Monday, December 2, 2013

The beginning of the end for...CHG??

Chlorhexidine. We love it, we just can't get enough of it, we are up to our neck in it and we cheer for it. Basically it's the greatest. But some of us have been concerned that the widespread use of CHG would lead to resistance, particularly in Acinetobacter.

There is a new report in PNAS by investigators in Australia and the UK that looked at gene expression in A. baumannii after chlorhexidine exposure. The most highly up-regulated genes were those encoding the RND efflux system AdeAB. Importantly, the investigators also identified a gene encoding a previously uncharacterized membrane protein, AceI, which they determined to be an active CHG efflux protein capable of transporting CHG out of the cell. This novel AceI was said to be a member of the PCE family of efflux systems.

And to give you a sense of the ubiquity and potential importance of these systems in Gram-negative bacteria, I offer this quote from the authors:

"The primary features of the A. baumannii chlorhexidine resistance response, i.e., up-regulation of genes encoding RND and PCE family efflux systems, are conserved in other γ-proteobacteria, as well as β-proteobacteria. Given the phylogenetic distance of these organisms, this similarity of regulatory responses to a compound that has only been synthesized since the early 20th century is intriguing. RND efflux systems are well recognized for their broad protective functions in Gram-negative bacteria and it is not unusual for these systems to constitute part of a general stress response and to mediate resistance to foreign compounds, particularly amphipathic antimicrobials such as chlorhexidine. However, the involvement of the PCE family proteins in seemingly specific resistance to chlorhexidine is unexpected. It is likely that the physiological function(s) of this transporter family were originally unrelated to chlorhexidine resistance and that these proteins provide a fortuitous intrinsic resistance capacity."

h/t Ayush Kumar and Dan Ricciuto

image source: wikipedia

9 comments:

  1. Thanks for pointing to this study, Eli. Rather than being the "beginning of the end", as you suggest, I think this is unfortunately our "suboptimal starting point". As this work shows, some gram negative organisms have instrinsic resistance capacity (and simple in vitro studies have shown many-fold higher MICs for gram negatives than for staphylococci and enterococci). This would lead one to predict that controlled trials would show a much greater impact on gram positive than on gram negative infections, which is indeed what they've shown (see the "we cheer" link above). As we've pointed out before in this blog, the most convincing data for the impact of CHG on BSI reduction are for coagulase negative staphylococci, and perhaps enterococci. For gram negatives and S. aureus....not so much. So while we can still love CHG, we do so knowing its considerable limitations.

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  2. This is interesting. We certainly didn't see a decrease in carbapenem-resistant Acinetobacter rates after implementing CHG baths as the sole intervention.

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  3. Thanks for your comments. I wish I shared Dan's optimism that we are using CHG knowing its limitations. My sense is that we (meaning a significant portion of hospital epi programs) are jumping off the high dive with our eyes closed. Universal bathing of all patients in ICUs, which pushes us towards MDR-GNRs like Acinetobacter seems to be a short term solution. Yes, this could be described as a suboptimal starting point. I also worry that CHG provides temporary cover for poor hand hygiene and suboptimal CLABSI insertion techniques, etc.

    Do you think there are any possibilities that CHG will be included in antimicrobial stewardship programs?

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  4. Very interesting idea, Eli, regarding CHG stewardship, especially given the fact that so much recent infection prevention progress consists of finding more places to put CHG.

    Let's see, we impregnate catheters with it, we incorporate it into central line dressings, we use it to prep sites prior to CL placement, we use it for oral care of ICU patients to prevent VAP, and we bathe ICU patients in it to prevent BSI. At least 4 of the 5 above approaches are supported by RCTs or cluster-RCTs, and I know of no other topical antimicrobial that comes close to that level of support.

    I agree that we need to have a high level of concern about impending loss of CHG due to emergence of resistance (or emergence of organisms with intrinsic resistance). How would we approach stewardship, though? Which particular uses should we forego? The question becomes particularly difficult in a "zero" environment. For example, the idea that a particular approach (such as antimicrobial impregnated catheters) should only be taken if CLABSI rate is > X is no longer tenable if X = 0. The Timsit study of CHG dressings, for example, had a control arm CLABSI rate (1.3/1K cath days) that was < than the rate at the end of the Keystone study (1.4), and still showed a dramatic reduction (to 0.4) in the CHG dressing arm.

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  5. All good points Dan. I haven't been impressed with the impregnated catheter data, so that is perhaps the 1 out of 5 not supported. I know the Timsit paper well since I wrote the editorial and implemented CHG dressings years ago when I was at Maryland.

    My issue with any RCT or cluster-RCT is that they usually cover a short time period. I think this fact and the "zero" culture combine to push use of agents that appear beneficial in the short run and are horrible long term solutions. For example, how would you incorporate shifting of nosocomial pathogens over years into an RCT?

    I think the solution is mathematical modeling with a long time horizon.

    A good example of the utility of models is this paper by Bergstrom and Lipsitch (http://www.pnas.org/content/101/36/13285.full) which determined that antimicrobial cycling would not reduce antimicrobial resistance. You likely could never do an RCT with the necessary time horizon to "prove" this finding and many of the initial studies showed dramatic reductions in resistance in the short term. However, these initial studies were clearly wrong in the long run, otherwise we would still be cycling.

    Another comment is that most of the studies in your 4 out of 5 were RCTs where they exposed an individual patient and an individual patient benefited. Unfortunately, when we are concerned for emergence of resistance or shifting in strains we need to do population level (whole ICU or whole hospital) studies and track the bacterial ecology in the population and environment over time. Unfortunately, few of these types of studies have been completed (or ever funded).

    Appreciate this discussion. It is hard to balance the individual vs the population and the present with the future. I am clearly on the population/future end of this CHG discussion but definitely appreciate the other side. I also realize I'm in the clear minority here, but feel it is useful to make these points. And I even hope I'm wrong.

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  6. Typical Eli, always focusing on the population/future. If we applied that kind of thinking in other areas, we'd still have fossil fuels going unused, and wouldn't have global warming to look forward to! Oh, wait...

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  7. One more thought. There is clearly clinical trial data for CHG, as mentioned. There is also good clinical trial data for systemic antimicrobial antibiotics like vancomycin. Yet we subject vancomycin to stewardship but not CHG. I just wonder if it is worth adding CHG to the list of antimicrobials that we consider for "protection" so that its obviously beneficial effects last for more years. Could we develop criteria for safe use? I think as you correctly mention Dan that in the "zero" culture the answer is probably no. However, it is the case that positive trial data shouldn't preclude stewardship, but rather should encourage stewardship since it suggests efficacy that we want to preserve.

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  8. Well, maybe it is 2 out of 5 down, we don't know. We recently discovered a large-scale medical literature error whereby the so-called "evidence for chlorhexidine" in skin antisepsis is largely based on clinical trial outcomes from using chlorhexidine-alcohol combinations (two antiseptics) and comparing these against single competitor antiseptics, tested under conditions where the clinical effects of chlorhexidine cannot be separated from those of the alcohol. On the other hand, it is well known from decades worth of standardized microbiological testing on skin that alcohols have about 10 times (~1 log) greater immediate activity on skin than chlorhexidine. What the chlorhexidine adds is persistent activity, which is, of course, only clinically relevant where there is a significant requirement for persistency, based on the physiology of the respective procedure. This is the case for central lines, as outlined by Dan above, but less so for other procedures. In this context it is interesting to note octenidine, an antiseptic available in Europe and Asia, which has similar microbiological properties as chlorhexidine (overall activity, persistency), but no resistance development yet. Clinical trial data for octenidine are very scarce at this point, but who knows, maybe there is an alternative for the future.
    See:
    http://www.ncbi.nlm.nih.gov/pubmed/22984485
    http://www.ncbi.nlm.nih.gov/pubmed/23838237

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  9. This freshly-appeared article fits well to this blog entry:
    Apisarnthanarak A, Hsu LJ, Lim TP, Mundy LM. Increase in Chlorhexidine Minimal Inhibitory Concentration of Acinetobacter baumannii Clinical Isolates after Implementation of Advanced Source Control. Infect Control Hosp Epidemiol 2014; 35: 98-99.
    http://www.jstor.org/stable/10.1086/674404

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