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

MRSA colonization: Is it a quantitative or qualitative relationship?

Leonard Mermel

Few studies have assessed the importance of quantitative differences in MRSA carriage at various body sites. Len Mermel et al. from Warren Alpert Medical School (Brown) has a new study out in the Journal of Clinical Microbiology that assessed the relationship between quantitative burden of MRSA colonization at various body sites and colonization at other sites. For example, if patients are heavily colonized in the anterior nares, are they more likely to be colonized elsewhere and carriage at which sites are related to heavy nares colonization?

In a cohort of patients known to be MRSA+ during the prior year, the study team collected swabs from the each nares, each axilla, each groin site, and the perineum. Swabs were tested for presence of MRSA using CHROMagar plates and log10 colony counts. 

In this known MRSA+ cohort, 53 of 60 patients were MRSA+ at at least 1 site and 29/123 cultures were only positive after broth enrichment.  75% (40/53) were colonized extranasally. Sensitivity ranged from 91% in the nares, 63% in the groin, 47% in the perineum down to 32% in the axilla. The greatest combined sensitivity was 98% for nares+groin.

Mean log10 counts were highest in the nares (1.95) and lowest in the axilla (0.87). As the colonization count increased in the nares, the number of distant sites colonized increased.  For each 1 log increase, the OR=2.1 for distant colonization. As far as risk factors, diabetes was associated with colonization in the perineum. One interesting finding was that mean log counts were lower in patients with a current or previous infection than in patients who had never been infected (1.6 vs 2.4, p=0.3)

Mermel LA et al J Clin Microbiol 2011

Staph: It's deeper than you think

For decades it's been known that the primary site of staphylococcal colonization is the anterior nares. Now there is a new, interesting paper in the Journal of Hospital Infection that provides a better understanding of colonization. Nasal swabs were performed on 37 cadavers and 9 were found to have colonization with S. aureus. The noses were then surgically removed and tissue sections taken. An antibody stain against S. aureus was applied to visualize the site of colonization. There were two important findings: (1) colonization only occurred distally in the stratified squamous epithelium (i.e., there was no colonization of the more proximal ciliated mucosa; and (2) in 6/9 cadavers, staph organisms were visualized in the hair follicle shaft, and in 2 the bacteria were visualized deep in the follicle. The presence of S. aureus deep in the hair follicle may explain why some patients do not decolonize or recolonize after decolonization with mupirocin since the drug may not be able to penetrate that deeply.