It’s transmission doc, but not as we know it

A groundbreaking study just published in PLOS Genetics provides new insight into the transmission dynamics of bacteria in the ICU setting using WGS. The ambitious authors performed WGS on virtually all bacterial isolates from ICUs in a US hospital for a year. The first surprise was that 12% of the bacteria considered clinically relevant were previously undescribed.

The next – and perhaps biggest – surprise was that whilst transmission of the usual suspect pathogens (MRSA, VRE etc) was rare, 9% of the other bacteria were shared by multiple patients, often with overlapping admissions (see the figure below). This suggests that there is a fair bit of transmission going on under the radar in the ICU setting.

Figure: Clonal lineages extending across multiple patients.

WGS ICU timeline

This study reminds me of one published in CID a few years ago showing that outbreaks of resistance probably occur regularly and usually undetected across multiple species.

So, is it time to start using WGS for all bacteria identified in the clinical laboratory? Not quite yet I don’t think: the analytical methods have not yet caught up with the sequencing technology. But this study is a glimpse of the future, no doubt about it.

Perspective from ECCMID 2014 Part I: a voice against ‘selective’ digestive decontamination (SDD)

eccmid 2014

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:

  • The use of antibiotics leads to antibiotic resistance, sooner or later. A number of studies suggest that SD is not associated with an increased overall prevalence of resistant bacteria (not least the impressive Daneman review). Indeed, one study showed that rates of resistance actually decreased on units using SD. However, these studies conflate the potential for reducing transmission (and hence reducing unit-level prevalence) with the risk of selecting resistant sub-populations, which both seem likely. One particular concern is the emerging data that SDD drives colistin resistance. Are we playing with fire by overusing our drug of last resort? Furthermore, the abundance of key antibiotic resistance genes doubled on units using SDD when using a microbiotic approach in a recent study.
  • Speaking of the microbiome, another speaker described antibiotics as a ‘microbiome-busing atomic bomb’, so perhaps we should rename SDD as ‘scorched earth decontamination’ (SED)! The importance of a happy, healthy microbiota is beginning to dawn on us. We need to make friends with our microbiome, not obliterate it with unindicated antibiotics.
  • The impressive studies showing the value of SDD have been performed in the Netherlands, which has a low rate of antibiotic resistance. Will SDD be as effective elsewhere, where the background rates of antibiotic resistance are higher? Indeed, the Daneman study showed a notable (although no statistically significant) increase in the prevalence of MRSA on units using SDD. Is this a case of ‘squeezing the MDRO balloon’?
  • SDD temporarily suppresses gut colonization with multidrug-resistant Gram-negative rods but rarely decolonizes permanently. From an infection control viewpoint, it should not change the ‘once positive, always postive’ status quo for resistant Enterobacteriaceae.

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).Huang ECCMID table

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.

  • We are still no closer to figuring out what works to control multidrug resistant Gram-negative rods (including CRE).
  • CDI does not seem to be emerging as a community pathogen, despite apparent increases.
  • Bacteriotherpy for synthetic faecal microbiota transplant (FMT, aka transpoosion) is getting close.
  • We need to stop polluting our plant by pumping antibiotics into our environment.
  • As one tweeter (@marina_manrique) put it, whole genome sequencing (WGS) has becoming a bit like the One Ring from Tolkein’s Lord of the Rings: ‘one ring to rule them all, one ring to bind them, one ring to bring them all, and in the outbreak find them (out – the other methods that is)’.

Picture credit: ‘Antibiotics’.

Look out: resistance outbreaks about!

We are all familiar with the idea of outbreaks. A noteworthy pathogen rears its ugly head leaving a trail of destruction in its wake (as in ‘Contagion’, or before that, ‘Outbreak’). (I credit ‘Outbreak’ with getting me into microbiology and epidemiology as an impressionable 15 year old by the way.) Or more commonly in hospitals, a ward experiences an increased incidence of a particularly resistant or virulent clone. But a recent study from some colleagues at the Centre for Clinical Infection and Diagnostics Research at St. Thomas’ Hospital in London turns the idea of ‘outbreak’ on its head by identifying surprisingly common outbreaks of resistance to a particular antibiotic across different species.

The horizontal transfer of resistance genes is generally considered to be a rare event relative to horizontal, clonal transmission of an outbreak pathogen (see Figure below). But the findings of this study suggest more promiscuous spread of resistance genes than you may expect.

ICU resistance

Figure: Horizontal transfer of resistance genes is generally considered to be the least common cause of ICU resistance.  

The team used some outbreak scanning software to interrogate laboratory reports from two ICUs between 2002 and 2009. Analysis of the large dataset, comprising almost 90,000 patient days, found that outbreaks occurred for two thirds of the 26 ‘species-groups’ studied. Only three of these were recognized at the time. Thirty-nine outbreaks of resistance were detected, the majority of which (87%) did not coincide with an increase in a particular ‘species-group’, supporting the fact that these were due to horizontal gene transfer between species.

The clustering of individual species into ‘species-groups’ is somewhat problematic, and may serve to over-emphasize the number of outbreaks that occurred. Quite a number of the outbreaks of the same ‘species-group’ and of resistance were very small – with 2 cases over a day or two. Also, clustering of the same species does not necessarily mean clonal transmission has occurred – you’d need to do molecular typing to prove that. Similarly, clustering of resistance across species to the same antibiotic does not necessarily mean horizontal gene transfer has occurred; multiple mechanisms could be involved. Notwithstanding these limitations, this is an important study and has changed the way that I think about hospital outbreaks.

Infection control interventions implemented to control recognized outbreaks on the ICU appeared to reduce the overall number of outbreaks of the same ‘species-group’, but did not affect the number of resistance outbreaks. So, it seems that different measures are necessary to control outbreaks of resistance. Perhaps the best weapon we have to combat outbreaks of resistance is to restrict our use of antibiotics. If we can reduce the selective pressure driving resistance, we should see less clonal outbreaks of resistant bacteria and less resistance outbreaks across species.

Article citation: Vlek AL, Cooper BS, Kypraios T, Cox A, Edgeworth JD, Auguet OT. Clustering of antimicrobial resistance outbreaks across bacterial species in the intensive care unit. Clin Infect Dis 2013; 57: 65-76.

Can the introduction of 6 copper items into ICU rooms really reduce the rate of HAI by >50%?

The recent article by Salgado et al.in the ICHE special edition is the long-awaited copper study: a multi-centre evaluation of the clinical impact of introducing 6 copper alloy high-touch sites into the rooms of patients on three ICUs. I’ve been looking forward to getting my hands on this study for some time!

copper bed

Patients (n=614 following exclusions) were randomized to intervention ‘copper’ rooms and control ‘non-copper’ rooms in three USA ICUs over an 11 month period. The only difference between the rooms was the presence of six items made of copper alloy, comprising bedrails, overbed tables, IV poles and visitor chair arms in all rooms and the nurse call button, computer mouse, computer palm rest and rim of a touch-screen monitor in other rooms.

Patients admitted to copper rooms were significantly less likely to acquire healthcare-associated infection (HAI) or colonization with MRSA / VRE (Figure).

evidence of copper for hai

Figure: difference in acquisition rate between patients admitted to ‘copper’ or ‘non-copper’ rooms

The authors also make an interesting association between the degree of contamination in patient rooms and the risk of acquisition. However, since sampling was performed weekly regardless of a patient’s infection or colonization status, it is not possible to determine whether this association is causal or simply due to the fact that infected / colonized patients are likely to shed more bacteria into the hospital environment.

The study team should be commended for the careful design and attention to detail in the execution of the study. For example, they performed a daily census of the items in the study to determine exactly who was exposed to copper surfaces, and for how long. This indicated that only half of the patients in ‘copper’ rooms were exposed to all six copper items for the duration of their stay, and 13% of patients in the ‘non-copper’ arm were exposed to some copper items during their stay. It’s important to note that the analysis was performed on an ‘intention to treat’ population, i.e. all patients randomized to the two groups, regardless of which items they were actually exposed to. It would have been interesting to see a sub-analysis on the ‘per protocol’ population (i.e. those patients admitted to ‘copper’ rooms and exposed to all six copper items vs. those patients admitted to ‘non-copper’ rooms and exposed to no copper items). Also, I’m not sure why they chose to analysis % acquisition rather than a comparison of rates between the groups. And then there’s the salary support and grant funding to some authors (not directly related to this study) from the Copper Development Association. Notwithstanding these limitations, it does seem that the introduction of copper high-touch surfaces does reduce the transmission of hospital pathogens.

The scale of the difference is incredible. And I mean just that. It lacks credibility. Many will dismiss the study simply because of the scale of the difference between the groups. So, can the introduction of 6 copper items into ICU rooms really reduce the rate of HAI by >50%?

The degree to which contaminated surfaces contribute to the transmission of pathogens is up for debate. I was asked to give a talk at APIC 2012 on the role of the environment. Prior to the talk, I asked the expert faculty a question: ‘What is your estimation of the % of allC. difficile transmission in hospitals that is mediated, directly or indirectly, by contamination of the inanimate environment?’ The answers ranged from 25-75%, reflecting the uncertainty on this issue.

A recently published study by Johns Hopkins provides some illuminating findings (albeit indirectly). Extrapolating unadjusted acquisition rates from all study cohorts indicates that if rooms had been disinfected using hydrogen peroxide vapour (HPV) after every discharge, the overall rate of acquisition of MDROs would have been halved. Whilst it’s not feasible to disinfect all rooms using HPV at patient discharge, this does add some weight to the scale of the reduction identified in this copper study.

It seems that the introduction of a handful of copper alloy high-touch sites had a profound impact on HAI rates. On reflection, I do believe it possible that the scale of reduction in study is “real”. However, questions remain over the practicality and durability of the widespread adoption of copper alloy surfaces in healthcare.

Article citation:

Salgado et al. Copper surfaces reduce the rate of healthcare-acquired infections in the intensive care unit. Infect Control Hosp Epidemiol 2013;34:479-486.

 

MDR-Acinetobacter baumannii beats MRSA in the war for ICU predominance

A. baumannii is a notorious nosocomial pathogen due to a combination of its environmental resilience, its association with antimicrobial resistance and its outbreak potential. Colonized patients and contaminated environments are thought to be the primary reservoirs for the nosocomial transmission of this pathogen.

A recent study from China suggests that carriers of MDR A. baumannii (MDR-AB) show stronger ability to contaminate their immediate environment than those carrying MRSA and that MDR-AB spreads more easily and rapidly among inpatients compared with MRSA. The 20-month study was conducted in a respiratory ICU (RICU) where active screening of patients and targeted environmental screening for MRSA and MDR-AB were performed. The environmental samples were collected from 6 sites on patients’ bed linens.

High levels of carriage and nosocomial acquisition were found among the 175 patients admitted to the RICU where 44% of the patients were MDR-AB positive (80% of which were hospital acquired) and 24% of patients were MRSA carriers (60% of which were hospital acquired). Interestingly, 15.4% of the patients were co-carriers of MRSA and MDR-AB.

Researchers found that bed linens were commonly contaminated with MRSA and MDR-AB and that the contamination rate for MDR-AB was significantly higher than that of MRSA. Of the 576 MRSA samples, 26.6% were positive, and 51.6% of the 1,176 MDR-AB swabs were positive. This is surprising given the strict daily extensive cleaning practices, thrice daily bed linen changes and stringent terminal sterilization immediately after discharge of carriers. Researchers used the weekly colonisation pressure adjusted by degree of bed linen contamination (WCPe) and weekly acquisition rate (WAR) as parameters to evaluate the potential spread of these pathogens among inpatients. They found a positive significant correlation between the WCPe and WAR values for both organisms but both the WCPe and WAR of MDR-AB were significantly higher than for MRSA.

This study shows that environmental contamination with MDR-AB and the rate of its nosocomial acquisition is significantly higher than those for MRSA, which may explain why MDR-AB is able to spread among inpatients more rapidly. Although the study found positive significant correlation between the WCPe and WAR in the subsequent weeks, this correlation does not necessarily indicate causality. Nevertheless, the authors conclude that reduction of environmental contamination close to MDR-AB positive patients is crucial in controlling MDR-AB transmission.

Article citation:

Sui W, Wang J, Wang H et al. Comparing the transmission potential of Methicillin-resistantStaphylococcus aureus and multidrug-resistant Acinetobacter baumannii among inpatients using target environmental monitoring. Am J Infect Control. 2012. doi: 10.1016/j.ajic.2012.08.007