Scholarly article on topic 'Emergence of New Delhi metallo-β-lactamase type 1-producing Enterobacteriaceae and non-Enterobacteriaceae: global case detection and bacterial surveillance'

Emergence of New Delhi metallo-β-lactamase type 1-producing Enterobacteriaceae and non-Enterobacteriaceae: global case detection and bacterial surveillance Academic research paper on "Health sciences"

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{"New Delhi metallo-β-lactamase" / NDM-1 / "Antibiotic resistance" / "Carbapenemase-resistant Enterobacteriaceae (CRE)" / Surveillance / "Systematic review"}

Abstract of research paper on Health sciences, author of scientific article — Greta Bushnell, Fanny Mitrani-Gold, Linda M. Mundy

Summary 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.

Academic research paper on topic "Emergence of New Delhi metallo-β-lactamase type 1-producing Enterobacteriaceae and non-Enterobacteriaceae: global case detection and bacterial surveillance"

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International Journal of Infectious Diseases

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

Greta Bushnella b, Fanny Mitrani-Goldb, Linda M. Mundyc*

a University of North Carolina, Chapel Hill, North Carolina, USA b GlaxoSmithKline, Research Triangle Park, North Carolina, USA c GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA



Article history:

Received 8 May 2012

Received in revised form 8 November 2012

Accepted 10 November 2012

Corresponding Editor: Eskild Petersen,

Skejby, Denmark


New Delhi metallo-b-lactamase NDM-1

Antibiotic resistance Carbapenemase-resistant Enterobacteriaceae (CRE) Surveillance Systematic review

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-b-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. Published by Elsevier Ltd. All rights reserved.

1. Introduction

Infections with multidrug-resistant Gram-negative bacteria are of major global concern given limited therapeutic options, untoward clinical outcomes, and excess costs of care.1,2 Heterogeneous resistance trends to cephalosporins, fluoroquinolones, and carba-penems exist among Enterobacteriaceae and non-Enterobacteriaceae, which add to the complexity of region-specific effective infection prevention and treatment strategies. Treatment of carbapenemase-resistant Enterobacteriaceae (CRE) now includes combination regimens of carbapenems, colistin, aminoglycosides, aztreonam, and tigecycline, as well as prolonged infusions of carbapenems.3-11 Gram-negative bacteria with the New Delhi metallo-b-lactamase

Corresponding author. Tel.: +1 610 917 6923; fax: +1 610 917 4818. E-mail address: (L.M. Mundy).

type-1 (NDM-1), produced by the blaNDM-1 gene, utilize at least one zinc atom at the active site to facilitate hydrolysis of a broad variety of b-lactams and carbapenems.12 The epidemiology of NDM-1 is compounded by interspecies dispersion and recognized implications for patient care, public health, antimicrobial surveillance

programs, and drug development.3,8,13-15

Initial case detection of NDM-1 production was characterized in a clinical urinary isolate of Klebsiella pneumoniae from a 59-year-old man who returned to Sweden after hospitalization in India in January 2008.16 This patient was concurrently colonized with an NDM-1-producing Escherichia coli in the stool.16 Subsequently, two NDM-1-producing E. coli strains from 2006 were retrospectively identified in stored clinical isolates from healthcare facilities in New Delhi, India via the SENTRY Antimicrobial Surveillance Program.17 Since 2008, NDM-1-producing bacteria have been reported via case detection, active and passive laboratory surveillance systems, national surveillance programs, and

1201-9712/$36.00 - see front matter © 2012 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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environmental surveillance studies.7,17-23 The most frequent detection of NDM-1 has been in K. pneumoniae and E. coli, with global spread associated with international travel, medical tourism, and potential exposures in the Balkan region and the Indian subcontinent.3,16,18,20,22,24-26 In Europe, a case series of subjects with NDM-1-producing Enterobacteriaceae has served as a template for linking clinical and laboratory case detection.7 From an epidemiological perspective, the global burden of disease associated with NDM-1-producing pathogens remains underrep-resented in the literature.3,27 The objective of this systematic review was to characterize the global distribution of human cases and surveillance studies for NDM-1-producing bacteria for the 3.5-year period since the initial case detection.

2. Methods

2.1. Systematic literature review

A comprehensive literature review was conducted using the PubMed search engine and the following key search terms: ''New Delhi Metallo-Beta-Lactamase" and ''NDM-1''. Search terms were limited to publications in the English language, publications in humans, and literature sources published from January 2008 (month and year of the clinical presentation of the NDM-1 index case) through July 6, 2011. Articles available through online advanced access were included and, in order to ascertain any citations that were not identified in the original literature search, relevant publications were examined for additional references to NDM-1-producing bacteria. Articles with complete text were analyzed and the relevant data from these publications were systematically collated into a tabulated format. Articles with only abstracts were included if the abstract contained sufficient information to meet the study inclusion criteria. NDM-1 publications were divided into two broad categories of either (1) case series and case reports of NDM-1-producing bacteria, or (2) active surveillance or environmental surveillance studies of NDM-1-producing bacteria. When additional information of interest for the systematic data collection was not in the publication, we attempted to contact the respective corresponding author to gather or to discern additional descriptive information for inclusion in the systematic review. Additional relevant data for 35 cases were obtained from corresponding authors of the original publications. Subsequent to the initial review of publications, we conducted a second structured literature search to assure capture of active laboratory surveillance programs and environmental surveillance studies of NDM-1-producing pathogens worldwide. This second literature review was conducted using the same search limits as the initial PubMed search with the following key search terms: ''New Delhi metallo-^-lactamase", ''NDM-1'', ''surveillance study'', and ''environmental study''. This search did not yield any additional NDM-1 surveillance or environmental studies.

2.2. Reported cases: data collection and study definitions

A case was defined as a patient for whom at least one clinical isolate of NDM-1-producing bacteria had been isolated, confirmed, and reported in the published literature. Demographic, clinical, and microbiological data were systematically collected from the case reports and case series. The demographic data included age, gender, and geographic location at the time of the NDM-1 specimen procurement. Exposure to the Indian subcontinent of south central Asia was defined as 'yes' for residence, travel, medical care, or hospitalization, or 'no' for either lack of exposure or uncertain for exposure. The clinical data included comorbid conditions, clinical status at hospital discharge or at last follow-up, recent travel history within 1 year prior to detection of NDM-1,

contact with other healthcare facilities, prior medical treatment or procedures, length of stay at the medical facility abroad, inter-country transfer, and any local transmission events with known contact of a travel-associated case. Microbiological data included the date of specimen collection, the bacterial species harboring NDM-1, specimen source(s) for both infected and colonized NDM-1 cases, and the multilocus sequence type (MLST), when available in the published literature. The MLST is a nucleotide sequence-based approach for the unambiguous characterization of bacterial isolates. Additional descriptive and microbiological data, if available, were also reviewed. Each reported case was categorized as either infection or presumed colonization. A case infection was defined as a report of NDM-1-producing bacteria in either (1) blood or another sterile body fluid specimen, or (2) clinical culture specimens from potentially non-sterile specimen sources such as the respiratory tract, wounds, urine, and other sources that were deemed to be associated with infection by the clinical investigative team. Cases with infection were further reviewed to determine if the infected case was also colonized with one or more NDM-1-producing bacteria, and if confirmed for colonization, the identified source(s) of colonization. A case of presumed colonization with NDM-1-producing bacteria was either (1) asymptomatic, (2) deemed to be colonized and without infection by the investigator/authors in either the initial report or follow-up correspondence, or (3) uncertain for infection or colonization by the original investigators, or if the author did not confirm colonization by personal communication, the case was categorized as presumed colonization. Specimens identified as urinary catheter, skin, and nose were categorically grouped as 'other' sources, and the source 'wound' included isolates from pus.

2.3. Laboratory and surveillance studies: data collection and study definitions

Identified surveillance studies for NDM-1-producing bacteria were assessed for geographic location of the patient at the time the clinical isolate was procured. Data included specimen source, date of specimen collection, number of NDM-1 isolates detected for each case, bacterial species, and when available, the MLST. The type of surveillance program, target pathogens, and denominator definitions were systematically recorded, given the variation in the laboratory detection methodologies and surveillance programs. The proportion of NDM-1-producing bacteria reported in each of these studies was contingent upon the criteria for screening restricted to either Gram-negative bacteria, Enterobacteriaceae, or CRE. All data were entered into Microsoft Excel for descriptive statistics and summary calculations.

3. Results

3.1. Literature review for case reports, case series, and surveillance studies

The systematic literature review yielded 94 publications with reports of NDM-1-producing bacteria published in print or online between January 2008 and July 6, 2011 and limited to humans and articles in English. Thirty-six publications were case reports or case series,16,18,21,24,28-59 and nine publications were surveillance studies;3,4,7,23,60-64 49 publications were excluded. Among excluded publications was the first published case report of NDM-2, a variant form of NDM, and a report on Acinetobacter baumannii isolates that lacked pertinent case details.38,65 After review of the identified publications and citations, an additional six case reports,20,66-70 two surveillance studies,17,71 and one Health Protection Agency report regarding carbapenem resistance and NDM-119 were included. These publications of NDM-1-producing

Figure 1. Two world maps illustrate (a) the international dissemination of human cases and (b) surveillance isolates with New Delhi metallo-b-lactamase (NDM-1)-producing Enterobacteriaceae and non-Enterobacteriaceae; data based on publications as of July 6, 2011.

Enterobacteriaceae and non-Enterobacteriaceae portray an international dissemination of case reports and series (Figure la) and surveillance isolates (Figure lb).

3.2. Case cohort

The final cohort comprised 60 reported unique cases with NDM-l-producing bacteria from independent and overlapping case reports and case series.16'18,20'21'24'28-59,66-70 Twenty-one cases (35%) were categorized as infection and 39 cases (65%) were categorized as presumed colonization with no clinical evidence of infection (Table 1). There were 29 males (48.3% of the total, with nine cases unknown for gender), most cases were adults (n = 44, 73.3% of the total; with 11 cases unknown for age), and a predominance (n = 27, 45%) of case detection in Europe (Table 1). Exposure to the Indian subcontinent of south central Asia was reported for 76.2% cases (n = 16) with NDM-1 infection versus 56.4% of cases (n = 22) with colonization. The frequency of reported case detection increased annually until 2011, with a four-fold increase in colonized cases between 2008 and 2009 and a four-fold increase in infected cases between 2009 and 2010. Crude mortality was higher among persons with infection (23.8%) versus presumed colonization (10.3%). The NDM-1-producing bacteria associated with the nine deaths were E. coli (n = 4), K. pneumoniae (n = 2), Pseudomonas aeruginosa (n = 2), A. baumannii (n = 1), and Providencia stuartii (n = 1); one case included detection of both NDM-1-producing E. coli and K. pneumoniae.

One or more NDM-1-producing bacteria were reported for each case, for a total of 84 NDM-1-producing bacterial isolates reported from the 60 unique cases (Table 2). The majority of reported NDM-1-producing bacteria (n = 78, 92.9%) were in the family Enterobacteriaceae, with K. pneumoniae and E. coli identified as the most frequently reported bacteria.13'34'47,57,72,73 Urine was the most frequent specimen source for cases with infection (n = 10, 41.7%) and with colonization (n = 20, 33.3%). One case from Canada remained colonized and untreated with NDM-1-producing Morganella morganii 5 months after initial detection, and another case had Providencia rettgeri urine colonization 3 months after the initial microbial detection.21 A case from Italy with enteric colonization of NDM-1-producing E. coli had sustained colonization 10 months after initial detection, with an interim toe infection attributed to NDM-1-producing E. coli.34

Seventeen of the 60 cases (28.3%) represented cases with NDM-1-producing bacteria at more than one body site (Table 3).16'21'24'31'33'34'36'41'42'47'48'53'54'59 The distribution of these 17 cases included infection (n = 2), colonization (n = 5), and dual infection and colonization (n = 10).

The MLST characterization was available for 34 of the 84 (40.5%) reported NDM-1-producing bacteria (Table 4). Among the 20 K. pneumoniae isolates, there were seven different MLST; sequence type (ST) 14 was the most frequently detected MLST, with cases from Sweden (n = 1, the index case), Sultanate of Oman (n = 1), Singapore (n = 1), and Kenya (n = 7).16,45-50 Among

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Table 1

Descriptive characteristics of 60 reported cases with NDM-1-producing bacteria stratified by infection versus presumed colonization

Descriptive variables Overall NDM-1 NDM-1

(n = 60) infection (n=21) colonizationa (n = 39)


Male 29 (48.3) 12 (57.1) 17 (43.6)

Female 22 (36.7) 6 (28.6) 16 (41.0)

Unknown 9 (l5.o) 3 (14.3) 6 (15.4)

Age (years)

<18 5 (8.3) 4 (19.0) 1 (2.6)

18-65 31 (51.7) 10 (47.6) 21 (53.8)

>65 13 (21.7) 3 (14.3) 10 (25.6)

Unknown 11 (18.3) 4 (19.0) 7(17.9)

Geographic region

Europe 27 (45.0) 10 (47.6) 17 (43.6)

North America 12 (20.0) 4 (19.0) 8 (20.5)

Asia 11 (18.3) 6 (28.6) 5 (12.8)

Africa 7(11.7) 0 (0.0) 7(17.9)

Australia 3 (5.0) 1 (4.8) 2(5.1)

Indian subcontinent exposure13

Yes 38 (63.3) 16 (76.2) 22 (56.4)

No (unknown/none) 22 (36.7) 5 (23.8) 17 (43.6)

Year of case detection

2007 3 (5.0) 1 (4.8) 2(5.1)

2008 4 (6.7) 1 (4.8) 3 (7.7)

2009 15 (25.0) 3 (14.3) 12 (30.8)

2010 28 (46.7) 13 (61.9) 15 (38.5)

2011 (through July 6) 3 (5.0) 1 (4.8) 2(5.1)

Uncertainc 7(11.7) 2 (9.5) 5 (12.8)

Crude mortalityd 9 (15.0) 5 (23.8) 4 (10.3)

Data are provided as number (%) unless denoted otherwise.

a Presumed colonization if infection not confirmed in report or by corresponding author.

b Residence, travel, medical care, or hospitalization to the region of south central Asia, comprising the countries of Pakistan, Bangladesh, India, Sri Lanka, and the Himalayan states of Nepal and Bhutan.

c Two infected cases and one colonized case detected between March 2009 and October 2010.

d Specimen sources associated with mortality and infection were blood (n = 3), urine (n = 1), and wound (n =1). The specimen sources associated with mortality and NDM-1 colonization were urine (n = 2), wound (n = 1), and simultaneous wound and enteric colonization (n = 1).

the 14 E. coli isolates, there were seven different MLST representing cases from North America (n = 3), Europe (n = 7), Australia (n = 1), Japan (n = 1), Norway (n = 1), and Switzerland (n = 1); 71.4% (n = 10) had presumed case exposure in the Indian

subcontinent 31,33,34,37,41-43,46,48,52,55,58,69,70

3.3. Laboratory and environmental surveillance for NDM-1-producing pathogens

During the 3.5-year interval since the index NDM-1 case report, 11 publications and data from the UK Health Protection Agency were reviewed for additional information related to laboratory-based or environmental surveillance for NDM-1-producing isolates (Table 5).3,4,7,17,19,23,60-64,71 Variation in detection of NDM-1 was evident, based on the years of surveillance and the surveillance strategy by type of bacteria or by type of indication or infection among the seven publication sources from the Indian subcontinent of central Asia3,17,23,61-64 and the six publication and data sources from the rest of world region.3,4,7,19,60,71 In the 20062007 SENTRY study, 1.0% (15/1443) of Enterobacteriaceae were retrospectively identified as NDM-1-producing bacteria.17 Clinical isolates with NDM-1 production were collected from New Delhi, Mumbai, and Pune; no NDM-1-producing bacteria were detected at any of the other 11 surveillance sites within India.17 In a later study of Enterobacteriaceae, 1.2% of specimens from Chennai versus 13.1% from Haryana were positive for NDM-1-producing bacteria.3 Among CRE specimens from India, 31-92% tested positive for NDM-1-producing bacteria.3,17,61,62 An environmental surveillance study conducted in New Delhi detected NDM-1-producing bacteria in 4% (n = 2/50) of drinking water samples, 30% (n = 51/ 171) of seepage samples, and in 0% of the control samples, sewage effluent.74 As of mid-March 2011 in the UK, the Health Protection Agency reported 88 isolates of NDM-1-producing CRE.19 A comprehensive study across China found 0.03% of clinical isolates (n = 4 of 11 298) tested positive for NDM-1 production; all four isolates were A. baumannii and three of the patients were neonates.32

4. Discussion

The current perspective on NDM-1-producing bacteria for human and environmental health is compounded by interspecies dispersion, diverse health care practices, and varied antimicrobial surveillance programs. This systematic literature review provides three contributions to the current understanding of NDM-1-producing bacteria related to epidemiology, clinical care, and implications for international surveillance and preparedness plans. From an epidemiological perspective, the 60 cases reported in the literature over a 3.5-year period represent a heterogeneous patient population with varied multidrug-resistant phenotypes, indicative of worldwide interspecies dissemination of blaNDM-1 on plas-mids.51,72,75 NDM-1 plasmids harbor a variety of co-resistance

Table 2

Distribution of 84 NDM-1-producing Enterobacteriaceae (n = 78) and non-Enterobacteriaceae (n = 6) detected in 60 cases stratified by case infection versus colonization and by specimen source

Bacteria Infection source (n = 24) Colonization source3 (n = 60) Total

Urine Blood Wound Respb Urine Stool Respb Wound Otherc

Klebsiella pneumoniae 5 1 1 2 13 8 4 2 4d 40

Escherichia coli 4 3 5 - 2 9 4 1 - 28

Providencia spp. - 1 - - 2 - - - - 3

Citrobacter freundii 1 - - - - - - - - 1

Morganella morganii - - - - 1 1 - 1 - 3

Enterobacter cloacae - - - - 1 - - 1 - 2

Proteus mirabilis - - - - - 1 - - - 1

Acinetobacter baumannii - 1 - - - - 1 1 1 4

Pseudomonas aeruginosa - - - - 1 - - 1 - 2

Total 10 6 6 2 20 19 9 7 5 84

a Presumed colonization if infection not confirmed in report or by corresponding author. b Resp = respiratory specimen of sputum, bronchoalveolar lavage, or other.

c Other = skin, nose, or urinary catheter.

d Source unknown for one case with Klebsiella pneumoniae presumed colonization.


Table 3

Descriptive case categorization of 17 reported cases with NDM-1-producing bacteria located at more than one body site and stratified as case with infection or colonization with one or two different NDM-1-producing bacteriaa

Case Gram-negative bacteria and infection type Ref.

Single bacterial pathogenb

Infected E. coli urosepsis (blood and urine) 53

E. coli infection (inguinal, perineum, and scrotal wounds) 59

Infected and colonized E. coli blood infection and E. coli respiratory tract colonization 24

K. pneumoniae abdominal wound infection and K. pneumoniae enteric and throat colonization 59

A baumannii endovascular infection and A baumannii colonization (skin, tracheal secretions, and wound) 36

K. pneumoniae RTI and K. pneumoniae nasal colonization 41

K. pneumoniae UTI and K. pneumoniae enteric colonization 54

E. coli toe infection and E. coli enteric colonization 34

E. coli blood infection and E. coli urine and sputum colonization 33

Colonized E. coli breast tumor colonization and enteric colonization 46

M. morganii urine and enteric colonization 21

K. pneumoniae decubiti and enteric colonization 59

Two different bacterial pathogensb

Infected and colonized K. pneumoniae UTI and E. coli enteric colonization 48

K. pneumoniae UTI and E. coli enteric colonization 16

K. pneumoniae UTI and E. coli and K. pneumoniae enteric colonization 42

Colonized M. morganii wound and E. cloacae pus colonization 31

K. pneumoniae respiratory colonization and E. coli enteric colonization 31

RTI, respiratory tract infection; UTI, urinary tract infection. a Presumed colonization if infection not confirmed in publication or by corresponding author. b NDM-1-producing bacterial pathogen reported in publication or by corresponding author.

determinants, including b-lactamase genes, quinolone resistance genes, and 16S rRNA methylase genes.75 How diverse sequence types in bacteria contribute to the dissemination of WaNDM-1 remains a source of ongoing investigation. The MLST data for E. coli and K. pneumoniae provide an incomplete, yet heterogeneous global distribution of NDM-1-producing Enterobacteriaceae, which suggests a non-clonal pattern of dissemination (Table 4). A recent, noteworthy study from a military hospital in Pakistan, published after our systematic review end-date, reported enteric prevalence

rates for NDM-1-producing bacteria of 27.1% for inpatients and 13.8% for outpatients.73 Another recent investigation of NDM-1-producing carbapenemases in K. pneumoniae from India, Sweden, and the USA, reported that the most frequently detected MLST sequence type was ST14, a finding consistent with what we identified for K. pneumoniae (Table 4).76 Notably, the investigators have suggested that ST14 and ST11 are likely to be important in the ongoing dissemination of blaNDM-1.76 These data, together with environmental surveillance data (Table 5), suggest that there is a

Table 4

Distribution of multilocus sequence types (MLST) reported in 31 cases with clinical isolates of NDM-1-producing Klebsiella pneumoniae (n = 20) and NDM-1-producing Escherichia coli (n = 14)a

Bacteria and MLST sequence type (ST) No. Geographic region of isolate detection and presumed case exposure (n) Detection by year/quarter (Q) Ref.

K. pneumoniae, n = 20

ST14 10 Sweden and India (1) 2008 Q1 16

Sultanate of Oman and India (1) 2009 Q1 45

Kenya and North America (7) 2007 Q2-2009 Q1 50

Singapore and Bangladesh (1) 2010 Q1 39

ST147 4 Australia and India (1) 2010 54

Canada and India (1) 2010 Q3 56

Switzerland and India (1) 2009-2010 48

France and Iraq (1) 2010 Q4 49

ST11 2 Norway and India (1) 2010 Q2 53

Singapore and India (1) 2010 Q1 39

ST15 1 Belgium and Montenegro (1) 2010 31

ST16 1 Canada and India (1) 2010 Q1 42

ST25 1 Switzerland and North America (1) 2009-2010 48

ST340 1 Sultanate of Oman and North America (1) 2009 Q3 45

E. coli, n = 14

ST101 4 Germany and India (1) 2009 Q4 69

Canada and India (1) 2010 42

Belgium and Pakistan (1) 2010 31

Australia and Bangladesh (1) Not available 70

ST405 3 Italy and North America (2) 2009 Q3 34

Canada and India (1) 2010 Q1 42

ST131 2 France and India (1) 2009 Q2 46

USA and India (1) 2010 Q2 37, 43

ST410 2 Switzerland and North America (1) 2009-2010 48

Norway and India (1) 2010 Q1 53

ST38 1 Japan and India (1) 2009 Q2 33, 58

ST782 1 Belgium and Montenegro (1) 2010 31

ST156 1 Spain and India (1) Not available 55

a Total greater than 100% as some cases had more than one clinical isolate sequenced.31,41'


Table 5

Laboratory and environmental surveillance studies reporting detection of NDM-1-producing bacteria from the Indian subcontinent of south central Asia (n = 7) and the rest of world regions (n = 6)a

City, study years (Ref.)

Source specimenb (n)

NDM-1 (n)


Geographic region: ¡ndian subcontinent of south central Asiac

14 cities/SENTRY, 2006-2007 (17)

Northeast tertiary hospital, August 2009 (63)

Mumbai tertiary hospital, August-November 2009 (62)

Chennai, through 2009 (3)

Haryana, through 2009 (3)

Mumbai, through 2009 (3) Varanasi/NA (3) Guwahat/NA (3)

Pakistan/multi-city, through 2009 (3) Mumbai tertiary center, 2009-2010 (61)

North India tertiary referral hospital and outpatient departments, February- July 2010 (64)

New Delhi, September-October 2010 (23)

Geographic region: rest of world UK, referrals to the ARMRL, through 2009 (3)

29 European Union member states, Iceland, and Norway, 2008-0ctober 2010 (7)

Europe, Asia, North America, Latin America, the South Pacific

and the Middle East, 2009 (4) UK, 2008-March 2011 (19)

France, February 2004-April 2011 (71)

China—multiple cities across the country, January 2009-September 2010 (60)

Enterobacteriaceae (1443) Carbapenem-resistant Enterobacteriaceae (CRE)(39)

Carbapenemase producers (26) Surgical site infection (15) Enterobacteriaceae (11) Vascular site infection (8) Enterobacteriaceae (2) CRE (24)

Enterobacteriaceae (3521) CRE (141)

Enterobacteriaceae (198) CRE (47)

Carbapenem-resistant Gram-negative

bacilli (310)

Enterobacteriaceae (57)

780 consecutive isolates

(E. coli, K. pneumoniae, Citrobacter spp,

Enterobacter aerogenes, P. mirabilis,

M. morganii)

64 metallo-ß-lactamase producers Drinking water samples (50)

Seepage samples (171) Effluent samples (70)

Enterobacteriaceae (NA) Carbapenemase-producers (73)

CRE and non-Enterobacteriaceae producing NDM-1 (cases, not isolates)

Ertapenem non-susceptible Enterobacteriaceae from 1A1 (235) 1+ carbapenemase gene (66) Enterobacteriaceae confirmed for NDM-1

Cases reported to the French Institute for Public Health Surveillance Sequential isolates of Gram-negative bacilli (A. baumannii, P. aeruginosa, E. coli, K. pneumoniae) screened for NDM-1 (11 298)

3e le 22

32 13 3

25; in eight cities 49

87i cases; speciation for 67 isolates

33;j only in isolates from India

9 casesk 4i

Escherichia coli (6); Enterobacter spp (3); Klebsiella pneumoniae (6)

E. coli; K. pneumoniae; Enterobacter cloacae

Klebsiella spp (10); E. coli (9); Enterobacter spp (2); Morganella morganii (1) E. coli (19); K. pneumoniae (14); E. cloacae (7); Proteus spp (2); Citrobacter freundii (1); Klebsiella oxytoca (1) K. pneumoniae (26)

Klebsiella spp (28); E. coli (13); Enterobacter spp (5); M. morganii (2); Citrobacter spp (1) E. coli (30); K. pneumoniae (12); Citrobacter spp (12)

C. freundii; E. coli; K. pneumoniae; Shigella boydii; Vibrio cholera; Aeromonas caviae

K. pneumoniae (21); E. coli (7); Enterobacter spp (5); C. freundii (2); M. morganii (1); Providencia spp (1) K. pneumoniae (31); E. coli (16); Enterobacter spp (4); C. freundii (3); M. morganii (2); Proteus mirabilis (1); Acinetobacter baumannii (10) K. pneumoniae (18); E. coli (8); E. cloacae (5); Providencia rettgeri (1); M. morganii (1)

K. pneumoniae (3); E. coli (3); C. freundii (1); P. mirabilis (l)k A. baumannii (4)

ARMRL, Antibiotic Resistance Monitoring and Reference Laboratory; 1A1, intra-abdominal infection; NA, not available.

a Duplicative reporting of NDM-1 isolates possible; Kumarasamy et al. included surveillance data for south central Asia and the rest of world regions, and is therefore counted twice.3

b Source specimen column provides details on the underlying population of isolates tested for NDM-1; in many instances the source population narrowed before testing for NDM-1 occurred, which is demonstrated with multiple rows per study location.

c Pakistan, Bangladesh, India, Sri Lanka, and the Himalayan states of Nepal and Bhutan.

d Specimen source: skin and skin structure infection (n = 7), bloodstream infection (BS1; n = 5), and respiratory tract infection (n = 3); MLST performed only for E. coli with ST101 (n = 4) and ST167 (n = 2).

e Specimen source: surgical site infection and peripheral vascular access site infections.

f Specimen source: urinary tract infection, pneumonia, and BS1.

g Specimen source: urine (n = 23), endotracheal tube (n =13), pus (n = 9), umbilical cord tip (n = 2), tissue (n = 2), blood (n = 2), catheter tip (n = 1), sputum (n = 1), and Foley catheter tip (n = 1).

h Specimen source from 29 patients: urine (n =15), blood (n = 3), sputum (n = 2), other (n = 6), and unknown (n = 3).

1 NDM-1 patients (not isolates) with one or more isolates of Enterobacteriaceae.

j MLST performed in K.pneumoniae and E. coli only; K.pneumoniae typing ST147 (n = 9),ST231 (n = 1),ST11 (n = 1),ST101 (n = 1),ST340(n = 1),ST391 (n =1),ST14(n =1), ST20 (n = 1), ST572 (n =1), and ST571 (n = 1); E. coli typing ST88 (n = 4), ST471 (n =1), ST2 (n =1), ST44 (n =1), and ST501 (n =1).

k 9 cases from 7 episodes (episode defined as either a sporadic case or >1 case related by an identified chain of transmission); 8 pathogens were reported for these 7 episodes.

' Specimen source: sputum (n = 2), blood (n = 1), and secretion (n = 1).

significant colonization burden of NDM-l-producing bacteria in some geographic regions that far exceeds current estimates of case infections.

From a clinical perspective, our systematic review provides a selective, yet in-depth summary of 60 reported human cases. The majority of cases (65%) represented colonization without evidence of infection, with some cases informative for long-term, asymptomatic colonization. These case presentations have implications for individual patients, healthcare institutions, and global surveillance. Notably, case detection requires astute clinical care combined with laboratory detection methods linked to well-coordinated reporting systems. Prompt case detection facilitates isolation of patients which, in turn, will optimize low colonization pressure for NDM-l-producing bacteria in healthcare institutions. Colonization pressure has been identified as an independent risk factor for acquisition of vancomycin-resistant enterococci, methi-cillin-resistant Staphylococcus aureus, P. aeruginosa, and Clostridium difficile in defined geographic units over the past 15 years.77-81 In healthcare settings with source patients infected or colonized with NDM-l-producing bacteria, infection prevention control strategies and attention to colonization pressure will be key factors in minimizing the spread of blaNDM-1 plasmids in defined geographic units.

The third notable contribution of this review pertains to current global surveillance and international preparedness plans. Recent reports and editorial commentaries suggest the need for a coordinated international monitoring system along with a global preparedness plan should an outbreak or endemicity of NDM-l-producing bacterial infections occur.9,13'15'39'72,82-84 Current surveillance systems are limited given the lack of standardized detection methods for carbapenemases, distinction between NDM-1 infection and colonization, and data on potential nonhuman reservoirs of NDM-1 such as the animal food chain.13 Detection and surveillance of carbapenemase-producing Entero-bacteriaceae and non-Enterobacteriaceae have become important for both the selection of appropriate antimicrobial therapy and implementation of infection control measures. As carbapenemase production cannot be inferred from a standard antimicrobial resistance profile, criteria are needed to help determine which isolates should be suspected and screened for carbapenemase production and to determine whether phenotypic or genotypic tests should be adapted for the confirmation of carbapenem resistance.13 The collective findings from this systematic review of human case reports, laboratory surveillance programs, and the environmental survey portray a complex array of microbial factors and a global antimicrobial armamentarium that has identifiable gaps for effective treatment paradigms.

We readily acknowledge several limitations associated with this systematic review. First, incident cases with NDM-1-produc-ing bacteria were likely underestimated given that systematic mandatory reporting of CRE and other highly-resistant Entero-bacteriaceae did not exist during the study period. Second, ascertainment bias in information and measurement, as well as reporting biases, were inherent in the study design given the recognized gaps in available information, lack of standardized microbial diagnostics, and resources available to characterize NDM-1-producing bacteria in resource-limited settings and in all geographic regions. Third, the association between exposure within the Indian subcontinent and NDM-1-producing bacteria may or may not be overestimated, as publication bias may be bidirectional and patients who reported exposure to the Indian subcontinent were perhaps more likely to be screened for NDM-1-producing bacteria. Fourth, the maps that portray the location of publications for cases and surveillance studies of NDM-1-produc-ing bacteria (Figure 1) likely underestimate global spread. Nonetheless, they provide a comparative benchmark with the

reports of K. pneumoniae carbapenemases (KPC) and other evolving carbapenemases.85 The first KPC was detected in a 1996 clinical isolate from North Carolina and there are now nine KPC variants.85,86 Fifth, as defined by our study and reported in our results, this review was restricted to NDM-1-producing bacteria and did not include subsequently characterized variant forms of NDM. Lastly, it is likely that case infections relative to case colonization are underestimated based on our study definitions and follow-up on clinical case data with corresponding authors. Nonetheless, epidemiological studies utilizing well-established base populations and a clear and standardized disease definition are optimal methods for estimating the incidence and prevalence of infections and colonization with NDM-1-producing bacteria.

This systematic literature review summarizes the epidemiology, clinical cases, and surveillance studies of NDM-1-producing bacteria over the 3.5-year interval since the initial characterization of a urinary isolate of NDM-1-producing K. pneumoniae. A global distribution of NDM-1-producing Enterobacteriaceae and non-Enterobacteriaceae is evident, linked to both human infection and colonization, and there are recognized implications for antimicrobial drug development programs and population health.3,8,13-15 Overall, the findings in this systematic review, compounded by the complexity of the genetic plasticity of blaNDM-1, support the need for astute clinical case recognition, reliable laboratory detection methods, secure infection control practices, and well-integrated surveillance systems.


The authors wish to acknowledge Michael Irizarry and Madelyn Caltabiano for their critical review of this manuscript.

Ethical approval: As a systematic review of published studies, there was no formal ethical approval.

Funding source: None; this systematic review was conducted by all authors within our defined roles and scope of work with the WWEpidemiology Department at GlaxoSmithKline.

Conflict of interest: All listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. GB is a student research assistant at GlaxoSmithK-line, FMG is a consultant to WWEpidemiology at GlaxoSmithKline, and LMM is an employee of WWEpidemiology at GlaxoSmithKline as of June 4, 2012.


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