Emerging Concepts in Periprosthetic Joint Infection Research: Intracellular Organisms

Abstract

Despite advances in the treatment of periprosthetic joint infection (PJI), recurrence is a concern for both patients and orthopaedic surgeons. Staphylococcal species are commonly implicated in PJI and are associated with more instances of treatment failure and recalcitrance relative to other organisms. A possible explanation for this is the ability of staphylococci to undergo phenotypic transformation into a quasidormant small colony variant (SCV) phenotype. These SCVs are difficult to culture and demonstrate increased resistance to targeted antibiotic therapy. Most importantly, SCVs are capable of intracellular invasion and may reside and proliferate within a variety of host cell types, including osteoblasts, osteocytes, fibroblasts, and circulating immune cells, such as neutrophils. In doing so, virulent organisms may interfere with normal host cell function while also converting these cells into reservoirs of bacteria that are sequestered from the extracellular environment and thus less vulnerable to standard antibiotic regimens. Additionally, these intracellular organisms may emerge from dormancy under certain conditions, including dysregulation or suppression of the host immune system, to return to their virulent state and cause recurrence of an infection. This phenomenon has been observed clinically, with reports in the literature describing cases of recurrent PJI and osteomyelitis, often many years later, caused by organisms previously thought to be eradicated. Furthermore, circulating immune cells containing intracellular organisms may also transport bacteria to other body sites before undergoing cellular lysis, leading to metastatic infection via a Trojan Horse mechanism. Previous reports have demonstrated intraosteoblastic infection with Staphylococcus aureus in clinical cases of recurrent osteomyelitis, while a recent study identified the same pathogen in osteocytes obtained from patients who have culturepositive PJI. While the translational application of these findings warrants further exploration, a better understanding of the clinical relevance of intracellular invasion could lead to the development of more optimal treatment strategies for eradicating infection and improving patient outcomes. (c) 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.