Evolving concepts in bone infection: redefining “biofilm”, “acute vs. chronic osteomyelitis”, “the immune proteome” and “local antibiotic therapy”

Abstract

Osteomyelitis is a devastating disease caused by microbial infection of bone. While the frequency of infection following elective orthopedic surgery is low, rates of reinfection are disturbingly high. Staphylococcus aureus is responsible for the majority of chronic osteomyelitis cases and is often considered to be incurable due to bacterial persistence deep within bone. Unfortunately, there is no consensus on clinical classifications of osteomyelitis and the ensuing treatment algorithm. Given the high patient morbidity, mortality, and economic burden caused by osteomyelitis, it is important to elucidate mechanisms of bone infection to inform novel strategies for prevention and curative treatment. Recent discoveries in this field have identified three distinct reservoirs of bacterial biofilm including: Staphylococcal abscess communities in the local soft tissue and bone marrow, glycocalyx formation on implant hardware and necrotic tissue, and colonization of the osteocyte-lacuno canalicular network (OLCN) of cortical bone. In contrast, S. aureus intracellular persistence in bone cells has not been substantiated in vivo, which challenges this mode of chronic osteomyelitis. There have also been major advances in our understanding of the immune proteome against S. aureus, from clinical studies of serum antibodies and media enriched for newly synthesized antibodies (MENSA), which may provide new opportunities for osteomyelitis diagnosis, prognosis, and vaccine development. Finally, novel therapies such as antimicrobial implant coatings and antibiotic impregnated 3D-printed scaffolds represent promising strategies for preventing and managing this devastating disease. Here, we review these recent advances and highlight translational opportunities towards a cure.

Therapeutics and delivery vehicles for local treatment of osteomyelitis

“…Often, biofilms are indicated. Although chronic OM has traditionally been defined as infection persisting longer than 6 weeks, because infections can vary by the causative agent, location, patient health, and other confounding factors, it is now more appropriately classified as a continuum 8,9 for which long-term administration of high dose antibiotics with or without surgical intervention is considered the minimum effective treatment. 7,10,11 Typical symptoms include bone necrosis, subsequent involucrum formation, and an increased risk of amputation.…”

“…12 Several phenotypic states of S. aureus are considered hallmarks of bacterial antibiotic resistance: small colony variants (SCVs), biofilms, Staphylococcus abscess communities (SAC), and colonization of the osteocytic canalicular networks of cortical bone. 8,13,14 An SCV refers to an S. aureus cell with markedly decreased metabolic activity compared to the wildtype. 13 The slower metabolic rate may be attributed to auxotrophies or downregulated citric acid cycle activity as seen in recent in vitro testing.…”

“…15 Due to altered metabolic activity, SCVs are more resistant to antibiotics and may be more apt to form biofilms. 8,13,16 A biofilm refers to colonies of bacteria that have adhered to implants, necrotic tissues, or other available niches, via surface adhesins. 8 These S. aureus cells may be surrounded by a selfproduced protective exopolysaccharide polymer ( Figure 1C,D).…”

New developments and future challenges in prevention, diagnosis, and treatment of prosthetic joint infection

“…There has been a recent push to utilize pathogen‐specific B cell responses and antibodies as diagnostic and prognostic markers of PJI, particularly Staphylococcus aureus PJI. This pathogen has evolved many strategies to efficiently evade host immune responses to cause chronic PJI 91,92 . Nonetheless, anti‐ S. aureus antibody responses during an infection can be utilized to diagnose S. aureus infections.…”

“…Microbiological culture from periprosthetic tissue is a necessary step for correct identification of an infecting organism in PJIs. Despite modern diagnostic methods, isolation of the infecting organism in the setting of PJI can be challenging, and approximately 15% are reported as culture‐negative 79,92,97–99 . One method to improve upon our current culture techniques includes implant sonication.…”