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Fracture-related infection

Abstract

Musculoskeletal trauma leading to broken and damaged bones and soft tissues can be a life-threating event. Modern orthopaedic trauma surgery, combined with innovation in medical devices, allows many severe injuries to be rapidly repaired and to eventually heal. Unfortunately, one of the persisting complications is fracture-related infection (FRI). In these cases, pathogenic bacteria enter the wound and divert the host responses from a bone-healing course to an inflammatory and antibacterial course that can prevent the bone from healing. FRI can lead to permanent disability, or long courses of therapy lasting from months to years. In the past 5 years, international consensus on a definition of these infections has focused greater attention on FRI, and new guidelines are available for prevention, diagnosis and treatment. Further improvements in understanding the role of perioperative antibiotic prophylaxis and the optimal treatment approach would be transformative for the field. Basic science and engineering innovations will be required to reduce infection rates, with interventions such as more efficient delivery of antibiotics, new antimicrobials, and optimizing host defences among the most likely to improve the care of patients with FRI.

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Fig. 1: Clinical course of a complex bone fracture, subsequent fracture-related infection and eventual recovery.
Fig. 2: Risk factors for the development of fracture-related infection.
Fig. 3: Localization of bacteria in distinct niches in fracture-related infection.
Fig. 4: Disruption of normal bone healing in fracture-related infection.
Fig. 5: Mechanisms of bone changes during bacterial infection in fracture-related infection.

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Acknowledgements

T.F.M., R.G.R. and E.M.S. acknowledge support from AOTrauma through the clinical priority program Bone Infection.

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Contributions

Introduction (T.F.M., W.-J.M., B.W. and R.G.R.); Epidemiology (T.F.M., W.-J.M., M.M., J.E.C. and M.D.); Mechanisms/pathophysiology (T.F.M., W.-J.M., M.M., M.I.H., J.E.C., B.W. and E.M.S.); Diagnosis, screening, and prevention (T.F.M., W.-J.M., M.M., A.V.D., J.E.C. and M.D.); Management (T.F.M., W.-J.M., M.M., A.V.D., J.E.C. and M.D.); Quality of life (T.F.M., W.-J.M. and M.M.); Outlook (T.F.M., W.-J.M., M.M., M.I.H., B.W., E.M.S. and R.G.R.); Overview of Primer (R.G.R.).

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Correspondence to R. Geoff Richards.

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Nature Reviews Disease Primers thanks P.C. Jutte, J. Parvizi, P.M. Rommens, U.C. Stockle and K.D. Tetsworth for their contribution to the peer review of this work.

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Glossary

Fracture-related infection

(FRI). Infection associated with a bone fracture, with or without operative management.

Osteomyelitis

Inflammation of bone and bone marrow, most commonly due to bacterial infection.

Peri-prosthetic joint infection

(PJI). Infection associated with an artificial joint involving bone, surrounding soft tissues and/or bacterial colonization of the surface of the implant.

Biomechanical instability

Movement across a fracture gap due to lack of fixation, or insufficient fixation.

Non-union

A fracture that does not heal within the usual time frame, and one later-stage outcome of an intermediate step called delayed union.

Closed fractures

Fractures that do not cause the overlying skin to break.

Complex fractures

Bone fractures further complicated by substantial soft tissue or bone damage.

Open fractures

Bone fractures where the overlying skin is breached.

Gustilo and Anderson (GA) classification

The most widely accepted, standardized classification system of open fractures, based on wound size, bone damage and vascular damage.

Injury severity scores

(ISS). A standardized system to score trauma severity that accounts for injuries to the musculoskeletal and other body systems.

Antimicrobial resistance

(AMR). The ability of microorganisms to withstand antimicrobial treatment.

Biofilm

A community of bacteria within a self-produced matrix of extracellular polymeric substances, which may also involve extracellular DNA or host-derived macromolecules, growing on a substrate such as an implanted fracture fixation device.

Staphylococcal abscess community

(SAC). An accumulation of many S. aureus bacterial cells within a self-produced fibrin pseudocapsule.

Accessory gene regulator

(Agr). The agr locus encodes a quorum-sensing and two-component regulatory system that controls expression of multiple virulence factors in S. aureus and S. epidermidis.

Surgical debridement

A surgical procedure to remove necrotic or infected tissue, which includes irrigation, excision and removal of foreign material.

Osteoblasts

Cells responsible for bone formation.

Mineralization

The addition of minerals (such as calcium or phosphorus) to callus, leading to calcified tissue.

Callus

Tissue formed at the fracture site during the healing process, with cartilaginous composition at earlier stages, transitioning to calcified tissue at a later stage.

Osteoclastogenesis

The formation of bone-resorbing cells, osteoclasts, from myeloid precursor cells.

Sequestra

Pieces of dead bone separated from surrounding bone due to infection and necrosis.

Cytokines

Large group of secreted proteins that are important for cell communication and signalling; during inflammation, they can have pro-inflammatory or anti-inflammatory effects.

Receptor activator of nuclear factor-κΒ ligand

(RANKL). A key mediator of bone resorption that stimulates the formation and activity of osteoclasts by binding to the RANK receptor.

Osteoclasts

Cells responsible for bone resorption.

Myeloid-derived suppressor cells

Immature monocytes or neutrophils that have immunosuppressive abilities; these cells proliferate in response to the prolonged presence of myeloid growth factors and inflammatory molecules.

Sinus tracts

Small channels from sites of infection to the surface of the skin.

Pathognomonic

A clinical sign or feature that is characteristic of a disease; in this context, it confirms that an infection is definitely present.

Empirical antibiotic therapy

Antibiotic therapy selection when pathogens are unknown but based on anticipated and likely causative organisms.

Rifampicin

A key antibiotic owing to its activity against staphylococcal biofilms and stationary phase bacteria.

Fluoroquinolones

A class of antibiotics that are particularly important owing to their anti-biofilm activity against Gram-negative bacterial biofilms.

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Moriarty, T.F., Metsemakers, WJ., Morgenstern, M. et al. Fracture-related infection. Nat Rev Dis Primers 8, 67 (2022). https://doi.org/10.1038/s41572-022-00396-0

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