Reflections from ECCMID: the pink, the blue, and the new

eccmid2016

I’ve recently returned from an enjoyable few days in Amsterdam for ECCMID. I’ve not been to a conference of this scale for a few years; there was a lot of good stuff to choose from so I’ve tried to stick to key updates for the purposes of this reflection!

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Are spores the secret of the success of FMT in treating recurrent CDI?

Characteristic of the aimes strain of b anthracis is the smooth

I have been following the literature around the use of faecal microbiota transplantation (FMT) for the treatment of recurrent Clostridium difficile infection (CDI). FMT is spectacularly effective but rather crude – and may have some associated risks, not least the possibility of transmissing infectious organisms we have not yet discovered! There is also the issue of administration. Compared with recurrent CDI, a duodenal infusion (aka tube up the backside) isn’t so bad – but an oral delivery would be preferable. The ‘crapsule’ (oral FMT) has been tested and is effective, but it requires a large number of crapsules to reach the required dose. So, the search is on to distill the effective elements of FMT into a format that can be delivered more easily. Some work has been done on exploring various combinations of live bacteria – with variable success.

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‘Crapsules’: the cure for Cdiff and more

crapsules brown pills

I gave a talk today at a Pint of Science event entitled “Crapsules: the cure for Cdiff and more”. You can download my slides here. Cdiff infection (CDI) is a nasty disease, usually occurring in those who have taken antibiotics in hospital. It’s characterised by frequent loose stools (often 5 or more movements per day) and frequent recurrence. Around 15-35% of patients with CDI will have a repeat episode. The mainstay treatment for recurrent CDI is antibiotics but the cure rate is poor at around 30%. Remarkably a ‘faecal microbiota transplantation’ (FMT) is way more effective, with a cure rate in excess of 90%.

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How big is C. difficile infection in the USA?

Clostridium-difficileThe New England Journal of Medicine recently published an article evaluating the burden of CDI in the USA. The huge CDC-led initiative collected data from 10 geographically distinct regions, identifying more than 15,000 cases. Around two-thirds of cases were classified as healthcare-associated (although only 25% were hospital-onset). This means that, prima facie, a third of CDI cases were community-associated. I find this proportion difficult to believe: I strongly suspect that many of these cases would have had healthcare-associated risk factors if the team were able to look hard enough. For example, they used a fairly standard 12 week look-back period to evaluate previous hospitalisation, but how would the data look if they’d used 12 months? Also, it’s usually only possible to evaluate previous hospitalisation in a single healthcare system, but many patients commute between various healthcare systems. The authors acknowledge in the discussion that this designation of “community-acquired” may be inaccurate based on the finding from a previous study whether healthcare-associated risk factors were identified in most patients, but only be a detailed phone interview.

Scaling up from the figures from the 10 regions, national estimates were around 500,000 cases and 29,000 deaths due to CDI per annum in the US. This estimate is approximately double previous estimates for the national CDI burden in the USA, probably reflecting the adoption of molecular methods for the detection of CDI. This scaling up included an interesting statistical adjustment to see how prevalence varied depending on how many sites use sensitive molecular methods to detect CDI.

A sub-study included the culture of C. difficile from 1625 patients. More than 15% of stool specimens from patients diagnosed as CDI failed to grow C. difficile, probably illustrating the limitations of culture methods more than anything else. NAP1 (027) represented around half of cases, and was significantly more common in healthcare-associated CDI. I think it’s fair to say that the initial fears that NAP1 was a super-strain have been allayed by the fact that it’s now so common and there hasn’t been a surge in CDI mortality.

Finally, around 21% of healthcare-associated cases suffered at least one recurrence. Thus, there is a real need to the roll out of the uber successful faecal microbiota transplantation for recurrent CDI. In fact, there should be around 70,000 faecal microbiota transplantations each year in the US right now (500,000 x 0.66 x 0.21); I suspect there are far fewer.

‘Crapsules’ spell the end for recurrent Clostridium difficile infection

Faecal microbiota transplantation (FMT) has shown remarkable efficacy for treating recurrent C. difficile infection (CDI). In fact, the randomized controlled trial to evaluate the effectiveness of FMT for recurrent CDI versus treatment with vancomycin was terminated early because FMT was so obviously superior, with a cure rate of more than 90% (see Figure 1, below).

Figure 1: Faecal microbiota transplant for recurrent CDI. Patients with recurrent CDI randomised to FMT (n=16), vancomycin (n=12) or vancomycin + bowel lavage (n=13). Colour scheme chosen carefully.van nood_blog

FMT is crude in every sense. You take donor stool, put it in a blender, sieve it, and deliver it to the recipient’s gut. I had the pleasure of watching a colleague prepare a dose of FMT in our laboratory in London last week. It really is a simple preparation. The delivery of the FMT to the recipient’s gut isn’t so much tricky as it is unpleasant for the recipient, with a tube required for the procedure.

So, could you deliver FMT orally? The answer according to a recent JAMA study is yes. The team from Boston in the US developed specially formulated capsules (aka ‘crapsules’) designed to deliver the FMT to the correct part of the gut. Of the 20 patients with recurrent CDI given a short 2 day course of ‘crapsules’, 14 (70%) resolved. The 6 non-responders were given a second course and 4 of these resolved, resulting in an overall resoluation rate of 90% (18/20). The quality of life benefits are obvious, and spelled out in the reduction in number of daily bowel movements (Figure 2, below). Although this wasn’t an RCT, so the patients knew they were getting the FMT and there could have been a placebo effect, the similarity in the rate of resolution between this study and the van Nood study (Figure 1) is striking.

Figure 2: Median number of bowel movements for 20 patients suffering from recurrent CDI treated with ‘crapsules’.Youngster blog

Oral FMT via ‘crapsules’ takes away the unpleasantness of the delivery for the recipient (if they can get over the ‘gross’ factor). But it doesn’t solve the lingering safety concerns associated with the procedure. We simply don’t have the tools to screen donor stool for problems we don’t yet know about. The experience from delivering hepatitis C virus to haemophiliacs in the 1980s in contaminated blood products from donors is salutary, and close to my heart since one of my good friends is still suffering the consequences of this. But, this risk has to be balanced against the urgent need of patients becoming increasingly desperate with recurrent CDI. If I had recurrent CDI, I’d be joining the queue for FMT.

The real solution to this problem is synthetic FMT. Lots of people are working on this at the moment – check our some of the work by Trevor Lawley on this. I am pretty certain that a simple bacterial cocktail will not make an effective synthetic FMT. There’s huge microbial and non-microbial diversity in the gut contents which will need to be replicated somehow. Clearly, some of this will be redundant, but it will take quite some time to pick through the constituent parts to derive an effective synthetic FMT. But I’m certain it will happen, and probably over the next decade.

Until then, ‘crapsules’ offer an alternative, effective way to deliver FMT, which is remarkably effective for resolving recurrent CDI. But recurrent CDI is just the start. There’s a host of other conditions that could potentially benefit from FMT. It may even be that ‘crapsules’ become a ‘new statin’: “a crapsule a day keeps the bad bugs away”?

Article citationYoungster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, Capsulized, Frozen Fecal Microbiota Transplantation for Relapsing Clostridium difficile Infection. JAMA 2014; in press.

Christmas 2014 Update

Christmas lights

Now that you have digested your Christmas turkey, I thought that it would be a good time to send out an update. These articles have been posted since the last update:

I’m in a rather reflective mood, so time to remind you of some of the key themes from 2014: Ebola, MERS-CoV, universal vs. targeted interventions, faecal microbiota transplantation (FMT), whole genome sequencing (WGS), carbapenem-resistant Enterobacteriaceae (CRE), and some interesting developments in environmental science. And what will we be still talking about come Christmas 2015? Let’s hope it won’t be Ebola, and I think that WGS will be a lab technique akin to a Vitek machine rather than subject matter for NEJM. But I think we still have ground to cover on whether to go for universal or targeted interventions, FMT, and improving our study designs in infection prevention and control. I can also foresee important studies on the comparative and cost-effectiveness of the various tools at our disposal.

And finally, before I sign off for 2014, a classic BMJ study on why Rudolf’s nose is red (it’s to do with the richly vascularised nasal microcirculation of the reindeer nose, apparently).

Image: Christmas #27.

Selective Digestive Decontamination (SDD) is dead; long live faecal microbiota transplantation (FMT)

crapsules

Ok, so the title may be a little premature, since this blog relates to a study with a sample size of exactly one. However, I do think it spells the beginning of the end for Selective Digestive Decontamination (SDD), especially when applied to suppress gut colonization with antibiotic-resistant bacteria.

A number of groups have looked at using SDD to ‘decolonise’ carriers of multidrug-resistant Gram-negative bacteria such as CRE. In one study, 20 CRE colonized patients in each arm given gentamicin + polymyxin (SDD arm) or placebo (Control arm). The results were rather modest (see chart below). Plus, SDD has substantial downsides in terms of the potential for developing further antibiotic resistance, and ‘collateral’ damage to the gut microbiota.

Figure: Modest impact of SDD to ‘decolonise’ the gastrointestinal tract of CRE carriers.

Saide-Oldes CRE decol

I’ve been waiting for some data on the effectiveness of faecal microbiota transplantation (FMT) to decolonise carriers of antibiotic resistant bacteria for some time. A case report at ID Week related how the ordeal of a 13 year old girl was ended by a faecal microbiota transplantation. After months of persistent colonization and infection, the impact of a single dose of FMT was startling: CRE carriage was eliminated and there was no further bacterial infection.

One of the push-backs against using FMT more regularly is that it’s a crude (in every sense) and labour-intensive procedure compared with an antibiotic capsule. But that was before the invention of ‘crapsules’ (aka oral FMT). Another ID Week abstract reports the successful delivery of oral FMT using crapsules. (And it’s amazing what great dinner party conversation ‘crapsules’ makes. Try it – you’ll see.)

So, I think it’s time for a cluster randomized trial to compare the impact of SDD and FMT; my money is on FMT!

Image: Barbara Krawcowicz.