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.

Robert C. Moellering, Jr., MD

The emails and text messages all carried very sad news today. Dr. Moellering died last night after a protracted illness. To quote from one email, many are left "with a very heavy heart and a sense of irreplaceable loss." Dr. Moellering was the Chair of Medicine at BIDMC during my fellowship and a mentor to many who passed through the New England Deaconess and Beth Israel Deaconess ID Divisions. On a personal level, beyond the knowledge and wisdom he imparted on me as a fellow, I will never forget receiving a reprint request from him upon the publication of my first post-fellowship paper. Certainly he already had a copy of the journal and certainly he had more important things to do. Others recalled similarly kind gestures.

Robert C. Moellering, Jr. was born in Lafayette, Indiana. He graduated from Valparaiso University (zoology) and received his MD from Harvard in 1962. He completed his residency and fellowship training at the Massachusetts General Hospital. From 1981 through 2005 he was Physician-in-Chief and Chairman of the Department of Medicine at the New England Deaconess Hospital and after the merger in 1996 at BIDMC. He was then the Shields Warren-Mallinckrodt Professor of Medical Research at Harvard Medical School. He published over 400 original articles in a broad range of areas including antimicrobial resistance and antibiotic therapy and was directly involved in laboratory research for over 35 years. One thing many will remember him for is his role as editor for the Sanford Guide to Antimicrobial Therapy. He was honored numerous times including receiving the Maxwell Finland Award from IDSA, the Hoechst-Roussel Award from ASM, the 2006 the Maxwell Finland Award for Scientific Achievement from NFID and the 2008 Alexander Fleming Award for Lifetime Achievement from IDSA.

Beyond his biography, I wanted to share two quotes from Dr. Moellering and a final one from Dr. Jerome Groopman delivered on the occasion of Dr. Moellering stepping down as Chair of Medicine.

“I served for the better part of 24 years as chairman of the department and also ran the faculty practice plan here. But I view administration as nothing more than a means to an end--a means to create more effective clinical and teaching programs in the department, and a way to ensure that I could have an impact on the training of physicians and the internal medicine house staff.”

“Teaching is the most important thing we do. Imparting knowledge to the next generation of physicians is incredibly important. It’s a privilege we are given in the academic setting. Not only does it give you a tremendous sense of satisfaction in that you’ve done something worthwhile, but it gives you some immediate gratification because you can watch students who go on to successful careers.”

Dr. Jerome Groopman: "How many of us has he supported on his shoulders? How many of us has he helped to move forward when we felt we didn't have the energy or endurance to continue? Those shoulders have carried enormous burdens, carried with a quiet confidence, through all the difficult times, the growth of the department, the merger…. Bob is loved because beyond his intellect, beyond his knowledge, beyond his hard work, he is filled with a unique form of kindness. Bob has true generosity of spirit. He sees your success as his success. This is his legacy."

References:

1) BIDMC Historical Biosketches - Amy Slansky 2005
2) NFID, 2006 Maxwell Finland Award

What's happening with Staphylococcus aureus?

Antimicrobial resistance surveillance systems are critically important for guiding empiric antibiotics, antimicrobial stewardship programs and hopefully therapeutic and prevention research efforts. While it is true that surveillance always seems to show things are getting worse, it's the speed with which things change that is also important. With that in mind there are two recent reports from a national surveillance study that provide important data in regards to the magnitude and trends of resistance and molecular epidemiology among S. aureus and MRSA clinical isolates. (COI alert: both were authored or co-author by Dan)

Both studies used a sample of 4,131 clinical specimens submitted as 100 consecutive isolates from 43 US Centers during the last half of 2011. The first study published in AAC reported MIC distributions of all isolates stratified by MRSA and MSSA. 51% were MRSA. Over 95% of both MRSA and MSSA isolates remained susceptible to ceftaroline, tigecycline, daptomycin, linezolid, vancomycin, tetracycline and TMP-SMX. Thus, both from an empiric and definitive therapy standpoint, we have many treatment options available. Of the 2,093 MRSA isolates, 60 (2.9%) were hVISA positive via either one or both available screening tests and 25 (1.2%) were confirmed as hVISA. This is three times higher than in 2009 when only 0.4% were hVISA. The paper nicely provides details concerning the sensitivity and specificity of the screening tests for those interested.

The authors also reported a significant increase in high-level mupirocin resistance from 2.2% in 2009 to 3.2% in 2011 when all isolates were analyzed and from 2.8% to 4.0% when restricted to MRSA. The authors correctly state that recent trials highlighting the efficacy of universal mupirocin decolonization will only lead to greater selective pressure for these strains and increase their prevalence. This needs to be watched carefully.

In this month's ICHE, the authors published an analysis highlighting the molecular epidemiology of the MRSA stains using the same cohort. 30% were hospital-onset by the 48-hour rule and 64% were PVL positive. USA300 dominated in all strata (source, age, census region) except from lower respiratory tract isolates and in patients greater than 65yo. Of the 173 spa types identified, 51% were t008 and 18% were t002. 48% of all MRSA strains were the composite type (USA300/t008/SCCmec IV). See the figure below comparing it to the next most prevalent composite type (USA100/t002/II), which was found in 11% of isolates. I encourage you to read the entirety of this paper, as the authors discuss the possibility that MDR-clones of USA300 could emerge since it's now firmly established in the healthcare environment. Hopefully Dan will chime in with some comments. My take-away: USA300 = MRSA and MRSA = USA300, at least for now.

Well child, Sick child

Who doesn't get a little bit nervous in a pediatric clinic waiting room? Even in an office that divides “sick” from “well” waiting areas, kids tend to move pretty freely, and of course the pathogens contained in respiratory droplets move even more freely. I always assumed that the risk from these exposures (of the “well-children” to the “sick-children” in ambulatory clinics) was fairly small, at least compared with the usual community exposures kids have at home, at day care, at the children’s museum, etc.

Our colleague Phil Polgreen and his group analyzed some “Big Data” (the Medical Expenditure Panel Survey) to try to determine if well-child visits are indeed a risk factor for subsequent influenza-like illness (ILI). Their findings are published in this month’s issue of Infection Control and Hospital Epidemiology, and confirm the suspicion that the ambulatory pediatric clinic is likely to contribute to viral respiratory pathogen transmission. The odds ratio for ILI after a well-child visit (within prior 2 weeks) was 1.54 (95% CI, 1.43-1.66), which seems pretty large, though the absolute risk was modest (~3% increased risk). However, if you consider the total number of such visits annually, the number (~800K) and cost ($500 million) of excess ILI cases is substantial.

Lisa Saiman has an excellent editorial discussing the implications of these findings, the main message being that we need to pay more attention to infection prevention in ambulatory settings. My only additional suggestion (which, admittedly, may be unrealistic for many clinics): forget about separate waiting rooms, instead have physically or temporally separate clinics for well-child versus sick-child visits (with clear signage to direct kids who happen to be sick during a well-child visit to the “sick-child” clinic).

Image: The Sick Child, by Gabriel Metsu, 1660

Same data, different conclusion

There's an interesting study in the March issue of Infection Control and Hospital Epidemiology led by Keith Kaye, which examines the hypothesis that the burden of patients in contact precautions has an impact on compliance with contact precautions. The study used surreptitious observers to record compliance with the components of contact precautions in eleven teaching hospitals. Approximately 1,000 observations were performed in the ICU and ward settings. The authors conclude: "As the proportion of patients in contact isolation increases, compliance with contact isolation precautions decreases." 

However, looking at the same data, I came to a different conclusion. I converted the bar graph (figure 2 in the paper) to a line graph which makes it easier to follow compliance with each component of contact precautions as the proportion of patients in contact precautions increases:

Now you can clearly see that the only problem with compliance as the burden of contact precautions increased was with hand hygiene prior to donning of gowns and gloves. Thus, decreased compliance with the contact precautions "bundle" was driven solely by the decrease in hand hygiene prior to patient contact. It has been shown in other studies that hand hygiene is lower prior to contact precautions. And I think there is a very simple reason that this occurs: you can't get the gloves on until your hands are completely dry. Hand hygiene before and after patient contact is an essential component of standard precautions. What sets contact precautions apart from standard precautions is the use of gowns and gloves, and the data in this study show no decrease in gown or glove use as the proportion of patients in contact precautions increases. In addition, the overall usage of gowns and gloves was surprisingly high.

So my conclusion would be that there is a negative correlation between the burden of contact precautions and hand hygiene prior to patient care. And maybe that's not so bad...

Photo: Liberty Voice

The CHG, CareFusion, NQF, Journal of Patient Safety (and perhaps more) Scandal

For the past month there has been an emerging and evolving scandal involving several key players in patient safety. From what I've gathered, Jonathan Stempel broke the story on January 9th in Reuters. There was a federal court case (U.S. ex rel. Kirk v. CareFusion Corp et al, U.S. District Court, District of Kansas, No. 10-02492) settled by CareFusion Corp after agreeing to pay $40.1 million for kickbacks to boost sales of CHG pre-surgical scrub and promote its off label use. Where this gets interesting is that a specific physician, Charles Denham, was named and apparently paid $11.6 million to promote ChloraPrep.

There is more to the story and for those interested, you should head over to Bob Wachter's excellent post describing the scandal and ProPublica's post with links to key documents including internal National Quality Forum (NQF) meeting proceedings. Briefly, Charles Denham the named physician was a key member of NQF and co-chair of the 2009 committee charged with updating their "Safe Practice" guidelines. It appears that he attempted to use his position to push 2% CHG, which is a formulation favored and produced by CareFusion. In addition, he was editor of the Journal of Patient Safety, a member of the Leapfrog Group (since resigned) and was highly connected in the patient safety movement.

It is all very concerning and in some ways sad. My major question is how can such important groups (Leapfrog and NQF) rely on someone to lead such important efforts when they've almost no background in patient safety including almost no research publications prior to becoming editor of the Journal of Patient Safety? It seems like that patient safety movement needs to identify and promote faculty within its ranks with strong scientific backgrounds and those without such strong ties to industry. The safety movement can't be about money, it just can't. I also wonder about CHG. A letter to the editor in the August 2013 ICHE by Maiwald and colleagues does a nice job highlighting some limitations in the current CHG literature. It's worth a read.

Flu: A ground-level view

This flu season seems to be having a huge impact, though the data from CDC don't seem to be giving a complete picture. It is clear that many states continue to be experiencing widespread activity, but the national data don't capture the severe morbidity and the mortality that is occurring in young adults due to H1N1. Just at my hospital we have had several young adults require ECMO. We have heard reports of hospitals having to borrow ventilators due to the number of patients with influenza associated ARDS, and we are aware of deaths due to hospitals exceeding their capacity to provide ECMO. There is the perception among many clinicians that the severity of disease seen this year exceeds that seen during the 2009 H1N1 pandemic. Part of the problem, at least in Virginia and many other states, is that influenza deaths in adults are not reportable, nor do we have accurate data on patients requiring mechanical ventilation or ECMO. Perhaps it's time to rethink influenza surveillance particularly since diagnostic testing has improved significantly over the past few years.