Journalist and Author
In all the latest bad news about bacteria becoming highly resistant — through carbapenem resistance, or the “Indian supergene” NDM-1 — there has been one hopeful thread: All of the organisms have remained susceptible to one very old, little-used drug called colistin.
That might be about to change. Which would be very, very bad news.
File under: Really not good news.
Deep in the back of the weekly bulletin of the Centers for Disease Control and Prevention, there is a note that NDM-1, the “Indian supergene,” has been isolated from a patient in a U.S. military field hospital in Bagram, Afghanistan.
It’s been a few months since NDM-1 was in the news, so let’s recap. The acronym (for “New Delhi metallo-beta-lactamase 1”) indicates an enzyme that allows common gut bacteria to denature almost all the drugs that can be used against them, leaving two or three that are inefficient or toxic. It was first identified in a resident of Sweden, of Indian origin, who had returned to India for a visit, was hospitalized there, went back to Sweden, and was hospitalized again.
Last fall, not long after the bloom of news about the “Indian superbug” NDM-1 — a newly identified enzyme that renders common gut bacteria indifferent to almost all antibiotics — I spoke to one of its lead researchers, Timothy Walsh of the University of Cardiff, about next steps in their research.
His work and his collaborators’ had demonstrated that many of the people infected with or carrying bacteria that incorporated the gene had undergone medical treatment in India and Pakistan, sometimes for elective surgery such as medical tourism, sometimes because they had been injured or ill while traveling. But not all, he said — and that was making them wonder whether the spread of NDM-1 had an environmental component. It was a plausible hypothesis given the apparent concentration of NDM-1 in India, a country whose sanitation systems have not kept up with its booming population. A recent UN report estimated that almost half of India’s residents — that would be up to 650 million people — lack treated drinking water and modern toilets. If you sat down to design a system to facilitate the spread of an enzyme carried by bacteria in the gut — that is, in feces — you couldn’t do better than what India already has.
“There has been very little work done or analysis done on the effect that (poor sanitation) would have on the spread of resistance and on carriage of NDM-1 within a normal population,” Walsh told me at the time. “There’s no water sampling for fecal flora or antibiotic-resistant flora.”
Well, now there is: Walsh and his collaborators have done it. And the news, as they suspected, is bad. [Read more…]
So it looks like the researchers who named NDM-1 — New Delhi metallo-beta-lactamase, the “Indian super-enzyme” that renders common gut bacteria impervious to all but one or two antibiotics — were right all along.
According to a study just published in Antimicrobial Agents and Chemotherapy, the problematic gene that produces it has been circulating in Indian hospitals since at least 2006.
Kinda undermines the claims by Indian politicians and the country’s health ministry that the resistance factor did not originate in India, but was given its name in an act of “malicious propaganda” aimed at undermining the subcontinent’s multimillion-dollar medical-tourism industry.
A brief recap: [Read more…]
Yesterday and today are early-publication days for the December issue of Emerging Infectious Diseases, the free peer-reviewed journal published by the Centers for Disease Control and Prevention. (Are you reading it? Why not? Your tax dollars pay for it. Go, now.) Among many interesting stories — more on those in later posts — there are two important, complex and saddening papers updating the relentless spread of the “Indian supergene,” New Delhi metallo-beta-lactamase or NDM-1.
(Pause for commentary: I hope we’ve put to rest by now the canard that naming this gene after New Delhi indicates some secret agenda to inflict stigma on the subcontinent’s burgeoning medical-tourism industry. It is a long-standing convention that the acquired metallo-beta-lactamases are named for their point of origin: Holland, Singapore, Germany, et al. You don’t see Vienna complaining, do you? ‘Nuf said.)
A brief recap, for those who spent August focused on something more interesting that bacterial resistance: NDM-1 is a gene that produces an enzyme that confers resistance on gram-negative bacteria to almost all the drugs used to treat them. The American Type Culture Collection, which sells isolates for research, recently published the table of resistance results, and it’s phenomenal: All Rs, all the way down. It was first identified in 2008 in a native of India, resident in Sweden, who had been hospitalized while on a visit back home; then found in the UK in 2009; and then found in the US in June this year. It renders bacteria that are common causes of hospital-acquired infections — Klebsiella, Acinetobacter, E. coli — resistant to all but one or two drugs. It’s extremely bad news. (My NDM-1 posts are here.)
It’s been clear since 2009 that NDM-1 is spreading around the world with great speed. The newest papers in EID confirm that and fill in the details — and wow, some of them are so sad.
The subcontinent can cease fretting over the naming of that new bacterial resistance factor NDM, for New Delhi. There’s a newer resistance factor in town, and this one stigmatizes… Italy.
Welcome, Verona integron-encoded metallo-beta-lactamase, or VIM.
To be precise, VIM isn’t new — its very first identification was at the Verona University Hospital in 1999 — but it has just been found in the United States for the first time. The CDC said Wednesday evening that it has identified VIM in an American woman who took a Mediterranean cruise this summer, got diarrhea, was hospitalized (twice) in Greece, developed sepsis and C. diff, and eventually was transferred home and hospitalized here for a further 26 days. In the US, she was found to be infected with Klebsiella pneumoniae, a gram-negative bacterium that’s a common cause of serious-hospital acquired infections — urinary tract infections, abdominal infections and pneumonias. This strain, though, was resistant to all the drugs usually used to treat Klebsiella. (The woman did recover.)
To anyone who followed the NDM-1 news a few weeks ago, this should sound familiar. (If you didn’t, here’s my archive. No, go ahead; we’ll wait.) A resident of one country is unexpectedly hospitalized in another. That second country happens to have high rates of a novel, serious resistance factor — in Greece, 50 percent of Klebsiella isolates in ICUs are multi-drug resistant — that clusters in the organisms most likely to cause hospital infections. The person picks up a resistant infection without knowing it, travels home, and transports the novel resistance factor into his or her home country.
And because the gene that directs production of the problematic enzyme resides on a mobile genetic element — meaning it can move easily from one bacterium or species to another — the public health authorities in the unlucky person’s home country begin a very nervous waiting game.
That’s what happened with the identification of NDM-1, which was first noted in a man of South Asian origin, living in Sweden, who was unexpectedly hospitalized in India in 2007 and then hospitalized again in Sweden in 2008. (NDM was found in the US in June.) Like NDM, VIM has spread across the world; within a few years of its original identification it was in France, Spain and Taiwan. Nor are those two enzymes the only bad actors — they’re merely the most recent and notable in successive waves of multi-drug resistance in gram-negative organisms that are washing across the world. (Almost all of them, by the way, are named for their points of origin. GIM, Germany. SPM, Sao Paolo. DIM, Dutch. And so on.)
And those waves (to torture my metaphor until it whimpers) are really just the most visible points of an ocean of gram-negative resistance that has flooded the globe, and certainly the US. And, just to slosh home the point: These resistance mechanisms knock out the drugs of last resort for gram-negatives, the carbepenems, and there are no new drugs to replace them. The drug-development pipeline for gram-positives such as MRSA has a few drops still rolling down it; the pipeline for gram-negatives, as the Infectious Diseases Society of America has documented in several reports, has just about dripped dry.
The CDC on Thursday warned labs and hospitals to start taking action, in ways that will at least require additional staff time and attention, and probably will cost extra money too :
Cases of (carbepenem-resistant Enterobacteriaceae) are a significant, emerging public health problem regardless of the mechanism of carbapenem resistance, and procedures to rapidly recognize and report CRE cases to infection prevention personnel should be in place in all acute and long-term–care facilities. Facilities that have not identified cases of CRE should undertake periodic laboratory reviews to identify cases. Patients with CRE should be managed using contact precautions, and patients exposed to CRE patients (e.g., roommates) should be screened.
The problem with writing about increases in antimicrobial resistance is that, sooner or later, you inevitably end up sounding like Chicken Little. (Or Cassandra. I’m not sure which is worse. Chicken Little is probably cuter.) Every one of these sounds like the worst possible news. Problem is, every one of them is… until the next one comes along.
Image of Klebsiella pneumoniae courtesy of the Public Health Image Library, CDC.
Just about a month ago, the disease-geek world was riveted by news of the “Indian superbug“: common bacteria carrying a newly recognized gene that confers profound multi-drug resistance, and that was linked to travel between Europe and South Asia, especially for medical tourism.
The gene, which directs production of an enzyme called NDM-1 for short, was briefly Bug of the Week, the spur for alarmist headlines in every Internet echo chamber and the target of denunciations by Indian politicians, who vilified the discovery as a Western “pharma conspiracy” spurred by envy of lucrative medical tourism.
And then, just as quickly as it popped into public consciousness, NDM-1 slid back under the news-radar horizon.
Or so it seemed. Researchers though remain deeply concerned about NDM-1, along with a wider array of dire resistance factors of which it has suddenly become the best-known. This week, I’m at ICAAC (the annual Interscience Conference on Antimicrobial Agents and Chemotherapy), an enormous 12,000-person meeting focused on infectious diseases and the drugs to treat them, and talk of NDM-1 is everywhere.
The news is not good. This new resistance factor has been found so far in the United States, Canada, Belgium, the Netherlands, Austria, France, Germany, Oman, Kenya, Australia, Hong Kong and Japan. Most of the isolates, the bacterial samples in which it has been identified, are susceptible to only one or two remaining antibiotics. One was susceptible to none.
“These resistant bugs,” Dr. Patrice Nordmann, a professor of clinical microbiology at the South-Paris Medical School, said in a briefing here, “have already spread all over the world.”
A brief recap:
NDM-1 was first spotted in 2008, in a 59-year-old man of South Asian origin who lived in Sweden. He was hospitalized on a visit home to New Delhi, had surgery, recovered, went back to Sweden and was hospitalized there again. At that point, physicians recognized that he had a urinary tract infection that was unusually drug-resistant. The infection was caused by a common bacterium, Klebsiella pneumoniae, but the Klebsiella possessed an unusual and worrisome ability to disable carbapenems, a class of drugs given for very resistant infections. They named the enzyme and the gene directing its production for the place where the man had apparently acquired it: New Delhi metallo-beta-lactamase, and blaNDM.
In 2009, the United Kingdom’s public-health agency sent out an alert saying the same resistance mechanism was appearing there and increasing rapidly, going from unknown in 2007 to 18 instances in the first half of 2009, most of them in people who had gone to India for medical care or had frequent family travel back and forth. In June this year, the US Centers for Disease Control and Prevention put out a bulletin about NDM-1’s first US appearance, in three patients in three different states (California, Massachusetts and Illinois), again with ties to South Asian medical care.
And then, confirming this really was something to be concerned about, last month the journal Lancet Infectious Diseases published the results of a survey for NDM-1 that the authors conducted with collaborators in India, Pakistan and the UK. They found it widely distributed in Klebsiella and E. coli in South Asia; in UK residents who had family or business ties to South Asia or had gone there for care; and also in people who had never left the UK. Shortly afterward, the World Health Organization warned governments that they should be taking this new arrival seriously.
In the few papers on NDM-1 that got rustled up in time for ICAAC, there are more details on NDM-1’s behavior in patients in Australia, Canada, Kenya and the US; the patients were infected with different organisms, but the organisms all possessed the same gene, and were all susceptible at best to one or two drugs, some new, some old and with toxic side-effects. What connects that handful of reports: much more detail on the mobile genetic elements where the NDM gene resides. It is on more than one plasmid; it can move freely between plasmids; the plasmids have been shown to move not just between individual bacteria, but also between species and genera. Overall, that adds up to a resistance mechanism that is spreading with remarkable speed — and bringing with it, as fellow-travelers on the same plasmids, even more resistance mechanisms that have not yet been delineated.
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(I can’t link to the work presented at ICAAC because it is not online, but the teams are: Nordmann and colleagues from the Hospital Bicetre in Paris; Timothy Walsh and team from University of Cardiff, who made the first identification in 2008; Brandi Limbago and colleagues from the CDC; and JDD Pitout et al. from the University of Calgary.)
But if you know a new resistance mechanism is spreading worldwide, what do you do about it? That’s the larger discussion percolating through the corridors here. Antibiotic resistance has always been a biological occurrence wrapped in layers of science, economics and politics. For NDM-1, the politics are especially difficult.
In South Asia, several of the researchers pointed out, antibiotic overuse is common, diarrheal disease is endemic, and municipal sanitation is available to only about half of the more than 1 billion population. That’s practically a recipe for the rapid spread of genetic material carried by gut bacteria — and the economic realities of the subcontinent make it unlikely that any of those conditions are going to be remedied soon. At the same time, the South Asian diaspora worldwide is millions of people, and no one wants to be in the position of blaming a country or a people for antibiotic Armageddon.
There’s a clear concern that everyday physicians may see cases of this and not know what they are seeing. These infections look like any other — or will, until the point when patients don’t get better. At that point, what appeared to be a simple urinary tract infection, for instance, can climb backward to the kidneys, enter the bloodstream, and turn deadly. “General practitioners are not used to seeing multi-drug resistant bacteria in the community,” Dr. Pitout said. “If this does become common, it will lead to a lot of failure of treatment.”
When H1N1 swine flu became a worldwide concern last year, and H5N1 flu five years before that, the World Health Organization mobilized an intricate network of influenza surveillance labs around the world to detect aberrant isolates and track their movement. Amazingly, there’s no such network for antibiotic resistance, Nordmann said. And though an international network for the detection of antibiotic resistance would have been useful before — to track the movement of MRSA, for instance — the researchers agreed it is critically needed now. But that’s not an easy demand to satisfy. The flu network is substantially supported by the governments of the countries where the labs are located (the US lab in the WHO network is within the flu division of the CDC). Governments may not have the money available, and may not agree this issue is as high a priority as the West believes.
This week, France will begin screening any new hospital patients, checking to see who has been treated in a South Asian hospital and so may be a source of NDM-1. That’s a first step, and a crucial one. “The only practical advice I can give at this moment is for physicians to ask their patients,” Pitout said. “And if you have been treated abroad and you develop a medical emergency and must be treated at home, it is very important to tell your physician.”
Image from the CDC’s Public Health Image Library.
The World Health Organization released a statement this afternoon, prompted by news of the NDM-1 multi-resistance gene. It’s worth taking a look: The agency recommends that countries around the world pay serious attention to the emergence of this resistance factor.
WHO calls for broad action within countries, from
hospital infection-control and antibiotic-stewardship programs, to
increased surveillance for the emergence of resistance, to
legislative control of over-the-counter sales. Those sound like (and are) minimal and rational suggestions — but they have the potential to be quite controversial in some countries, from India where OTC antibiotic purchases are a major economic sector, to the US where best practices for hospital control of resistant organisms continue to be, umm, vociferously debated.
The WHO says:
Those called upon to be alert to the problem of antimicrobial resistance and take appropriate action include consumers, prescribers and dispensers, veterinarians, managers of hospitals and diagnostic laboratories, patients and visitors to healthcare facilities, as well as national governments, the pharmaceutical industry, professional societies, and international agencies.
WHO strongly recommends that governments focus control and prevention efforts in four main areas:
- surveillance for antimicrobial resistance;
- rational antibiotic use, including education of healthcare workers and the public in the appropriate use of antibiotics;
- introducing or enforcing legislation related to stopping the selling of antibiotics without prescription; and
- strict adherence to infection prevention and control measures, including the use of hand-washing measures, particularly in healthcare facilities.
The WHO has been working on antibiotic resistance for a while now, though the effort seems to be continually obscured by urgent news of outbreaks such as SARS, H5N1, H1N1 and so on. Here’s their short fact sheet, detailed program page, and Global Strategy for Containment of Antibiotic Resistance (sadly 9 years old, so it predates the emergence of community MRSA, not to mention NDM-1).
Sorry to drop out of sight, constant readers; a little medical emergency at Casa Superbug, but all better now. There are some new developments regarding the novel resistance factor NDM-1, which renders Gram-negative bacteria resistant to almost all antibiotics:
Before we get too much further from the initial news, I want to go back over
the history of NDM-1’s discovery — because, as with so many superbugs that take the public by surprise (recall the furor when the CDC’s estimate of 19,000 MRSA deaths a year was published in late 2007), it turns out that there have actually been alarm bells ringing on this for a while. Largely, of course, unheard.
The first finding was in an older man of South Asian origin, living in Sweden, who went back to India in 2007, was hospitalized in New Delhi as a result of longstanding health problems, returned to his new home, was hospitalized there also in January 2008, and was discovered there to be carrying this resistance factor. The first public description of his case was made in
October 2008, during a poster session at the annual ICAAC meeting (Interscience Conference on Antimicrobial Agents and Chemotherapy). That was later expanded to a journal article that was published in Antimicrobial Agents and Chemotherapy in
December 2009; the full text is online in PubMed Central.
In the interim, though, the UK’s Health Protection Agency published its first alert, in
July 2009, describing 19 patients carrying this resistance in 2008 and the first half of 2009, 9 of whom had received medical care in South Asia:
One UK patient, who developed a bloodstream infection with an E. coli that produced NDM-1 enzyme had received treatment for a haematological malignancy in both India and the UK; two others had undergone cosmetic surgery in India and one of these presented to a UK hospital with a wound infection that grew a mixed microbial flora including K. pneumoniae with NDM-1 enzyme; others had received renal or liver transplantation in Pakistan.
Meanwhile, other researchers in Europe were becoming alert to the threat that NDM-1 posed if it were to spread widely; English researchers warned of it in
September 2009, and Scandinavian researchers did the same in
November 2009.
And in
June 2010, the CDC published its first report and warning of NDM-1 in patients in the US, noting that all three, who lived in different states, had received medical care in India.
But what’s important to note is that, despite the surprise and indignation coming from South Asia after the publication of last week’s Lancet Infectious Diseases papers (article, editorial) describing the spread of NDM-1, the existence of that resistance factor has been discussed in Indian medicine since sometime last year.
From
August to November 2009. a team of physicians at the Hinduja National Hospital and Medical Research Centre in Mumbai surveyed their ICU patients, and found 22 isolates carrying NDM-1. Their paper was submitted very quickly, in
December 2009, and published in March 2010 in the Journal of the Association of Physicians of India:
We sought to identify NDM-1 positive strains among the carbapenem resistant Enterobacteriaceae isolates at our tertiary care centre. In a short span of 3 months, we identified 22 such organisms. The physicians at our institute follow the hospital antibiotic policy and do not indiscriminately use carbapenems. However being a tertiary centre we receive transfer in cases / referrals from other hospitals… The identification of NDM-1 in 22 of 24 isolates is a worrisome development indeed. NDM-1 being present among Enterobacteriaceae has the potential for further dissemination in the community. Such dissemination may endanger patients undergoing major treatment at centres in India and this may have adverse implications for medical tourism. Besides stringent infection control in hospitals, good sanitation in the community is also needed to contain the spread of such clones. (Deshpande et al., JAPI 2010)
News of their finding must have percolated through Indian medicine, because in
January 2010 — before their paper was published — a worried letter discussing NDM-1, by a South Asian scientist working at the Royal Infirmary of Edinburgh, was published in the Indian Journal of Medical Microbiology:
The virtual nonexistence of antibiotic policies and guidelines in India to help doctors make rational choices with regard to antibiotic treatment is a major driver of the emergence and spread of multidrug resistance in India. This is augmented by the unethical and irresponsible marketing practices of the pharmaceutical industry, and encouraged by the silence and apathy of the regulating authorities. Poor microbiology services in most parts of the country add to the problem. (Krishna, IJMM 2010, DOI: 10.4103/0255-0857.66477)
And in
March 2010, Dr. K. Abdul Ghafur of the Apollo Hospital in Chennai published a passionate and despairing call to arms (“An obituary — on the death of antibiotics!“) alongside the Mumbai team’s findings. The full text is online and it is worth reading in its entirety:
Our country, India, is the world leader in antibiotic resistance, in no other country antibiotics been misused to such an extent. Microbes are the ultimate warriors. They have sophisticated weapons and use ingenious methods of attacks. They have always been many steps ahead of us. Even in the twenty first century with all the developments in the modern medicine, when we face microbes, we feel helpless. Whatever weapons we had in the form of antibiotics, we ourselves have ruined them. Indian medical community has to be ashamed of the NDM-1 (“New Delhi Metallo-1”) gene. Even though we have not contributed to carbapenem development, we have contributed a resistance gene with a glamorous name. The overuse of antibiotics is embedded in our Indian gene. It is an Indian tradition. (Ghafur, JAPI 2010)
That Ghafur’s plea went unheard is all the more striking — because for almost a decade, Indian researchers had been reporting, in their own journals, a steady and troubling expansion of carbapenem resistance in Indian hospitals. More on that when I post next.
One of the frustrations of being a working journalist and a blogger is that, when a big blog-story breaks, you’re likely already to be working on something else. And so it is, unfortunately, with NDM-1: I’m on a magazine assignment and will be off interviewing people when I should be blogging.
(This s a great time to recommend that, for any breaking infectious disease news, you follow Crof at H5N1 (@crof) and Michael Coston at Avian Flu Diary (@Fla_Medic), who are dedicated, thoughtful, nimble and smart.)
Since I last posted, there’s been lots of additional coverage of the “Indian superbug.” Much of it, blog and media, is just echo chamber cannibalizing of the earliest reports (including but certainly not only mine), but there are some important new developments worth noting, which I’ll list below.
There are also some important points that are getting lost in the echo-chamber bounce: First, it is not correct to say that every person who acquired this was seeking cheap medical care or engaged in medical tourism; a few of them were treated on an emergency basis while traveling, and a few have no apparent healthcare tie. So this is not a situation of people seeking to save money and, as some commenters seem to be suggesting, receiving their karmic payback. (C’mon: Seriously?) Second, it is also not correct to say that every case of this has been linked to a hospital — it’s quite clear in the Lancet ID paper that in South Asia, a number of the cases were community infections. So it is not just a case of hospitals that are dirty or have poor infection control (which by the way is a problem in the US as well, right?); NDM-1 is already a community bug, which will make detection and defense much more complex.
OK, curated list:
First, if you’re interested in more from me, CNBC asked me to write up a piece about NDM-1, which ran Thursday; and Friday morning I was on the WNYC-FM (and nationally syndicated) radio show The Takeaway.
Second, the list of potential victims of NDM-1 is growing. Most of them have survived, so marking their cases is really a way of measuring the resistance factor’s previously undetected spread:
The UK has released a new statement, updating its earlier warning, and says it has found “around 50” cases carrying NDM-1, an update from the Lancet ID paper. (Side note: This statement, and the earlier warnings, came from the UK’s Health Protection Agency. The UK has just announced that it will be shutting down that agency in a cost-cutting measure. Great timing.)
The government of Hong Kong has announced that it has seen one case of NDM-1, but the patient recovered.
Canada has disclosed that it has had two cases, not the one mentioned in the Lancet ID editorial, in two different provinces.
Australia says that it has had three cases scattered across the country.
Belgium has announced one death.
And finally — sadly but probably not surprisingly — India is objecting to the stigma of being characterized as the source of NDM-1. The study’s first author has disassociated himself from the paper and members of the government are claiming a “pharma conspiracy.” Medical tourism has become a significant industry in India, and it is true some of these reports cast doubt on its safety. But still, I find this reaction disappointing.
Evading the stigma of an emerging disease is not a new impulse: Recall how the government of China suppressed for 6 months the news of the start of the SARS epidemic. They did not stop the epidemic, of course — it eventually sicked more than 8000 people across the globe and killed about 775 — but their suppression of the details of its spread kept other jurisdictions from mounting a defense in time. From my teaching gigs in Hong Kong I can testify how much bitterness endures in Hong Kong over this.
China’s actions in 2002-03 led to the enactment of the new International Health Regulations by the WHO, which specify that, because expanding epidemics take no notice of borders, it is inappropriate for any government to attempt to impede the free flow of information about their spread. India is a signatory to the IHRs.
I am not suggesting that India is attempting any suppression of news about NDM-1 — there’s no evidence of that — but the volatile language being used does concern me. I acknowledge that India is an extremely open society, with degrees of political expression that can sound surprising from this distance. But let’s hope the government takes its commitment to the IHRs as seriously as any signatory should.
