CRE – too weak to spread!?



In the May issue of ICHE, Weber et al. published their findings of a study looking at the environmental contamination of rooms occupied  by patients colonized or infected with CRE. In addition to their observations they actively inoculated test surfaces with 102 CRE (which I find rather low). They found that the contamination in the patients’ room was infrequent (8.4%) and at low levels (5.1 CFU/120cm2). With the single exception of K. pneumoniae on formica, alle CRE had a less than 15% survival at 24 hours and a 0% survival after 72 hours.

Should we just conclude that the chance of CRE transmission from the environment is very low?

I believe that this conclusion would be too early and probably wrong. The survival of micro-organisms in the environment is clearly strain dependent and while the authors used clinical isolates they did not mention if they included a strain that has proven its ability to spread (eg. outbreak isolates). In general multi-resistant bacteria may loose some of their fitness – including the ability to survive in the environment – but survival studies like those of Kramer et al. show survival of multiple weeks for E. coli and Klebsiella spp.

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Do you know your CRE from your CRAB?

I gave a talk today at a meeting on combating carbapenem-resistant organisms. My angle was to clearly differentiate the epidemiology of the Enterobacteriaceae (i.e. CRE) from the non-fermenters (most importantly carbapenem-resistant A. baumannii – CRAB), and you can download my slides here.

I’ve blogged before about how confusing the terminology surrounding multidrug-resistant Gram-negative rods has become. Non-expert healthcare workers have little chance in distinguishing CRE from CPE from CRO from CPO. So we need to help them by developing some clear terminology, given the gulf in epidemiology between CRE and CRAB (see below).

CRE and CRAB are like apples and pears: they share some basic microbiology but that’s about where the comparison ends!CRE CRAB

So, I think we should talk in terms of CRE (and CPE for confirmed carbapenemase carriers), and CRNF (or CRAB for A. baumannii and CRPA for P. aeruginosa). I don’t think that CRO is a useful term – in fact, I find it rather confusing. Carbapenem resistance in Enterobacteriaceae (CRE) and A. baumannii (CRAB) are both emerging problems, but they are not the same problem.

Diagnosis of CRE: time to throw away those agar plates?

CRE are an emerging threat to healthcare systems worldwide. Most guidelines recommend screening and isolation of carriers. But relying on conventional agar-based culture presents a dual threat of poor sensitivity (depending on which method is used) and slow turnaround time, with a minimum overnight incubation before a presumptive positive result. PCR solves both of these problems – but at a cost. I gave a talk today at a BD seminar considering whether it’s time to switch to PCR diagnostics for the detection of CRE. You can download my slides here. (The title of the talk “Time to throw away those agar plates” was inspired by a talk by Dr Dan Diekema at a recent SHEA conference.)

There are a number of options for CRE screening, summarized in the flow chart below:

Flow chart: Overview of laboratory methods for the diagnosis of CRE. (To be precise, throughout the blog I really mean CPE most of the time, but I’m using CRE for consistency with other blogs…)CPE diagnosis

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CRE “trafficking” plasmids through hospital surfaces

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):

File written by Adobe Photoshop? 4.0

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.

Acinetobacter contamination: is anywhere safe?

A study from New York City describes an environmental survey of contamination with antibiotic-resistant Gram-negative bacteria on surfaces in the community. The authors hypothesise that resistant Gram-negatives could be carried by staff, patients and visitors beyond the confines of the hospital.

Almost 500 environemntal samples were collected from surfaces in the public areas of six hospitals and surrounding communities (<1 mile from the hospital) (443 samples), with a further surfaces from communities >1.5 miles from any hospital as a control (50 samples). A total of 70 GNR were identified (Figure), mostly fairly inoccousous species from a human disease viewpoint. However, some potential human pathogens were identified (Table).

Figure: breakdown of Gram-negative rods identified from surfaces in public areas of the hospital and surrounding community.GNR contam

Table: potential human pathogens identified from surfaces in public areas of the hospital and surrounding community.

n % Species
15 3.0 Acinetobacter baumannii
3 0.6 Citrobacter freundii
2 0.4 Escherichia coli
2 0.4 Stenotrophomonas maltophilia
1 0.2 Enterobacter cloacae

Some other important findings:

  • All of the A. baumannii isolates were resistant to ceftazidime, and one was resistant to imipenem (i.e. carbapenem-resistant). Eleven of the 15 were clonally related to one another and to a patient isolate from one of the hospitals.
  • One of the S. maltophilia isolates carried an integron-encoded VIM carbapenemase, which is potentially transmissible to other Gram-negative species (including Enterobacteriaceae).  
  • Each sample was cultured in an enrichment broth, and the broth was probed for the presence of a range of beta-lactamase genes (including ESBLs and carbapenemases). No beta-lactamases were detected (other than the S. maltophilia isolate). I suspect the picture would have been rather difference in New Dehli!
  • Although the survey included both surfaces in public areas of hospitals and in the community, it seems that most of the A. baumannii were identified on surfaces in the community.

So, is it a surprise to see environmental contamination with antibiotic-resistant Gram-negatvies on touch-surfaces in the community? Not really, A. baumannii in particular can survive on surfaces for ages, and ‘mimics’ Gram-positive bacteria in terms of its environmental longevity (i.e. months / years). That said, I performed a similar study looking for MRSA on touch surfaces in the community in London, and didn’t find any. More importantly, do we need to do anything about this? As the authors state, A. baumannii can be virtually impossible to eliminate from hospital surfaces without resorting to hydrogen peroxide vapour. So is it time to roll hydrogen peroxide vapour into your local Pizza Hut? Clearly not. You’d hope that cleaning and disinfection protocols, which should deal with this sort of contamination, are already established in these public places, but it would be prudent to reinforce these basic hygienic practices. Also, I agree with the authors that these findings represent and opportunity for the promotion of hand hygiene in the community.

The authors use strong words to describe NYC as ‘plagued’ with resistant Gram-negative bacteria, and a ‘dismal failure to control A. baumannii.’ If this epidemic continues, we can expect to see the focus of the problem – and the target for our interventions – shift from the acute hospital setting to encompass the community.

Prevalence survey illustrates the difference between CRE and CPE

I recently posted an article on the difference between CPE and CRE, which is neatly illustrated by a prevalence survey from Alder Hey Children’s Hospital in Liverpool. In case you didn’t read my CPE/CRE blog (shame on you), here’s a reminder of the difference between the two:

Carbapenem-resistant Enterobacteriaceae (CRE) – Enterobacteriaceae that are resistant to carbapenems by any mechanism, including the production of an acquired carbapenemase or the production of an ESBL or AmpC combined with porin loss.

Carbapenemase-producing Enterobacteriaceae (CPE) – Enterobacteriaceae that are resistant to carbapenems by means of an acquired carbapenemase.

At Alder Hey, a large children’s hospital in Liverpool, a prevalence survey was performed between September 2011 and August 2012. All clinical and screening specimens were included; rectal screens were collected on admission and weekly from all patients in the ICU and HDU. 24 patients with CRE were identified, five (21%) from clinical specimens and 19 (79%) from rectal screens. The prevalence of CRE in rectal screens was 4.5% (19/421). Four of the 19 patients identified by screening specimens only went on to develop an infection, so 9 (38%) of patients ended up with a CRE cultured from a clinical specimen.

The majority (71%) of the 24 isolates were resistant to carbapenems by AmpC or ESBL combined with impermeability; seven (29%) were CPE, 4 with NDM and three with KPC (Figure). Typing indicated that the 3/4 NDM producing Klebsiella pneumoniae isolates were clonal, and they were clustered in space and time, which may indicate a small outbreak.

CRE alder hey Figure. Composition of CRE at Alder Hey Children’s Hospital. 

Carbapenem-resistance due to the production of an ESBL or AmpC combined with porin loss may lead to treatment failure, but it is often unstable and may impose a fitness cost, meaning that these strains rarely spread. Hence, carbapenem resistance conferred by an acquired carbapenemases is the key problem. This study helps to define the prevalence of CRE (and, more importantly CPE) in the population. We are not given a denominator for the clinical specimens, so the prevalence of CRE amongst clinical specimens cannot be calculated. However, the fact that around 5% of patients admitted to ICU / HDU were carrying CRE is a concern, although the prevalence of CPE on the rectal screens was lower at 1.7% (7/421).

Currently, the prevalence and epidemiology of CRE and CPE is poorly defined in the UK so this useful prevalence survey from Alder Hey is welcome. However, we urgently need more research from other hospitals to scale the CRE problem.

Article citation: Drew et al. Emergence of carbapenem-resistant Enterobacteriaceae in a UK paediatric hospital. J Hosp Infect 2013;84:300-304.

Dissecting the CRE epidemic in Italy

Italy flagCarbapenem-resistant Enterobacteriaceae (CRE) present unique challenges to infection prevention and control. Firstly, unlike MRSA and C. difficile, CRE can be caused by multiple genetic determinants (typically KPC, VIM, NDM and OXA-48 types) in multiple species. The combination of resistance determinants and species may have distinct characteristics with transmission and control implications. Further, there is a larger pool of resistance determinants for horizontal transfer. Secondly, CRE colonize the gastrointestinal tract, so deconlonization therapy is likely to be limited to suppressing the amount of CRE in the gut; elimination of the carrier state, which has been a mainstay of prevention and control interventions for MRSA, seems unlikely. Thirdly, pan-drug resistant CRE has already been reported and the pipeline for new agents is virtually empty, meaning that effective therapeutic options will be increasingly limited.

Data from EARS-Net suggests that the prevalence of CRE among bloodstream infections is low in most parts of Europe, with a gradual year-on-year increase. In Greece though, rates are exceptionally high, with the proportion of K. pneumoniae invasive isolates resistant to carbapenems increasing from 27.8% in 2005 to 68.2% in 2011. Also, rates in Cyprus are on the rise with 0% reported in 2006 up to to 15.7% in 2011. In the UK, rates of carbapenem resistance amongst K. pneumoniae have remained consistently <1% for the same period. Disturbingly, there has been a dramatic increase in the prevalence of carbapenem-resistant K. pneumoniae in the last few years in Italy, from 1% in 2009 to 15% in 2010 to 27% in 2011.

CRE Europe [Chart: Changes in proportion of carbapenem resistance in K. pneumoniae invasive isolates. Data from EARS-Net.]

A recent Eurosurveillance article reports a national survey of carbapenem resistance in Italy. 25 laboratories across the country participated and analyzed all consecutive, non-duplicate Enterobacteriaceae clinical isolates for six weeks in mid 2011. A total of 7,154 isolates were collected from inpatients and 6,595 isolates from outpatients. The highlight findings are:

  • 3.5% of inpatient isolates and 0.3% of outpatient isolates carbapenem resistant.
  • Carbapenem-resistant K. pneumoniae (CR-KP) the most problematic CRE, with 11.9% of K. pneumoniae isolates CR.
  • Substantial geographical variation in resistance rate, ranging from 0 to 33% for CR-KP.
  • KPC accounted for 90% of CRE enzymes; one CR-KPC clone predominated (CC-258).
  • Resistance to other agents was common amongst KPC-producing K. pneumoniae; 22% were resistant/non-susceptible to colistin, 21% to tigecycline and 16% to gentamicin; 1.5% were non-susceptible to all three.

This study raises several challenging questions. What do you do with a CR-KP isolate causing an infection that is also resistant to colistin, gentamicin and tigecycline? This seems to be true pan-resistance, with supportive care the only option.

Why is KP the outstanding CRE, specifically the CC-258 clone? What does it have that the other CRE lack? K. pneumoniae seems to survive better on surfaces that other Enterobacteriaceae, and has been associated with more hospital outbreaks than other Enterobacteriaceae historically. However, further research is required to answer this question.

Can the worrying trend of CRE in Italy be reversed? An aggressive, national intervention was successful in Israel, and there are some local success stories in Italy. However, brining the situation under control in Italy will require an aggressive, national programme that must be implemented immediately. Otherwise, CR-KP will quickly become endemic and probably impossible to bring under control.

The authors should be complimented for performing a timely study, but I do wonder whether the situation is considerably worse now, 12 months later, given the shape of the national epi curve.

Citation: Giani T, Pini B, Arena F, Conte V, Bracco S, Migliavacca R, the AMCLI-CRE Survey Participants, Pantosti A, Pagani L, Luzzaro F, Rossolini GM. Epidemic diffusion of KPC carbapenemase-producing Klebsiella pneumoniae in Italy: results of the first countrywide survey, 15 May to 30 June 2011. Euro Surveill 2013;18(22):pii=20489.

Image permission: Original image obtained from