An unusual and interesting outbreak of CPE was published recently in Clinical Infectious Diseases. Several key points: don’t rely solely on a PCR detecting the “Big 5” carbapenemases (NDM, KPC, OXA-48, IMP, VIM) – at some point you need to test for phenotypic carbapenemase activity; WGS can really help us in unravelling complex transmission routes; and covert plasmid propagation within and between species is a reality.
An interesting new Italian study has identified the mcr-1 gene, a plasmid-mediated colistin resistance gene, in 8% of environmental Enterobacteriaceae isolates. This suggests that environmental Enterobacteriaceae and perhaps even environmental surfaces themselves could be important reservoirs in the spread of mcr-1 and colistin resistance.
A recent US study has investigated CPE contamination of sinks, drains, and wastewater. Carbapenemase-producing bacteria were identified throughout the drainage and water system, from drains in patient rooms, right through to wastewater sampled through manholes adjacent to the hospital. My main question in all of this is whether this huge reservoir of carbapenemases in hospital wastewater is a risk for patients. The lack of genetic similarity between isolates in hospital wastewater and isolates from patients suggest not, but I suspect there’s an indirect link and these carbapenemases find their way into isolates affecting humans, which is supported by genetic links between the plasmids carrying the carbapenemases.
There has been a lot of concern in scientific journals and the mainstream media about colistin resistance in Enterobacteriaceae caused by plasmid-mediated resistance genes (the mcr genes). However, an article published today by our group suggests that mutational colistin resistance rather than plasmid-mediated mcr genes is a more pressing clinical threat.
The risk of interspecies transmission of carbapenemase genes is a real concern. We can barely get our heads around many different types of carbapenemase in a whole host of Gram-negative bacteria (compare the relative simplicity of methicillin resistance in S. aureus: a single gene, in a single species). Throw in interspecies horizontal transmission of carbapenemases and things get really tricky! Do we implement different control strategies to try to interrupt the transmission of carbapenemases (in contrast to the organisms themselves)? Could you have a multispecies outbreak of a carbapenemase on your hands and not even realise it?
A team from the NIH Clinical Center in the US present a fascinating study, exploring the transmission of carbapenemase-encoding plasmids in unprecedented detail. The intro does a good job of introducing the ‘triple threat’ from CRE: pan-drug resistance, sharply increasing prevalence, and the potential for the horizontal transfer of carbapenemase genes between Enterobacteriaceae species. They introduce the idea of “plasmid trafficking”, which evokes images of shady bacteria dealing in antibiotic resistance genes (a la the infamous cartoon below):
NIH is a hospital that takes CRE seriously, after being stung by an outbreak in 2011. A quick look at who they screen for CRE illustrates just how seriously they take the threat:
- ICU / high-risk patients screened twice weekly.
- All patients screened monthly.
- Admissions from other hospitals screened for CRE…twice (and given pre-emptive contact precautions until negative cultures are confirmed, for good measure).
They also performed some environmental sampling and recovered several CRE from the hospital environment. This will surprise some, but Enterobacteriaceae do have the potential to survive on surfaces for longer than you may expect.
Surveillance cultures identified 10 patients with KPC-producing Enterobacteriaceae and environmental surveillance identified 6 KPC-producing Enterobacteriaceae. They combined these with several historic isolates from the 2011 outbreak, and a couple of imported isolates to give a sample size of 20 isolates. They wanted to dig deeper into these isolates to explore whether or not they shared any plasmids. And here’s where it gets rather complicated. Conventional whole genome sequencing produces many short reads (100-500 bp) but these cannot distinguish between plasmids and chromosome-encoded genes. Therefore, the authors used a technique called single-molecule, real-time (SMRT) to generate longer reads (around 1000 bp) that make it possible to distinguish between plasmids and chromosome-encoded genes. [I know that I’ve over-simplified this clever genomics massively – but I’ll quickly get out of my depth otherwise!]
The report presents a picture of rare patient-to-patient nosocomial transmission (only 1 of 10 patients were thought to be in-hospital acquisitions), continual importation of diverse CRE, and a complex network of even more diverse plasmids. To illustrate the diversity, one strain of CRE contained no fewer than three distinct KPC-encoding plasmids!
The authors find some evidence of environmental spread of carbapenemase-encoding plasmids, with the carbapenemase-encoding plasmid from a patient matching plasmids recovered from different species of Enterobacteriaceae found in the patient’s environment. What the authors did not demonstrate is transmission of carbapenemase-encoding plasmids from the environment to patients – but I wouldn’t want to be admitted to a room with CRE lurking in the hospital environment!
There’s quite a bit of science around the horizontal transmission of plasmids within biofilms. Combine this with the recent finding of biofilms on dry hospital surfaces, and you have a concerning new angle on how CRE may be transmitted in hospitals.
Image credit. Nick Kim, with permission.
Article citation: Conlan S, Thomas PJ, Deming C et al. Single-molecule sequencing to track plasmid diversity of hospital-associated carbapenemase-producing Enterobacteriaceae. Sci Transl Med 2014; 6: 254ra126.