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Int J Antimicrob Agents. 2018 Jun;51(6):867-874. doi: 10.1016/j.ijantimicag.2018.01.015. Epub 2018 May 22.

Whole-genome sequencing enabling the detection of a colistin-resistant hypermutating Citrobacter werkmanii strain harbouring a novel metallo-β-lactamase VIM-48.

Author information

1
Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany; German Center for Infection Research (DZIF), partner site Tübingen, Tübingen, Germany. Electronic address: silke.peter@med.uni-tuebingen.de.
2
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
3
Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany; German Center for Infection Research (DZIF), partner site Tübingen, Tübingen, Germany.
4
Medical Center, Department of Hematology, Oncology, Immunology, Rheumatology & Pulmonology, University of Tübingen, Tübingen, Germany.
5
Medical Center, Department of Hematology, Oncology, Immunology, Rheumatology & Pulmonology, University of Tübingen, Tübingen, Germany; Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), partner site Tübingen, Tübingen, Germany.

Abstract

Citrobacter spp. harbouring metallo-β-lactamases (MBLs) have been reported from various countries and different sources, but their isolation from clinical specimens remains a rare event in Europe. MBL-harbouring Enterobacteriaceae are considered a major threat in infection control as therapeutic options are often limited to colistin. In this study, whole-genome sequencing was applied to characterise five clinical isolates of multidrug-resistant Citrobacter werkmanii obtained from rectal swabs. Four strains possessed a class 1 integron with a novel blaVIM-48 MBL resistance gene and the aminoglycoside acetyltransferase gene aacA4, whilst one isolate harboured a blaIMP-8 MBL. Resistance to colistin evolved in one strain isolated from a patient who had received colistin orally for 8 days. Genomic comparison of this strain with a colistin-susceptible pre-treatment isolate from the same patient revealed 66 single nucleotide polymorphisms (SNPs) and 26 indels, indicating the presence of a mutator phenotype. This was confirmed by the finding of a SNP in the mutL gene that led to a significantly truncated protein. Additionally, an amino acid change from glycine to serine at position 53 was observed in PmrA. Mutations in the pmrA gene have been previously described as mediating colistin resistance in different bacterial species and are the most likely reason for the susceptibility change observed. To the best of our knowledge, this is the first description of a colistin-resistant Citrobacter spp. isolated from a human sample. This study demonstrates the power of applying next-generation sequencing in a hospital setting to trace and understand evolving resistance at the level of individual patients.

KEYWORDS:

Colistin resistance; IMP; Mutator phenotype; Next-generation sequencing; VIM

[Indexed for MEDLINE]

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