Carbapenemase-producing Enterobacteriaceae in the UK: metallo-beta-lactamase: repeated importation from Indian subcontinent (UN HPA, 2009, edited)

[Giuseppe]

Carbapenemase-producing Enterobacteriaceae in the UK: NDM (New Delhi Metallo-)b -lactamase: repeated importation from Indian subcontinent (UN HPA, 2009, edited)

[Source: United Kingdom, Health Protection Agency, full PDF Document (LINK). Edited.]

National Resistance Alert 3 ADDENDUM

Carbapenemase-producing Enterobacteriaceae in the UK: NDM (New Delhi Metallo-)b -lactamase: repeated importation from Indian subcontinent

• Numbers of carbapenemase-producing Enterobacteriaceae referred to ARMRL continue to increase sharply
• Many recently referred carbapenemase producers have NDM (New Delhi Metallo)-b-lactamase
• Many patients with NDM-1 positive isolates have recent medical contact in India or Pakistan, where the enzyme is accumulating swiftly, probably via efficient plasmid transfer
• Patterns of human travel and migration mean that repeated future challenge of the UK healthcare system by producers of NDM-1 enzyme is to be expected
• Most producers are resistant to ALL antibiotics except polymyxins and tigecycline and may pose a serious treatment challenge in severe infections
• Vigilance and good infection control are essential to minimise transmission and accumulation in the UK

Background

In January 2009 we issued a National Resistance Alert concerning carbapenemases in UK Enterobacteriaceae.

This followed consultation with ARHAI and stressed:
(i) the growing number of producer isolates referred to the HPA?s Antibiotic Resistance Monitoring & Reference Laboratory (ARMRL) (8 in all years to 2007; ultimately 21 in 2008);
(ii) the diversity of these, variously with metallo (VIM or IMP), KPC and OXA-48 enzymes and
(iii) that many producer isolates were from patients previously hospitalised in Greece, Turkey and Israel.

This addendum is issued:
(i) because the number of referred producers continues to increase sharply (>40 so far in 2009) and
(ii) because a novel enzyme, NDM-1 (New Delhi Metallo b-Lactamase) is increasingly dominant.

NDM-1 is strongly linked to India and Pakistan and many of the UK cases have recent medical exposure in the Indian-subcontinent. Recognition of risk patients and prevention of transmission in the UK is critical, since most producers are resistant to ALL reliable antibiotics.


Basis for alert
During 2008 ARMRL investigated 17 referred Enterobacteriaceae with known carbapenemases, as detailed in National Resistance Alert 3. We also received 4 isolates that had a metallo -carbapenemase phenotype (i.e. strong EDTA/imipenem synergy), but lacked known carbapenemase genes. We have since identified their enzyme as NDM-1, a type first described in 2008 in a patient transferred from India to Sweden: he had an infection with NDM -1+ K. pneumoniae, and gut carriage of E. coli with the enzyme.

Up to 20/6/2009 we received 17 further producers . The total of 21 UK producers compris e K. pneumoniae (14), E. coli (4), Enterobacter spp., (1) and C. freundii (2), from 18 patients and 16 hospitals scattered across England, with one in Scotland. NDM-1 has become the most frequent carbapenemase in isolates referred to ARMRL, and the most widely scattered. Even when producers belong to the same species they are diverse in strain type with only one possible transmission, involving two patients.

Case follow-up is ongoing but, strikingly, 12/18 patients have names linked to the Indian subcontinent and at least 8 have had medical contact in India or Pakistan. They include one patient dividing treatment for haematological malignancy between India and the UK and another who developed a wound infection following cosmetic surgery in India. Denominators are weak, but surveys co-ordinated by Prof Walsh at the University of Cardiff, Wales suggest that NDM-1 is widely distributed in India and one of ARMRL?s collaborators has found producer E. coli in Karachi, Pakistan. Work by Prof Walsh?s group suggests promiscuous plasmid transfer as a mode of dissemination, and the diversity of producers referred to ARMRL supports this.

Allowing patterns of human travel and migration, and the many UK residents who receive medical treatment in India, we believe that UK healthcare will be repeatedly challenged by imported producers. These organisms mostly are resistant to ALL antibiotics except polymyxins and, less consistently, tigecycline. The activity of obscure agents (fosfomycin, arbekacin and isepamicin) and novel compounds is under investigation, but none is readily available for therapy. In these circumstances it is vital to detect producers and to prevent their o nward transmission.


Actions advised

• Be alert to the increase in carbapenemase-producing Enterobacteriaceae, and the growing importance of NDM -1 enzyme
• Recognise exposure to healthcare systems in India and Pakistan as additional major risk factors for infection or colonization with multiresistant, carbapenemase-producing Enterobacteriaceae
• Refer ALL carbapenem-resistant Enterobacteriaceae to ARMRL, except (i) Proteus spp. and Morganella spp. with borderline resistance only to imipenem (common in these genera) and (ii) E. cloacae with intermediate resistance to ertapenem only, as these are generally just derepressed for AmpC. NDM production will be investigated promptly.
• Patients infected with producers should be isolated to prevent onward transmission in hospitals; carriage in the patient?s faecal flora should be examined for producers of the same or different species; similar screening of close unit contacts should be strongly considered.

Queries to:
David Livermore or Neil Woodford, Antibiotic Resistance Monitoring and Reference Laboratory, Centre for Infections, HPA Colindale. Tel 020-8327-6511/7223 or 7255; david.livermore@hpa.org.uk or neil.woodford@hpa.org.uk; queries on relevant infection control to Barry Cookson, Laboratory of Healthcare-Associated Infection, 0208-327-7249 barry.cookson@hpa.org.uk

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[Anne]

Re: Carbapenemase-producing Enterobacteriaceae in the UK: NDM (New Delhi Metallo-)b -lactamase: repeated importation from Indian subcontinent (UN HPA, 2009, edited)

There is health tourism in india : plastic surgery, transplantations

http://www.health-tourism-india.com/

[Gert van der Hoek]

Re: Carbapenemase-producing Enterobacteriaceae in the UK: NDM (New Delhi Metallo-)b -lactamase: repeated importation from Indian subcontinent (UN HPA, 2009, edited)

Characterization of a New Metallo-β-Lactamase Gene, blaNDM-1, and a Novel Erythromycin Esterase Gene Carried on a Unique Genetic Structure in Klebsiella pneumoniae Sequence Type 14 from India

Received June 10, 2009; Revised August 7, 2009; Accepted September 10, 2009.

ABSTRACT

A Swedish patient of Indian origin traveled to New Delhi, India, and acquired a urinary tract infection caused by a carbapenem-resistant Klebsiella pneumoniae strain that typed to the sequence type 14 complex.

The isolate, Klebsiella pneumoniae 05-506, was shown to possess a metallo-β-lactamase (MBL) but was negative for previously known MBL genes.

Gene libraries and amplification of class 1 integrons revealed three resistance-conferring regions; the first contained blaCMY-4 flanked by ISEcP1 and blc. The second region of 4.8 kb contained a complex class 1 integron with the gene cassettes arr-2, a new erythromycin esterase gene; ereC; aadA1; and cmlA7. An intact ISCR1 element was shown to be downstream from the qac/sul genes. The third region consisted of a new MBL gene, designated blaNDM-1, flanked on one side by K. pneumoniae DNA and a truncated IS26 element on its other side.

The last two regions lie adjacent to one another, and all three regions are found on a 180-kb region that is easily transferable to recipient strains and that confers resistance to all antibiotics except fluoroquinolones and colistin.

NDM-1 shares very little identity with other MBLs, with the most similar MBLs being VIM-1/VIM-2, with which it has only 32.4% identity.

As well as possessing unique residues near the active site, NDM-1 also has an additional insert between positions 162 and 166 not present in other MBLs.

NDM-1 has a molecular mass of 28 kDa, is monomeric, and can hydrolyze all β-lactams except aztreonam.

Compared to VIM-2, NDM-1 displays tighter binding to most cephalosporins, in particular, cefuroxime, cefotaxime, and cephalothin (cefalotin), and also to the penicillins. NDM-1 does not bind to the carbapenems as tightly as IMP-1 or VIM-2 and turns over the carbapenems at a rate similar to that of VIM-2.

In addition to K. pneumoniae 05-506, blaNDM-1 was found on a 140-kb plasmid in an Escherichia coli strain isolated from the patient's feces, inferring the possibility of in vivo conjugation.

The broad resistance carried on these plasmids is a further worrying development for India, which already has high levels of antibiotic resistance.

Full article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2786356/

[Gert van der Hoek]

Re: Carbapenemase-producing Enterobacteriaceae in the UK: NDM (New Delhi Metallo-)b -lactamase: repeated importation from Indian subcontinent (UN HPA, 2009, edited)

Today's blog of Mike Coston on NDM-1 is highly recommended:

NDM-1: A New Acronym To Memorize

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