New Delhi metallo-beta-lactamase Dr.T.V.Rao MD
Antibiotic Misuse • Antibiotic misuse, (sometimes called antibiotic abuse or antibiotic overuse) refers to the misuse and overuse of antibiotics which has serious effects on public health. Antibiotic resistant bacteria is a growing threat and becoming increasingly common. This overuse creates multi-antibiotic resistant life threatening infections by "super bugs", sometimes out of relatively harmless bacteria. Antibiotic abuse also places the patient at unnecessary risk of adverse effects of antibiotics.
Superbug. • Antibiotic resistance develops through gene action or plasmid exchange between bacteria of the same species. If a bacterium carries several resistance genes, it is called multiresistant or, informally, a superbug.
Origin of Antibiotic Résistance • The widespread use of antibiotics both inside and outside of medicine is playing a significant role in the emergence of resistant bacteria.
Metallo-beta-lactamase(NDM-1) • ND Metallo-beta-lactamase (NDM-1) is a gene that makes bacteria resistant to antibiotics of the carbapenem family. It encodes a type of beta-lactamase enzyme called a carbapenemase. Bacteria that carry this gene are often referred as "superbugsgene transfer.
NDM-1 • NDM-1 symptoms are reported to be associated with the bacteria it attaches to. The currently known bacteria's hosting this gene are E.Coli and Klebsiella pneumoniae. The majority of the patients treated to date who are positive for NDM-1 were those with urinary tract infections, bacteraemia, or pneumonia NDM-1 is the gene responsible for the newest superbug. NDM-1 genes can live inside different bacteria and is resistant to currently available antibiotics.
New Delhi metallo-beta-lactamase Why everyone concerned ? • There are currently no new drugs in the research pipelines that aim to stop NDM-1.To date, some strains of E.coli and Klebseilla pneumoniae are known carriers of the gene, but the gene can be transmitted from one strain of bacteria to another through horizontal gene transfer.
Naming the strain as New Delhi creates controversy • The gene was named after New Delhi, the capital city of India, as it was first described by Yong et al. in 2009 in a Swedish national who fell ill with an antibiotic-resistant bacterial infection that he acquired in India . 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."
CDC reports Three Enterobacteriaceae isolates carrying a newly described resistance mechanism, the New Delhi metallo-beta-lactamase (NDM-1) , were identified from three U.S. states at the CDC antimicrobial susceptibility laboratory. This is the first report of NDM-1 in the United States, and the first report of metallo-beta-lactamase carriage among Enterobacteriaceae in the United States
Blame on India Is it justified ? • 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."
CDC reports the new genetic mechanisms • The isolate, Klebseilla pneumoniae 05-506, was shown to possess a metallo-beta-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 bla(CMY-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
Genetic origin of the NDM-1 • An intact ISCR1 element was shown to be downstream from the qac/sul genes. The third region consisted of a new MBL gene, designated bla(NDM-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.
Molecular configuration of NDM-1 • 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 beta-lactams except aztreonam. Compared to VIM-2, NDM-1 displays tighter binding to most Cephalosporins.
NDM genetic coding differs from other recent isolates • 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, bla(NDM-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
blaNDM-1 is expressed in... • Isolates, which include an Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae, carry blaNDM-1, which confers resistance to all beta-lactam agents except aztreonam (a monobactam antimicrobial) ; all three isolates were aztreonam resistant, presumably by a different mechanisms.
CLSI guidelines for assessing the antibiograms pattern • All patients colonized or infected with CRE or carbapenemase-producing Enterobacteriaceae should be placed on contact precautions. Acute care facilities should establish a protocol, in conjunction with CLSI guidelines, to detect nonsusceptibility and carbapenemase production in Enterobacteriaceae, particularly Klebseilla spp. and Escherichia coli, and immediately alert epidemiology and infection control staff members if identified
Phenotypic detection with Hodge test a Minimal requirement • Carbapenem resistance and carbapenemase production conferred by blaNDM-1 is detected reliably with phenotypic testing methods currently recommended by the Clinical and Laboratory Standards Institute , including disk diffusion testing and the modified Hodge test
Young and Old are Vulnerable • Young and elderly patients will be particularly susceptible to the 'superbugs', which have emerged recently and are immune to almost all antibiotics
CDC infection control guidance • CDC infection control guidance for carbapenem-resistant Enterobacteriaceae also is appropriate for NDM-1--producing isolates . This includes recognizing carbapenem-resistant Enterobacteriaceae when cultured from clinical specimens, placing patients colonized or infected with these isolates in contact precautions, and in some circumstances, conducting point prevalence surveys or active-surveillance testing among other high-risk patients.
CDC advises • CDC asks that carbapenem-resistant isolates from patients who have received medical care within 6 months in India or Pakistan be forwarded through state public health laboratories to CDC for further characterization. Infection control interventions aimed at preventing transmission, as outlined in current guidance
Are we losing the Value of Carbapenems • Carbapenems are the only antibiotics reliably active against many otherwise multi-resistant gram-negative opportunist bacteria, particularly those with extended-spectrum beta-lactamases (ESBLs) The growing emergence and diversity of carbapenemase producing strains is therefore a major concern.
Do we have options to treat ? • Treatment presents major challenges. Most isolates with NDM-1 enzyme are resistant to all standard intravenous antibiotics for treatment of severe infections
Diagnosis and Isolation of Patients is a priority • All patients colonized or infected with CRE or carbapenemase-producing Enterobacteriaceae should be placed on contact precautions. Acute care facilities should establish a protocol, in conjunction with CLSI guidelines, to detect nonsusceptibility and carbapenemase production in Enterobacteriaceae, particularly Klebseilla spp. and Escherichia coli, and immediately alert epidemiology and infection control staff members if identified.
Surveillance helps effective care to prevent spread • The goal of active surveillance is to identify undetected carriers of carbapenem-resistant or carbapenemase-producing Klebseilla spp.and E. coli. Identification of other cases among patients with epidemiologic links to persons with confirmed infection suggests patient-to-patient transmission ; in such instances, infection prevention measures should be vigorously reinforced, and surveillance cultures repeated periodically (e.g., weekly) until no new cases are identified
Hand hygiene • That early detection through use of targeted surveillance and introduction of strict infection control measures (including reinforcement of hand hygiene and contact precautions) can help control the spread
Sanitation reduces the spread of Strains • Best means of NDM-1 prevention is to provide adequate cleaning and sanitizing of all areas is the best means of preventing further spread of the Those displaying NDM-1 symptoms should insure the areas they are in are sanitized to prevent spread to those around them. Hospitals and doctors are under advise to stay on top of the cleanliness issue.
The spread of NDM-1 can be contained with .. • The spread of NDM-1 within health-care facilities can be curbed through strict infection-control measures, including patient isolation and hand washing.
Modernize the Microbiology Laboratories • India and other Developing countries should strengthen the Role of Medical Microbiologists , the Governments and the other private medical establishments should invest in good infrastructure for effective functioning of Diagnostic Microbiology laboratories.
Voice your Concern • The current event on New Delhi strain has created scientific, political, and economic, concerns to our upcoming Nation. There are much more challenges a ahead to our colleagues. It is time that all New generation of Microbiologists voice our concern to the Health authorities to invest in good Infrastrure to equip our Diagnostic laboratories. Please tell everyone if infections are not controlled no Amount of Medical progress in other branches will sustain for long. Dr.T.V.Rao MD firstname.lastname@example.org
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