Safer.

AHRQ.

Negative study of the month, C. difficile edition

I like a good negative study, particularly when it’s a multicenter randomized trial about preventing our most problematic healthcare-associated infection. So let’s take a moment to appreciate this work from Amy Ray and colleagues.

These investigators randomized 16 hospitals to either standard cleaning or “enhanced cleaning”, which meant monitoring of environmental services personnel with feedback of performance (measured using fluorescent markers for cleaning and environmental cultures for disinfection). They measured the outcome of healthcare-onset, healthcare-facility associated C. difficile infection (HO-HFCA CDI). The study was powered to have >95% power to detect a 25% reduction in HO-HFCA CDI in intervention hospitals (and 70% power to detect a 15% reduction).

Bottom line: the intervention led to clear improvement in cleaning (better removal of fluorescent markers) and disinfection (reduction in % of C. difficile + environmental cultures in CDI rooms from 13% to 3%--which was the approximate rate of contamination in non-CDI rooms). Unfortunately, there was no reduction in HO-HCFA CDI during the intervention period, and no difference between control and intervention hospitals (see figure below and article for details).

Few people know more about CDI than Curtis Donskey (senior author of this study), so I encourage you to read their interpretation of these negative findings. They cover several potential explanations--the one I find most convincing is that the portion of HO-HCFA CDI attributable to organism acquisition during hospital admission may be smaller than we realize. Thus I agree that we need more studies to help us “identify effective strategies to reduce the incidence of healthcare-associated CDI.” 

I’ve already weighed in with my opinion on the most effective strategy.

Anyway, bravo to Ray and colleagues for an excellent addition to our knowledge about CDI prevention!

Wherein I reveal the top 3 approaches for preventing C. difficile disease!

1. Antibiotic stewardship

2. Antibiotic stewardship

3. Antibiotic stewardship

I’ve listed these in order of importance. Supporting evidence is accumulating, including three recent papers that I found very interesting:

Dingle, et al. Lancet Infect Dis 2017. This observational study from Oxfordshire, UK combined overall CDI rates, antibiotic use data, and whole genome sequencing to determine whether declining CDI rates were more likely driven by reduced antibiotic use or by transmission prevention efforts. The results are nicely summarized in Figure 2 from their manuscript (see below). It’s extremely cool to see how the big reduction in fluoroquinolone (FQ) use from 2005-2007 was followed by the near-extinction of FQ-resistant isolates. The disappearance of these FQ-R genotypes accounted for the entirety of the significant CDI reduction seen in Oxfordshire. If infection prevention approaches were a major driver of the CDI reduction, one would’ve expected to see at least some reduction in the non-FQ-R genotypes. Equally interesting: as FQ use crept up, rates of FQ-R CDI didn't follow, possibly due to eradication of these genotypes from asymptomatically colonized, or due to the still-lower usage (or usage in different populations). Anyway, there’s a lot of great detail in this report, so read it yourself, but the results support the centrality of stewardship to CDI prevention. LATE ADDENDUM: See this post by Marc Bonten and this Wellcome Open Research article for important caveats to the above "simple interpretation" of this study.

Anderson, et al. Lancet 2017. I’m kind of embarrassed that we haven’t weighed in on this one yet, since the Benefits of Enhanced Terminal Room (BETR) Disinfection study is definitely “BETR” than most infection prevention studies. It’s a cluster-randomized, multicenter, crossover study that compares standard disinfection to bleach, UV-C, and bleach + UV-C for terminal room disinfection after occupancy by patients with MRSA, VRE, multiple-drug resistant Acinetobacter, or CDI. The outcome is acquisition of colonization or infection with the index organism by the subsequent room occupant. One reason I haven’t blogged about the study yet is that I really don’t know what to make of it. It’s a great study, but some of the results are confusing or counterintuitive, and don't make me want to rush out and buy more UV robots (full disclosure: we have a whole army of them at our hospital already, all of which were purchased prior to the results of this study). For rational takes on the entirety of the study I’ll outsource to our colleagues Jon Otter and Marc Bonten at Reflections IPC. As for the C. difficile results (see below for per-protocol results from Table 3 of the manuscript), UV-C didn’t reduce CDI risk beyond that of standard bleach disinfection. For the purposes of this blog post, I’m going to concur with the authors’ contention that “the environment might not play as large a role in C. difficile transmission as previously suspected” (or at least not as large a role when you’ve already cleaned said environment with bleach). It’s all about the antibiotic stewardship, baby!

Widmer, et al. Clin Infect Dis 2017. This is the laziest, least resource-intensive of these three studies, and also my favorite. What better way to determine whether an intervention to prevent transmission is effective than to just stop doing it and see what happens? [I’m now picturing Andreas Widmer leaning back on his office chair, feet on his desk, overseeing a decade of not placing CDI patients in contact isolation.]  I’m kidding, of course, in fact they did quite a lot of sampling of the contacts of these CDI patients (451 of them) to assess for transmission events. The upshot: only 2 (!) proven (and 4 probable) transmission events were documented using genome sequencing over the decade, and no outbreaks occurred. Of note, they did place those with “severe incontinence” in contact isolation (really, this is in the spirit of Standard Precautions), and all CDI patients were assigned a dedicated toilet. Oh, and they also had no active antibiotic stewardship during this time period, but report a >90% adherence to hand hygiene (paging Eli!). 

To sum up: three interesting studies, and the combined results lead me to conclude that, assuming I have a limited budget with which to reduce CDI, I’d be wise to invest most of it in active antibiotic stewardship.

Playing Nice: Infection Control and Clinical Microbiology in the Pay-For-Performance Era

As it's probably clear, it's been a great honor for me to work (and blog) with Dan and Mike over the past 8! years. One of the things that stands out when talking shop is their ability to see both sides of an argument even while pushing for the changes they support. Many times, their ability to see both sides clearly is possible because they've lived both sides - Mike has been an ID chief and hospital epidemiologist and is now our CQO and Dan is an ID chief, hospital epidemiologist and clinical microbiologist. You know, if I was a fellow or faculty member looking for a hospital epidemiologist position with great mentorship and support, I would move to Iowa...but I digress.

One specific area where understanding competing goals is critically important is the interplay between the increasing sensitivity and precision of microbiologic tests and the growing pressure to reduce HAI. As you can imagine, with 3% of CMS payments potentially at risk, anything that could impact HAI rates in a negative fashion is bound to be a flashpoint for hospital administrators. With that in mind, I point you to Dan's excellent commentary just published in JCM that examines the implications of advances in microbiological testing on HAI rates and provides specific suggestions for how hospital epi programs and clinical microbiology labs can work together to respond to these changes.

Initially, Dan provides three scenarios where changes in the micro lab could directly impact HAI rates (1) The effect of MALDI-TOF on CLABSI rates (2) The shift from EIA to nucleic-acid amplification tests (NAAT) for C. difficile detection and (3) Pressure to block urine culture ordering to reduce CAUTI. After delving into the current CMS reimbursement landscape, the unintended consequences of improvements in diagnostic testing and the use/misuse of surveillance definitions, he provides six valuable recommendations that clinical microbiology labs (CML) and infection prevention programs (IPP) should consider:

(1) CML leadership should select diagnostic approaches with the goal of improving individual patient outcomes

(2) Hospital and IPP leadership should not pressure the CML to alter diagnostic practices based on the need to demonstrate lower HAI rates for pay-for-performance measures. 

(3) Public health authorities (CDC/NHSN) must be proactive in adjusting HAI metrics to changing CML technology

For recommendations 4-6, you're gonna have to read his commentary. But a hint at #6 -  CML and IPP leadership need to collaborate and advocate for their needs, because, unlike at Iowa, both sides aren't always present in the mind of a single person.

Here we go again: Active detection and isolation, C. difficile edition

An interesting study in JAMA Internal Medicine, likely to generate a lot of discussion, addresses the use of “active detection and isolation” (ADI) for control of C. difficile disease. This quasi-experimental, single-center study employed PCR screening (tcdB detection) of all patients admitted through the emergency department (patients admitted from other locations were excluded, as were “short stay” patients), and those that were found to carry toxigenic C. difficile were admitted into a kind of “quasi-isolation”—gloves were used, but not gowns or private rooms. So all-in-all, a very pragmatic (and somewhat idiosyncratic) intervention. Healthcare-associated C. difficile disease rates declined after the intervention, which students of prior quasi-experimental studies of ADI for MRSA and VRE will find unsurprising. 

At this point, I will outsource my blog post to Jon Otter and Martin Kiernan at the Reflections IPC blog. Go on, head over there for an excellent pro-con post about this study, and vote on the question posed at the end of the post. Then come back here to read my only additional observation…..I can wait (spoiler alert: I agreed with Jon).

OK, you’re back: the only thing I have to add to Jon and Martin’s excellent post is this: we’ve been here before. Recall the persuasive quasi-experimental studies (many single-center, some multicenter) of MRSA and/or VRE ADI published over the course of a couple decades. When better designed studies were eventually performed and published (e.g. STAR*ICU, REDUCE-MRSA, MOSAR, this one by Harbarth and colleagues that doesn't have a catchy acronym)—you know, studies that included concurrent control groups (control groups are for losers!), it became evident that ADI wasn’t the key to MRSA or VRE control. I think we’re headed down that road again, this time with C. difficile. Who’s going to step up and organize the multicenter, cluster-randomized trial we need to do now? Or perhaps better to ask: who is going to pay for it?

What happens when you flush a toilet?

Many of you know that I'm not a fan of the uncovered toilet in hospital rooms or anywhere for that matter. Over at Fast Company, they have an amazing post with high-speed video (included above) from Lydia Bourguiba, an MIT professor who studies fluid dynamics and disease. The focus of this 1000-2000 frame per second video is the small particle or aerosol transmission that occurs after a toilet is flushed, think C. difficile. Enjoy! Oh, and sorry to ruin your breakfast or lunch.

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.

C. difficile and Hospital Process Measures: What Works?

One of the more difficult things to cover is a study that you've already written about in an accompanying editorial. It's quite hard to come up with anything "new" to write that you haven't already written. Such is the case with a very nice study examining hospital process measures and C. difficile infections just published in BMJ Quality and Safety by Nick Daneman and colleagues from Sunnybrook Health Sciences Centre in Toronto.

Using results of a mandatory CDI prevention practices survey they compared facility-level processes measures and patient level (via ICD-10 codes) CDI rates in 159 Ontario hospitals. Specifically, they looked at implementation of six hospital-level measures: (1) isolation at diarrhea onset, (2) audit of antibiotic use, (3) audit of environmental cleaning, (4) vancomycin as first line therapy and (5) on-site diagnostic testing and (6) reporting of rates to senior leadership. Somewhat surprisingly, none of the process measures were associated with lower risk of CDI.

In the editorial, Nasia Safdar and I wrote:

"First, the authors identified low self-reported implementation of most CDI prevention practices, with only 27% of facilities reporting isolation of all patients at onset of diarrhoea, and 16% reporting auditing of antibiotic stewardship practices. Low adherence rates for these two practices in particular are concerning because prompt institution of contact precautions is necessary to reduce nosocomial transmission of C. difficile. And antimicrobial stewardship is at least as important as infection prevention practices, if not more so, for reducing CDI."

"This study also highlights the importance of implementation science research to tackle the vexing yet pervasive problem of low and variable adherence to evidence-based interventions for reducing HAI, including CDI. The scope of this study did not extend to exploring barriers to implementation or an in-depth assessment of the self-reported practices that may help inform implementation strategies to increase uptake of proven practices."

and of course my favorite part:

"Last, increasing the evidence base for preventing CDI by undertaking pragmatic randomised controlled trials of novel interventions incorporating efficacy and effectiveness is essential to successfully bridge the quality chasm that currently exists in CDI prevention."

Reference: Daneman N. et al. BMJ Qual Saf. 2015 Apr 24 (open access)

Safety and efficacy of nontoxigenic C. difficile spores in preventing recurrent CDI

Lead Author: Dr. Dale Gerding

We have written and spoken often on the efficacy of fecal transplants in treating recurrent C. difficile infections. Wouldn't it be great if there was a way to prevent recurrent CDI in the first place? What if "good" C. difficile strains that lack toxin production genes could be used to out compete bad strains and prevent recurrent CDI?

There is a new study just published in JAMA that evaluates the safety and efficacy of a nontoxigenic C. difficile strain M3 (VP20621; NTCD-M3) in preventing recurrent CDI in those patients initially treated with metronidazole and/or oral vancomycin. In the four-arms of the phase 2, double-blind placebo-controlled trial they compared patients given oral liquid formulation of NTCD-M3, 10^4 spores/day for 7 days (n = 43), 10^7 spores/day for 7 days (n = 44), or 10^7 spores/day for 14 days (n = 42), or placebo for 14 days (n = 44).

Recurrent CDI occurred in 13/43 (30%) of placebo patients and only 14/125 (11%) of patients treated with NTCD-M3 patients (odds ratio [OR], 0.28; 95% CI, 0.11-0.69; P = .006). Fecal colonization with the NTCD-M3 strain was reported in 69% of treated patients and was associated with lower recurrence: 2/86 (2%) recurrence if colonized vs. 12/39 (31%) recurrence in treated but uncolonized patients (OR, 0.01; 95% CI, 0.00-0.05). Side effects such as abdominal pain, diarrhea and serious side effects were actually higher in the placebo groups. If this smaller study's findings are confirmed in larger trials, we may just have a new treatment for the prevention of recurrent CDI. Very cool.

Check out the video interview with lead author Dr. Dale Gerding, another related video and the JAMA Associate Editor's podcast covering this article and other important studies.

The Power of Poop

If you needed even more reasons to move to Iowa, you now have another - an HAI-related Grand Rounds by esteemed co-blogger Mike. I might have gone with Tao of Poo(h), but who can ignore Poop's Power?

Update: Webcast (audio + slides) of the talk is now available.

Guest Post: Ebola and the Reversal of Transmission Dynamics

L. Silvia Munoz-Price, MD PhD

This is a guest post by Dr. Silvia Munoz-Price, Enterprise Epidemiologist at Froedtert & Medical College of Wisconsin Institute for Health and Society/Department of Medicine.

There is an interesting phenomenon occurring during this Ebola outbreak. The relationship between health care workers and personal protective equipment (PPE) has shifted. Let’s state a fact: up until now, most Infection Control providers have permanently struggled to ensure compliance with the use of gowns, gloves, and hand hygiene among healthcare workers. Even though all healthcare workers know these interventions (PPE and hand hygiene) are necessary to prevent transmission of pathogens among patients, healthcare workers persist being non-compliant with these measures. Why do we continue behaving this way? This is probably due to several factors, but one of the most relevant ones might be our inability to pinpoint whose non-compliance end up causing acquisition of hospital pathogens to individual patients. So, when patient X gets Clostridium difficile colitis on day 15 of hospital stay, who among the dozens of providers in contact with patient X caused this transmission? Nobody can tell. The result is a lack of accountability of medical teams.

This topic reminds me of healthcare worker’s attire. We know that white coats are laundered on average every 14 days but scrubs are spontaneously laundered by providers every day. The former is in contact with patients and the latter is in contact with the provider’s skin. Why this difference in laundering frequency? Could it be that we care of our well being much more than what we care of our patients?

Many times I have discussed with hospital leadership about why there is such a difference in compliance with protocols between airplane pilots and healthcare workers. We thought this difference was probably due to the fact that if airplane pilots are not compliant…they die. In comparison, if healthcare workers are not compliant with hand hygiene or PPE usage…nothing happens to them.

Ebola has clarified this point for us. This tiny virus has successfully reversed the transmission dynamic in hospital settings. Now healthcare workers are not the only one spreading disease across the unit …now healthcare workers are actually getting sick if they are not compliant with infection control practice. What is the result? We are frantically re-learning how to cover every inch of our bodies before and after patient contact. That said, I understand that the mortality in West Africa has been very high, which is causing a generalized state of panic, but so far we are observing that patients treated early and adequately seem to do just fine. Compare this with C. difficile colitis among our immunocompromised patients which causes thousands of infections a year. I understand that C. difficile is not in CNN 24/7, and fails to have an exotic name, but it can certainly be as devastating and much harder to treat than Ebola in US healthcare settings. So, let’s reflect on our current state of generalized paranoia. Maybe patients with C. difficile, CRE, MRSA, VRE acquired in the hospital should run the same press campaigns 24/7 clamoring for better compliance with PPEs and hand hygiene among healthcare providers.

So, let’s think again about our behavioral drivers to comply with PPE and hand hygiene…maybe the answer to improved compliance with these interventions is to have a strain of C. difficile that would make healthcare providers sick.

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?

The enemy within

There are a couple studies out this month, one in CID (from WashU) and one in ICHE (from Houston), that carry the same message: a substantial portion (13-15%) of asymptomatic hospitalized adults carry toxigenic strains of Clostridium difficile in their GI tracts. Coming on the heels of this NEJM study using whole-genome sequencing to describe the genetic diversity of C. difficile strains, these studies advance an evolving narrative—that many cases of C. difficile-associated disease (CDAD) are not attributable to in-hospital transmission from other symptomatic patients (and thus are impervious to transmission-prevention approaches such as hand hygiene, contact precautions, and enhanced environmental disinfection). The major take-away point for me: it's all about the stewardship! Knowing that 15% of patients harbor toxigenic C. difficile should only increase the urgency of antimicrobial stewardship efforts.

The other major implication of these studies relates to the predictive value of highly sensitive PCR tests that target the toxin gene(s). To quote from the authors conclusion in Koo, et al:

“In the healthcare setting, where the majority of diarrhea cases are not attributable to CDAD and the prevalence of asymptomatic C. difficile colonization is greater than the frequency of CDAD, NAAT detection of asymptomatic colonization among healthcare-associated diarrhea patients may be contributing to a significant number of CDAD false positives.”

The UK have already changed their surveillance recommendations to require a toxin ELISA as confirmation of every positive PCR test. With lab-identified C. difficile now publicly reportable, I suspect more US centers will switch to two-step algorithms and/or begin restricting access to PCR-based assays to reduce the false positivity problems.

Enhanced scanning EM of C. difficile from the CDC's Public Health Image Library

Patient - Wash Thy Own Hands!

There has been increasing attention over the past decade in engaging patients in patient safety. In infection control this trend has manifest through efforts to have patients monitor and encourage hand hygiene compliance among health care workers. In a related trend, there is also increased interest in patients washing their own hands in a framework called "patient-centered hand hygiene." My understanding of this approach is that having patients clean their own hands could potentially increase their engagement in infection control initiatives including encouraging health care workers to practice hand hygiene. This approach might also have the additional benefit in decreasing the organism burden on patients' hands and interrupting direct or indirect transmission of MDROs in healthcare settings.

It is with this background that Kundrapu and colleagues at CWRU and the Cleveland VA completed a randomized trial of soap and water versus alcohol hand rub in reducing C. difficile spore burden on patients' hands. Forty-four infected or colonized patients were included in the study. Hand cultures were positive in 32% of patients with CDI and 38% of colonized patients prior to hand hygiene. As you can see from the figure below, soap and water significantly reduce the proportion of positive cultures and mean CFUs, while alcohol hand rub did not. Interestingly, around 10% of patients still had C. difficile recovered after washing with soap and water. Seems like a trial is in order to determine the role of patient hands in transmission and whether cleaner patient hands reduces the incidence of CDI and other MDROs in hospital settings. One major limitation is that this intervention could not be implemented in settings where the need is the greatest, namely ICUs, since most patients would be too sick to wash their hands.

Using NHSN C. difficile Infection Rates? Mind your denominator!

Over here in the US hinterland we're completing a systematic review of MDRO outcomes for CDC in cooperation with investigators in Salt Lake City. At the moment we're tackling C. difficile and are busily pouring through the literature. We've come across many good studies, such as an ICHE paper from early 2013 by Gase and colleagues from the New York State Dept. of Health that compared NY State CDI surveillance to NHSN in 30 hospitals. The authors noted an 80% agreement between the methods and thus recommended that NY State adopt the NHSN LabID method because of ease of implementation.

Building on that study, Haley and colleagues also from the NY State Dept of Health completed an analysis of the sources of bias in NHSN "Hospital Onset" CDI rate calculations using data from 124 NY hospitals. Their findings were published in the January 2014 issue of ICHE and were accompanied by a nice editorial by two of my former Maryland colleagues Jessina McGregor and Anthony Harris. The NY authors looked at how auditing, including outside labs, age adjustment and exclusion of "patient days not at risk in the denominator" would improve the calculation of hospital-onset CDI rates. As you can see by the portion of Table 2 that I pasted below, most of the corrections had minimal impact on the average hospital-onset CDI rates.  However, "exclusion of patient-days not at risk" had a huge impact on the calculated HO-CDI rate. The correct rate after controlling for all factors was 11.6/10,000 patient days; however, excluding auditing or outside labs, or age adjustment had minimal impact, whereas not excluding patient days not at risk from the denominator led to a rate that was 45% lower (6.4/10,000 pt-days).

The reason that eliminating "patient-days not at risk" from the denominator had such a huge impact is that the CDC NHS definition excludes CDI cases that occur in the first three days from the numerator but does not exclude patient-stays less than three days from the denominator. For example, a patient that stays only two days would not be at risk from contributing a HO-CDI case to the numerator but contributes their patient-days to the denominator.

This has several important implications.  One, not removing the patient days not at risk results in reported CDI rates that were much lower than they actually are. This occurs since many if not most patients have stays that are shorter than 4 days.  Second, as the authors state, "HO-CDI rates at hospitals with shorter LOS are biased downward more than the rates at hospitals with longer LOS." It seems to me that this artificially hurts the rates at tertiary-care and academic medical centers more than it would smaller community hospitals. We always hear how academic hospitals are falling behind, but it may have something to do with how rates are calculated, especially if we are including the wrong patient-days in the denominator.  It seems like this would be an easy fix - hospitals could just exclude the first three days from their patient-day calculations.  I hope this happens.

Great news for patients with C. difficile

At this point in time, I've performed about 50 fecal transplants. I find these procedures to be both a blessing and a curse. They are amazingly effective for patients with recurrent C. difficile. Many of my patients have had chronic diarrhea for months, and are unable to leave their homes. So imagine how incredible it is for them to be cured within 24 hours of a fecal transplant. I have heard over and over, "you have given me back my life." And I have to admit it's a blessing for me, too. Rarely in medicine do we see such rapid and dramatic cures. What's not to like about this? How could it be a curse?

Well, as we have blogged before, the logistics of fecal transplantation are difficult and there are a number of barriers. While most patients don't have difficulty finding a donor (usually a family member), some elderly patients don't have a donor. Cost is also a barrier. Donor testing is not covered by insurance, so the out-of-pocket cost is up to $1500. For poor patients, this is quite a problem, and I've had patients whose family members all chipped in to pay for donor testing. Then the donor has to "perform" at a specified date and time (and sometimes they can't).

The transplant I did yesterday was fairly typical. I went to the clinic to pick up the donor specimen and ran it to the lab (10-15 minute round trip), where our laboratory technician began the dirty work of homogenizing the stool sample in a blender and filtering it. While she was doing that, I ran back to the clinic, got the informed consent, inserted the NG tube and sent the patient to X-ray for confirmation of tube placement. The queue in x-ray can be up to 45 minutes. While the patient was in X-ray, I ran back to the lab, picked up the prepared specimen and returned to clinic. When the patient returned, I injected the NG tube with the fecal slurry, flushed the tube with some water, then removed the tube. On most days, all of this takes 2-3 hours of my time. If insurance pays us, we collect less than $75. During the same time period, my colleagues will generate charges that are roughly 6-9 fold higher than mine. Since most of us now work in an RVU-based compensation model, it should be apparent why so few physicians do this work. But I can't not do it, even though it reduces my salary. I feel morally compelled to help these patients who are so desperate, particularly when I know that the odds are very high that I can cure them with a simple procedure.

Yesterday I stumbled on OpenBiome's website and as I explored it I was nearly euphoric. OpenBiome is a non-profit started by four students (a molecular biology PhD candidate, an MBA candidate, an MPA candidate, and an MD/MBA candidate) at Harvard, MIT and Princeton. The company provides processed, frozen human stool from donors that have been carefully selected and screened for multiple infectious diseases at least twice, at a cost that's 1/6 the price of me testing one donor, and 5 to 14-fold cheaper than the drugs that these patients have taken without success. And OpenBiome's goal is to reduce the price even more as they scale up their operation. I had a long conversation today with James Burgess from OpenBiome. He knew so much about C. diff that I assumed he was the medical student, but he's actually the MBA student. He was excited to tell me about their work and I was incredibly impressed. They have covered all the bases, including banking serum from donors for future testing should a patient develop an unusual infection.

So Kudos to OpenBiome! Many patients will benefit from their ingenuity and generosity. And they'll make my job a whole lot easier.

Please, please don't try this at home!

Today, I ran across a letter in the American Journal of Infection Control that left me nearly apoplectic. In the letter, the authors argue that nonhospitalized patients with C. difficile infection should be on contact precautions while AT HOME! Let's think this through this, people. Are we going to confine an elderly person to their bedroom, and wear gowns and gloves when we walk into that room? If grandma eats dinner with the family are they all going to sit at the table wrapped in plastic? What about Fluffy the cat? Gowns and gloves for her, too?

There's actually an excellent population-based study that evaluated the risk of infection in household contacts. Over 2,000 C. difficile index cases were evaluated, and the risk of infection in household contacts was 0.4%. Let's use some common sense: if the infected person can have their own bathroom that would be great, clean the bathroom with bleach, and practice good hand hygiene. But for God's sake, let's not make it a leprosarium.

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.

New CDC report on antibiotic resistance

Yesterday, the CDC released a new report on antibiotic resistant infections (full text here). It's a nicely done, mostly nontechnical report that seems primarily designed to raise awareness. There's not much new in the report except some updated estimates on the impact of these infections, which probably explains why the New York Times relegated its coverage to page 13. That piece, which quotes Eli, notes that the impact estimates are lowish, and CDC officials acknowledge that the estimates were intentionally conservative. As we've noted previously in this blog, we need more funding for prevention studies, new drugs, and better stewardship to protect the drugs we currently have.