Briefing on ESBLs, CREs and other carbapenem-resistant organisms

There is currently a lot of interest in a group of bacteria collectively called “multidrug-resistant Gram-negative rods (MDR-GNR)”. This is a mixed group of various bacterial species and genera, with resistance to a variety of antibiotics. The flow-chart below illustrates the key groups. (Click image to enlarge.)


Enterobacteriaceae and non-fermenters
There are two families of Gram-negative bacteria that
are resistant to key antibiotics: the Enterobacteriaceae
and non-fermenters. The Enterobacteriaceae
(If you want to know how to pronounce ‘Enterobacteriaceae’, this should help), including Klebsiella pneumoniae and E. coli, are the big concerns:

-    Enterobacteriaceae can be highly resistant to antibiotics
-    Enterobacteriaceae are able to spread rapidly
     within a healthcare environment
-    Enterobacteriaceae have the potential to
     establish a community reservoir
-    Enterobacteriaceae invasive infections
     have a high mortality.

A person with carbapenem resistance who is infected with Enterobacteriaceae has a 50% change of dying. The non-fermenters include Acinetobacter and
Pseudomonas. Although these bacteria typically have a high level of antibiotic resistance they are not that pathogenic and are rarely fatal. Therefore, the resistant Enterobacteriaceae
are the real concern.

Resistant Enterobacteriaceae: CRE and ESBL

Both carbapenemases and extended-spectrum beta-lactamases (ESBL) are enzymes produced by bacteria to break down (“hydrolyse”) beta-lactam antibiotics. These enzymes occur within the Enterobacteriaceae bacterial family, which includes E. coli and Klebsiella. They can cause infections such as UTIs, SSIs and BSIs, and can also colonise the gut without causing symptoms. Enterobacteriaceae that are resistant to carbapenems by any mechanism are called carbapenem-resistant Enterobacteriaceae (CRE) (those that produce carbapenemases are called ‘carbapenemase-producing Enterobacteriaceae’ (CPE)) and Enterobacteriaceae that produce ESBL enzymes are called ‘ESBLs’.
ESBLs produce an extended spectrum enzyme than breaks down and destroys most of the beta-lactams antibiotics such as penicillin and cephalosporins. But ESBLs have no effect on carbapenems (e.g., meropenem), the remaining beta-lactam antibiotic, so carbapenems are used to treat ESBLs.
Now we are seeing the bacteria product stronger  beta-lactamases (carbapenemases) and these break down and destroy the remaining beta-lactam, carbapenem. So CREs are much stronger and more serious because few, if any, antibiotics are left to treat these.

Acronyms – CRO, CPO, CRE, CPE

All the acronyms start with CConfused
This is based on a type of very strong antibiotic called carbapenem. It is delivered intravenously and has always had a very effective broad spectrum of activity against all bacteria. Now we are starting to see Gram-negative bacteria (also Gram-positive but the worry is around the Gram-negatives) becoming resistant to the carbapenem antibiotics which often means they are resistant to all other types of antibiotics. In the acronyms below, C refers to either the ‘carbapenem’ antibiotic itself, or the ‘carbapenemase’ enzyme that breaks it down.

P or R
P = producing and R = resistant
P is always twinned with carbapenemase (i.e. carbapenemase-producing) and R is always twinned with carbapenem (i.e. carbapenem-resistant). Put another way, you can’t have ‘carbapenemase-resistant’ or ‘carbapenem-producin.

O or E
O = organism and E = Enterobacteriaceae
If you wish to refer to the Enterobacteriaceae use ‘E’. If you wish to refer to a wider group of bacteria encompassing both the Enterobacteriaceae and non-fermenters, use ‘O’.

Putting it all together

Carbapenem-resistant organism (CRO)
These are all organisms (non-fermenters and Enterobacteriaceae) resistant to carbapenems by a variety of ways – some by mutation, some inherent and some by producing a carbapenemase enzyme that breaks down the antibiotic.

Carbapenemase-producing organism (CPO)
These are all organisms (non-fermenters and Enterobacteriaceae) resistant to carbapenems by producing carbapenemase enzymes that break down the antibiotic. CPO are a subset of CRO.

Carbapenem-resistant Enterobacteriaceae (CRE)
Enterobacteriaceae that are resistant to carbapenems by a variety of ways – some by mutation, some inherent and some by producing a carbapenemase enzyme that breaks down the antibiotic.

Carbapenemase-producing Enterobacteriaceae (CPE)
Enterobacteriaceae that are resistant to carbapenems by producing carbapenemase enzymes that break down the antibiotic. CPE are a subset of CRE. The PHE Toolkit uses the term ‘carbapenemase-producing Enterobacteriaceae’.

Risk of CRE infections
(click the image to enlarge)

How CRE take over CRE_infection-journey2-web


Could a daily squirt of quat improve hospital hygiene?

A study from China has evaluated the impact of a daily spray of a QAC polymer as an adjunct to wiping with bleach. The study was performed on a ward with some MRSA-positive and MRSA-negative. The study design was neat, with bed spaces sampled at 0800 and 1200, with or without the application of the QAC polymer (although it's a shame they didn't randomise the intervention). It's fair to say the paper is "data rich", so pulling out the key findings is challenging, but here goes:

– 56% of bed spaces were contaminated with MRSA, at a concentration of 1-276 cfu/cm^2
– No MRSA was identified on surfaces in the QAC polymer spray arm
– The proportion of sites yielding staphylococci was 78% in the control arm, and 11% in the QAC polymer spray arm.

This study is impressive in terms of the reduction of bacterial contamination. Clearly, there is no clinical outcome, which would require a much more extensive study. But I would expect this degree of reduction in environmental contamination to make some impact on ongoing transmission.

There are a few practical challenges to consider though when using this sort of product.

spray– Is it safe to apply? The authors cite that the product is 98% water so should generate no dangerous aerosols. But surely a dangerous aerosol could be created from the 2% active ingredients, mindful of the fact that aerosolisation of QAC disinfectants was outlawed by the US CDC in the 1970s on safety grounds.
– Would this be applied around an inpatient? How wet does it make the surfaces, and how long does it take to dry?
– How labour-intensive is the application, and how much do you rely on the operator to assure complete coverage?
– How much does it cost?
– Is it really feasible to spray every surface in every ward once per day?
– How would this approach (spraying a quat and using bleach) compare with using a disinfectant that already has a quat in it?

Leaving practical questions aside, there is some promise in this sort of approach. And we need to continue to explore the potential of antimicrobial surfaces to augment hospital hygiene.



There has been much coverage in the media this week for a new paper in the American Journal of Infection Control from the Cardiff group under the leadership of Prof Jean-Yves Maillard. We blogged on the detail of this paper last week, but in summary the paper demonstrated variability in the ability of a range of detergent wipes to remove bacteria and spores from surfaces. NHS Choices has a more balanced view of this paper than the rather sensationalist reporting elsewhere.

Most headlines have suggested that nurses are spreading superbugs around the ward by using wet wipes. The study shows that detergent wipes do not remove pathogens from surfaces in significant numbers. This is not a new finding and hardly surprising as a detergent wipe aims to be the first step in the cleaning process and is not a disinfection stage on its own. Also, it's worth noting that the risk of spreading germs using detergent is not restricted to wipes - this has been reported for "mop and bucket" type application of detergent also. So, would you see the same results with a disinfectant wipe? The answer is no, since disinfectant wipes are formulated to remove dirt and kill microbes in a single step.

The key difference between a detergent and a disinfectant wipe is that pathogens not removed by the wiping action will be destroyed by the action of the disinfectants contained within the wipe. It is also important to use combined disinfectant and detergent wipes as Disinfectant Wipes that do not contain any form of detergent will have only limited cleaning properties and so the disinfectants may not be effective.


The silent burden of neonatal C. difficile colonisation and contamination

baby_nappyWe worry often about asymptomatic colonisation (aka 'silent carriage') of a range of hospital pathogens – MRSA, VRE, CRE – but not C. diff. Screening for C. diff colonisation in the absence of diarrhoea is rarely performed. One of the interesting nuances of C. diff ecology is the high rate of colonisation in babies.

A US study surveyed the rate of asymptomatic C. diff carriage and environmental contamination in a neonatal intensive care unit (NICU). 9 (26%) of the 35 babies sampled were asymptomatic carriers, which is no surprise and in line with other studies. The levels of environmental contamination identified were actually pretty low. Only 2 (1.7%) of 120 sites sampled yielded C. diff in samples collected from the NICU, paediatric units and a haematology / oncology unit. More focussed sampling in the NICU did identify a higher rate environmental contamination – with half of the 'diaper' (aka nappy) scales contaminated.

It's not clear why the levels of environmental C. diff identified in this study were lower than in others. Perhaps the hospital had C. diff pretty much under control? Perhaps the lab methods were not optimal? Either way, the levels of contamination identified in the NICU are consistent with the levels of asymptomatic colonisation, and a potential risk for onward transmission.

So, should we start routinely sampling patients without diarrhoea for C. diff carriage? Should we start routinely sampling their environment? The jury is out on these questions, but asymptomatic carriers of C. diff can certainly be a source of environmental contamination.



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