No 10 - 2012

Carbapenem resistant enterobacteria

Carbapenems (doripenem, ertapenem, meropenem) are betalactam antibiotics of a very broad spectrum including nearly all gram-positive and gram-negative bacteria, aerobic as well as anaerobic. Carbapenems is one of the only classes of antibiotics that can be used for treatment of infections with heavily multi-resistant bacteria such as ESBL-producing Klebsiella pneumoniae. Frequently, no or only suboptimal antibiotics (tigecycline, colistin) are available in the treatment of infections with carbapenem-resistant enterobacteria (CPE). Resistance is caused by the presence of various carbapenemases of which the most frequently occurring are K. pneumoniae carbapenemase (KPC), Oxacillinase β-lactamase (OXA), Verona integron-encoded metallo-β-lactamase (VIM) and New Delhi metallo-β-lactamase (NDM).

The genes that encode these enzymes are often transferable and can therefore spread from bacterium to bacterium (horizontal spreading) as well as via clonal (vertical) spreading. In particular, this is the case for KPC and OXA-producing K. pneumoniae. Recently, major outbreaks including these were reported from Holland, Italy and Poland. Additionally, VIM and KPC-producing bacteria occur endemically in Greece. The occurrence of NDM is particularly high in Pakistan and India, but cases have been reported from nearly all parts of the world.

CPE carrier state

CPE (and other multi-resistant enterobacteria) comprise a particular problem as they can be carried in the intestine without causing symptoms. There are no documented methods to cure such carrier state. Antibiotic treatment may contribute to sustain the carrier state and lead to multiplication and increased excretion. Particularly in hospitals and nursing homes, this may cause problems. India has now also reported a high prevalence of NDM-1-producing bacteria in the community and expectedly many Danes returning from e.g. India will carry CPE in their intestinal flora.

CPE Screening

The ECDC (European Centre for Disease Prevention and Control) and the CDC (Centers for Disease Control) in the USA recommend CPE-screening in patients transferred from hospitals abroad and patients suspected of forming part of an outbreak. Carbapenem resistance can be detected phenotypically (viz. through resistance testing), but confirmation requires molecular-biological methods, which also facilitates characterization of the enzyme type.

Danish CPE cases

Currently, Denmark does not systematically screen and monitor CPE, however, in recent years Danish departments of clinical microbiology have, on a voluntary basis, submitted CPE isolates for verification and gene typing at Statens Serum Institut which has at its disposal methods facilitating the detection of the most common CPE genes. 

Table 1 presents the 15 cases of CPE detected in Denmark since 2008.

2008 saw the first case of VIM-producing K. pneumoniae ever detected in Denmark, and 2010 brought another case. Both patients had previously been admitted to hospital in Greece. In 2009, the first cases of KPC-2-producing K. pneumoniae were observed. These cases had also been admitted to Greek hospitals. 2010 brought the first Danish case of NDM-1, EPI-NEWS 46/10. The patient had been admitted to hospital in Bosnia-Herzegovina and was one of the first NDM-1 cases in Europe to be linked to the Balcans.

In 2011, another two cases of NDM-1 were found. One was linked to Egypt, the other to Pakistan. Furthermore, 2011 saw seven cases of OXA-48 in patients from Libya. All 15 cases of CPE have thus been detected in connection with screenings. None of the patients had symptomatic infections; all were carriers of the bacteria. With the exception of one case, the known Danish CPE cases were all imported. There is no knowledge of secondary spreading at Danish hospitals or nursing homes.

Commentary

Of the 15 CPE cases observed in Denmark in the 2008-11-period, ten were detected in 2011 and most of these were imported from Libya. The increasing occurrence of CPE in Europe and now also in Denmark is worrying. Not only are these infections extremely difficult to treat with antibiotics, the bacteria also carry the potential to establish and spread endemically at hospitals and in the community. This is in line with what was previously seen for ESBL-producing bacteria. Due to the seriousness of this issue, the ECDC encourages systematic monitoring of these bacteria in all European countries.

It is essential to be particularly aware of any occurrence of multi-resistant enterobacteria in patients transferred after admission to hospitals abroad.

(A. M. Hammerum, F. Hansen, B. Kristensen, Dept. for Microbiological Monitoring and Research, R.C Dessau, DCM Slagelse, D.S. Hansen, DCM Hillerød, K. Fuursted, DCM, Aarhus University Hospital, Skejby, U.S. Justesen, B. Gahrn-Hansen, DCM, Odense University Hospital, K. Schønning, P. Littauer, A. Friis-Møller, J.B. Nielsen, DCM, Hvidovre Hospital, H. Schønheyder, DCM, Aalborg Hospital, Aarhus University Hospital)