Klebsiella pneumoniae, the bacterium in which NDM-1 was first identified. Description: This inoculated MacConkey agar culture plate cultivated colonial growth of Gram-negative, small rod-shaped and facultatively anaerobic Klebsiella pneumoniae bacteria. K. pneumoniae bacteria are commonly found in the human gastrointestinal tract, and are often the cause of hospital acquired, or nosocomial infections involving the urinary and pulmonary systems.

Arrival of the germ in US casts a spotlight on global spread of drug-resistant bacteria

GoogleNews.com, by Stephen Smith, Boston Globe Staff / September 14, 2010 A person infected with a “superbug’’ that is sparking fears around the world was treated earlier this year in a Massachusetts hospital, disease trackers said yesterday. The patient had recently traveled from India, a hot spot for the germ, which is immune to many common antibiotics.

The patient was treated at Massachusetts General Hospital and isolated, a measure that prevented the germ from spreading, said Dr. David Hooper, chief of the hospital’s infection control unit.

“You’ve got to always be vigilant,’’ Hooper said. “We are concerned, not alarmed. With good infection control and following guidelines, they can be held at bay.’’

A medical officer at the US Centers for Disease Control and Prevention said the Massachusetts patient survived, as did the only other two US patients with infections blamed on the superbug, which appears to have been contained.

All three patients developed urinary tract infections that carried a genetic feature that made their cases harder to treat.

Known by the medical shorthand NDM-1 — it stands for New Delhi metallo-beta-lactamase — the gene allows bacteria to escape some of the strongest antibiotics available, a process known as drug resistance.

“It leaves treating physicians with few treatment options,’’ said Dr. Alex Kallen, a CDC officer.

The arrival of NDM-1 in the United States casts a spotlight more widely on the problem of drug-resistant bacteria, which have caused outbreaks in hospitals, gyms, and schools. A germ called MRSA has received the most attention, but it has plenty of company.

“This is just another example of these multidrug-resistant [germs] that we are going to have to come to grips with,’’ said Dr. Alfred DeMaria, top disease tracker for the Massachusetts Department of Public Health.

Global health specialists attending a major meeting of microbiologists and infectious disease doctors in Boston this week said they are particularly concerned about NDM-1 because of its emergence in India.

Antibiotics are cheap and available over the counter in South Asia, specialists said, fueling inappropriate use and, consequently, the development of drug resistance. Poor sanitation can further spread NDM-1, which thrives in germs that proliferate in the gut.

“There are certain factors in the Indian subcontinent that are going to make this spread quite widely,’’ said Timothy Walsh, the Cardiff University scientist who helped discover the germ. “It’s very easy for us to forget in the Western world how desperate the conditions are in some of these countries.’’

The US cases — the other patients were treated in California and Illinois — also illustrate how swiftly germs can spread in an era of jet travel. Scattered cases of NDM-1 infections have been reported elsewhere in Asia, as well as in Europe and Canada.

“ All three of the US patients had been in India, and two — including the person treated at Mass. General — underwent medical procedures in hospitals while they were there, Kallen said. The patient treated in Boston was an Indian citizen with cancer who had undergone surgery and chemotherapy in that country before coming to Massachusetts, the CDC physician said.

Neither of the patients who spent time in Indian hospitals is believed to have traveled to that country as part of medical tourism — the practice of US and European patients going abroad for surgeries that can cost less

Germs with NDM-1 are typically spread through poor hygiene and not by coughing or sneezing, Walsh said. In India, children playing in sewage could be exposed to the superbug.

In the United States, DeMaria said, the threat posed by the germs is most acute in hospitals. “They don’t cause infection in people walking down the street,’’ he said. “If somebody’s in an intensive care unit on a ventilator with a tube in their trachea, they’re at risk for these organisms. If someone has had extensive abdominal surgery with lots of open wounds, they’re at risk.’’

Only two antibiotics possess a measure of effectiveness against bacteria riddled with NDM-1, doctors said: an old drug called colistin and tigecycline.

The paucity of drugs reflects not only the strength of the superbug but also the long-neglected development of new antibiotics.

While compounds are being studied in labs and some are undergoing human testing, scientists and physicians at the Boston meeting, the Interscience Conference on Antimicrobial Agents and Chemotherapy, expressed little hope that the antibiotic medicine cabinet will expand significantly in coming years.

“There’re some antibiotics that have been talked about at this meeting,’’ Walsh said. “Trouble is we’ve got one or two that look promising, and what we need are six to eight to cover our options.’’

Stephen Smith can be reached at stsmith@globe.com.

Increase Your Knowledge of NDM-1

More about NDM-1

New Delhi metallo-beta-lactamase

New Delhi metallo-beta-lactamase (NDM-1) is an enzyme that makes bacteria resistant to a broad range of beta-lactam antibiotics. These include the antibiotics of the carbapenem family, which are a mainstay for the treatment of antibiotic-resistant bacterial infections. The gene for NDM-1 is one member of a large gene family that encodes beta-lactamase enzymes called carbapenemases. Bacteria that produce carbapenemases are often referred to in the news media as “superbugs” because infections caused by them are difficult to treat. Such bacteria are usually only susceptible to polymyxins and tigecycline.

NDM-1 was first identified in December 2009 in a patient hospitalised in New Delhi with an infection caused by Klebsiella pneumoniae. It was later detected in bacteria in India, Pakistan, the United Kingdom, the United States, and Canada. The most common bacteria that make this enzyme are Gram negative such as Escherichia coli and Klebsiella pneumoniae, but the gene for NDM-1 can spread from one strain of bacteria to another by horizontal gene transfer.

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. He died despite being administered colistin, a powerful antibiotic. A doctor involved in his treatment said, “He was involved in a car accident during a trip to Pakistan. He was hospitalized with a major leg injury and then repatriated to Belgium, but he was already infected”.
Enzyme function

Structure of the carbapenem backbone.

Carbapenems are a class of beta-lactam antibiotics which are capable of killing most bacteria by inhibiting the synthesis of one of their cell wall layers. The carbapenems were developed to overcome antibiotic resistance mediated by bacterial beta-lactamase enzymes. However, 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. The NDM-1 enzyme is one of the class B metallo-beta-lactamase; other types of carbapenemase are class A or class D beta-lactamases. (The class A Klebsiella pneumoniae carbapenemase (KPC) is currently the most common carbapenemase, which was first detected in North Carolina, USA, in 1996 and has since spread worldwide. A later publication indicated that Enterobacteriaceae that produce KPC were becoming common in the United States.)

The resistance conferred by this gene (blaNDM-1) 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 of NDM-1
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.

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. 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.” 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.

Structure of colistin, one of the few antibiotics able to treat NDM-1 positive bacterial infections.

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.

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. 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.

On August 21, 2010 Ontario, Canada had its first confirmed case of the “superbug” in Brampton. There have been other confirmed cases in British Columbia and Alberta.

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.

On September 6, 2010 Japan detected its first ever case of the NDM-1 enzyme. In May 2009, a Japanese man in his 50’s who had recently returned from holidaying in India was struck with a fever and hospitalized, later making a full recovery. Hospital officials have confirmed that tests carried out after the patients recovery were positive for the NDM-1 enzyme.

Response From India
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. 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. 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. The Indian Ministry of Health released a statement “strongly refuting” 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.

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.

More about NDM-1………

MedicalNewsToday.com, September 14, 2010 — NDM-1, which stands for New Delhi metallo-beta-lactamase-1 is a gene (DNA code) carried by some bacteria. If a bacteria strain carries the NDM-1 gene it is resistant to nearly all antibiotics, including carbapenem antibiotics – also known as antibiotics of last resort.

Carbepenems are the most powerful antibiotics, used as a last resort for many bacterial infections, such as E. coli and Klebsiella. The NDM-1 gene makes the bacterium produce an enzyme which neutralizes the activity of carbepenem antibiotics.

A bacterium carrying the NDM-1 gene is the most powerful superbug around.

Put simply:

  • NDM-1(New Delhi metallo-ß-lactamase-1) is the gene (the DNA code) found in some types of bacteria
  • This gene makes the bacteria produce an enzyme called a carbapenemase – making carbepenem antibiotics ineffective (as well as virtually all other antibiotics).
  • Carbepenem antibiotics are extremely powerful and used to fight highly resistant bacteria (when other antibiotics have not worked).
  • There are no current antibiotics to combat NDM-1
  • There is no research in the pipeline on drugs to combat NDM-1
  • A bacterium with the NDM-1 DNA code has the potential to be resistant to all our current antibiotics, as well as new antibiotics which may come into the market in the near future.

The DNA code can easily jump from one bacteria strain to another through horizontal gene transfer. IF NDM-1 jumps to an already antibiotic-resistant bacterium, there is a risk of seriously dangerous infections which would spread rapidly from human-to-human. These infections might be untreatable.

UK doctors say they had only ever seen a few cases which are resistant to carbapenems – and these had not been able to transfer resistance to other bacteria. The fact that NDM-1 can easily transfer to different bacteria strains is very worrying, they say.

Currently (12 August 2010) we know that some strains of bacteria, such as E. coli and Klebsiella pneumoniae carry the NDM-1 gene.

The origin of NDM-1
The gene was discovered by Young and team and was named after New Delhi, the Indian capital. The gene is widespread in India and Pakistan, especially in hospitals.

Europeans who have undergone hospitalization in the Indian subcontinent have brought NDM-1 back to Europe. A significant number of Europeans who brought the gene back to Europe had undergone cosmetic surgery in India/Pakistan because it is cheaper there.
How untreatable is this superbug?
So far, doctors in the UK have managed to fight these infections with a combination of several different medications. However, scientists have detected some bacterial strains that are resistant to ALL antibiotics.

The only way to currently combat the spread of NDM-1 is through surveillance, prompt identification and isolation of infected patients, disinfecting hospital equipment, and thorough hand-hygiene procedures in hospitals. This is going to be a challenge and will require international cooperation.

Reason to Avoid Medical Tourism

NDM-1 Superbug Sends Shockwaves of Fear Across the Globe

GoogleNews.com, September 14, 2010 — Cheaper is not always better.

Patients looking for lower cost surgery often turn to countries like India and Pakistan to get it. But some come home with results they hadn’t expected.

We’re not talking about botched cosmetic surgery, although that happens. What some patients have been coming back with lately is even worse: A newly mutated gene that’s resistant to currently available antibiotics.

Dubbed NDM-1, this newest Superbug has a lot of people worried. NDM-1 is short for New Delhi metallo-beta-lactamase and so far it’s been identified in patients in the U.S., Britain, South Asia, Canada, the Netherlands, India and Australia. Several of the infections can be traced back to India, Pakistan and Bangladesh where infected individuals had recently traveled to receive medical care.

The fact that the NDM-1 Superbug is resistant to most of the known antibiotics is a huge concern. But it’s just one of the troublesome issues. The other concern is that, although no deaths have been officially reported, people may be dying from exposure to NDM-1.Health officials don’t believe for a moment that a lack of officially documented cases means NDM-1 hasn’t caused any deaths.

They believe that if people visiting India, Pakistan and Bangladesh have been infected, it’s likely that large numbers of people living there are also being infected. They believe it’s possible that some have even died as a result.

Poverty makes monitoring the death rate in developing countries difficult. The sad and unfortunate truth is that poor people living in developing countries die all the time and their deaths often go unnoticed. When they’re not noticed by anyone but family, those deaths usually aren’t investigated. How many deaths will ultimately be attributed to NDM-1 might never be known because of poor record-keeping.

After decades of debate, the Food and Drug Administration appears poised to issue stronger rules on antibiotics, intended to reduce what it calls a clear risk to humans.  The questions over antibiotics come at a time when animal confinement methods and other aspects of so-called factory farming are also under attack.  At Elite Pork, a large pork farm in Ralson, Iowa, pigs are fed antibiotics for weeks after weaning to ward off possible illness.

Brian C. Frank for The New York Times

The New York Times, by Erik Eckholm, September 14, 2010  —  RALSTON, Iowa — Piglets hop, scurry and squeal their way to the far corner of the pen, eyeing an approaching human. “It shows that they’re healthy animals,” Craig Rowles, the owner of a large pork farm here, said with pride.

Mr. Rowles says he keeps his pigs fit by feeding them antibiotics for weeks after weaning, to ward off possible illness in that vulnerable period. And for months after that, he administers an antibiotic that promotes faster growth with less feed.

Dispensing antibiotics to healthy animals is routine on the large, concentrated farms that now dominate American agriculture. But the practice is increasingly condemned by medical experts who say it contributes to a growing scourge of modern medicine: the emergence of antibiotic-resistant bacteria, including dangerous E. coli strains that account for millions of bladder infections each year, as well as resistant types of salmonella and other microbes.

Now, after decades of debate, the Food and Drug Administration appears poised to issue its strongest guidelines on animal antibiotics yet, intended to reduce what it calls a clear risk to human health. They would end farm uses of the drugs simply to promote faster animal growth and call for tighter oversight by veterinarians.

The agency’s final version is expected within months, and comes at a time when animal confinement methods, safety monitoring and other aspects of so-called factory farming are also under sharp attack. The federal proposal has struck a nerve among major livestock producers, who argue that a direct link between farms and human illness has not been proved. The producers are vigorously opposing it even as many medical and health experts call it too timid.

Scores of scientific groups, including the American Medical Association and the Infectious Diseases Society of America, are calling for even stronger action that would bar most uses of key antibiotics in healthy animals, including use for disease prevention, as with Mr. Rowles’s piglets. Such a bill is gaining traction in Congress.

“Is producing the cheapest food in the world our only goal?” asked Dr. Gail R. Hansen, a veterinarian and senior officer of the Pew Charitable Trusts, which has campaigned for new limits on farm drugs. “Those who say there is no evidence of risk are discounting 40 years of science. To wait until there’s nothing we can do about it doesn’t seem like the wisest course.”

With the backing of some leading veterinary scientists, farmers assert that the risks are remote and are outweighed by improved animal health and lower food costs. “There is no conclusive scientific evidence that antibiotics used in food animals have a significant impact on the effectiveness of antibiotics in people,” the National Pork Producers Council said.

But leading medical experts say the threat is real and growing. Proponents of strong controls note that the European Union barred most nontreatment uses of antibiotics in 2006 and that farmers there have adapted without major costs. Following a similar path in the United States, they argue, would have barely perceptible effects on consumer prices.

Resistance can evolve whenever drugs are used against bacteria or other microbes because substrains that are less susceptible to the treatment will survive and multiply.

Drug use in humans, including overuse and misapplication, clearly accounts for a large share of the surge in antibiotic resistant infections, a huge problem in hospitals in particular. Yet biologists and infectious disease specialists say there is also enormous circumstantial and genetic evidence that antibiotics in farming are adding to the threat.

Livestock and poultry have been identified as the most likely sources of drug-resistant strains of microbes like salmonella and campylobacter that have caused outbreaks of severe intestinal illness in people and of E. coli strains that cause serious bladder, blood and other infections. (Resistant strains have not been implicated in the recent outbreak of salmonella contamination in eggs.)

In a letter to Congress in July, Dr. Thomas R. Frieden, director of the Centers for Disease Control and Prevention, cited “compelling evidence” of a “clear link between antibiotic use in animals and antibiotic resistance in humans.”

As drug-resistant strains of microbes evolve on the farms, they are passed along in meat sold in grocery stores. They can infect people as they handle the uncooked product or when eating, if cooking is not thorough. The dangerous strains can also enter the environment via manure or the clothes of farm workers.

Genetic studies of drug-resistant E. coli strains found on poultry and beef in grocery stores and strains in sick patients have found them to be virtually identical, and further evidence also indicated that the resistant microbes evolved on farms and were transferred to consumers, said Dr. James R. Johnson, an infectious-disease expert at the University of Minnesota. Hospitals now find that up to 30 percent of urinary infections do not respond to the front-line treatments, ciprofloxacin and the drug known as Bactrim or Septra, and that resistance to key newer antibiotics is also emerging. E. coli is also implicated in serious blood, brain and other infections.

“For those of us in the public health community, the evidence is unambiguously clear,” Dr. Johnson said. “Most of the E. coli resistance in humans can be traced to food-animal sources.”

The proposed Food and Drug Administration guidelines focus on the use of antibiotics to speed growth. Just how antibiotics have this effect, which has been known for decades, is unclear, but scientists suspect that the drugs improve the absorption of nutrients as they prevent low-grade disease.

Mr. Rowles, the proprietor of Elite Pork and a trained veterinarian himself, estimates that by feeding his pigs an antibiotic in their final months he is saving $1 to $3 per animal in feed costs. For the consumer, this is negligible, but from his perspective it looms larger because, he said, in good years his net profit is only $7 to $10 per animal.

More contentious is the routine use of antibiotics to prevent disease, as Mr. Rowles and other pork producers do with newly weaned pigs.

Dr. James McKean, an extension veterinarian at Iowa State University, said experience in Denmark, Europe’s leading pork producer, showed that ending the practice would result in more illness, suffering and death among pigs, and cause a jump in antibiotic treatments of actual disease.

Dr. McKean estimated that a ban on most nontreatment uses of antibiotics would raise the cost of pork by 5 cents a pound.

Others counter that farmers in Denmark have learned to hold down illness in young pigs by extending the weaning period, altering feeds and providing more space and veterinary scrutiny of the animals. Some of the drugs used in prevention by farmers like Mr. Rowles would also be permitted under the measure before Congress because they are not used in human medicine.

“In the end, the producers will do what is right,” Mr. Rowles said. “We will make sure we deliver a product that meets the needs of consumers.”

“My only concern is that we make decisions in a scientific fashion, not a political fashion,” he said.