Thank you for visiting nature.com.
You are using a browser version with limited support for CSS.
To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer).
In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.
Advertisement Nature Reviews Disease Primers volume 8 , Article number: 67 ( 2022 ) Cite this article 1 Altmetric Metrics details 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.
This is a preview of subscription content, access via your institution Subscribe to Nature+ Get immediate online access to the entire Nature family of 50+ journals .99 monthly Subscribe to Journal Get full journal access for 1 year .00 only .00 per issue All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Buy article Get time limited or full article access on ReadCube. .00 All prices are NET prices.
Metsemakers, W.
J. et al.
Fracture-related infection: a consensus on definition from an international expert group.
Injury 49 , 505, 510 (2018).
This paper describes the first consensus definition for FRI and is a seminal work in FRI.
CAS PubMed Google Scholar Metsemakers, W.
J. et al.
General treatment principles for fracture-related infection: recommendations from an international expert group.
Arch.
Orthop.
Trauma Surg. 140 , 1013, 1027 (2020).
PubMed Google Scholar GBD 2019 Fracture Collaborators.
Global, regional, and national burden of bone fractures in 204 countries and territories, 1990, 2019: a systematic analysis from the Global Burden of Disease Study 2019.
Lancet Healthy Longev. 2 , e580, e592 (2021).
Google Scholar Wildemann, B. et al.
Non-union bone fractures.
Nat.
Rev.
Dis.
Primers 7 , 57 (2021).
PubMed Google Scholar Papakostidis, C. et al.
Prevalence of complications of open tibial shaft fractures stratified as per the Gustilo, Anderson classification.
Injury 42 , 1408, 1415 (2011).
PubMed Google Scholar Court-Brown, C.
M. & McQueen, M.
M.
Global forum: fractures in the elderly.
J.
Bone Jt Surg.
Am. 98 , e36 (2016).
Google Scholar iHealthcareAnalyst.
Bone fracture repair device market .3 billion by 2029. iHealthcareAnalyst https://www.ihealthcareanalyst.com/global-bone-fracture-repair-devices-market/ (2022).
McQuillan, T.
J., Cai, L.
Z., Corcoran-Schwartz, I., Weiser, T.
G. & Forrester, J.
D.
Surgical site infections after open reduction internal fixation for trauma in low and middle human development index countries: a systematic review.
Surg.
Infect. 19 , 254, 263 (2018).
Google Scholar Gustilo, R.
B., Merkow, R.
L. & Templeman, D.
The management of open fractures.
J.
Bone Jt Surg.
Am. 72 , 299, 304 (1990).
CAS Google Scholar Obremskey, W.
T. et al.
Musculoskeletal infection in orthopaedic trauma: assessment of the 2018 International Consensus Meeting on Musculoskeletal Infection.
J.
Bone Jt Surg.
Am. 102 , e44 (2020).
Google Scholar Morgenstern, M. et al.
The effect of local antibiotic prophylaxis when treating open limb fractures: a systematic review and meta-analysis.
Bone Jt Res. 7 , 447, 456 (2018).
CAS Google Scholar Kortram, K. et al.
Risk factors for infectious complications after open fractures; a systematic review and meta-analysis.
Int.
Orthop. 41 , 1965, 1982 (2017).
PubMed Google Scholar Gortler, H. et al.
Diabetes and healing outcomes in lower extremity fractures: a systematic review.
Injury 49 , 177, 183 (2018).
PubMed Google Scholar Tacconelli, E. & Pezzani, M.
D.
Public health burden of antimicrobial resistance in Europe.
Lancet Infect.
Dis. 19 , 4, 6 (2019).
PubMed Google Scholar Centers for Disease Control and Prevention.
Infographic: Antibiotic Resistance: The Global Threat.
Center for Global Health https://www.cdc.gov/globalhealth/infographics/antibiotic-resistance/antibiotic_resistance_global_threat.htm (2019).
The World Bank.
Drug-resistant infections: a threat to our economic future.
The World Bank . https://www.worldbank.org/en/topic/health/publication/drug-resistant-infections-a-threat-to-our-economic-future (2017).
Vedadhir, A.
A., Rodrigues, C. & Lambert, H.
Social science research contributions to antimicrobial resistance: protocol for a scoping review.
Syst.
Rev. 9 , 24 (2020).
PubMed PubMed Central Google Scholar Metsemakers, W.
J. et al.
Antimicrobial resistance, the COVID-19 pandemic, and lessons for the orthopaedic community.
J.
Bone Jt Surg.
Am. 103 , 4, 9 (2021).
Google Scholar Cassini, A. et al.
Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis.
Lancet Infect.
Dis. 19 , 56, 66 (2019).
PubMed PubMed Central Google Scholar David, M.
Z. & Daum, R.
S.
Community-associated methicillin-resistant Staphylococcus aureus : epidemiology and clinical consequences of an emerging epidemic.
Clin.
Microbiol.
Rev. 23 , 616, 687 (2010).
CAS PubMed PubMed Central Google Scholar Kuehl, R. et al.
Time-dependent differences in management and microbiology of orthopaedic internal fixation-associated infections: an observational prospective study with 229 patients.
Clin.
Microbiol.
Infect. 25 , 76, 81 (2019).
CAS PubMed Google Scholar Rupp, M. et al.
Is there a difference in microbiological epidemiology and effective empiric antimicrobial therapy comparing fracture-related infection and periprosthetic joint infection?
A retrospective comparative study.
Antibiotics https://doi.org/10.3390/antibiotics10080921 (2021).
Article PubMed PubMed Central Google Scholar Sudduth, J.
D. et al.
Open fractures: are we still treating the same types of infections?
Surg.
Infect. 21 , 766, 772 (2020).
Google Scholar Hu, F., Wang, M., Zhu, D. & Wang, F.
CHINET efforts to control antimicrobial resistance in China.
J.
Glob.
Antimicrob.
Resist. 21 , 76, 77 (2020).
PubMed Google Scholar Peng, J. et al.
Epidemiological, clinical and microbiological characteristics of patients with post-traumatic osteomyelitis of limb fractures in Southwest China: a hospital-based study.
J.
Bone Jt Infect. 2 , 149, 153 (2017).
PubMed PubMed Central Google Scholar Wang, B. et al.
Epidemiology and microbiology of fracture-related infection: a multicenter study in Northeast China.
J.
Orthop.
Surg.
Res. 16 , 490 (2021).
PubMed PubMed Central Google Scholar Pollard, T.
C., Newman, J.
E., Barlow, N.
J., Price, J.
D. & Willett, K.
M.
Deep wound infection after proximal femoral fracture: consequences and costs.
J.
Hosp.
Infect. 63 , 133, 139 (2006).
CAS PubMed Google Scholar Edwards, C., Counsell, A., Boulton, C. & Moran, C.
G.
Early infection after hip fracture surgery: risk factors, costs and outcome.
J.
Bone Jt Surg.
Br. 90 , 770, 777 (2008).
CAS Google Scholar Anderson, D.
J. et al.
Clinical and financial outcomes due to methicillin resistant Staphylococcus aureus surgical site infection: a multi-center matched outcomes study.
PLoS ONE 4 , e8305 (2009).
PubMed PubMed Central Google Scholar Dudareva, M. et al.
The microbiology of chronic osteomyelitis: changes over ten years.
J.
Infect. 79 , 189, 198 (2019).
PubMed Google Scholar World Health Organization.
Antimicrobial resistance.
World Health Organization https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance (2021).
Trampuz, A. & Zimmerli, W.
Diagnosis and treatment of infections associated with fracture-fixation devices.
Injury 37 (Suppl. 2), S59, S66 (2006).
PubMed Google Scholar Fang, C. et al.
Infection after fracture osteosynthesis, Part I.
J.
Orthop.
Surg. 25 , 2309499017692712 (2017).
Google Scholar Zimmerli, W.
Clinical presentation and treatment of orthopaedic implant-associated infection.
J.
Intern.
Med. 276 , 111, 119 (2014).
CAS PubMed Google Scholar Depypere, M. et al.
Pathogenesis and management of fracture-related infection.
Clin.
Microbiol.
Infect. 26 , 572, 578 (2020).
CAS PubMed Google Scholar Chen, A.
F., Wessel, C.
B. & Rao, N.
Staphylococcus aureus screening and decolonization in orthopaedic surgery and reduction of surgical site infections.
Clin.
Orthop.
Relat.
Res. 471 , 2383, 2399 (2013).
PubMed PubMed Central Google Scholar Berthelot, P. et al.
Is nasal carriage of Staphylococcus aureus the main acquisition pathway for surgical-site infection in orthopaedic surgery.
Eur.
J.
Clin.
Microbiol.
Infect.
Dis. 29 , 373, 382 (2010).
CAS PubMed Google Scholar Metsemakers, W.
J. et al.
Prevention of fracture-related infection: a multidisciplinary care package.
Int.
Orthop. 41 , 2457, 2469 (2017).
PubMed Google Scholar Moriarty, T.
F. et al.
Orthopaedic device-related infection: current and future interventions for improved prevention and treatment.
EFORT Open Rev. 1 , 89, 99 (2016).
PubMed PubMed Central Google Scholar Duckworth, A.
D. et al.
Deep infection after hip fracture surgery: predictors of early mortality.
Injury 43 , 1182, 1186 (2012).
PubMed Google Scholar Hudek, R. et al.
Cutibacterium acnes is an intracellular and intra-articular commensal of the human shoulder joint.
J.
Shoulder Elb.
Surg. 30 , 16, 26 (2021).
Google Scholar Burns, T.
C. et al.
Microbiology and injury characteristics in severe open tibia fractures from combat.
J.
Trauma.
Acute Care Surg. 72 , 1062, 1067 (2012).
PubMed Google Scholar Oliveira, P.
R. et al.
The incidence and microbiological profile of surgical site infections following internal fixation of closed and open fractures.
Rev.
Bras.
Ortop. 51 , 396, 399 (2016).
PubMed PubMed Central Google Scholar Johnson, E.
N., Burns, T.
C., Hayda, R.
A., Hospenthal, D.
R. & Murray, C.
K.
Infectious complications of open type III tibial fractures among combat casualties.
Clin.
Infect.
Dis. 45 , 409, 415 (2007).
PubMed Google Scholar Mertens, B. et al.
Isavuconazole in the treatment of Aspergillus fumigatus fracture-related infection: case report and literature review.
Antibiotics 11 , 344 (2022).
PubMed PubMed Central Google Scholar Koehler, P., Tacke, D. & Cornely, O.
A.
Bone and joint infections by Mucorales, Scedosporium, Fusarium and even rarer fungi.
Crit.
Rev.
Microbiol. 42 , 158, 171 (2016).
PubMed Google Scholar Law, M.
D.
Jr. & Stein, R.
E.
Late infection in healed fractures after open reduction and internal fixation.
Orthop.
Rev. 22 , 545, 552 (1993).
PubMed Google Scholar Murdoch, D.
R. et al.
Infection of orthopedic prostheses after Staphylococcus aureus bacteremia.
Clin.
Infect.
Dis. 32 , 647, 649 (2001).
CAS PubMed Google Scholar Masters, E.
A. et al.
Evolving concepts in bone infection: redefining “biofilm”, “acute vs. chronic osteomyelitis”, “the immune proteome” and “local antibiotic therapy”.
Bone Res. 7 , 20 (2019).
PubMed PubMed Central Google Scholar Masters, E.
A. et al.
Identification of penicillin binding protein 4 (PBP4) as a critical factor for Staphylococcus aureus bone invasion during osteomyelitis in mice.
PLoS Pathog. 16 , e1008988 (2020).
This paper identifies mechanisms of S. aureus invasion of bone OLCN and is a major discovery in the field.
CAS PubMed PubMed Central Google Scholar Nishitani, K. et al.
Quantifying the natural history of biofilm formation in vivo during the establishment of chronic implant-associated Staphylococcus aureus osteomyelitis in mice to identify critical pathogen and host factors.
J.
Orthop.
Res. 33 , 1311, 1319 (2015).
PubMed PubMed Central Google Scholar Brandt, S.
L., Putnam, N.
E., Cassat, J.
E. & Serezani, C.
H.
Innate immunity to Staphylococcus aureus : evolving paradigms in soft tissue and invasive infections.
J.
Immunol. 200 , 3871, 3880 (2018).
CAS PubMed Google Scholar Farnsworth, C.
W. et al.
Adaptive upregulation of clumping factor A (ClfA) by Staphylococcus aureus in the obese, type 2 diabetic host mediates increased virulence.
Infect.
Immun. https://doi.org/10.1128/iai.01005-16 (2017).
Article PubMed PubMed Central Google Scholar Muthukrishnan, G. et al.
Humanized mice exhibit exacerbated abscess formation and osteolysis during the establishment of implant-associated Staphylococcus aureus osteomyelitis.
Front.
Immunol. 12 , 651515 (2021).
CAS PubMed PubMed Central Google Scholar Varrone, J.
J., Li, D., Daiss, J.
L. & Schwarz, E.
M.
Anti-glucosaminidase monoclonal antibodies as a passive immunization for methicillin-resistant Staphylococcus aureus (MRSA) orthopaedic infections.
Bonekey Osteovision 8 , 187, 194 (2011).
PubMed PubMed Central Google Scholar Yokogawa, N. et al.
Immunotherapy synergizes with debridement and antibiotic therapy in a murine 1-stage exchange model of MRSA implant-associated osteomyelitis.
J.
Orthop.
Res. 36 , 1590, 1598 (2018).
CAS PubMed PubMed Central Google Scholar Hofstee, M.
I. et al.
A murine Staphylococcus aureus fracture-related infection model characterised by fracture non-union, staphylococcal abscess communities and myeloid-derived suppressor cells.
Eur.
Cell Mater. 41 , 774, 792 (2021).
CAS PubMed Google Scholar Rauch, S. et al.
Abscess formation and alpha-hemolysin induced toxicity in a mouse model of Staphylococcus aureus peritoneal infection.
Infect.
Immun. 80 , 3721, 3732 (2012).
CAS PubMed PubMed Central Google Scholar Thammavongsa, V., Missiakas, D.
M. & Schneewind, O.
Staphylococcus aureus degrades neutrophil extracellular traps to promote immune cell death.
Science 342 , 863, 866 (2013).
CAS PubMed PubMed Central Google Scholar Tebartz, C. et al.
A major role for myeloid-derived suppressor cells and a minor role for regulatory T cells in immunosuppression during Staphylococcus aureus infection.
J.
Immunol. 194 , 1100, 1111 (2015).
CAS PubMed Google Scholar Masters, E.
A. et al.
Distinct vasculotropic versus osteotropic features of S. agalactiae versus S. aureus implant-associated bone infection in mice.
J.
Orthop.
Res. 39 , 389, 401 (2021).
CAS PubMed Google Scholar Soe, Y.
M., Bedoui, S., Stinear, T.
P. & Hachani, A.
Intracellular Staphylococcus aureus and host cell death pathways.
Cell Microbiol. 23 , e13317 (2021).
CAS PubMed Google Scholar Tuchscherr, L., Loffler, B. & Proctor, R.
A.
Persistence of Staphylococcus aureus : multiple metabolic pathways impact the expression of virulence factors in small-colony variants (SCVs).
Front.
Microbiol. 11 , 1028 (2020).
PubMed PubMed Central Google Scholar Glatt, V., Evans, C.
H. & Tetsworth, K.
A concert between biology and biomechanics: the influence of the mechanical environment on bone healing.
Front.
Physiol. 7 , 678 (2016).
PubMed Google Scholar Duchamp de Lageneste, O. et al.
Periosteum contains skeletal stem cells with high bone regenerative potential controlled by Periostin.
Nat.
Commun. 9 , 773 (2018).
PubMed PubMed Central Google Scholar Bahney, C.
S. et al.
Cellular biology of fracture healing.
J.
Orthop.
Res. 37 , 35, 50 (2019).
PubMed Google Scholar Maruyama, M. et al.
Modulation of the inflammatory response and bone healing.
Front.
Endocrinol. https://doi.org/10.3389/fendo.2020.00386 (2020).
Article Google Scholar Hoff, P. et al.
Immunological characterization of the early human fracture hematoma.
Immunol.
Res. 64 , 1195, 1206 (2016).
CAS PubMed Google Scholar Morgenstern, M. et al.
Diagnostic challenges and future perspectives in fracture-related infection.
Injury 49 (Suppl. 1), S83, S90 (2018).
PubMed Google Scholar Metsemakers, W.
J. et al.
Infection after fracture fixation: current surgical and microbiological concepts.
Injury 49 , 511, 522 (2018).
CAS PubMed Google Scholar Mbalaviele, G., Novack, D.
V., Schett, G. & Teitelbaum, S.
L.
Inflammatory osteolysis: a conspiracy against bone.
J.
Clin.
Invest. 127 , 2030, 2039 (2017).
PubMed PubMed Central Google Scholar Wei, S., Kitaura, H., Zhou, P., Ross, F.
P. & Teitelbaum, S.
L.
IL-1 mediates TNF-induced osteoclastogenesis.
J.
Clin.
Invest. 115 , 282, 290 (2005).
CAS PubMed PubMed Central Google Scholar Lam, J. et al.
TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand.
J.
Clin.
Invest. 106 , 1481, 1488 (2000).
CAS PubMed PubMed Central Google Scholar Dewhirst, F.
E., Stashenko, P.
P., Mole, J.
E. & Tsurumachi, T.
Purification and partial sequence of human osteoclast-activating factor: identity with interleukin 1 beta.
J.
Immunol. 135 , 2562, 2568 (1985).
CAS PubMed Google Scholar O’Brien, C.
A., Gubrij, I., Lin, S.
C., Saylors, R.
L. & Manolagas, S.
C.
STAT3 activation in stromal/osteoblastic cells is required for induction of the receptor activator of NF-κB ligand and stimulation of osteoclastogenesis by gp130-utilizing cytokines or interleukin-1 but not 1,25-dihydroxyvitamin D 3 or parathyroid hormone.
J.
Biol.
Chem. 274 , 19301, 19308 (1999).
PubMed Google Scholar Hofbauer, L.
C. et al.
Interleukin-1α and tumor necrosis factor-α, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells.
Bone 25 , 255, 259 (1999).
CAS PubMed Google Scholar Shiratori, T. et al.
IL-1β induces pathologically activated osteoclasts bearing extremely high levels of resorbing activity: a possible pathological subpopulation of osteoclasts, accompanied by suppressed expression of Kindlin-3 and Talin-1.
J.
Immunol. 200 , 218, 228 (2018).
CAS PubMed Google Scholar Jimi, E. et al.
Interleukin 1 induces multinucleation and bone-resorbing activity of osteoclasts in the absence of osteoblasts/stromal cells.
Exp.
Cell Res. 247 , 84, 93 (1999).
CAS PubMed Google Scholar Putnam, N.
E. et al.
MyD88 and IL-1R signaling drive antibacterial immunity and osteoclast-driven bone loss during Staphylococcus aureus osteomyelitis.
PLoS Pathog. 15 , e1007744 (2019).
CAS PubMed PubMed Central Google Scholar Wang, Y. et al.
Interleukin-1β and tumor necrosis factor are essential in controlling an experimental orthopedic implant-associated infection.
J.
Orthop.
Res. 38 , 1800, 1809 (2020).
CAS PubMed PubMed Central Google Scholar Yang, D. et al.
Novel insights into Staphylococcus aureus deep bone infections: the involvement of osteocytes. mBio 9 , e00415-18 (2018).
PubMed PubMed Central Google Scholar Claro, T. et al.
Staphylococcus aureus protein A binding to osteoblast tumour necrosis factor receptor 1 results in activation of nuclear factor kappa B and release of interleukin-6 in bone infection.
Microbiology 159 , 147, 154 (2013).
CAS PubMed Google Scholar Widaa, A., Claro, T., Foster, T.
J., O’Brien, F.
J. & Kerrigan, S.
W.
Staphylococcus aureus protein A plays a critical role in mediating bone destruction and bone loss in osteomyelitis.
PLoS ONE 7 , e40586 (2012).
CAS PubMed PubMed Central Google Scholar Claro, T. et al.
Staphylococcus aureus protein A binds to osteoblasts and triggers signals that weaken bone in osteomyelitis.
PLoS ONE 6 , e18748 (2011).
CAS PubMed PubMed Central Google Scholar Bertelli, A.
M. et al.
Staphylococcus aureus protein A enhances osteoclastogenesis via TNFR1 and EGFR signaling.
Biochim.
Biophys.
Acta 1862 , 1975, 1983 (2016).
PubMed Central Google Scholar Loughran, A.
J. et al.
Impact of sarA and phenol-soluble modulins on the pathogenesis of osteomyelitis in diverse clinical isolates of Staphylococcus aureus .
Infect.
Immun. 84 , 2586, 2594 (2016).
CAS PubMed PubMed Central Google Scholar Cassat, J.
E. et al.
A secreted bacterial protease tailors the Staphylococcus aureus virulence repertoire to modulate bone remodeling during osteomyelitis.
Cell Host Microbe 13 , 759, 772 (2013).
CAS PubMed PubMed Central Google Scholar Rasigade, J.
P. et al.
PSMs of hypervirulent Staphylococcus aureus act as intracellular toxins that kill infected osteoblasts.
PLoS ONE 8 , e63176 (2013).
CAS PubMed PubMed Central Google Scholar Hendrix, A.
S. et al.
Repurposing the nonsteroidal anti-inflammatory drug diflunisal as an osteoprotective, antivirulence therapy for Staphylococcus aureus osteomyelitis.
Antimicrob.
Agents Chemother. 60 , 5322, 5330 (2016).
CAS PubMed PubMed Central Google Scholar Spaan, A.
N., van Strijp, J.
A.
G. & Torres, V.
J.
Leukocidins: staphylococcal bi-component pore-forming toxins find their receptors.
Nat.
Rev.
Microbiol. 15 , 435, 447 (2017).
CAS PubMed PubMed Central Google Scholar Johnson, C.
T. et al.
Lysostaphin and BMP-2 co-delivery reduces S. aureus infection and regenerates critical-sized segmental bone defects.
Sci.
Adv. 5 , eaaw1228 (2019).
CAS PubMed PubMed Central Google Scholar Klosterhalfen, B. et al.
Local and systemic inflammatory mediator release in patients with acute and chronic posttraumatic osteomyelitis.
J.
Trauma 40 , 372, 378 (1996).
CAS PubMed Google Scholar Sabaté-Brescó, M. et al.
Fracture biomechanics influence local and systemic immune responses in a murine fracture-related infection model.
Biol.
Open 10 , bio057315 (2021).
PubMed PubMed Central Google Scholar Kobayashi, S.
D., Malachowa, N. & DeLeo, F.
R.
Neutrophils and bacterial immune evasion.
J.
Innate Immun. 10 , 432, 441 (2018).
CAS PubMed PubMed Central Google Scholar Wagner, C. et al.
Polymorphonuclear neutrophils in posttraumatic osteomyelitis: cells recovered from the inflamed site lack chemotactic activity but generate superoxides.
Shock 22 , 108, 115 (2004).
CAS PubMed Google Scholar Wagner, C. et al.
T lymphocytes in implant-associated posttraumatic osteomyelitis: identification of cytotoxic T effector cells at the site of infection.
Shock 25 , 241, 246 (2006).
CAS PubMed Google Scholar Bröker, B.
M., Mrochen, D. & Péton, V.
The T cell response to Staphylococcus aureus .
Pathogens 5 , 31 (2016).
PubMed Central Google Scholar Prabhakara, R. et al.
Suppression of the inflammatory immune response prevents the development of chronic biofilm infection due to methicillin-resistant Staphylococcus aureus .
Infect.
Immun. 79 , 5010, 5018 (2011).
CAS PubMed PubMed Central Google Scholar Baht, G.
S., Vi, L. & Alman, B.
A.
The role of the immune cells in fracture healing.
Curr.
Osteoporos.
Rep. 16 , 138, 145 (2018).
PubMed PubMed Central Google Scholar Silversides, J.
A., Lappin, E. & Ferguson, A.
J.
Staphylococcal toxic shock syndrome: mechanisms and management.
Curr.
Infect.
Dis.
Rep. 12 , 392, 400 (2010).
PubMed Google Scholar Sokhi, U.
K. et al.
Immune response to persistent Staphyloccocus aureus periprosthetic joint infection in a mouse tibial implant model.
J.
Bone Miner.
Res. https://doi.org/10.1002/jbmr.4489 (2021).
Article PubMed Google Scholar Holtfreter, S., Kolata, J. & Broker, B.
M.
Towards the immune proteome of Staphylococcus aureus , the anti- S. aureus antibody response.
Int.
J.
Med.
Microbiol. 300 , 176, 192 (2010).
CAS PubMed Google Scholar Muthukrishnan, G. et al.
Serum antibodies against Staphylococcus aureus can prognose treatment success in patients with bone infections.
J.
Orthop.
Res. 39 , 2169, 2176 (2021).
CAS PubMed Google Scholar Nishitani, K. et al.
IsdB antibody-mediated sepsis following S. aureus surgical site infection.
JCI Insight https://doi.org/10.1172/jci.insight.141164 (2020).
Article PubMed PubMed Central Google Scholar Govaert, G.
A.
M. et al.
Diagnosing fracture-related infection: current concepts and recommendations.
J.
Orthop.
Trauma 34 , 8, 17 (2020).
PubMed Google Scholar Onsea, J. et al.
Validation of the diagnostic criteria of the consensus definition of fracture-related infection.
Injury https://doi.org/10.1016/j.injury.2022.03.024 (2022).
Article PubMed Google Scholar Govaert, G.
A.
M. & Glaudemans, A.
Nuclear medicine imaging of posttraumatic osteomyelitis.
Eur.
J.
Trauma Emerg.
Surg. 42 , 397, 410 (2016).
CAS PubMed PubMed Central Google Scholar Zhang, Q. et al.
Comparative diagnostic accuracy of respective nuclear imaging for suspected fracture-related infection: a systematic review and Bayesian network meta-analysis.
Arch.
Orthop.
Trauma Surg. 141 , 1115, 1130 (2021).
PubMed Google Scholar van den Kieboom, J. et al.
Diagnostic accuracy of serum inflammatory markers in late fracture-related infection: a systematic review and meta-analysis.
Bone Jt J. 100-B , 1542, 1550 (2018).
Google Scholar Sigmund, I.
K. et al.
Limited diagnostic value of serum inflammatory biomarkers in the diagnosis of fracture-related infections.
Bone Jt J. 102-B , 904, 911 (2020).
Google Scholar McNally, M., Govaert, G., Dudareva, M., Morgenstern, M. & Metsemakers, W.
J.
Definition and diagnosis of fracture-related infection.
EFORT Open Rev. 5 , 614, 619 (2020).
PubMed PubMed Central Google Scholar Dudareva, M. et al.
Providing an evidence base for tissue sampling and culture interpretation in suspected fracture-related infection.
J.
Bone Jt Surg.
Am. 103 , 977, 983 (2021).
CAS Google Scholar Onsea, J. et al.
Accuracy of tissue and sonication fluid sampling for the diagnosis of fracture-related infection: a systematic review and critical appraisal.
J.
Bone Jt Infect. 3 , 173, 181 (2018).
PubMed PubMed Central Google Scholar Dudareva, M. et al.
Sonication versus tissue sampling for diagnosis of prosthetic joint and other orthopedic device-related infections.
J.
Clin.
Microbiol. 56 , e00688-18 (2018).
PubMed PubMed Central Google Scholar Morgenstern, M. et al.
The value of quantitative histology in the diagnosis of fracture-related infection.
Bone Jt J. 100 - B , 966, 972 (2018).
CAS Google Scholar Lack, W.
D. et al.
Type III open tibia fractures: immediate antibiotic prophylaxis minimizes infection.
J.
Orthop.
Trauma 29 , 1, 6 (2015).
PubMed Google Scholar Vanvelk, N. et al.
Duration of perioperative antibiotic prophylaxis in open fractures: a systematic review and critical appraisal.
Antibiotics https://doi.org/10.3390/antibiotics11030293 (2022).
Article PubMed PubMed Central Google Scholar American Academy of Orthopaedic Surgeons.
Prevention of surgical site infection after major extremity trauma: clinical practice guideline.
American Academy of Orthopaedic Surgeons https://www.aaos.org/globalassets/quality-and-practice-resources/dod/ssitrauma/ssitraumacpg.pdf (2022).
Metsemakers, W.
J., Moriarty, T.
F., Nijs, S., Pape, H.
C. & Richards, R.
G.
Influence of implant properties and local delivery systems on the outcome in operative fracture care.
Injury 47 , 595, 604 (2016).
PubMed Google Scholar Major Extremity Trauma Research Consortium (METRC) Effect of intrawound vancomycin powder in operatively treated high-risk tibia fractures: a randomized clinical trial.
JAMA Surg. 156 , e207259 (2021).
Google Scholar Zalavras, C.
G.
Prevention of infection in open fractures.
Infect.
Dis.
Clin.
North Am. 31 , 339, 352 (2017).
PubMed Google Scholar Kaysinger, K.
K., Nicholson, N.
C., Ramp, W.
K. & Kellam, J.
F.
Toxic effects of wound irrigation solutions on cultured tibiae and osteoblasts.
J.
Orthop.
Trauma 9 , 303, 311 (1995).
CAS PubMed Google Scholar Crowley, D.
J., Kanakaris, N.
K. & Giannoudis, P.
V.
Debridement and wound closure of open fractures: the impact of the time factor on infection rates.
Injury 38 , 879, 889 (2007).
CAS PubMed Google Scholar Lineaweaver, W. et al.
Topical antimicrobial toxicity.
Arch.
Surg. 120 , 267, 270 (1985).
CAS PubMed Google Scholar Bhandari, M. et al.
A trial of wound irrigation in the initial management of open fracture wounds.
N.
Engl.
J.
Med. 373 , 2629, 2641 (2015).
CAS PubMed Google Scholar Dirschl, D.
R. et al.
High pressure pulsatile lavage irrigation of intraarticular fractures: effects on fracture healing.
J.
Orthop.
Trauma 12 , 460, 463 (1998).
CAS PubMed Google Scholar Owens, B.
D., White, D.
W. & Wenke, J.
C.
Comparison of irrigation solutions and devices in a contaminated musculoskeletal wound survival model.
J.
Bone Jt Surg.
Am. 91 , 92, 98 (2009).
Google Scholar Costa, M.
L. et al.
Effect of negative pressure wound therapy vs standard wound management on 12-month disability among adults with severe open fracture of the lower limb: the WOLLF randomized clinical trial.
JAMA 319 , 2280, 2288 (2018).
PubMed PubMed Central Google Scholar Greene, L.
R.
Guide to the elimination of orthopedic surgery surgical site infections: an executive summary of the Association for Professionals in Infection Control and Epidemiology elimination guide.
Am.
J.
Infect.
Control 40 , 384, 386 (2012).
PubMed Google Scholar Barlam, T.
F. et al.
Executive summary: implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America.
Clin.
Infect.
Dis. 62 , 1197, 1202 (2016).
PubMed Google Scholar Goff, D.
A. et al.
A global call from five countries to collaborate in antibiotic stewardship: united we succeed, divided we might fail.
Lancet Infect.
Dis. 17 , e56, e63 (2017).
PubMed Google Scholar Tetsworth, K. & Cierny, G.
III Osteomyelitis debridement techniques.
Clin.
Orthop.
Relat.
Res. 360 , 87, 96 (1999).
Google Scholar Foster, A.
L. et al.
The influence of biomechanical stability on bone healing and fracture-related infection: the legacy of Stephan Perren.
Injury 52 , 43, 52 (2021).
PubMed Google Scholar Rittmann, W.
W. & Perren, S.
M.
Cortical Bone Healing after Internal Fixation and Infection: Biomechanics and Biology (Springer, 1974).
This book is the seminal work on the interaction between the benefits of fracture stability for healing, even in the presence of infection.
Morgenstern, M. et al.
The influence of duration of infection on outcome of debridement and implant retention in fracture-related infection.
Bone Jt J. 103-B , 213, 221 (2021).
Google Scholar Depypere, M. et al.
Recommendations for systemic antimicrobial therapy in fracture-related infection: a consensus from an international expert group.
J.
Orthop.
Trauma 34 , 30, 41 (2020).
PubMed Google Scholar Bernard, L. et al.
Antibiotic therapy for 6 or 12 weeks for prosthetic joint infection.
N.
Engl.
J.
Med. 384 , 1991, 2001 (2021).
CAS PubMed Google Scholar Li, H.
K. et al.
Oral versus intravenous antibiotic treatment for bone and joint infections (OVIVA): study protocol for a randomised controlled trial.
Trials 16 , 583 (2015).
CAS PubMed PubMed Central Google Scholar Li, H.
K. et al.
Oral versus intravenous antibiotics for bone and joint infection.
N.
Engl.
J.
Med. 380 , 425, 436 (2019).
CAS PubMed PubMed Central Google Scholar Zimmerli, W., Widmer, A.
F., Blatter, M., Frei, R. & Ochsner, P.
E.
Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial.
Foreign-Body Infection (FBI) Study Group.
JAMA 279 , 1537, 1541 (1998).
This paper revealed the crucial role for rifampicin in the treatment of staphylococcal implant-related biofilm infections and set the standard of care for decades thereafter.
CAS PubMed Google Scholar Karlsen, O.
E. et al.
Rifampin combination therapy in staphylococcal prosthetic joint infections: a randomized controlled trial.
J.
Orthop.
Surg.
Res. 15 , 365 (2020).
PubMed PubMed Central Google Scholar Widmer, A.
F., Gaechter, A., Ochsner, P.
E. & Zimmerli, W.
Antimicrobial treatment of orthopedic implant-related infections with rifampin combinations.
Clin.
Infect.
Dis. 14 , 1251, 1253 (1992).
CAS PubMed Google Scholar Beldman, M. et al.
If, when, and how to use rifampin in acute staphylococcal periprosthetic joint infections, a multicentre observational study.
Clin.
Infect.
Dis. 73 , 1634, 1641 (2021).
CAS PubMed PubMed Central Google Scholar Tsegka, K.
G., Voulgaris, G.
L., Kyriakidou, M., Kapaskelis, A. & Falagas, M.
E.
Intravenous fosfomycin for the treatment of patients with bone and joint infections: a review.
Expert Rev.
Anti Infect.
Ther. 20 , 33, 43 (2022).
CAS PubMed Google Scholar Martinez-Pastor, J.
C. et al.
Outcome of acute prosthetic joint infections due to gram-negative bacilli treated with open debridement and retention of the prosthesis.
Antimicrob.
Agents Chemother. 53 , 4772, 4777 (2009).
CAS PubMed PubMed Central Google Scholar Lee, Y. et al.
Rifamycin resistance, rpoB gene mutation and clinical outcomes of Staphylococcus species isolates from prosthetic joint infections in Republic of Korea.
J.
Glob.
Antimicrob.
Resist. 28 , 43, 48 (2022).
CAS PubMed Google Scholar Telles, J.
P., Cieslinski, J. & Tuon, F.
F.
Daptomycin to bone and joint infections and prosthesis joint infections: a systematic review.
Braz.
J.
Infect.
Dis. 23 , 191, 196 (2019).
PubMed PubMed Central Google Scholar Hall Snyder, A.
D., Vidaillac, C., Rose, W., McRoberts, J.
P. & Rybak, M.
J.
Evaluation of high-dose daptomycin versus vancomycin alone or combined with clarithromycin or rifampin against Staphylococcus aureus and S. epidermidis in a novel in vitro PK/PD model of bacterial biofilm.
Infect.
Dis.
Ther. 4 , 51, 65 (2014).
PubMed Central Google Scholar Mihailescu, R. et al.
High activity of Fosfomycin and Rifampin against methicillin-resistant staphylococcus aureus biofilm in vitro and in an experimental foreign-body infection model.
Antimicrob.
Agents Chemother. 58 , 2547, 2553 (2014).
PubMed PubMed Central Google Scholar Oliva, A. et al.
Activities of fosfomycin and rifampin on planktonic and adherent Enterococcus faecalis strains in an experimental foreign-body infection model.
Antimicrob.
Agents Chemother. 58 , 1284, 1293 (2014).
PubMed PubMed Central Google Scholar Trautmann, M., Meincke, C., Vogt, K., Ruhnke, M. & Lajous-Petter, A.
M.
Intracellular bactericidal activity of fosfomycin against staphylococci: a comparison with other antibiotics.
Infection 20 , 350, 354 (1992).
CAS PubMed Google Scholar Metsemakers, W.
J. et al.
Evidence-based recommendations for local antimicrobial strategies and dead space management in fracture-related infection.
J.
Orthop.
Trauma 34 , 18, 29 (2020).
PubMed Google Scholar Garabano, G., Del Sel, H., Rodriguez, J.
A., Perez Alamino, L. & Pesciallo, C.
A.
The effectiveness of antibiotic cement-coated nails in post-traumatic femoral and tibial osteomyelitis, comparative analysis of custom-made versus commercially available nails.
J.
Bone Jt Infect. 6 , 457, 466 (2021).
CAS PubMed PubMed Central Google Scholar Neut, D. et al.
Biomaterial-associated infection of gentamicin-loaded PMMA beads in orthopaedic revision surgery.
J.
Antimicrob.
Chemother. 47 , 885, 891 (2001).
CAS PubMed Google Scholar Schwarz, E.
M. et al.
Adjuvant antibiotic-loaded bone cement: concerns with current use and research to make it work.
J.
Orthop.
Res. 39 , 227, 239 (2021).
CAS PubMed Google Scholar Malat, T.
A., Glombitza, M., Dahmen, J., Hax, P.
M. & Steinhausen, E.
The use of bioactive glass S53P4 as bone graft substitute in the treatment of chronic osteomyelitis and infected non-unions, a retrospective study of 50 patients.
Z.
Orthop.
Unf. 156 , 152, 159 (2018).
Google Scholar Iliaens, J. et al.
Fracture-related infection in long bone fractures: a comprehensive analysis of the economic impact and influence on quality of life.
Injury 52 , 3344, 3349 (2021).
PubMed Google Scholar Morgenstern, M. et al.
The AO trauma CPP bone infection registry: epidemiology and outcomes of Staphylococcus aureus bone infection.
J.
Orthop.
Res. 39 , 136, 146 (2021).
CAS PubMed Google Scholar Walter, N. et al.
Long-term patient-related quality of life after fracture-related infections of the long bones.
Bone Jt Res. 10 , 321, 327 (2021).
Google Scholar Hotchen, A.
J., Dudareva, M., Corrigan, R.
A., Ferguson, J.
Y. & McNally, M.
A.
Can we predict outcome after treatment of long bone osteomyelitis?
Bone Jt J. 102-B , 1587, 1596 (2020).
Google Scholar Ziegler, P. et al.
Quality of life and clinical-radiological long-term results after implant-associated infections in patients with ankle fracture: a retrospective matched-pair study.
J.
Orthop.
Surg.
Res. 12 , 114 (2017).
PubMed PubMed Central Google Scholar Thakore, R.
V. et al.
Surgical site infection in orthopedic trauma: a case-control study evaluating risk factors and cost.
J.
Clin.
Orthop.
Trauma 6 , 220, 226 (2015).
PubMed PubMed Central Google Scholar Metsemakers, W.
J., Smeets, B., Nijs, S. & Hoekstra, H.
Infection after fracture fixation of the tibia: analysis of healthcare utilization and related costs.
Injury 48 , 1204, 1210 (2017).
PubMed Google Scholar Malizos, K. et al.
Fast-resorbable antibiotic-loaded hydrogel coating to reduce post-surgical infection after internal osteosynthesis: a multicenter randomized controlled trial.
J.
Orthop.
Traumatol. 18 , 159, 169 (2017).
PubMed PubMed Central Google Scholar Ter Boo, G.
J. et al.
Local application of a gentamicin-loaded thermo-responsive hydrogel allows for fracture healing upon clearance of a high Staphylococcus aureus load in a rabbit model.
Eur.
Cell Mater. 35 , 151, 164 (2018).
PubMed Google Scholar Ter Boo, G.
A. et al.
Injectable gentamicin-loaded thermo-responsive hyaluronic acid derivative prevents infection in a rabbit model.
Acta Biomater. 43 , 185, 194 (2016).
PubMed Google Scholar Vallejo Diaz, A. et al.
Local application of a gentamicin-loaded hydrogel early after injury is superior to perioperative systemic prophylaxis in a rabbit open fracture model.
J.
Orthop.
Trauma. 34 , 231, 237 (2020).
PubMed Google Scholar Boot, W. et al.
A hyaluronic acid hydrogel loaded with gentamicin and vancomycin successfully eradicates chronic methicillin-resistant Staphylococcus aureus orthopedic infection in a sheep model.
Antimicrob.
Agents Chemother. https://doi.org/10.1128/AAC.01840-20 (2021).
Article PubMed PubMed Central Google Scholar Foster, A.
L. et al.
Single-stage revision of MRSA orthopedic device-related infection in sheep with an antibiotic-loaded hydrogel.
J.
Orthop.
Res. 39 , 438, 448 (2021).
CAS PubMed Google Scholar Onsea, J. et al.
Bacteriophage therapy as a treatment strategy for orthopaedic-device-related infections: where do we stand.
Eur.
Cell Mater. 39 , 193, 210 (2020).
CAS PubMed Google Scholar Uyttebroek, S. et al.
Safety and efficacy of phage therapy in difficult-to-treat infections: a systematic review.
Lancet Infect.
Dis. 22 , e208, e220 (2022).
CAS PubMed Google Scholar Adjei-Sowah, E. et al.
Development of bisphosphonate-conjugated antibiotics to overcome pharmacodynamic limitations of local therapy: initial results with carbamate linked sitafloxacin and tedizolid.
Antibiotics https://doi.org/10.3390/antibiotics10060732 (2021).
Article PubMed PubMed Central Google Scholar Proctor, R.
A.
Recent developments for Staphylococcus aureus vaccines: clinical and basic science challenges.
Eur.
Cell Mater. 30 , 315, 326 (2015).
CAS PubMed Google Scholar Yokogawa, N. et al.
Immunotherapy synergizes with debridement and antibiotic therapy in a murine 1-stage exchange model of MRSA implant-associated osteomyelitis.
J.
Orthop.
Res. 36 , 1590, 1598 (2018).
CAS PubMed PubMed Central Google Scholar US National Library of Medicine.
ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04763759 (2022).
Estelles, A. et al.
A high-affinity native human antibody disrupts biofilm from Staphylococcus aureus bacteria and potentiates antibiotic efficacy in a mouse implant infection model.
Antimicrob.
Agents Chemother. 60 , 2292, 2301 (2016).
CAS PubMed PubMed Central Google Scholar Ghimire, A., Skelly, J.
D. & Song, J.
Micrococcal-nuclease-triggered on-demand release of vancomycin from intramedullary implant coating eradicates Staphylococcus aureus infection in mouse femoral canals.
ACS Cent.
Sci. 5 , 1929, 1936 (2019).
CAS PubMed PubMed Central Google Scholar Li, C., Foster, A.
L., Han, N.
H.
B., Trampuz, A. & Schuetz, M.
A bibliometric analysis of clinical research on fracture-related infection.
BioMed.
Res.
Int. 2022 , 8171831 (2022).
PubMed PubMed Central Google Scholar Rupp, M. et al.
Can necrotic bone be objectively identified in chronic fracture related infections? , First clinical experience with an intraoperative fluorescence imaging technique.
Injury 51 , 2541, 2545 (2020).
PubMed Google Scholar Colton, C., Buckley, R. & Camuso M.
Principles of management of open fractures: Classification of open fractures.
AO Foundation https://surgeryreference.aofoundation.org/orthopedic-trauma/adult-trauma/further-reading/principles-of-management-of-open-fractures#classification-of-open-fractures (2018).
Wang, X. et al.
Increased intracellular activity of MP1102 and NZ2114 against Staphylococcus aureus in vitro and in vivo.
Sci.
Rep. 8 , 4204 (2018).
PubMed PubMed Central Google Scholar Becker, K., Kriegeskorte, A., Sunderkötter, C., Löffler, B. & von Eiff, C.
Chronisch rezidivierende Infektionen der Haut und Weichgewebe durch Staphylococcus aureus [German].
Hautarzt 65 , 15, 25 (2014).
CAS PubMed Google Scholar Moriarty, T.
F. et al.
Bone infection: a clinical priority for clinicians, scientists and educators.
Eur.
Cell Mater. 42 , 312, 333 (2021).
CAS PubMed Google Scholar Download references T.F.M., R.G.R. and E.M.S. acknowledge support from AOTrauma through the clinical priority program Bone Infection.
These authors contributed equally: T.
Fintan Moriarty and Willem-Jan Metsemakers.
AO Research Institute Davos, Davos, Switzerland T.
Fintan Moriarty, Marloes I.
Hofstee & R.
Geoff Richards Center for Musculoskeletal Infections, Department of Orthopaedic and Trauma Surgery, University Hospital Basel, Basel, Switzerland T.
Fintan Moriarty & Mario Morgenstern Department of Trauma Surgery, University Hospitals Leuven, Leuven, Belgium Willem-Jan Metsemakers Department of Development and Regeneration, KU Leuven, Leuven, Belgium Willem-Jan Metsemakers Department of Orthopedics and Traumatology, Hospital Alma Mater de Antioquia, Medellín, Colombia Alejandro Vallejo Diaz Department of Orthopedics and Traumatology, Universidad Pontificia Bolivariana, Medellín, Colombia Alejandro Vallejo Diaz Department of Paediatrics, Vanderbilt University Medical Center, Nashville, TN, USA James E.
Cassat Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA James E.
Cassat Department of Biomedical Engineering, Vanderbilt University Medical Center, Nashville, TN, USA James E.
Cassat Experimental Trauma Surgery, Department of Trauma, Hand and Reconstructive Surgery, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany Britt Wildemann Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium Melissa Depypere Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical Bacteriology and Mycology, KU Leuven, Leuven, Belgium Melissa Depypere Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA Edward M.
Schwarz School of Veterinary Science, Aberystwyth University, Aberystwyth, UK R.
Geoff Richards You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar 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.).
Correspondence to R.
Geoff Richards .
The authors declare no competing interests.
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.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. (FRI).
Infection associated with a bone fracture, with or without operative management.
Inflammation of bone and bone marrow, most commonly due to bacterial infection. (PJI).
Infection associated with an artificial joint involving bone, surrounding soft tissues and/or bacterial colonization of the surface of the implant.
Movement across a fracture gap due to lack of fixation, or insufficient fixation.
A fracture that does not heal within the usual time frame, and one later-stage outcome of an intermediate step called delayed union.
Fractures that do not cause the overlying skin to break.
Bone fractures further complicated by substantial soft tissue or bone damage.
Bone fractures where the overlying skin is breached.
The most widely accepted, standardized classification system of open fractures, based on wound size, bone damage and vascular damage. (ISS).
A standardized system to score trauma severity that accounts for injuries to the musculoskeletal and other body systems. (AMR).
The ability of microorganisms to withstand antimicrobial treatment.
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. (SAC).
An accumulation of many S. aureus bacterial cells within a self-produced fibrin pseudocapsule. (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 .
A surgical procedure to remove necrotic or infected tissue, which includes irrigation, excision and removal of foreign material.
Cells responsible for bone formation.
The addition of minerals (such as calcium or phosphorus) to callus, leading to calcified tissue.
Tissue formed at the fracture site during the healing process, with cartilaginous composition at earlier stages, transitioning to calcified tissue at a later stage.
The formation of bone-resorbing cells, osteoclasts, from myeloid precursor cells.
Pieces of dead bone separated from surrounding bone due to infection and necrosis.
Large group of secreted proteins that are important for cell communication and signalling; during inflammation, they can have pro-inflammatory or anti-inflammatory effects. (RANKL).
A key mediator of bone resorption that stimulates the formation and activity of osteoclasts by binding to the RANK receptor.
Cells responsible for bone resorption.
Immature monocytes or neutrophils that have immunosuppressive abilities; these cells proliferate in response to the prolonged presence of myeloid growth factors and inflammatory molecules.
Small channels from sites of infection to the surface of the skin.
A clinical sign or feature that is characteristic of a disease; in this context, it confirms that an infection is definitely present.
Antibiotic therapy selection when pathogens are unknown but based on anticipated and likely causative organisms.
A key antibiotic owing to its activity against staphylococcal biofilms and stationary phase bacteria.
A class of antibiotics that are particularly important owing to their anti-biofilm activity against Gram-negative bacterial biofilms.
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
Reprints and Permissions 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 Download citation Accepted : 13 September 2022 Published : 20 October 2022 DOI : https://doi.org/10.1038/s41572-022-00396-0 Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article.
Provided by the Springer Nature SharedIt content-sharing initiative Advertisement Nature Reviews Disease Primers ( Nat Rev Dis Primers ) ISSN 2056-676X (online) © 2022 Springer Nature Limited Sign up for the Nature Briefing newsletter , what matters in science, free to your inbox daily. source