Author: Jon Otter (@jonotter)

Perspective from ECCMID Part IV: We need to stop polluting our planet with antibiotics

Jon Otter (@jonotter) Antibiotic resistance, Conferences , , ,

Effluent

Professor Joakim Larsson gave a frankly chilling lecture on antibiotic pollution and its impact on the environmental resistome. Antibiotic resistance genes are fairly common in soil bacteria, and indeed, pre-date the use of antibiotics. Furthermore, the reservoir of resistance genes in soil bacteria seems to have increased since the 1940s when we began using antibiotics. This creates a huge reservoir of resistance determinants to the tune of some 1030 bacteria, an unimaginably massive number that we can only begin to understand through analogy. Fortunately, there is not a free flow of antibiotic resistance genes from environmental to hospital bacteria. However, where there’s close contact and selective pressure, transfer of resistance genes from environmental bacteria to hospital pathogens does occur. Prof Larsson introduced the idea of ‘minimal selective concentration (MSC)’, the cost-benefit equation for bacteria carrying antibiotic resistance genes.

This problem is driven by the appropriate and inappropriate use of antibiotics in human medicine, agriculture and aquaculture. Indeed, we all know about the high rates of NDM-1 in the New Delhi water supply; the modern day John Snow’s water pump handle (although the solution is not as obvious)? Another important driver is antibiotic contaminated effluent from pharmaceutical factories producing antibiotics. A large amount of pharmaceutical production of antibiotics occurs in emerging markets, such as India. There are tight regulations on what factories are allowed to release into their surrounding environment in many countries, but some are largely unregulated. One plant in India released phenomenal amounts of one particular antibiotic, ciprofloxacin, in waste water: 44kg per day. To put this in context, that’s almost 5x the amount of the same antibiotic consumed by the whole of Sweden per day, and the concentration of the antibiotic in the waste water was higher than therapeutic levels of the drug in humans! Unsurprisingly, this provides a strong selective pressure for the development of antibiotic resistance in the bacteria surrounding the factories. There are special treatments available to reduce or eliminate antibiotic contamination of factory waste (e.g. active carbon filtration or ozone treatment). But incentives are required to ensure that these technologies are implemented in the resource-limited settings where the factories are based.

Prof Larsson is planning some research to help to understand the relationship between environmental bacteria and hospital pathogens, for example, through his ‘NoCURE’ (Novel Carbapenemases – UnRaveling the Environmental reservoir) project, and the BacMet database for registering biocide and metal resistance genes, which are both worth checking out. As we come towards the end of antibiotics, the last thing we need to be doing is polluting our planet with antibiotics, which provides a selective pressure for the development of resistant bacteria, some of which will find their way into hospitals sooner or later.

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

Image: ‘Effluent tank’ by Bob Shand.

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

Jon Otter (@jonotter) C. difficile, Conferences , , , , ,

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.

Perspective from ECCMID 2014 Part II: What to do about MDR-GNR?

Jon Otter (@jonotter) Acinetobacter, Conferences, CRE , , , , , ,

 gram neg

I was hoping that the ECCMID 2014 session on ‘Outbreaks of MDR Gram-negative bacteria: what works and what does not work?’ would bring some answers from large, controlled studies to improve the evidence base for MDR-GNR control. I’m sorry to report that most of what was presented only served to highlight the limitations of the evidence base! There’s a bit of a Catch 22 here: in most settings, the problem lies in outbreaks, but the answers lie in large, adequately controlled cluster randomized studies in endemic settings.

  • Dr Weterings from NL provided a rather bleak start to the session, reporting an outbreak of carbapenem-resistant K. pneumoniae in a hospital and nursing home. Environmental cultures regularly grew the outbreak strain (including a shared glucose meter) and the control measures that were effective in the hospital were more challenging to implement in the nuring home.
  • Dr Gonzalez-Galan found a bundle of interventions dramatically effective to reduce the rate of endemic MDR A. baumannii. The bundle comprised surveillance, hand hygiene audit, and a checklist for environmental cleaning and contact precautions compliance. But which element of the bundle worked, and were any elements redundant?
  • Dr Cohen reported an MDR A. baumannii outbreak in Israel affecting 70% of ventilated patients at its peak, which forced colistin as the empiric VAP therapy. Proper disinfection of the ventilators brought the problem under control. Similarly, an endoscoy-associated ESBL K. pneumoniae outbreak in Norway (reminescient of the NDM outbreak in Chigago) was controlled by implementing proper endoscope disinfection.
  • Probably the most useful presentation of the session was from Dr Cataldo preseting a systematic review of interventions for MDR-GNR. Most studies (78% of the 86 included) were in outbreak settings, and plagued by low quality. Nonetheless, bundles were 2x more effective than single interventions (45% vs. 28%). The study struggled to determine convincingly which element of the bundles was most effective, but hand hygiene, contact precations and education came through as the pillars of effective bundles.
  • Dr Dettenkofer showed that an educational intervention improved compliance with standard precautions (especially hand hygiene and to a lesser extent the inappropriate use of examination gloves for some procedures). However, ‘standard precations’ are far from standard, and it seems that you need to go further than standard precautions to control MDR-GNR.
  • Dr Hussein showed that standing over healthcare workers and telling them to wash their hands improved compliance (unsurprisingly!). I venture that hospitals would only take this measure in extreme circumstances, although hand hygiene “enforcers” are not without precedent.
  • Dr Perencevich reported that the Hawthrone effect tends to strike after 15 mins of observation, so hand hygiene observations should be kept short and sweet. (Incidentally, hand hygiene compliance was higher among doctors than nurses in this study; I think it’s the first time I’ve ever seen it this way around!)
  • Dr Hansen presented data from the PROHIBIT collaborative, who found that alcohol based hand rub usage tracks the prevalence of antimicrobial resistance across Europe. However, the rate of red and yellow cards in the Euro 2008 football championships also correlates with antimicrobial resistance rates across Europe, and national consumption of chocolate correlates with the national rate of Nobel laureates: collelation doesn’t necessarily mean causation!
  • Finally, Dr Langelar reported that the Dutch national healthcare inspectorate visits were effective in raising standards. But was this papering the cracks or effecting culture change?
  • I am sure there were lots of good posters on this topic too, but I didn’t get very far with those. Perhaps somebody else did and would like to provide some additional information?

Dr Evelina Tacconnelli gave a thoughtful talk comparing the various international guidelines for MDR-GNR, reflecting on the recently published ESCMID version. The subject is broad, specifically in terms of which MDR-GNR, and in which setting. Guidelines for CRE in a general hospital population would look quite different to guidelines for CRAB in the ICU. Dr Tacconnelli focused on the areas of controvosy: isolation for ESBL carriers, how to prioritise limited side rooms (see useful ‘Lewisham’ isolation prioritization tool in Appendix 6 of these Irish guildelines), selective digestive decontamination, and the need for bundles. Finally, Dr Tacconnelli referenced a neat model for the effectiveness of various infection control interventions for controlling the spread CRKP. This is a clever study, and probably useful, but much like Berta (showing my age), incorrect inputs result in meaningless (or worse, misleading) outputs.

Dr Anna-Pelagia Magiarakos discussed some of the challenges of implementing guidelines, reminiscent of Dr Evonne Curren’s recent talk on a similar subject. One important point is to have some guidelines to implement! Countries lacking guidelines for the control of MDR-GNR tend to have higher rates (ECDC and PROHIBIT data). Once you have some guidelines, barriers to implementation need to be overcome: time, culture, resources, lack of understanding or belief that they will work, competence, habit, routines and “ivory tower” guidelines written by those detacted from the coal-face, to name but a few!

So are we any closer to knowing what works to control MDR-GNR following ECCMID 2014? Bundles are more effective than single interventions, but we still don’t know which elements of the bundle are most important, and this will vary by pathogen and setting. We need more studies like the commendable but complex MOSAR Lancet ID study.

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

Image credit: Iqbal Osman.

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

Jon Otter (@jonotter) Antibiotic resistance, Conferences , , , , , , ,

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’.

What does lab diagnosis of MDR-GNR have to do with SURFing?

Jon Otter (@jonotter) CRE , , , , ,

I met the Service Users Research Forum (SURF) yesterday, and they asked me to give a presentation on the emergence and detection of multidrug-resistant Gram-negative bacteria (you can download my slides here). I found these slides by Dr Katie Hopkins (PHE) useful in preparing mine. It was my first interaction with a patient-led research group and I enjoyed the meeting very much. I found the SURF members and their academic support team from the University of West London to be engaged, engaging, knowledgeable and thirsty for knowledge. Their questions were insightful and their suggestions were thought-provoking. Informal discussions on a current research proposal (for enhanced surveillance of carbapenem-resistant Gram-negatives) gave me some useful ideas; researchers can easily lose sight of the patient perspective. I can see why funders such as NIHR now insist on seeing patient involvement in the development of research proposals and I am sure I will be SURFing again in the near future!

I put together the flow chart below to try and summarise the diagnostic approach to the lab detection of MDR-GNR. I would appreciate any thoughts you have on this flow chart…

surf mdrgrn

Chronic wound? No problem – a splash of oxygen peroxide should do the trick

Jon Otter (@jonotter) Wound care , , , , ,

JWC

I was involved in a recently published RCT of a novel wound care system (‘BioxyQuell’), which trailed the application of an aqueous oxygen peroxide (AOP, aka aqueous ozone) lavage on venous leg ulcers. The study isn’t perfect, but the results are encouraging and should serve as a basis for further evaluations.

The RCT was performed in the community setting. Sixty-one patients were enrolled if they had chronic venous leg ulcers, and randomised to either 6 AOP treatments or sham placebo treatments with sterile water over 2 weeks. AOP and placebo arms were both treated with standard-of-care compression bandaging between treatments and for the duration of the study. Patients who completed the initial 8 week RCT were enrolled into a follow-up study evaluating wound healing at 12 weeks, 6 and 12 months. The key results are:

  • No significant difference in wound healing at 8 weeks (the primary outcome). But, something surprising happened during the follow-up study: every single one of the AOP treated patients had healed by 12 months vs. 50% in the placebo arm (Figure 1). Could it really be that a 2 week AOP treatment period has such a remarkable impact on long-term wound healing? It’s just about plausible if there was some pretty fundamental change to the wound bed. But I’d need to see some more data to be convinced!
  • Almost 50% of patients in the placebo arm were healed by 8 weeks. The inclusion criteria required a chronic leg ulcer more than 3 months old, so why did 50% of placebo patients heal? I suspect the answer lies in good compression bandaging, which was mandated during the trial. There’s a temptation to apply the bandages too loosely to be effective to improve patient comfort.
  • AOP patients were significantly less likely to be withdrawn from the study due to wound infection during the first 4 weeks of the RCT (Figure 2). This stark difference makes sense: AOP is a biocide with the capacity to dismantle biofilms, which are involved in wound infection.
  • Pain and bacterial contamination were significantly lower in the AOP arm during the treatment phase. Wound size was also significantly reduced in the AOP arm when accounting for patients with deteriorating infected wounds.

Figure 1: Wound healing in the AOP and placebo arm during the RCT (up to 8 weeks) and follow-up study (up to 12 months).

BxQ healing

Figure 2: Patient withdrawals due to wound infection during the first 8 weeks of the RCT.

BxQ withdrawal

As ever, the study raises as many if not more questions than it answers:

  • What is the optimal treatment regimen for AOP? Is two weeks enough? Is three treatments per week about right (and feasible)? Put another way, how would this study have looked if the AOP treatment was performed for 4 weeks instead of 2? The fact that improvements in wound size reduction, pain, bacterial contamination and withdrawal due to wound infection trailed off after the 2 week treatment period indicates that a longer treatment period should be explored.
  • What is the best application of AOP in healthcare? Acute care? Primary care? Trauma? Diabetic foot?
  • Is ‘wound healing’ the right outcome measure? Perhaps prevention of withdrawals due to wound infection is the most important finding of this study. And don’t underestimate the value of the reduced pain in the AOP arm – the ulcers are very painful and make sufferers pretty miserable!

This was a fair sized randomised, sham placebo controlled, double blinded study performed with tight inclusion and exclusion criteria in the community setting. This sort of RCT is surprisingly rare in the wound care literature. However, it was terminated early (due to lack of significant difference in wound healing and the fact that it took years to recruit a decent number of patients) and the primary outcome (wound healing at 8 weeks) was non-significant. Nonetheless, wound size, pain and bacterial contamination were reduced by AOP treatment, the long-term reductions in wound healing are tantalizing, and reduced withdrawals due to wound infection are tangible.

Article citation: O’Halloran PD, Winter PK, Otter JA, Adams NM, Chewins J. Aqueous oxygen peroxide treatment of VLUs in a primary care-based randomised, doubleblind, placebo-controlled trial. J Wound Care 2014;23:176-90.

Post script: in memoriam

The statistician who formulated and executed the statistical analysis for this study, Carla White, sadly died (too young) during the latter stages of getting this article published. I am sorry not to have the opportunity to work with her again.

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

Jon Otter (@jonotter) C. difficile , , , , ,

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.

APIC New England 2014 Conference Report: ‘The how, when, & where of C. diff – can you “C” the difference?’

Jon Otter (@jonotter) Conferences , , ,

apic new england logo

I was privileged to be asked to speak at the APIC New England Conference today in Springfield, Massachusetts. It was a vibrant day, and congratulations to the organizing committee for putting on such an enjoyable event.

Marie-Louise Landry MD – Continuing conundrums and controversies in the laboratory diagnosis of Clostridium difficile.

Dr Landy, a virologist by trade, began by reflecting on the fact that CDI is relatively new phenomenon, discovered in the late 1970s and initially thought to be viral! Having briefly presented the clinical problem and pathogenesis of CDI, Dr Landry got to the nitty gritty of how to test for CDI. You can choose to target the toxin, bacteria or bacteria capable of producing toxin:

  • Toxin: cytotoxicity cell culture assay (complex and requires overnight incubation) or enzyme immuno assay (terrible sensitivity).
  • Bacteria: culture (slow and doesn’t tell you much) or rapid GDH antigen assay (sensitive, but requires a confirmatory test of toxigenicity).
  • Bacteria capable of producing toxin: toxigenic culture (requires incubation) or Nucleic Acid Amplification Test (NAAT) such as PCR or LAMP (rapid, expensive).

To be honest, before Dr Landry’s talk, I thought that testing for CDI was pretty much sorted: GDH as a sensitive screening test following by PCR to detect the toxin gene for GDH positives. However, Dr Landry presented a compelling case that whilst GDH makes sense as a screening test, detecting the toxin gene via PCR is only half the story: the real gold-standard test is a cytotoxicity cell culture assay to confirm that the disease-causing toxin is present. Cost & clinical association makes compelling case for cell culture cytotoxicity assays; convenience for PCR! Indeed is the initial enthusiasm for PCR CDI testing waning as reality sets in (like the famous ‘Going and Coming’ by Rockwell)?

A final point for discussion: you can have the best laboratory diagnostics in the world, but if you’re testing inappropriate specimens, you’ll end up with false positives. We need a firm “no diarrhea, no CDI diagnostics” rule!

Curtis Donskey MD – Controlling the spread of C. difficile: a multifaceted approach

Dr Donskey began by considering that no healthcare facility is an island, and that long-term care facilities are an integral part of CDI spread. Dr Donskey spent most of the talk considering the environmental considerations related to CDI. Why does cleaning fail? Due to poor implementation: a research team with a bucket of bleach can eliminate C. difficile from surfaces! Various tools are available to help us tackle C. difficile environmental contamination. However, fluorescent markers and UVC did not eliminate C. difficile contamination whereas carefully enhanced disinfection did; bleach goes round corners better than UV, apparently. A related (and under-reported) unintended consequence of introduction a “no-touch” room disinfection (NTD) system such as UVC is that cleaners stop cleaning, mistaking UVC for magical cleaning robots! Plus, you could find yourself spending more time screening than cleaning, to the extent that those tasked with monitoring the cleaning process would be better deployed by getting their hands dirty! Dr Donskey covered a number of other important environmental issues: who cleans what (“the nurses thought EVS were doing it; EVS thought the techs were doing it; nobody was doing it”), the need for daily disinfection, pre-emptive and extended isolation, the potential and under-recognized importance of proper daily bathing for CDI patients, and the potential contamination risk from asymptomatic carriers. The final word: “getting doctors to prescribe antibiotics appropriately is like getting EVS to clean properly: an ongoing challenge.” Oh, and he finished on a song.

Jon Otter PhD (who invited him?) – No-touch room disinfection (NTD) systems: when to use them and how to choose between them (Can you ‘C’ the difference?)

You can download my slides from the talk here.

The talk was loosely based around a review paper recently published in JHI. The increased risk from the prior room occupant argues for doing a better job of terminal disinfection. The goal of hospital disinfection is controversial: the ‘Pragmatist’ says a reduction in contamination is good enough, whereas the ‘Prior room occupantist’ says elimination of pathogens is required. I presented some data suggesting that transmission risk ∝ contamination level; ergo reduction in transmission ∝ decontamination level? The NTD scene is a four-horse race currently, with hydrogen peroxide vapour (HPV), aerosolized hydrogen peroxide (AHP), ultraviolet C (UVC), and the relatively new kid on the block, pulsed xenon UV (PX-UV). Each system has its pros and cons so which is best? My view is that will depend on the scenario: if you have a carbapenem-resistant Acinetobacter baumannii in your ICU, then the ‘belt and braces’ approach of HPV is warranted. However, if you have MRSA colonization on a medical ward, a ‘quick and easy’ UV treatment may the only feasible option.

To try to keep everybody awake after lunch, I polled the audience on a few questions (Figure). I was not surprised that most people had not used an NTD system. However, I was surprised that so few people selected UV in the scenarios!

APIC NE q1 APIC NE q2 APIC NE scenarios

Figure. Question 1: Should all acute hospitals be using a ‘no-touch’ automated room disinfection (NTD) system for terminal disinfection of some patient rooms? Question 2: Has your hospital has used the following NTD systems? Scenario 1: A patient with carbapenem-resistant A. baumannii is discharged from the ICU. Scenario 2: A patient with MRSA colonization is discharged a general medical unit. Scenario 3: A patient with recently resolved CDI is discharged from a general medical unit (‘Enhanced’ = enhanced conventional methods).

Mike McCarthy – Sustaining your gains in infection control initiatives

Mike McCarthy rounded off the day with an engaging overview of his experience from a number of industries of how to ‘sustain your gains’. There’s a temptation from administrators to dismantle the team once it has been shown to work; clearly, the results will disappear with the people! Mike gave useful advice on how to embed change in an individual and organization. Do not confuse respect for people with respect for their bad practices. We need to be good coaches of best practice – reinforce proper execution; correct improper execution. The typical number of audits is “once and done”, but this not enough to form good habits. Establishing a new habit takes 60-90 days of work to reach the happy state of ‘unconscious competence’. People like data-led feedback (we’re all nerds at heart), which results in tangible performance management and improvement.  So, implement a checklist, audit it, provide positive reinforcement and feedback and your gain will be sustained!

Points for discussion:

  • Laboratory diagnostics are only part of the story. We need to focus on making sure only appropriate specimens are tested. Dr Donskey mentioned that a shocking 12% of their stool specimens were not tested due to sample leaking or labeling errors. Unfortunately, the stools most likely to be from CDI are also most likely to be liquid! Conversely, testing formed stools doesn’t do anybody any favours.
  • Do we need to focus on asymptomatic toxigenic C. difficile carriers and, if so, how?
  • How far can conventional methods go in tacking environmental contamination with C. difficile and is it time to turn to NTD systems, at least some of the time?
  • How best to sustain our gains?

IFIC 2013 Conference Report

Jon Otter (@jonotter) Conferences , , ,

ific argentina logo

The 13th International Federation of Infection Control (IFIC) meeting took place in Buenos Aires, Argentina in October 2013. A colleague who attended sent me some notes from the meeting, which I was not able to attend. I found the notes useful, so thought I’d share them (albeit a little late)!

Pro-Con debates

The first was on government regulations in infection control. The Pro delivered by H Baguio from Uruguay and Con by M Borg from Malta. H Baguio gave examples where government regulations have had impact on infection rates, citing the case of MRSA in the UK and reductions in bacteraemia, UTI and KPC prevalence after governmental regulation and auditing introduced in Uruguay. M Borg gave examples were governmental interventions did not improve the situation:  for example, a 5x increase in the cost of medical waste disposal due to an insistence on considering it hazardous, when much could be considered non-hazardous. Also, there is a suggestion that since CLABSIs became non-refundable by the US government, many hospitals have started using peripheral lines over central lines to avoid financial loss. Another possible consequence is a less active attempt to detect infections in US hospitals, and a reticence to admit high-risk patients to avoid infection. However, in general the debate was not really pro-con as both admitted that some sort of government regulation is needed but they were not the only solution. This was reflected in the final results: 50% pro and 50% con.

The second debate was about universal vs. targeted MRSA screening. T. Boswell was arguing for universal screening, while E Lingaas of Norway was for targeted. There were good arguments from both sides but the vote suggested a swing towards targeted screening. I think the debate would have been more interesting if it as about universal screening for all pathogens of interests such as the emerging MDR Gram-negative bacteria. Whether you choose universal or targeted screening will depend on your country and healthcare setting. In countries with high carriage prevalence, universal screening will be more beneficial, especially when using quick and cheap diagnostic tests. For countries with low prevalence, targeting screening probably makes more sense. However, choose your targeted screening approach carefully: I performed a study recently where we found that reverting to our targeted screening approach would miss around 50% of carriers!

Selected talks

Stella Maimone (Buenos Aires, Argentina): “Infection control: the other side of the moon”

Stella was the first registered infection control nurse in Argentina. Most IC nurses in Argentina have been trained by her. She gave a general talk on IC in Latin America (LA) based mainly on the differences between Latin America and developed countries in IC. She noted that most LA countries ministries of health have some sort of infection surveillance systems including in Argentina. However, the data are not publicly available (at least in Argentina) which is a major difference between LA vs. USA and Europe.

Although LA countries are aware of the cost of HAIs, they have limited resources and it is not possible to reproduce the same IC policies that are implemented in US and UK (e.g. CDC guidelines) in LA. The reasons for that are: limited resources, different culture, LA people don’t like to be controlled (i.e. governmental regulations will have limited effect), and LA people think short term hence IC policies aimed at results in the distant future will not be adopted.

Hence for effective IC policies in LA, the limited resources of the countries/hospitals, the wider culture of society, and the ‘micro culture’ of the healthcare community must be taken into consideration.

Maria Clara Padoveze (University of Sao Paulo, Brazil): “Help! An outbreak!”

This was an interactive session with Q & A throughout. The informative talk covered outbreak definition and detection, but did not address outbreak control and infection control interventions in detail, which was a shame. Maria highlighted a useful website for performing quick literature reviews on various outbreaks from round the world: www.outbreak-database.com. This gives you an up-to-date (ish) report of outbreaks from around the world. If you register (free) you can access advance search where you can search per country for example.

Celeste Lucero (Argentina): “MDROs: a new world war”

This helpful overview began with an overview of how organisms acquire multidrug resistance. Celeste mentioned the WHONET-Argentina, which is a WHO Collaborating Centre for Surveillance of Antimicrobial Resistance in the country. Celeste offered a few examples including the CTXM-2, which is endemic in Argentina, and the emergence of CTXM-15 and OXA-163. She also mentioned that many Acinetobacter baumannii are now only treatable by Tigicycline and Colistin, and that rates of KPC have been increasing since 2010. To compound matters, Argentina had its first reported NDM-1 in 2013. I left the talk without a clear picture of prevalence of MDROs in Argentia, which may reflect the paucity of accurate epi data.

Martin Kiernan (UK): “Taking infection prevention to the next level”

Martin gave a talk on the UK experience in IC, citing examples of the impressive reductions achieved in the UK for MRSA and C. difficile, and the various interventions to achieve these reductions. He mentioned that the problem now is MDR Gram-negatives such as E. coli and Klebsiella pneumoniae. His talk focused on how to change the IC culture in a hospital, including getting everyone engaged.

Syed Sattar (University of Ottawa, Canada): “The role of high-touch environmental surfaces in the spread of HAI: strategies to minimize the risks”

The talk began by outlining the factors that determine the risk of transmission from an environmental surfaces: probability of contamination; ability of pathogen to survive on the surface; transmission potential (e.g. porous surfaces are poor at transmitting pathogens, hence focus more on hard surfaces); location and frequency of direct contact with the surface (e.g. via hands or mucous membranes). He then went to define which pathogens to focus on. He warned not to focus on the high profile pathogens or the “pathogen of the month” such as HIV or H1N1 as these are less resistant in the environment and easily killed by disinfectants. Pathogens to focus on are: C. difficile spores; norovirus and other non-enveloped viruses such as rotavirus; MRSA; Acinetobacter; VRE.

The remainder of the talk was around liquid disinfectants and wiping. He specifically highlighted the problem with disinfectants/wipes, which are effective at spreading contamination if they don’t actually kill pathogens. He outlined the results of one of his studies, where they tested a number of disinfectants with wiping action and found that all except one did not kill all pathogens and also did spread them to other surfaces.

Some key papers mentioned in the conference:

1-   Zimlichman E, et al. Health Care-Associated Infections: A Meta-analysis of Costs and Financial Impact on the US Health Care System. JAMA Intern Med. 2013. Previously reviewed on the blog here.

2-   Limb M. Variations in collecting data on central line infections make comparison of hospitals impossible, say researchers. BMJ. 2012 Sep 21;345:e6377.

3-   Sattar SA, Maillard JY. The crucial role of wiping in decontamination of high-touch environmental surfaces: review of current status and directions for the future. Am J Infect Control. 2013 May;41(5 Suppl):S97-104.

2014 Spring Update

Jon Otter (@jonotter) Updates , , , , ,

Easter Bunny

It’s been a busy quarter on the blog; please see below for the blog posts since the Christmas update (which now seems like a long time ago!).

The SHEA and HIS/IPS spring conferences provided much food for thought. Also, I was delighted to host a guest blog from Prof Sally Bloomfield on What do we mean by ‘cleaning’ and ‘disinfection’?, which prompted some fascinating discussion. If you’re interested in contributing a guest blog, these are always welcome, so please let me know.

Thanks as ever for the comments – please do keep them coming.

Regards

Jon

Photo credit: ‘Easter Bunny’ by Jimmy Hilario.