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Systematic review of carbapenem-resistant Enterobacteriaceae causing neonatal sepsis in China

  • Yijun Ding
  • Yajuan WangEmail author
  • Yingfen Hsia
  • Mike Sharland
  • Paul T. Heath
Open Access
Research

Abstract

Background

Carbapenems are β-lactam antibiotics which are used to treat severe infections caused by multidrug resistant Enterobacteriacea. The recent emergence and rapid spread of Enterobacteriaceae resistant to carbapenems is a global concern. We undertook a systematic review of the antibiotic susceptibility and genotypic characteristics of carbapenem-resistant Enterobacteriaceae in Chinese neonates.

Methods

Systematic literature reviews were conducted (PubMed/Medline, Embase, Wanfang medical online databases, China National Knowledge Infrastructure (CNKI) database) regarding sepsis caused by carbapenem-resistant Enterobacteriaceae in Chinese neonates aged 0-30 days.

Results

17 studies were identified. Eleven patients in the six studies reported the source of infection. Ten patients (10/11, 90.9%) were hospital-acquired infections. Genotypic data were available for 21 isolates in 11 studies (20 K. pneumoniae, 1 E. coli). NDM-1 was the most frequently reported carbapenem-resistant genotype (81.0%, 17/21). Carbapenem-resistant Klebsiella pneumoniae and Escherichia coli were resistant to many antibiotic classes with the exception of colistin and fosfomycin. Sequence type 105 (ST105) was the most commonly reported K. pneumoniae ST type (30.8%; 4/13), which was from the same hospital in Western China. ST17 and ST20 were the second and third most common K. pneumoniae ST type, 23.1% (3/13) and 15.4% (2/13) respectively. The three strains of ST17 are all from the same hospital in central China. The two strains of ST20, although not from the same hospital, belong to the eastern part of China.

Conclusions

Klebsiella pneumoniae with the NDM-1 genotype was the leading cause of neonatal carbapenem resistant sepsis in China. Hospital acquired infection is the main source of carbapenem resistant sepsis. There is currently no licenced antibiotic regimen available to treat such an infection in China. Improved surveillance, controlling nosocomial infection and the rational use of antibiotics are the key factors to prevent and reduce its spread.

Keywords

Klebsiella pneumoniae Escherichia coli Neonate Genotype Carbapenem-resistant 

Abbreviations

K. pneumonia

Klebsiella pneumonia

E. coli

Escherichia coli

ESBL

extended-spectrum β-lactamase

KPC

K. pneumoniae carbapenemase

MBLs

metallo-β-lactamases

NDM

New Delhi metallo-β-lactamase

VIM

verona integrin-encoded metallo-beta-lactamases

IMP

imipenem-resistant Pseudomonas

OXAs

oxacillinases

CHINET

chinese antimicrobial resistance surveillance network

CLSI

Central Laboratory Standards Institute

MIC

minimal inhibitory concentration

MHT

Modified Hodge test

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance

CNKI

China National Knowledge Infrastructure

AMR

antimicrobial resistance

NEC

necrotizing enterocolitis

CRKP

carbapenem-resistant Klebsiella pneumonia

CREC

carbapenem-resistant Escherichia coli

CRE

carbapenem-resistant Enterobacteriaceae

CROs

carbapenem resistant organisms

Background

According to the global reports, in 2013, 51.8% of the 6.3 million children under the age of five died of infectious diseases, while 44% (276.1 million) died during the neonatal period. Neonatal sepsis is the third leading cause of neonatal death, killing 0.421 million neonates worldwide in 2013 [1]. The overall incidence of neonatal sepsis in four Asian centres (including mainland China, Thailand, Macau, and Malaysia) was 26.1 (95% CI 24.5 to 27.8) per 1000 admissions and Klebsiella spp. was the most common Gram negative organism causing most deaths [2]. Laxminarayan et al. [3] reported that 214 000 of 690, 000 annual neonatal deaths (31%) associated with sepsis are potentially attributable to antimicrobial resistance. Carbapenems are beta-lactam antibiotics which are used to treat severe infections caused by multidrug resistant Enterobacteriaceae, such as Klebsiella pneumoniae (K. pneumoniae) and Escherichia coli (E. coli). The recent emergence and rapid spread of Enterobacteriaceae resistant to carbapenems is therefore of global concern [4].

Resistance to carbapenems includes production of carbapenemases or a combination of structural mutations and production of other β-lactamases, such as extended-spectrum β-lactamase (ESBL) and AmpC cephalosporinases. Bacteria that produce carbapenemases, enzymes that hydrolyze carbapenems, can break down other β-lactam antibiotics including penicillins, cephalosporins, and monobactams [5]. Carbapenemases can be divided into class A (e.g. K. pneumoniae carbapenemase, KPC), class B metallo-β-lactamases [MBLs, e.g. New Delhi metallo-β-lactamase (NDM), Verona integrin-encoded metallo-beta-lactamases (VIM), Imipenem-resistant Pseudomonas (IMP)] and class D β-lactamases (e.g. oxacillinases OXAs). Class C β-lactamases are rarely reported [4].

Recent studies suggest that carbapenem resistance is increasing in China. A national report using data from CHINET (a Chinese antimicrobial resistance surveillance network) has shown that the overall prevalence of imipenem-resistant K. pneumoniae increased from 3.0% to 20.9% and meropenem-resistance from 2.9% to 24.0% between 2005 and 2017. These data included both children and adults and most of the samples were from sputum and urine. Among the five children’s hospitals, the resistance rate of K. pneumoniae isolated from one hospital to imipenem was 2.5%, while from the other four hospitals resistance rates ranged from 32.1% to 45.5%. Little information was available on age ranges and types of samples [6]. This systematic review aimed to summarize the current data from both English and Chinese language sources on the antibiotic susceptibility and genotypic characteristics of carbapenem-resistant Enterobacteriaceae (K. pneumoniae and E. coli) causing neonatal sepsis in China.

Methods

Definitions

Carbapenem-resistance was defined as resistance to any one of meropenem, imipenem, or ertapenem according to the US Central Laboratory Standards Institute (CLSI). In 2015 the breakpoint was changed from 2010. Laboratories using Enterobacteriaceae minimal inhibitory concentration (MIC) interpretive criteria for carbapenems described in M100-S20 (January 2010) performed the modified Hodge test (MHT), Carba NP test and/or a molecular assay when isolates of Enterobacteriaceae were suspicious for carbapenemase production based on impipenem or meropenem MICs of 2–4 ug/ml or ertapenem MIC of 2 ug/ml in 2015 [7]. Carbapenem-resistant K. pneumoniae or E. coli sepsis was defined as a laboratory confirmed culture of K. pneumoniae or E. coli obtained from the blood accompanied with signs and symptoms of infection [8]. Neonates were defined as age 0-30 days [9].

Search strategy and selection criteria

This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance (PRISMA) [10]. We searched the published literature from PubMed/Medline, Embase, China National Knowledge Infrastructure (CNKI) and Wanfang med online databases between January 1, 2000, and June 28, 2018. We used the search terms (“beta-lactamases/or carbapenemase, or carbapenem resistance/resistant or drug resistance or carbapenemase* or carbapenem adj1 resist* or MBL or metallo-b-lactamase or VIM or NDM or OXA or oxacillinase or IMP or KPC or Klebsiella pneumoniae carbapenemase or OmpK”) AND (“Enterobacteriaceae/or enterobacteriaceae or Escherichia/or Escherichia or Escherichia coli or Klebsiella or Klebsiella/Klebsiella pneumoniae/Klebsiella oxytoca”) AND (“China or Chinese”) AND (“neonate or newborn or infant”) for English databases. We used search terms (“Carbapenems or Carbapenem”) AND (“antibiotic resistance”) AND (“infant”, OR “neonatal”) for Chinese databases. We limited the searches to Chinese territories, including Taiwan, Hong Kong, and Macau. The full search strategy is available in Additional file 1: Table S1.

Inclusion and exclusion criteria

We include studies with original data on carbapenem-resistant K. pneumoniae or E. coli sepsis in neonates, which contained any antimicrobial resistance (AMR) or genotype data, or showed the proportion of carbapenem resistant isolates of all Gram negative isolates, or clinical data (including patient demographics, underlying conditions, and antibiotic treatment). We only included blood stream infections. The full details of inclusion and exclusion criteria are presented in Additional file 2: Table S2.

Statistical analysis

Descriptive analysis was performed to investigate the distribution of genotype and MLST typing. Antimicrobial resistance rates were reported by median with interquartile interval (IQI).

Results

Literature search and study selection

We identified 491 studies from Chinese and English database searches: 81 from CNKI, 214 from Wanfang med database, 96 from Pubmed/Medline and 100 from Embase (the flow chart is shown in Fig. 1). A total of 17 studies met the inclusion criteria and were included for final review, of these 11 (64.7%) reported genotype (including carbapenemase, β-lactamase genes and AmpC cephalosporinases genes) distribution and 9 (52.9%) reported AMR and clinical data. Only 6 studies reported treatment outcomes and gave the proportion of carbapenem-resistant isolates relative to all Gram-negative isolates. The full list of studies included in the review is available in Additional file 3: Table S3.
Fig. 1

Search strategy and process of study selection

Demographics and clinical presentations of K. pneumoniae or E. coli infections

All 17 studies were from tertiary hospitals. Based on the Government economic divisions of China, 7 studies were from Eastern China, 6 studies from Central China, and 4 studies from Western China. Only 9 of 17 studies reported clinical data, including patient demographics, underlying conditions, and antibiotic treatment. A total of 16 infants were included in these 9 studies. Eight of 16 patients were reported to have underlying conditions, including 6 with lung disease, 2 with necrotizing enterocolitis (NEC) and 2 with recent surgery. Ten patients in these 9 studies reported antibiotic treatment: 5 received meropenem alone, 1 ceftazidime alone, 3 patients had received two antibiotics (piperacillin/sulbactam and ceftazidime; imipenem and amikacin; meropenem and ciprofloxacin) and 1 patient had received more than three antibiotics. Eight patients in these 4 studies had received antibiotics prior to the onset of the relevant infection: 5 received meropenem, 1 received panipenem and 2 didn’t report the type the antibiotics. Clinical treatment outcomes were reported in 13 patients from 6 studies; 3 died and their deaths were attributed to the infection. Eleven patients of the six studies reported the source of infection. Ten patients (10/11, 90.9%) were hospital-acquired infections, while only one was considered to be a vertical transmission.

The proportion of carbapenem resistant strains of all Gram negative strains

Only 6 studies (35%; 6/17) reported the proportion of carbapenem resistant isolates relative to all Gram-negative isolates causing sepsis. Overall, 39 (5.3%) carbapenem resistant K. pneumoniae and E. coli isolates were reported of out of a total of 740 Gram-negative isolates.

Antimicrobial resistance genotype and Multilocus Sequence Type (MLST)

Genotypic data were available for 21 isolates in 11 studies (20 K. pneumoniae, 1 E coli). The most commonly reported genotype was NDM-1 (81.0%, 17/21), followed by KPC-2 (9.5%, 2/21) and IMP-4 (9.5%, 2/21). 15 isolates from 9 studies were tested β-lactamase genes, 66.7% (10/15) isolates carried TEM and SHV genotypes, and 80.0% (12/15)carried CTX-M. 7 isolates from 5 studies were Amp C gene positive, and more than half of them were CMY-4/30 (57.1%; 4/7).

Antibiotic susceptibility results were reported from 19 isolates in 9 studies. The resistance rates of carbapenem-resistant Klebsiella pneumoniae (CRKP) and carbapenem-resistant Escherichia coli (CREC) to second-, third-, and fourth-generation cephalosporins were 100% (IQI 100%–100%). All isolates were susceptible to colistin and fosfomycin (Table 1). MLST was identified for 14 isolates (13 K. pneumoniae and 1 E.coli) from 8 studies. ST105 was the most common K. pneumoniae ST type (30.8%; 4/13), followed by ST17 and ST 20 with 23.1% (3/13) and 15.4% (2/13), respectively (Table 2).
Table 1

The proportion of isolates demonstrating antimicrobial resistance

First author

Publication year

Sample

Sample size (number)

Aztreonam  %

Levofloxacin %

Ciprofloxacin  %

Gentamicin  %

Amikacin  %

Tigecyclin  %

Imipenem  %

Meropenem  %

Ertapenem

Cefatriaxone  %

He et al.

2017

KP

5

100

     

100

100

 

100

Jiang et al.

2012

KP

1

0

0

 

0

0

 

0

100

100

 

Jin et al.

2015

KP

1

100

0

 

0

0

0

100

100

100

 

Zheng et al.

2016

KP

4

0

0

0

 

0

0

100

100

  

Liu et al.

2013

KP

1

100

100

100

100

  

100

   

Zhang et al.

2015

KP

3

0

0

0

0

0

 

100

100

 

100

Zhang et al.

2015

KP

1

  

100

 

100

0

100

100

100

100

Qin et al.

2014

E.coli

1

100

0

100

100

0

0

100

 

100

 

KP

1

100

0

0

100

0

100

100

 

100

 

Jin et al.

2017

KP

1

100

0

 

0

0

0

100

100

100

100

Meidan

   

100

0

50

0

0

0

100

100

100

100

IQI 25%

   

0

0

0

0

0

0

100

100

100

100

IQI 75%

   

100

0

100

100

0

0

100

100

100

100

First author

Publication year

Sample

Sample size (number)

Cefotaxime  %

Ceftazidim  %

Cefepime  %

Cefoxitin  %

Fosfomycin  %

Piperacillin

 %

PIP/TZB

 %

Colsitin

He et al.

2017

KP

5

     

100

  

Jiang et al.

2012

KP

1

100

100

100

100

  

0

 

Jin et al.

2015

KP

1

100

100

100

100

0

 

100

0

Zheng et al.

2016

KP

4

 

100

 

100

 

100

100

 

Liu et al.

2013

KP

1

100

100

100

     

Zhang et al.

2015

KP

3

100

100

100

  

100

  

Zhang et al.

2015

KP

1

100

100

100

100

  

100

 

Qin et al.

2014

E.coli

1

 

100

100

 

0

 

100

0

KP

1

 

100

100

 

0

 

100

0

Jin et al.

2017

KP

1

 

100

100

100

0

 

100

0

Meidan

   

100

100

100

100

0

100

100

0

IQI 25%

   

100

100

100

100

0

100

100

0

IQI 75%

   

100

100

100

100

0

100

100

0

E. coli, Escherichia coli; KP, Klebsiella pneumoniae; PIP/TZB, piperacillin/tazobactam

Table 2

Distribution of antimicrobial resistance genotypes and MLSTs among carbapenem-resistant isolates

First Author

Economic division

Hospital level

Year of publication

Year data collection

Sample source

CLSI

Criteria (year)

Studies type

Community acquired or hospital acquired infection

Organisms and sample size (n)

Resistance gene

MLST

Carbapenemase (n)

β-lactamase genes

Amp C

He JR et al.

Central China

Tertiary hospitals

2017

2016.9–2016.10

Blood

2015

Case reports

UNK

KP (n = 5)

bla NDM-1 (n = 5)

Jiang MJ et al.

Eastern China

Tertiary hospitals

2012

2009.7

Blood

2011

Case reports

UNK

KP (n = 1)

bla KPC-2 (n = 1)

bla CTX-M-14 (n = 1), bla SHV-2 (n = 1)

bla DHA-1 (n = 1)

Xu C et al.

Eastern China

Tertiary hospitals

2015

2013.4–2013.5

Blood

2013

Case reports

Hospital acquired

KP (n = 1)

bla NDM-1 (n = 1)

bla TEM-1 (n = 1),

ST22 (n = 1)

Yao MZ et al.

Eastern China

Tertiary hospitals

2003

1997.1–2002.8

Blood

UNK

Cross-sectional study

UNK

KP (n = 1)

Jiang DQ et al.

Western China

Tertiary hospitals

2017

2013.1–2016.12

Blood

UNK

Cross-sectional study

UNK

KP (n = 2)

Song HY, et al.

Eastern China

Tertiary hospitals

2012

2009.1–2010.12

Blood

UNK

Cross-sectional study

UNK

KP (n = 1)

Zhang ZM et al.

Central China

Tertiary hospitals

2014

2011–2013

Blood

UNK

Cross-sectional study

UNK

KP (n = 18)

E. coli (n = 9)

Tai SH, et al.

Central China

Tertiary hospitals

2017

2014.1–2016.6

Blood

2013

Cross-sectional study

UNK

KP (n = 1)

Tian HR, et al.

Western China

Tertiary hospitals

2016

2013.1–2014.12

Blood

UNK

Cross-sectional study

UNK

KP (n = 7)

Chen S et al.

Western China

Tertiary hospitals

2014

2009.1–2010.12

Blood

2010

Cross-sectional study

Hospital acquired infection

KP (n = 1)

bla IMP-4 (n = 1)

Jin Y, et al.

Eastern China

Tertiary hospitals

2015

2012.8–2013.9

Blood

2013

Cross-sectional study

Hospital acquired infection

KP (n = 1)

bla NDM-1 (n = 1)

bla TEM-1 (n = 1), bla CTX-M -14 (n = 1),

bla DHA-1 (n = 1)

ST20 (n = 1)

Zheng R, et al.

Western China

Tertiary hospitals

2016

2014.1–2014.3

Blood

2013

Cross-sectional study

Hospital acquired infection

KP (n = 4)

bla NDM-1 (n = 4), bla IMP-4 (n = 1)

bla CTX-M-15 (n = 4), bla SHV-1 (n = 4)

ST105

(n = 4)

Liu Y, et al.

Eastern China

Tertiary hospitals

2013

2010.6–2010.9

Blood

2009

Cross-sectional study

UNK

KP (n = 1)

bla KPC-2 (n = 1)

bla SHV-12 (n = 1), bla TEM-1 (n = 1), bla CTX-M -14 (n = 1),

UD (n = 1)

Zhang XY, et al.

Central China

Tertiary hospitals

2015

2012.8–2013.3

Blood

2012

Case report

Hospital acquired infection (n = 2)

vertical transmission infection

(n = 1)

KP (n = 3)

bla NDM-1 (n = 3),

TEM-1 (n = 3), bla CTX-M-15 (n = 3), bla SHV-1(n = 3),

bla CMY-4

(n = 3)

ST17 (n = 3)

Zhang Y, et al.

Central China

Tertiary hospitals

2015

2013.2.18

Blood

2014

Case report

Hospital acquired infection (n = 1)

KP (n = 1)

0

SHV-11 (n = 1), TEM-53 (n = 1),

0

ST65 (n = 1)

Qin SS, et al.

Central China

Tertiary hospitals

2014

2011.6–2012.6

Blood

2012

Cross-sectional study

UNK

KP (n = 1)

bla NDM-1 (n = 1)

bla TEM-1 (n = 1), CTX-M-15(n = 1)

ST966 (n = 1) 

E.coli (n = 1)

bla NDM-1 (n = 1)

bla TEM-1(n = 1)

bla CMY-30 (n = 1)

ST40 (n = 1)

Jin Y, et al.

Eastern China

Tertiary hospitals

2017

2013.7.29

Blood

2014

Cross-sectional study

UNK

KP (n = 1)

bla NDM-1 (n = 1)

bla TEM-1(n = 1), bla CTX-M-15 (n = 1)

bla DHA-1 (n = 1)

ST20 (n = 1)

CRE, carbapenem resistant Enterobacteriaceae; E coli, Escherichia coli; KP, Klebsiella pneumoniae; NDM, New Delhi Metallo-beta-lactamase-1; Amp C, AmpC cephalosporinases; MLST, Multilocus sequence types; UD, unidentified

Discussion

This is the first review of carbapenem-resistant Enterobacteriaceae (CRE) sepsis in Chinese neonates. Although the prevalence of adults and children with infections resistant to imipenem and meropenem reported by CHINET in 2017 increased significantly, the samples were mainly derived from non-sterile body fluids, and the data for children were not broken down by age. This review has demonstrated that there are very limited recent data on carbapenem resistant isolates in neonates in China. CRKP is reported more than CREC. NDM-1 was the most commonly reported carbapenemase genotype, consistent with previous reports from Asia [11], but different to reports from the United States, where KPC is the most common genotype identified in children [12]. It is worth noting that the CLSI breakpoints for carbapenem changed in 2010 and in 2015, the CDC revised the definition for CRE. In this review, 12 studies provided CLSI reference standards. Among the 12 studies, only one adopted the CLSI standard of 2015, and the others adopted the CLSI standard of before 2015.

In 2017, the World Health Organization published a list of priority pathogens in order to inform global AMR research. CRE is one of the highest priority pathogens for the development of new antibiotics [13], but there are few new antibiotics available. Cefiderocol, is a novel catechol-substituted siderophore cephalosporin with potent activity against meropenem-non susceptible Enterobacteriaceae [14], including metallo-β-lactamases (NDM-1, VIM, IMP). This is the most clinically advanced drug active against NDM carbapenem resistant organisms (CROs) infections [15], but no paediatric studies have yet commenced recruitment. The current standard treatment for NDM CRE infections is polymyxin based combination therapy [16]. However, polymixin E has complex pharmacokinetics requiring hydrolysis of the prodrug colistimethate sodium to colistin, making this less suitable for neonates and infants, and there are no pharmacokinetics data for polymixin B in neonates [17]. Other older, off patent drugs that have potential activity against CROs include fosfomycin and tigecycline, but again, these have no published PK data in neonates. In our study, we found that the currently reported carbapenem-resistant Enterobacteriaceae sepsis in neonate is mainly nosocomial infection. In view of the fact that there is no appropriate antibiotics to treat carbapenem resistant bacteria infection in neonates, it is very important to strengthen epidemiological surveillance, stringent standard infection control practices in healthcare settings, and to enhance the rational use of antibiotics.

Notes

Acknowledgements

Not applicable.

Authors’ contributions

The concept of the estimates and the technical oversight of the paper was P.H, Y.W and M. S. The reviews, analyses, and first draft of the manuscript were undertaken by Y.D. Other specific contributions were made by YH, MS, PH, YD and YH undertook the data abstraction. YD and YH undertook the statistical analyses. All authors read and approved the final manuscript.

Funding

This work was supported by Beijing Hospitals Authority Youth Programme (Grant Number: QML 20181207), National Natural Science Foundation of China (Grant Number: 81872676), Beijing Natural Science Foundation (Grant Number: 7192063), Special Fund of the Pediatric Medical Coordinated Development Center of Beijing Municipal Administration of Hospitals (Grant Number: XTYB201806).

Ethics approval and consent to participate

This paper is a systematic review, so ethical approval and consent is not required.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Supplementary material

12941_2019_334_MOESM1_ESM.docx (16 kb)
Additional file 1: Table S1. Search terms.
12941_2019_334_MOESM2_ESM.docx (14 kb)
Additional file 2: Table S2. Inclusion and exclusion criteria.
12941_2019_334_MOESM3_ESM.docx (36 kb)
Additional file 3: Table S3. Characteristics of studies included and data type extracted for neonatal sepsis caused by carbapenem-resistant isolates.

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© The Author(s) 2019

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors and Affiliations

  1. 1.Department of NeonatologyBeijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthBeijingChina
  2. 2.Paediatric Infectious Diseases Research Group, Institute for Infection and ImmunitySt. George’s University of LondonLondonUK
  3. 3.Queen’s University Belfast, School of PharmacyBelfastUK

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