Carbapenemase_producing_K__pneumoniae__ST258_. Carbapenemase_producing_K__pneumoniae__ST258_

Since 21/9/17 a cluster of nine patients colonised by a novel Klebsiella pneumoniae ST258 variant has been detected at a tertiary care London teaching hospital with over 1500 beds across 3 sites. Seven acquisitions are linked to the surgical intensive care unit (SITU) and 2 are linked to secondary transmission in the coronary care unit. The ST 258 K. pneumoniae has been reported in literature to cause extensive outbreaks. It’s association with the carbapenemase KPC has been of concern as it confers resistance to a number of commonly used broad spectrum antibiotics, albeit some antibiotics remain effective notably gentamicin , Colistin (although COL-R variants of ST258 and its SLVs have been reported and are widespread in e.g. Italy) and the recently licensed novel inhibitor combination Ceftazidime-avibactam (CAZ-AVI). However this novel strain is, we believe, unique globally because it has acquired an OXA-48-like carbapenemase in addition to the KPC and it also exhibits high level resistance to ALL aminoglycosides because it has acquired the ArmA 16S rRNA methyltransferase. Especially concerning is that sensitivity to CAZ-AVI is good for most KPC or OXA-48 harbouring bacteria, but many isolates of this novel strain are resistant or have only borderline susceptibility to CAZ-AVI. These findings have been confirmed by molecular testing and reference antimicrobial sensitivity testing at Colindale. CAZ-AVI resistance may be selected in KPC producers in vitro and has been linked with mutations in the omega loop of the KPC enzyme, which serve to enhance ceftazidimase activity, while reducing carbapenemase activity; in consequence, bacteria with these mutant KPC enzymes regain susceptibility to meropenem. The same mutant KPC enzymes have now been described in bacteria isolates from cases of CAZ-AVI clinical failure in the USA. We urgently need to understand the mechanisms of CAZ-AVI resistance in these UK isolates, which represent the first hospital ‘outbreak’ (albeit of colonization) of CAZ-AVI KPC producers. In contrast to lab mutants and clinical isolates with omega loop changes, these London isolates remain highly resistant to carbapenems. Additional cases which maybe relevant to understanding the molecular basis of this outbreak and evolution of resistance 1. Two months prior to the detection of the first case a patient had been admitted for a long time in the SITU with blaKPC K.pneumoniae ST 258 (detected 24/7/2017). This patient was later found to have a blaOXA-48 E. coli on 11/09/2017 albeit on a different ITU. 2. One subsequent patient also had blaOXA-48 E. coli in addition to blaKPC blaOXA-48 K.pneumoniae ST 258. 3. One has had a mixture of blaKPC K.pneumoniae ST 258 and blaKPC blaOXA-48 K. pneumoniae ST 258. 4. One patient was detected with blaKPC K.pneumoniae ST 258 around the time of the outbreak but not epidemiologically linked to the outbreak. 5. Environmental samples were taken as part of outbreak investigations and three sinks were found colonised with blaKPC blaOXA-48 K.pneumoniae ST 258. PUBLIC HEALTH URGENCY: This outbreak involves a novel variant of K. pneumoniae ST258, which is recognised internationally as a high-risk clone (HiRiC) and has established outbreak potential, and is capable of national spread. The novel variant produces two different carbapenemases and has enhanced antimicrobial resistance; it is resistant even to the newly-licensed agent ceftazidime-avibactam, ruling out a further treatment option. Understanding the molecular characteristics of these strains is crucial to prevent onward spread, for directing resources, predictive antimicrobial sensitivity and surveillance reporting. 1) This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute please see http://www.sanger.ac.uk/datasharing/