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Table 1 Use cases for whole-genome sequencing (WGS) in mitigating the public health impact of antimicrobial resistance (AMR)

From: Exploiting genomics to mitigate the public health impact of antimicrobial resistance


Uses of WGS/workflow

Main findings

Advantages of using WGS

Use case 1: International surveillance—determining the population structure and epidemiology of carbapenem-resistant K. pneumoniae (CR-Kp) across Europe [18]

 Primary reservoirs and transmission dynamics of CR-Kp across Europe are incompletely understood.

Hospital laboratories across Europe submitted consecutive clinical isolates of CR-Kp, along with a comparator susceptible isolate for sequencing.

CR-Kp largely resulted from carbapenemase acquisition; nosocomial acquisition was the main cause of CR-Kp spread.

Provided a benchmark for ongoing surveillance of CR-Kp. Highlighted the role of nosocomial spread.

Use case 2: Enhancing the national surveillance of antimicrobial resistance in the Philippines [11]

 National laboratory-based surveillance had shown increasing AMR prevalence over the10 years previously, but understanding of the epidemiology and drivers of AMR were lacking.

WGS capability was introduced to the existing surveillance programme. Retrospective sequencing of MDR GNB obtained prior to the introduction was undertaken and analysed with phenotypic and epidemiological data to provide baseline data and inform control measures.

Drivers of carbapenem resistance at different levels of the healthcare system were identified, including a localised outbreak of plasmid-driven CR-Kp affecting a specific hospital, through the detection of the introduction and country-wide spread of a high-risk epidemic clone, E. coli ST410.

Detailed understanding of the epidemiology and drivers of AMR enabled the introduction of effective infection control measures. Data were contributed to international AMR surveillance efforts, improving the global coverage.

Use case 3: Investigating an MRSA outbreak in a neonatal unit [19]

 Phenotypically similar MRSA isolates were identified from patients on a neonatal unit over a 6-month period but could not be linked temporally or geographically, suggesting that the full extent of the outbreak had not been identified.

All MRSA isolates obtained from patients on the neonatal unit over a 6-month period underwent WGS regardless of phenotypic characteristics. MRSA isolates with antibiograms similar to the outbreak strain, identified from the community, and screening samples taken elsewhere in the hospital were also sequenced.

Two previously excluded isolates were identified as being part of the outbreak by phylogenetic analysis, allowing temporal links between cases to be established. A wide transmission network beyond the neonatal unit was identified.

WGS allowed a large number of isolates to be tested and related strains to be accurately identified, thereby enabling full outbreak reconstruction. Combining WGS data with clinical and epidemiological data enabled the identification of outbreak source and successful instigation of infection control measures.

Use case 4: Investigating the direction of transmission in an A. baumannii outbreak in a UK hospital [20]

 Molecular typing of a cluster of A. baumannii isolates obtained in a UK hospital suggested a clonal outbreak, but the chain of transmission between cases could not be established from the existing laboratory, clinical, and epidemiological data.

A cluster of isolates obtained from patients with identical molecular typing profiles and antibiograms underwent WGS analysis to inform the understanding of the direct transmission between patients.

Phylogenetic analysis enabled the identification of the index case and the subsequent chain of transmission to be determined. One patient/isolate was shown to be unrelated and was excluded from the outbreak investigation.

WGS-enabled directionality of transmission can be determined, allowing accurate reconstruction of the outbreak.

Use case 5: Contact tracing and detection of secondary cases of TB [21]

 Screening and detection of secondary cases of TB are essential for TB control. Accurate identification of case clusters and transmission networks is hampered by the limited resolution provided by molecular typing.

Clinical TB isolates in the Netherlands in 2016 were analysed by both molecular typing and WGS. The degree of discrimination and accuracy in identifying potentially related cases was compared between the two methods.

WGS was better able to decimate the relatedness of isolates, clustering a smaller proportion of isolates as related compared with molecular typing (25% vs. 14%) and increasing proportion confirmed as epidemiologically linked (57% vs. 31%).

WGS facilitated the identification of transmission events, facilitating contact tracing as well as informing the wider understanding of TB control.

Use case 6: Identifying the drivers of AMR in atypical enteropathogenic E. coli (aEPEC) strains isolated from children < 5 years in four sub-Saharan African countries and three South Asian countries [22]

 The frequency, mechanisms, and drivers of AMR in intestinal isolates of E. coli in children in the community in many countries worldwide were unknown.

Phenotypic susceptibility and WGS of isolates were analysed and correlated with antimicrobial use, disease status (symptomatic/asymptomatic), phylogenetic lineage, and geographic location.

High rates of AMR were shown, with 65% of isolates resistant to at least 3 antimicrobial drug classes. A diverse range of genetic mechanisms of AMR was shown, with geographic location and the associated antimicrobial use pattern being the strongest predictors of AMR.

WGS was used to provide a detailed analysis of AMR across a large geographical area, providing insights into the AMR epidemiology, spread, and drivers.

Use case 7: Investigating colistin resistance detected in commensal E. coli in food stock animals in China [23]

 Routine surveillance had detected a sharp increase in the rates of colistin resistance in colonising bacteria from pigs in China, but the mechanism of this resistance was not known.

Conjugation experiments were undertaken to confirm the presence of plasmid-associated, transmissible colistin resistance. WGS of the plasmids was used to identify the gene responsible.

The sequence of the plasmid-associated colistin resistance gene was identified and designated mcr-1.

The genetic basis of a new, AMR mechanism was identified and described, allowing ongoing surveillance, as well as informing investigation and detection of this emerging threat in other settings.

Use case 8: Detecting of transmitted drug resistance (TDR) in newly diagnosed, treatment naïve HIV-1-positive patients [24]

 Multiple genetic mutations contribute to HIV drug resistance. Mutations often only affect a fraction of the viral population in any given patient (low-level variants), but, if present in combination with other mutations or at key sites, likely contribute to treatment failure. Existing methods are insufficiently sensitive to detect low-level variants that can compromise treatment.

NGS was used to detect TDR, including low-level variants affecting ≥ 2% or more of the viral population, in treatment-naïve, clinical trial participants enrolled across 35 countries worldwide with a HIV viral load > 1000 copies/ml.

NGS revealed many low-level variants that were undetected by existing methods. Significant geographic diversity was seen in the prevalence of different TDR mutations.

NGS provided a more comprehensive assessment of TDR prevalence in individual patients, and in different regions of the world, helping guide empiric treatment choice and understanding of clinical outcomes in different patients and settings.

Use case 9: Understanding the epidemiology of MDR and XDR pathogens amenable to control by vaccination [25, 26]

 AMR is increasingly threatening the success of treatment for typhoid fever. Resistance to the last effective oral agent, azithromycin, was detected in Bangladesh and subsequently in Pakistan, but the genetic mechanism and the likely hood of dissemination were unknown.

Clinical isolates of azithromycin-resistant S. Typhi were analysed by WGS. The phylogenetic analysis enabled the contextualisation of the strains within contemporaneous S. Typhi isolates in both settings.

Phylogenetic analysis showed that resistant isolates in Bangladesh and Pakistan resulted from the independent acquisition of mutations in the same gene highlighting the extent of selection pressure on azithromycin and the imperative need for disease control by vaccination.

WGS was used to identify and investigate two separate outbreaks of azithromycin-resistant S. Typhi. These data helped provide the impetus to roll out novel typhoid conjugate vaccines to control infection.