, southern Europe (Italy, Portugal, and Spain), South Africa, and Texas of United States of America [179,180], and is associated with various carbapenemases. However, neonatal CRKP of ST307 was mainly reported from Asia (China, Bangladesh, and Vietnam) [72,181] (S5 Table and S6 Dataset). On the other hand, ST258 and its derivate ST512 are widely acknowledged as the major international high-risk type of CRKP in adults [174,182] but were only sporadically found in neonates (S5 Table). The above findings suggest that major CRKP lineages in neonates may be different from those in adults, which warrants further studies. In addition, the common associations of carbapenemases with particular plasmid replicon types in strains of different clonal background suggest possible major vehicles mediating the horizontal transmission of certain carbapenemase-encoding genes, resulting in CRKP affecting neonates. Well-designed epidemiological and genomic studies are required to untangle such plasmid-mediated transmissions of carbapenem resistance to/from and among pathogens for neonatal infections.

As we focused on the prevalence, we did not examine risk factors of neonatal CRKP infection in this study, but such risk factors have been identified in previous studies [44,99,146,183,184]. Some of these risk factors are identical to those for CRKP infection in nonneonatal patients including mechanical ventilation, prolonged length of stay, and prior exposure to antimicrobial agents (in particular carbapenems), while some others are specific for neonates including premature birth, low birth weight, and the use of umbilical vein catheters [44,99,146,183,184]. In this study, we focused on carbapenem resistance, while ESBLs also represent a challenge for clinical management [185]. Although large-scale multisite studies addressing the prevalence of ESBL-producing K. pneumoniae in neonates are still lacking, several single-site studies have demonstrated a 15% to 90.6% [186–190] prevalence of ESBL genes in neonatal K. pneumoniae strains. We also found 77.01% of the 535 neonatal CRKP genomes containing genes encoding CTX-M, the major type of ESBLs (S6 Dataset). This suggests a high prevalence, which is not within the scope of the present study but warrants further investigation.

The strength of this study is the comprehensive review of all available studies comprising 127,583 neonates across 30 countries and the hybrid approach of incorporating publicly available genomes of K. pneumoniae complex of neonatal origins and carrying carbapenemase genes into analysis. Such a hybrid approach allows maximizing the utilization of all data and then generating more extensive and in-depth views of neonatal CRKP infections. We are aware of limitations of this study. First, although we attempted to estimate the prevalence of CRKP infections in all neonates, we were unable to identify relevant studies comprising nonhospitalized ones. As a result, we could only estimate the prevalence of CRKP infections in hospitalized neonates. Second, only a limited number of studies were eligible for analysis. Due to the limited available and obtainable data, we were unable to perform a meta-analysis in addition to a systematic review for the prevalence of neonatal CRKP infections. Third, the geographic coverage of eligible studies is incomplete and biased. Most included studies were from LMICs in Africa and Asia, while no data from North America and Oceania and very few from South America were eligible for analysis. This is largely due to the fact that although CRKP have been well reported in North America and Oceania, these articles reporting CRKP there did not specify whether neonates were involved (e.g., [191,192]), data specific for neonates could not be separated from other populations (e.g., [193,194]), or data on CRKP could not be separated from those on carbapenem-resistant Enterobacterales (CRE) (e.g., [195,196]). To mitigate this problem, we also utilized all publicly available CRKP genomes of neonatal origins for providing complementary information for strain typing and carbapenemases. Notably, 38% genomes included for analysis were not linked to studies pooled for estimating the prevalence, publicly available genomes themselves could be largely biased, and we only included CRKP genomes with carbapenemases. Therefore, the genomes were unable to provide information about the prevalence of neonatal CRKP infections but are still precious sources for providing crucial information for clonal background and carbapenemase types complementing that from literature. Fourth, the included studies were remarkably heterogeneous in quality, design, study populations (NICU and non-NICU), and methods for defining carbapenem resistance, identifying species and typing strains. The heterogeneity generates a wide range of estimated prevalence of neonatal CRKP infections, which was subjected to variations when new data become available. These limitations are primarily driven by data gaps and data sparsity. Well-designed studies of neonatal CRKP infections using standardized protocols are needed to be performed in and reported from more countries, in particular those in Americas, Europe, and Oceania, and such data could be incorporated for future iterations to increase the robustness of estimating the global prevalence. Networks comprising multiple countries such as the BARNARDS network for LMICs [15,34] could be a viable choice. Despite these limitations, we believe that this study is a unique contribution for understanding CRKP in hospitalized neonates and provides much-needed insights for addressing disease burden, informing infection control, and guiding clinical management.

We believe that our findings have important implications for research, surveillance, treatment, and infection control. First, our study highlights that neonatal CRKP infection is a significant burden for public health worldwide. The problem of neonatal CRKP infection may be exaggerated along with the increased consumption of antimicrobial agents. The global antimicrobial consumption in children has increased by 46% between 2000 and 2018 [197], which could be largely attributed to the increase in LMICs [198]. Alarmingly, as pathogens resistant to WHO-recommended ampicillin and gentamicin have been increasingly identified, carbapenems have become the first-line choice for treating neonatal cases of sepsis in some LMICs [2]. Consequently, the emergence of CRKP in neonatal infections is of increasing concern. Therefore, CRKP in neonates warrant further studies and more, large-scale, rigorous surveillance at national or regional levels. Second, unlike the well-known high-risk CRKP lineages ST258 [199], ST11 [200], and ST307 [179], ST17 receives much less attentions. The association of ST17 CRKP with neonates is of particular interest, and more studies are required to elucidate the emergence and dissemination of this lineage in neonates. Third, the finding that most neonatal CRKP strains have genes encoding MBLs could inform treatment. It is worth of pointing out that the distribution of carbapenemases varies across regions, and even hospitals and the prediction of the predominant carbapenemases should be based on the local epidemiology. However, the dominance of MBLs in neonatal CRKP in many parts of the world is alarmingly. Combinations of a β-lactam and a newer β-lactamase inhibitor including ceftazidime-avibactam [201,202], meropenem-vaborbactam [201,202], and imipenem-relebactam [201] are recommended as the major choice to treat infections caused by CRE including CRKP [201]. The newer β-lactamase inhibitors avibactam, vaborbactam, and relebactam have good activities against most serine-based β-lactamases such as carbapenemase KPC but are unable to inhibit MBLs such as IMP, NDM, and VIM [203]. For MBL-producing CRE, ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam are therefore not effective. The combination of ceftazidime-avibactam and aztreonam, which is stable to the hydrolysis by MBLs [204,205], is recommended against MBL-producing CRE [201]. Cefiderocol is another choice against MBL-producing CRKP but is not available in many countries [201,202]. Polymyxin B or E (colistin) could be an alternative but is commonly associated with poorer outcomes comparing with β-lactams [201]. Nonetheless, the common presence of MBLs in neonatal CRKP strains accentuates the call for developing MBL inhibitors, which have not been approved for clinical use, but significant advances have been made in this realm [206].

In conclusion, we estimated that the pooled prevalence of neonatal CRKP infection was 0.3% (95% CI, 0.2% to 0.3%) with a 22.9% (95% CI, 13.0% to 32.9%) pooled mortality of infected neonates based on literature. We observed very diverse clonal backgrounds of neonatal CRKP strains, which indicates multiple origins. We identified that ST17, ST11, and ST15 were widespread CRKP lineages in neonates, and such lineages warrant rigorous monitoring. We found that most neonatal CRKP strains have genes encoding MBLs, in particular NDM, rendering approved antimicrobial agents containing newer β-lactamase inhibitors such as ceftazidime-avibactam, the mainstream choices against CRKP, ineffective. The above findings highlight that CRKP is a significant threat to neonates, in particular to those in LMICs, and characterize neonatal CRKP infections to inform infection control and treatment. To combat neonatal CRKP infections, rigorous surveillance will lay a foundation by revealing the local epidemiology of the strains and the carbapenemases and needs to be established or enhanced with considering measures like environmental sampling and active screening for those in high risks. For managing neonatal CRKP infections, antimicrobial agents with coverage for MBLs may be the initial choice and then could be tailored when the susceptibility testing results become available.

Supporting information

S1 Text. PRISMA checklist.

https://doi.org/10.1371/journal.pmed.1004233.s001

(DOCX)

S2 Text. Protocol for this study.

https://doi.org/10.1371/journal.pmed.1004233.s002

(DOCX)

S1 Fig. Species identification methods.

MALDI-TOF MS, matrix-assisted laser desorption/ionization time-of-flight mass-spectrometer; mNGS, metagenomic next-generation sequencing; WGS, whole genome sequencing.

https://doi.org/10.1371/journal.pmed.1004233.s003

(DOCX)

S1 Table. Sample types of neonatal CRKP strains.

https://doi.org/10.1371/journal.pmed.1004233.s004

(DOCX)

S2 Table. Mortality of CRKP-infected neonates.

https://doi.org/10.1371/journal.pmed.1004233.s005

(DOCX)

S3 Table. CRKP colonization rates in neonates.

https://doi.org/10.1371/journal.pmed.1004233.s006

(DOCX)

S4 Table. Species identification for strains of CRKP in studies using whole genome sequencing.

https://doi.org/10.1371/journal.pmed.1004233.s007

(DOCX)

S5 Table. All STs of neonatal CRKP strains.

https://doi.org/10.1371/journal.pmed.1004233.s008

(DOCX)

S6 Table. Profiles of new STs compared with their nearest neighbour.

https://doi.org/10.1371/journal.pmed.1004233.s009

(DOCX)

S7 Table. Carbapenemases in neonatal CRKP strains with information for STs.

https://doi.org/10.1371/journal.pmed.1004233.s010

(DOCX)

S8 Table. The association of carbapenemases with plasmid replicon types.

https://doi.org/10.1371/journal.pmed.1004233.s011

(DOCX)

S9 Table. Strain types and virulence factors of the 35 identified possibly hypervirulent neonatal CRKP strains.

https://doi.org/10.1371/journal.pmed.1004233.s012

(DOCX)

S1 Dataset. All included articles.

https://doi.org/10.1371/journal.pmed.1004233.s013

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S2 Dataset. Quality assessment for cross-sectional studies.

https://doi.org/10.1371/journal.pmed.1004233.s014

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S3 Dataset. Quality assessment for cohort studies.

https://doi.org/10.1371/journal.pmed.1004233.s015

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S4 Dataset. Quality assessment for case-control studies.

https://doi.org/10.1371/journal.pmed.1004233.s016

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S5 Dataset. Methods for determining carbapenem resistance.

https://doi.org/10.1371/journal.pmed.1004233.s017

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S6 Dataset. All 535 genomes.

https://doi.org/10.1371/journal.pmed.1004233.s018

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S7 Dataset. ST17 harboring CTX-M.

https://doi.org/10.1371/journal.pmed.1004233.s019

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References

  1. 1. Fleischmann C, Reichert F, Cassini A, Horner R, Harder T, Markwart R, et al. Global incidence and mortality of neonatal sepsis: a systematic review and meta-analysis. Arch Dis Child. 2021;106(8):745–752. Epub 2021/01/24. pmid:33483376; PubMed Central PMCID: PMC8311109.
  2. 2. Laxminarayan R, Matsoso P, Pant S, Brower C, Rottingen JA, Klugman K, et al. Access to effective antimicrobials: a worldwide challenge. Lancet. 2016;387(10014):168–175. Epub 2015/11/26. pmid:26603918.
  3. 3. Lawn JE, Blencowe H, Oza S, You D, Lee AC, Waiswa P, et al. Every newborn: progress, priorities, and potential beyond survival. Lancet. 2014;384(9938):189–205. Epub 2014/05/24. pmid:24853593.
  4. 4. Liu L, Oza S, Hogan D, Perin J, Rudan I, Lawn JE, et al. Global, regional, and national causes of child mortality in 2000–13, with projections to inform post-2015 priorities: an updated systematic analysis. Lancet. 2015;385(9966):430–440. Epub 2014/10/05. pmid:25280870.
  5. 5. Zaidi AK, Huskins WC, Thaver D, Bhutta ZA, Abbas Z, Goldmann DA. Hospital-acquired neonatal infections in developing countries. Lancet. 2005;365(9465):1175–1188. Epub 2005/03/30. pmid:15794973.
  6. 6. Laxminarayan R, Bhutta ZA. Antimicrobial resistance-a threat to neonate survival. Lancet Glob Health. 2016;4(10):e676–e677. Epub 2016/09/17. pmid:27633421.
  7. 7. Rodrigues C, Passet V, Rakotondrasoa A, Diallo TA, Criscuolo A, Brisse S. Description of Klebsiella africanensis sp. nov., Klebsiella variicola subsp. tropicalensis subsp. nov. and Klebsiella variicola subsp. variicola subsp. nov. Res Microbiol. 2019;170(3):165–170. Epub 2019/03/01. pmid:30817987.
  8. 8. Saxenborn P, Baxter J, Tilevik A, Fagerlind M, Dyrkell F, Pernestig AK, et al. Genotypic characterization of clinical Klebsiella spp. isolates collected from patients with suspected community-onset sepsis, Sweden. Front Microbiol. 2021;12:640408. Epub 2021/05/18. pmid:33995300; PubMed Central PMCID: PMC8120268.
  9. 9. Donay JL, Mathieu D, Fernandes P, Pregermain C, Bruel P, Wargnier A, et al. Evaluation of the automated phoenix system for potential routine use in the clinical microbiology laboratory. J Clin Microbiol. 2004;42(4):1542–1546. Epub 2004/04/09. pmid:15071001; PubMed Central PMCID: PMC387561.
  10. 10. Rodrigues C, Passet V, Rakotondrasoa A, Brisse S. Identification of Klebsiella pneumoniae, Klebsiella quasipneumoniae, Klebsiella variicola and related phylogroups by MALDI-TOF Mass Spectrometry. Front Microbiol. 2018;9:3000. Epub 2018/12/07. pmid:30581423; PubMed Central PMCID: PMC6294014.
  11. 11. He Y, Guo X, Xiang S, Li J, Li X, Xiang H, et al. Comparative analyses of phenotypic methods and 16S rRNA, khe, rpoB genes sequencing for identification of clinical isolates of Klebsiella pneumoniae. Antonie Van Leeuwenhoek. 2016;109(7):1029–40. Epub 2016/05/06. pmid:27147066.
  12. 12. Srinivasan R, Karaoz U, Volegova M, MacKichan J, Kato-Maeda M, Miller S, et al. Use of 16S rRNA gene for identification of a broad range of clinically relevant bacterial pathogens. PLoS ONE. 2015;10(2):e0117617. ARTN e0117617 WOS:000349444900191 pmid:25658760
  13. 13. Wen SCH, Ezure Y, Rolley L, Spurling G, Lau CL, Riaz S, et al. Gram-negative neonatal sepsis in low- and lower-middle-income countries and WHO empirical antibiotic recommendations: A systematic review and meta-analysis. PLoS Med. 2021;18(9):e1003787. Epub 2021/09/29. pmid:34582466; PubMed Central PMCID: PMC8478175 following competing interests: SCW has previously received research grant from GSK. DLP has board memberships with Merck, Shionogi, Achaogen, AstraZeneca, Leo Pharmaceuticals, Bayer, GlaxoSmithKline, Cubist, Venatorx and Accelerate. DLP has received payment from Pfizer for lectures. DLP also has grants pending with Shinogi and Merck.
  14. 14. Okomo U, Akpalu ENK, Le Doare K, Roca A, Cousens S, Jarde A, et al. Aetiology of invasive bacterial infection and antimicrobial resistance in neonates in sub-Saharan Africa: a systematic review and meta-analysis in line with the STROBE-NI reporting guidelines. Lancet Infect Dis. 2019;19(11):1219–1234. Epub 2019/09/17. pmid:31522858.
  15. 15. Thomson KM, Dyer C, Liu F, Sands K, Portal E, Carvalho MJ, et al. Effects of antibiotic resistance, drug target attainment, bacterial pathogenicity and virulence, and antibiotic access and affordability on outcomes in neonatal sepsis: an international microbiology and drug evaluation prospective substudy (BARNARDS). Lancet Infect Dis. 2021;21(12):1677–1688. Epub 2021/08/14. pmid:34384533; PubMed Central PMCID: PMC8612937.
  16. 16. Stewardson AJ, Marimuthu K, Sengupta S, Allignol A, El-Bouseary M, Carvalho MJ, et al. Effect of carbapenem resistance on outcomes of bloodstream infection caused by Enterobacteriaceae in low-income and middle-income countries (PANORAMA): a multinational prospective cohort study. Lancet Infect Dis. 2019;19(6):601–610. Epub 2019/05/03. pmid:31047852.
  17. 17. Schwaber MJ, Carmeli Y. Carbapenem-resistant Enterobacteriaceae: a potential threat. JAMA. 2008;300(24):2911–2913. pmid:19109119.
  18. 18. Williams PCM, Isaacs D, Berkley JA. Antimicrobial resistance among children in sub-Saharan Africa. Lancet Infect Dis. 2018;18(2):E33–E44. WOS:000423814000001 pmid:29033034
  19. 19. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30(15):2114–2120. pmid:24695404; PubMed Central PMCID: PMC4103590
  20. 20. Shen W, Le S, Li Y, Hu F. SeqKit: A cross-platform and ultrafast toolkit for FASTA/Q file manipulation. PLoS ONE. 2016;11(10):e0163962. Epub 2016/10/05. pmid:27706213; PubMed Central PMCID: PMC5051824.
  21. 21. Bankevich A, Nurk S, Antipov D, Gurevich AA, Dvorkin M, Kulikov AS, et al. SPAdes: a new genome assembly algorithm and its applications to single-cell sequencing. J Comput Biol. 2012;19(5):455–477. pmid:22506599
  22. 22. Jain C, Rodriguez RL, Phillippy AM, Konstantinidis KT, Aluru S. High throughput ANI analysis of 90K prokaryotic genomes reveals clear species boundaries. Nat Commun. 2018;9(1):5114. Epub 2018/12/07. pmid:30504855; PubMed Central PMCID: PMC6269478.
  23. 23. Parks DH, Imelfort M, Skennerton CT, Hugenholtz P, Tyson GW. CheckM: assessing the quality of microbial genomes recovered from isolates, single cells, and metagenomes. Genome Res. 2015;25(7):1043–1055. Epub 2015/05/16. pmid:25977477; PubMed Central PMCID: PMC4484387.
  24. 24. Lam MMC, Wick RR, Watts SC, Cerdeira LT, Wyres KL, Holt KE. A genomic surveillance framework and genotyping tool for Klebsiella pneumoniae and its related species complex. Nat Commun. 2021;12(1):4188. Epub 2021/07/07. pmid:34234121; PubMed Central PMCID: PMC8263825.
  25. 25. Feldgarden M, Brover V, Gonzalez-Escalona N, Frye JG, Haendiges J, Haft DH, et al. AMRFinderPlus and the Reference Gene Catalog facilitate examination of the genomic links among antimicrobial resistance, stress response, and virulence. Sci Rep. 2021;11(1):12728. Epub 2021/06/18. pmid:34135355; PubMed Central PMCID: PMC8208984.
  26. 26. Carattoli A, Zankari E, García-Fernández A, Voldby Larsen M, Lund O, Villa L, et al. In silico detection and typing of plasmids using PlasmidFinder and plasmid multilocus sequence typing. Antimicrob Agents Chemother. 2014;58(7):3895–3903. Epub 2014/04/30. pmid:24777092; PubMed Central PMCID: PMC4068535.
  27. 27. Mairi A, Touati A, Bessai SA, Boutabtoub Y, Khelifi F, Sotto A, et al. Carbapenemase-producing Enterobacteriaceae among pregnant women and newborns in Algeria: Prevalence, molecular characterization, maternal-neonatal transmission, and risk factors for carriage. Am J Infect Control. 2019;47(1):105–108. WOS:000454772600023 pmid:30220617
  28. 28. Hassuna NA, AbdelAziz RA, Zakaria A, Abdelhakeem M. Extensively-drug resistant Klebsiella pneumoniae recovered from neonatal sepsis cases from a major NICU in Egypt. Front Microbiol. 2020;11:1375. Epub 2020/07/09. pmid:32636828; PubMed Central PMCID: PMC7317144.
  29. 29. Ghaith DM, Zafer MM, Said HM, Elanwary S, Elsaban S, Al-Agamy MH, et al. Genetic diversity of carbapenem-resistant Klebsiella Pneumoniae causing neonatal sepsis in intensive care unit, Cairo. Egypt. Eur J Clin Microbiol. 2020;39(3):583–591. WOS:000519554500023 pmid:31773363
  30. 30. Labi AK, Nielsen KL, Marvig RL, Bjerrum S, Enweronu-Laryea C, Bennedbæk M, et al. Oxacillinase-181 carbapenemase-producing Klebsiella pneumoniae in neonatal intensive care unit, Ghana, 2017–2019. Emerg Infect Dis. 2020;26(9):2235–2238. Epub 2020/08/21. pmid:32818427; PubMed Central PMCID: PMC7454046.
  31. 31. Shatalov A, Awwad F, Mangue P, Foqahaa RJ. Predominance of multi-drug resistant Klebsiella pneumonia and other Gram negative bacteria in neonatal sepsis in Equatorial Guinea. Open J Med Microbiol. 2015;5(4):254–258.
  32. 32. Taoufik L, Hanchi AA, Fatiha B, Nissrine S, Rabou MFM, Nabila S. Emergence of OXA-48 carbapenemase producing Klebsiella pneumoniae in a neonatal intensive care unit in Marrakech, Morocco. Clin Med Insights Pediatr. 2019;13:1–5. WOS:000462014100001 pmid:30899152
  33. 33. Chabah M, Chemsi M, Zerouali K, Alloula O, Lehlimi M, Habzi A, et al. Healthcare-associated infections due to carbapenemase-producing Enterobacteriaceae: Bacteriological profile and risk factors. Med Mal Infect. 2016;46(3):157–162. Epub 2016/02/22. pmid:26897308.
  34. 34. Sands K, Carvalho MJ, Portal E, Thomson K, Dyer C, Akpulu C, et al. Characterization of antimicrobial-resistant Gram-negative bacteria that cause neonatal sepsis in seven low- and middle-income countries. Nat Microbiol. 2021;6(4):512–523. Epub 2021/03/31. pmid:33782558; PubMed Central PMCID: PMC8007471.
  35. 35. Onyedibe KI, Bode-Thomas F, Afolaranmi TO, Okolo MO, Banwat EB, Egah DZ. Bacteriologic profile, antibiotic regimen and clinical outcome of neonatal sepsis in a university teaching hospital in north central Nigeria. Br J Med Med Res. 2015;7(7):567–579.
  36. 36. Brinkac LM, White R, D’Souza R, Nguyen K, Obaro SK, Fouts DE. Emergence of New Delhi Metallo-beta-Lactamase (NDM-5) in Klebsiella quasipneumoniae from neonates in a Nigerian Hospital. mSphere. 2019;4(2):e00685–18. ARTN e00685-18. WOS:000465544000008.
  37. 37. Medugu N, Iregbu KC. Trends in profiles of bacteria causing neonatal sepsis in Central Nigeria Hospital. African J Clin Exp Microbiol. 2017;18(1):49–52.
  38. 38. Morkel G, Bekker A, Marais BJ, Kirsten G, van Wyk J, Dramowski A. Bloodstream infections and antimicrobial resistance patterns in a South African neonatal intensive care unit. Paediatr Int Child Health. 2014;34(2):108–114. Epub 2014/03/14. pmid:24621234.
  39. 39. Kopotsa K, Mbelle NM, Sekyere JO. Epigenomics, genomics, resistome, mobilome, virulome and evolutionary phylogenomics of carbapenem-resistant Klebsiella pneumoniae clinical strains. Microb Genomics. 2020;6(12). ARTN 00047410.1099/mgen.0.000474. WOS:000603125400008.
  40. 40. Lebea MM, Davies V. Evaluation of culture-proven neonatal sepsis at a tertiary care hospital in Johannesburg, South Africa. S Afr J Child Health. 2017;11(4):170–173. WOS:000423859800005
  41. 41. Ramsamy Y, Mlisana KP, Allam M, Amoako DG, Abia ALK, Ismail A, et al. Genomic analysis of carbapenemase-producing extensively drug-resistant Klebsiella pneumoniae isolates reveals the horizontal spread of p18-43_01 plasmid encoding blaNDM-1 in South Africa. Microorganisms. 2020;8(1):137. ARTN 137. WOS:000514650700041.
  42. 42. Essel V, Tshabalala K, Ntshoe G, Mphaphuli E, Ntshoe G, Shonhiwa AM, et al. A multisectoral investigation of a neonatal unit outbreak of Klebsiella pneumoniae bacteraemia at a regional hospital in Gauteng Province, South Africa. Samj S Afr Med J. 2020;110(8):783–790. WOS:000577102900031 pmid:32880307
  43. 43. Reddy K, Bekker A, Whitelaw AC, Esterhuizen TM, Dramowski A. A retrospective analysis of pathogen profile, antimicrobial resistance and mortality in neonatal hospital-acquired bloodstream infections from 2009–2018 at Tygerberg Hospital, South Africa. PLoS ONE. 2021;16(1):e0245089. Epub 2021/01/15. pmid:33444334; PubMed Central PMCID: PMC7808607.
  44. 44. Ballot DE, Bandini R, Nana T, Bosman N, Thomas T, Davies VA, et al. A review of multidrug-resistant Enterobacteriaceae in a neonatal unit in Johannesburg, South Africa. BMC Pediatr. 2019;19(1):320. Epub 2019/09/09. pmid:31493789; PubMed Central PMCID: PMC6731552.
  45. 45. Mzimela BW, Nkwanyana NM, Singh R. Clinics outcome of neonates with carbapenem-resistant Enterobacteriaceae infections at the King Edward VIII Hospital’s neonatal unit, Durban, South Africa. S Afr J Infect Dis. 2021;36(1). ARTN a223. WOS:000617770800001.
  46. 46. Kayange N, Kamugisha E, Mwizamholya DL, Jeremiah S, Mshana SE. Predictors of positive blood culture and deaths among neonates with suspected neonatal sepsis in a tertiary hospital, Mwanza-Tanzania. BMC Pediatr. 2010;10:39. Artn 39. WOS:000279953200001. pmid:20525358
  47. 47. Battikh H, Harchay C, Dekhili A, Khazar K, Kechrid F, Zribi M, et al. Clonal spread of colistin-resistant Klebsiella pneumoniae coproducing KPC and VIM carbapenemases in neonates at a Tunisian university hospital. Microb Drug Resist. 2017;23(4):468–472. Epub 2016/11/02. pmid:27802107.
  48. 48. Kabwe M, Tembo J, Chilukutu L, Chilufya M, Ngulube F, Lukwesa C, et al. Etiology, antibiotic resistance and risk factors for neonatal sepsis in a large referral center in Zambia. Pediatr Infect Dis J. 2016;35(7):e191–e198. Epub 2016/04/01. pmid:27031259.
  49. 49. Farzana R, Jones LS, Rahman MA, Andrey DO, Sands K, Portal E, et al. Outbreak of hypervirulent multidrug-resistant Klebsiella variicola causing high mortality in neonates in Bangladesh. Clin Infect Dis. 2019;68(7):1225–1227. Epub 2018/09/12. pmid:30204843.
  50. 50. Liu Y, Li XY, Wan LG, Jiang WY, Yang JH, Li FQ. Acquisition of carbapenem resistance in multiresistant Klebsiella pneumoniae isolates of sequence type 11 at a university hospital in China. Diagn Microbiol Infect Dis. 2013;76(2):241–243. WOS:000319717500024 pmid:23518183
  51. 51. Yin L, He L, Miao J, Yang W, Wang X, Ma J, et al. Actively surveillance and appropriate patient placement in contact isolation dramatically decreased carbapenem-resistant Enterobacterales infection and colonization in paediatric patients in China. J Hosp Infect. 2020;105(3):486–494. WOS:000548762800022 pmid:32243954
  52. 52. Wang F, Jiang J, Shi G, Wang J, Zhou S. Anti-infective treatment of purulent meningitis caused by carbapenem-resistant Klebsiella pneumoniae in a newborn: a case report. Transl Pediatr. 2020;9(5):713–719. Epub 2020/11/20. pmid:33209736; PubMed Central PMCID: PMC7658775.
  53. 53. Yin L, He L, Miao J, Yang W, Wang X, Ma J, et al. Carbapenem-resistant Enterobacterales colonization and subsequent infection in a neonatal intensive care unit in Shanghai, China. Infect Prev Pract. 2021;3(3):100147. Epub 2021/10/15. pmid:34647006; PubMed Central PMCID: PMC8498732.
  54. 54. Weng BW, Zhang XY, Hong WC, Yan CB, Gong XH, Cai C. A case of sepsis due to carbapenem-resistant Klebsiella pneumoniae in an extremely low-birth weight infant treated with Trimethoprim-Sulfamethoxazole. Infect Drug Resist. 2021;14:2321–2325. WOS:000665089500001 pmid:34188498
  55. 55. Jin Y, Song XF, Liu Y, Wang YC, Zhang BC, Fan H, et al. Characteristics of carbapenemase-producing Klebsiella pneumoniae as a cause of neonatal infection in Shandong, China. Exp Ther Med. 2017;13(3):1117–1126. WOS:000397004700050 pmid:28450951
  56. 56. Huang X, Cheng XJ, Sun PF, Tang CJ, Ni F, Liu GY. Characteristics of NDM-1-producing Klebsiella pneumoniae ST234 and ST1412 isolates spread in a neonatal unit. BMC Microbiol. 2018;18(1):186. ARTN 186. WOS:000450468700001.
  57. 57. Yin D, Zhang L, Wang A, He L, Cao Y, Hu F, et al. Clinical and molecular epidemiologic characteristics of carbapenem-resistant Klebsiella pneumoniae infection/colonization among neonates in China. J Hosp Infect. 2018;100(1):21–28. WOS:000443153800005 pmid:29763630
  58. 58. Zhou JJ, Yang JW, Hu FP, Gao KJ, Sun JF, Yang JM. Clinical and molecular epidemiologic characteristics of ceftazidime/avibactam-resistant carbapenem-resistant Klebsiella pneumoniae in a neonatal intensive care unit in China. Infect Drug Resist. 2020;13:2571–2578. WOS:000553310800003 pmid:32801794
  59. 59. Kong ZY, Liu XM, Li CX, Cheng SY, Xu F, Gu B. Clinical molecular epidemiology of carbapenem-resistant Klebsiella pneumoniae among pediatric patients in Jiangsu Province, China. Infect Drug Resist. 2020;13:4627–4635. WOS:000600626800005 pmid:33376368
  60. 60. Yin DD, Dong D, Li K, Zhang L, Liang JL, Yang Y, et al. Clonal dissemination of OXA-232 carbapenemase-producing Klebsiella pneumoniae in neonates. Antimicrob Agents Chemother. 2017;61(8):e00385–17. ARTN e00385-17. WOS:000406259400041.
  61. 61. Chen D, Hu X, Chen F, Li H, Wang D, Li X, et al. Co-outbreak of multidrug resistance and a novel ST3006 Klebsiella pneumoniae in a neonatal intensive care unit: A retrospective study. Medicine (Baltimore). 2019;98(4):e14285. Epub 2019/01/27. pmid:30681632; PubMed Central PMCID: PMC6358387.
  62. 62. Liu JX, Yu J, Chen F, Yu JJ, Simner P, Tamma P, et al. Emergence and establishment of KPC-2-producing ST11 Klebsiella pneumoniae in a general hospital in Shanghai, China. Eur J Clin Microbiol Infect Dis. 2018;37(2):293–299. WOS:000423152100013 pmid:29282569
  63. 63. Zhang YW, Zeng J, Liu WE, Zhao F, Hu ZD, Zhao CJ, et al. Emergence of a hypervirulent carbapenem-resistant Klebsiella pneumoniae isolate from clinical infections in China. J Infection. 2015;71(5):553–560. WOS:000368479700007 pmid:26304687
  64. 64. Patil S, Chen HY, Guo CN, Zhang XL, Ren PG, Francisco NM, et al. Emergence of Klebsiella pneumoniae ST307 co-producing CTX-M with SHV and KPC from paediatric patients at Shenzhen Children’s Hospital, China. Infect Drug Resist. 2021;14:3581–3588. WOS:000692592500003 pmid:34511949
  65. 65. Jin CM, Shi R, Jiang X, Zhou FX, Qiang JX, An CS. Epidemic characteristics of carbapenem-resistant Klebsiella pneumoniae in the pediatric intensive care unit of Yanbian University Hospital, China. Infect Drug Resist. 2020;13:1439–1446. WOS:000534618200001
  66. 66. Yang YX, Liu J, Muhammad M, Liu HT, Min ZS, Lu J, et al. Factors behind the prevalence of carbapenem-resistant Klebsiella pneumoniae in pediatric wards. Medicine. 2021;100(36):e27186. ARTN e27186. WOS:000704826900027.
  67. 67. Kong ZY, Cai R, Cheng C, Zhang CL, Kang HQ, Ma P, et al. First reported nosocomial outbreak of NDM-5-producing Klebsiella pneumoniae in a neonatal unit in China. Infect Drug Resist. 2019;12:3557–3566. WOS:000496807600001 pmid:31814744
  68. 68. Dong F, Lu J, Wang Y, Shi J, Zhen JH, Chu P, et al. A five-year surveillance of carbapenemase-producing Klebsiella pneumoniae in a pediatric hospital in China reveals increased predominance of NDM-1. Biomed Environ Sci. 2017;30(8):562–569. Epub 2017/08/16. pmid:28807096.
  69. 69. Qiao F, Wei L, Feng Y, Ran S, Zheng L, Zhang Y, et al. Handwashing sink contamination and carbapenem-resistant Klebsiella infection in the intensive care unit: a prospective multicenter study. Clin Infect Dis. 2020;71(Suppl 4):S379–S385. Epub 2020/12/29. pmid:33367578.
  70. 70. Chen CM, Wang M, Li XP, Li PL, Tian JJ, Zhang K, et al. Homology analysis between clinically isolated extraintestinal and enteral Klebsiella pneumoniae among neonates. BMC Microbiol. 2021;21(1):25. Epub 2021/01/13. pmid:33430787; PubMed Central PMCID: PMC7802202.
  71. 71. Wang SY, Zhao J, Liu N, Yang F, Zhong YM, Gu XM, et al. IMP-38-producing high-risk sequence type 307 Klebsiella pneumoniae strains from a neonatal unit in China. mSphere. 2020;5(4):e00407–20. ARTN e00407-20. WOS:000568742700005.
  72. 72. Pei N, Li Y, Liu C, Jian Z, Liang T, Zhong Y, et al. Large-scale genomic epidemiology of Klebsiella pneumoniae identified clone divergence with hypervirulent plus antimicrobial-resistant characteristics causing within-ward strain transmissions. Microbiol Spectr. 2022;10(2):e0269821. Epub 2022/04/14. pmid:35416698; PubMed Central PMCID: PMC9045374.
  73. 73. Wang B, Pan F, Wang C, Zhao W, Sun Y, Zhang T, et al. Molecular epidemiology of carbapenem-resistant Klebsiella pneumoniae in a paediatric hospital in China. Int J Infect Dis. 2020;93:311–319. Epub 2020/02/19. pmid:32068096.
  74. 74. Jin Y, Dong CZ, Shao CH, Wang Y, Liu Y. Molecular epidemiology of clonally related metallo-beta-lactamase-producing Klebsiella pneumoniae isolated from newborns in a hospital in Shandong, China. Jundishapur J Microbiol. 2017;10(9):e14046. ARTN e14046. WOS:000416175900002.
  75. 75. Cienfuegos-Gallet AV, Zhou Y, Ai W, Kreiswirth BN, Yu F, Chen L. Multicenter genomic analysis of carbapenem-resistant Klebsiella pneumoniae from bacteremia in China. Microbiol Spectr. 2022;10(2):e0229021. Epub 2022/03/02. pmid:35230130; PubMed Central PMCID: PMC9045280.
  76. 76. Wei L, Feng Y, Wen HX, Ya H, Qiao F, Zong ZY. NDM-5-producing carbapenem-resistant Klebsiella pneumoniae of sequence type 789 emerged as a threat for neonates: a multicentre, genome-based study. Int J Antimicrob Agents. 2022;59(2):106508. ARTN 106508. WOS:000791112900002.
  77. 77. Li J, Hu X, Yang L, Lin Y, Liu Y, Li P, et al. New Delhi metallo-beta-lactamase 1-producing Klebsiella pneumoniae ST719 isolated from a neonate in China. Microb Drug Resist. 2020;26(5):492–496. Epub 2019/11/16. pmid:31730396.
  78. 78. Luo K, Tang J, Qu Y, Yang X, Zhang L, Chen Z, et al. Nosocomial infection by Klebsiella pneumoniae among neonates: a molecular epidemiological study. J Hosp Infect. 2021;108:174–180. Epub 2020/12/09. pmid:33290814.
  79. 79. Yu J, Tan K, Rong Z, Wang Y, Chen Z, Zhu X, et al. Nosocomial outbreak of KPC-2- and NDM-1-producing Klebsiella pneumoniae in a neonatal ward: a retrospective study. BMC Infect Dis. 2016;16(1):563. Epub 2016/10/14. pmid:27733128; PubMed Central PMCID: PMC5062924.
  80. 80. Zhou J, Li GP, Ma XJ, Yang QW, Yi J. Outbreak of colonization by carbapenemase-producing Klebsiella pneumoniae in a neonatal intensive care unit: Investigation, control measures and assessment. Am J Infect Control. 2015;43(10):1122–1124. WOS:000362093600024 pmid:26149749
  81. 81. Jin Y, Shao C, Li J, Fan H, Bai Y, Wang Y. Outbreak of multidrug resistant NDM-1-producing Klebsiella pneumoniae from a neonatal unit in Shandong Province, China. PLoS ONE. 2015;10(3):e0119571. Epub 2015/03/24. pmid:25799421; PubMed Central PMCID: PMC4370709.
  82. 82. Zhang XY, Li XP, Wang M, Yue HJ, Li PL, Liu YP, et al. Outbreak of NDM-1-producing Klebsiella pneumoniae causing neonatal infection in a teaching hospital in mainland China. Antimicrob Agents Chemother. 2015;59(7):4349–4351. WOS:000360896000086 pmid:25941224
  83. 83. Zhu J, Sun L, Ding B, Yang Y, Xu X, Liu W, et al. Outbreak of NDM-1-producing Klebsiella pneumoniae ST76 and ST37 isolates in neonates. Eur J Clin Microbiol Infect Dis. 2016;35(4):611–618. Epub 2016/01/25. pmid:26803822.
  84. 84. Yu J, Wang Y, Chen Z, Zhu X, Tian L, Li L, et al. Outbreak of nosocomial NDM-1-producing Klebsiella pneumoniae ST1419 in a neonatal unit. J Glob Antimicrob Resist. 2017;8:135–139. Epub 2017/01/23. pmid:28109845.
  85. 85. Zheng R, Zhang Q, Guo Y, Feng Y, Liu L, Zhang A, et al. Outbreak of plasmid-mediated NDM-1-producing Klebsiella pneumoniae ST105 among neonatal patients in Yunnan, China. Ann Clin Microbiol Antimicrob. 2016;15:10. Epub 2016/02/21. pmid:26896089; PubMed Central PMCID: PMC4761218.
  86. 86. Yu FY, Ying QH, Chen C, Li TJ, Ding BX, Liu Y, et al. Outbreak of pulmonary infection caused by Klebsiella pneumoniae isolates harbouring blaIMP-4 and blaDHA-1 in a neonatal intensive care unit in China. J Med Microbiol. 2012;61(7):984–989. WOS:000307206700014
  87. 87. Chen S, Feng W, Chen JH, Liao W, He NH, Wang Q, et al. Spread of carbapenemase-producing Enterobacteria in a southwest hospital in China. Ann Clin Microb Anti. 2014;13:42. ARTN 42. WOS:000341054700001.
  88. 88. Li PL, Wang M, Li XP, Hu FH, Yang M, Xie YX, et al. ST37 Klebsiella pneumoniae: development of carbapenem resistance in vivo during antimicrobial therapy in neonates. Future Microbiol. 2017;12(10):891–904. WOS:000408437400009 pmid:28699768
  89. 89. Zou H, Shen Y, Li CL, Li QH. Two phenotypes of Klebsiella pneumoniae ST147 outbreak from neonatal sepsis with a slight increase in virulence. Infect Drug Resist. 2022;15:1–12. WOS:000741414900001 pmid:35023933
  90. 90. Bai Y, Shao C, Hao Y, Wang Y, Jin Y. Using whole genome sequencing to trace, control and characterize a hospital infection of IMP-4-producing Klebsiella pneumoniae ST2253 in a neonatal unit in a tertiary hospital, China. Front Public Health. 2021;9:755252. Epub 2022/01/04. pmid:34976919; PubMed Central PMCID: PMC8715938.
  91. 91. Pang F, Jia XQ, Song ZZ, Li YH, Wang B, Zhao QG, et al. Characteristics and management of Enterobacteriaceae harboring IMP-4 or IMP-8 carbapenemase in a tertiary hospital. Afr Health Sci. 2016;16(1):153–161. Epub 2016/07/01. pmid:27358627; PubMed Central PMCID: PMC4915421.
  92. 92. Ma MS, Wang DH, Sun XJ, Li ZH, Wang C. Risk factors for Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae colonization in neonates. Zhongguo Dang Dai Er Ke Za Zhi. 2014;16(10):970–974. pmid:25344173.
  93. 93. Jasani B, Kannan S, Nanavati R, Gogtay NJ, Thatte U. An audit of colistin use in neonatal sepsis from a tertiary care centre of a resource-limited country. Indian J Med Res. 2016;144:433–439. WOS:000392936400017 pmid:28139542
  94. 94. Marwah P, Chawla D, Chander J, Guglani V, Marwah A. Bacteriological profile of neonatal sepsis in a tertiary-care hospital of northern India. Indian Pediatr. 2015;52(2):158–159. Epub 2015/02/19. pmid:25691192.
  95. 95. Singh SK, Gupta M. blaOXA-48 carrying clonal colistin resistant-carbapenem resistant Klebsiella pneumoniae in neonate intensive care unit, India. Microb Pathog. 2016;100:75–77. Epub 2016/10/28. pmid:27622347.
  96. 96. Mukherjee S, Naha S, Bhadury P, Saha B, Dutta M, Dutta S, et al. Emergence of OXA-232-producing hypervirulent Klebsiella pneumoniae ST23 causing neonatal sepsis. J Antimicrob Chemother. 2020;75(7):2004–2006. WOS:000562411300046 pmid:32155265
  97. 97. Sharma S, Banerjee T, Kumar A, Yadav G, Basu S. Extensive outbreak of colistin resistant, carbapenemase (blaOXA-48, blaNDM) producing Klebsiella pneumoniae in a large tertiary care hospital, India. Antimicrob Resist Infect Control. 2022;11(1):1. Epub 2022/01/08. pmid:34991724; PubMed Central PMCID: PMC8740481.
  98. 98. Banerjee T, Wangkheimayum J, Sharma S, Kumar A, Bhattacharjee A. Extensively drug-resistant hypervirulent Klebsiella pneumoniae from a series of neonatal sepsis in a tertiary care hospital, India. Front Med (Lausanne). 2021;8:645955. Epub 2021/03/26. pmid:33763435; PubMed Central PMCID: PMC7982647.
  99. 99. Datta S, Roy S, Chatterjee S, Saha A, Sen B, Pal T, et al. A five-year experience of carbapenem resistance in Enterobacteriaceae causing neonatal septicaemia: predominance of NDM-1. PLoS ONE. 2014;9(11):e112101. Epub 2014/11/19. pmid:25406074; PubMed Central PMCID: PMC4236051.
  100. 100. Nagaraj G, Shamanna V, Govindan V, Rose S, Sravani D, Akshata KP, et al. High-resolution genomic profiling of carbapenem- resistant Klebsiella pneumoniae isolates: A multicentric retrospective Indian study. Clin Infect Dis. 2021;73:S300–S307. WOS:000743393200007 pmid:34850832
  101. 101. Gajul SV, Mohite ST, Mangalgi SS, Wavare SM, Kakade SV. Klebsiella Pneumoniae in septicemic neonates with special reference to extended spectrum beta-lactamase, AmpC, metallo beta-lactamase production and multiple drug resistance in tertiary care hospital. J Lab Physicians. 2015;7(1):32–37. Epub 2015/05/08. pmid:25949057; PubMed Central PMCID: PMC4411807.
  102. 102. Naha S, Sands K, Mukherjee S, Roy C, Rameez MJ, Saha B, et al. KPC-2-producing Klebsiella pneumoniae ST147 in a neonatal unit: Clonal isolates with differences in colistin susceptibility attributed to AcrAB-TolC pump. Int J Antimicrob Agents. 2020;55(3):105903. Epub 2020/01/20. pmid:31954832.
  103. 103. Mukherjee S, Bhattacharjee A, Naha S, Majumdar T, Debbarma SK, Kaur H, et al. Molecular characterization of NDM-1-producing Klebsiella pneumoniae ST29, ST347, ST1224, and ST2558 causing sepsis in neonates in a tertiary care hospital of North-East India. Infect Genet Evol. 2019;69:166–175. Epub 2019/01/25. pmid:30677535.
  104. 104. Ahmad N, Ali SM, Khan AU. Molecular characterization of novel sequence type of carbapenem-resistant New Delhi metallo-beta-lactamase-1-producing Klebsiella pneumoniae in the neonatal intensive care unit of an Indian hospital. Int J Antimicrob Agents. 2019;53(4):525–529. Epub 2018/12/24. pmid:30578964.
  105. 105. Khajuria A, Praharaj AK, Kumar M, Grover N, Aggarwal A. Multidrug resistant NDM-1 metallo-beta-lactamase producing Klebsiella pneumoniae sepsis outbreak in a neonatal intensive care unit in a tertiary care center at central India. Indian J Pathol Micr. 2014;57(1):65–68. WOS:000334842200012 pmid:24739834
  106. 106. Naha S, Sands K, Mukherjee S, Saha B, Dutta S, Basu S. OXA-181-Like Carbapenemases in Klebsiella pneumoniae ST14, ST15, ST23, ST48, and ST231 from Septicemic Neonates: Coexistence with NDM-5, Resistome, Transmissibility, and Genome Diversity. mSphere. 2021;6(1):e01156–20. ARTN e01156-20. WOS:000647699800042.
  107. 107. Bhattacharjee B, Bardhan T, Chakraborty M, Basu M. Resistance profiles and resistome mapping of multidrug resistant carbapenem-hydrolyzing Klebsiella pneumoniae strains isolated from the nares of preterm neonates. Int J Antimicrob Agents. 2019;53(4):535–537. Epub 2018/12/21. pmid:30572009.
  108. 108. Roy S, Viswanathan R, Singh AK, Das P, Basu S. Sepsis in neonates due to imipenem-resistant Klebsiella pneumoniae producing NDM-1 in India. J Antimicrob Chemother. 2011;66(6):1411–1413. WOS:000290587800039 pmid:21393155
  109. 109. Govindaraju G, Arumugam V, Mageswari TU, Rajaiah B, Ramakrishnan S. Sepsis in neonates: Prevalence of micro-organisms and their susceptibility pattern in neonatal intensive care unit of a tertiary care hospital–a retrospective study. J Basic Clin Pharm. 2020;11:11–16.
  110. 110. Khalid S, Ahmad N, Ali SM, Khan AU. Outbreak of Efficiently Transferred Carbapenem-Resistant blaNDM-Producing Gram-Negative Bacilli Isolated from Neonatal Intensive Care Unit of an Indian Hospital. Microb Drug Resist. 2020;26(3):284–289. WOS:000481012600001 pmid:31397624
  111. 111. Datta S, Mitra S, Viswanathan R, Saha A, Basu S. Characterization of novel plasmid-mediated beta-lactamases (SHV-167 and ACT-16) associated with New Delhi metallo-beta-lactamase-1 harbouring isolates from neonates in India. J Med Microbiol. 2014;63:480–482. WOS:000338478500020
  112. 112. Ahmad N, Khalid S, Ali SM, Khan AU. Occurrence of blaNDM variants among Enterobacteriaceae from a neonatal intensive care unit in a northern India hospital. Front Microbiol. 2018;9:407. Epub 2018/03/23. pmid:29563908; PubMed Central PMCID: PMC5845868.
  113. 113. Tagare A, Kadam S, Vaidya U, Deodhar J, Pandit A. Multidrug resistant Klebsiella pneumoniae in NICU–what next? Trend of antibiotic resistance. J Pediatr Infect Dis. 2015;5:119–124.
  114. 114. Kiaei S, Moradi M, Hosseini-Nave H, Ziasistani M, Kalantar-Neyestanaki D. Endemic dissemination of different sequence types of carbapenem-resistant Klebsiella pneumoniae strains harboring blaNDM and 16S rRNA methylase genes in Kerman hospitals, Iran, from 2015 to 2017. Infect Drug Resist. 2019;12:45–54. WOS:000454475300001 pmid:30613156
  115. 115. Adler A, Solter E, Masarwa S, Miller-Roll T, Abu-Libdeh B, Khammash H, et al. Epidemiological and microbiological characteristics of an outbreak caused by OXA-48-producing Enterobacteriaceae in a neonatal intensive care unit in Jerusalem, Israel. J Clin Microbiol. 2013;51(9):2926–2930. Epub 2013/06/28. pmid:23804390; PubMed Central PMCID: PMC3754643.
  116. 116. Abe R, Oyama F, Akeda Y, Nozaki M, Hatachi T, Okamoto Y, et al. Hospital-wide outbreaks of carbapenem-resistant Enterobacteriaceae horizontally spread through a clonal plasmid harbouring blaIMP-1 in children’s hospitals in Japan. J Antimicrob Chemother. 2021;76(12):3314–3317. WOS:000728183500033 pmid:34477841
  117. 117. Stoesser N, Giess A, Batty EM, Sheppard AE, Walker AS, Wilson DJ, et al. Genome sequencing of an extended series of NDM-producing Klebsiella pneumoniae isolates from neonatal infections in a Nepali hospital characterizes the extent of community- versus hospital-associated transmission in an endemic setting. Antimicrob Agents Chemother. 2014;58(12):7347–7357. Epub 2014/10/01. pmid:25267672; PubMed Central PMCID: PMC4249533.
  118. 118. Khan E, Irfan S, Sultan BA, Nasir A, Hasan R. Dissemination and spread of New Delhi Metallo-beta-lactamase-1 Superbugs in hospital settings. J Pak Med Assoc. 2016;66(8):999–1004. WOS:000384921100019. pmid:27524536
  119. 119. Humayun A, Siddiqui FM, Akram N, Saleem S, Ali A, Iqbal T, et al. Incidence of metallo-beta-lactamase-producing Klebsiella pneumoniae isolates from hospital setting in Pakistan. Int Microbiol. 2018;21(1–2):73–78. WOS:000439010100008 pmid:30810920
  120. 120. Ahmed M, Yasrab M, Khushdil A, Qamar K, Ahmed Z. Neonatal sepsis in a tertiary care hospital: bacteriological profile and its antibicrobial sensitivity. Pakistan Armed Forces Medical Journal. 2018;68(6):1654–1658.
  121. 121. Sana F, Satti L, Zaman G, Gardezi A, Imtiaz A, Ahmed A, et al. Pattern of Gram-negative bloodstream infections and their antibiotic susceptibility profiles in a neonatal intensive care unit. J Hosp Infect. 2018;98(3):243–244. WOS:000426316700007 pmid:29128348
  122. 122. Heinz E, Ejaz H, Scott JB, Wang N, Gujaran S, Pickard D, et al. Resistance mechanisms and population structure of highly drug resistant Klebsiella in Pakistan during the introduction of the carbapenemase NDM-1. Sci Rep. 2019;9(1):2392. ARTN 2392. WOS:000459094800073.
  123. 123. Asfour SS, Alaklobi FA, Abdelrahim A, Taha MY, Asfour RS, Khalil TM, et al. Intravenous ceftazidime-avibactam in extremely premature neonates with carbapenem-resistant Enterobacteriaceae: Two case reports. J Pediatr Pharmacol Ther. 2022;27(2):192–197. pmid:35241992
  124. 124. Haider F, Dar ZP, Gupta A, Yaqoob S, Singh M. Multidrug resistance pattern in bacteriological isolates of neonatal septicemia in NICU of a tertiary care center. Int J Microbiol Res. 2018;5(3):307–312.
  125. 125. Berglund B, Hoang NTB, Tarnberg M, Le NK, Welander J, Nilsson M, et al. Colistin- and carbapenem-resistant Klebsiella pneumoniae carrying mcr-1 and blaOXA-48 isolated at a paediatric hospital in Vietnam. J Antimicrob Chemother. 2018;73(4):1100–1102. WOS:000429019600037 pmid:29253209
  126. 126. Kk S, Ekedahl E, Hoang NTB, Sewunet T, Berglund B, Lundberg L, et al. High diversity of blaNDM-1-encoding plasmids in Klebsiella pneumoniae isolated from neonates in a Vietnamese hospital. Int J Antimicrob Agents. 2022;59(2):106496. Epub 2021/12/19. pmid:34921976.
  127. 127. Le NK, Wertheim HF, Vu PD, Khu DTK, Le HT, Hoang BTN, et al. High prevalence of hospital-acquired infections caused by gram-negative carbapenem resistant strains in Vietnamese pediatric ICUs a multi-centre point prevalence survey. Medicine. 2016;95(27):e4099. ARTN e4099. WOS:000380372400052. pmid:27399106
  128. 128. Berglund B, Hoang NTB, Lundberg L, Le NK, Tarnberg M, Nilsson M, et al. Clonal spread of carbapenem-resistant Klebsiella pneumoniae among patients at admission and discharge at a Vietnamese neonatal intensive care unit. Antimicrob Resist Infect Control. 2021;10(1):162. ARTN 162. WOS:000720713000001.
  129. 129. Levast M, Poirel L, Carrer A, Deiber M, Decroisette E, Mallaval FO, et al. Transfer of OXA-48-positive carbapenem-resistant Klebsiella pneumoniae from Turkey to France. J Antimicrob Chemother. 2011;66(4):944–945. WOS:000288551300042 pmid:21393135
  130. 130. Vergadi E, Bitsori M, Maraki S, Galanakis E. Community-onset carbapenem-resistant Klebsiella pneumoniae urinary tract infections in infancy following NICU hospitalisation. J Pediatr Urol. 2017;13(5):495.e1–e6. ARTN 495.e1. WOS:000414212400030.
  131. 131. Janvari L, Damjanova I, Lazar A, Racz K, Kocsis B, Urban E, et al. Emergence of OXA-162-producing Klebsiella pneumoniae in Hungary. Scand J Infect Dis. 2014;46(4):320–324. WOS:000333045600012 pmid:24552581
  132. 132. Esposito EP, Gaiarsa S, Del Franco M, Crivaro V, Bernardo M, Cuccurullo S, et al. A novel IncA/C1 group conjugative plasmid, encoding VIM-1 metallo-beta-lactamase, mediates the acquisition of carbapenem resistance in ST104 Klebsiella pneumoniae Isolates from neonates in the intensive care unit of V. Monaldi Hospital in Naples. Front Microbiol. 2017;8:2135. Epub 2017/11/23. pmid:29163422; PubMed Central PMCID: PMC5675864.
  133. 133. Gona F, Bongiorno D, Aprile A, Corazza E, Pasqua B, Scuderi MG, et al. Emergence of two novel sequence types (3366 and 3367) NDM-1-and OXA-48-co-producing K. pneumoniae in Italy. Eur J Clin Microbiol. 2019;38(9):1687–1691. WOS:000481757500013. pmid:31165962
  134. 134. Monaco F, Di Mento G, Cuscino N, Conaldi PG, Douradinha B. Infant colonisation with Escherichia coli and Klebsiella pneumoniae strains co-harbouring blaOXA-48 and blaNDM-1 carbapenemases genes: a case report. Int J Antimicrob Agents. 2018;52(1):121–122. WOS:000436591800021 pmid:29753131
  135. 135. Geraci DM, Bonura C, Giuffre M, Saporito L, Graziano G, Aleo A, et al. Is the monoclonal spread of the ST258, KPC-3-producing clone being replaced in southern Italy by the dissemination of multiple clones of carbapenem-nonsusceptible, KPC-3-producing Klebsiella pneumoniae? Clin Microbiol Infect. 2015;21(3):E15–E17. WOS:000367383300001 pmid:25658574
  136. 136. Bonfanti P, Bellu R, Principe L, Caramma I, Condo M, Giani T, et al. Mother-to-child transmission of KPC carbapenemase-producing Klebsiella pneumoniae at Birth. Pediatr Infect Dis J. 2017;36(2):228–229. WOS:000394352500021 pmid:27846056
  137. 137. Principe L, Meroni E, Conte V, Mauri C, Di Pilato V, Giani T, et al. Mother-to-child transmission of KPC-producing Klebsiella pneumoniae: potential relevance of a low microbial urinary load for screening purposes. J Hosp Infect. 2018;98(3):314–316. WOS:000426316700022 pmid:29042234
  138. 138. Maida CM, Bonura C, Geraci DM, Graziano G, Carattoli A, Rizzo A, et al. Outbreak of ST395 KPC-producing Klebsiella pneumoniae in a neonatal intensive care unit in Palermo, Italy. Infect Control Hosp Epidemiol. 2018;39(4):496–498. WOS:000428538000023 pmid:29444730
  139. 139. Agosta M, Bencardino D, Argentieri M, Pansani L, Sisto A, Degli Atti MLC, et al. Prevalence and molecular typing of carbapenemase-producing Enterobacterales among newborn patients in Italy. Antibiotics (Basel). 2022;11(4):431. ARTN 431. WOS:000785399400001.
  140. 140. Giuffrè M, Bonura C, Geraci DM, Saporito L, Catalano R, Di Noto S, et al. Successful control of an outbreak of colonization by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae sequence type 258 in a neonatal intensive care unit, Italy. J Hosp Infect. 2013;85(3):233–236. Epub 2013/10/01. pmid:24074641.
  141. 141. Ripabelli G, Tamburro M, Guerrizio G, Fanelli I, Flocco R, Scutella M, et al. Tracking multidrug-resistant Klebsiella pneumoniae from an Italian hospital: molecular epidemiology and surveillance by PFGE, RAPD and PCR-based resistance genes prevalence. Curr Microbiol. 2018;75(8):977–987. WOS:000436239400003 pmid:29523910
  142. 142. Ciccia M, Ambretti S, Guerra L, Sandri F. Verona integron-encoded metallo-beta-lactamase-producing Klebsiella pneumoniae sepsis in an extremely premature infant. Case Rep Perinat Med. 2018;7(2). UNSP 20180011. WOS:000442662400015.
  143. 143. Almeida TL, Mendo T, Costa R, Novais C, Marcal M, Martins F, et al. Carbapenemase-producing Enterobacteriaceae (CPE) newborn colonization in a Portuguese neonatal intensive care unit (NICU): Epidemiology and infection prevention and control measures. Infect Dis Rep. 2021;13(2):411–417. WOS:000667094300001 pmid:34062713
  144. 144. Dubodelov DV, Lubasovskaya LA, Shubina ES, Mukosey IS, Korostin DO, Kochetkova TO, et al. Genetic determinants of resistance of hospital-associated strains of Klebsiella pneumoniae to β-lactam antibiotics isolated in neonates. Genetika. 2016;52(9):1097–1102. pmid:29369564.
  145. 145. Akturk H, Sutcu M, Somer A, Aydin D, Cihan R, Ozdemir A, et al. Carbapenem-resistant Klebsiella pneumoniae colonization in pediatric and neonatal intensive care units: risk factors for progression to infection. Braz J Infect Dis. 2016;20(2):134–140. Epub 2016/02/13. pmid:26867474.
  146. 146. Bor M, Ilhan O. Carbapenem-resistant Klebsiella pneumoniae outbreak in a neonatal intensive care unit: risk factors for mortality. J Trop Pediatr. 2021;67(3). Epub 2020/08/12. pmid:32778897.
  147. 147. Ulu-Kilic A, Alp E, Percin D, Cevahir F, Altay-Kurkcu C, Ozturk A, et al. Risk factors for carbapenem resistant Klebsiella pneumoniae rectal colonization in pediatric units. J Infect Dev Countr. 2014;8(10):1361–1364. WOS:000343791200021 pmid:25313618
  148. 148. Drew RJ, Turton JF, Hill RLR, Livermore DM, Woodford N, Paulus S, et al. Emergence of carbapenem-resistant Enterobacteriaceae in a UK paediatric hospital. J Hosp Infect. 2013;84(4):300–304. WOS:000322218900004 pmid:23831281
  149. 149. Saavedra SY, Bernal JF, Montilla-Escudero E, Arevalo SA, Prada DA, Valencia MF, et al. Complexity of genomic epidemiology of carbapenem-resistant Klebsiella pneumoniae isolates in Colombia urges the reinforcement of whole genome sequencing-based surveillance programs. Clin Infect Dis. 2021;73:S290–S299. WOS:000743393200006 pmid:34850835
  150. 150. Rada AM, De La Cadena E, Agudelo C, Capataz C, Orozco N, Pallares C, et al. Dynamics of blaKPC-2 dissemination from non-CG258 Klebsiella pneumoniae to other Enterobacterales via IncN plasmids in an area of high endemicity. Antimicrob Agents Chemother. 2020;64(12):e01743–20. ARTN e01743-20. WOS:000592366500042.
  151. 151. Perez JAE, Escobar NMO, Castro-Cardozo B, Marquez IAV, Aguilar MIG, de la Barrera LM, et al. Outbreak of NDM-1-producing Klebsiella pneumoniae in a neonatal unit in Colombia. Antimicrob Agents Chemother. 2013;57(4):1957–1960. WOS:000316119100059 pmid:23357776
  152. 152. Magda Sánchez DJM. Detección rápida de Enterobacterias productoras de carbapenemasas en hisopados rectales de pacientes neonatos colonizados. Infection. 2021;25(2):89–92.
  153. 153. Falco A, Ramos Y, Franco E, Guzmán A, Takiff H. A cluster of KPC-2 and VIM-2-producing Klebsiella pneumoniae ST833 isolates from the pediatric service of a Venezuelan Hospital. BMC Infect Dis. 2016;16(1):595. Epub 2016/10/25. pmid:27770796; PubMed Central PMCID: PMC5075218.
  154. 154. Rada AM, De La Cadena E, Agudelo C, Capataz C, Orozco N, Pallares C, et al. Dynamics of blaKPC-2 dissemination from non-CG258 Klebsiella pneumoniae to other Enterobacterales via IncN plasmids in an area of high endemicity. Antimicrob Agents Chemother. 2020;64(12). Epub 2020/09/23. pmid:32958711; PubMed Central PMCID: PMC7674068.
  155. 155. Wang S, Zhao J, Liu N, Yang F, Zhong Y, Gu X, et al. IMP-38-producing high-risk sequence type 307 Klebsiella pneumoniae strains from a neonatal unit in China. mSphere. 2020;5(4). Epub 2020/07/03. pmid:32611699; PubMed Central PMCID: PMC7333572.
  156. 156. Gona F, Bongiorno D, Aprile A, Corazza E, Pasqua B, Scuderi MG, et al. Emergence of two novel sequence types (3366 and 3367) NDM-1- and OXA-48-co-producing K. pneumoniae in Italy. Eur J Clin Microbiol Infect Dis. 2019;38(9):1687–1691. Epub 2019/06/06. pmid:31165962.
  157. 157. Li J, Hu X, Yang L, Lin Y, Liu Y, Li P, et al. New Delhi metallo-β-Lactamase 1-producing Klebsiella pneumoniae ST719 isolated from a neonate in China. Microb Drug Resist. 2020;26(5):492–496. Epub 2019/11/16. pmid:31730396.
  158. 158. Brinkac LM, White R, D’Souza R, Nguyen K, Obaro SK, Fouts DE. Emergence of New Delhi metallo-β-Lactamase (NDM-5) in Klebsiella quasipneumoniae from neonates in a Nigerian hospital. mSphere. 2019;4(2). Epub 2019/03/15. pmid:30867330; PubMed Central PMCID: PMC6416368.
  159. 159. Naha S, Sands K, Mukherjee S, Saha B, Dutta S, Basu S. OXA-181-like carbapenemases in Klebsiella pneumoniae ST14, ST15, ST23, ST48, and ST231 from septicemic neonates: coexistence with NDM-5, resistome, transmissibility, and genome diversity. mSphere. 2021;6(1). Epub 2021/01/15. pmid:33441403; PubMed Central PMCID: PMC7845606.
  160. 160. Yin D, Dong D, Li K, Zhang L, Liang J, Yang Y, et al. Clonal dissemination of OXA-232 carbapenemase-producing Klebsiella pneumoniae in neonates. Antimicrob Agents Chemother. 2017;61(8). Epub 2017/05/24. pmid:28533245; PubMed Central PMCID: PMC5527636.
  161. 161. Russo TA, Marr CM. Hypervirulent Klebsiella pneumoniae. Clin Microbiol Rev. 2019;32(3):e00001–19. Epub 2019/05/17. pmid:31092506; PubMed Central PMCID: PMC6589860.
  162. 162. Lawn JE, Cousens S, Zupan J, Lancet Neonatal Survival Steering T. 4 million neonatal deaths: when? Where? Why? Lancet. 2005;365(9462):891–900. Epub 2005/03/09. pmid:15752534.
  163. 163. Lo WU, Cheung YY, Lai E, Lung D, Que TL, Ho PL. Complete sequence of an IncN plasmid, pIMP-HZ1, carrying blaIMP-4 in a Klebsiella pneumoniae strain associated with medical travel to China. Antimicrob Agents Chemother. 2013;57(3):1561–1562. Epub 2013/01/01. pmid:23274671; PubMed Central PMCID: PMC3591870.
  164. 164. Vargas JM, Moreno Mochi MP, Nunez JM, Caceres M, Mochi S, Del Campo Moreno R, et al. Virulence factors and clinical patterns of multiple-clone hypermucoviscous KPC-2 producing K. pneumoniae. Heliyon. 2019;5(6):e01829. Epub 2019/07/10. pmid:31286076; PubMed Central PMCID: PMC6587045.
  165. 165. Chaalal N, Touati A, Yahiaoui-Martinez A, Aissa MA, Sotto A, Lavigne JP, et al. Colistin-resistant Enterobacterales isolated from chicken meat in western Algeria. Microb Drug Resist. 2021;27(7):991–1002. Epub 2021/01/12. pmid:33428521.
  166. 166. Marques C, Belas A, Aboim C, Cavaco-Silva P, Trigueiro G, Gama LT, et al. Evidence of sharing of Klebsiella pneumoniae strains between healthy companion animals and cohabiting humans. J Clin Microbiol. 2019;57(6):e01537–18. Epub 2019/04/05. pmid:30944193; PubMed Central PMCID: PMC6535590.
  167. 167. Hooban B, Fitzhenry K, O’Connor L, Miliotis G, Joyce A, Chueiri A, et al. A longitudinal survey of antibiotic-resistant Enterobacterales in the Irish environment, 2019–2020. Sci Total Environ. 2022;828:154488. Epub 2022/03/13. pmid:35278563.
  168. 168. Aires-de-Sousa M, Lopes E, Goncalves ML, Pereira AL, Machado ECA, de Lencastre H, et al. Intestinal carriage of extended-spectrum beta-lactamase-producing Enterobacteriaceae at admission in a Portuguese hospital. Eur J Clin Microbiol Infect Dis. 2020;39(4):783–790. Epub 2019/12/25. pmid:31873863.
  169. 169. Alouache S, Estepa V, Messai Y, Ruiz E, Torres C, Bakour R. Characterization of ESBLs and associated quinolone resistance in Escherichia coli and Klebsiella pneumoniae isolates from an urban wastewater treatment plant in Algeria. Microb Drug Resist. 2014;20(1):30–38. Epub 2013/08/21. pmid:23952363.
  170. 170. Löhr IH, Hülter N, Bernhoff E, Johnsen PJ, Sundsfjord A, Naseer U. Persistence of a pKPN3-like CTX-M-15-encoding IncFIIK plasmid in a Klebsiella pneumonia ST17 host during two years of intestinal colonization. PLoS ONE. 2015;10(3):e0116516. Epub 2015/03/05. pmid:25738592; PubMed Central PMCID: PMC4349654.
  171. 171. Markovska R, Stankova P, Stoeva T, Ivanova D, Pencheva D, Kaneva R, et al. Fecal carriage and epidemiology of extended-spectrum beta-lactamase/carbapenemases producing Enterobacterales isolates in Bulgarian hospitals. Antibiotics (Basel). 2021;10(6):747. Epub 2021/07/03. pmid:34202982; PubMed Central PMCID: PMC8234131.
  172. 172. Pankok F, Taudien S, Dekker D, Thye T, Oppong K, Wiafe Akenten C, et al. Epidemiology of plasmids in Escherichia coli and Klebsiella pneumoniae with acquired extended spectrum beta-lactamase genes isolated from chronic wounds in Ghana. Antibiotics (Basel). 2022;11(5):689. Epub 2022/05/29. pmid:35625333.
  173. 173. Peirano G, Sang JH, Pitondo-Silva A, Laupland KB, Pitout JD. Molecular epidemiology of extended-spectrum-beta-lactamase-producing Klebsiella pneumoniae over a 10 year period in Calgary, Canada. J Antimicrob Chemother. 2012;67(5):1114–1120. Epub 2012/02/16. pmid:22334607.
  174. 174. Munoz-Price LS, Poirel L, Bonomo RA, Schwaber MJ, Daikos GL, Cormican M, et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis. 2013;13(9):785–796. Epub 2013/08/24. pmid:23969216; PubMed Central PMCID: PMC4673667.
  175. 175. Qi Y, Wei Z, Ji S, Du X, Shen P, Yu Y. ST11, the dominant clone of KPC-producing Klebsiella pneumoniae in China. J Antimicrob Chemother. 2011;66(2):307–312.
  176. 176. Wyres KL, Holt KE. Klebsiella pneumoniae population genomics and antimicrobial-resistant clones. Trends Microbiol. 2016;24(12):944–956. Epub 2016/10/11. pmid:27742466.
  177. 177. Navon-Venezia S, Kondratyeva K, Carattoli A. Klebsiella pneumoniae: a major worldwide source and shuttle for antibiotic resistance. FEMS Microbiol Rev. 2017;41(3):252–275. Epub 2017/05/19. pmid:28521338.
  178. 178. David S, Reuter S, Harris SR, Glasner C, Feltwell T, Argimon S, et al. Epidemic of carbapenem-resistant Klebsiella pneumoniae in Europe is driven by nosocomial spread. Nat Microbiol. 2019;4(11):1919–1929. Epub 2019/07/29. pmid:31358985; PubMed Central PMCID: PMC7244338.
  179. 179. Peirano G, Chen L, Kreiswirth BN, Pitout JDD. Emerging antimicrobial-resistant high-risk Klebsiella pneumoniae clones ST307 and ST147. Antimicrob Agents Chemother. 2020;64(10). Epub 2020/08/05. pmid:32747358; PubMed Central PMCID: PMC7508593.
  180. 180. Cañada-García JE, Moure Z, Sola-Campoy PJ, Delgado-Valverde M, Cano ME, Gijón D, et al. CARB-ES-19 multicenter study of carbapenemase-producing Klebsiella pneumoniae and Escherichia coli from all Spanish provinces reveals interregional spread of high-risk clones such as ST307/OXA-48 and ST512/KPC-3. Front Microbiol. 2022;13:918362. Epub 2022/06/30. pmid:35847090; PubMed Central PMCID: PMC9279682.
  181. 181. Yang Y, Yang Y, Chen G, Lin M, Chen Y, He R, et al. Molecular characterization of carbapenem-resistant and virulent plasmids in Klebsiella pneumoniae from patients with bloodstream infections in China. Emerg Microbes Infect. 2021;10(1):700–709. Epub 2021/03/20. pmid:33739229; PubMed Central PMCID: PMC8023600.
  182. 182. Pitout JD, Nordmann P, Poirel L. Carbapenemase-producing Klebsiella pneumoniae, a key pathogen set for global nosocomial dominance. Antimicrob Agents Chemother. 2015;59(10):5873–5884. Epub 2015/07/15. pmid:26169401; PubMed Central PMCID: PMC4576115.
  183. 183. Chang D, Sharma L, Dela Cruz CS, Zhang D. Clinical epidemiology, risk Factors, and control strategies of Klebsiella pneumoniae infection. Front Microbiol. 2021;12:750662. Epub 2022/01/08. pmid:34992583; PubMed Central PMCID: PMC8724557.
  184. 184. Almeida TL, Mendo T, Costa R, Novais C, Marçal M, Martins F, et al. Carbapenemase-producing Enterobacteriaceae (CPE) newborn colonization in a Portuguese neonatal intensive care unit (NICU): epidemiology and infection prevention and control measures. Infect Dis Rep. 2021;13(2):411–417. Epub 2021/06/03. pmid:34062713; PubMed Central PMCID: PMC8162345.
  185. 185. Stapleton PJ, Murphy M, McCallion N, Brennan M, Cunney R, Drew RJ. Outbreaks of extended spectrum beta-lactamase-producing Enterobacteriaceae in neonatal intensive care units: a systematic review. Arch Dis Child Fetal Neonatal Ed. 2016;101(1):F72–F78. Epub 2015/09/14. pmid:26369370.
  186. 186. Benenson S, Levin PD, Block C, Adler A, Ergaz Z, Peleg O, et al. Continuous surveillance to reduce extended-spectrum β-lactamase Klebsiella pneumoniae colonization in the neonatal intensive care unit. Neonatology. 2013;103(2):155–160. Epub 2012/12/11. pmid:23235260.
  187. 187. Eibach D, Belmar Campos C, Krumkamp R, Al-Emran HM, Dekker D, Boahen KG, et al. Extended spectrum beta-lactamase producing Enterobacteriaceae causing bloodstream infections in rural Ghana, 2007–2012. Int J Med Microbiol. 2016;306(4):249–254. Epub 2016/05/10. pmid:27222489.
  188. 188. Tola MA, Abera NA, Gebeyehu YM, Dinku SF, Tullu KD. High prevalence of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae fecal carriage among children under five years in Addis Ababa, Ethiopia. PLoS ONE. 2021;16(10):e0258117. Epub 2021/10/01. pmid:34597328; PubMed Central PMCID: PMC8486131.
  189. 189. Zakir A, Regasa Dadi B, Aklilu A, Oumer Y. Investigation of extended-spectrum β-lactamase and carbapenemase producing gram-negative bacilli in rectal swabs collected from neonates and their associated factors in neonatal intensive care units of Southern Ethiopia. Infect Drug Resist. 2021;14:3907–17. Epub 2021/09/23. pmid:34588786; PubMed Central PMCID: PMC8476106.
  190. 190. Frenk S, Rakovitsky N, Temkin E, Schechner V, Cohen R, Kloyzner BS, et al. Investigation of outbreaks of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae in three neonatal intensive care units using whole genome sequencing. Antibiotics (Basel). 2020;9(10). Epub 2020/10/16. pmid:33081087; PubMed Central PMCID: PMC7650633.
  191. 191. Marchaim D, Chopra T, Perez F, Hayakawa K, Lephart PR, Bheemreddy S, et al. Outcomes and genetic relatedness of carbapenem-resistant Enterobacteriaceae at Detroit medical center. Infect Control Hosp Epidemiol. 2011;32(9):861–71. Epub 2011/08/11. pmid:21828966; PubMed Central PMCID: PMC4067763.
  192. 192. Turnidge JD, Gottlieb T, Mitchell DH, Coombs GW, Daly DA, Bell JM, et al. Enterobacteriaceae sepsis outcome programme annual report, 2013. Commun Dis Intell Q Rep. 2014;38(4):E327–E333. Epub 2015/01/30. pmid:25631595.
  193. 193. Aquino-Andrade A, Merida-Vieyra J, Arias de la Garza E, Arzate-Barbosa P, De Colsa Ranero A. Carbapenemase-producing Enterobacteriaceae in Mexico: report of seven non-clonal cases in a pediatric hospital. BMC Microbiol. 2018;18(1):38. Epub 2018/04/21. pmid:29673319; PubMed Central PMCID: PMC5907697.
  194. 194. Adelman MW, Bower CW, Grass JE, Ansari UA, Soda EA, See I, et al. Distinctive features of ertapenem-mono-resistant carbapenem-resistant Enterobacterales in the United States: A cohort study. Open Forum Infect Dis. 2022;9(1):ofab643. Epub 2022/01/18. pmid:35036469; PubMed Central PMCID: PMC8754373.
  195. 195. Guh AY, Bulens SN, Mu Y, Jacob JT, Reno J, Scott J, et al. Epidemiology of carbapenem-resistant Enterobacteriaceae in 7 US communities, 2012–2013. JAMA. 2015;314(14):1479–1487. pmid:26436831; PubMed Central PMCID: PMC6492240
  196. 196. Yaffee AQ, Roser L, Daniels K, Humbaugh K, Brawley R, Thoroughman D, et al. Notes from the Field: Verona integron-encoded metallo-beta-lactamase-producing carbapenem-resistant Enterobacteriaceae in a neonatal and adult intensive care unit—Kentucky, 2015. MMWR Morb Mortal Wkly Rep. 2016;65(7):190. Epub 2016/02/26. pmid:26914726.
  197. 197. Browne AJ, Chipeta MG, Haines-Woodhouse G, Kumaran EPA, Hamadani BHK, Zaraa S, et al. Global antibiotic consumption and usage in humans, 2000–18: a spatial modelling study. Lancet Planet Health. 2021;5(12):e893–e904. Epub 2021/11/15. pmid:34774223; PubMed Central PMCID: PMC8654683 Bill & Melinda Gates Foundation. All other authors declare no competing interests.
  198. 198. Van Boeckel TP, Gandra S, Ashok A, Caudron Q, Grenfell BT, Levin SA, et al. Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. Lancet Infect Dis. 2014;14(8):742–750. Epub 2014/07/16. pmid:25022435.
  199. 199. Chen L, Mathema B, Pitout JDD, DeLeo FR, Kreiswirth BN. Epidemic Klebsiella pneumoniae ST258 is a hybrid strain. Mbio. 2014;5(3):e01355–14. ARTN e01355-14. WOS:000338875900012.
  200. 200. Qi Y, Wei Z, Ji S, Du X, Shen P, Yu Y. ST11, the dominant clone of KPC-producing Klebsiella pneumoniae in China. J Antimicrob Chemother. 2011;66(2):307–312. Epub 2010/12/07. pmid:21131324.
  201. 201. Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious Diseases Society of America guidance on the treatment of extended-spectrum beta-lactamase producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa). Clin Infect Dis. 2021;72(7):e169–e183. Epub 2020/10/28. pmid:33106864.
  202. 202. Paul M, Carrara E, Retamar P, Tangden T, Bitterman R, Bonomo RA, et al. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (endorsed by European society of intensive care medicine). Clin Microbiol Infect. 2022;28(4):521–547. Epub 2021/12/20. pmid:34923128.
  203. 203. Livermore DM, Mushtaq S, Warner M, Zhang J, Maharjan S, Doumith M, et al. Activities of NXL104 combinations with ceftazidime and aztreonam against carbapenemase-producing Enterobacteriaceae. Antimicrob Agents Chemother. 2011;55(1):390–394. Epub 2010/11/03. pmid:21041502; PubMed Central PMCID:PMC3019623.
  204. 204. Nordmann P, Poirel L, Walsh TR, Livermore DM. The emerging NDM carbapenemases. Trends Microbiol. 2011;19(12):588–595. Epub 2011/11/15. pmid:22078325.
  205. 205. Yong D, Toleman MA, Giske CG, Cho HS, Sundman K, Lee K, et al. Characterization of a new metallo-beta-lactamase gene, blaNDM-1, and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob Agents Chemother. 2009;53(12):5046–5054. Epub 2009/09/23. pmid:19770275; PubMed Central PMCID: PMC2786356.
  206. 206. Mojica MF, Rossi MA, Vila AJ, Bonomo RA. The urgent need for metallo-beta-lactamase inhibitors: an unattended global threat. Lancet Infect Dis. 2022;22(1):e28–e34. Epub 2021/07/12. pmid:34246322; PubMed Central PMCID: PMC8266270.