Int J Infect Dis. 2013 May;17(5):e325-33.

Emergence of New Delhi metallo-β-lactamase type 1-producing Enterobacteriaceae and non-Enterobacteriaceae:  global case detection and bacterial surveillance.

Mitrani-Gold F1, Bushnell G2, Mundy LM1

1WorldWide Epidemiology at GlaxoSmithKline, Research Triangle Park, NC; 2University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC

 

Abstract:

Objective:  A systematic review of the literature was conducted to summarize the descriptive and molecular epidemiology of human cases and surveillance reports with New Delhi metallo-β-lactamase type 1 (NDM-1)-producing bacteria reported worldwide from January 2008 through July 6, 2011.  Methods:  A comprehensive literature review was conducted to identify publications of NDM-1-producing bacteria.  Studies were divided into two broad categories of (1) case series and case reports of NDM-1-producing bacteria, or (2) active surveillance and environmental surveillance studies of NDM-1-producing bacteria.  Results: Sixty cases with NDM-1-producing bacteria were reported in the 3.5-year interval since the index case detection.  The majority of reported cases represented colonization without evidence of infection (n= 39, 65%); urine was the most common specimen source for cases with infection (41.7%) and colonization (33.3%).  Seventeen cases (28.3%) had NDM-1-producing bacteria at more than one body site.  Klebsiella pneumoniae and Escherichia coli were the most frequent bacteria detected, and the multilocus sequence type data from 34 E. coli and K. pneumoniae clinical isolates provided an incomplete, yet heterogeneous global distribution of NDM-1-producing bacteria. The majority of cases (63.3%) had exposure to the Indian subcontinent of south central Asia, and laboratory surveillance systems, as well as an environmental survey from India, suggest a presence of environmental reservoirs for potential human infection and colonization with NDM-1-producing bacteria. Conclusions: The majority of case reports with NDM-1-producing bacteria had presumed colonization, not infection, with one or more bacteria.  The available human case reports and surveillance data suggest a global distribution of NDM-1-producing Enterobacteriaceae and non- Enterobacteriaceae. © 2012 International Society for Infectious Diseases (1).

 

Supplement:

Our systematic review was conducted to characterize the global burden of New Delhi metallo-β-lactamase type-1(NDM-1) producing bacteria, based on the descriptive and molecular epidemiology reported in the initial 3.5 years after detection of the index case.  Real world clinical and epidemiological data from case reports, case series, and environmental surveillance were summarized for geographic, temporal, and molecular associations to provide a comprehensive synopsis of NDM-1 emergence and transmission (1).  The systematic review characterized the emergence of NDM-1 producing bacteria among clinical cases by infection versus colonization status, the foci of the specimen source, recent travel history or contact with healthcare facilities, and patient outcomes.  Since publication of the systematic review, there have been significant developments in understanding and describing NDM-1 and NDM variants.

Carbapenem-hydrolyzing beta-lactamases, belonging to the metallo-β-lactamases, pose serious threats to the efficacy of carbapenemsCarbapenem-hydrolyzing beta-lactamases, inclusive of NDM-1, belong to the molecular class B metallo-β-lactamases (Table 1).  The NDM-1 enzyme, initially identified in 2008, has shown rapid worldwide dissemination (1).  The most recently reported NDM-1 producing isolates were identified in South and Central America (2-4).  While NDM-1 production occurs most frequently among Escherichia coli and Klebsiella pneumoniae, this plasmid-mediated resistance has been reported among a diverse group of Gram-negative Enterobacteriaceae and non-Enterobacteriaceae including Acinetobacter baumannii, Vibrio cholera, Shigella boydii, and Salmonella sp. (5-7).  The genes encoding NDM-1 also harbor multiple antibiotic resistance genes and can spread within and between genuses (Figures 1a and 1b) (8, 9).  The Indian subcontinent remains a reservoir of NDM-1 producing bacteria, although recent outbreaks have occurred elsewhere (10, 11).  The reported per capita consumption of carbapenems in India has been estimated to be 8 fold that of the Netherlands (12).  Additionally, selective pressure attributed to over the counter antibiotic consumption, combined with high population density, lack of water purity, and sanitary practices have been associated with the emergence of NDM-1 in the Indian subcontinent (13).  In other geographic regions, there is evidence to support autochthonous and community acquisition of NDM-1 (14, 15).  A 2013 outbreak of NDM-1 in Colorado, represents the largest United States (US) outbreak to date, and highlights the risk of spread among persons receiving medical care (16).  To date, most NDM-1 producing bacteria remain susceptible to colistin, but there are reports of colistin resistance (17).

Five novel NDM variants have been detected that differ from NDM-1 by a single amino acid substitution.  In A. baumannii, NDM-2 isolates have been reported from Israel, Egypt, the United Arab Emirates, and Palestine (18-21).  Clinical isolates with NDM-4, NDM-5, and NDM-6 producing E. coli have been detected in patients with a history of hospitalization in India (22-24).  A Czech patient previously hospitalized in Sri Lanka was identified with NDM-4 producing E. cloacae (25).  NDM-4 producing E. coli was isolated in a Danish patient previously hospitalized in Vietnam (26), and NDM-7 producing E. coli was identified in a patient with chronic urinary tract infection in France (27).

In summary, our systematic review provided am in depth overview of the global burden of NDM-1 producing bacteria identified in case reports, case series, and surveillance data in the 3.5 year interval after the index case detection.  While our review primarily focused on the current understanding of NDM-1 epidemiology, clinical care, and surveillance challenges, the aggregate data had implications for the epidemiological challenges associated with global tracking of emerging drug-resistant bacterial threats.  One of the World Health Organization’s tenets for global surveillance of antimicrobial resistance is to initiate “strengthened surveillance and laboratory capacity” (28).  While independent, laboratory-based detection and reporting of emerging bacterial threats remains essential, future global surveillance initiatives may evolve to include structured ascertainment of microbial isolates linked with anonymized clinical data.

Disclosure:  This supplement was funded by WorldWide Epidemiology at GlaxoSmithKline (GSK), LLC.  FMG is a GSK consultant, GB in a doctoral student at the University of North Carolina Gillings School of Global Public Health, and LMM is a GSK employee and eligible for stock ownership.

 

References: 

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  2. Perez J, Escobar N, Cardozo B, Marquez I, Aguilar M, de la Barrera L, et al. Outbreak of NDM-1-Producing Klebsiella pneumoniae in a Neonatal Unit in Colombia. Antimicrob Agents Chemother 2013; 57(4):1957-1960.
  3. Waterman P, McGann P, Snesrud E, Clifford R, Kwak Y, Munoz-Urbizo I, et al. Bacterial Peritonitis Due to Acinetobacter baumannii Sequence Type 25 with Plasmid-Borne New Delhi Metallo-β-Lactamase in Honduras.  Antimicrob Agents Chemother 2013; 57(9):4584-4586.
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  7. Darley E, Weeks J, Jones L, Daniels V, Wooton M, MacGowan A, et al. NDM-1 polymicrobial infections including Vibrio cholerae. Lancet 2012; 13; 380(9850):1358.
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  9. Ho PL, Lo WU, Yeung MK, Lin CH, Chow KH, et al. Complete Sequencing of pNDM-HK Encoding NDM-1 Carbapenemase from a Multidrug-Resistant Escherichia coli Strain Isolated in Hong Kong. PLoS ONE 2011; 6(3): e17989. (doi:10.1371/journal.pone.0017989)  – add if figures are included.
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  28. World Health Organization. Meeting Report 2012 Technical Consultation:  Strategies for Global Surveillance of Antimicrobial Resistance. Accessed on April 24th, 2014 at:   http://apps.who.int/iris/bitstream/10665/90975/1/WHO_HSE_PED_2013.10358_eng.pdf

 

Table 1.  Molecular Grouping of Carbapenemasestab11Broad spectrum
2Preferential hydrolysis of carbapenems
3Zn1 ligand for subclass B2 is inhibitory to enzymatic activity
4Preferential hydrolysis of cephalosporins

 

fig1a

Figure 1a.  An overview of the blaNDM-1 encoding plasmid (pNDM-HK) originating from a patient with Escherichia coli in Hong Kong. 9. The outermost circle represents the coordinate of the complete plasmid circle and the 28.9 kb variable region is displayed in red. The open reading frames (ORFs) are annotated in the second circle, with arrows representing the direction of transcription. Coding sequences with and without pEL60 homologs are displayed in grey and black, respectively. All IS26 elements are displayed in green. The variable resistant region is coded in the same color scheme as in Figure1b.  The third circle depicts the functional sequence blocks. The G+C plot depicted in the inner circle (mean 51.5%), ranging from high to low is displayed in gray and black respectively.

 

fig1b

Figure 1b.  Schematic representation of the DNA sequences surrounding the blaNDM-1 genes in Escherichia coli 271 NDM-1 encoding plasmid, pNDM-HK, pkpANDM-1 and comparison with the sequences in pCTX-M-3 and pKP048.9

Comparison of pNDM-HK, pCTX-M-3 and pKP048.  The regions flanked by IS26 (green color) and the surrounding sequences are represented above.  Gaps in the alignment are shown in dotted lines. Arrows show the direction of transcription, while similar colors and labels are used to represent homologous genes. The lengths of the arrows are drawn in proportion to the length of the genes or open reading frames (ORFs). The homologous genes found in all three plasmids are displayed in light blue; homologous genes found in pNDM-HK and pCTX-M3 are in yellow; and homologous genes in pNDM-HK and pKP048 are in blue. The genes unique to the three plasmids are displayed in red, black, brown, or purple. Comparison of the regions surrounding NDM-1 gene show that the mobilization of the NDM-1 gene in the different plasmids,  involves complex and different genetic events in the past and supports the idea that antimicrobial use is the driving force for horizontal spread of NDM-1.

Other abbreviations and symbols: D, genes that are truncated; Tn, transposon; ldh, lactate dehydrogenase; blaNDM-1,New Delhi metallo-b-lactamase gene; blaTEM-1, class A beta-lactamase gene; blaDHA-1, class C beta-lactamase gene; ampR, LysR family blaDHA-1regulator; aacC2, aminoglycoside acetyltransferase gene; armA, 16S rRNA methylase gene; mel, macrolide efflux protein; mph2, macrolide 29-phosphotransferase gene; intl1, class 1 integrase; dhfr, dihydrofolate reductase gene; aadA2, aminoglycoside adenyltransferase gene; sapB, peptide transport system permease gene; sapA, peptide transport periplasmic protein, cinA, competence damage-inducible protein A; sdr, short-chain dehydrogenase/reductase gene; qnrB4, quinolone resistance protein; psp operon, transcriptional activator and phage shock proteins; purR, LacI family transcription regulator; and linF, lincosamide nucleotidyltransferase gene. The following were putative transposase: ISCR1, tnpU, tnpAcp2, tnpD,D tnpATn1 and insL.

The accession numbers were: plasmid encoding NDM-1 in E. coli 271 (HQ162469), pNDM-HK (GenBank accession HQ451074), pkpANDM-1 (FN396877), pCTX-M-3 (AF550415), pKP048 (FJ628167) and pMUR050 (AY522431). doi:10.1371/journal.pone.0017989.g002

 

Figures 1a. and 1b. adapted from : Ho PL, Lo WU, Yeung MK, Lin CH, Chow KH, et al. (2011) Complete Sequencing of pNDM-HK Encoding NDM-1 Carbapenemase from a Multidrug-Resistant Escherichia coli Strain Isolated in Hong Kong. PLoS ONE October 2010; 6(3): e17989. doi:10.1371/journal.pone.0017989

Copyright: © 2011 Ho 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.

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