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Hospital hygiene faces cross-cutting and methodological challenges that are time consuming and require specialised knowledge. In outbreak situations German federal states can request assistance from infectious disease epidemiologists at the Robert Koch Institute (RKI). The presented study describes the successful collaboration of local hygienists, microbiologists, clinicians, health authorities and the epidemiologists of the RKI in the investigation of an outbreak of multidrug-resistant Enterobacter (E.) cloacae in 2009 in a children's hospital. The outbreak was discovered in July 2009 when E. cloacae was detected in 12 patients in the neonatal and paediatric intensive care unit (NICU). Hygiene measures were intensified for infection control, and the RKI was invited by the responsible regional health authorities in October 2009 to assist in the outbreak investigation. We conducted a retrospective matched case-control study to identify risk factors for E. cloacae colonisation and infection. We identified a case as any child in the NICU from 1st May to 5th October 2009 with laboratory confirmation of the outbreak clone. Controls were patients staying in the NICU (> 72 h before the case's diagnosis) and swab-negative for the outbreak clone. We used standardised questionnaires to collect demographic and medical information. Matched odds ratios (mOR) were calculated by bivariate and multivariable conditional logistic regression. Environmental investigations were conducted. We identified 28 colonised and 3 bacteraemic cases. 29 matched case-control pairs were included in the study. Multivariable analysis revealed an association between E. cloacae diagnosis and the receipt of oral drugs at the bed-side from multidose packaging (mOR=1.8/drug; p=0.006). No specific drug was identified; microbiological investigation of drugs was negative. This multiresistant E. cloacae outbreak was most likely distributed by oral application using contaminated multidose drug packaging extrinsically contaminated via hands of personnel. No further cases occurred for 6 weeks after protocols for handling oral drugs were changed (smaller packaging, patient-based storage, and limited circulation time). Special attention and thorough hygiene protocols are needed for the distribution of oral medication. In NICUs the use of multi-dose medications should be avoided. The cooperation between locally available expertise and infectious disease epidemiologists enabled the discovery of a previously unidentified risk factor., (© Georg Thieme Verlag KG Stuttgart · New York.)