The end of antibiotic stewardship, 2013 edition

Back in the 1990's when I was a wide-eyed ID fellow, I'd wonder out loud to my co-fellows Sara Cosgrove and Dan Levy why it was that we needed an oncologist's approval to prescribe chemotherapy but any clinician could prescribe antibiotics. My reasoning was that if you make a mistake with chemotherapy in a cancer patient, you only harm that one patient, but when untrained clinicians prescribe antibiotics all willy-nilly they harm the whole planet. Well, it's 2013 and I'm still wide-eyed and have the sinking feeling that antibiotic prescriptions are about to go way beyond willy-nilly. And I'm a bit scared.

The reason for my worry is this paper by Hanne Albert and colleagues in the European Spine Journal. In the study, patients with 6-months of low back pain and Modic 1 changes on MRI were randomized to 100 days of antibiotics (amoxicillin + clavulanic acid). The reasoning behind antibiotics for back pain is a study that found P acnes and C propinquum in surgical specimens from lumbar herniated disks. Anyway, the study reported improved primary and secondary outcomes with treatment and no change with placebo.

So why am I worried?  Just look at the headlines from my google search above. I would normally link to these articles, but I don't want to send traffic to posts that aren't appropriately skeptical of this single trial and the public health implications of giving everyone with back pain 100 days of antibiotics. One UK surgeon was even reported to have said this finding is worthy of the Nobel Prize. Yikes.

For an appropriately skeptical and balanced discussion of this study and the surrounding hype, please read this Observation in BMJ by GP Margaret McCartney. After I read the study and Dr. McCartney's excellent commentary, I forwarded them onto Sara Cosgrove. It was therapeutic for me to share my concerns with an old friend. But now I'm back to panicking.

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.

Who is Maurice Hilleman?

This will be the correct response if Alex Trebek ever says: “American vaccinologist credited with saving more lives than any other scientist in the 20th century”. It amazes me that Hilleman is not a household name, and that he didn’t win a Nobel prize. Even after paying close attention during medical school, internal medicine residency, and two fellowships (in infectious diseases and clinical microbiology), I had very little understanding of his immense contributions to infection prevention until I begin reviewing the mumps vaccine literature during the Iowa mumps outbreak in 2006.


So please, take a few minutes to read this excellent NY Times piece about Hilleman.

"Nightmare" on Hospital Street

Not sure how we missed last week's JAMA medical news piece featuring our very own co-blogger Dan, but I suspect we might have been distracted by something pretty terrible. The article highlights the rise of carbepenem (CRE) and 3rd-generation cephalosporin-resistant Klebsiella pneumonia strains originally described in ICHE by Braykov et al. The CDC's Arjun Srinivasan emphasized that these strains are almost exclusively hospital-associated and now is the time for hospitals to implement the latest CRE recommendations from the CDC 2012 toolkit.

Dan "emphasized the importance of infection control basics such as ensuring a high rate of hand hygiene adherence among staff and making sure that surfaces and equipment are properly disinfected."  And said "If you don't shore up those things, screening [for CRE] isn't going to help."

I'll just paste in my favorite section: "An additional problem is the piecemeal approach to tracking these infections. Only 6 states require facilities to report CRE cases. “We need a more coordinated response,” Diekema said. He explained that the CDC is doing as much as it can with the resources it has, but underfunding of public health at the national and state levels makes it difficult to mount a more coordinated national effort to contain the spread of these infections. More research is also needed on the best strategies for environmental disinfection, ensuring adherence to hand hygiene and other measures that would prevent the spread of health care–acquired infections."

CRE isn't just a nightmare, it's a recurring nightmare. And just like the nine Nightmare on Elm Street films, it'll get worse over time. Especially if we continue with the current "piecemeal approach" prevention plan.

Source: Bridget Kuehn, JAMA 4/27/2013
Image source: wikipedia

Using QxMD's READ iOS? click here

The Environment and HAI – Where does Biological Plausibility Come In?

This May's Infection Control and Hospital Epidemiology (ICHE) contained a randomized trial of copper-coated surfaces in ICU settings which reported a 50-70% reduction in several aggregate outcomes that included hospital-acquired infections and colonization with MRSA and VRE.  In this guest blog post, physician-scientists Dr. Matthias Maiwald from the KK Women’s and Children’s Hospital in Singapore and Dr. Stephan Harbarth from University of Geneva Hospitals in Geneva, Switzerland question the plausibility of these findings and put them in the larger context of what actually causes HAIs.

In 1965, Sir Austin Bradford Hill published a landmark paper, entitled “The Environment and Disease: Association or Causation?” in which he outlined what would become known as the “Bradford Hill Criteria.” The “Hill Criteria” help distinguish association from causation in epidemiological research. One of nine criteria was biological plausibility. Quoting: “It will be helpful if the causation we suspect is biologically plausible. But this is a feature I am convinced we cannot demand. What is biologically plausible depends upon the biological knowledge of the day.” As commented elsewhere, the spirit of this criterion is to check whether the proposed causation violates any of the known laws and facts of science of biology, and as Hill outlines, this depends on currently available knowledge. It is said that Hill did not intend the criteria to be applied rigidly in the sense of a checklist approach; instead, he regarded them as “viewpoints” that would merely help in the assessment.

Fast-forward to the May 2013 Special Topic Issue of ICHE concerning the role of the environment in infection prevention. In the issue’s introduction, Weber and Rutala quote figures from a 1991 article by Weinstein concerning the biologically plausible sources of healthcare-acquired infections (HAIs): “patients’ endogenous flora, 40-60%; cross infection via the hands of personnel, 20-40%; antibiotic-driven changes in flora, 20-25%; and other (including contamination of the environment), 20%.”

In the same issue, an article by Salgado and colleagues caught our attention. This clinical trial compares 614 patients randomly placed into standard ICU rooms or into rooms where 6 frequently-touched items (e.g. bed rails, overbed tables, intravenous poles, etc.) had been replaced with copper alloy surfaces. The measured primary outcomes, according to the paper’s methods, were:
   (a) any HAIs and
   (b) colonization with methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE). Besides HAI and colonization, outcomes presented in the results section included the numbers of patients who had
   (c) both HAI and colonization,
   (d) HAI and/or colonization,
   (e) HAI only but no colonization (i.e. number of patients who had HAI minus the ones who had both HAI and colonization), and
   (f) colonization only but no HAI.

Are you confused? Separate data for outcomes in each trial arm were only reported for (d-f) but not (a-c).

For HAI and/or colonization (d), the article reported what amounted to a 49% reduction in the copper rooms vs. non-copper rooms (21 vs. 41 patients; p=.02), for HAI only (e) a 62% reduction in the copper rooms (10 vs. 26; p=.013), and for colonization only (f), a 67% reduction (4 vs. 12; p=.063, NS). What was was not reported were the numbers of patients with (a) HAI and (b) colonization, listed separately for each trial arm, but the article concluded – in the discussion – that copper surfaces in rooms reduced the risk of HAIs by more than half. Conventional wisdom, however, would suggest that (a) any HAIs and (b) any colonization events, would be the most biologically relevant outcomes, and that it may not be so informative to combine these two events (under d) in the same statistical calculation, because they are biologically very different from each other. So, we extracted the missing numbers from the other numbers presented and arrived at (a) HAIs 17 vs. 29, and (b) colonization, 11 vs. 15 events. Putting these into our statistics calculator, they were – non-significant.

Now, let us revisit possible transmission routes in hospitals. We have: (i) endogenous transmission, from within the patient’s own flora, (ii) exogenous transmission via direct transfer, (e.g. as in handborne without surfaces), and (iii) exogenous transmission via surfaces and secondary transmission from surfaces onto the patients. If we look at (a) HAIs and (b) colonization with MRSA or VRE, then all three pathways can lead to HAIs, while only the two exogenous pathways can lead to colonization. If there is a >50% reduction of HAIs through copper surfaces (pathway iii), this would mean that the overall proportion of transmission from pathways (i) and (ii) plus the proportion of transmission from the remaining non-copper surfaces in the copper-treated rooms among pathway (iii) among all HAIs together would contribute less than 50% to overall HAIs.

The obvious question comes to mind: is that consistent with the known proportions of the different pathways leading to HAIs? The preliminary answer, given the Weinstein data (see above), would be, “given the biological knowledge of the day, apparently not.” It is also noted that the overall numbers of HAI and colonization events in the present article are relatively small.

Finally, anyone of us engaging in research can accidentally have outcomes that are surprising or do not quite add up with existing knowledge in the field. That is, in our opinion, where the intended purpose and scope of a discussion section of an article comes in, and where the Hill Criteria provide important food for thought. As one of us has put forward (Teleclass Feb. 7, 2013) on a different occasion and concerning a different topic, we would welcome the broad application of a check for biological plausibility when findings from clinical trials – and even systematic reviews – are reported. But we are not confident that our voices will be heard.

Image of Sir Austin Bradford Hill, source: toxipedia

Surveillance under pressure

There’s a great success story now published online in ICHE. The CDC, using National Nosocomial Infection Surveillance (NNIS) and National Healthcare Safety Network (NHSN) data, estimates that 100-200K central line associated bloodstream infections (CLABSIs) have been prevented since 1990 through implementation of evidence-based prevention practices. This accomplishment should be celebrated as a demonstration of the real progress that has been made in hospital infection prevention. As Mary Dixon-Woods and our fellow blogger Eli point out in an accompanying editorial, however, these results are also a time to reflect on how much surveillance has changed since 1990.

The CLABSI surveillance that we once performed exclusively to guide local prevention efforts is now used for much different purposes, with rates reported publicly and soon to have a real impact on each hospital’s bottom line. The pressure to bring CLABSI rates to “zero”, by any means necessary, gets passed along from hospital administrators to unit directors and infection prevention programs, turning CLABSI rates into what Mary and Eli correctly describe as a “reactive measure.” To quote their editorial,

“the more that organizations are incentivized by the prospect of shaming or financial penalties to decrease sensitivity—and thus not to find cases—the less certain it is that they are reporting a valid assessment of their infection rate”

It is instructive to examine what happens in other professions when intense pressure is brought to bear on a metric. Five minutes on The Google is enough to inform about what happens when law enforcement is under pressure to lower crime rates, or when teachers are under pressure to improve student test scores. Are police officers and teachers more inclined to “cheat” than are those tasked with counting infections in hospitals? Do officers who misclassify a burglary as a theft after receiving a call from a commander really have nothing in common with the IP program that misclassifies a primary CLABSI as secondary after a call from a unit director or hospital administrator?

This increased pressure is also felt at the CDC and NHSN, as a metric that was initially designed for one purpose is now appropriated for very different purposes. We recently performed an email survey of over 50 prominent hospital epidemiologists to gather their opinions about the direction of surveillance over the next decade. The results can be found here. Some of the highlights:

• Over 75% of those surveyed thought it likely or extremely likely that their local surveillance efforts will erode to focus only on those linked to payment policies or state/federal requirements.
• All thought that HAI surveillance metrics linked to payment policies and state/federal mandates would continue to grow to include more outcome and process measures.
• Respondents felt that pay-for-performance metrics were most likely to drive practice change (moreso than public disclosure of data, use of data by practitioners, or release of national summary statistics).
• Fewer than half thought it was likely that fully automated metrics from existing data elements would replace manual review of records for HAI determination.
• About half of respondents thought that the increased attention to HAI prevention from payment policies, mandates and public reporting has made patients safer (13% thought it hadn’t, and 40% thought the jury was still out).
• Almost 80% of respondents thought that infection prevention experts and clinical providers should have a much larger role in developing and modifying state/federal reporting requirements.

In other words, there is real concern in the HAI prevention community that the increased attention to HAIs, the drive to “zero”, the link to payment policies and public reporting requirements, is a double-edged sword. It has resulted in some tangible successes (CLABSI reductions being a prime example), but threatens to undermine our ability to respond nimbly to emerging local priorities by consuming all of our time and energy, and by producing data that no longer accurately reflect the true rate of adverse outcomes. To quote again from Mary and Eli:

"Undermining our surveillance system to serve ill-designed demands for accountability means that it may no longer be useful for monitoring and driving patient-safety improvements. That would truly be a shame."

Prevention Fund love (finally!)

At long last, someone is showing a little backbone in trying to protect the Prevention and Public Health Fund.  The fact that it's the Senator from Iowa makes it all the sweeter.  Go Tom!  The money quote from Senator Harkin:

"I am greatly disappointed that the administration chose to help pay for the Affordable Care Act in fiscal year 2013 by raiding the Public Health and Prevention Fund. The Prevention Fund works. Thanks to this funding, more children are being immunized. More people are quitting smoking. More communities are fighting chronic disease. More people are being screened for hepatitis C. Robbing prevention when we know these efforts can improve people's health and lower healthcare costs goes against the very mission of healthcare reform."

h/t to Mike for e-mailing me the link.