MSSA and MRSA: Both are dangerous!

Jessica Ericson and co-workers recently published a remarkable investigation of invasive Staphylococcus aureus infection in hospitalized infants. In it they describe a retrospective multicenter study of 348 NICUs in which a group of 3888 infants suffered invasive S. aureus infection between 1997 and 2012. They compare the demographics and mortality of infants with invasive MRSA and MSSA; determine the relative annual proportions of MSSA and MRSA; and calculate the risk of death after an invasive MSSA and MRSA infection. It's a fascinating study and I recommend reading it.

Among other results, they find that infant mortality following invasive MRSA and MSSA infection is essentially the same. Moreover, in their cohort of patients, MSSA was responsible for a larger burden of disease and death in infants than MRSA. Based on their findings, and consistent with previous studies, the authors recommend that

Measures to prevent S. aureus infection should include MSSA in addition to MRSA.

This is an important point. The goal of infection prevention is to protect patients; both MRSA and MSSA are deadly, so we should be mindful of each. Commonly, patients are screened for MRSA carriage only, and isolated and decolonized if found to be positive. Previous research suggests that it may be possible to reduce the incidence of both MRSA and MSSA infection by screening for S. aureus universally, and this latest study shows why this is critically important.

After drafting this post I realized that Mike Edmond, on the Controversies in Hospital Infection Prevention blog, had already written a great piece in connection with this paper. You should read the post. In it, he captures the issue powerfully in a single line: 

I often joke that I've never had a patient tell me that they don't want a MRSA infection, but they'll take an MSSA infection. 

Indeed, both pathogens deserve attention and respect, as has long been known. 

(image source: Wikipedia)

Rift Valley fever and the problem of forecasting

The notion that prediction is difficult, especially about the future, is absolutely true in the domain of infectious disease. Despite the difficulty we must try, and I think there's reason for hope, given recent studies utilizing powerful machine learning techniques and diverse data. There's much innovation being brought to the issue.

Recently, a topic I've written about in the past has appeared in the news: Forecasting of Rift Valley fever (RVF) in East Central Africa. Bernard Bett has written a thoughtful piece on the PLoS Translational Global Health blog, which I recommend reading, examining the gamut of public health tools and responses needed in order to combat RVF. He begins by framing the issue succinctly, 

Recent climate predictions suggest East Africa may be in line for an epidemic of Rift Valley fever -- an infectious disease which can hit people, their livestock and livelihoods, and national economies hard. Data from the Climate Prediction Centre and the International Research Institute for Climate and Society suggest there is a 99.9% chance there will be an El Niño occurrence this year, with a 90% chance it will last until March/April 2016. At least two of the most recent Rift Valley fever epidemics in East Africa -- those in 1997/98 and 2006/2007 -- were associated with El Niño weather patterns, with Kenya suffering losses amounting to US$32 million in the most recent. Given the strong predictions of an El Niño occurrence, and the established association between El Niño and Rift Valley fever risk, countries in the Horn of Africa need to start laying out measures to manage the developing risk. . . 

The health, economic, and social costs of this disease are well known and there is a wealth of research establishing both RVF epidemiology and its strong ties to climate (including El Niño) and the environment. Nonetheless, there was little early response undertaken given remotely sensed (i.e., satellite-based) RVF forecasting in 2006-07. Peter Roeder described the situation in a 2007 ProMED post (archive 20070112.0164),

It is interesting, if rather disheartening, to watch another RVF epizootic emerge and evolve in eastern Africa and to note that it is such a close recapitulation of events that occurred in 1997/8 and decades before. It is a recapitulation not only with respect to disease evolution but also in terms of national and international preparedness—or lack of it. Those who followed ProMED in those days will be aware that the epizootic attracted intense international attention and was closely reported in postings, which contain much useful information. Despite seminal work on developing early warning systems based on remote sensing . . . it seems that the capacity to respond has not improved greatly in the high-risk countries in Africa. 

We are presently seeing the emergence of a very powerful El Niño, possibly one of the strongest in the historical record, and this was forecast in mid-August of this year. While such a climate forecast, especially when combined with other data, could reasonably be interpreted as a 2-3 month warning of the potential for RVF in parts of Africa, it's important to appreciate the complexity of acting on such information. As I wrote in 2012,

A recent, comprehensive set of case studies of the 2006–2007 outbreak in East Central Africa was published in the American Journal of Tropical Medicine and Hygiene (August 2010), and many of the nuances are described there. For example, current preparations of the Smithburn vaccine have a shelf life of approximately 4 years. Outbreaks in the Horn of Africa region occur aperiodically, with a mean of near 10 years between outbreaks. Veterinary health authorities cannot spend scarce resources on continually replenishing a stock of RVF vaccine when other needs are present continuously. Nor can manufactures maintain large stocks that are likely to expire before sale. Thus, vaccine may not be available at any given time. Nonetheless, waiting until there is a need to manufacture vaccine is problematic.

In other words, although vaccination is a powerful strategy for protecting against RVF virus transmission, maintaining vaccine stocks isn't straightforward. Moreover, simply having vaccine available isn't enough: Effective and safe administration triggered by any early warning, such as the one described in the impressive study of Anyamba et al in 2009, is complicated. In the case of the 2006-07 outbreak, for example, by the time a warning was issued, early outbreak areas were already inundated by rains, making travel and delivery of supplies difficult. In fact, in some scenarios it may take up to 150 days from a RVF vaccine order until the successful acquisition of vaccine-associated herd immunity -- much greater than the few weeks of advanced warning the state of the art can current supply. (Note: There's a distinction between a statistical forecast for a specific disease and simply noting that the strongest El Nino in decades is going to mess with everything.)

If a disease forecast is to have impact, many factors must come into alignment, including the forecast supplying sufficient lead time, decisionmakers having enough confidence in the forecast to act, and the existence of a public health infrastructure capable of supporting an effective (and potentially complex) response. These are important issues to keep in mind when thinking about surveillance and early warning, regardless of the disease and setting.

(image source: Wikipedia)

MERS as (another) messenger of prevention

It's hard for me to know how to interpret the MERS situation in South Korea. At a high level, a recently recognized viral respiratory pathogen has traveled halfway around the world and is causing morbidity and mortality in a small section of an immunologically naive population. It appears to be associated with hospitals. What do we take away from this? Lessons will be learned when the event subsides and people study what happened, but to me, MERS reminds us that outbreaks of pathogens for which there are no vaccines or drug therapies underscore the importance of prevention.

When possible, preventing pathogens from physically reaching or entering a host by respiratory, percutaneous, alimentary, blood et al pathways is preferable to relying on pharmaceutics. Drugs tend to be complex and costly to develop, can take a long time to enter the marketplace, and -- especially in the case of antibiotics and antivirals -- they can become obsolete over time. Moreover, drugs are often toxic to the patient. Prevention is applicable in situations when appropriate drugs don't exist (e.g., for newly emerged pathogens), when it isn't possible to administer drugs in a timely manner, or when patients cannot tolerate them. 

Consider two anecdotes related to the spread of MERS virus in South Korean hospitals. As described by Choe Sang-Hun, it appears that the index patient in the South Korean event had "coughed and wheezed his way through four hospitals before officials figured out, nine days later, that he had something far more serious and contagious." Furthermore, ED wait times in Korea can be extraordinarily long by US standards. Another patient, who waited two-and-a-half days in the emergency department before a hospital bed became available, infected 55 additional individuals during their wait. Apparently, 2.5 days isn't an unusually long waiting time in some Seoul hospitals. 

Applying effective prevention measures to patients suspected of infection is the only way of stopping the chain of transmission in such environments. Unfortunately, it is unclear how to achieve good infection control for MERS and a range of other pathogens. Eli Perencevich described the issue clearly, as usual, in the Controversies in Hospital Infection Prevention blog recently: 

. . . we don't actually know how to achieve good infection control for MERS and the other diseases he [Tom Frieden] mentioned [measles, DR-TB, SARS, Ebola]. If only we invested in studies to understand how to best implement PPE in these [hospital] settings. One could imagine improved PPE technology, refined PPE donning and doffing algorithms and enhanced environmental cleaning as potential targets for future studies examining optimal protection from MERS. Not coincidentally, many of these are the same targets that Mike, Dan and I mentioned in our Ebola+PPE editorial several months ago. If we invest in infection prevention technology and implementation research, our health care system will be safer regardless of the pathogen du jour.

And that's the point that MERS makes me think about. Yes we need antimicrobials and vaccines that work against specific pathogens, of course we do, but developing such drugs is a major effort. Biochemical pathways must be understood, pathogen life histories and survival strategies must be elucidated, and the host response must be characterized among many, many other things. Doesn't it make sense that research on pathogen-agnostic approaches to prevention, which don't require such specific and complex information, might be simpler and broadly applicable? 

Investing in research on infection prevention approaches, and how to implement them sustainably in realistic clinical environments, would pay benefits far beyond helping to thwart the spread of exotic and newly emerged pathogens. We may learn how to better control and prevent the usual suspects of hospital associated infection, which, afterall, are responsible for a tremendous burden of disease day in and day out.

(image source: Wikipedia)

The digital epidemiology of Staphylococcus aureus

Digital epidemiology encompasses an emerging set of analytic techniques and approaches to data collection. Data in these studies are almost always born digital -- they are not recorded or transcribed by hand -- and often the research involves online networks in one guise or another. While these methods are being utilized increasingly, studies combining both digital network data and microbiological data on the spread of hospital associated pathogens have, so far as I know, been missing. 

Obadia et al have published an exemplary study doing just this for the case of MRSA and MSSA in a long term care center. Many researchers have in the past adopted a very reasonable and plausible hypothesis regarding the spread of staph in hospitals: namely, that it depends to a large extent upon person to person contact. If that's true, then obviously the ways in which patients and healthcare workers (HCWs) interact with one another, i.e., the patient-patient and patient-HCW contact networks, must be important for understanding spread. To my knowledge, until this study, nobody has really documented this with clarity at the individual level.

Obadia et al have illustrated this relationship between staph infection and contact network structure quite clearly by utilizing wireless proximity sensing and spa typing. They demonstrate how to employ digital technology to measure who interacts with whom, how frequently, and for how long, over long periods of time, and how to combine that data with microbiological surveillance in order to observe how transmission depends on the web of contacts in a facility. The authors found that close proximity interaction (CPI) paths existed between those colonized with like staph strains, and that those path lengths were significantly shorter than paths between random pairs in the study population. This is in agreement with what is expected from the transmission hypothesis. Their study also highlighted the importance of HCWs as links in the chain of contacts between infected patients.

One important implication of this work is that it might be possible to prevent infections by managing and monitoring close contact paths between patients and patients and between HCWs and patients. The approach may also be useful for developing targeted surveillance strategies that can detect spread and break the contact pathways most likely to result in further spread. I recommend reading the paper, and also the excellent comments regarding it by Eli Perencevich at the Controversies in Hospital Infection Prevention blog.

Overall, I think this study is a great illustration of the power of digital epidemiology methods for gathering detailed data in order to understand how disease is spread in the real -- as opposed to the simplified, theoretical -- world. We need more like it to inform both our thinking about hospital associated infections and analytic models of such pathogens.

(image source: CDC)

New antibiotics: Prevention is important, too!

Losee Ling et al recently described a new antibiotic compound, called teixobactin, that kills pathogens without detectable resistance. The abstract of their study notes that

. . . We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.

It's a beautiful study, and obviously everybody hopes these implications are realized, and soon; new drugs are very badly needed. Eli Perencevich, writing in the blog Controversies in Hospital Infection Prevention, summarizes some of the important results from the study and also offers an important perspective,

I agree with Dr. William Schaffner's comments in the NY Times as he called the study/method “ingenious” yet also cautioned that "it’s at the test-tube and the mouse level, and mice are not men or women, and so moving beyond that is a large step, and many compounds have failed.” I would add one additional caveat  -- teixobactin had little activity against most Gram-negative bacteria including E. coli, Klebsiella and Pseudomonas. . . . Since the real resistance crisis is in multi drug-resistant Gram-negatives (think CRE, NDM-1), we better get back to digging in the dirt.

Certainly, these and other Gram negatives are important. As I've mused before, it's critically important to research infection prevention approaches in addition to investing in new drug development. We must understand how to prevent infections from occurring and spreading in healthcare (and other) settings before new drugs are introduced. It is clear that we do not possess this understanding, at least on any significant scale or in any sustainable way, at present.

(image source: CDC)

New antibiotics on the horizon: Are we ready?

A previous blog asked:

Who wouldn't agree that we need an invigorated pipeline of new, effective, and safe antimicrobial drugs to help us counter the specter of resistance? But it does make me wonder: Is it really a good idea to place new weapons in our arsenal when we have demonstrated few reasons to think that we will use them responsibly?

A reinvigoration of the drug pipeline may be starting, given news that a major drug company is re-engaging its research on antibiotics. Moreover, this week we learned about a new highly potent drug, and another one that was just approved by the FDA, for skin infections. Other new drugs are under development as well.

It seems poignant to think about how to make it safe to employ new antibiotics on a wide scale so as not to risk the emergence of new resistance. It's a complex issue, but here are some thoughts.

• Antimicrobial stewardship programs need to implemented across all healthcare settings. Using antimicrobials in a targeted, appropriate fashion is important for preventing acquisition of new resistance. Progress is being made in some settings (notably children's hospitals), but programs need to be instituted across the board.

• HAI rates need to be reduced to very low levels across institutions and patient populations. Low rates are important for preventing the spread of resistant infections once they emerge. Substantial opportunities remain to improve infection prevention programs in hospitals.  

• Patient expectations for drug therapy for common ailments need to be managed. Patients often pressure doctors for antibiotics for common symptoms (e.g., sore throat, congestion), even when etiology (viral versus bacterial) is unclear. Public health messaging, including the use of social media, is important for changing this. 

Undoubtedly, additional things are important as well. I haven't mentioned, for example, the issues surrounding the intensive use of antibiotics in animal farming, the emergence of antibiotic resistance organisms surrounding those practices, and the potential for causing human colonization and disease. If you have additional thoughts, please comment.

An important question is how we can measure progress in these areas. Surveillance for antimicrobial stewardship policy compliance and HAI rates within an institution seems more straightforward than monitoring these across regions. Likewise, monitoring public perception and expectations for antibiotic prescribing practice is complex. Perhaps this is an area where social media monitoring can play a role. Regardless of the difficulties, measuring such things is critical if we are to manage drug resistance moving forward.

(image source: CDC)

What are we doing to ourselves?

An interesting idea emerged from conversation over dinner with a colleague recently: While it is clear that hand hygiene is foundational for both hospital and community infection prevention, there may be an immunological price to the now all-pervasive focus on hand hygiene in the general population.

Let me explain. Hygiene is one of the pillars of public health and infection prevention, though we still struggle to practice what we know globally. Semmelweis showed us the need for clean hands in the clinical environment, and the notion of ridding hands of germs has evolved since then. Today, alcohol based hand rubs (ABHRs) are prominent in daily life. People rub their hands with "hand sanitizer" before eating out, after riding the bus, after using the restroom, and even at their desks throughout the day. What could possibly go wrong with such an awareness of hand hygiene?

Potentially, nothing. The importance of hand hygiene is undisputed and indisputable in infection prevention. That said, I often see people using ABHR very frequently throughout the day and it makes me wonder if such use of ABHR is eroding not only the transient flora of our hands, but also the resident flora. What is on our hands ultimately ends up challenging the immune system, via oral ingestion, absorption through rubbing the eyes, or inoculation via scrapes and cuts on the hands and fingers. Constantly challenging the immune system with a diversity of biologic agents gives rise to broad immunity.

Might we be eroding the frequency and diversity of that challenge, and thus the strength and diversity of the immunological protection, with such pervasive use of ABHR? This general notion, that cleanliness might have deleterious, unintended community-level consequences, is not new. It's been discussed within the context of polio, for example, and there is speculation about inverse relationships between cleanliness and asthma.

I'll close by noting that ABHR is but one of the several tools society currently employs to kill the spectrum of microbes in our immediate environment. There are also antimicrobial wipes and antimicrobial soaps. The weapons of mass microbial destruction are many and proliferating. They obviously have their place in the clinic but, regarding their sometimes near-obsessive use in the community, are they helping or hurting us in the long run?

(image source: David Hartley)

Travel and infection: The global mixing bowl

"Healthy travellers to countries where carbapenemases-producing Enterobacteriaceae (CPE) are endemic might be at risk for their acquisition, even without contact with the local healthcare system." So begins a recent Eurosurveillance report by Ruppé and coworkers describing acquisition of CPE by healthy travelers to India. The study describes data from the VOYAG-R project, which has many objectives, including measuring the rate of acquisition of multidrug-resistant Enterobacteriaceae (MRE) in people returning from travel Latin America, Sub-Saharan Africa, and Asia and the length of MRE carriage after trips. 

CRE was the topic of a previous blog post; such pathogens are associated with significant morbidity and mortality (especially in transplant patients and those with hematological malignancies) and are increasing in incidence globally. They are difficult to detect and treat, and are important in hospital infection prevention. The Ruppé et al study reports the acquisition of CPE in three healthy French travelers returning from India. The travelers reported no contact with hospitals or healthcare centers while traveling, leading the authors to conclude that the findings are "worrisome as they attest to the development of a community reservoir for CPE, at least in India."

The study illustrates many important issues, including that those traveling to high prevalence regions are at risk for becoming colonized with CPE. Once colonized, they can carry CPE back to their origination. One can think of such regions has having a high epidemiologic weight for the global propagation of CPE. Such movement of CPE and related pathogens has been described previously. In one example, importation of MRE strains producing NDM-1, OXA-48, and ESBL into the Netherlands after a patient received healthcare in Egypt was observed. In other cases, the acquisition of CPE cannot necessarily be attributed to travel or other risk factors, but what is clear is that such pathogens have spread over large distances and are now regularly observed in many areas. 

Other pathogens are known to exhibit transient colonization, though data are frequently rare and highly variable. The picture of latent introduction of CPE is probably also relevant for other bacteria of interest in hospital epidemiology. Such a picture highlights the need for surveillance, yes, but also for effective hospital infection prevention and control. As has been pointed out, this can be difficult, especially for CRE. We need a better understanding of the mechanical pathways of infection in order to design and implement better prevention practices. 

(image source: Wikipedia)

Infection prevention knowledge: Permutations on "known" and "unknown"

Pathogens are everywhere, and we are increasingly aware of how widely they can be disseminated in healthcare environments. Researchers have found, for example, that

• Well-child visits are a risk factor for subsequent influenza-like illness visits. Infections are thought to spread in waiting and exam rooms.

• Hospital water taps can be contaminated with bacteria including Legionella spp., Acinetobacter spp. and other Gram-negatives. 

• Hospital surfaces and equipment are sometimes contaminated with nosocomial pathogens including Clostridium difficile, VRE, and MRSA.

• Doctors' ties and white coats are anything but sterile.

• Toilet seats can harbor MRSA and probably other pathogens. 

• Hospital privacy curtains can be contaminated with pathogenic bacteria including MRSA and VRE.

• Stethoscopes can carry MSSA and MRSA, among others. 

The list could go on and on. We know that many pathogens can persist on surfaces for a considerable time, and while it's not clear the extent to which contaminated surfaces play a role in HAI in general, there is reason to believe they are important in many infections. The unfortunate reality is that patients suffer nosocomial infection; contaminated surfaces can only add to the risk of infection.

I never thought I'd invoke Donald Rumsfeld in a discussion of infection control, but he once described a useful construct for thinking about infection prevention (among other things). He's quoted as saying

. . . there are things we know that we know. There are known unknowns; that is to say, there are things that we now know we don't know. But there are also unknown unknowns – there are things we do not know we don't know.

If we add another, obvious, category -- things we don't know that we know -- then a 2x2 table can be written for types of knowledge. Done for infection prevention and control, it might look like the table below.

It would be interesting to organize what we know and don't know into such a table. That's a big thing to do; it requires assessing what specific practices are truly evidence-based ("known knowns", like have been described for central line infections and ventilator-associated pneumonia), identifying best practices that aren't necessarily well studied ("unknown knowns"), and enumerating gaps in our knowledge ("known unknowns", such as the role of contaminated surfaces in HAI). Of course, we can never identify the things we don't realize that we don't know (the "unknown unknowns"), but the hope would be to ultimately understand the other three quadrants well enough so that we are sure that the unknown unknowns aren't important. Obviously, that's hard to do.  

It seems to me that seriously trying to fill in the quadrants is an important step towards a complete theoretical picture of infection. Probably the "known knowns" quadrant is smaller than we would hope, and the "known unknowns" quadrant is significant. I wonder how large the "unknown knows" category -- the things we don't realize we know -- is?

(image source: the E. coli micrograph, Wikipedia; the 2x2 table, David Hartley)