DETECTIVE: Dissemination and resistance mechanisms of carbapenem-resistant Gram-negative bacilli

Modern genomic technologies and development of genome analysis tools have been successfully applied to improve our understanding of the emergence, spread, short term evolution, and transmission of clinically important MDR bacteria. Genomic analysis has allowed us to determine with fine scale resolution the role played by inter-hospital patient transfer in national and international dissemination of MDR pathogens. It has allowed us to determine the selective forces which drive the evolution of MDR pathogens in the hospital and within patients and the clinical impact this can impose. Genomic analysis has also been used to identify outbreaks, potential sources of outbreaks, and inform successful interventions to bring an end to outbreaks within hospitals.
The scale of the MDR problem in Chinese hospitals is reaching alarming levels. The incidence of morbidity and mortality associated with MDR infections in China has grown year-on-year in the 21st century. Most alarming is the rise in the incidence of infections caused by A. baumannii, E. coli and K. pneumoniae which are resistant to carbapenems, that last line of antibiotics available to treat infections with MDR pathogens. The national CHINET network of clinical microbiology laboratories of 34 sentinel hospitals across China (www.chinets.com) report that in 2017, E. coli, K. pneumoniae and A. baumannii were the top three bacterial species recovered from clinical samples. There were 13,337 known cases of carbapenem resistant A. baumannii (69.3% carbapenem resistance prevalence), 6,434 cases of carbapenem resistant K. pneuomoniae (23% carbapenem resistance prevalence), and 845 cases of carbapenem resistant E. coli (2.3% carbapenem resistance prevalence). It is therefore vital that genomic level investigations of these bacteria are implemented in China immediately, to allow the breakthroughs in understanding transmission, spread, and infection control that have been afforded in the Western world.

The proposed research to be conducted by the network will be organised around three independent but inter-connected projects:

1) Investigate the reservoirs and routes of transmission of carbapenem resistant K. pneumoniae

2) Investigate the community carriage dynamics of carbapenem resistant E. coli leading to the continuous introduction of strains into hospitals and subsequent infections.

3) Investigate the reservoirs and routes of transmission of carbapenem resistant Acinetobacter baumannii.

The proposed research to be conducted by the network will be organised around three independent but inter-connected projects:

1) Investigate the reservoirs and routes of transmission of carbapenem resistant K. pneumoniae

2) Investigate the community carriage dynamics of carbapenem resistant E. coli leading to the continuous introduction of strains into hospitals and subsequent infections.

3) Investigate the reservoirs and routes of transmission of carbapenem resistant Acinetobacter baumannii.

Each project will implement a deep sampling protocol where all ICU patients in our three partner hospitals, the ICU environment and ICU staff will be sampled for carriage of carbapenem resistant strains in our three target pathogens. All isolates will be genome sequenced by our partner hospitals using Illumina sequencing platforms. Data will be collated and analysed via dedicated CLIMB servers to allow us to investigate connected networks of these AMR pathogens in the Chinese clinical setting, and model transmission and dissemination routes. We will also implement the MinIon platform in the partner hospitals allowing us to develop real-time genomic epidemiology of AMR pathogens within the Chinese hospitals. And we will utilise the extensive data set we produce to perform a GWAS investigation of uncharacterised genetic loci which enhance MIC levels to carbapenem drugs beyond know carbapenemase enzymes.

The proposed research could have real impact across a number of disciplines:
Infection control professionals: The release of our entire combined data set will allow infection control practitioners and infectious disease modellers to create and test new models for effective control of drug resistant gram negative infections in China. These models should also then be scalable to other LMIC across the Asian continent with similar socio-demographic challenges, and hospital infrastructure such as India, Vietnam, Thailand and many more. We would be supportive of the use of our data for this purpose and have identified key individuals to communicate regularly with throughout the duration of the project, including Prof David Aanensen who is currently co-ordinating AMR genomic surveillance across all continents.
Currently there is political pressure on clinical microbiologists and ID physicians to conduct effective surveillance and control of drug resistant gram negative infections as well as set and meet targets for reductions in numbers of health care associated infections. Our data set should provide new knowledge to allow them to more effectively target their screening and testing procedures to enable more robust surveillance and monitoring of these infections. By presenting our data at ESCMID, and ABPHM we will efficiently reach this audience. This dissemination process will also be supplemented via the contact network of the clinical co-investigators.
Rapid diagnostics and novel antimicrobial developers: Our genome data set will allow the most comprehensive analysis to date of genetic loci associated with increases in MIC to carbapenems. This could support the development of novel diagnostic assays allowing identification of high risk clones of clinical isolates with increased MIC in a single test. Dr McNally has excellent working relationships with such companies undertaking work of this type through FP7 and TSB grants
Patients: Our end goal is to improve patient health and the clinical outcomes of those infected with multi drug resistant gram negative infections in Chinese hospitals. Our data set will allow the first informed infection control decisions to be made regarding CPE Klebsiella, E. coli and Acinetobacter which are relevant to Chinese hospitals. The value of molecular epidemiology data for such purposes has been clearly exemplified with similar work undertaken for the control of Clostridium difficile and MRSA and has contributed to the development of effective control measures and substantial reductions in both infections in the western world. Even a slight reduction in the incidence of MDR gram negative infections within 2-3 years of the conclusion of this study could have enormous benefits to both patient health and the economic fitness of Chinese health care.