Maryn McKenna

Journalist and Author

Drug residues and drug resistance in water: Not good

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When we talk about the emergence of antibiotic resistance, two factors usually get the blame: the overuse of antibiotics in human medicine and in agriculture. In both cases, the drugs’ presence exert selective pressure on bacteria, encouraging them to develop or acquire resistance genes that will protect them.

But there’s another way that bacteria are exposed to antibiotics. It’s through wastewater: residues from antibiotic manufacturing, retail drugs dumped because they are expired or no longer needed, and sewage — because a percentage of the drugs we take (and give to animals) pass through our bodies unused, and also pass intact through municipal wastewater treatment when it exists.

I wrote about this a bit last September, just after this blog launched, in the context of how difficult it can be to get rid of prescription drugs that you no longer need or want. (Plea: Don’t flush them.) But a new paper in PLoS One underlines that this problem is much bigger than the bottles cluttering your medicine cabinet.

For several years, faculty from several universities in Sweden have been tracking the content of wastewater flowing into a river near Hyderabad in India, a city that is a center of generic drug manufacturing. (For a sense of how saturated the local environment is with pharma firms — more than 90 — check the map at right.) Previously, they had found levels of fluoroquinolones  high enough to kill fish and permeating drinking-water wells in villages. (For humans, the most familiar fluoroquinolone is Cipro.) For this paper, researchers looked specifically at bacteria living in parts of the river where that industrial pharma effluent is flowing, to see whether they were developing resistance in response to that exposure.

Answer: Oh, yeah. Using a method called “multiplexed massively parallel pyrosequencing” (which I love just saying out loud), the team analyzed the bacterial DNA and found it loaded with resistance genes that would confer protection to multiple classes of antibiotics: fluoroquinolones, aminoglycosides and sulfonilamides. At three sites downstream of the key wastewater plant that processes the effluent, known resistance genes accounted for 1.7% of all the DNA they analyzed. Along with those genes, they also found two previously unknown plasmids that contained genes conferring resistance to fluoroquinolones (qnrD) and sulfa drugs (sul2).

It’s important to say that the bacteria in the river that were harboring these resistance genes were not disease-causing bacteria. It’s also important to say that is only minimally relevant. Once resistance factors arise, they move with surprising speed between bacteria and also across bacterial species. In the downstream samples, they also found abundant integrons and transposons that would allow the genes to move, reinforcing the case that resistance was evolving at these spots because of the antibiotic-laden effluent.

This Indian river is a hot spot because of the concentration of manufacturing along it — but it’s not the only offender. Last year, Chinese scientists reported on very high levels of oxytetracycline stimulating bacterial resistance in a river in China. In January, British scientists reported similar results for a river in Cuba. And as I said last fall, the US Geological Survey has found pharmaceutical residues in 80% of the 139 US streams they sampled in 2002.

National and international health agencies, and medical societies and NGOs, have programs that seek to reduce the overuse of antibiotics in human medicine. There’s increasing pressure, as we talk about here all the time, to push back against the overuse of antibiotics in farming. But the thought that antibiotics are spreading freely in groundwater, lakes and rivers is truly disturbing. Curbing that will require a whole different level of effort.

Cite: Kristiansson E, Fick J, Janzon A et al. 2011 Pyrosequencing of Antibiotic-Contaminated River Sediments Reveals High Levels of Resistance and Gene Transfer Elements. PLoS ONE 6(2): e17038. doi:10.1371/journal.pone.0017038

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NDM-1: More Evidence It Started in India

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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…]

Polio in India: Many steps up… and a long one back

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Discouraging news from India, in the long campaign of polio eradication that has seen so many ups and downs (my last post on polio here): A girl who was vaccinated against polio in one of the enormous national campaigns held every few months there has become paralyzed. But not for the reason that is usual in India, that the vaccine did not take and she became infected with wild-type polio. Instead, her paralysis was caused by the vaccine virus itself, mutating back to infectiousness and causing what’s known as vaccine-derived polio or VDPV.

As reported in the Telegraph of Calcutta and the Deccan Chronicle, the 9-year-old’s case raised alarms because she lives in the state of Tamil Nadu, which has been polio-free for 4 years. Then she was discovered to be infected with polio virus type 2, which was eliminated in India 10 years ago but still is being vaccinated against, in case it returns. (There are three types.) She is one of three children in India to develop VDPV this year; 15 chldren there did last year. Ironically, only a few days before her case was announced, another newspaper, the Deccan Herald, cautioned that the possibility of VDPV was a “ticking time bomb” that could derail polio eradication if not closely watched.

VDPV is one of the ever-present complexities of polio eradication. It poses a significant risk to the campaign’s end-game that really hasn’t been publicly discussed.
[Read more…]

NDM-1: The World Health Organization warns governments

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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).

NDM-1: The early warnings

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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:

  • Germany has announced its first identifications — plural, apparently. (Bloomberg News)
  • Vietnam says it has also recorded its presence.  (Thanh Nien Daily, h/t H5N1)
  • And France says that it will begin testing for the gene’s presence in bacteria carried by patients being admitted to hospitals, in hopes of keeping the plasmid from transferring to other bacterial species and creating a wider resistance problem. (Agence France Presse) This is a reasonable fear; it is analogous to the process by which MRSA became vancomycin-resistant (VRSA), by acquiring the gene for vancomycin resistance from VRE, vancomycin-resistant Enterococcus. But there’s much more to be said about what it will take for a hospital to keep this bug from entering or spreading; more on that in a future post.

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.

More on NDM-1

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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.

NDM-1: Novel, global, complex and a serious threat

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There’s news today in the journal Lancet Infectious Diseases of the further spread of a troubling new resistance problem that I first talked about in June: Gram-negative bacteria carrying a novel resistance factor that has been dubbed New Delhi metallo-beta-lactamase, or NDM-1.

In writing about resistant bacteria, it’s difficult to avoid overusing superlatives — but this resistance mechanism has spread widely, been transported globally, and brings common bacteria up to the brink of untreatable. It already has been found in India and Pakistan, Sweden, the Netherlands, Australia, Canada and the US, and has been distributed not just by travel but specifically by medical tourism. It has the potential to become an extremely serious global threat.

News break: CDC alert on imported novel resistance

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There’s a troubling item in this afternoon’s issue of the CDC’s Morbidity and Mortality Weekly Report or MMWR: The first report in the United States of a novel resistance mechanism that renders gram-negative bacteria extremely drug-resistant and that has been linked to medical care carried out in India or Pakistan.

The short item describes three isolates (E. coli, Klebsiella pneumoniae and Enterobacter cloacae) found in three patients in three states between January and June of this year. All three isolates produced New Delhi metallo-beta-lactamase (NDM-1), which has never been recorded in the US before. Because of that novel mechanism, the three isolates were resistant to the carbapenems usually used on the most serious gram-negative infections, in fact to all beta-lactam antibiotics (penicillins, cephalosporins, carbapenems, monobactams, etc.) except for one monobactam, aztreonam — and they were also resistant to aztreonam through another mechanism that hasn’t been identified yet. All three of the patients found carrying this novel resistance factor had undergone medical care in South Asia recently.

This may be the first finding of this mechanism in the US, but it’s been causing alarm in Europe for at least two years.

[Read more…]