Do single rooms prevent HCAI? This suggest suggests YES for norovirus, but no for C. difficile infection and E. coli BSI

There are pros and cons of increasing the proportion of single rooms. One of the commonly-cited pros is a reduction in HCAI. A recent UK study provides some evidence that C. difficlie infection, and MSSA /  E. coli BSIs are not reduced by a move to a hospital with more single rooms, but that norovirus control is more effective when you have more single rooms.

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A rapid reflection from Infection Prevention 2017: HCAI ranking according to DALY

I am heading home from an outstanding Infection Prevention 2017. There was a fair bit of discussion about hospital-associated pneumonia (HAP). HAP does not get the attention it deserves and there is more that we can and should be doing to prevent it. Although, we need to keep an eye out for unintended consequences in tackling HAP.

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Crapsules part 2

How do you like your crap? Fresh or frozen?

Schermafbeelding 2016-01-19 om 22.44.47Since Jon’s post on crapsules is one of the most favorite on the blog, I assumed that many of you might enjoy a sequel.

Clostridium difficile infections (CDI), most certainly after the emergence of hypervirulent strains at the beginning of this millennium, have become a major cause of morbidity and mortality in hospital and (to a lesser degree) community patients. One in four patients will suffer from recurrent CDI and treatment options are limited. Consequently, fecal microbiota transplantation (FMT) has become a valuable alternative, but is not readily available. Using frozen FMT would make the logistics far easier and finally something frozen seems to be as good as fresh, according to this JAMA study!

Cost of CDI – New estimate, but how accurate?

bank-17626_640To be honest I’m a bit fed up with quoting the £4000 per CDI case that was calculated by Mark Wilcox and colleagues back in 19 0 plonk (1996 to be exact) and so I was quite excited to stumble across a new estimate from Merseyside whilst browsing ‘Value in Health‘, one of my usual reads. Well, possibly not.. although perhaps it should be – and it does support open access.

Nakamura and colleagues presented an abstract at the 18th International Society for Pharmacoeconomics and Outcomes Research (ISPOR) meeting and have calculated the mean extra cost of a patient with CDI to be £10,956.82, although as the authors point out, how much of this is attributable to the extra cost of CDI rather than the multiple co-morbidities that likely contributed to the infection leading to the antibiotic treatment, which led to the CDI continues to elude us. The authors are continuing to work on this and I await their final findings with interest, however for now I’ll settle for £11,000 per case as opposed to the 1996 figure of £4000 (data collected in 1995) and is probably more realistic than just allowing for inflation that has averaged at 2.8% pa, which would have made it £6868. As we know (well all of us apart from the Treasury), health inflation is way ahead of normal financial indicators.

Fidaxomicin reduces C. difficile environmental contamination

It is well-established that fidaxomicin reduces the recurrence rate of C. difficile infection (CDI), but this study from my old research group at GSTT / KCL is the first to evaluate the impact of treatment with fidaxomicin on environmental contamination. The bottom line is that patients treated with fidaxomicin had less C. difficile contamination than patients treated with vancomycin / metronidazole.

In total, the rooms of 38 / 66 (57.6%) patients treated with metronidazole / vancomycin had one or more positive environmental cultures compared with 25 / 68 (36.8%) patients treated with fidaxomicin (P = 0.02). Similarly, when considering all of the sampled environmental sites (four per room), 68 / 264 (25.8%) were positive in patients treated with metronidazole / vancomycin compared with 47 / 272 (17.3%) in patients treated with fidaxomicin (P = 0.02) (see Figure below).

Fidax CDI

Figure: Environmental contamination with C. difficile in the rooms of patients treated with fidaxomicin vs. vancomycin / metronidazole.

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Reflections from HIS 2014, Part I: Updates on C. difficile, norovirus and other HCAI pathogens


The 2014 Healthcare Infection Society (HIS) Conference was in Lyon, France, and combined with SFH2 (The French Society for Hospital Hygiene). Congratulations to all involved (especially Martin Kiernan and Prof Hilary Humphreys) for such a stimulating programme, and enjoyable conference. The abstracts from the oral presentations can be downloaded here, and the posters here. I plan to share some of my reflections on key conference themes over the next few days:

Prof Wing-Hong Seto – Airborne transmission and precautions – facts and myths

Prof Seto’s energy and enthusiasm lit up the stage, just like a few years ago in Geneva for ICPIC. Prof Seto spent his lecture convincingly debunking the idea that airborne transmission of respiratory viruses is common, notwithstanding some data that, prima facie, suggests this. Only very few pathogens require obligate airborne transmission (e.g. TB); some have preferential airborne transmission (e.g. measles); and some have potential airborne transmission (respiratory viruses). There is some evidence that respiratory viruses such as influenza can be transmitted via the airborne route, but the most important route of transmission will depend on context. One important point is that studies demonstrating airborne “transmission” using PCR rather than viral culture as an endpoint, or using artificial aerosol generation should not be taken as definitive evidence of airborne transmission. Prof Seto’s view is that medical masks are sufficient to prevent the transmission of respiratory viruses, as demonstrated by his own work during SARS. Finally, we can forget the requirement for negative pressure isolation rooms: open doors and windows yields a whopping 45 air changes per hour!

Prof Mark Wilcox – Is Clostridium difficile infection (CDI) underestimated due to inappropriate testing algorithms?

Prof Wilcox began by reporting an unusual epidemic: “PCRitis”, which can cloud rather than clarify accurate diagnosis of CDI. Perhaps the most important point made by Prof Wilcox is that the ultimate “gold standard” for CDI should be clinical, and not laboratory based. Prof Wilcox spent most of his time reflecting on the recent multicentre European study of CDI underdiagnosis in Europe. There are some real shockers in here: the reported rate of CDI in Romania was 4 cases per 1000 patient days vs. closer to 100 per 1000 patient days when samples from the same patients were tested in the reference lab. This is no surprise in a sense because only 2/5 local laboratories were using optimal methods. However, even in the UK where around 80% of local labs are using optimal methods, around 2-fold more cases were identified in the reference vs. the local laboratory. Clearly, if we’re going to have a hope of controlling the spread of C. difficile in Europe, laboratory diagnosis needs to improve.



Norovirus is especially topical in the UK given the recent PHE announcement about unusually high rates of norovirus in the NHS. The prolific Dr Ben Lopman (CDC) began by explaining the ‘image problem’ that norovirus has in US hospitals, where it is considered an uncommon cause of gastroenteritis. In fact, a systematic review found that norovirus cases around 20% of acute gastroenteritis. However, I would say it’s just not possible to get an accurate assessment of how common norovirus is on a population level due to chronic under-reporting. When we had an outbreak of ”norovirus” in the Otter household, the last thing we felt like doing was submitting a specimen, and I suspect we are not alone in this! Although norovirus is usually mild and self-limiting, it is by no means benign: one Lopman study suggested that it is responsible for 20% of deaths due to gastroenteritis not caused by C. difficile in those ages >65. And then there’s the infection control challenges. Due to the exquisitely low infectious dose, 2g of stool from an infected individual is enough to infect the entire human population! Plus, it is shed in high titre, stable in the environment, and resistant to many disinfectants. Rather depressingly, it seems that effective interventions to control norovirus teeter around the cost-effectiveness threshold. More optimistically though, prospects for vaccines look promising.

Prof Marion Koopmans then described the huge diversity within the “norovirus” family, spanning more phylogenic space than many single species occupy. For chapter and verse on nomenclature, see Norovirus Net. It’s difficult to know what works to control norovirus due to dynamic outbreak settings combined with multiple interventions. One key aspect for control is understanding shedding profiles of infected, recovered and asymptomatic individuals. Whilst all can shed norovirus, much like Ebola, those who are symptomatic are by far the highest risk for transmission. Finally, our inability to culture norovirus in the lab has been an important barrier to understanding the virus; a recent study (in Science no less) suggests that a working lab model for culturing norovirus may be just around the corner.

Dr Lennie Derde – Rapid diagnostics to control spread of MDR bacteria at ICU

Given the turnaround times of conventional culture (24 hours to preliminary results – at best), rapid PCR-based diagnostics make sense in principle. But do they work in practice? There is some evidence that rapid diagnostics may work to reduce MRSA transmission, although other studies suggest that they don’t make a difference. In order to put rapid diagnostics to the test Dr Derde et al. ran the impressive MOSAR study. This study suggest that screening and isolation by conventional or rapid methods does not help to prevent the transmission of MDROs in the ICU, but I don’t think we should take that away from this study, not least due to the fact that many units were already doing screening and isolation during the baseline period!

New insights from whole geneome sequencing (WGS)

WGS is trendy and trending in the infection prevention and control sphere. Prof Derrick Crook gave an engaging overview of the impact that WGS has made. It’s analogous to the manual compilation and drawing of maps to GPS; you wouldn’t dream of drawing a map by hand now that GPS is available! Desktop 15 minute WGS technology will be a reality in a few years, and it will turn our little world upside down. The major limiting step, however, is that mathematics, computer science and computational biology are foreign to most of us. And we are foreign to most of them! But, these issues are worth solving because the WGS carrot is huge, offering to add new insight into our understanding of the epidemiology of pathogens associated with HCAI. For example, Prof Crook WGS study on C. difficile suggests that transmission from symptomatic cases is much less common than you’d expect. So if the C. difficile is not coming from symptomatic cases, where is it coming from? Contact with animals and neonates in the community are plausible sources However, I was surprised that Prof Crook didn’t mention the large burden of asymptomatic carriage of toxigenic C. difficile, which must be a substantial source for cross-transmission in hospitals.

WGS has yielded similar insight into the epidemiology of TB and MRSA, outlined by Drs Timothy Walker and Ewan Harrison, respectively. One challenging idea from Dr Harrison is how much of the “diversity cloud” that exists within an individual is transferred during a transmission event? Finally, WGS can turn a ‘plate of spaghetti’ of epidemiological links to a clear transmission map, as was the case during a CRE outbreak at NIH in the USA.

Look out for some more reflections from HIS posted over the next few days…

Perspective from ECCMID Part III: CDI synthetic “repoopulation” (bacteriotherapy) closer than you think & “CA-CDI” still pie in the sky

Bacteriotheraphy for CDI is closer than you think

As our understanding of the importance of a happy, healthy microbiota develops, it seems increasingly clear to me that bacteriotherapy (administration of a controlled multi-species dose of bacteria) is a real prospect for the treatment of CDI (and most likely other conditions). This is illustrated by the dramatic effectiveness of faecal microbiota transplantation (FMT) for recurrent CDI. FMT is pretty crude, in every sense; synthetic FMT would be safer and more palatable. But I hadn’t realized how far the research towards available bacteriotherphy for CDI had advanced. Dr Trever Lawley gave an expert overview of his research programme, which is pointed in this direction.

Dr Lawley began by describing the human microbiota as a fingerprint: it’s consistent and unique. The microbiota is highly organized, to reflect its function, resulting in microenvironments. Antibiotics are like an atomoic bomb, resulting in huge perturbation of the gut microbiota. The idea of bacteriotheraphy to redress the balance is not new. Pioneers of bacteriotherapy (aka “repoopulation”) for CDI date back to at least 1989.

So, which bacteria get the nod to be included in the synthetic mix? It’s not an easy question, since examining the massively populous human microbiota is a daunting prospect and requires the application of novel tools (see Fig 1 of this excellent open-access review for a useful summary of the methods to examine the human microbiota and microbiome). Human trials and mouse model indicate that single species theraphy and probiotics are equivocal at best. These are blunt weapons to complement the nuclear fall out of the antibiotic A bombs! Dr Lawley’s reaseach has found an irreducible minimum of 6 species that are necessary for effective bacteriotherapy (in mice at least). Now all that is required is to find a common growth medium…oh, and do some humans trials!

Another speaker, Dr Cornley, mentioned another approach to preventing CDI: the prophylactic administration of metronidazole. If you’re read my Perspective from ECCMID on Selective Decontamination, you can probably guess which approach I’d choose.

“CA-CDI” still pie in the sky

A number of speakers contributed to the debate on whether “community-acquired” CDI is on the rise. Dr Scott Weese outlined the potential for foodborne risk of CDI, beginning with a ‘disclosure’ that we can all relate to: “I like to eat but I don’t like foodborne illness”! C. difficile is present in food animials (especially young ones) and strains are shared with humans. Rates of carriage are low, but Dr Weese made a good point on cumulative exposure. If 2% of burgers are C. difficile contaminated, I eat C. difficile on my 98th burger (not exactly, but you get the point). Plus, C. difficile spores can survive usual cooking times (which is not so relevant for me: I like my burger meat rare)! The carriage of C. difficile in animals combined with the high carriage of C. difficile in small human animals means that exposure to C. difficile is probably a daily event. But is this a risk? For a healthy 25 year old in the community, probably no. For a haematology inpatient, probably yes.

Dr Marjolein Hensgens considered whether CDI is still primarily nosocomial. The distinction of community vs. hospital onset is easy, but community vs. hospital acquisition is much more challenging and epidemiological disitinctions are approximate at best. For example, in the UK, a “Trust-apportioned” (=hospital acquired) case requires a specimen from an inpatient who has been in the same hospital for at least 4 days. Any readmission (even if they were in the hospital the previous week) is considered “non Trust-apportioned”, but it’s important to remember that this is not the same as “community-acquired”. The fact that the Trust-apportioned and non Trust-apportioned cases track each other so closely in the UK reductions suggests that almost all cases were healthcare-associated (Figure 1).

CA-CDI_2Figure 1: the number of CDI cases reported to Public Health England, defined as “Trust-apportioned” or “non Trust-apportioned” from 2007 onwards.  

An important US study suggested a stepwise increase in CA-CDI. However, this apparent increase could be explained by a number of other factors. Firstly, a high proportion of patients with apparent CA-CDI actually have had healthcare exposoure of some kind if you look hard enough (82% in this study). So this upward trend in “CA-CDI” could very well be HA-CDI with unrecognized healthcare exposures. Secondly, it is difficult to know whether there have been any changes in the number of diarrhoeal stools tested in the community. Infectious diarrohea has always been common in the community, but is rarely tested for CDI. Thirdly, comparing the epidemiology of patients who develop CDI in the community with those who develop CDI in hospitals could result in a misleading picture. A more appropriate comparator would be patients who have non-CDI diarrhea in the community. Finally, does WGS prove that hospital acquisition of CDI is now rare? No, it only proves that transmission from known symptomatic CDI cases is less frequent than you may expect. There are many other sources for hospital acquisition of CDI, not least asymptomatic carriers. We’re surrounded by C. difficile so of course a degree of CA-CDI occurs. But is it increasing? I still think no – or at least, not rapidly due to phase-shift in epideimogogy (that we saw with the emergence of CA-MRSA in the late 1990s).

You can view some other ‘Perspectives from ECCMID’ here.

Image: C. difficile‘ by AJ Cann.

How much Clostridium difficile infection is hospital-acquired? Part II

I wrote a blog last year on the excellent New England Journal of Medicine Oxford CDI study, which showed that a surprisingly high proportion (45%) of new CDI cases were genetically unrelated to recent CDI cases. This is not quite the same thing as evaluating how much CDI is hospital-acquired, mainly because the test used to detect CDI in the study has been phased out due to poor sensitivity, patients and staff were not screened for asymptomatic C. difficile carriage, and the environment was not sampled, so there was a large, unrecognized, hospital-based C. difficile reservoir from which horizontal transmission almost certainly occurred. A study published at the end of 2013 provides evidence that one of these potential reservoirs for transmission – asymptomatic carriage by other patients – is substantial.

The study was performed by a team from the University of Pittsburg Medical Centre. All patients screened for VRE during 5 months in 2009 were also screened for C. difficile carriage. Stool samples from symptomatic patients were also cultured. All toxigenic C. difficile were typed by multilocus variable number of tandem repeats analysis (MLVA). A total 56 C. difficile isolates from symptomatic CDI cases defined as healthcare-associated (HA-CDI) were available for typing. In addition, toxigenic C. difficile was identified in 226 (7.5%) of 3006 patients, and these isolates were also. Of the 56 HA-CDI isolates, 30% were genetically related to isolates from symptomatic cases, 29% to isolates from asymptomatic carriers, and 30% were unrelated to other isolates (Figure).

curry CDI

Figure. Proportion of HA-CDI cases genetically related to isolates from symptomatic cases, asymptomatic carriers and unrelated to other isolates.

The study provides a somewhat skewed view of asymptomatic C. difficile carriage since only patients considered at a high risk of carrying VRE were screened (admissions from other hospitals, ICU patients and long-stay inpatients). This meant that 75% of admissions were not screened for C. difficile carriage. Symptomatic cases are often described as the “tip of the ice berg”; in this study, three quarters of the ice berg remained submerged.

The authors performed an environment survey in the rooms of six asymptomatic C. difficile carriers and found that 5/6 rooms (48% of 25 sites) were contaminated with toxigenic C. difficile. And this is in a hospital that routinely uses bleach for disinfecting patient care areas! It’s interesting to note that transmission appeared to occur from the prior room occupant in 4/56 (8%) of HA-CDI cases, two of which were from asymptomatic carriers.

Another finding was that 158 patients had CDI diagnosed during the study period but 22% of these were counter-intuitively classified as carriers. This is perhaps because the lab performed a cytotoxin cell culture assay from both formed and unformed stools. We need to apply the “no diarrhea, no diagnosis” rule!

One other consideration is the molecular typing method used: MLVA. This is less discriminatory that the whole genome sequencing (WGS) used by the Oxford team. With WGS, strain relatedness is a question of how many single nucleotide variants (SNVs). With MLVA, it’s a question of distance of separation on a phylogenic tree. But you have the same fundamental problem: how do you define genetic relatedness? In reality, strain relatedness is an arbitrary line in the sand and our understanding of molecular clock speed is a work in progress.

So, is it time to screen and isolate asymptomatic carriers of toxigenic C. difficile? One of the arguments against this is that “asymptomatic carriers don’t have diarrhea, so therefore, don’t shed much C. difficile”. However, the environmental findings of this study, and others, suggest that asymptomatic carriers shed almost as much C. difficile as do symptomatic cases. I expect to see some controlled studies in the near future that should provide outcome data to help us to decide whether to pull the trigger on screening and isolation for asymptomatic carriers of toxigenic C. difficile.

Despite sampling only 25% of the asymptomatic carriage ice berg, apparent transmission from symptomatic CDI cases and asymptomatic C. difficile carriers was approximately equal. Plus, the study did not consider staff carriers or ancient environmental reservoirs. Thus, it seems that the large majority of C. difficile is acquired in hospital, but not necessarily from symptomatic CDI cases.

Article citation: Curry SR, Muto CA, Schlackman JL et al. Use of multilocus variable number of tandem repeats analysis genotyping to determine the role of asymptomatic carriers in Clostridium difficile transmission. Clin Infect Dis 2013; 57: 1094-1102.

How much Clostridium difficile infection is hospital-acquired?

B0006630 Clostridium difficile

This is a very impressive New England Journal of Medicine study from an Oxford University based group, using whole genome sequencing to really dissect relatedness of C. difficile isolates over a 5 year period. The study evaluates how many cases of C. difficile infection (CDI) were caused by isolates that were genetically related to previous symptomatic cases. This is not quite the same thing as evaluating how much CDI is hospital-acquired, mainly because the test used to detect CDI in the study has been phased out due to poor sensitivity, patients and staff were not screened for asymptomatic C. difficile carriage, and the environment was not sampled, so there was a large, unrecognized, hospital-based C. difficile reservoir from which horizontal transmission almost certainly occurred.

A major problem was the use of an Enzyme Immuno Assay (EIA) test kit to detect CDI. Whist these tests were used pretty much universally in the UK at the time of the study, they have now been shown to be very unsatisfactory. The sensitivity of EIA for the detection of CDI has been as low as 50% in some studies. Put another way, for every case of CDI that is detected, one goes undetected. This is crucially important in the context of this study, where the undetected CDI cases would contribute to the burden of asymptomatic carriers, which together would contribute to transmission. It’s also worth noting that C. difficile could not be cultured from 25% of stool samples that were EIA-positive, suggesting that the test may have had poor specificity too. The authors did try to ‘control’ for this problem, by effectively assuming that all stool specimens tested for CDI were positive in a sensitivity analysis, but this did not really help in explaining genetically related cases with no discernable epidemiological links.

There is also a technical point about the definition of ‘genetically distinct’ in terms of whole genome sequencing. If two isolates differ by 11 base pairs across the whole genome, do they originate from the same strain? It’s difficult to tell. In this study, they used a fairly conservative measure of relatedness: >10 single nucleotide variants (SNVs) was considered ‘genetically distinct’, and ≤2 SNVs was considered ‘genetically related’. This may have over-estimated apparent genetic heterogeneity. To be fair, the authors did perform a careful ‘validation’ study to determine the clock speed of mutation in their isolates by sequencing the first and list isolates obtained from a sample of patients, finding that 0-2 SNVs were expected for isolates <124 days apart. Even using these conservative measures of relatedness, the majority (55%) of isolates were related (‘not genetically distinct’ to be precise) to others in the collection (≤10 SNVs) and around a third of isolates were ‘genetically related’ to others in the collection (≤2 SNVs).

The authors performed detailed work to explore epidemiological associations between genetically related isolates (Figure). No acute- or community-based epidemiological links could be identified for 36% of the 333 genetically related cases, which perhaps supports the presence of unrecognized symptomatic cases or asymptomatic carriers.

CDI eyreFigure: Epidemiology relationships between 333 genetically related cases. ‘Ward contact’ = shared time on the same ward; ‘Hospital contact’ = shared time in the same hospital, without direct ward contact; ‘Ward contamination’ = admitted to the same ward within 28 days of the discharge of a symptomatic patient; ‘Same GP’ = no hospital contact, but shared the same GP; ‘Same postcode’ = no hospital contact, but shared the same postal code).

The overall rate of CDI was low, at <1 per 1000 patient days and it is noteworthy that the prevalence of genetically related and genetically distinct cases declined during the study period. I suspect if the same study had been performed for the period of 2000-2005, when more hospital transmission was almost certainly occurring, then a far higher proportion of isolates would have been genetically related.

I fear that this study will be used by some to ‘prove’ that horizontal transmission of C. difficile in healthcare settings is now uncommon, and most hospital-onset cases can be explained away by “CA-CDI”. Due to the poor sensitivity of the diagnostic kit combined with the likelihood of asymptomatic human carriage and environmental contamination, this study does not answer the question of how much CDI is hospital-acquired. It does, however, suggest that horizontal transmission from known symptomatic cases may be less common that we thought.

Article citation: Eyre DW, Cule ML, Wilson DJ et al. Diverse sources of C. difficile infection identified on whole-genome sequencing. N Engl J Med 2013; 369: 1195-1205.

Photo credit: Annie Cavanagh. Wellcome Images.