Clinical Implementation of Routine Whole-genome Sequencing for Hospital Infection Control of Multi-drug Resistant Pathogens.

BACKGROUND: Prospective whole-genome sequencing (WGS)-based surveillance may be the optimal approach to rapidly identify transmission of multi-drug resistant (MDR) bacteria in the healthcare setting. METHODS: We prospectively collected methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), carbapenem-resistant Acinetobacter baumannii (CRAB), extended-spectrum beta-lactamase (ESBL-E), and carbapenemase-producing Enterobacterales (CPE) isolated from blood cultures, sterile sites, or screening specimens across three large tertiary referral hospitals (2 adult, 1 paediatric) in Brisbane, Australia. WGS was used to determine in silico multi-locus sequence typing (MLST) and resistance gene profiling via a bespoke genomic analysis pipeline. Putative transmission events were identified by comparison of core genome single nucleotide polymorphisms (SNPs). Relevant clinical meta-data were combined with genomic analyses via customised automation, collated into hospital-specific reports regularly distributed to infection control teams. RESULTS: Over 4 years (April 2017 to July 2021) 2660 isolates were sequenced. This included MDR gram-negative bacilli (n = 293 CPE, n = 1309 ESBL), MRSA (n = 620), and VRE (n = 433). A total of 379 clinical reports were issued. Core genome SNP data identified that 33% of isolates formed 76 distinct clusters. Of the 76 clusters, 43 were contained to the 3 target hospitals, suggesting ongoing transmission within the clinical environment. The remaining 33 clusters represented possible inter-hospital transmission events or strains circulating in the community. In 1 hospital, proven negligible transmission of non-multi-resistant MRSA enabled changes to infection control policy. CONCLUSIONS: Implementation of routine WGS for MDR pathogens in clinical laboratories is feasible and can enable targeted infection prevention and control interventions.

Unexpected benefit of COVID-19 hospital restrictions: Reduction in patients isolating with multidrug resistant organisms after restrictions were lifted.

BACKGROUND: During the COVID-19 pandemic, measures to prevent microorganism transmission were implemented across hospitals, including wearing compulsory surgical masks, minimising non-urgent procedures and restricting visitors. Previously, concerns have been raised that MRO-associated deaths could rise during a future pandemic through superimposed bacterial infections, inappropriate antibiotic use and reduced focus on preventing MRO infections. METHODS: In the state of Queensland, Australia with a population of 5 million, only a short first wave of coronavirus cases occurred and restrictions were quickly scaled back. This presented a natural experiment of pre-, during and post-COVID-19 restriction timings to evaluate the effectiveness of heightened prevention measures on multidrug resistant organism (MRO) infections. Patient isolation days and MRO types were collected weekly from routine infection control reports, at a large public hospital, from 28th January 2020 to 24th July 2020. In this interrupted time series design, we employed Poisson mixed effect regression modelling to evaluate the difference in incidence of patient isolation days between time periods. RESULTS: Compared to pre-COVID, patient isolation days reduced during COVID restrictions (incidence rate ratio 0.65, 95%CI: 0.59, 0.70; p < 0.001) and increased again post-COVID restrictions, but did not return to pre-COVID levels (0.87, 95%CI: 0.80, 0.95; p = 0.001). The efficiency of isolating patients improved after COVID-19 with fewer bed closures required. CONCLUSION: Heightened infection control awareness, hand sanitation and mask wearing after COVID-19 restrictions were lifted appear to effectively prevent common hospital-acquired MRO infections.

Evaluating the economic effects of genomic sequencing of pathogens to prioritise hospital patients competing for isolation beds.

Objective This study compared the costs and patient movements of a new hospital protocol to discontinue contact precautions for patients with non-multiresistant methicillin-resistant Staphylococcus aureus (nmMRSA), based on whole-genome sequencing (WGS) of pathogens with current practice. Methods A hybrid simulation model was constructed and analysed over a 12-month time horizon. Six multidrug-resistant organisms and influenza were modelled concurrently where infected patients competed for isolation beds. Model inputs included pathogen incidence, resources for WGS, staff and contact precautions, hospital processes, room allocations and their associated costs. Data were sourced from aggregated records of patient admissions during 2017-18, clinical records and published reports. Results The WGS protocol resulted in 389 patients isolated (44% of current practice), 5223 'isolation bed days' (56%) and 268 closed-bed days (88%). Over 1 year, the mean (±s.d.) total cost for the WGS protocol was A$749243±126667; compared with current practice, the overall cost savings were A$690864±300464. Conclusion Using WGS to inform infection control teams of pathogen transmission averts patients from isolation rooms and reduces significant resources involved in implementing contact precautions. What is known about the topic? There are an estimated 265000 hospital-acquired infections (HAI) in Australia each year. WGS can accurately identify the genetic lineage among HAIs and determine transmission clusters that can help infection control staff manage patients. Economic appraisals are lacking to inform whether pathogen genomics services should be adopted within already-stretched hospital budgets. What does this paper add? An isolation protocol using pathogen genomics to provide additional information on the relatedness of a pathogen between colonised patients showed favourable results for healthcare costs and patient flow. Using WGS, in a confirmatory role, to discontinue certain patients from contact precautions and isolation rooms resulted in cost savings of A$690864 across 1 year for a single major hospital. What are the implications for practitioners? Using pathogen WGS services for infection control potentially curbs hospital spending, averts patient isolations and improves patient flow within hospitals.

Cost-effectiveness analysis of whole-genome sequencing during an outbreak of carbapenem-resistant Acinetobacter baumannii.

Background: Whole-genome sequencing (WGS) shotgun metagenomics (metagenomics) attempts to sequence the entire genetic content straight from the sample. Diagnostic advantages lie in the ability to detect unsuspected, uncultivatable, or very slow-growing organisms. Objective: To evaluate the clinical and economic effects of using WGS and metagenomics for outbreak management in a large metropolitan hospital. Design: Cost-effectiveness study. Setting: Intensive care unit and burn unit of large metropolitan hospital. Patients: Simulated intensive care unit and burn unit patients. Methods: We built a complex simulation model to estimate pathogen transmission, associated hospital costs, and quality-adjusted life years (QALYs) during a 32-month outbreak of carbapenem-resistant Acinetobacter baumannii (CRAB). Model parameters were determined using microbiology surveillance data, genome sequencing results, hospital admission databases, and local clinical knowledge. The model was calibrated to the actual pathogen spread within the intensive care unit and burn unit (scenario 1) and compared with early use of WGS (scenario 2) and early use of WGS and metagenomics (scenario 3) to determine their respective cost-effectiveness. Sensitivity analyses were performed to address model uncertainty. Results: On average compared with scenario 1, scenario 2 resulted in 14 fewer patients with CRAB, 59 additional QALYs, and $75,099 cost savings. Scenario 3, compared with scenario 1, resulted in 18 fewer patients with CRAB, 74 additional QALYs, and $93,822 in hospital cost savings. The likelihoods that scenario 2 and scenario 3 were cost-effective were 57% and 60%, respectively. Conclusions: The use of WGS and metagenomics in infection control processes were predicted to produce favorable economic and clinical outcomes.

Genomic surveillance, characterization and intervention of a polymicrobial multidrug-resistant outbreak in critical care.

Background. Infections caused by carbapenem-resistant Acinetobacter baumannii (CR-Ab) have become increasingly prevalent in clinical settings and often result in significant morbidity and mortality due to their multidrug resistance (MDR). Here we present an integrated whole-genome sequencing (WGS) response to a persistent CR-Ab outbreak in a Brisbane hospital between 2016-2018.Methods. A. baumannii, Klebsiella pneumoniae, Serratia marcescens and Pseudomonas aeruginosa isolates were sequenced using the Illumina platform primarily to establish isolate relationships based on core-genome SNPs, MLST and antimicrobial resistance gene profiles. Representative isolates were selected for PacBio sequencing. Environmental metagenomic sequencing with Illumina was used to detect persistence of the outbreak strain in the hospital.Results. In response to a suspected polymicrobial outbreak between May to August of 2016, 28 CR-Ab (and 21 other MDR Gram-negative bacilli) were collected from Intensive Care Unit and Burns Unit patients and sent for WGS with a 7 day turn-around time in clinical reporting. All CR-Ab were sequence type (ST)1050 (Pasteur ST2) and within 10 SNPs apart, indicative of an ongoing outbreak, and distinct from historical CR-Ab isolates from the same hospital. Possible transmission routes between patients were identified on the basis of CR-Ab and K. pneumoniae SNP profiles. Continued WGS surveillance between 2016 to 2018 enabled suspected outbreak cases to be refuted, but a resurgence of the outbreak CR-Ab mid-2018 in the Burns Unit prompted additional screening. Environmental metagenomic sequencing identified the hospital plumbing as a potential source. Replacement of the plumbing and routine drain maintenance resulted in rapid resolution of the secondary outbreak and significant risk reduction with no discernable transmission in the Burns Unit since.Conclusion. We implemented a comprehensive WGS and metagenomics investigation that resolved a persistent CR-Ab outbreak in a critical care setting.