Multiple hypervirulent methicillin-sensitive Staphylococcus aureus lineages contribute towards poor patient outcomes in orthopedic device-related infections

Staphylococci are the most common cause of orthopedic device-related infections (ODRIs), with Staphylococcus aureus responsible for a third or more of cases. This prospective clinical and laboratory study investigated the association of genomic and phenotypic variation with treatment outcomes in ODRI isolates. Eighty-six invasive S. aureus isolates were collected from patients with ODRI, and clinical outcome was assessed after a follow-up examination of 24 months. Each patient was then considered to have been “cured” or “not cured” based on predefined clinical criteria. Whole genome sequencing and molecular characterization identified isolates belonging to globally circulating community- and hospital-acquired pandemic lineages. Most isolates were phenotypically susceptible to methicillin and lacked the SCC mec cassette (MSSA), but contained several (hyper) virulence genes, including toxins and biofilm genes. While recognizing the role of the host immune response, we identify characteristics of isolate genomes that, with larger datasets, could help contribute to infection severity or clinical outcome predictions. While this and several other studies reinforce the role antibiotic resistance (e.g., MRSA infection) has on treatment failure, it is important not to overlook MSSA that can cause equally destructive infections and lead to poor patient outcomes. Importance Staphylococcus aureus is a prominent cause of orthopedic device-associated infections, yet little is known about how the infecting pathogen, and specifically the repertoire of genome-encoded virulence factors can impact treatment outcome. Past studies have focused on distinguishing commensal from invasive S. aureus isolates but in this study, we aim to investigate traits in infecting isolates that influence patient outcomes. Invasive S. aureus isolates were collected from orthopedic-device related infection patients and categorized according to the success of subsequent treatment (“cured” /”not cured”), as determined following hospital discharge two years after initial presentation. Several MSSA hypervirulent clones were associated with a “not cured” clinical outcome. Improved understanding of the bacterial traits associated with treatment failure in ODRI will inform the risk assessment, prognosis, and therapy of these infections. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT02971657 ### Clinical Protocols ### Funding Statement This work was funded by AO Trauma as part of the Clinical Priority Program, Bone Infection. All high-performance computing was performed on MRC CLIMB, funded by the Medical Research Council (MR/L015080/1). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The clinical data and S. aureus collection was part of a prospective study performed between November 2011 and September 2013 at BGU Murnau in Germany which was approved by the local ethical committee Ethik-Kommission der Bayerischen Landesarztekammer under approval number 12063 and registered with https://clinicaltrials.gov with identifier [NCT02971657][1]. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Illumina short read sequence data are archived on the Sequence Read Archive. All assembled genomes are shared on figshare (doi.org: 10.6084/m9.figshare.7926866) and are available on our public Staphylococcal Bacterial Isolate Genome Sequence Database (BIGSdb): https://sheppardlab.com/resources/. Collection also shared on the pathogen watch website (https://pathogen.watch/collection/7rgjyrzz3xoc-post-and-pascoe-et-al-2022-hypervirulent-mssa-from-odri). Isolate genealogy with associated meta-data is visualized on microreact [110]: https://microreact.org/project/Post-Pascoe-Saureus/0f0c26fb. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02971657&atom=%2Fmedrxiv%2Fearly%2F2022%2F10%2F22%2F2022.10.21.22280349.atom