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)

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)

Update: Vaccines as a tool in the post-antibiotic era

After posting the piece on vaccines yesterday, a new study by BA Diep et al was brought to my attention in which the surface proteome of a prevalent strain of MRSA was determined. Work such as this is important for identifying potential antigen combinations that could be included in future multicomponent Staphylococcus aureus vaccines.

Moreover, today the WHO published a report on antimicrobial resistance. It notes, inter alia, that

Greater emphasis should be placed on prevention, including strengthening hygiene and infection prevention and control measures, improving sanitation and access to clean water, and exploring a more widespread use of vaccines. Although preventive vaccines have become available for several bacterial infections, their application is still limited.

It's clear that a multifaceted approach is needed to deal with the antimicrobial resistance problem. The WHO study, and related commentary, helps to frame and build awareness of the issue. New vaccines could help.

(image source: WHO)

Vaccines: A tool for the post-antibiotic era?

In honor of World Immunization Week this week, I recently read two books by Paul Offit: Vaccinated: One Man's Quest to Defeat the World's Deadliest Diseases and The Cutter Incident: How America’s First Polio Vaccine Led to the Growing Vaccine Crisis. Both are excellent. Vaccinated is essentially a biography of Maurice Hilleman, but it also reviews how several of the important vaccines currently in use were developed and marketed. The Cutter Incident tells the story of incompletely inactivated lots of polio vaccine manufactured by Cutter Laboratories, which caused 40,000 cases of polio nationwide in 1955, including 200 cases of paralysis and 10 deaths. There are many pearls and much wisdom to be found in the pages of these two books; I recommend reading them.

Certainly the utility of vaccines is well demonstrated and their development and application is one of the major accomplishments of modern medicine. In the US alone the improvement of population health as vaccines have become available is remarkable. Globally, it has been estimated that vaccines prevent nearly 6 million deaths annually worldwide.

The books got me thinking about future potential vaccines. In one passage, Offit recounts the development of a pneumococcal vaccine and quotes Robert Austrian talking about the rationale for his work:

The only alternative then to protect those at high risk of early death is to prevent them from becoming ill.

This beautiful and simple idea -- a medical and public health truism if ever there was one ("an ounce of prevention is worth a pound of cure") -- strikes me as relevant to HAI and antibiotic resistant infections. Think what healthcare might be like if there were vaccines for many of the bacterial infections that are currently problematic and often resistant to antibiotics, like Staphylococcus aureus, Clostridium difficile, and Neisseria gonorrhoeae.

Several antibacterial vaccines are available, including ones for pertussis, tetanus, diphtheria, meningococcus, pneumococcus, Haemophilus influenzae type b (Hib) disease, cholera, typhoid, and anthrax. However, there are reasons that vaccines for S. aureus, C. diff, and N. gonorrhoeae (as well as others) don't yet exist. For one, the immunology can be complex, as Offit explains in the discussion of the pneumococcal vaccine. Proctor describes the situation for Staph aureus in a recent review, as do Fowler and Proctor in another review. Also, the cost of developing, testing, and licensing can be steep relative to the profits of a licensed, marketed vaccine. Yet another issue is the specter of adverse events, both real and perceived. On this point, Offit notes that

. . . a technology that would clearly save lives sits on the shelf. "We could make a group B strep vaccine tomorrow," said one senior pharmaceutical company scientist. "But it would have to be given to pregnant women and we couldn't handle the liability." 

Dempsey et al offers a recent, interesting, and partially validating study to this view of a potential group B strep (GBS) vaccine. Such issues are difficult.

That being said, perhaps vaccines should be emphasized more in the conversation regarding antibiotic resistance. I've wondered in the past about the effectiveness of developing new antibiotics when there seems to be little reason to believe, given the past track record, that they will be used responsibly. A new generation of antibiotic drugs could become useless within a few years if effective antibiotic stewardship isn't practiced globally. Vaccines, if they could be made, may offer protection against what may soon be untreatable infections. Or put differently, perhaps vaccines could be an important tool in a post-antibiotic era.

Of course, there are issues to be better understood and addressed. Recent work illustrates that Bordetella pertussis is evolving in response to the vaccine, raising the possibility that future vaccines may be associated with similar dynamics. Also, vaccines to human commensals like Staphylococcus aureus might promote overgrowth of other commensal organisms. Studies have investigated this for the case of Streptococcus vaccination and MRSA colonization and infection. Moreover, it's unclear whether people would really embrace more vaccinations given the current and recent climate surrounding vaccines.

Regardless, one seldom hears about vaccines in the conversation about antibiotic resistance. It seems like funding should address making new vaccines as well as development of new antibiotic drugs -- because Robert Austrian was right. 

(image source: CDC/PHIL)

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)