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What caused the outbreak of ESBL-producing Klebsiella pneumoniae in a neonatal intensive care unit, Germany 2009 to 2012? Reconstructing transmission with epidemiological analysis and whole-genome sequencing
  1. Sebastian Haller1,2,
  2. Christoph Eller3,4,
  3. Julia Hermes2,
  4. Martin Kaase5,
  5. Matthias Steglich3,
  6. Aleksandar Radonić6,
  7. Piotr Wojtek Dabrowski7,
  8. Andreas Nitsche6,
  9. Yvonne Pfeifer3,
  10. Guido Werner3,
  11. Werner Wunderle8,
  12. Edward Velasco2,
  13. Muna Abu Sin2,
  14. Tim Eckmanns2,
  15. Ulrich Nübel3,9
  1. 1Postgraduate Training for Applied Epidemiology, Berlin, Germany, affiliated to the European Programme for Intervention Epidemiology Training, European Centre for Disease Prevention and Control, Stockholm, Sweden
  2. 2Division of Healthcare-Associated Infections, Surveillance of Antimicrobial Resistance and Consumption, Department for Infectious Disease Epidemiology, Robert Koch Institute, Berlin, Germany
  3. 3Division of Nosocomial Pathogens and Antibiotic Resistances, Department for Infectious Diseases, Robert Koch Institute, Wernigerode, Germany
  4. 4Department of Laboratory Medicine, University Hospital Halle, Halle, Germany
  5. 5Department of Medical Microbiology, Ruhr-University Bochum, Bochum, Germany
  6. 6Centre for Biological Threats and Special Pathogens, Highly Pathogenic Viruses, Robert Koch Institute, Berlin, Germany
  7. 7Central Administration Department, Information Technology, Robert Koch Institute, Berlin, Germany
  8. 8Department of Public Health, Gesundheitsamt Bremen (Local Public Health Service), Bremen, Germany
  9. 9DZIF Group on Microbial Genome Research, Leibniz Institute DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen), Braunschweig, Germany
  1. Correspondence to Dr Sebastian Haller; HallerS{at}


Objective We aimed to retrospectively reconstruct the timing of transmission events and pathways in order to understand why extensive preventive measures and investigations were not sufficient to prevent new cases.

Methods We extracted available information from patient charts to describe cases and to compare them to the normal population of the ward. We conducted a cohort study to identify risk factors for pathogen acquisition. We sequenced the available isolates to determine the phylogenetic relatedness of Klebsiella pneumoniae isolates on the basis of their genome sequences.

Results The investigation comprises 37 cases and the 10 cases with ESBL (extended-spectrum beta-lactamase)-producing K. pneumoniae bloodstream infection. Descriptive epidemiology indicated that a continuous transmission from person to person was most likely. Results from the cohort study showed that ‘frequent manipulation’ (a proxy for increased exposure to medical procedures) was significantly associated with being a case (RR 1.44, 95% CI 1.02 to 2.19). Genome sequences revealed that all 48 bacterial isolates available for sequencing from 31 cases were closely related (maximum genetic distance, 12 single nucleotide polymorphisms). Based on our calculation of evolutionary rate and sequence diversity, we estimate that the outbreak strain was endemic since 2008.

Conclusions Epidemiological and phylogenetic analyses consistently indicated that there were additional, undiscovered cases prior to the onset of microbiological screening and that the spread of the pathogen remained undetected over several years, driven predominantly by person-to-person transmission. Whole-genome sequencing provided valuable information on the onset, course and size of the outbreak, and on possible ways of transmission.


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