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)

Microbial ecology: Keeping one step ahead of the bad bugs

Two papers were published recently that apply notions of bacterial interference and competition rather elegantly. The first was a study by Dale Gerding et al on administering nontoxigenic Clostridium difficile spores to prevent recurrent C. diff infection. The study aimed to determine the safety, fecal colonization, recurrence rate, and optimal dosing schedule of nontoxigenic C. difficile, and the authors found that

Among patients with CDI who clinically recovered following treatment with metronidazole or vancomycin, oral administration of spores of NTCD-M3 was well tolerated and appeared to be safe. Nontoxigenic C. difficile strain M3 colonized the gastrointestinal tract and significantly reduced CDI recurrence. 

It's a fascinating study and I recommend reading it. In addition to contemplating this as a potential future treatment for recurrent CDI, it's intriguing to wonder if patients could have their GI tracts colonized by nontoxigenic C. diff prophylactically before receiving antibiotics associated with CDI.

The other study, by Alice Deasy et al, demonstrates how nasal inoculation with the commensal Neisseria lactamica inhibits carriage of N. meningitidis in young adults. N. lactamica is a commensal occupying the same ecological niche (the nasopharynx) as the pathogenic organism N. meningitidis, which is associated with epidemic meningitis. They observed a significant inhibition of meningococcal carriage in carriers of N. lactamica, which was attributed to displacement of existing meningococci and to inhibition of new acquisition. Their findings suggest N. lactamica as a potential "novel bacterial medicine to suppress meningococcal outbreaks". Again, I recommend reading the complete study.

The notion of exploiting microbial ecology is appealing for many reasons, including that it doesn't require developing intrinsically new pharmacologic compounds and that it may have no significant side effects. At the same time, its important to remember previous trials employing bacterial interference, such as the deliberate colonization of newborn children with "low virulence" Staph. aureus, so that old missteps aren't repeated.

(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)

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)