Laura Marks M.D., Ph.D. (Year 2)
ABSTRACT
The epidemic of invasive Staphylococcus aureus infections poses a significant public health and economic burden. Invasive S. aureus infections may result in a spectrum of disease including uncomplicated bacteremia, osteoarticular infections, and often deadly endovascular infections. To date, data on origin of isolates causing invasive infections among people who use drugs is lacking, and it is unknown if these strains originate from skin colonization or the drugs themselves. Additionally, there is no reliable way to prognosticate which individuals will have mild disease courses or who will succumb to more devastating and often fatal outcomes.
In this research, we will leverage prior work funded by the Longer Life Foundation which has resulted in the accrual of a rich biospecimen bank including staphylococcal isolates from 100 patients, and associated patient sera, to investigate both pathogen and patient factors related to disease severity and outcomes.
LAY SUMMARY
The bacterium Staphylococcus aureus causes a wide range of infections with varying disease. While some patients may develop few to no symptoms as a result of infection, others have rapid often fatal disease courses. We propose to use previously collected patient samples to determine if bacterial genetics and/or patient metabolites produced as a result of infection can predict who will have a mild illness vs. who might have a fatal infection.
Progress Report — Final (Year 2 of 2)
The overarching goal of this project was to better understand the pathogenesis of Staphylococcus aureus infections and transmission among people who inject drugs (PWID), and to identify factors contributing to severe and recurrent S. aureus bloodstream infections.
Year 1: Building the Biorepository
The first year of LLF funding was used to develop a biorepository of S. aureus strains from the blood, skin, and drug preparation equipment of 100 patients presenting with S. aureus bloodstream infections — 50 with injection drug use-associated infections and 50 matched controls — complemented by patient demographics, detailed clinical data, and survey data on individual drug use practices.
Year 2: Genomic and Transmission Analyses
In the second year, strains underwent whole-genome sequencing to characterize sources and transmission of injection drug use-associated bloodstream infections. Key findings:
- Colonization rates with S. aureus were not significantly different between PWID and non-PWID patients hospitalized with bloodstream infections.
- Colonizing strains were clonal with bloodstream isolates in both groups; however, PWID could also develop bloodstream infections caused by strains found on drug use equipment — distinct from their own colonizing strain.
- This supports the hypothesis that S. aureus bacteremia in PWID can arise both from an individual’s own colonizing strain and from contaminated shared injection equipment.
Transmission Cluster Analysis
Social network analysis of isolates meeting transmission cluster criteria (<15 core-genome SNPs) was merged with clinical and behavioral survey data. Nonsterile injection practices — particularly shared needles and syringes — were significantly associated with transmission clusters of injection drug use-related invasive staphylococcal infections, supporting the role of syringe sharing in spreading S. aureus among PWID.
Recurrent Infection Analysis
Among 48 PWID with recurrent infections who underwent whole-genome sequencing:
- Incomplete antibiotic therapy was associated with relapse with the same strain.
- Isolated bacteremia and ongoing injection drug use were associated with reinfection with unrelated strains.
- Antibiotic resistance did not accumulate even in relapsed cases; reinfections involved new sequence types unrelated to the index strain.
Chemokine and Metabolomic Analysis
Chemokine and metabolomic profiling of patient sera was performed alongside comparative genomic analysis of strains with prolonged bacteremia. While metabolomics did not clearly predict bacteremia duration or fatal outcomes, chemokine signatures differed significantly between PWID and matched controls. Many analytes found at lower levels in PWID are known to be required for clearance of S. aureus infection, which may help explain the prolonged bacteremia observed in this population.
Impact and Next Steps
These findings have direct implications for harm reduction policy and public health interventions targeting PWID, underscoring the importance of cleaning injection sites, avoiding shared drug use equipment, and comprehensive harm reduction education. Since the initial LLF funding period, this work has served as preliminary data for an R21 grant on the pathogenesis of xylazine-associated infections in PWID, which was awarded in July 2025. Manuscripts describing the results of this LLF project in detail are in preparation and expected to be submitted in early 2026.