Following hot on the heels of a series of studies showing that daily bathing using chlorhexidine reduces the risk of HCAI, a recent study suggests that chlorhexidine daily bathing does not reduce HCAI. The headline finding is that chlorhexidine bathing did not reduce HCAI. Before throwing out the chlorhexidine with the bathwater, it’s worth considering the limitations of the study.
There has been much impressive research of late around the use of chlorhexidine daily bathing to reduce the burden of skin contamination and protect patients from infection. This is quickly becoming en vogue, especially for ICU settings in the USA. But what is compliance like with this intervention, and how do you measure compliance? The studies that have measured compliance previous have said “Yes, this patient was given a chlorhexidine wash today”, but have rarely gone so far as to measure the actual concentration of chlorhexidine on the patient’s skin.
So I’m really quite interested in seasonality of infections. I first became interested in it when looking at increases in E. coli bacteraemia for ARHAI (report here) because of Jennie Wilson’s excellent paper showing seasonality of gram negative bacteraemia, echoed by similar observations and conjecture on warmer weather, more infection. This is true in hospitals as well as the community. Why would this be? We have tussled with increasing E. coli bacteraemia in the UK for a few years now. Goes up every summer, does not return to the baseline, goes up again next summer etc., etc.. Other countries have also reported this. I have heard some suggest this is due to longer hours of daylight leading to more barbeques and more sexual activity. Given that the majority of infections in the UK are >70 years of age, my senior years have no fears for me then.
The idea of “source control” – using chlorhexidine to reduce the amount of bacteria on a patient’s skin – makes a lot of sense. There’s mounting evidence that chlorhexidine daily bathing works for Gram-positive pathogens, especially in the ICU.1 For example, one of the first thorough studies of chlorhexidine gluconate (CHG) daily bathing showed that the amount of VRE on the skin, in the environment and transmitted to others were all reduced by implementing CHG daily bathing.2 A number of more recent high-quality studies have provided evidence that CHG daily bathing in the ICU setting helps to prevent the transmission of Gram-positive bacteria (see Table below – although note that studies have not been universally positive for CHG).
Table: Studies evaluating the impact of chlorhexidine daily bathing (with or without other interventions) including data on Gram-negative bacteria.
| Study | Setting | Design | Intervention | Results |
| Noto 2015 3 | ICU | Cluster RCT | Daily CHG | No significant reduction in HCAI (composite measure including CLABSI, CAUTI, VAP and CDI) |
| Derde 2014 4 | ICU | Time series analysis | Daily CHG plus hand hygiene | Reduction in all MDROs and MRSA (but not VRE or ESBLs) |
| Seyman 2014 5 | ICU | Before-after | Weekly CHG ‘douche’ | Reduction in BSI but not CLABSI; slight reduction in Gram-negative BSI (n too small for statistical analysis) |
| Hayden 2014 6 | LTAC | Before-after | Bundle (including daily CHG) | Acquisition of CRE fell from 4 to 2 per 100 patient weeks |
| Martínez-Reséndez 2014 7 | ICU | Before-after | Daily CHG plus hand hygiene | Reductions in all infections, and in A. baumannii VAP rate |
| Apisarnthanarak 2014 8 | ICU | Before-after | Bundle (including daily CHG) | Reductions in a. baumannii infection and colonization |
| Climo 2013 9 | ICU | Cluster RCT | Daily CHG | Reductions in MRSA / VRE acquisition and all BSI; BSI mainly CoNS (no significant reduction in Gram-negative BSI or CLABSI) |
| Milstone 2013 10 | Paed ICU | Cluster RCT | Daily CHG | BSI reduced; mainly CoNS (no significant reduction in Gram-negative BSI or CLABSI) |
| Munoz-Price 2010 11 | LTAC | Before-after | Bundle (including daily CHG) | CRE carriage prevalence fell from 21% to 0% |
| Evans 2010 12 | ICU | Before-after | Daily CHG | Rate of CLABSI reduced; A. baumannii colonisation reduced but not significantly |
| Popovich 2009 13 | ICU | Before-after | Daily CHG | Rate of CLABSI reduced; A. baumannii infection rate reduced but not significantly |
| Bleasdale 2007 14 | ICU | Cross-over | Daily CHG | Number of Gram-negative BSI in each arm too small for analysis |
| Gould 2007 15 | ICU | Before-after | Daily CHG + mupirocin | Number of Gram-negatives too small for analysis |
| Camus 2005 16 | ICU | RCT | Daily CHG + mupirocin | Number of Gram-negative acquisitions similar in intervention vs. control groups |
The question of whether CHG is effective for the prevention and control of Gram-negative bacteria is rather more complicated. The main issue is that Gram-negative bacteria are less susceptible to CHG than Gram-positive bacteria.17 In theory, this shouldn’t be a problem because the amount of CHG applied to skin (10,000 mg/L) is much higher than the minimum inhibitory concentration (MIC) of most Gram-negative bacteria.17 However, it’s worth noting that the concentration of CHG measured on the skin of patients being treated with CHG in one study was considerably lower than the amount applied (15-312 mg/L before the daily bath and 78-1250 mg/L after the daily bath).18 Nonetheless, in this same study, CHG was found to be effective in reducing the skin burden of CRE on patients in a long-term acute care hospital (see Figure, below).18 So, should CHG bathing be applied to combat MDR-GNR?
Figure: Impact of chlorhexidine gluconate (CHG) daily bathing on skin colonization with KPC-producing K. pneumoniae in 64 long-term acute care patients (difference is statistically significant, p=0.01).
A number of studies have implemented CHG as part of a bundle of interventions to control various MDR-GNR. For example, a team from Thailand found that an intervention aimed at improving environmental hygiene combined with CHG brought an outbreak of A. baumannii under control.8 The National Institute of Health Clinical Center19 has included CHG bathing as a component of a successful CRE control bundle, and the same goes for long-term acute care hospitals.6,11 Meanwhile, a Dutch study found that implementing CHG bathing combined with improving hand hygiene failed to reduce the acquisition rate of ESBL Enterobacteriaceae.4 A Mexican study implemented CHG bathing combined with improved hand hygiene and reported a significant reduction in VAP due to A. baumannii.7 However, in all of these studies, it is not possible to tell whether it was the CHG or another element of the bundle that made the difference (or not, in the case of the Dutch study).
No study has been designed specifically to evaluate the impact of CHG daily bathing alone on the rate of Gram-negative bacteria infection or colonization, although rate of Gram-negative bacterial infection or colonization has been reported in several studies of CHG. A small number of high-quality studies that have evaluated CHG as a single intervention including randomization have failed to demonstrate a reduction on Gram-negative BSIs and CLABSIs (see the Climo9, Mlistone10 and Camus16 data from the Table above). Also, a non-randomised before-after study in a trauma ICU reported a non-significant reduction in Acinetobacter species colonization.12 Several other studies mention the rate of Gram-negative infection or colonization in passing, but the numbers are too small for meaningful statistical analysis (see Seyman,5 Popovich13, Bleasdale,14 and Gould15). Although these studies do not provide convincing evidence that CHG works for Gram-negative bacteria, it’s important to remember that they were not powered to evaluate the impact of CHG on Gram-negative bacteria.
One final point to consider is the potential for the development of CHG resistance. Units using CHG universally have reported an increase in the presence of bacteria with reduced CHG susceptibility.20-22 However, the actual degree of reduced susceptibility is moderate, meaning that the clinical importance of this reduced susceptibility is debatable. It is true to say, though, that the potential for meaningful reduced susceptibility is greater in Gram-negative bacteria than in Gram-positive bacteria due to their higher baseline MIC and manifold mechanisms of resistance to biocides and antibiotics.17
So, does CHG bathing work for Gram-negative bacteria? Based on current data, we simply don’t know.
References:
Image: John Loo.
Not content with a single well-planned study to provide information on what works to control multidrug-resistant organisms (MDROs) in the ICU, the MOSAR study group published an interrupted time series and a cluster randomized trial of various interventions in the Lancet ID. This makes the study rather complex to read and follow, but there are a number of important findings.
Interrupted time series – ‘hygiene’ intervention (chlorhexidine and hand hygiene)
Following a 6-month pre-intervention period, a 6-month interrupted time series of a ‘hygiene’ intervention (universal chlorhexidine bathing combined with hand-hygiene improvement) was performed. The key outcomes were twofold: whether there was a change in trend during each phase, and whether there was a step-change between the phases. The hygiene intervention effected a trend change reduction in all MDROs combined and MRSA individually, but not in VRE or ESBLs (Table). However, there was no step-change compared with the baseline period.
Table: Summary of reduced acquisition of all MDROs combined, or MRSA, VRE and ESBLs individually.
Cluster RCT – screening and isolation
In the 12-month cluster RCT of screening and isolation, the 13 ICUs in 8 European countries were randomized to either rapid screening (PCR for MRSA and VRE plus chromogenic media for ESBL-Enterobacteriaceae) or conventional screening (chromogenic media for MRSA and VRE only). When analysed together, the introduction of rapid or conventional screening was not associated with a trend or step-change reduction in the acquisition of MDROs (Table). In fact, there was an increase in the trend of MRSA acquisition. When comparing rapid with conventional screening, rapid screening was associated with a step-change increase in all MDROs and ESBLs.
Discussion
In summary, this is an excellent and ambitious study. The lack of impact on ESBL transmission in particular is disappointing, and may lead towards more frequent endogenous transmission for this group. The results do indicate screening and isolation did little to control MDRO transmission in units with improved hand hygiene combined with universal chlorhexidine. However, we need a ‘no screening and isolation’ vs. ‘screening and isolation’ cluster RCT before we ditch screening and isolation.
I enjoyed this year’s ECCMID in Barcelona very much, and came away feeling scientifically, culturally and culinarily enriched! Many thanks to the organizers for such a broad and interesting programme. One of the most interesting sessions was the very final session, on controlling MDROs in the ICU. The session boiled down to the pros and cons of three approaches to decolonization: selective digestive decontamination (SDD), mupirocin for MRSA nasal decolonization, and chlorhexidine gluconate (CHG) bathing. The faculty of Dr Brun-Buisson, Dr Harbarth, Dr Bonten and Dr Huang made it an engaging session.
Selective digestive decontamination (SDD)
The problem is antibiotic resistant bacteria, particularly in the ICU. Is the solution really indiscriminate use of antibiotics to temporarily suppress the load of antibiotic resistant bacteria in the gut? It doesn’t make a lot of sense to me either.
Selective oral decontamination (SOD) or selective digestive decontamination (SDD) is not a new concept, and has been around for some 45 years. Only recently have impressive studies emerged demonstrating that SDD and, to a lesser extent, SOD suppress the load of antibiotic resistant bacteria in the gut, reduce mortality and reduce transmission (de Jonge, de Smet and Daneman). But it’s not without collatoral:
I appreciate that I’m presenting a polarized and rather one-side case against SDD here. But for me, whether SDD works is the wrong question: is it the right thing to do? If (perish the thought) I’m a patient in the ICU, then SDD works for me. However, if I’m working on an ICU in 2024 wondering what to do with a pan-drug resistant Gram-negative bacterium, SDD (in 2014) doesn’t work for me.
Mupirocin
Dr Huang presented the key findings from her impressive study of universal CHG combined with MUP. Mupirocin resistance in S. aureus can be low-level mutational) or high-level (acquisition of the Mup resistance genes). The use of MUP has been associated with the development of both high- and low- level resistance. Indeed, several updates from ECCMID show this. For example, Dr Sarah Deeny’s poster showed that low-level resistance appeared to develop during hospitalization. Plus, a study from our group showing that detection of phenotypic high- or low-level mupirocin resistance only represents three quarters of the picture, since carriage of mupirocin resistance determinants remains “silent” 25% of the time.
So, the key question hanging over Dr Huang’s study is the value of universal MUP over and above universal use of CHG. Dr Huang presented an excellent analysis table on this point, which I’ve reproduced below:
Table: Weighing the pros and cons of universal mupirocin use (reproduced with permission from Dr Huang).
One of Dr Huang’s most powerful arguments was that the burden of mupirocin use is in decolonizing a large number of patients prior to elective surgery. Ergo, if you’re going to save MUP, then save it for the highest risk patients (e.g. ICU patients). However, the counter here is that local use of MUP is likely to drive local MUP resistance on the ICU. So, I still feel that we should not recommend the universal use of MUP.
Chlorhexidine
Dr Bonden, Dr Huang and Dr Harbarth reviewed the impressive studies that CHG bathing provides strong protective effects against a range of MDROs (for example Climo, Milstone and Vernon studies). These studies are not without their critics – some say that the effect on reducing relatively benign coagulase-negative staphylococci BSI amplifies the overall effect. However, both the data and rationale are stong: if you reduce the amount of MDRO on the patients’ skin (‘source control’), you reduce the chances of endogeneous infection, and transmission to others. Unlike antibiotics, CHG is a biocide with a less specific molecular target, which makes resistance more challenging from a bacterial viewpoint. However, reduced susceptibility to chlorhexidine must be monitored carefully. A number of studies have hinted that reduced susceptibility to chlorhexide may be an emerging problem, (for example Batra, Otter and Lee.) But increases in bacterial MICs (for Gram-positive bacteria at least) appear to be a long way below the applied concentration. However, it’s worth noting that the measured CHG skin concentration in one study (15-312 mg/L before the daily bath and 78-1250 mg/L after the daily bath) was much lower than the applied CHG concentration (10,000 mg/L). This is around the CHG MIC for some Gram-negatives and potentially brings the subtly reduced susceptibility to CHG reported in MRSA into play. On balance though, the rationale and data on reduced susceptibility are cautionary but not enough to recommend against universal use in the ICU given the clinical upside.
Conclusion
What shoud be the standard of care for ICU patients? My current view is: universal CHG, targeted mupirocin for MRSA decolonization and absolutely no SDD!
Headlines from ECCMID
I’ll be posting some blogs on some of these topics over the coming days. You can view some other ‘Perspectives from ECCMID’ here.
Picture credit: ‘Antibiotics’.
A seminal study recently published in the New England Journal of Medicine evaluated the impact of universal decolonization vs. targeted screening and / or decolonization to prevent ICU infection. The study has the potential to fundamentally change practice in ICUs around the world. However, I have two major problems with the study, namely mupirocin and chlorhexidine.
Study design and results. The authors describe their design as a ‘pragmatic’ randomized controlled trial, which should serve as a model for other studies. There were several variables that the authors could not change, for example, the fact that some US states mandate universal screening whereas others do not. They were able to cleverly incorporate this into their stratified randomization process so that the integrity of the study was not compromised.
The study was large, with 74,256 patients admitted to 74 ICUs in 43 hospitals randomized to the following groups during the intervention phase:
Group 1: Targeted screening and isolation.
Group 2: Targeted screening, isolation and decolonization (using intranasal mupirocin and chlorhexidine bathing).
Group 3: Universal decolonization (using intranasal mupirocin and chlorhexidine bathing).
The study compared the hazard ratio for MRSA clinical cultures, all-pathogen bloodstream infections and MRSA bloodstream infections in the 12 month pre-intervention vs. the 18 month intervention period for each of the groups. The main finding was that universal decolonization (Group 3) was associated with significantly lower rates of MRSA clinical cultures and all-pathogen bloodstream infection, and reduced rates of MRSA bloodstream infection (Chart). Target screening and isolation (Group 1) was the least effective strategy and targeted screening, isolation and decolonization (Group 2) had intermediate effectiveness (Chart).
[Chart: hazard ratios and 95% confidence intervals comparing the pre-intervention with the intervention period in each of the three groups. Group 1: Targeted screening and isolation; Group 2: Targeted screening, isolation and decolonization; Group 3: Universal decolonization.]
Major problems: My major issue with the study is the universal (aka indiscriminate) use of mupirocin and, to a lesser extent, chlorhexidine. MRSA are able to acquire low-level resistance to mupirocin through mutations in ileS or high-level resistance through the acquisition of mupA. I can’t help thinking that the authors underestimate the risk of driving mupirocin resistance with their comment in the discussion: ‘Mupirocin resistance has been reported in some studies of MRSA decolonization, but not all such studies.’ It is frankly naive to think that universal use of mupirocin for each ICU admission will not result in the widespread development of mupriocin resistance. Thus, the comment in the accompanying editorial urging caution in implementing the universal use of mupirocin is warranted.
The situation is not as clear-cut with chlorhexidine. Clinically significant reduced susceptibility to chlorhexidine in S. aureus has been hard to define for a number of reasons:
Notwithstanding these limitations, it is clear that the implementation of chlorhexidine based decolonization drives an increase in the carriage of genes associated with reduced susceptibility to chlorhexidine, and this may be clinically relevant based on studies from London and Geneva. For example, a recent article from my research lab in London found that the implementation of universal chlorhexidine-based decolonization was associated with the selection of qacA linked with a higher chlorhexidine MIC in one dominant endemic MRSA clone (CC22), but not another (CC30). The slower reduction in the CC22 MRSA bloodstream infection rate suggests that carriage of qacA confers a selective advantage.
So, will the introduction of universal decolonization result in resistance to mupirocin and chlorhexidine? The answer for mupirocin is a resounding yes; the answer for chlorhexidine is currently not clear.
Other limitations: It’s always easy to snipe at a high-profile study, but there do seem to be some important limitations. First, nasal screens alone were performed in patients admitted to Groups 1 and 2. The sensitivity of nasal screens alone can be as low as 50%, so the inclusion of other screening sites are preferable to improve sensitivity. The implications of missing many carriers on admission in Groups 1 and 2 are obvious.
Second, although the trend was in the same direction, there was no significant reduction on MRSA bloodstream infections for patients in Group 3. In fact, the crude rate of MRSA bloodstream infection was rather high in all three groups (0.5 to 0.7 per 1000 patient days in all groups during the baseline and intervention periods). For reference, the rate of MRSA bloodstream infection at Guy’s and St. Thomas’ NHS Foundation Trust in London was lower than this at the peak of the MRSA problems in 2003, approximately 10 times lower by 2008 and has fallen further since then. So, why the relatively high rate of MRSA bloodstream infection across the board in this study?
Third, while randomization is the “gold standard” in terms of study design, by chance, three of four hospitals that performed bone marrow and solid organ transplantation ended up in Group 3, which skewed this population somewhat. The study was large enough to “smooth out” this skew, but small studies that attempt randomization should take note. In a recent study with Johns Hopkins, we only had 6 units to play with so decided not to randomize but instead roughly “matched” the units in the two arms, which may be a better approach in smaller studies.
Fourth, it does not seem that any attempt was made to ensure that patients in Groups 1 and 2 were bathed daily. While bathing with chlorhexidine impregnated cloths has been shown to be superior to bathing with soap and water, it is not possible to determine whether daily bathing or chlorhexidine were most important.
Finally, compliance will never be 100%. Only 81% of patients in Group 3 actually received chlorhexidine and 86% received mupriocin, and only approximately 90% of patients in Group 2 that were due decolonization received chlorhexidine and mupriocin. However, the authors did achieve a very high compliance (in the high 90s) with admission screening in Groups 1 and 2.
Summary: The authors should be complimented for performing such a detailed and useful study. Unfortunately, the protocol was not configured to assess the relative contribution of mupirocin and chlorhexidine to the reductions in infection. Given the likely emergence of mupirocin resistance, future studies should drop the universal use of mupirocin all together and see how far universal chlorhexidine alone can go; recent data suggest it will go a long way. Indeed, the UK has managed to make a dramatic, national reduction in the rate of MRSA bloodstream infection without implementing universal mupirocin.
I have grave concerns about the universal use of mupirocin for all ICU admissions and, perish the thought, for all hospital admissions. To decide on implementing universal mupriocin use with a plan to keep an eye on resistance rates seems remiss (to put it politely) since the likelihood of widespread resistance is so high. I am less concerned about the universal use of chlorhexidine, although reduced susceptibility needs to be monitored carefully.
The accompanying editorial was entitled ‘Screening inpatients for MRSA – the case is closed’. For me, the only closed case emerging from this study is that universal, indiscriminate use of mupriocin is a bad idea. Antibiotics have caused the problem; they are not the solution.
Article citation: Huang et al. Targeted versus universal decolonization to prevent ICU infection. New Engl J Med 2013 May 29. [Epub ahead of print].
Reflections on Infection Prevention and Control 