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Ab resistance , Carbapenemases & NDM-1 : 

Ab resistance , Carbapenemases & NDM-1 Prepared by : Belal A El-Dabour Supervision : Dr.Abdelraouf El-Manama

Antibiotic Misuse : 

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.

Slide 3: 

Penicillinase was the first β-lactamase to be identified: it was first isolated by Abraham and Chain in 1940 from Gram-negative E. coli. Superbugs produce ESBL which stands for Extended Spectrum Beta-Lactamase, enzymes that have developed a resistance to antibiotics like penicillin. They mediate resistance to extended-spectrum (third generation) cephalosporins (eg. ceftazidime, cefotaxime, and ceftriaxone) and monobactams (eg. aztreonam) but do not affect cephamycins (eg. cefoxitin and cefotetan) or carbapenems (eg. meropenem or imipenem).

Slide 4: 

The ESBLs are frequently plasmid encoded. Plasmids responsible for ESBL production frequently carry genes encoding resistance to other drug classes (for example, aminoglycosides). Therefore, antibiotic options in the treatment of ESBL-producing organisms are extremely limited. The carbapenems were developed to overcome antibiotic resistance mediated by bacterial beta-lactamase enzymes. Carbapenems are famously stable to β-lactamases and extended-spectrum-β-lactamases. Carbapenems are the treatment of choice for serious infections due to ESBL-producing organisms, yet carbapenem-resistant isolates have recently been reported.

Slide 5: 

Carbapenems are the most powerful antibiotics known, since they are able to contain such a diverse array of bacterial infections. They are usually saved for use as a measure of last resort, so as not to encourage the development of resistance against them. Such antibiotics are typically administered intravenously in hospitals. This class of antibiotics is able to kill most bacteria that produce beta-lactamase inhibitors, because its structure is slightly different than the other classes of beta-lactam antibiotics.

Slide 6: 

New strains of enteric bacteria have developed, however, that do carry a resistance gene that enables them to degrade the beta-lactams of carbapenems. they are mostly Enterobacteriaceae, they can also be, rarely, Pseudomonas aeruginosa isolates. Carbapenemases are a diverse group of b-lactamases that are active not only against carbapenems but also against all b-lactam drugs except for Aztreonam. Many are members of Metallo B-lactamases family. (Class C)

Carbapenemases : 

Carbapenemases Aztreonam is stable to the metallo-β-lactamases but many IMP and VIM producers are resistant, owing to other mechanisms. IMP-type carbapenemases : 17 varieties of which are currently known, became established in Japan in the 1990s. VIM (Verona integron-encoded metallo-β-lactamase) was reported from Italy in 1999 and now includes 10 members. KPC (K. pneumoniae carbapenemase) (Class A): currently the most common carbapenemase, which was first detected in North Carolina, USA, in 1996 and has since spread worldwide. NDM-1 (New Delhi metallo-β-lactamase).


!!SUPER “SUPERBUGS" Such bacteria are usually only susceptible to polymyxins and tigecycline. The most common bacteria that make this enzyme are Gram negative such as Escherichia coli , Klebsiella pneumoniae, and Acinetobacter

What is NDM-1? : 

What is NDM-1? NDM-1 stands for New Delhi metallo-beta-lactamase, which is an enzyme produced by certain strains of bacteria that have recently acquired the genetic ability to make this compound. The enzyme is active against other compounds that contain a chemical structure known as a beta-lactam ring. Unfortunately, many antibiotics contain this ring, including the penicillins, cephalosporins, and the carbapenems. bacteria that produce NDM-1 are resistant to all commonly used beta-lactam antibiotics, including carbapenems.

Slide 10: 

Some antibiotics like aminoglycosides and fluoroquinolones do not contain beta-lactam rings. Unfortunately, the bacteria that have acquired NDM-1 have also acquired other resistance factors and most are already resistant to aminoglycosides and fluoroquinolones. The addition of NDM-1 production has the ability to turn these bacteria into true superbugs (bacteria resistant to usually two or more antibiotics) which are resistant to virtually all commonly used antibiotics.

Origin and spread : 

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. 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. In March 2010 a study in a hospital in Mumbai found that most carbapenem-resistant bacteria isolated from patients carried the blaNDM-1 gene.

Slide 12: 

In May 2010, a case of infection with E. coli expressing NDM-1 was reported in Coventry in the United Kingdom. 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. As of June 2010, there were three reported cases of Enterobacteriaceae isolates bearing this newly described resistance mechanism in the US, the Centers for Disease Control and Prevention (CDC) stated that "All three U.S. isolates were from patients who received recent medical care in India.“ In July 2010, a team in New Delhi 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.

First death : 

First death In August 2010, the first reported death due to a bacteria expressing the NDM-1 enzyme was recorded as a Belgian man who had become infected while being treated in a hospital in Pakistan.

The Lancet Infectious Diseases : 

The Lancet Infectious Diseases A study by a multi-national team was published in the August 2010 eported 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. 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.

Molecular : 

Molecular The gene that encodes for NDM-1 is called blaNDM-1 and has been identified on bacterial chromosomes and plasmids. Cases of NDM-1 infection are usually caused by gram negative bacteria from the Enterobacteriaceae family. To date, strains of Klebsiella, Escherichia, and Acinetobacter genera of bacteria are known to possess the gene for NDM-1.

Slide 16: 

NDM-1 was found in a cluster of genes that is easily transferable to recipient strains and that confers resistance to all antibiotics except fluoroquinolones and colistin. hydrolyze all beta-lactams except aztreonam. 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. Compared to VIM-2, NDM-1 displays tighter binding to most Cephalosporins.

infection with NDM-1 producing bacteria : 

infection with NDM-1 producing bacteria

Slide 19: 

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. Symptoms do not differ between bacteria that express NDM-1 and those that do not. However, patients who have bacteria producing NDM-1 will not respond to most conventional antibiotics and are at high risk for complications.

New Delhi metallo-beta-lactamase Why everyone concerned ? : 

New Delhi metallo-beta-lactamase Why everyone concerned ?

Slide 21: 

NDM-1 is a newly identified problem, only recognized since about December 2009 in the medical literature. To date, there have fewer than 100 cases identified outside of the Indian subcontinent, so this is not a pandemic like bird flu or swine flu. However, the number of cases is growing and the concern is that these highly resistant bacteria could supplant more antibiotic-sensitive strains.

Slide 22: 

There are currently no new drugs in the research pipelines that aim to stop NDM-1. NDM-1 is very efficient and is associated with resistance to other Abs. 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.

Slide 23: 

Infection experts are alarmed about the spread of multi-drug resistance facilitated by the gene NDM-1 that can easily jump from one strain of bacteria to another. If it ends up in a bacterium which is already resistant to many other antibiotics then it could produce infections that are almost impossible to treat. If this happens, the antibiotic arsenal that has been built up over the last 80 years will be seriously compromised.

How are bacteria that produce NDM-1 identified? : 

How are bacteria that produce NDM-1 identified? Strains that produce NDM-1 will show resistance to penicillins, cephalosporins, and carbapenems. Because carbapenem resistance is still relatively rare, resistance to these agents should raise suspicion of NDM-1, although not all of these resistant strains will be NDM-1 strains. If the patient has recently been to an area where NDM-1 is common, like India or Pakistan, this increases the probability that the strain is producing NDM-1.

What is the treatment for an infection caused by bacteria that make NDM-1? : 

What is the treatment for an infection caused by bacteria that make NDM-1?

Slide 26: 

Treatment is guided by the antibiotic resistance pattern. Many NDM-1 strains are resistant to all antibiotics except for colistin. Colistin is an older antibiotic that has not been used much in recent decades, because it is somewhat more toxic than other antibiotics. A few NDM-1 strains have been sensitive to tigecycline (Tygacil), but this agent should be used cautiously in serious infections because it does not achieve high levels in the bloodstream. A few strains have also been sensitive to aztreonam

What is the prognosis for a person infected with NDM-1 producing bacteria? : 

What is the prognosis for a person infected with NDM-1 producing bacteria? NDM-1 infections can be successfully treated if they are identified early and if colistin or other appropriate agents are used promptly. antibiotic sensitivity testing is standard in clinical laboratories and can be used to identify carbapenem-resistant strains and to guide antibiotic therapy. However, antibiotic sensitivity testing usually takes two days because the bacteria must be cultured in the laboratory , which delays the treatment and complicates the patient’s condition.



Prevention : 

Prevention The risk of person-to-person spread of NDM-1 infection can be reduced by practicing good hand hygiene. This includes washing or disinfecting hands after using the bathroom and before preparing food. In hospitals, patients with suspected NDM-1 infections should be placed in a private room and cover gowns and gloves should be used by health-care personnel. Other barrier methods should be used if contamination is likely (for example, eye protection if splashing is possible). Hospitals should ensure that their laboratories are equipped to test for carbapenem resistance and hospital infection-control programs should review resistance patterns regularly.

Slide 30: 

To reduce the risk that NDM-1 will develop in bacteria, it is important to use existing antibiotics wisely. Carbapenem antibiotics should only be used when bacteria are resistant to older agents. Antibiotics should always be dosed appropriately.


IS INDIA REALLY RESPONSIBLE ? The Indian health ministry has disputed the conclusion of the August 2010 Lancet study that the gene originated in India, describing this conclusion as "unfair" and stating that Indian hospitals are perfectly safe for treatment. 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 The Indian Ministry of Health released a statement "strongly refut[ing]" naming the enzyme "New Delhi”. 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.


HOWEVER, 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. 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.


THE LANCET APOLOGY .. On January 12th 2011, the editor of The Lancet, Richard Horton apologized and acknowledged that naming a superbug after New Delhi was an “error”.