Maryn McKenna

Journalist and Author

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.

Necessary background: One major way that microbiologists classify bacteria is on the basis of the organisms’ cell membranes; some have a single membrane, and others have two separated by fluid. The groups are identified by their response to a 4-step staining process, called Gram stain for the Danish physician who invented it in the 1880s. Cells that pick up the first stain applied, which is usually violet but sometimes blue, are single-walled; cells that resist the bath of the first stain, but pick up a lighter tint from another chemical in a later step, are double-walled. The single-membrane, dark-stained organisms are dubbed Gram-positive; the double-membrane organisms are known as Gram-negative.

Here’s why that distinction is so important for understanding antibiotic resistance: Most of the drugs that kill or control bacteria act by attaching to or penetrating through cell membrane. The double membrane of the Gram-negatives presents a greater obstacle to drug-molecule interference than the single membrane of the Gram-positives — and thus makes developing drugs that can control Gram-negatives a more complex task. Hence, while there’s abundant concern about the narrowing drug pipeline for Gram-positives including MRSA, there is even more alarm about the dearth of new drugs for Gram-negatives (as captured last year in this article from Clinical Infectious Diseases).

The novel resistance factor that is described today in Lancet ID appears only in Gram-negatives, primarily in E. coli and K. pneumoniae but also in other species. Bacteria that have acquired this mechanism are resistant to multiple classes of drugs commonly used against Gram-negatives: beta-lactams, fluoroquinolones, aminoglycosides, and most troublingly carbapenems, generally considered the drug class of last resort for those organisms. Several of the isolates found in the study were susceptible only to colistin, a drug that dates back to the 1960s and is considered toxic to the kidneys, and tigecycline, which was only licensed in the US in 2005. Several responded only to aztreonam. One was susceptible to nothing.

The real threat in today’s news, though, is not only how resistant these organisms have become; it is also how they got that way, and how and by what means they are spreading.

As the Lancet ID paper reports, NDM-1 resides on a plasmid — a snippet of DNA, not on a chromosome, that reproduces on its own and can move freely between organisms. Intuitively, you would think that bacteria either inherit resistance from their progenitors or develop it on their own when they encounter a drug. Plasmids short-circuit both those processes, allowing resistance to spread rapidly within a single bacterial generation to organisms that have never experienced the drug they are acquiring defenses against. And as the paper testifies, NDM-1 has spread: The authors surveyed for NDM-1 in India, Pakistan and the UK, and found it both widely distributed in South Asia, and also present in UK residents who had family or business ties to South Asia, or had gone to the subcontinent for medical care. And unlike some resistant organisms, the bacteria carrying NDM-1 were not confined to the bug-friendly environment of hospitals or the the debilitated systems of hospital patients. Instead, it was out in the community, causing common illnesses such as urinary tract infections.

There are a couple of points embedded in that report that bear unpicking because they are so foreboding.

First, that this is happening in India, which not only harbors some of the world’s largest manufacturers of generics, but also (and possibly synergistically) has some of the world’s highest rates of antibiotic use. Some Indian researchers have been warning for years that the subcontinent is on the verge of a homebrewed crisis of drug resistance (Indian Journal of Bioscience, Indian Journal of Medical Microbiology, Indian Journal of Medical Ethics).

Second, that it is linked to medical care, and especially to medical tourism — which has become a booming international industry, not only for elective options such as cosmetic surgery, but because it offers an inexpensive way to perform major procedures that health systems might once have wanted to have done close to the patient’s home. A study covered last January by The Independent in London recommended shipping UK patients to India for care, suggesting it could save the beleaguered health service more than $200 million.

And third, that these isolates were found in community infections caused by common organisms such as E. coli. That testifies not only to their wide distribution, but also to how difficult it might be to conduct surveillance for their presence — or, put another way, how easily they could evade detection while they continue to spread. It is not likely that physicians are going to culture every UTI that comes their way, either in the resource-poor developing world or in the overstressed conditions of Western medicine.

One example of the importance of surveillance: That’s how NDM-1’s first appearance in the United States was detected, via three isolates from three states that were tested at the CDC’s national labs in the first half of this year. In a bulletin in June (the subject of my first post on NDM-1), the CDC urged clinicians to be alert for resistant infections in any patients who reported receiving medical care in India or Pakistan.

Unfortunately, given the drought of new drugs for Gram-negatives, surveillance may be the best bet for controlling or at least slowing NDM-1’s further spread. It’s the urgent recommendation of the author of a companion Lancet ID editorial, also published today (and who appears to have seen Canada’s first case):

The spread of these multiresistant bacteria merits very close monitoring and worldwide, internationally funded, multicentre surveillance studies, especially in countries that actively promote medical tourism. Patients who have had medical procedures in India should be actively screened for multiresistant bacteria before they receive medical care in their home country. …The consequences will be serious if family doctors have to treat infections caused by these multiresistant bacteria on a daily basis.

 Cites:
Kumarasamy KK, Toleman MA, Walsh TR et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. The Lancet Infectious Diseases, early online publication, 11 August 2010doi:10.1016/S1473-3099(10)70143-2
Pitout JDD, The latest threat in the war on antimicrobial resistance. The Lancet Infectious Diseases, early online publication, 11 August 2010. doi:10.1016/S1473-3099(10)70168-7

Guest Q&A: Jeanine Thomas and World MRSA Day

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I want to introduce you all to a MRSA campaigner, Jeanine Thomas of Chicago. Jeanine — whose story will be told in SUPERBUG — is the founder of World MRSA Day, a worldwide event of activism and grieving that will take place Friday, Oct. 2. There will be simultaneous observances in the UK, and a candlelight vigil in Salt Lake City that evening.

Tomorrow, Oct. 1, Jeanine will be at Loyola University in Chicago to lead a press conference, commemoration for MRSA victims, and award ceremony for notable MRSA campaigners, and to urge those harmed by MRSA to observe October as MRSA Awareness Month.

In advance of the observances, I asked Jeanine to talk to SUPERBUG about her experience and her activism.

Tell us about your personal experience with MRSA.
I was infected with MRSA after ankle surgery in 2000. I came back to the ER — my incisions were black and oozing a large amount of pus and I was in teribble pain — and was admitted. Three days later my culture came back positive for MRSA. I was not put on the right antibiotic; the infection went into my bloodstream and bone marrow and I went into septic shock and multiple organ failure in the middle of the night. The night nurses were able to pull me back and save me. I had seven more surgeries to save my leg from amputation, spent a month in the hospital, and then was confined to bed on a cocktail of antibiotics for 5 more months. I also contracted C. difficile. I now have a destroyed ankle joint and a severely compromised immune system.

You started a MRSA patients’ group. Tell us about the group and why you did that.
I started MRSA Survivors Network in 2003 to give support, raise awareness and educate others. There was so little out there about this disease. I never wanted anyone else to go through what I had.

You used your experience with MRSA to help pass patients-rights legislation in Illinois. Please talk a little about the bill.
In 2003, I helped push the “Hospital Report Card Act” that then-state senator Obama introduced, to have infection rates reported. As the consumer representative on the state board for the HRCA, I saw that state health officials and doctors did not even want to have MRSA reported as a disease. So I decided I must take action and in 2006 we introduced the “MRSA Screening and Reporting Act.” It passed in 2007, the first in the country, and mandated that all ICU and other at-risk patients be screened for MRSA and infection rates reported. Since then, the Illinois Hospital Association has reported that inpatient infection rates have dropped, but they see many more CA-MRSA cases because of the screening.

How and why did you come up with the idea for World MRSA Day?
In January of 2009 I was thinking of ways to raise awareness and the idea of launching World MRSA Day and a MRSA Awareness Month popped into my head. There are awareness days for every other diisease and as MRSA is pandemic, we need global awareness. I did not know how successful I could be the first year during a recession, but the response was surprising, and I was able to launch the campaigns.

Tell us what you hope will change in the aftermath of having had this worldwide event.
I hope that awareness of MRSA as an epidemic in the US and a pandemic sweeping the globe will be revealed, and that action from the World Health Organization, Department of Health and Human Services, the CDC, governments and health departments will happen. I want all of them to declare MRSA an epidemic. This should have happened years ago, but let’s move forward now. Their inaction has caused this disease to proliferate. I also want the public to be aware of MRSA as we are all in this together and every single person on this planet is at risk. Prevention is key to saving lives.

1st Global Health Blog Carnival: The posts are in!

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Readers, there has been a metric ton of new MRSA research released in the past few days, and I am slogging my way through it. (On your behalf. No, no, no need to thank me.)

So, more to come. But in the meantime, I wanted to draw your attention to the aggregated posts of the Global Health Blog Carnival, which I mentioned yesterday. They are listed at Christine Gorman’s very fine blog Global Health Report. Malaria, decision-making, anti-smoking, current health v. future health … oh, go click. I’ll be back soon.

Prevention v. treatment (1st Global Health Blog Carnival!)

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Constant readers, about a dozen of us who are interested in global health are co-blogging today in a Global Health Blog Carnival. If you are on Twitter, search the hashtag #ghnews. If you’re not, we will try to get them all linked somewhere. This was organized (to the degree that blogger organize, which as you can guess is like herding small felines) by reporter and blogger Christine Gorman, formerly of TIME Magazine.

Our theme for today is prevention v. treatment. Fortuitously, the New England Journal of Medicine today is publishing an editorial (for which they have posted the free full text) that reminds us of the full burden and cost of MRSA. Drs. Cesar A. Arias and Barbara E. Murray say:

Faced with this gloomy picture, 21st-century clinicians must turn to compounds developed decades ago and previously abandoned because of toxicity — or test everything they can think of and use whatever looks active. …
It is more difficult than ever to eradicate infections caused by antibiotic-resistant “superbugs,” and the problem is exacerbated by a dry pipeline for new antimicrobials with bactericidal activity against gram-negative bacteria and enterococci. A concerted effort on the part of academic researchers and their institutions, industry, and government is crucial if humans are to maintain the upper hand in this battle against bacteria — a fight with global consequences. (NEJM 360(5):439-443)

As we’ve discussed time and time again, MRSA is increasingly common worldwide and increasingly costly to treat. Moreover, what has been presented by some as the first line of prevention for hospital-acquired MRSA — active surveillance and testing programs, also called “search and destroy” — is deeply controversial.

So what’s the next step? Well, in the past, when medicine has wanted to nullify an infectious disease threat, it did not rely only on surveillance or asepsis; it developed a vaccine. And there have been a few efforts to develop a MRSA vaccine, which are recapped in a new article in Infectious Disease Clinics of North America (yes, that’s a journal):

The most extensively tested vaccine against S aureus, which is a capsular polysaccharide-based vaccine known as StaphVAX, showed promise in an initial phase 3 trial, but was found to be ineffective in a confirmatory trial, leading to its development being halted. Likewise, a human IgG preparation known as INH-A21 (Veronate) with elevated levels of antibodies to the staphylococcal surface adhesins ClfA and SdrG made it into phase 3 testing, where it failed to show a clinical benefit. … Given the multiple and sometimes redundant virulence factors of S aureus that enable it to be such a crafty pathogen, if a vaccine is to prove effective, it will have to be multicomponent, incorporating several surface proteins, toxoids, and surface polysaccharides. (23 (1): 153-171)

Several longtime MRSA researchers, including Dr. Robert S. Daum of the University of Chicago, who wrote the first paper calling attention to community-associated MRSA in 1998, have called for a vaccine to be made a research priority.

Any thoughts, constant readers? In the public mind, right now, vaccines are at a low point: People are turning away from them, manufacturing problems have led to shortages, and pharma no longer finds vaccine manufacturing a lucrative business sector. If a MRSA vaccine were developed, would you take it yourself before surgery, or give one to your children?

GlobalPost launches and SUPERBUG is there

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Constant readers, I am thrilled to let you know that SUPERBUG is among a select list of blogs invited to be featured on GlobalPost, a gutsy and innovative new online news site that launches today.

GlobalPost is the creation of Charles M. Sennott, formerly an award-winning foreign correspondent and bureau chief for the Boston Globe, and Philip Balboni, founder and former president of New England Cable News. The service links 65 foreign correspondents living in 46 countries. The founders say in their introductory note that they are:

…acutely aware of the fact that quality journalism in America is threatened more profoundly today than at any time in our history from an unprecedented combination of forces: the transformational power of technology and the internet, the dramatic erosion in the economic underpinnings of the traditional media, and a steady migration of the most devoted consumers of news as well as younger people to new content platforms, most importantly the web.
GlobalPost is a direct response to these forces. Our mission is to provide Americans, and all English-language readers around the world, with a depth, breadth and quality of original international reporting that has been steadily diminished in too many American newspapers and television networks. GlobalPost is at the leading edge of what we hope and believe will become a new flowering of journalism in the digital age, built around new models of financial support.

The site has a number of pages and options, and a notable commitment to transparency in its reporting. Sennott takes new visitors through the details in his editor’s blog. For an outside take on why GlobalPost is worth reading and supporting, read editor and digital consultant Ken Doctor’s thoughtful take.

I know that all of you who gather here regularly already understand the irrelevance of borders to infectious disease control. (For just a few recent examples, see the MRSA outbreak in a Prince Edward Island hospital, the astonishing lack of hand-washing in British health care, and the movement of the pig strain of MRSA from the Dominican Republic to New York City.)

And therefore I know you understand the crucial importance of reliable journalism from abroad. So please welcome this intriguing effort and visit the new site. I’ve placed a GlobalPost button in the right-hand column.

(And just to add, because it’s important to say such things: No money is changing hands here. I don’t get paid for being featured there, and there are no revenues accruing anywhere else. Also, nothing about being featured on GlobalPost changes anything we do or say here: The site remains on Blogger, and your comments stay within this community and continue to be moderated by me.)