On the road this week, and a reading rec

Constant readers, I'm teaching this week at the University of Georgia's Grady College of Journalism and New Media Institute, so blogging will be light. If you're in the Athens or Atlanta area, please come say hello, I'll also be speaking publicly:

• Tuesday: 4 p.m., Room 175 of the University of Georgia's Coverdell Center for Biomedical and Health Sciences, Athens.
• Wednesday: 6 p.m., the Vaccine Dinner Club of Emory University (Whitehead Health Science Center Administration Building), Atlanta.
• Thursday: 4:15 p.m., Athens-Clarke County Library, Baxter Street, Athens.

Here's a press release that UGa kindly put out about the events.

Meanwhile, some reading: When we're talking about MRSA control, we often talk, somewhat lightly, about isolating people within a hospital or nursing home in order to control MRSA's spread. For instance, isolation is the key technique on which "search and destroy" hinges.

In today's New York Times, Dr. Abigail Zuger writes a thoughtful column on the historic roots and present-day challenges of putting patients into isolation. It's very much worth reading, particularly for understanding why tending to patients in isolation is such a time-burden for health care staff. Also, her description of how C. diff spreads will make you want to wash your hands immediately.

More soon.

New CDC flu numbers: This may not go well

(Constant readers: Apologies for the slow blogging. Casa Superbug's little medical crisis from a week ago has recurred, and things are a bit distracting. Back to normal soon, I hope.)

In public health, one of the numbers you hear most often — and especially so the past few years — is 36,000. That's the number of deaths that the CDC estimates occur in an average year from influenza.

Or rather, estimated. Because today, in its weekly bulletin MMWR and also in a teleconference for the press, the CDC announced that it is discarding that widely used number, in favor of newer numbers from newer studies that take into account the wide variation in illness and death from one flu season to the next.

The new estimate is: 23,607. Or, a range that goes from 3,349 to 48,614. Or, in the language recommended by a CDC scientist and a communications specialist in the press call, "tens of thousands of people [who] may die each year in an average flu season."

If that sounds difficult to communicate in a concise manner, well, the reporters on the CDC call today clearly thought so too. And while reporting study results forthrightly is transparent, and more precise numbers are almost always better, I can't help but wonder whether this attempt at precision and transparency will not be received well. After all, we are only a few months (or a few weeks, depending whose end date you accept) away from the dribbling conclusion of a worldwide pandemic that was taken so not-seriously by the public that, in the US, 71 million doses of H1N1 vaccine went unused — and in Europe, some public representatives alleged that the entire emergency was a concoction by pharmaceutical companies.

Given that history, putting out a public message that flu kills fewer people than we thought — but is, still, a serious disease that should be planned for and vaccinated against — sounds like a hard sell.

Here's how today's new numbers came about:

The mortality rate from flu has always been difficult to assess: People die of influenza directly, but they also die of underlying conditions — heart disease or chronic obstructive pulmonary disease, among others — that might not kill the person if influenza were not putting an extra strain on the system. In either case, but especially in the latter, the death may not be attributed to flu, particularly if the victim has not been tested for the presence of the flu virus.

So, to arrive at an estimate, the CDC has used a statistical model. As explained in the briefing today by Dr. David Shay of the CDC's Influenza Division:

We have two categories that we look at... One is death certificates that have an underlying diagnosis of pneumonia or influenza. 99% of those deaths are actually coded as pneumonia. So, that's to make an estimate of deaths in a particular season from pneumonia that are associated with flu. And typically, that's about 8.5% of deaths over the time period that we looked at...  The broader category of respiratory and circulatory deaths we think encompasses the full picture of influenza-associated deaths, including things such as people who might die because of worsening chronic obstructive pulmonary disease or worsening congestive heart failure that results in death after an infection. And we estimate that about 2% of that broader category in any typical year is associated with influenza.

One other factor affects flu mortality: Which flu strain type is dominant in the season being measures. Flu is generally taken to cause the most severe disease, and the greatest number of deaths, in the elderly; but some strains cause more severe disease than others, and some (H1N1 "swine" flu, for instance) attack the young, who are healthier and less likely to die, more than they do the old. Again, Shay:

[I]t's important to keep in context, which we don't really describe in this article because of space, that there's at least four factors that affect sort of flu mortality in any particular year, and those four would be the specific strain or influenza strains that are in circulation, sort of the length of the season or how long influenza is circulating in the united states, how many people get sick, because of course, the more people get sick, there is more likely to be more serious outcomes, and finally, who gets sick.

In the study released today, the CDC did two things: It broadened the range of flu seasons from which it took data to feed into the statistical model, and it took a second look at the years on which the previous model, the one that produced the 36,000-death estimate, was based.

When the range of years was broadened to 31 flu seasons (1976-77 to 2006-07), here's what shook out:

• For deaths from influenza and pneumonia: from 961 in 1986-87 to 14,715 in 2003-04, an average of 6,309
• For deaths from respiratory and circulatory complications: from 3,349 in 1986-87 to 48,614 in 2003-04, an average of 23,607.

(When asked which number should be used for shorthand, Shay said: "The broader category of respiratory and circulatory deaths we think encompasses the full picture of influenza-associated deaths.")

When the 36,000-death estimate was re-examined, Shay said:

The 36,000 number that's often used pertains to a very specific time period from 1990 to 1999. And in that decade, where we had prominent circulation of H3N2 viruses, they were prominent in eight of the nine seasons that are contained within the data that were used to make that estimate, and those are, as you know, typically more severe seasons. We had a high mortality for that nine-year period.

According to the MMWR analysis, mortality rates in the H3N2 years were 2.7 times higher than in years when other types were dominant.

So that's the rationale behind today's dialed-down numbers. Here's the potential problem with it: It just took me about 1,000 words to (somewhat talkily) explain. It requires patience and detail to impart, which in the current media environment are in very short supply. As one of the participants on the call said today:

I'm really scratching my head here wondering what I'm going to use, because we really don't have a lot of time ... to present a lot of numbers, and I think in a sense to say that the range is 3,000 or 3,300 to 49,000 raises a lot of questions, and I think we don't have time to answer those questions in every report. And I also wonder if it's not a bit misleading to use 3,300 as the bottom number since it's been 20 years since it was that low, and even in the last 20 years, the mortality has never been much below 12,000.

You see the problem.

To repeat: This is an effort at transparency and accountability; those are worth applauding. But it's also a nuanced and difficult health-communication message, launched into a zeitgeist already tuned toward conspiracy theories and a media marketplace with little time or expertise to counter them.

Pessimistically, I wonder how long it will be before this message gets transformed into something like, "See? I told you so. Flu isn't that big a deal after all." I hope the CDC is prepared when it does.

(Here's today's MMWR article, the transcript of the press briefing, and a Q&A on the new calculation. The cite is: Morbidity and Mortality Weekly Report, "Estimates of Deaths Associated with Seasonal Influenza --- United States, 1976--2007." August 27, 2010. 59(33);1057-1062)

Friday comic relief

I give you: the Singing Doctors! (via damagedcare.com):

NDM-1: The World Health Organization warns governments

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

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

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

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