Dispatches: Pan-drug-resistant doom – are we there yet?

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Guest blogger and Acute Medicine trainee Dr Nicola Fawcett (bio below) writes…As the local Prophet of Antibiotic Resistance Doomsday to our population of hospital physicians, I’m always interested in finding out if the pan-drug-resistant superbug has emerged that is going to wipe us all out, for credibility purposes if nothing else. (Resistance Is Coming! Prepare thyself! Wash thy hands and document thy indication and duration or face Everlasting audits and perpetual personal protective equipment!). For the record – I’m actually a Registrar in Acute and General (Internal) Medicine. I’m doing some time in the world of ID/Micro/Genomics in the hope that it will help me work out whether it’s ok to just hand out co-amoxifrusiclavamide + nebs to everyone if not sure what’s going on. However  this question seems rather inextricably linked to antibiotic resistance, and having spent some time now with people who seem to know what they’re doing,  I’m increasingly flabbergasted at the massive divide between the views of microbiologists who see the latest data, and the views of the common garden hospital physician. Therefore my side-mission, if you like, has become to spread the good, or rather, spectacularly bad news that antimicrobial resistance is currently spreading around our biosphere at a scale and speed at which we simply cannot react fast enough.

Being the evidenced-based prophet that I am, I thought I’d use a recent trip to the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) to hear from the people who know what they’re doing, and get a heads up on any signs of pan-drug-resistant-doom. In a highly scientific method, I went to the ECCMID online library and entered the phrase “pan-drug”. Simple, efficient and, it turns out, quite productive. 3 results, all posters. Though I note this is in hospitals that have the resources for resistance monitoring, for molecular investigation, and for sending posters and delegates to European Microbiology Conferences. And this is in hospitals that are laudably prepared to investigate and report their data in the era where hospitals are being sued for MDRO outbreaks (although these are cases brought for non-disclosure), and taking responsible measures to control MDRO spread results in toxic press coverage, especially when they happen somewhere near the intended location of an impending royal sproglet.

So a quick look at these pan-drug-resistant reports. Have we found Terminatia 2000? Well not quite, at first look. The first two report pan-drug resistant Pseudomonas and pan-drug resistant Acinetobacter, which I gather from other microbiologists I asked about this, are slightly old-hat in the microbiology PDR world. Of more interest, a hospital in Greece reports an outbreak of pan-drug-resistant Providencia. In itself, a fairly low-virulence organism, but in the outbreak isolates they found multiple resistance mechanisms – blaVIM-1, blaSHV-5, blaTEM-1, blaOXA-10 and blaVEB-1 beta lactamases and rmtB 16sRNA methylase, all apparently carried on the same super-plasmid. Oh wonderful. In fact, super plasmids seemed to be a common theme in many of the MDRO sessions and posters at ECCMID.

The real question underlying this is: where are these plasmid-spreading friends-of-Providencia residing? One might  draw on lessons from another ECCMID theme – that of institutions seeing rapidly spreading carbapenem resistance – (from 8 to 284 resistant  isolates in 2 years), and in diverse species – as well as the usual E.coli/Klebsiella, add in Enterobacter cloacae species, Serratia, Kluyvera, Citrobacter… where would these all reside – gut...sewage…drains? The above story may sound depressingly familiar to those who have studied the UVA.KPC Outbreak. (I’ve had the benefit of learning from the awesome Amy Mathers, Nicole Stoesser and Anna Sheppard who worked on this.)

One might imagine plasmid-sharing communities, sitting, proliferating, and dealing survival elements in a perfect, anthropogenic resistance-generating-bio-reactor, somewhere in the perfect storm of selection without eradication, perhaps with sub-lethal doses of antibiotic and biocide imposed on a microbial community with the resources to survive and adapt and spread. “Need some carbapenem resistance?” one might say. “Yup, I’ve got that. Some gentamicin resistance too for you? Comes free, and trust me, once you’ve tried it, you’ll never be able to live without it. You can even have some biocide resistance too whilst I’m at it, so when they do a clean, it’ll just remove the competition!” There they are, transferring resistance elements on integrons, transposons, plasmids, every level – maybe directly, maybe as beneficiaries of the understudied bacteriophage network, plasmids jumping between strains and species, to reach highly transmissible clones and spread further. it is becoming abundantly clear that in highly-DNA-sharing bacteria (like the Enterobacteriaceae) we need to stop thinking just bacteria, and also think DNA. (This paper by Fernando Baquero was my ‘Aha’ moment in this!) Quoting just a tiny sample of the literature (it’s not just me…): “The spread of NDM-1(carbapenemase) is probably due to the high mobility of the NDM-1 plasmids as opposed to clonal dissemination”- Mataseje 2014. “The spread of the KPC (carbapenemase) gene may be facilitated by its localisation on plasmids and transposons and also by efficient clones.”- Pereira 2014.

I think microbiologists mostly have their head around this (hey it’s old news too!), but I’d hazard a guess that most clinicians, and most policymakers certainly don’t. A key defense of antibiotic use in farm animals is to point out, quite correctly, that to date there is very little evidence that resistant bacteria in animals have been shown to cause human infection. Plasmid sharing, however, has been shown to go on. One may go all playground and debate who really got what from who, but it’s missing the point. The steps that are required to combat resistance are to slow down or stop the creation and spread, not just of resistant bacteria, but of resistance-conveying transposable elements and plasmids. These things can jump from non-human to human-associated, given the right conditions and vectors.  And one small jump for a resistance gene can create a giant headache for mankind. The OXA-48 carbapenem resistance gene currently running havoc around Central Europe hand-in-hand with Klebsiella probably originated in an innocuous marine bacteria, Shewanella, and managed to jump ship, probably first to Serratia, and then onwards, to a highly-shareable Klebsiella-friendly plasmid or three.The epidemic resistance plasmids, and high-risk clones we see in hospital are the downstream step, probably, of years of resistance pressure in wastewater, sewagefarms, aquaculture, and yes, hospital use as well.

So, I’d hazard a guess that whilst pan-drug-resistant antibiotic doom hasn’t been widely reported yet, it is probably a plasmid already with us, or at least the great-granddaddy of it, sitting in a drain or surface somewhere. Probably in a place where carbapenem resistance is already widespread in the normal, environmental microflora. There it is, waiting for it’s one-in-a-trillion chance to encounter a vector organism that will bring the it to the attention of some highly human-adapted Enterobacteriaceal strain, where it will spread, and change, maybe picking up a few more resistance genes in the process, and spread again. Once it is endemic, all it needs is one final jump into a high-virulence organism and Bob is your very worried and probably very ill, proverbial uncle. And all that is preventing these meetings of perfect medical disaster is the ticking clock of time. Not very much time, if these outbreaks predict the future. Maybe as little as two years between first report and major, ineradicable outbreak of untreatable infection.

New antibiotics are coming, but they’re not coming that fast. It’s very clear that, rather than sitting back and waiting for pharma to save us, we need to slow down this massively-efficient-resistance-generating pathway we seem, through human activity, to have created. Many groups have their roles to play. As clinicians, we can do our bit – rigorous infection control measures, sensible antibiotic use. Microbiologists play their role  in surveillance, control, and progressing the understanding of how these strains and elements spread. All this can help us, if you like, slow the boulder of epidemic-pan-drug-resistant infection that is rolling inexorably towards us. And we can hope that efforts to create new antibiotics help us perhaps learn to run a bit faster – but at the moment, bacteria, and DNA, are currently moving at a speed that is far, far outpacing our best efforts.

So what will I take back to my colleagues when they ask me about post-antibiotic era doom? Well, it may not be here yet, but it’s probably lurking, and assembling itself as we speak.

Bio

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Nicola Fawcett is an Acute Medicine Trainee  and currently a MRC Clinical Research Fellow with the Crook/Peto Group at the Nuffield Department of Medicine in Oxford, currently undertaking a D.Phil studying antibiotic resistance in the gut microbiome. Twitter: @drnjfawcett.

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Notes – as mentioned above – credit for all this thinking goes to members of my research group, and many many other microbiologists through conferences, Twitter and beyond who have been good enough to share and debate their views with me. Mostly, I’m just describing their thinking, as best I understand, in ways that I hope a general physician may understand. I asked last week whether there was any point in telling physicians about doom. Perhaps if you use it to communicate what is going on, and what role we play, then it starts to become relevant. I asked a group of doctors recently after a stewardship session about the most important message, and for them it was the plasmid/mobile genetic element story and the wider picture – this piece is an attempt to communicate this. I have attempted where possible to try not to be over-dramatic, but do wish to try to represent and communicate the true level of concern that I have encountered from specialists in the area. If I have made any significant errors or omissions, please tell me. Dialogue, views, are welcome!

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