Assessing the situation of AMR of bacteria in Vietnam, determining genomic characteristics and associated factors of common AMR-bacteria in Vietnam

Antimicrobial resistance (AMR) is now deemed to be the biggest global threat facing humanity in the 21C. AMR has taken center stage as a global health issue yet most non-specialists are unaware the impact AMR will have on global populations, and how AMR will effect international communities in 2020/2025. Recent announcements from Prime Minister David Cameron, the UK Chief Medical Officer (Professor Sally Davies), and the US president, Barak Obama, is clear evidence that this starting to attract UK and international scientific and political traction. Additionally the World Health Organization recently published a mapping exercise on regional capacity and SE Asia, including Viet Nam lacked many basic reporting structures on multiple drug resistance (MDR). Therefore in keeping with the general notion of "One World Health" there clearly needs to better alignment and engagement between the "developed world" and low-middle income countries.

There have been ad-hoc studies on AMR in Viet Nam; however, the majority of these are small in number and importantly do not blend clinical and basic scientific data. Those studies that have been done tend to focus only on a resistance mechanisms such as, for example, the carbapenem (penicillin-like compounds used in last resort infections) - resistant mechanism called NDM-1. Despite the fact that NDM-1 is now present in Viet Nam and causing antibiotic failures and no doubt impacting on mortality we know very little of its true impact, or indeed any other type of AMR mechanism. Thus far studies in Viet Nam have been sporadic and lack meaningful clinical data to truly attribute risk factors such as AMR. This application addresses these knowledge gaps by undertaking the following:

1. Comprehensive approach to the problem of infection and AMR in Viet Nam. This application is unique in that it combines clinical epidemiology with molecular biology (whole genome sequencing) to assess the impact of AMR in patients in Viet Nam. We have selected four Vietnamese medical centres where we will employ and train staff to collect clinical data following ethical consent. The National Institute of Hygiene and Epidemiology will carry out antibiotic resistance testing and basic molecular biology. This comprehensive approach to studying infections is the first of its type in not only Vietnam but also SE Asia.
2. Provide meaningful infrastructure and sustainable research excellence in Viet Nam. The UK lab will purchase a sequencer and the Vietnamese research fellows will travel to the UK and train in sequencing and bioinformatics; at the end of the two-year period the sequencer will be installed in Viet Nam providing essential molecular infrastructure. The Vietnamese research fellows will be equipped to independently run genomic sequencing in Viet Nam.
3. Establish a Vietnamese national AMR surveillance network. This application also seeks to implement a national AMR network in accordance with the WHO "one world health" mantra. This comprehensive and unique approach will identify risk factors for infection and AMR, and allow identification of interventions positively impacting on mortality.
4. Improving patient welfare in Viet Nam. The data from this study will identify groups of patients most at risk from infections and AMR. These groups could be based on age (infant versus adult), socio-economic status (type of dwelling, level of sanitation), type of job (farmer, hospital worker etc.) etc. etc. but will provide meaningful data for identifying high-risk patient groups. By understanding these risk factors we will be able to implement interventions resulting in better patient care.

In the UK we will very closely with our Vietnamese colleagues to ensure close communication and engagement through social media and web-based communication portals. We also will establish a Vietnamese public education program (written in Vietnamese and French) to reach local people unaware of AMR issues in Viet Nam.

The National Institute of Hygiene and Epidemiology (NIHE) in Viet Nam, in partnership with Cardiff University (UK), propose a programme focused on the burden of antimicrobial resistance (AMR) in pathogenic bacteria in Viet Nam and will use data and outcomes as an exemplar for South East Asia. The steep rise of MDR/XDR in Viet Nam endangers the overall effectiveness of antibiotic treatment which will increase the burden of infectious diseases even more particularly in HRPGs emphasising the need for antibiotic stewardship and better patient management.

We will address four broad over-lapping research challenges:
1. Clinical Epidemiology: provide detailed and focused clinical demographics on high- risk patient groups (HRPGs) most vulnerable to AMR infections e.g. neonates, ICU and post-surgical infections [6,11].
2. Pathogen Biology: development of molecular tools for analysing and visualizing functional genomics data on bacteria for identification and characterization of novel resistance determinants and virulence factors.
3. Genomic Epidemiology, Evolution and Population Genetics: development of bioinformatics tools for analysing, manipulating, visualizing and archiving data from large-scale genomics studies.
4. Integrating bacterial genomics: combining clinical information and relevant molecular epidemiological data.

The key deliverables are the following:
1. Deliver a full picture of antimicrobial resistant in four leading hospitals in Viet Nam from 2015-2017.
2. Detail the evolution of MDR/XDR, including the direction (horizontal gene transfer) of inheritance.
3. Provide scientific evidences (burden of AMR, epidemiology of AMR, risk factor for infection and outcome with AMR) in Viet Nam in order to develop intervention strategies.
4. International support for emerging Vietnamese researchers.

Despite widespread acceptance of the importance of multi-drug resistance (MDR) vast gaps exist in its dissemination, impact and burden on infections in low-middle income countries (LMICs). We use will Gram-negative infections as an exemplar, combining clinical and molecular epidemiology in a unique setting to understand the risk factors driving MDR and its impact on poor communities. Both the UK and Vietnamese partners are highly experienced to implement such a program. Moreover, this application will deliver molecular capabilities and training in Vietnam to ensure sustainable drug resistance programs beyond the lifetime of the grant.

The following groups will be direct beneficiaries of this research:

1. National Institute of Hygiene and Epidemiology. The direct benefit of this grant application will be the principal Vietnamese collaborator. The UK partner will share expertise, provide training in whole genome sequencing and at the beginning of the grant give the Illumina MiSeq to the NIHE which will be supported from the UK budget. This approach will build infrastructure and sustainability in intellectual property to help establish a Vietnamese national network in AMR and develop a new generation of Vietnamese scientists equipped to deal with MDR/XDR infections.
2. Vietnamese population. There are many serious infrastructural and cultural issues affecting the burden of infection and MDR in the Vietnamese population. By understanding the risk factors for infections and AMR, interventions, both physical and educational can be implemented to improve patient wellbeing and mortality. For example comparing hospitals dealing with different socio-economic cohorts we will be able to assess the impact of living quality and sanitation on acquiring infections and will be able to also compare different population age groups e.g. neonates versus paediatrics, natural births versus cesareans etc.
3. Vietnamese Hospitals. We will seek to enroll at four large hospitals across Vietnam (Vietduc hospital, 108 Center Army hospital, Saint Paul hospital and Thanh hospital) with the desire of improving patient management. This data will have an immense influence on future projections and impact of MDR and therefore Vietnamese healthcare strategies at local, regional and national level, including; the potential screening of patients, screening of wards, infection control improvements, improved categorizing infections and optimizing antimicrobial therapy for MDR.
4. Vietnamese National Policy Makers. As well as having a real-time live website, the NIHE has considerable political influences and we will make six monthly reports to local and national Vietnamese health agencies. Most notably, we will focus on the impact of MDR on local patient populations, highlight the need for better protocols to prevent infection e.g. Clean Your Hands Campaign, and seek additional funding beyond the life-time of the grant.
5. MSF/WHO/Pasteur Institute. Médecins Sans Frontières and the WHO has considerable interest in LMICs and in particular on the impact and burden of infections. The UK PI is an advisor to MSF and the WHO and is also an advisory to BIRDY (neonatal infection program run by the Pasteur Institute including Vietnam) and will be able to liaise and communicate data when necessary.
6. Cardiff University. The PI already has many international programs but few in SE Asia. The training of the Vietnamese research fellows will provide an awareness of national and regional-specific issues in infection and AMR and will allow the opportunity for great interactions and collaborations in the future. The visits of the Vietnamese collaborators will be a rewarding experience as will be training the nurses and providing support for the MSc and PhD research programs.