Project GÜCCI - Genome-based surveillance of transmissible colistin and carbapenem resistances of Gram-negative pathogens (2019-2021)

The team in GÜCCI (from left to right): Prof. Dr. Lothar Kreienbrock (TiHo), Dr. Yvonne Pfeifer (RKI), Dr. Jörg Hans (RUB), Dr. Niels Pfennigwerth (RUB), Dr. Jens Andre Hammerl (BfR), Prof. Dr. Sören Gatermann (RUB), Dr. Katja Hille (TiHo), Prof. Dr. Guido Werner (RKI) (persons missing: Dr. Bernd Neumann, RKI; Prof. Dr. Annemarie Käsbohrer, BfR)

Infections with multiple and carbapenem-resistant Enterobacteriales (CPE like E. coli, Klebsiella pneumoniae, etc.) are feared complications, especially in hospitalized, seriously ill and elderly patients. Such infections can be associated with an increased disease burden and mortality, and also hardly allow for therapeutic alternatives. In at least half of the carbapenem-resistant E. coli and K. pneumoniae isolates, resistance is mediated by enzymes called carbapenemases. The genes for this are often located on transferable plasmids, which are disseminated both clonally (by cell division) and by gene transfer, including transfer across species and genus boundaries (horizontal gene transfer).

The antibiotic colistin is an important therapeutic option for infections with CPE. During the course of therapy, colistin can lose its efficacy owing to the selection of resistant bacteria, but also to the acquisition of resistance genes of the mcr type. The relevant and so far known genes mcr-1 to mcr-8 are mostly localized on plasmids that are transferable between bacterial isolates of different species and genera.

In Germany, the reservoir of transmissible carbapenem resistance is found in the area of stationary, human medical care, where clusters of infections and colonisations with CPE occur epidemically. In recent years, CPE have been detected occasionally in farm animals, in hobby animals and in food; there has also been evidence in environmental samples.

The reservoir of mcr-mediated colistin resistance is found in farm animals and is associated with the use of this drug. First studies from Germany showed a wide spread of mcr-mediated colistin resistance in E. coli in farm animals. In contrast, there is little evidence of mcr-mediated colistin resistance in human enterobacterial isolates. However, the detection of colistin resistance in human clinical isolates is incomplete, as it is usually only tested in the presence of carbapenem resistance. In addition, there are methodological difficulties in recording resistance using standard microbial diagnostic procedures.

On the one hand, the available data illustrate the possibilities of the spread of both resistance determinants via clonal transmission and horizontal gene transfer. On the other hand, the cross-sectoral dimension of this One Health problem becomes apparent, offering a clear lack of coordinated action and investigation as well as of additional epidemiological information for understanding resistance transfer.

Besides the characterization of the isolates and their resistance properties, the epidemiological information collected in parallel is of great importance. This is particularly important for the tracing of an outbreak. However, such information is also essential when it comes to the question of the origin of sporadic infection or resistance transfer. Therefore, it seems to be imperative that the metadata belonging to the samples are extended in the data entry routine beyond the previous level (usually sample source, sampling location and sampling date). It is desirable to harmonize the procedures here as well (e.g. by means of appropriate catalogs).

 The main objectives of GÜCCI are

1. the evaluation of complex outbreak scenarios with a focus on horizontal resistance transfer, including the results of modern sequence-based typing techniques
2. the derivation of generally applicable standards and essential prerequisites for a valid data evaluation,
3. an identification of favorable factors and obstacles to their immediate implementation;
4. the development of strategies for combining clinical epidemiological information with genome data; and
5. a transfer of knowledge to the qualified professional public.

In a cross-sectoral approach, two selected antibiotic resistances with very high public health relevance are being addressed. The aim is to gain scientific knowledge with a direct public health relevance, i.e. to better assess the risk potential

1. mcr-mediated colistin resistance in animal and food isolates and its relevance for human pathogenic isolates, and
2. carbapenemase-producing Enterobacteriales in animals and food as a possible reservoir of resistance development in human isolates.

In addition, the project will serve as a model for the urgently needed implementation of a core technology for genome-based pathogen and resistance surveillance in leading institutions of public health and veterinary public health and for epidemic evaluation and assessment.

Coordinator: Robert Koch Institute, Wernigerode Branch, Department of Infectious Diseases, Division Nosocomial Pathogens and Antibiotic Resistances, Wernigerode, Germany

Partner 1: Federal Institute for Risk Assessment (BfR), Department of Biological Safety, Division Epidemiology, Zoonoses and Antibiotic Resistance, Berlin, Germany

Partner 2: Ruhr-University Bochum, Department of Medical Microbiology, National Reference Centre for Multidrug-resistant bacteria, Bochum, Germany

Partner 3: Institute for Biometry, Epidemiology and Information Processing, Foundation of the University of Veterinary Medicine Hannover, Hannover, Germany

Funding period: 2019 – 2021

Funding: Federal Ministry for Health (BMG)

Relevant references:

Weber RE, Pietsch M, Frühauf A, Pfeifer Y, Martin M, Luft D, Gatermann S, Pfennigwerth N, Kaase M, Werner G, Fuchs S. IS26-mediated transfer of bla_NDM-1 as the main route of resistance transmission during a polyclonal, multispecies outbreak in a German hospital. Frontiers in Microbiology 2019, 10: 02817 (doiDigital Object Identifier: 10.3389/fmicb.2019.02817)

Irrgang A, Tenhagen BA, Pauly N, Schmoger S, Kaesbohrer A, Hammerl JA. Characterization of VIM-1-producing E. coli isolated from a German fattening pig farm by an improved isolation procedure. Front Microbiol 2019 Oct 1;10:2256. (doi: 10.3389/fmicb.2019.02256. eCollection 2019)

Pfennigwerth N, Kaminski A, Korte-Berwanger M, Pfeifer Y, Simon M, Werner G, Jantsch J, Marlinghaus L, Gatermann S. Evaluation of six commercial products for colistin susceptibility testing in Enterobacterales. Clin Microbiol Infect 2019 May 28 (pii: S1198-743X(19)30119-3. doi: 10.1016/j.cmi.2019.03.017)

Becker L, Kaase M, Pfeifer Y, Fuchs S, Reuss A, von Laer A, Abu Sin M, Korte-Berwanger M, Gatermann S, Werner G. Genome-based analysis of carbapenemase-producing Klebsiella pneumoniae isolates from German hospital patients, 2008-2014. Antimicrob Resist Infect Control 2018 May 2;7:62. (doi: 10.1186/s13756-018-0352-y. eCollection 2018)

Hammerl JA, Borowiak M, Schmoger S, Shamoun D, Grobbel M, Malorny B, Tenhagen BA, Käsbohrer A. mcr-5 and a novel mcr-5.2 variant in Escherichia coli isolates from food and food-producing animals, Germany, 2010 to 2017. J Antimicrob Chemother. 2018 May 1;73(5):1433-1435 (doi:10.1093/jac/dky020)

Hille K, Roschanski N, Ruddat I, Woydt J, Hartmann M, Rösler U, Kreienbrock L. Investigation of potential risk factors for the occurrence of Escherichia coli isolates from german fattening pig farms harbouring the mcr-1 colistin resistance gene. International Journal of Antimicrobial Agents. 2018; 51(2): 177-180 (doi: 10.1016/j.ijantimicag.2017.08.007)

Becker L, Fuchs S, Pfeifer Y, Semmler T, Eckmanns T, Korr G, Sissolak D, Friedrichs M, Zill E, Tung M-L, Dohle C, Kaase M, Gatermann S, Rüssmann H, Steglich M, Haller S, Werner G. Whole genome sequence analysis of CTX-M-15-producing Klebsiella isolates allowed dissolving a supposed outbreak scenario and deducing a strain-specific triplex PCR. Frontiers in Microbiology. (2018) 9: 322 (doi: 10.3389/fmicb.2018.00322)

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