New Delhi metallo-beta-lactamase 1

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Klebsiella pneumoniae, the bacterium in which NDM-1 was first identified.

New Delhi Metallo-beta-lactamase (NDM-1)[1] is a newly-identified enzyme that makes bacteria resistant to broad range of beta-lactam antibiotics. This includes antibiotics of the carbapenem family that were a mainstay for the treatment of other antibiotic-resistant bacteria. The gene for NDM-1 is one member of a large gene family that encode beta-lactamase enzymes called carbapenemases. Bacteria that carry such genes are often referred to in the news media as "superbugs", since infections with these bacteria are very hard to treat successfully. Indeed, the United Kingdom Health Protection Agency has stated that "most isolates with NDM-1 enzyme are resistant to all standard intravenous antibiotics for treatment of severe infections."[2]

NDM-1 was first identified in December 2009 in a patient who was hospitalised in New Delhi with a Klebsiella pneumoniae infection. It has since been detected in bacteria in India, Pakistan, the United Kingdom and the United States. The most common organisms expressing this enzyme are the Gram-negative bacteria Escherichia coli and Klebsiella pneumoniae, but the gene for NDM-1 can be transmitted from one strain of bacteria to another through horizontal gene transfer. The emergence of resistant Gram-negative bacteria is in contrast to the more familiar antibiotic resistant bacteria such as Methicillin-resistant Staphylococcus aureus (MRSA), which are Gram-positive.

Function

Structure of the carbapenem backbone.

Carbapenems are a class of beta-lactam antibiotics were, until recently, capable of killing most bacteria by inhibiting the synthesis of one of their cell wall layers. The carbapenems were developed to be less sensitive to inactivation by the beta-lactamase enzymes that had evolved in bacteria resistant to antibiotics such as penicillin. The blaNDM-1 gene produces NDM-1, which is a carbapenemase beta-lactamase - an enzyme that hydrolyzes and inactivates these carbapenem antibiotics.

Carbapenemases are particularly dangerous resistance mechanisms, since they can inactivate a wide range of different antibiotics.[3] The NDM-1 enzyme one of the class B metallo-beta-lactamase, other types of carbapenemase are class A or class D beta-lactamases.[4] The class A Klebsiella pneumoniae carbapenemase (KPC) is currently the most common type of this enzyme, which was first detected in North Carolina, USA, in 1996 and has since spread worldwide.[5] A later publication indicated that Enterobacteriaceae that produce KPC were becoming common in the United States.[6]

The following antibiotics are inactivated by the enzyme:

The resistance conferred by this gene therefore aids the expansion of bacteria that carry it throughout a human host, since they will face less opposition/competition from populations of antibiotic-sensitive bacteria, which will be diminished by the original antibacterial treatment.

Origin and spread

The NDM-1 enzyme was named after New Delhi, the capital city of India, as it was first described by Yong et al. in December 2009 in a Swedish national who fell ill with an antibiotic-resistant bacterial infection that he acquired in India.[7] The infection was unsuccessfully treated in a New Delhi hospital and after the patient's repatriation to Sweden, a carbapenem-resistant Klebsiella pneumoniae strain bearing the novel gene was identified. The authors concluded that the new resistance mechanism "clearly arose in India, but there are few data arising from India to suggest how widespread it is."[7] In March 2010 a study in a hospital in Mumbai found that the majority of carbapenem-resistant bacteria isolated from patients carried the blaNDM-1 gene.[8]

In May 2010 a case of infection with E. coli expressing NDM-1 was reported in Coventry in the United Kingdom.[9] The patient was a man of Indian origin who had visited India 18 months previously, where he had undergone dialysis. In initial assays the bacteria was fully resistant to all antibiotics tested, while later tests found that it was susceptible to tigecycline and colistin. The authors warned that international travel and patients' use of multiple countries' healthcare systems could lead to the "rapid spread of NDM-1 with potentially serious consequences".

As of June 2010, there were three reported cases of Enterobacteriaceae isolates bearing this newly described resistance mechanism in the US, the CDC stated that "All three U.S. isolates were from patients who received recent medical care in India."[10] However, US experts have stated that it is unclear if this strain is any more dangerous than existing antibiotic-resistant bacteria such as methicillin-resistant Staphylococcus aureus, which are already common in the USA.[11]

File:Colistin structure.svg
Structure of colistin, one of the few antibiotics able to treat NDM-1 positive bacterial infections.

In July 2010 a team in New Deli reported a cluster of three cases of Acinetobacter baumannii bearing blaNDM-1 that were found in the intensive care unit of a hospital in Chennai, India in April 2010. As previously, the bacteria were fully resistant to all the aminoglycoside β-lactam and quinolone antibiotics, but were susceptible to tigecycline and colistin. This particularly broad spectrum of antibiotic resistance was heightened by the strain bearing expressing several different resistance genes in addition to blaNDM-1.[12]

A study by a multi-national team was published in the August 2010 issue of the journal The Lancet Infectious Diseases. This examined the emergence and spread of bacteria carrying the blaNDM-1 gene. This reported on 37 cases in the United Kingdom, 44 isolates with NDM-1 in Chennai, 26 in Haryana and 73 in various other sites in Pakistan and India.[1] The authors' analysis of the strains showed that many carried blaNDM-1 on plasmids, which will allow the gene to be readily transferred between different strains of bacteria by horizontal gene transfer. All the isolates were resistant to multiple different classes of antibiotics, including beta-lactam antibiotics, fluoroquinolones, and aminoglycosides, but most were still susceptible to the polymyxin antibiotic colistin.

In early August 2010 a chemical compound, GSK-299423, was found to significantly fight against antibiotic-resistant bacteria by making such bacteria unable to reproduce, citing a likely treatment to the NDM-1 strain.[13][14][15][16]

Indian response

The Indian health ministry has disputed the conclusion of the August 2010 Lancet study that the gene originated in India or Pakistan, describing this conclusion as "unfair" and stating that Indian hospitals are perfectly safe for treatment.[17] Indian politicians have described linking this new drug resistance gene to India as “malicious propaganda” and blamed multinational corporations for what they describe as selective malignancy.[17][18] A Bharatiya Janata Party politician has instead argued that the journal article is bogus and represented an attempt to scare medical tourists away from India.[19] The Indian Ministry of Health released a statement "strongly refut[ing]" naming the enzyme "New Delhi".[20] The primary author of the 2010 Lancet study, who is based in the University of Madras, has stated that he does not agree with the part of the article that advises people to avoid elective surgeries in India.[21]

In contrast, an editorial in the March 2010 issue of the Journal of Association of Physicians of India blamed the emergence of this gene on the widespread misuse of antibiotics in the Indian healthcare system, stating that Indian doctors have "not yet taken the issue of antibiotic resistance seriously" and noting little control over the prescription of antibiotics by doctors and even pharmacists.[22] The Times of India states that there is general agreement among experts that India needs both an improved policy to control the use of antibiotics and a central registry of antibiotic-resistant infections.[21]

See also

References

  1. ^ a b Kumarasamy; et al. (2010). "Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study". The Lancet Infectious Diseases. doi:10.1016/S1473-3099(10)70143-2. {{cite journal}}: Cite has empty unknown parameter: |month= (help); Explicit use of et al. in: |author= (help)
  2. ^ "Health Protection Report". health protection Agency. 3 July 2009.
  3. ^ Queenan AM, Bush K (2007). "Carbapenemases: the versatile beta-lactamases". Clin. Microbiol. Rev. 20 (3): 440–58, table of contents. doi:10.1128/CMR.00001-07. PMC 1932750. PMID 17630334. {{cite journal}}: Unknown parameter |month= ignored (help)
  4. ^ Miriagou V, Cornaglia G, Edelstein M; et al. (2010). "Acquired carbapenemases in Gram-negative bacterial pathogens: detection and surveillance issues". Clin. Microbiol. Infect. 16 (2): 112–22. doi:10.1111/j.1469-0691.2009.03116.x. PMID 20085605. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ Nordmann P, Cuzon G, Naas T (2009). "The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria". Lancet Infect Dis. 9 (4): 228–36. doi:10.1016/S1473-3099(09)70054-4. PMID 19324295. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ Cuzon G, Naas T, Nordmann P (2010 Feb). Pathol Biol (Paris) (in French). 58 (1): 39–45. PMID 19854586. {{cite journal}}: Check date values in: |date= (help); Missing or empty |title= (help); Unknown parameter |trans_title= ignored (|trans-title= suggested) (help)CS1 maint: multiple names: authors list (link)
  7. ^ a b Yong D, Toleman MA, Giske CG, Cho HS, Sundman K, Lee K, Walsh TR. (2009). "Characterization of a new metallo-beta-lactamase gene, bla(NDM-1), and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India". Antimicrob Agents Chemother. 53 (12): 5046–54. doi:10.1128/AAC.00774-09. PMC 2786356. PMID 19770275. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Deshpande Payal, Rodrigues Camilla, Shetty Anjali, Kapadia Farhad, Hedge Ashit, Soman Rajeev (2010). "New Delhi Metallo-β lactamase (NDM-1) in Enterobacteriaceae: Treatment options with Carbapenems Compromised". Journal of Association of Physicians of India. 58: 147–150.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Muir A, Weinbren MJ (2010). "New Delhi metallo-beta-lactamase: a cautionary tale". J. Hosp. Infect. 75 (3): 239–40. doi:10.1016/j.jhin.2010.02.005. PMID 20435372. {{cite journal}}: Unknown parameter |month= ignored (help)
  10. ^ Detection of Enterobacteriaceae Isolates Carrying Metallo-Beta-Lactamase --- United States, 2010
  11. ^ McNeil Jr., Donald G. (11 August 2010). "Antibiotic-Resistant Bacteria Moving From South Asia to U.S." The New York Times. Retrieved 13 August 2010.
  12. ^ Karthikeyan K, Thirunarayan MA, Krishnan P (2010). "Coexistence of blaOXA-23 with blaNDM-1 and armA in clinical isolates of Acinetobacter baumannii from India". J Antimicrob Chemother. doi:10.1093/jac/dkq273. PMID 20650909. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ http://www.fiercebiotech.com/story/299423-gsk-cites-progress-new-gen-antibiotic/2010-08-05
  14. ^ Bax BD; et al. (4 August 2010). "Type IIA topoisomerase inhibition by a new class of antibacterial agents". Nature. doi:10.1038/nature09197. {{cite journal}}: Explicit use of et al. in: |author= (help) (primary source)
  15. ^ Alazraki, Melly (6 August 2010). "GlaxoSmithKline Finds Compound That Could Help Fight 'Superbugs'". dailyfinance.com. Retrieved 13 August 2010.
  16. ^ http://www.indiastudychannel.com/resources/124111-NDM-Origin-Symtoms-Cure-for-NDM.aspx
  17. ^ a b Pandey, Geeta (12 August 2010). "India rejects UK scientists' 'superbug' claim". BBC News. Retrieved 13 August 2010.
  18. ^ "Linking India to superbug unfair and wrong, says India". Hindustan Times. 12 August 2010. Retrieved 13 August 2010.
  19. ^ http://expressbuzz.com/nation/superbug-an-mnc-conspiracy-bjp-leader/197607.html
  20. ^ Sharma, Sanchita (13 August 2010). "'Don't blame superbug on India, it's everywhere'". Hindustan Times. Retrieved 13 August 2010.
  21. ^ a b Narayan, Pushpa (13 August 2010). "Indian author says superbug report is fudged". The Times of India. Retrieved 13 August 2010.
  22. ^ Abdul Ghafur K (2010). "An obituary- On the Death of antibiotics!". Journal of Association of Physicians of India. 58. {{cite journal}}: Unknown parameter |month= ignored (help)

External links

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