1. Infection is the commonest major complication after open trauma and a high level of clinical suspicion is key for early diagnosis.
2. A multidisciplinary approach is mandatory, including orthopaedic and plastic surgeons, microbiology and infectious disease consultants, and radiologists.
3. Evaluation of both local and systemic host factors that predispose to infection, are essential before commencing treatment.
4. Diagnostic work-up commences ideally after stopping antibiotics in stable patients and includes blood cultures if febrile, X-rays for implant loosening and bone changes, ultrasound-guided aspiration, and/or deep tissue sampling. Microbiological diagnosis may be difficult using traditional techniques and culture-negative cases should be treated proactively by a dedicated multidisciplinary team (MDT).
5. Cornerstones of effective treatment are the prompt removal of sessile bacteria within the biofilm by aggressive wound excision and the elimination of planktonic bacteria by targeted, culture-specific antimicrobial chemotherapy.
6. Removal of internal fixation devices is usually required except in early infection due to low-virulence organisms. Treatment by implant retention and antibiotic suppression should be part of a clear MDT plan and failure of treatment demands reevaluation.
Infection is the most feared and challenging complication in the treatment of open tibial fractures. Microorganisms can adhere as a biofilm on the surface of damaged bone, necrotic tissue, and internal fixation devices, and become resistant to phagocytosis and most antimicrobial agents (1). Established infection can delay healing and recovery, cause permanent functional loss, and potentially lead to amputation of the affected limb. The incidence of infection after severe open tibial fractures was reported to be over 30% in the 1980s and 1990s (2, 3). Although there is evidence of a possible reduction in incidence in the past decade (4), the Lower Extremity Assessment Project (LEAP) study has shown that severe lower extremity trauma continues to be associated with infective complications necessitating additional operative treatment in a significant number of cases (5). Furthermore, greater bacterial virulence and increasing age and associated co-morbidities of the fracture population ensure that infection after open trauma remains a challenge.
Definition and classification
There are no agreed criteria for diagnosing fracture infection (3, 6). The Centers for Disease Control (CDC) guidelines for surgical site infection (SSI) are often quoted but the complexity of an infected fracture is not covered by these guidelines (3, 7). Although comprehensive definitions are lacking, there is an accepted classification of infection after trauma according to the time of onset, which reflects the extent of biofilm formation and fracture-healing status, with implications for treatment (3, 8).
1. Early infections (less than 2 weeks) are easily diagnosed clinically since the classic signs of infection (swelling, redness, pain) are usually present in addition to delayed wound healing and drainage, haematoma, and accompanying pyrexia. Virulent organisms, like Staphylococcus aureus are common pathogens and an immature biofilm may be present (9). Osteomyelitis and accompanying inflammation and osteolysis will not have developed and fracture instability is unlikely at this early stage (3).
2. Delayed infections (2–10 weeks) may be associated with signs consistent with either early or late infection but infections are typically due to less virulent organisms, such as Staphylococcus epidermidis (9). The biofilm is more mature and relatively resistant to antibiotic therapy and host defences. In addition, bacterial bone invasion and osteomyelitis will be more advanced, with implications for fracture healing and stability (10, 11).
3. Late-onset infections (more than 10 weeks) are characterised by subtle signs of infection, without systemic manifestation, and are usually caused by low-virulence organisms (9). Fracture healing may be complete or incomplete but chronic inflammation (osteomyelitis) causes local tissue damage and osteolysis potentially leading to fixation instability, with implications for the residual hardware. Periosteal new bone produces an involucrum in response to the persistent low-grade inflammation caused by the infection and these changes often necessitate extensive and repeated wound excision, resulting in bone- and soft tissue defects (12).
Acute cases should be carefully monitored and local signs of infection must be considered diagnostic, even in the presence of negative cultures. Delayed wound healing and drainage or an active sinus are definitive signs of infection. Persistent elevation or a secondary rise in C-reactive protein is a useful indicator of infection (13). Plain radiology findings are usually normal in early infection and callus formation and the presence of hardware may mask the later subtle radiological features of infection (14). Whilst serial radiographs are useful to assess fracture healing and implant stability, computed tomography (CT) provides more bone architecture detail as well as signs of implant loosening (3). Markers for active infection such as cortical reaction, sequestra, sinuses, and abscess formation in the adjacent soft tissue may also be evident on CT scans (15). Whilst magnetic resonance imaging (MRI) is useful to evaluate soft tissue involvement and intramedullary infection, metal artefacts, bone oedema, and scarring may mimic infection and impair correct evaluation (16).
Nuclear imaging modalities are sensitive but not specific, especially when underlying bone abnormalities are present and discrimination between infection and post-traumatic bone formation is difficult (3, 17). Hybrid imaging (single-photon emission computed tomography (SPECT)/CT) can localise the suspected infection and facilitate the discrimination between bone- and soft tissue infection. Sensitivities over 95% and specificities from 75–99% have been reported in acute and subacute bone- and soft tissue infection (17).
Pathogens present in open wounds tend to evolve from initial contamination with multiple low-virulence pathogens to early infections including nosocomial organisms, which may be multi-drug resistant, through to mature infections caused by Staphylococci (18). Infection is usually due to metabolically quiescent bacteria growing in protected biofilms on the metal implants and in necrotic bone, which makes the pathogens difficult to identify using traditional culture techniques (19). At least three tissue biopsies should be taken in regions of perceived infection such as necrotic bone tissue or non-unions and around the implant (9). Bone biopsies are the diagnostic gold standard, particularly in delayed and chronic infection (20). If the same microorganism is cultured from at least two separate biopsies, it is probably relevant. A single positive biopsy of a virulent species such as S. aureus or Escherichia coli may also represent an infection. Antibiotics should be stopped for at least 2 weeks before sampling to avoid transforming bacterial species into viable but non-culturable forms when the cultures may become falsely negative (21, 22). Extended culture for up to 14 days of incubation may identify difficult-to-culture pathogens, but interpretation of extended culture results must be correlated with the clinical picture (23). Patients with clear clinical signs of infection but negative cultures should be treated as infected (24).
Other techniques to improve the yield of positive cultures, especially after pre-treatment with antibiotics, include sonication of removed hardware and molecular methods using polymerase chain reaction (PCR) (25, 26).
An evaluation of the local and systemic host risk factors is essential before considering treatment (Box 13.1). High-risk local factors include severe soft tissue and bone damage and compromised local vascularity. Systemic factors include a previous history of infection and compromised physiology including smoking, diabetes, peripheral vascular disease, alcoholism, and polytrauma (12). Infection with virulent organisms in a patient with local and systemic risk factors may preclude complex reconstructive procedures, and limited non-ablative surgery with antibiotic suppression or amputation should be considered (27).
Aeromedical evacuation of both civilian and military trauma victims by long-distance air flight is increasingly common. Recent studies of inter-hospital transfers of trauma victims have highlighted frequent wound contamination with highly resistant bacteria, particularly in patients nursed in an intensive care setting (28). Resistant organisms associated with inter-country transfer include multi-resistant Acinetobacter spp. and Klebsiella pneumoniae, methicillin-resistant S. aureus (MRSA), vancomycin-resistant Enterococci, and multi-resistant Clostridium difficile (29). Sound infection prevention strategies are essential to prevent dissemination of multi-resistant organisms from patients who have been admitted to hospitals in other countries. In addition, clinicians may also need to individualise empiric antibiotic prescribing patterns to reflect the risk of multi-resistant organisms in transferred patients.
The principles of treatment include the removal of sessile (anchored) bacteria within the biofilm by wound excision and the elimination of planktonic (free-floating) bacteria by targeted antimicrobial chemotherapy. An effective wound excision combined with high-dose antibiotics achieves a rapid reduction in the bacterial load (3). An MDT approach is essential to address the fracture and soft tissue components, identify the pathogens, and deliver effective antimicrobial therapy whilst optimising the health of the host (30).
Wound excision combined with copious low-pressure saline lavage is a cornerstone of treatment, and radical excision of necrotic and infected tissue, both bone and soft tissue, may be required. Wound excision should not be limited by concerns of creating a bone or soft tissue defect because failing to excise compromised tissues may leave viable bacterial behind within the biofilm, which will lead to recurrence of the disease (31, 32). Multiple tissue samples from different surgical sites should be obtained using sterile instruments. Haematomas must be drained as they are an excellent growth medium for bacteria (9). The index operation should also include an evaluation of fracture stability with removal of unstable fixation and revision fixation as required (Box 13.2). An adequate soft tissue envelope is essential and flap cover may be necessary. Alternatively, negative pressure dressings are employed between serial wound excision prior to definitive soft tissue cover.
Initial intravenous broad-spectrum therapy is started after multiple microbial samples have been obtained at wound excision and continued until the pathogens and their sensitivities are identified. The duration of intravenous therapy depends on pathogen virulence and antibiotic sensitivities, as well as the initial host response to treatment. Patients with clinically infected wounds but negative cultures should be treated aggressively with empirical coverage for Gram positive and Gram negative microbes, including MRSA (24).
If the hardware is retained, the aim of antibiotic therapy is suppression of the infection until the fracture has healed and the hardware can be removed (9). However, curative treatment with implant retention is only effective with a biofilm-active antibiotic, such as rifampicin against Staphylococci and quinolones against Gram negative organisms (Box 13.2) (35, 36, 37). Rifampicin must be combined with a second antibiotic to prevent the development of resistance. Quinolones such as ciprofloxacin or levofloxacin are effective oral partners to rifampicin against Staphylococci (38). Bacteria resistant to biofilm-active antibiotics will not be eradicated if the internal fixation is retained and hardware removal is strongly recommended (1, 3).
Application of antimicrobials at the site of infection can achieve high local antibiotic concentrations, which may be useful in cases with impaired vascularity and as an aid for dead-space management (3). Common carries include non-resorbable polymethylmethacrylate (PMMA) and resorbable materials such as calcium sulfate. However, there is no clear evidence for the addition of local antibiotics to systemic therapy. In addition, colonisation of bone cement, particularly after antibiotics have been eluted, may promote ongoing infection or even induce antibiotic resistance (39) and calcium sulfate preparations may be associated with chronic wound discharge (3).
Hardware colonisation and biofilm formation are relatively immature (40, 41) and retention of the fixation device may be considered as wound excision will reduce the bacterial load and may clear an immature biofilm and systemic antibiotics will treat the remainder of the infection. However a number of prerequisites must be fulfilled (Box 13.2). Effective wound excision and irrigation must be performed, which may not be possible with intramedullary fixation. In addition, the fixation must be stable, advanced signs of established infection should not present, and the infecting organisms must be sensitive to antibiotics (42). A 12-week course of antibiotics is recommended with retained implants or up to 6 weeks after implant removal (9, 43). Once the fracture has healed, implant removal is recommended to reduce the risk of recurrent infection (44).
The biofilm is more mature and osteomyelitis is becoming increasingly established and the surgical decision-making should tend towards radical wound excision and implant revision, particularly if there has been a delay in diagnosis and treatment or if infection has recurred after initial therapy. In a study of patients who developed infection within 6 weeks of fracture fixation treated with wound excision, antibiotics, and hardware retention, fracture healing was achieved in only 71% of the patients. In addition, open fractures and intramedullary fixation were predictors for treatment failure (45). In a similar study of infections within 16 weeks of fixation, successful union was reported in 68%, although 38% of patients with successful bone healing required hardware removed for persistent infection after union and only 49% of the original study group achieved healing and were free of infection after 6 months (44).
Inflammation and osteolysis are usually evident in infections developing after 10 weeks and instability of the fracture fixation is often present, resulting in delayed or non-union (3). In addition, involucra and fibrous tissue in the infected area act as a barrier around necrotic bone necessitating an extensive wound excision with possible creation of bone- and soft tissue defects. Preoperative imaging studies are helpful to assess the extent of fracture healing and to plan the resection margins but staged procedures are commonly required. Antibiotic spacers may be useful adjuncts for dead-space management and local antibiotic delivery. Hardware removal is mandatory but bone stability must be preserved and external fixation can be a temporary or definitive solution.
1. Zimmerli W, Trampuz A, Ochsner PE. Prosthetic-joint infections. N Engl J Med. 2004;351(16):1645–54.Find this resource:
2. Patzakis MJ, Wilkins J. Factors influencing infection rate in open fracture wounds. Clin Orthop Rel Res. 1989;243(0009-921X (Print)):36–40.Find this resource:
3. Metsemakers WJ, Kuehl R, Moriarty TF, Richards RG, Verhofstad MHJ, Borens O, et al. Infection after fracture fixation: current surgical and microbiological concepts. Injury. 2016;49:511–22.Find this resource:
4. Ktistakis I, Giannoudi M, Giannoudis PV. Infection rates after open tibial fractures: are they decreasing? Injury. 2014;45(7):1025–7.Find this resource:
5. Harris AM, Althausen PL, Kellam J, Bosse MJ, Castillo R, Lower Extremity Assessment Project (LEAP) Study Group, et al. Complications following limb-threatening lower extremity trauma. J Orthop Trauma. 2009;23(1):1–6.Find this resource:
6. Cook GE, Markel DC, Ren W, Webb LX, McKee MD, Schemitsch EH. Infection in orthopaedics. J Orthop Trauma. 2015;29(Suppl 12):S19–23.Find this resource:
7. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for Prevention of Surgical Site Infection, 1999. Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am J Infect Control. 1999;27(2):97–132; quiz 133–4; discussion 96.Find this resource:
8. Willenegger H, Roth B. [Treatment tactics and late results in early infection following osteosynthesis]. Unfallchirurgie. 1986;12(5):241–6.Find this resource:
9. Trampuz A, Zimmerli W. Diagnosis and treatment of infections associated with fracture-fixation devices. Injury. 2006;37(Suppl 2):S59–66.Find this resource:
10. Lovati AB, Romanò CL, Bottagisio M, Monti L, De Vecchi E, Previdi S, et al. Modeling Staphylococcus epidermidis-induced non-unions: subclinical and clinical evidence in rats. PLoS One. 2016;11(1):e0147447.Find this resource:
11. Bilgili F, Balci HI, Karaytug K, Sariyilmaz K, Atalar AC, Bozdag E, et al. Can normal fracture healing be achieved when the implant is retained on the basis of infection? An experimental animal model. Clin Orthop Relat Res. 2015;473(10):3190–6.Find this resource:
12. Willey M, Karam M. Impact of infection on fracture fixation. Orthop Clin North Am. 2016;47(2):357–64.Find this resource:
13. Neumaier M, Scherer MA. C-reactive protein levels for early detection of postoperative infection after fracture surgery in 787 patients. Acta Orthop. 2008;79(3):428–32.Find this resource:
14. Wheat J. Diagnostic strategies in osteomyelitis. Am J Med. 1985;78(6b):218–24.Find this resource:
15. Gross T, Kaim AH, Regazzoni P, Widmer AF. Current concepts in posttraumatic osteomyelitis: a diagnostic challenge with new imaging options. J Trauma. 2002;52(6):1210–19.Find this resource:
16. Ledermann HP, Kaim A, Bongartz G, Steinbrich W. Pitfalls and limitations of magnetic resonance imaging in chronic posttraumatic osteomyelitis. Eur Radiol. 2000;10(11):1815–23.Find this resource:
17. Love C, Palestro CJ. Nuclear medicine imaging of bone infections. Clin Radiol. 2016;71(7):632–46.Find this resource:
18. Yun HC, Murray CK, Nelson KJ, Bosse MJ. Infection after orthopaedic trauma: prevention and treatment. J Orthop Trauma. 2016;30(Suppl 3):S21–6.Find this resource:
19. Costerton JW, Post JC, Ehrlich GD, Hu FZ, Kreft R, Nistico L, et al. New methods for the detection of orthopedic and other biofilm infections. FEMS Immunol Med Microbiol. 2011;61(2):133–40.Find this resource:
20. Zuluaga AF, Galvis W, Jaimes F, Vesga O. Lack of microbiological concordance between bone and non-bone specimens in chronic osteomyelitis: an observational study. BMC Infect Dis. 2002;2:8.Find this resource:
21. Pasquaroli S, Zandri G, Vignaroli C, Vuotto C, Donelli G, Biavasco F. Antibiotic pressure can induce the viable but non-culturable state in Staphylococcus aureus growing in biofilms. J Antimicrob Chemother. 2013;68(8):1812–17.Find this resource:
22. Malekzadeh D, Osmon DR, Lahr BD, Hanssen AD, Berbari EF. Prior use of antimicrobial therapy is a risk factor for culture-negative prosthetic joint infection. Clin Orthop Relat Res. 2010;468(8):2039–45.Find this resource:
23. Schwotzer N, Wahl P, Fracheboud D, Gautier E, Chuard C. Optimal culture incubation time in orthopedic device-associated infections: a retrospective analysis of prolonged 14-day incubation. J Clin Microbiol. 2014;52(1):61–6.Find this resource:
24. Gitajn IL, Heng M, Weaver MJ, Ehrlichman LK, Harris MB. Culture-negative infection after operative fixation of fractures. J Orthop Trauma. 2016;30(10):538–44.Find this resource:
25. Yano MH, Klautau GB, da Silva CB, Nigro S, Avanzi O, Mercadante MT, et al. Improved diagnosis of infection associated with osteosynthesis by use of sonication of fracture fixation implants. J Clin Microbiol. 2014;52(12):4176–82.Find this resource:
26. Greenwood-Quaintance KE, Uhl JR, Hanssen AD, Sampath R, Mandrekar JN, Patel R. Diagnosis of prosthetic joint infection by use of PCR-electrospray ionization mass spectrometry. J Clin Microbiol. 2014;52(2):642–9.Find this resource:
27. Cierny G, 3rd, Mader JT, Penninck JJ. A clinical staging system for adult osteomyelitis. Clin Orthop Relat Res. 2003(414):7–24.Find this resource:
28. Maegele M, Gregor S, Steinhausen E, Bouillon B, Heiss MM, Perbix W, Wappler F, et al. The long-distance tertiary air transfer and care of tsunami victims: injury pattern and microbiological and psychological aspects. Crit Care Med. 2005;33(5):1136–40.Find this resource:
29. Rogers BA, Aminzadeh Z, Hayashi Y, Paterson DL. Country-to-country transfer of patients and the risk of multi-resistant bacterial infection. Clin Infect Dis. 2011;53(1):49–56.Find this resource:
30. Ziran BH, Rao N, Hall RA. A dedicated team approach enhances outcomes of osteomyelitis treatment. Clin Orthop Relat Res. 2003(414):31–6.Find this resource:
31. Patzakis MJ, Zalavras CG. Chronic posttraumatic osteomyelitis and infected nonunion of the tibia: current management concepts. J Am Acad Orthop Surg. 2005;13(6):417–27.Find this resource:
32. Simpson AH, Deakin M, Latham JM. Chronic osteomyelitis. The effect of the extent of surgical resection on infection-free survival. J Bone Joint Surg Br. 2001;83(3):403–7.Find this resource:
33. Daver NG, Shelburne SA, Atmar RL, Giordano TP, Stager CE, Reitman CA et al. Oral step-down therapy is comparable to intravenous therapy for Staphylococcus aureus osteomyelitis. J Infect. 2007;54(6):539–44.Find this resource:
34. Spellberg B, Lipsky BA. Systemic antibiotic therapy for chronic osteomyelitis in adults. Clin Infect Dis. 2012;54(3):393–407.Find this resource:
35. Widmer AF, Gaechter A, Ochsner PE, Zimmerli W. Antimicrobial treatment of orthopedic implant-related infections with rifampin combinations. Clin Infect Dis. 1992;14(6):1251–3.Find this resource:
36. Zimmerli W, Widmer AF, Blatter M, Frei R, Ochsner PE. Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. Foreign-Body Infection (FBI) Study Group. Jama. 1998;279(19):1537–41.Find this resource:
37. Aboltins CA, Dowsey MM, Buising KL, Peel TN, Daffy JR, Choong PF, et al. Gram-negative prosthetic joint infection treated with debridement, prosthesis retention and antibiotic regimens including a fluoroquinolone. Clin Microbiol Infect. 2011;17(6):862–7.Find this resource:
38. Senneville E, Joulie D, Legout L, Valette M, Dezèque H, Beltrand E, et al. Outcome and predictors of treatment failure in total hip/knee prosthetic joint infections due to Staphylococcus aureus. Clin Infect Dis. 2011;53(4):334–40.Find this resource:
39. Hake ME, Young H, Hak DJ, Stahel PF, Hammerberg EM, Mauffrey C. Local antibiotic therapy strategies in orthopaedic trauma: Practical tips and tricks and review of the literature. Injury. 2015;46(8):1447–56.Find this resource:
40. Costerton JW. Biofilm theory can guide the treatment of device-related orthopaedic infections. Clin Orthop Relat Res. 2005(437):7–11.Find this resource:
41. Nishitani K, Sutipornpalangkul W, de Mesy Bentley KL, Varrone JJ, Bello-Irizarry SN, Ito H, 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. 2015;33(9):1311–19.Find this resource:
42. Merritt K, Dowd JD. Role of internal fixation in infection of open fractures: studies with Staphylococcus aureus and Proteus mirabilis. J Orthop Res. 1987;5(1):23–8.Find this resource:
43. Trebse R, Pisot V, Trampuz A. Treatment of infected retained implants. J Bone Joint Surg Br. 2005;87(2):249–56.Find this resource:
44. Rightmire E, Zurakowski D, Vrahas M. Acute infections after fracture repair: management with hardware in place. Clin Orthop Relat Res. 2008;466(2):466–72.Find this resource:
45. Berkes M, Obremskey WT, Scannell B, Ellington JK, Hymes RA, Bosse M, et al. Maintenance of hardware after early postoperative infection following fracture internal fixation. J Bone Joint Surg Am. 2010;92(4):823–8.Find this resource:
46. Tsang ST, Mills LA, Frantzias J, Baren JP, Keating JF, Simpson AH. Exchange nailing for nonunion of diaphyseal fractures of the tibia: our results and an analysis of the risk factors for failure. Bone Joint J. 2016;98-b(4):534–41.Find this resource:
47. Palmer MP, Altman DT, Altman GT, Sewecke JJ, Ehrlich GD, Hu FZ, et al., Can we trust intraoperative culture results in nonunions? J Orthop Trauma. 2014;28(7):384–90.Find this resource: