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)

Bacterial interference and the deliberate colonization of patients

Beginning in the mid-1940s and lasting until the late 1960s, the world saw a dramatic pandemic of staphylococcal infections. This post describes a curious historical episode in research aimed at controlling Staph outbreaks toward the end of that period.

One of the fundamental ideas in ecology is that, depending on the environment and properties of individuals, some types of individuals can out compete other types. When this happens, the less successful individuals can become incompletely or completely displaced. In the 1960s, the idea of microbial competition was actively applied to clinical medicine in a fascinating series of studies, which ultimately ended in tragedy. These studies investigated an idea known as "bacterial interference": the inability of a strain of a bacterium, in this case Staphylococcus aureus, to colonize a particular site of a host following deliberate colonization of that site with another strain of the bacterium.

The notion of using bacterial interference for controlling or preventing epidemics of Staph in hospital nurseries was evaluated and several trials were carried out. How this idea came about and how the studies were done is fascinating and is described in Boris, 1968 and references therein. As the nose is one of the main ecological niches of Staph aureus in humans, newborns were deliberately colonized with an apparently apathogenic strain of Staph aureus (called "strain 502A", after the phage typing scheme then in use) by swabbing the nose and the umbilical stump shortly after birth.

The results were dramatic. Clinical and epidemiological observation revealed a striking lack of staphylococcal disease in the infant study population and in their families. As Shinefield et al 1966 summarized the situation:

It has been clearly demonstrated that artificial colonization of the nasal mucosa of newborns with one strain of Staphylococcus aureus interferes with subsequent acquisition of a second strain of S aureus. This deliberate colonization of infants shortly after birth with a staphylococcal strain of low virulence (strain 502A) has been employed to protect infants from colonization and disease with virulent epidemic strains of S aureus.

The studies on children in university hospital environments were extended to children in a community hospital setting in Light et al, 1967, and found to be effective. Boris et al 1964 applied the idea to adults.

There were reservations discussed in the literature, however. An echo of that concern can be seen in an August 3, 1968, issue of the British Medical Journal, in a short report on a NEJM paper by Light et al describing observations of bacterial interference (not involving deliberate colonization) between Staph aureus and Pseudomonas. In the report, an anonymous author referred to the trials evaluating deliberate colonizations, mentioning that

Ethical objections have been raised to this procedure, but it seems no more objectionable from this standpoint than the use of living vaccines.

Unfortunately, adverse effects soon became known, including a death from infection with the 502A strain. Writing in 1972, Houck et al reported on complications associated with bacterial interference trials. A passage from the abstract describes the death due to septicemia,

An infant of a diabetic mother developed septicemia and meningitis, probably secondary to passing an umbilical vein catheter through the colonized umbilical stump. Staphylococcus aureus 502A and Escherichia coli were isolated from blood culture before death and from autopsy cultures of blood and peritoneum. A meningeal culture grew S aureus 502A. Gram-positive cocci were identified in liver, lung, heart, and meninges. 

They also noted that 

Only two (0.5%) minor 502A infections were seen in 444 spontaneously colonized infants. The benefits of S aureus 502A programs far outweigh their hazards. Disease due to the 502A strain is more frequent when the inoculum applied to the infant is large than when it is kept below 4,000 bacteria. The fatal case emphasizes that bacteria of extremely low virulence may produce serious disease in compromised hosts and that catheterization through a contaminated umbilical stump may induce bacteremia.

Although I haven't done an extensive search for bacterial interference programs after the publication of Houck et al 1972, these activities seem to have terminated after the death.

There are so many things to ponder regarding this curious episode in the 1960s, including how the one death in a few hundred patients, interpreted by Houck et al as a risk far outweighing the hazards, contrasts with current thresholds for attributable risk. Another is the remark that pathogens "of extremely low virulence may produce serious disease in compromised hosts", and how that notion is similar to the practice of avoiding live virus vaccines in recovering HSCT patients during immune system reconstitution.

Recently, Mukherjee and coworkers observed that the beneficial fungal yeast Pichia inhibits growth of pathogenic fungi, including Candida. Candida causes oral candidiasis (thrush) in immunocompromised and immunosuppressed patients. This is exciting; one of the study authors commented

One day, not only could this lead to topical treatment for thrush, but it could also lead to a formulation of therapeutics for systemic fungal infections in all immunocompromised patients . . . In addition to patients with HIV, this would also include very young patients and patients with cancer or diabetes.

I think it's important to know about the history of bacterial interference interventions so that past issues can be recognized and actively avoided in related future investigations.

(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)