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BugSeq Case Study: Providence Health Care

Introduction

Next generation sequencing (NGS) is transforming clinical microbiology. It has enabled an unprecedented understanding of microbes, from taxonomic identification to prediction of antimicrobial resistance and transmission. BugSeq’s turnkey bioinformatics platform enables the automated analysis of NGS for clinical and public health laboratories.

Providence Health Care In our inaugural case study, we had the opportunity to connect with the Medical Microbiologists and Molecular Scientists at St. Paul’s Hospital, Providence Health Care to understand what is involved in building a sequencing program. Providence Health Care provides patient and family centered health care to all British Columbians. St. Paul’s Hospital is a major academic tertiary-care hospital with over 700 inpatient beds, and provides care to some of Vancouver’s most vulnerable populations.

User Case Study

Could you provide a brief background on the Shigella sonnei cluster?

Our hospital and microbiology laboratory had previously been aware of transmission within the community we serve, as there had been documented clusters of shigellosis in men who have sex with men (MSM). However, the increased detection of S. sonnei infections starting in 2021 was concerning because of the severity of disease (invasive bloodstream infections) and lack of treatment options using oral antibiotics (multidrug resistant). Most patients did not require hospitalization, but the inability to provide an oral antibiotic presented a challenge for both treating the patient and for possibly limiting onward transmission in the community. For those admitted to hospital, it exerted a significant pressure on bed flow and infection prevention and control (IPAC) in the ED and inpatient units to find available private rooms as well as the microbiology laboratory to provide a rapid diagnosis. The Microbiology laboratory at St. Paul’s Hospital supported this process through the implementation of PCR on stool samples for patients with high clinical suspicion for shigellosis, in addition to routine stool cultures and susceptibility testing.

What were the main challenges your team faced when investigating this cluster?

There are numerous challenges in response to such a significant increase in multidrug resistant (MDR) S. sonnei in our community. From the laboratory perspective, some of the key challenges were providing a rapid diagnosis to ensure appropriate patient management, investigating the discordance between PCR positive and culture negative samples, and coordinating with clinicians and Public Health to mitigate transmission. Although we suspected relatedness between the cases of MDR S. sonnei, it was important to quickly characterize and confirm relatedness in order to better understand the current epidemiology. Our microbiology laboratory had existing NGS capacity, though primarily in amplicon based sequencing rather than whole genome sequencing (WGS). Similar to many clinical laboratories, bioinformatics was a significant challenge for us, as we do not have an in-house bioinformatics specialist to analyze the volume of sequence data generated. The collaboration with BugSeq enabled us to comprehensively analyze the sequencing data quickly while the cluster investigation was still ongoing, including different strain typing methodologies (MLST, cgMLST, reMLST, PopPUNK and global genotype) as well as plasmid typing.

How have you found BugSeq to help with overcoming these challenges?

The collaboration between BugSeq and Providence Health Care has been very productive, helping to advance our clinical sequencing program. Without existing bioinformatics infrastructure and personnel in our laboratory, timely response to emerging diseases or outbreaks/clusters with genomics data may not be possible. In addition to typing the S. sonnei strains, BugSeq analysis enabled genotypic confirmation of antimicrobial resistance, as well as investigate genomic predictors of resistance for antibiotics not routinely tested for Shigella such as tetracycline and carbapenems.

What feedback can you provide on your experience working with BugSeq?

We have worked with BugSeq for several years now, and it feels more like a partnership. In our experience, it has been more than just submitting a sequence to a bioinformatics company and getting a result back. There is ongoing discussion regarding the analyses, feedback regarding unexpected results, and receptiveness to our suggestions/requests. BugSeq has been responsive to our feedback, and provide quick and accurate results for our sequencing needs.

How else have you used BugSeq in your clinical laboratory?

While the clinical investigation of the MDR S. sonnei cluster was the priority, our work also extended to a research collaboration with veterinary colleagues exploring the role of rats in this community. While not causal, we showed relatedness between S. flexneri in human cases presenting to our hospital and S. flexneri from rats in the same community.

In our microbiology/virology laboratory, the primary use of our next-generation sequencer is for the detection of antiviral drug resistance (AVDR) mutations. We have also collaborated with BugSeq in the evaluation of performing cytomegalovirus AVDR at our laboratory rather than being sent out to a reference laboratory to reduce the turnaround time inherent in any send out test. We have also explored a similar tool for hepatitis B AVDR (manuscript in preparation).

In addition, for interesting and novel cases that arise on microbiology rounds, we have utilized BugSeq to further investigate discordant antibiotic susceptibility results. Recently, we managed a patient with a bloodstream infection, identified as a CTX-M-producing E. coli by direct PCR. Various phenotypic testing methods could not verify this isolate as an ESBL (extended-spectrum beta-lactamase)-producer, and through NGS, it was determined that there was a frameshift in the blaCTX-M gene that explained the discordant results (abstract to be presented at AMMI Canada-CACMID 2024).

Where do you believe next generation sequencing in clinical microbiology is heading?

Sequencing has evolved so quickly over the past 10 – 20 years, and the sequencing technologies have become more accessible to clinical laboratories. It has become well-established at public health laboratories for surveillance, particularly through the COVID-19 pandemic. However, as NGS becomes more accessible, it can be utilized beyond surveillance and be a key diagnostic modality for clinical diagnostics. Historically, one of the rate-limiting steps of NGS was bioinformatics, which BugSeq has been able to support in our laboratory.

What will you be working on in 2024 onwards?

Our laboratory will continue to find additional ways to incorporate NGS into clinical diagnostics. In addition, we hope to go live with our CMV AVDR testing, which was previously developed but delayed due to the pandemic. It will be exciting to launch this testing for clinical use, and we hope to potentially expand testing for other antivirals such as letermovir (UL56 and UL89).

Conclusion

As outlined here, BugSeq users are driving significant improvements to patient and population health through adoption of NGS. The ease and affordability of sequencing leaves bioinformatics as the last barrier - which BugSeq solves. BugSeq’s platform has been validated across hundreds of laboratories and bundles everything required to scale sequencing today.

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