Double-barreled news today from the US Centers for Disease Control and Prevention. In an analysis of several sets of hospital data, gathered by the agency and also purchased from independent databases, the CDC said it found that more than 37 percent of prescriptions written in hospitals involved some sort of error or poor practice, increasing the risk of serious infections or antibiotic resistance. And in a surprise announcement timed to the release of the federal draft budget, the agency said it is in line to receive $30 million to enhance its work combating antibiotic resistance in the US.
It’s been a little more than a year since the first-ever clinical trial of fecal transplants — the practice of infusing diluted donor stool into the colon of someone suffering from Clostridium difficile infection — demonstrated that the low-tech process not only works to overcome the disease’s painful, life-disrupting diarrhea, but works better than the standard treatment of antibiotics.
That finding confirmed what gastroenterologists had known for a while — not to mention what patients who had sought out the procedure, in the United States or in other countries, could confirm from their own experience of being rapidly and, for the most part, permanently cured.
Despite that result, and despite significant pent-up demand from patients and physicians both, fecal transplants’ status in US medicine has barely budged in the ensuing year. The procedure is caught in a bind at the Food and Drug Administration, which has struggled to define under which of its regulatory authorities the transplants fall. Last May, the agency proposed forcing physicians who wanted to perform the procedure — many of whom were already doing so — to obtain a cumbersome Investigational New Drug application beforehand. After an outcry, the agency backed off, but many practitioners had been spooked, and many patients (judging by my email at least) returned to seeking out the procedure in a semi-underground manner.
In Nature last week, a team of researchers (including gastroenterologist Colleen Kelly, MD, who heads a US clinical trial that is still underway) argued for a way out of the paralysis. They propose that the FDA evaluate stool infusions not under the rules for drugs, with all the clinical trial requirements that implies, but rather under the rules for tissues such as blood, cartilage, skin and bone.
Hi constant readers: I am traveling again, and while I’m in a far time zone, news has broken that you might be interested in. So while I don’t have a full understanding myself yet of what’s going on, I’m going to throw up what I’ve got, because I know how many people are interested in this.
Briefly: The US Food and Drug Administration has decided to bring the semi-outlawed — but very safe and very effective — procedure called “fecal transplant” under its auspices, ruling that to perform it, physicians must have applied for an “investigational new drug application,” or IND. This requires a lot of advance paperwork, 30 days of consideration, and does not return not a guaranteed yes. For the transplants, which have been performed informally but carefully by a growing number of physicians as a treatment (and often cure) for devastating C. difficile infection, it may improve safety, but it can’t help but impose obstacles and delay. (My past posts on fecal transplants here and here.)
Since I started electing to do blog coverage of scientific meetings, I’ve run into an unfortunate reality. On any meeting day, there are one or two presentations that either are strikingly newsworthy or fit into an ongoing topic that I’m already interested in, and that therefore I feel obliged to write about. That means I’m unable to cover dozens, sometimes hundreds, of other interesting papers and posters.
I feel bad about this, especially when authors stop what they are doing to talk to me. So here’s my admittedly insufficient remedy: a quick round-up of a few of the hundreds of intriguing presentations this past week at the biennial International Conference on Emerging Infectious Diseases. (Program here; it’s a pdf, abstracts not individually searchable.) Apologies to everyone whom I didn’t get to.
Several related pieces of news today from the International Conference on Emerging Infectious Diseases:
- The number of people who are dying from illnesses that involve vomiting and diarrhea more than doubled between 1999 and 2007, and most of the increase was due to Clostridium difficile.
- Disease outbreaks caused by imported foods are rising, and tainted foods are coming into the United States from a wider array of countries than before.
Lara Thompson was 26 when her life fell apart.
She was living in Rhode Island and working in HIV prevention research when she unexpectedly developed nausea and diarrhea. It was early 2008, a few weeks after New Year’s, and she thought she might have picked up a stomach virus at a holiday gathering, or stressed her system with overindulgence. She expected the symptoms would pass after a few days. They didn’t.
“In three weeks, I dropped 15-20 pounds,” she says now. “I couldn’t keep anything in; I would have to run to the bathroom at a moment’s notice. I was so lethargic I had to stay home from work.”
When she consulted her doctor, she found out what was bothering her was more complex than a virus. Somehow, her intestinal lining had become infected with Clostridium difficile, or C. diff, a tough and persistent bacterium that has been rising in incidence and gaining antibiotic resistance, becoming increasingly difficult to treat.
It’s an accepted concept by now that taking antibiotics in order to quell an infection disrupts the personal microbiome, the population of microorganisms that we all carry around in our guts, and which vastly outnumbers the cells that make up our bodies. That recognition supports our understanding of Clostridium difficile disease — killing the beneficial bacteria allows C. diff room to surge and produce an overload of toxins — as well as the intense interest in establishing a research program that could demonstrate experimentally whether the vast industry producing probiotic products is doing what it purports to do.
But implicit in that concept is the expectation that, after a while — after a course of antibiotics ends — the gut flora repopulate and their natural balance returns.
What if that expectation were wrong?
So, antibiotic resistance: We care about it, right? The World Health Organization does: It made antimicrobial resistance the theme of this year’s World Health Day. The Centers for Disease Control and Prevention does. The journal Lancet Infectious Diseases says it’s a “global health concern.” The major association for infectious disease physicians has pleaded for attention. Two separate sets of legislators have introduced two bills in Congress.
You’d think, with all those calls for attention, that combating antibiotic resistance would be a priority in the United States. But if we can take how much we spend to research a problem as a gauge of how much we care about it, then antibiotic resistance is no priority at all.
As in: For every death from AIDS, the US federal research establishment awards approximately $69,000 in grant funds. And for every death from MRSA, it awards $570.
People who are interested in infections that are transmitted in hospitals (umm, ghouls like me) have a special sick relish for Clostridium difficile, or in its short form, C. diff. C. diff lives in the intestines, part of a complex population of many bacteria — you did know there are more bacteria in your body than there are cells that belong to you, right? — but it roars out of control if those other bacteria are wiped out by a course of antibiotics, especially clindamycin. Removing the other bacteria clears out space for C. diff to reproduce in much greater numbers; the toxins it produces irritate the lining of the intestine, producing colitis, and triggering fever, cramps and diarrhea, and in the worst cases, sepsis. miscarriage and death.
C. diff colitis is one of the most common and serious hospital-acquired infections because — if you’re reading this over breakfast, you might want to stop eating now — severe diarrhea in a hospital patient who is confined to a bed and using a bedpan tends to get everywhere. Really, everywhere: bed linens and bedrails, floors and walls, stethoscopes, telephones, computer keyboards, and the hands of the healthcare personnel who operate those devices and then touch another patient.
C. diff persists so spectacularly because in the outside air, it forms a hard-shelled spore that protects its genetic material from assault — including from the alcohol in the hand gel that most healthcare workers use to clean their hands in between patients, and from the stomach acid of patients who swallow it. (See, I told you to stop eating.) Because of that, and because it’s such a devastating infection, hospitals toil incredibly hard at sanitizing to get rid of it.
C. diff colitis is a stubborn and ugly infection. Earlier this summer, an Illinois man named Ed Corboy Jr. described his mother Joan’s experience with it to the Infectious Diseases Society of America:
I watched helplessly as [she] grew weaker, more dehydrated, and nearly died. She was started on intravenous fluids and standard antibiotics while in the hospital two different times that December. Her blood pressure dipped dangerously low on many occasions. She had lost almost 55 pounds in the previous five months, and she was so profoundly exhausted, tired, and wasting away that it became apparent in early January she might die from this. She could hardly get to a bedside commode without two people helping her. Prior to this she was able to walk to her bathroom with her walker on her own for years.
Starting about 10 years ago, C. diff got dramatically more problematic: more virulent, more resistant to treatment, and more commonly occurring in people who would not have been expected to have it — often, healthy young people who had not been in hospitals, who seemed to be developing the illness in the outside world. Two CDC researchers said in 2008:
In the United States, the number of hospital discharges where (C. diff associated diarrhea, CDAD) was listed as any diagnosis doubled between 2000 and 2003, with a disproportionate increase for persons aged > 64 years. By 2003, regional reports of CDAD outbreaks from hospitals throughout the US and in Quebec, Canada emerged, describing severe disease associated with greater numbers of complications, including colectomies, treatment failures, and deaths. In 2004, the attributable mortality rate of nosocomial CDAD in Quebec hospitals was 6.9%, compared to 1.5% among Canadian hospitals in 1997. In the US, death certificate data suggest mortality rates due to CDAD increased from 5.7 per million population in 1999 to 23.7 per million in 2004. (Gould, Critical Care, 2008)
The reason for the surge has been understood to be the emergence of a new, hypervirulent strain of C. diff that produces up to 20 times more toxin than earlier ones. (C. diff nomenclature will make your brain hurt, but the strain is generally known as NAP1/027/BI, toxinotype III.) But increased virulence doesn’t explain the increased incidence, and the transmission patterns of the new strain have been murky.
An emerging line of inquiry suggests that the transmission patterns become much more clear if you look in a different place for the bacterium’s origin: not in hospitals, but in food.
C. diff has been identified in live pigs, cows and chickens. The bacterium has been found in retail meat in the United States and in Canada (in three separate studies), and in salad greens in Scotland. And in a paper published this month, the main authors from those Canada studies establish that minimum recommended cooking temperatures for ground beef don’t kill C. diff spores.
(You’re really not eating now, right?)
So, OK: But are the C. diff strains found in animals the same ones that are causing human disease? The answer turns out to be Yes. Several researchers have found overlaps, in 2007, 2009 and earlier this year, in a study with the perfect title: “Innocent bystander or serious threat?”.
And in what looks certain to be a provocative presentation, a team of researchers from Houston is going to present a paper at the annual meeting of the Infectious Diseases Society of America in a few weeks, titled: “Potential Foodborne Transmission of Clostridium Difficile Infection In a Hospital Setting.” (Uh-oh.)
The case for C. diff as a foodborne illness still isn’t made. In an excellent paper published last month, L. Hannah Gould and Brandi Limbago of the CDC go over the findings so far, and detail what evidence and further research are still needed.
It is reasonable to assume that the general public is and has been often exposed to low numbers of potentially infectious C. difficile spores. There is currently limited epidemiologic evidence to support or refute the hypothesis that C. difficile is transmitted by the foodborne route; the presence of C. difficile on retail foods suggests but does not prove that some proportion of infections is acquired this way. The food supply may thus serve as a source of new strains causing human infections; alternatively, food could be another constant and normally innocuous exposure. (Gould, Emerging Infectious Diseases, 2010)
What’s really interesting, though, is that microbiologists aren’t the only ones noticing this accumulation of evidence. C. diff as a possible foodborne pathogen caught the attention of foodborne-illness attorney Bill Marler early last year. If Marler — the most aggressive and, I suspect, successful foodborne-injury lawyer on the planet, dating back to the 1993 Jack-in-the-Box outbreak — is starting to notice the evidence tying C. diff outbreaks to food, there might be a lot more attention paid to this connection fairly soon.
Image of C. diff by Janice Carr, courtesy of Public Health Image Library, CDC.
The ongoing fight over long-term Lyme disease treatment has to be one of the most ferocious in health care. If you don’t live in the Northeast or upper Midwest, Lyme disease may not be on your radar, so here’s a super-quick version: There are patients and physicians who say that Lyme disease symptoms persist following the 28 days of antibiotic treatment that is the standard recommendation of the CDC and the Infectious Diseases Society of America, and also say that patients benefit from additional antibiotic regimens — sometimes IV, sometimes oral — that can last months more. The CDC, IDSA and some other medical authorities say there is no evidence to support these regimens. The ongoing bitterness has extended to antitrust charges by the Connecticut Attorney General that forced a re-evaluation of the IDSA guidelines, which physicians follow and insurance companies refer to when authorizing payment. The disagreements have continued into this year.
I’ve been curious about the long-term Lyme regimens from the antibiotic-resistance POV: whether giving Lyme patients such long courses of antibiotics would encourage the development or spread of resistant organisms. (NB, I don’t know of any research that would answer that question, but if anyone does, cites would be welcome.)
Today, though, I spotted a new paper that describes an unintended consequence I hadn’t thought of: the death of a Lyme patient from Clostridium difficile or C.diff, an infection that becomes more likely after long courses of antibiotics.
Quick lesson: C. diff (here’s the CDC info page) is a toxin-producing bacteria that causes a life-threatening infection of the gut. It’s normally resident in the intestines, but can roar out of control when prolonged courses of antibiotics wipe out the gut’s complex and very abundant population of bacteria. (Ed Yong’s post from a few days ago has excellent detail on the gut microbiome.) C. diff is rising in incidence, becoming drug-resistant, and also is extraordinarily difficult to eradicate from hospital environments — because it is spore-forming and thus protected against the alcohol in the hand gels that hospitals have encouraged in order to balance the need for hand hygiene with the time consumed by hand washing.
The paper, a letter to Clinical Infectious Diseases by representatives of the Minnesota Department of Health (Holzbauer et al., DOI: 10.1086/654808), describes the experience of a 52-year-old woman who had Lyme-like symptoms for about 5 years. She consulted a doctor in June 2009, was tested for Lyme, and was put on 5 weeks of doxycycline. She got better, but then her symptoms returned, and she sought care from a different physician who prescribed an additional 2- to 4-month course of two other antibiotics.
Five weeks after initiating this therapy, the patient developed diarrhea for 3 days and received a diagnosis of C. difficile colitis. … The patient was started on oral metronidazole therapy but was hospitalized 2 days later with severe abdominal pain secondary to diffuse colitis and abdominal ascites. The next morning, she experienced cardiac arrest twice and succumbed to cardiac arrest during an emergency [removal of her colon].
I’ve been talking to Lyme patients recently, including some who decided to take long-term antibiotic regimens. Some of them describe themselves as sick enough to take any risk in an attempt to get better. I wonder whether it’s made clear to them how substantial the risks might be.