Progress on HAI progress: CDC portals and data

I spent about 2 hours with the new CDC HAI Progress Report – loosen your belt, it’s a big meal!  We probably had mixed perceptions about the recent alert to the 2016 HA progress report. Loads of information and analysis condensed down to a handful of bullets, all pointing to improvements in patient safety! The (very pleasant) surprise to me was that the format and delivery of the report has advanced to digital!! CDC has added the HAI progress report to the existing (and now updated) HAI AR Patient Safety Atlas Portal If you stop reading now – at least click on that link and explore and I will call this blog a success!

This report is several steps forward.  First, it pushes all of us to go to a place where we, being inquisitive minds, can wander and perhaps connect some dots within and between datasets. With the digitalization and visualization provided in the portal, the novice and experienced can more easily access and utilize these data. One can click through four distinct datasets, which now include state-summary statistics HAI infection rates/SIRs, inpatient stewardship activities, outpatient antibiotic prescribing rates, and inpatient antibiotic resistance metrics.

Now – the email alert. This year, well 2016 data, is the first to use the 2015 “re-baseline” efforts.

Unstated, but implied – the re-baseline effort includes the use of MBI (mucosal barrier injury) LCBSI as an event excluded from reported CLABSI rates, exclusion of yeasts (or low colony counts) from CAUTI rates, exclusion of “infection present on admission” for SSI (along with better patient-level risk adjustment), first use of risk adjusted metrics for VAE, and maybe slightly better models using more contemporary data for MRSA and CDI. 

With that said, 2016 performance suggests nationally patients are safer overall compared to the experience of 2015. Other than VAE which decreased by only 2%, everything else declined about 7-10% (I am rounding) compared to 2015. I understand many of the problems with risk adjustment and reporting bias that make these surveillance events poor performance measures for individual hospitals – but on the national level – I think these data do suggest fewer infections (o.k., perhaps some  widespread under-reporting—mixed reports on validation efforts in place).

Next – the overview of the current HAI Progress Report.   Although at first glance it seems the same as the info posted in the emails – CDC is offering more ways to track progress nationally – the number of states showing improvements (or worsening) compared to 2015, as well as the number states currently performing at levels better (or worse) then their 2016 contemporaries: 12 state perform better on at least 3 infection types compared to other states at the same time (2016). Now positive deviance nerds need to learn from these states to help the other states (or perhaps identify accuracy and validation issues at these states). The contemporary juxtaposition of SIRs is new, perhaps confusing (especially with CDC’s arcane explanation on how to interpret this: “SIRs statistically significantly lower than the 2016 national SIR are considered better than the 2016 national SIR”; curious if it ends up being useful to state programs. This year also is the first with more detail on inpatient rehabilitation facilities and long-term acute care facilities. Fewer data mean fewer statistical significant results, but these data are ripe for academic partners to latch onto as they try to partner with ARHQ, CDC, and state-programs to branch out into stewardship and prevention efforts in these types of facilities.

Finally, the portal – access it here.  Use the table view. No graphics to export for HAIs, only for other datasets. My pet peeve is that CDC still refused to list the no. of SSIs reported next to the number of surgical procedures reported to allow a crude attack rate. We still need to go to the technical tables for these values and calculate ourselves (see below). CDC, please stop making us jump through this hoop to be able to use attack rates for other purposes like planning studies, clinical trials, vaccine research! To all researchers and data nerds - the detailed technical tables should be downloaded examined (here), perhaps parsed out to our students and trainees, and used for different purposes that simply a “reporting requirement”.  I know there are many limitations to the accuracy of any one facilities reports and likely aggregate data up to the state or national level. However, as a long time national surveillance nerd all too familiar with the warts and ugliness of surveillance data, they do inform us, approximate the truth, and can help us ask the right questions and target the right populations. The more eyes using these data the more transparent the process will become, more uses of the data will be identified, patient safety should improve, and CDC will become more accountable to update (c’mon, where’s 2015 and 2016 NHSN AR data?! update the portal please!!),  maintain, and advance the public accessibility of useful data in our field.

Antimicrobial Stewardship and C. difficile Therapy: It's Complicated

The CDC's Get Smart About Antibiotics Week (November 16-22, 2015) is upon us. To do our part, we bloggers are using this (and hopefully other) posts to "Highlight Get Smart Week on your website" as CDC suggested as an Activity Idea. Of course, the problem with getting smart about antibiotics is that it's really complicated. Sure, reducing unnecessary antibiotic use (e.g. don't treat viruses) seems simple, but the toolkits necessary to assist primary care physicians aren't yet fully developed (e.g. improved rapid diagnostics). And don't even think about inpatient stewardship. I've yet to see antibiotic selection guided by the existence of bacterial multidrug efflux pumps, for example, but hopefully that's coming too. This is not meant to be discouraging, it's just to say that we have a long road ahead and we must keep pushing forward with stewardship-focused basic science studies and clinical trials including implementation science.

With all that in mind, I came across what appears to be an important paper in the November 15 issue of JID by Brittany Lewis and colleagues at Memorial Sloan-Kettering. The authors asked a fairly simple question - what happens to gut flora when it's treated with C. difficile specific therapies and how does antibiotic selection alter colonization resistance to C. difficile, VRE, CRE and E. coli challenges. The authors designed their study around a typical antimicrobial stewardship question: should we treat C. difficile infection (CDI) with metronidazole, vancomycin or both?

Using a mouse model (9 mice per treatment-time point), each was treated for 3 days with metronidazole, vancomycin or both. Fecal samples were then tested for bacterial population diversity (16s sequencing) and susceptibility to C. difficile spore inoculation at 1, 3, 7, 14 and 21 days. As you can see in the figure below, most metronidazole-treated mice could not support C. difficile growth (red circles) after seven days, while many who received vanco or vanco+metro remained susceptible to infection out to 3 weeks. At 7 days and 14 days, 11% and 0% of metronidazole-treated mice were susceptible, respectively. In those treated with vanco, 89% were susceptible at day 3 and 100% were susceptible at day 7. This suggests that vancomycin might increase risk for recurrent infection compared to metronidazole.

Given those findings, it is not surprising that mice treated with metronidazole alone maintained a relatively stable microbiota (See figure below - click to enlarge), which could explain their reduced susceptibility to C. difficile. Among those treated with vanco or vanco+metro, mice with higher levels of disrupted microbial communities were less able to suppress C. difficile growth.

Perhaps more importantly in our fight against antibacterial resistance, a second aim of their study (see figure below) found that mice treated with vancomycin (pink circles) were far more susceptible to VRE, carbapenem-resistant K. pneumoniae and E. coli than metronidazole treated (black circles) or untreated mice (open circles) for at least two weeks post therapy.

In summary, in this sophisticated mouse model, exposure to oral vancomycin was associated with higher risk of C. difficile, a prolonged highly disrupted microbiota and an elevated risk of VRE, CRKP and E. coli colonization compared to those treated with metronidazole alone. There seems to be an increased push to treat CDI patients with oral vancomycin, but given these findings, one wonders if increased utilization of PO vancomycin might be right for an individual patient (although there might be higher recurrence), but wrong for society with increased emergence of VRE, CRKP and other pathogens. After reviewing this study, I'm surely a bit smarter about antibiotics, but unsure of how to treat patients with CDI...and so it goes.

The Poop Cafe

Well, another week has gone by and we haven't posted much of significance. Summer is officially over around here with students piling back into Iowa City. There's no more parking, it's harder to find an open treadmill at the gym and lines at The Java House are much longer these days. Which brings me to a new coffee house craze sweeping (apparently) through Asia - the poop cafe. Who wouldn't want to drink a cappuccino out of a toilet-shaped mug or chow down on a poo-shaped scone all while wearing a poop hat?

So, in the spirit of the last summer weekend and as a reminder of how crappy we have been about blogging this summer, I give you these pictures below....at least they'll be useful for you're next C. difficile talk.

Coordination of what?

I’m glad that the new CDC Vitals Signs report, based upon a modeling study of the impact of regionally-coordinated interventions to reduce healthcare associated infections (HAIs) due to selected multiple drug resistant organisms (MDROs) and C. difficile, is gaining some media attention. The investigators modeled three different scenarios for control: (1) status quo, (2) “augmented” efforts at selected individual facilities, and (3) augmented activities coordinated across a health care network. Using data from various sources to inform the model (Emerging Infections Program and National Healthcare Safety Network for disease burden; Orange County, California and the VA system for patient movement across healthcare facilities; and experience from the UK and Israel for reductions in MRSA, C. difficile, and carbapenem-resistant Enterobacteriaceae (CRE) after national interventions), the model suggests that prevention approaches coordinated by public health authorities could reduce HAIs due to CRE by 55-74%.

This analysis has several limitations, most of which are pointed out by the authors in their discussion—models are models. And I don’t think anyone disagrees that coordinating infection prevention activities across healthcare systems is a desirable goal. The sad fact, though, is that we are very far from achieving this goal. I think Judy Stone has a good take on this, here. Furthermore, even if public health funding were increased enough to provide resources for state and regional coordination of MDRO control, the impact would depend upon each facility’s capacity to implement basic infection control practices (as the authors point out, “Optimizing implementation of basic infection control practice within individual facilities will be of fundamental importance to this effort”).

So while we wait for the inevitable boost in public health funding that is sure to come from our current Congress, we should remain focused on improving the basic “horizontal” infection control practices of individual facilities. It is not possible to know in advance which patient harbors a life-threatening bacterial pathogen (resistant or not), so it is best to assume that everyone does.

Adventures in the microbiome (part 1)

There's a really interesting new paper in Clinical Infectious Diseases on a novel treatment for recurrent C. difficile infection. In this retrospective, uncontrolled experience, 25 patients with recurrent C. difficile infection (mean number of relapses = 4, median days of illness = 135) were treated with either metronidazole or oral vancomycin, along with kefir (5 oz three times daily). The antibiotics were given for 2 weeks at a standard dose (i.e., vancomycin 125 mg every 6 hours). In the next 2 week period, it was given at 3 times standard dose once every 72 hours (i.e., 375 mg), followed by 2 weeks of 2 times standard dose every 72 hours, then 2 weeks of standard dose every 72 hours. This strategy is known as staggered and tapered antibiotic withdrawal (STAW). The kefir was continued for 2 months after the antibiotic was discontinued.

I had to learn about kefir as I knew very little about it. It's essentially milk in which the lactose has been fermented by bacteria. It contains 10 strains of bacteria at a concentration of 7-10 billion CFU/cup. Thus, it's a big gun probiotic, and comes in several different flavors and forms (liquid, frozen, yogurt, cheese). You can find it in most grocery stores.

The end result was that 84% of the patients treated with STAW + kefir were diarrhea-free at 9 months. Again, this was an uncontrolled study, but nonetheless quite intriguing. I will certainly try this regimen in patients with recurrent C. difficile as an option for patients who either don't want to have a fecal transplant or would like to try this before resorting to transplant. I also wonder whether we should be serving kefir to hospitalized, nonimmunosuppressed patients as a prophylactic strategy for C. difficile. This weekend, I'll sample some of the products myself.

Tomorrow, I'll tell you about another interesting manipulation of the gut microbiome.

Stewardship Effective in C. difficile Prevention: A Meta-Analysis

As Dan mentioned last week, when 15% of asymptomatic hospitalized adults carry toxigenic strains of Clostridium difficile, it should alert us to focus on antimicrobial stewardship as a way to prevent CDI. But how effective are stewardship programs and does it matter what type of program you implement in your hospital? If only there was some sort of systematic review or meta-analysis to guide or decision making.

As if on queue, Leah Feazel and Marin Schweizer at University of Iowa published such a review and meta-analysis titled "Effect of antibiotic stewardship programmes on Clostridium difficile incidence" in JAC earlier this spring. Typical of projects completed by Marin and her group, they thoroughly combed the literature for papers. Here they identified 891 articles, reviewed 78 full articles and included 16 studies in their final analysis. Over all, stewardship programs were associated with a 52% reduction in CDI incidence. Importantly, programs appeared effective when implemented in whole hospital or geriatric settings and when utilizing a persuasive approach or a restrictive approach. I've provided the forest plot of studies below. An additional note is that the studies utilized various quasi-experimental study designs and based on the funnel plot, there appeared to be little publication bias.

Key points: (1) Stewardship works for CDI prevention, but it would have been nice if there was at least one funded RCT or cluster-RCT. (2) The meta-analytic approach, that Marin has pushed through her reviews of SSI bundles and hand hygiene interventions, is a fantastic way to guide medical decision making and should be considered for inclusion in future HAI guidelines. The reality is that infection prevention studies overwhelmingly utilize quasi-experimental designs. Why not identify the highest-quality QE studies and rigorously meta-analyze them as done here?

Another kibosh

Increasingly, my work life seems to revolve around C. diff. Yesterday I performed three fecal transplants. All were elderly patients who had been suffering with recurrent C. difficile for many months. Using stool from OpenBiome's stool bank greatly simplified my job and made the entire process much easier for the patients. Since OpenBiome's donors are extensively screened, the patients did not have to identify a donor and bear the unreimbursed costs of donor screening. Family members of all three patients commented on the ease of the process, and were quite happy with not having to identify a donor. The daughter of one patient who been transplanted previously with a directed donor, specifically commented on her preference for using a standard donor. And as always, the patients and family members were incredibly grateful and very happy to think about life without vancomycin. I left clinic feeling as though I had made a real difference by providing these patients a therapy that still is unfortunately relatively rare. One of the patients yesterday had to travel three hours to see me for this very simple, yet highly effective treatment.

Last night, on the way home, one of our infectious diseases fellows called me to discuss fecal transplant for a critically ill patient in the ICU who was failing all the drugs we have available to treat C. difficle. I happily told him that fecal transplant should not be a problem as we have frozen stool now available in the pharmacy.

This morning I spoke by phone with a woman whose mother is hospitalized two hours away after having multiple recurrences of C. difficile regarding coming to Richmond for transplant. And a patient that I transplanted a few weeks ago (the first patient I transplanted with donor stool from OpenBiome) called to tell me how well he was doing.

It seemed as though the whole fecal transplant process was finally working very smoothly. But as I went to bed last night, I took a final look at my phone and saw an email from a colleague with a link to new information from the FDA on fecal transplant. Those of you who follow this blog may recall that the FDA had previously proposed that all fecal transplants would require an IND number; however, this requirement was later relaxed. I was stunned by the FDA's proposed new rule. Since the FDA seems to write in a different language, I will paste their verbiage here:

After publication of the July 2013 Guidance, FDA has continued to review this area and is clarifying its enforcement policy.  FDA intends to exercise this discretion on an interim basis, provided that:

1. The licensed health care provider treating the patient obtains adequate informed consent from the patient or his or her legally authorized representative for the use of FMT products.  The informed consent should include, at a minimum, a statement that the use of FMT products to treat C. difficile is investigational and a discussion of its potential risks.
2. The FMT product is obtained from a donor known to either the patient or the treating licensed health care provider. 
3. The stool donor and stool are qualified by screening and testing performed under the direction of the licensed health care provider for the purpose of providing the FMT product to treat his or her patient.  

FDA does not intend to exercise enforcement discretion for the use of an FMT product when the FMT product is manufactured from the stool of a donor who is not known by either the patient or the licensed health care provider treating the patient, or when the donor and donor stool are not qualified under the direction of the treating licensed health care provider. 

So it seems that the FDA is not happy with the concept of banked stool from standard donors and would prefer directed donors. If I test a donor once for infections and that donor is known to the patient, I don't need an IND. But, if I obtain the stool from a stool bank that has a small number of highly selected donors that are tested serially every 60 days, and the stool is quarantined to avoid the problem of an infected donor in a seronegative window period, I need an IND? The blood bankers actually discourage the use of directed donors as the directed donor may be less likely to disclose risk factors for infectious diseases. There is no reason to think that would be different here.

I called the number on the FDA's announcement. The person I talked to was polite but I felt as if I was talking to someone in a parallel universe. After 10 minutes, I didn't feel like I had any better understanding of the issue. She told me that there were no data that fecal transplant is effective for C. difficile. Really? I reminded her that the randomized controlled trial published in the New England Journal was stopped early because it worked so well. She could not tell me whether I could even get an IND if I was using product from a stool bank, though later implied it could only be used in a clinical trial. She transferred me to "Manufacturing" and felt sure they could help me. The person in Manufacturing was not even aware of the announcement and said that I need to talk to someone in "Vaccines." Between this issue and the IV zanamivir issue, I have come to the conclusion that the FDA is so isolated and so sucked into the parallel universe of its bureaucracy that's it's lost touch with its mission.

While I might not be able to understand what the FDA is saying, here is what I do know: recurrent C. difficile is a terrible illness that is becoming increasingly common. In a subset of patients, antibiotics are not curative. It destroys quality of life, and if untreated in the elderly leads to wasting and ultimately death. A simple treatment is highly effective in curing the infection. And a group of really bright students in Boston found a creative solution to make stool transplants readily available and quite safe for patients. But a behemoth bureaucracy chooses to stand in the way.

Word of the day: crapsule

There's a great article in The Atlantic on fecal transplants for C. difficile infection (free full text here). What I like about this piece is that it describes the very real barriers to fecal transplantation without any sugar coating. It also highlights the work of Dr. Bruce Hirsch, an infectious disease doctor who crafts capsules with fecal bacteria (or "crapsules" as he calls them) so that patients can be transplanted without an NG tube or colonoscopy.

Photo:  Salon.com

Seek and ye shall find? Not so much...

Our understanding of the epidemiology of C. difficile infections continues to evolve. Dan recently blogged on a new paper that shows that a high proportion of healthcare associated cases are not due to transmission in the hospital. Another new paper in BMC Infectious Diseases (full text here) takes a look at an important question: are colonized healthcare workers involved in the transmission of Clostridium difficile in the hospital setting? At a large hospital in Australia a convenience sample of 128 healthcare workers (mostly nurses) had stool samples tested for C. difficile. Over 40% had known contact with C. difficile infected patients. Specimens were tested by ELISA and culture. No carriers were found. Given how difficult it is to get stool samples from HCWs, the authors should be commended.

Two other similar studies have been performed in the last 5 years. One found no colonized HCWs out of 112 tested, and the other found 4 of 30 (13% positive). So based on limited data it appears that colonization of healthcare workers probably does not play a major role in the transmission dynamics of C. difficile, though larger studies are needed.

Photo: Maddie Meyer/The Washington Post

Everything old is new again, with WGS!

As we’ve pointed out, whole genome sequencing (WGS) is the hottest new tool to help us decipher the epidemiology of healthcare-associated pathogens. Last week’s NEJM included a study using WGS to investigate the molecular epidemiology of C. difficile disease (CDD) in Oxfordshire, UK. In a 3.6 year study that included 1223 CDD patient isolates, the investigators found that only 333 were genetically related to at least one previously obtained isolate. Of those 333, only 126 (38%) had nosocomial exposure to the earlier patient. And the finding receiving the most attention: 45% of strains isolated were genetically distinct from all previous isolates.

The take home point? In current hospital settings (where we isolate every known CDD patient and use enhanced environmental measures to try to eradicate their C. difficile spores), symptomatic CDD cases are no longer the major reservoir for C. difficile acquisition. Focusing only on transmission prevention, then, will have a limited impact (antimicrobial stewardship, anyone?). Most obviously, further work is clearly needed to identify other sources of exposure and acquisition of C. difficile.

This may come as news to many, but probably not to Matt Samore, who made a similar observation….in 1994.

Annual cost of HAIs in the US = $10 billion

A new paper in JAMA Internal Medicine aims to give us an update on the impact of healthcare associated infections in the US. Given all the focus on HAIs, particularly with the rollout of value based purchasing, this is an important study. The investigators performed a systematic review, which included papers that were published this year, to determine attributable cost estimates, used NHSN data for incidence estimates, then performed Monte Carlo simulation. Total cost of the 5 major infections (CLABSI, CAUTI, VAP, SSI and C. difficile) was estimated to be $9.8 billion per year. The table below shows the breakdown by infection type.

Eli may want to comment on the methodology of the study and the validity of the results, but I suspect these numbers will be cited frequently.

Multidisciplinary, multifaceted approach to C. difficile prevention - It works!

Clostridium difficile - bad.

Many good people doing a lot of good things to prevent C. difficile - Priceless

That's the basic summary of a recent report in The Joint Commission Journal on Quality and Patient Safety by Len Mermel and colleagues at Rhode Island Hospital. Faced with a high burden of CDI, they implemented a series of six "interventions" targeting C. difficile between 2006 and 2012.  These interventions were: (1) develop a C. difficile hospital infection control plan based on a risk assessment; (2) monitor hospitalwide morbidity and mortality associated with C. difficile infection; (3) improve sensitivity of C. difficile toxin detection in stool specimens using a PCR assay; (4) enhance environmental cleaning of patient rooms and equipment; (5) develop a C. difficile infection treatment plan; and (6) conduct other interventions including attempting antimicrobial stewardship.

Overall, the results were impressive with a 70% reduction in incidence. From a peak of 12.2 cases per 1000 discharges in 2006 rates fell to 3.6/1,000 discharges in 2012 with comparable declines in CDI-related mortality. Using time-series analysis they reported a change in slope of quarterly healthcare-associated CDI cases per 1000 discharges after each intervention, which you can see in the figure below. The slopes of each line are associated with (from left to right) the (1) pre-intervention period, (2) education, outcome reporting and room cleaning monitoring, (3) bleach product use for room cleaning, (4) PCR testing (5) additional room cleaning personal hired with defined responsibilities, (6) equipment cleaning training and monitoring.

Here is the link to the full text of the article (subscription required). Is it me or should Joint Commission's journal be open access in 2013?

CDI? Think PPI

Following up on last years MMWR that reported that "nearly 75% of all Clostridium difficile infections (CDI) related to U.S. health care have their onset outside of hospitals", CDC researchers have released a new study in JAMA Internal Medicine looking specifically at the epidemiology of community-associated CDI. The study used data from the Emerging Infections Program, which began to actively collect CDI data in 10 states starting in 2009. This report uses data from 984 patients collected over 29 months with true community-onset CDI, as they excluded community-onset, healthcare facility associated infections.

Somewhat surprisingly, 36% of patients had not received antibiotics and 18% had no outpatient health care exposure. Not surprisingly, 31% of those who had not been exposed to antibiotics had been exposed to PPIs.  I highlighted the risk of CDI from PPIs in my ICPIC talk last month when I discussed this meta-analysis by Kwok and colleagues. In this CDC study, those patients lacking significant outpatient healthcare exposure were also more likely to be exposed to infants and household members with active outpatient healthcare exposure suggesting a potential route of transmission. I agree with the authors primary conclusion that a reduction of outpatient PPI use may be necessary to reduce the risk of CDI. As Mike' pointed out four years ago, PPIs are also associated with HAP, VAP, and SBP, so there are many reasons to be concerned about PPIs.

There is an excellent accompanying editorial by some guy named Kent Sepkowitz, who discusses the "PPI-zation" of the US and the difficulties facing any public health initiative targeting PPIs. For one, PPIs are the third most utilized drug in the US and they are addictive since discontinuation is associated with withdrawal symptoms.  For another, unlike antibiotics, PPIs are widely available over the counter and supported by huge advertising campaigns. Looks like PPIs are here to stay...

A pleasant surprise....

Yesterday, the FDA quietly posted an announcement regarding the requirement for submitting an investigational new drug (IND) application by physicians who perform fecal transplantation. In part, it says:

Some health care providers have stated that applying IND requirements will make FMT unavailable and have suggested that an alternative regulatory approach is needed to ensure the widespread availability of FMT for individuals with C. difficile infection unresponsive to standard therapies. 

The agency acknowledges these concerns and intends to exercise enforcement discretion regarding the IND requirements for the use of FMT to treat C. difficile infection not responding to standard therapies provided the treating physician obtains adequate informed consent from the patient or his or her legally authorized representative for the use of FMT products. Informed consent should include at a minimum, a statement that the use of FMT products to treat C. difficile is investigational and a discussion of its potential risks. 

FDA intends to exercise this discretion while the agency develops appropriate policies for the study and use of FMT products under IND. The agency intends to issue guidance reflecting the agency’s intention to exercise enforcement discretion.

During this time FDA strongly encourages compliance with the IND regulations, and stands ready to work with sponsors who are interested in conducting clinical trials.

I've read this a couple of times, and I'm not sure exactly what this means. Can fecal transplantation now be performed without an IND as long as there is informed consent? It sounds as though further information is forthcoming. Nonetheless, it appears to be a step in the right direction. Kudos to the patients and their families for making their voices heard. Yesterday, one of my patients spoke about her experience here:

NBC12.com - Richmond, VA News

FDA shoots self in the foot

Last week I blogged about the FDA's ruling to classify human stool as an investigational new drug, making it more difficult for patients with recurrent C. difficile infection to undergo fecal transplantation, an incredibly effective therapy.

I was scheduled to perform a fecal transplant on a patient this morning, but notified her a few weeks ago that we could not proceed because of the new ruling. She asked to keep the appointment with me anyway. She presented to clinic this morning and informed me that she had performed the transplant at home a few days ago. And she was happy to report that she was feeling much better!

As it turns out, I have at least 3 more patients in the process of preparing for self-administered fecal transplant at home. The instructions for doing so are readily available on the internet. I suspect this do-it-yourself movement will now become widespread. It's ironic that the attempt by the FDA to regulate this procedure in the interest of safety appears to be driving a completely unregulated and more risky response.

Someone should have reminded the FDA that unlike the usual investigational new drug, which is impossible to obtain outside of a highly regulated and structured mechanism, human stool is readily available, easy to procure, and impossible to regulate. These patients are highly motivated, know the data on effectiveness, and won't be told no!

Photo:  Vendor Alley

The kibosh

Over the past several days I have spent a lot of time talking to patients, trying to explain why I've had to cancel their upcoming fecal transplant. The FDA has ruled that stool is an investigational new drug (IND), which now imposes a huge bureaucratic hurdle to getting a much needed therapy for patients with recurrent or intractable C. difficile infection. Today's Omaha World-Herald covers the new ruling and features our fellow blogger Dan Diekema. 

Even before the FDA did this, there were already hurdles for patients who are really suffering a great deal. First, there are few physicians who are providing this therapy. I have had patients drive over 8 hours to come for a treatment that is quite primitive but amazingly effective. For the doctor it's time consuming and the reimbursement is very poor. Nonetheless, I have felt morally compelled to provide this therapy and as a result I have many thankful patients. Then there is the issue of insurance companies not covering the cost of donor testing, which costs $1500-2000. Now there's the additional burden of the FDA red tape and the numerous documents required by institutional review boards.

So now I must apply for an IND number, which requires that I send the FDA my protocol. On the 30th day after receipt of my documents the FDA will let me know whether I can proceed. When I talked to the FDA officer yesterday she informed me that the FDA is only interested in fecal transplants with regards to safety. They want to ensure that donors are appropriately screened. Thus, I need to send them my protocol for donor testing and then I will get a ruling. I asked the officer what the FDA was looking for and was told that they can't say but will either approve or not approve my protocol. Now wouldn't it have made more sense for the FDA to review the literature and consult experts about what optimal testing of donors and safeguards should be for the procedure and simply require practitioners to follow their guideline instead of the guess-what-I'm-thinking-and-wait-30-days game?

Ok, enough Debbie Downer. Now something positive: here's an article about a pathology resident at Emory University, Dr. Hunter Johnson, who goes beyond the call of duty and serves as a stool donor. In the article he talks about how important it is to perform on command. I learned that lesson the hard way. When I first starting performing fecal transplants, I explained to patients the important exclusions for donor selection, such as no recent foreign travel and no recent antibiotics. But I never thought to tell patients that choosing a donor who has problems with constipation is probably not a wise choice until the day the patient arrived for a transplant with his donor but with no stool specimen in hand. Constipation is now on my list of exclusion criteria for donors!

Photo of Dr. Hunter Johnson by Eric S. Lesser, NBC News.com

Hat tip: Kathy Kreutzer 

Hand Hygiene Causes Obesity

Subtitle: "Or how you can associate almost anything with a weak study design."

One of my favorite epidemiological study designs is the temporal association "ecological" study that attempts to infer causation by showing one exposure increasing and one outcome increasing and then implying that the exposure is causing the outcome. You know, "Hey, they are both going up so one thing causes another." Vaccine use and autism rates anyone?  So, just for fun I've produced the graph above and as you can see, through the efforts of CDC, WHO, VA and many individually hard-working IPs, hospital epidemiologists and clinicians hand hygiene compliance has increased. And as you can also see obesity is also increasing, ergo hand hygiene causes obesity!  Just try to disprove it!

Now, why am I wasting time with such an exercise? Because there is a paper in this June's ICHE that uses a similar study design and comes to an equally incorrect and perhaps dangerous conclusion.  The study used 2008-2011 data from Ontario to compare yearly hand hygiene compliance rates to quarterly MRSA rates and monthly CDI rates. The study found that despite increases in hand hygiene compliance there was little change in MRSA and CDI rates over this period. The author then concluded: "This study supports the emerging evidence that once a threshold level of hand hygiene compliance is achieved, there is very little if any benefit to attempting to achieve higher rates of hand hygiene compliance among healthcare providers."

Well, except that you can't conclude that from such a study design. For one, the author didn't have exposure and outcome from the same time periods. Why would we think average hand hygiene compliance over an entire year would correlate with monthly CDI rates and quarterly MRSA rates?  And how can we not consider other factors at play like the emergence of NAP1 or CA-MRSA during this period? Maybe there's even a Simpson's Paradox here, but that's a topic for another day. Oh, and keep washing your hands. I doubt we've reached a "threshold" of compliance!

Addendum: Probably the biggest flaw in this study is the accuracy of the reported hand hygiene compliance rates. No doubt the rates are lower than reported.

Proof.

Finally, the purists out there who require demonstration of efficacy by a randomized clinical trial before attempting a novel therapy can now breathe a great sigh of relief. The New England Journal of Medicine has just published an RCT that demonstrates the clinical utility of fecal transplantation for C. difficile infection. In fact, fecal transplants worked so well that the trial was terminated early after an interim analysis.

Patients in the study all had C. difficile infection with at least one relapse. They were randomized to one of three study arms: (1) a 4-day course of oral vancomycin followed by bowel lavage then fecal transplant via nasoduodenal tube; (2) a 14-day course of oral vancomycin; or (3) oral vancomycin plus bowel lavage. In the transplant group, 13 of 16 patients were cured after 1 fecal infusion (2 of the remaining 3 were cured after a second infusion). In contrast only 4 of 13 in the vanco group, and 3 of 13 in the vanco plus lavage group were cured. Bottom line: fecal transplantation had an overall cure rate of 96%.

There remain two barriers for patients to access this highly effective therapy: (1) very few physicians perform the procedure, in part, I think, because there is no reimbursement despite the several person-hours required to prepare the fecal solution and administer it; and (2) insurance companies will not reimburse for donor testing, which costs approximately $1500.

So we've proven what we already knew. Now it's time to look at more interesting questions: does fecal transplantation work for irritable bowel syndrome and inflammatory bowel disease?

Graphic:  Andrea Levy, Cleveland Plain Dealer.

Should we go over (to) the Cliff?

There's been a lot of talk in the US about "the cliff," specifically the fiscal cliff. Should we go over the cliff? Is the cliff just a curb?  What should we do? Panic! In response, the GOP has started pushing "Plan B," which will apparently require all Americans to receive emergency contraception if they're pregnant. This has some merit since if we no longer exist, we can't really run up the budget deficit, now can we.

Anyway, this is ostensibly an infection prevention blog, so I better get back on topic.  In the annual Christmas issue of the BMJ, investigators from the Netherlands have reported a novel method for speeding up the diagnosis of Clostridium difficile infection. The name of their novel method?  Cliff.  Just as I expected, they call or email the CDC and ask Cliff McDonald what he thinks! NO? What?

It turns out that they've trained a beagle named Cliff to diagnosis C. difficile by smell (thank goodness it's not taste). Anyone who has done an ID fellowship or even a medical internship gets pretty good at recognizing the unique small of C. diff, so we know this could work. It turns out to work pretty well. Cliff's nose detected C. difficile positive clinical samples with a sensitivity of 83% and a specificity of 98%. Not too shaggy.

Addendum: A 2007 CID study reported self-selected nurses had a sensitivity of 55% and specificity of 83% in diagnosing C. diff, while an earlier study reported that nurses had a sensitivity and specificity of 84% and 77% for predicting C. diff using factors that included odor. I would like to see Cliff dual it out with these nurses in a future trial. Daniel Uslan suggested Cliff vs "Sniff": an RCT.

Chlorhexidine: Also prevents general malaise and existential crises

We can now add Clostridium difficile to the long list of maladies that can be prevented by the zealous application of chlorhexidine (in this study, a 4% aqueous solution, first thrice-weekly and then daily, hospital-wide). Yes, I realize that this study (from our good friends in Nebraska) was quasi-experimental (lacking a concurrent control group), and I realize that it was funded by a manufacturer of chlorhexidine (a company whose name I cannot spell or pronounce).

Potential confounders include changes in diagnostic testing during the course of the study (but these changes should have made a decrease more difficult to detect, because they moved to increasingly sensitive assays), and the introduction of other C. difficile control measures (pre-emptive isolation and bleach disinfection were introduced a couple years before the start of this study, but could have had some delayed impact). Finally, there is the biological plausibility issue—if chlorhexidine isn’t sporicidal, how could it impact C. difficile rates? The authors suggest it could be due to physical removal of spores, and/or to killing of vegetative bacteria or prevention of spore germination. All seem plausible, but require further study.