Carbapenem-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.
[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 http://www.freestock.ca.
Reflections on Infection Prevention and Control 
Do we know if this ST is widely present without carbapenem resistance? By analogy with ST131 in E coli you might expect that it would be and it is worth noting that ST131 was not present in an ST study of archived E coli bacteraemia in Paris prior to 2003. These new and endemic strains appear to sometimes come out of nowhere but of course when prevalence rises so rapidly one must consider an obscure common source as well as cross-infection. At an early stage a fully documented open food history in the last 6 months to a year to determine non-eaten products and examination of water sources before they become contaminated from human endemicity might offer clues
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Rod, thanks very much for this comment.
It seems to me that CC258 K. pneumoniae was rarely if ever reported since 2009 and always seems to be associated with KPC production. There is evidence of spread from Greece, to Europe and then to the USA and elsewhere.
There is perhaps a parallel with S. aureus and MRSA. In general, successful MRSA lineages seem to have arisen from successful MSSA lineages. However, there is a distinct difference between the molecular types causing MRSA and MSSA infections, with MSSA infections having considerably more genetic diversity. I expect to see a similar picture developing with CRE. Successful clones will emerge from circulating clones.
Interesting point about the possibility of a common source. I would say that areas of local high prevalence argue for cross-transmission. You’d expect to see a more sporadic picture if there was an obscure common source.
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Jon ! This is really bad news to hear about the CRE Epi in Italy. We should first look at the trend the way Italian Physicians use antimicrobials particularly in focused areas or region of CRE resistance. Although now this is not just an Italian issue it is a global public health issue which healthcare community and Health Authorities need to focus on. Because if the big guns stop working and the superbugs (KP) shows stubbornness then it is a real threat. Few years back when we used to hear about ESBL responding only to Carpenems I was really worried at that time that something soon would happen next that this important weapon would soon get resistance against ESBL and that what actually happened hence an ESBL leads to CRE. It is true that the world is very small global village anything arise anywhere sooner or later spread everywhere.
Jon, again I would say Physician’s prescribing behavior is what we need to address. This is an unending story but solution to the problem is in our hands. Healthcare Organization needs to have qualified Infection Control Physicians with back ground in Microbiology and ID can, to considerable degree lessen this problem helping our treating physicians manage their cases well with these big guns in order to save it for our future. One time I receive a call from a treating Physician that that the culture grew an MDRO isolate but with pan-resistant so he was asking me what to do for the patient. I asked him please STOP all antibiotics for 72 hours and lets see what happens. Later we found out patient was improving without antibiotic on 3rd day and was afebrile. Just saying this that the problem is in our own hands and concept about Antibiotic usage based on C/S and the way we interpret it. But the good thing was that physicians were very cooperative which really helped us reduce antibiotic resistance in critical patients. There are so many precious tools for appropriate antibiotic use on the net we should make good use of it.
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Fida, I agree that we need to tighten antibiotic prescribing practice and culture. But I fear that restricting the use of carbapenems will not prevent the continue emergence of CRE. I would expect to see more CRE outbreaks even if prescribing practices improve. However, there is a chance we can stop CRE from becoming endemic if we act now to improve surveillance, infection control and antibiotic abuse.
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