Animal Models to Develop New Regimens for S. aureus Implant-Associated Infections - Staphylococcus aureus is the leading cause of serious deep-seated osteoarticular and implant- associated infections. S. aureus orthopedic implant-associated infections are difficult to treat, requiring surgery and / or prolonged systemic antibiotics (weeks-months). They are also associated with extended disability and rehabilitation, contributing to worse overall outcomes. Although infection rates of orthopedic implant-associated infections have remained at 1-2% after primary and 3-6% after revision arthroplasty, inpatient costs average $25,000-$107,000 per case, and an annual healthcare burden of $3 billion in the U.S. alone. The increasing prevalence of methicillin-resistant S. aureus (MRSA) in the U.S. and worldwide, poses yet another challenge for the treatment of these infections, requiring prolonged intravenous antibiotics. We have developed animal models of S. aureus orthopedic implant-associated infections that replicate key pathological features of human disease as well as novel, clinically translatable positron emission tomography (PET) bioimaging for holistic, noninvasive longitudinal measurements in live subjects - bacteria-specific detection of S. aureus infections [11C-para-aminobenzoic acid (PABA), selectively metabolized via the bacterial folate pathway] and 11C-rifampin, 18F-linezolid, 18F-sutezolid, all chemically identical to the parent antibiotic, to measure antibiotic area under the curve (AUC). Recently, we conducted first-in-human 11C-PABA (Ordonez et al. JCI Insight 2022) and 11C-rifampin (Gordon et al. Sci Transl Med. 2021) PET studies in healthy volunteers and newly identified patients with S. aureus orthopedic implant infections, respectively. We show that rifampin bone exposures are substantially lower than previously thought (based on single time-point biopsy studies). Pharmacokinetic modeling of this rich PET data enabled the development of optimized, shorter rifampin-based treatments for S. aureus orthopedic implant infections, which ameliorated the development of antibiotic resistant bacteria, reduced mutations conferring bacterial persistence, and mitigated adverse bone remodeling. Here, we will leverage our expertise in bioimaging, pharmacology and animal model approaches to perform comprehensive proof-of-principle studies and gain mechanistic insights into the interplay of spatiotemporally compartmentalized antibiotic exposures (rifampin, linezolid and sutezolid) and bacterial evolution / acquired drug resistance (ADR) during antibiotic treatments, to establish relapse-free cure for S. aureus orthopedic implant infections. Integration of findings from animal and human studies will enable us to refine our models and address clinically relevant challenges. Knowledge gained from these studies will not only provide unique mechanistic insights into bacterial evolution and ADR and inform the development of novel, short, oral-only therapeutic (antibiotic) regimens for S. aureus orthopedic implant infections, but will also be a major stride towards developing precision medicine tools for at-risk patients with complicated S. aureus infections.
