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Abstract

Fracture related infections (FRIs) are a disabling condition causing significant concern within the orthopaedic community. FRIs have a huge societal and economic burden leading to prolonged recovery times and the potential for becoming chronic conditions or being life-threatening. Despite its importance in our field, the surgical community has just recently agreed on a definition which, added to the lack of surgical trials assessing preventive and treatment interventions have limited our understanding and precipitated wide variations in surgeons’ practice. This article aims to review the current practices that can be supported with high-quality evidence. Currently, we have a limited body of high-quality evidence on FRI prevention and treatment. A handful of measures have proven effective, such as the use of prophylactic antibiotics, the use of saline and low pressure as the preferred irrigation solution and the safety of delaying initial surgical débridement more than 6 hours without impacting infection rates for open fracture wounds débridement. Future multicentre trials, properly powered, will shed light on current areas of controversy regarding the benefit of different preoperative and perioperative factors for the prevention and treatment of FRIs. Higher quality evidence is needed to guide surgeons to offer an evidence-based approach to prevent FRI occurrence and to treat patients suffering from them.

Keywords

fracture infection osteomyelitis bone infection surgical site infection implant associated infection

Introduction

Bone tissue can become infected through the dissemination of microorganisms in the bloodstream or by spreading from nearby tissue. When a bone fractures it can become infected, which can often impair bone healing, produce persistent pain at the fracture site, and potentially lead to devastating outcomes. Fracture related infection (FRI) is a relatively new term, coined to englobe all types of infections affecting bone tissue after a fracture, including infections after fracture fixation, but also those occurring after closed or open fractures treated without orthopaedic implants, amongst others. Given the wide spectrum of conditions included and the recent adoption of this new terminology, the epidemiology and burden of FRI is still not well understood. However, evidence suggests that around 1-to-2% of closed fractures and up to 30% of open fractures that undergo surgical fixation will develop a FRI.^1,2

The individual and society burden and costs associated with the occurrence of FRIs are major. Patients with FRIs after tibial fractures had a 6.5-fold increase in medical expenses and 7.7 times longer hospital stays compared with uninfected patients.³ Thakore et al. reported that median costs per patient with infections after fracture fixation doubled to over US$ 108,000 per patient when infected.⁴ Furthermore, recent evidence shows that FRI is a problem that seems to be on the rise despite the advances in antibiotic and pre-and-perioperative protocols.⁵ In Germany, a 28% increase was observed in 10 years (2008–2018), explained mainly by a higher growth rate of FRIs in older patients (≥90 years). Population ageing is associated with an increase in the rates of fragility fractures which, in conjunction with this age group higher comorbidities and poorer soft tissue quality, will undoubtedly lead to an increase in FRIs.

One of the biggest challenges has been to standardize what a FRI is. Most evidence comes from populations with slightly different conditions and a lack of uniform diagnostic criteria, which has precluded the orthopaedic community from having comparable data and drawing stronger conclusions. Moreover, some principles have been extrapolated or adapted from evidence gathered for the treatment of surgical site infections (SSIs) or periprosthetic joint infection (PJI), or studies combining bone and joint infections, without having been properly assessed in the FRI specific population.

The aim of this review is to summarize what practices for the management of patients with FRIs can be supported by high-quality levels of evidence. Therefore, we will discuss recommendations for the prevention and treatment of FRIs arising from randomized controlled trials (RCTs) and/or evidence synthesis or meta-analysis from level I or II studies and rate them using the GRADE system.⁶

Definition

One of the challenges when talking about FRIs is to agree on its definition. Metsemakers et al. found that most RCTs in fracture care lacked a standardized definition for FRI.⁷ In recent years, the FRI Consensus Group was created in a joint effort between the AO Foundation and the European Bone and Joint Infection Society, and a consensus definition was proposed.⁸

The term FRI was adopted to embrace all infections that occur in the presence of a fracture, including early and late infections associated with fractures treated with orthopaedic implants, infections associated with either closed or open fractures treated without internal fixation, and hematogenous infections arising after a fracture. This definition included certain diagnostic criteria which were recently updated by the FRI Consensus Group.⁹ Several confirmatory criteria were identified, and each one alone allows for a definitive diagnosis of FRI. Six suggestive criteria were also identified. Details are shown in Table 1.

Table 1.

FRI Consensus group confirmatory and suggestive criteria.

Confirmatory criteria	Suggestive criteria
Clinical evaluation signs	Clinical evaluation signs
Fistula	Local - systemic (e.g. local redness, swelling, fever)
Sinus	New onset joint effusion
Wound breakdown	Persistent, increasing, or new onset wound drainage
Purulent drainage of the presence of pus	Radiological and/or nuclear imaging signs
—	Increased serum inflammatory markers (ESR, WBC, CRP
Surgical findings	Surgical findings
Phenotypically indistinguishable pathogens identified by culture from at least 2 separate deep tissue/implant specimens	Pathogenic microorganism identified from a single deep tissue/implant specimen
Presence of microorganisms in deep tissue specimens, confirmed by using specific staining techniques for bacteria and fungi	—
Presence of > 5 PMNs/HPF in chronic/late onset cases (e.g. fracture nonunion)	—

(1) Prevention of fracture-related infections

Optimal strategies for the prevention of FRIs are not completely understood. Several guidelines have been published to reduce the incidence of SSIs, by the WHO and the CDC.^10,11 Unfortunately, most of the included recommendations come from non-fracture-related literature and the orthopaedic community has already raised concerns regarding the appropriateness of this definition in orthopaedics.^8,12,13 We will proceed to review the evidence of preventive strategies:

(a) Preoperative measures

Surgical theaters conditions

There are no level I or II studies comparing how operating rooms (OR) settings affect the rates of FRIs. However, several studies have assessed how OR settings might impact bacterial contamination as a surrogate outcome for FRI rates. Oguz et al. assessed the airborne bacterial contamination in the ORs during orthopedic surgery in a RCT.¹⁴ 80 patients underwent minor orthopedic surgery in ORs with and without a unidirectional turbulent free laminar airflow system. The patients were randomized to warming with a forced air or an electric warming system. The authors evaluated several factors including: (1) lack of unidirectional, turbulent free laminar airflow; (2) duration of surgery; (3) patient warming system; and (4) number of health professionals in the OR. Measurements of airborne bacteria numbers were conducted in the ORs. Multivariate analysis showed that the absence of unidirectional turbulent free laminar airflow and longer duration of surgery increased bacterial counts significantly, while the type of patient warming system and the number of health professionals had no influence.

Similarly, Darouchi et al. evaluated the association of airborne colony-forming units (CFU) at incision sites during implantation of prostheses with the incidence of either incisional or prosthesis-related surgical site infections.¹⁵ In this RCT, 300 patients undergoing either total hip arthroplasty, instrumented spinal procedures, or vascular bypass graft implantation were randomly assigned (1:1 ratio) to either the intervention group (air barrier system) or the control group (routine OR atmospheric conditions). CFU density at the incision site was significantly lower in the intervention group (p < 0.001). In addition, the density of airborne CFU at the incision site during the procedures was significantly related to the incidence of implant infection (CFU densities were 4 times greater in procedures with implant infection vs. no implant infection, p = 0.021). Recently, lower particle loads in knee and shoulder replacement surgery have been reported associated with the presence of laminar flow in the ORs.^16,17 However, these trials are of small sample size and also use surrogate outcomes (particle loads), in this case as potentially leading to lower bacterial contamination. If these interventions will correlate with lower rates of PJI and FRI is unknown.

Skin preparation solutions

Three are the most common solutions used in skin preparation in orthopaedic surgery: chlorhexidine, iodine, and alcohol.¹⁸ Alcohol tends to be used in combination with other antiseptic agents, due to its short duration of action. Darouiche et al. performed a multicentric RCT in 849 patients undergoing clean-contaminated surgery to either receive chlorhexidine-alcohol or povidone-iodine skin solution.¹⁹ Their primary outcome was the incidence of SSIs within 30 days. They found a significant decrease in SSIs with the use of chlorhexidine (9.5% vs. 16.1%; p = 0.004; RR, 0.59; 95% CI, 0.41–0.85). This benefit was seen in preventing both superficial and deep SSIs, but not against organ-space SSIs. Unfortunately, no orthopaedic patients were included in this study. High-quality data regarding this topic is lacking in orthopaedic trauma literature. As such, there is no consensus on which solution to recommend. Nevertheless, there are a couple of big trials ongoing that are part of the PREP-IT program, PREPARE and Aqueous-PREP, that aim to compare chlorhexidine-alcohol or povidone-iodine skin solutions and will recruit around 10,000 patients (8,000 with closed fractures and 2,000 with open fractures) undergoing surgical fixation.^20,21 Their primary outcome is the rate of SSIs up to 90-days. It is possible that their results can provide conclusive evidence in this matter.

Skin hair management.

To our knowledge, there is only one RCT study assessing the effect of skin hair management in orthopaedics. Marecek et al. examined the effect that preoperative axillary hair removal had on bacterial load around the shoulder.²² In this study, the authors clipped one randomly selected axilla in 85 healthy male volunteers. Aerobic and anaerobic culture specimens were taken from the clipped and unclipped axillae. After this, each shoulder was prepared with 2% chlorhexidine gluconate and 70% isopropyl alcohol and repeated culture specimens were then taken. They found no difference in the burden of P. acnes between the clipped and unclipped axillae before or after surgical preparation (p = 0.109, p = 0.344, respectively). There was a significantly greater bacterial burden in the clipped shoulder compared with the unclipped shoulder before preparation (p < 0.001) but not after preparation (p = 0.285). A significant reduction was observed in total bacterial load and P. acnes load for both axillae after surgical preparation (p < 0.001 for all). The authors concluded that axillary hair removal has no effect on the burden of P. acnes in the axilla.

Tanner et al. recently updated a previous Cochrane systematic review to determine the effect that preoperative hair removal had on SSI rates.²³ Findings from 25 studies suggested that there may be little difference in risk of SSI when clippers or depilatory cream are used (low-certainty evidence) compared with no hair removal. However, there are probably fewer SSIs when hair is not removed compared with shaving with a razor (moderate-certainty evidence). Lastly, their findings showed that there may be a small reduction in SSIs when hair is removed on the day of, rather than the day before, surgery. Unfortunately, this data comes from studies conducted in other specialties so it is unclear if it will apply similarly in relation to orthopedics and FRI rates.

(b) Perioperative management

Drapes

Antimicrobial drapes have been proposed to have a dual action, acting both as a physical and antimicrobial barrier to counter bacterial contamination of the surgical wounds.^24,25 Hesselvig et al. with the ICON study group assessed the effect of antimicrobial drapes in intraoperative contamination (as a proxy for periprosthetic joint infection [PJI]).²⁶ In this non-blinded, multicenter RCT, 1659 participants undergoing primary knee arthroplasty were assigned to an operation with or without an antimicrobial drape. The primary outcome was the difference in the proportion of contaminated patients between groups. They found that the use of iodinated drapes reduced contamination (10% procedures where iodinated drapes were used vs 15% when they were not; OR 0.61 [95% CI 0.43 to 0.87]; p = 0.005). After controlling for confounding variables, not using an antimicrobial drape significantly increased contamination risk RR 1.6 (95% CI 1.08 to 2.35; p = 0.02). The authors concluded that the use of antimicrobial drapes resulted in lower contamination risk, suggesting that antimicrobial drapes might be useful in infection prevention, but clearly stating that there is a need for further studies to investigate their effect on infection rates. In addition to this, Mundi et al. conducted a systematic review and meta-analysis to evaluate if the use of adhesive drapes influenced infection rates in orthopaedic surgery.²⁷ Five studies and 2266 patients were included. They found a reduction in wound contamination with the use of adhesive drapes (OR 0.49 [95% CI 0.34 to 0.72]; p < 0.001). The available evidence was inconclusive to determine whether intraoperative drape peeling (intentional or inadvertent) influenced the risk of wound contamination and, the two included studies that analyzed SSIs reported no infections in either arm; therefore, they were not able to draw conclusions on whether adhesive drapes affected the risk of SSI.

In summary, adhesive drapes, including those with antimicrobial properties have shown to decrease the risk of wound contamination during orthopaedic procedures. However, if drape adhesion is compromised and peel back occurs at the wound edge, this benefit may disappear with an increased risk of wound contamination. Current available evidence comes from studies performed in populations other than fracture patients (hip and knee arthroplasty, spine surgery and shoulder arthroscopy) and is inconclusive to determine the effect of adhesive drapes on the risk of FRI.

Double gloving

A Cochrane review done in 2006 included RCTs involving single, double, and triple gloving.²⁸ Only two trials had SSIs as the primary outcome, and both reported no infections. Fourteen trials analyzed double versus single gloving and found an increased risk of perforations when using a single glove (OR 4.10, 95% CI 3.30–5.09). Only one study compared triple gloving versus double gloving and found an increased risk of perforation when using two gloves. Therefore, double gloving decreases perforations but there is no high-quality evidence regarding how gloving practices impact FRI rates.

Timing of surgical débridement in open fractures

Despite the open fracture management dogma of doing the surgical irrigation and débridement (I&D) within 6 h from fracture occurrence, current evidence challenges this practice. Pollak et al. evaluated the relationship between the timing of I&D in patients with open fractures and the development of subsequent infection in a secondary analysis of the LEAP study.²⁹ In this study, 315 patients with severe high-energy lower extremity injuries were treated with aggressive débridement, antibiotic administration, fracture stabilization, and timely soft-tissue coverage. The times from injury to admission and operative débridement as well as a wide range of other patient, injury, and treatment-related characteristics that have been postulated to affect the risk of infection were studied. Eighty-four patients (27%) developed an infection within the first 3 months after the injury. No significant differences were found between patients who developed an infection and those who did not when the groups were compared regarding the time from the injury to the first I&D, the time from admission to the first I&D, or the time from the first I&D to soft-tissue coverage. However, they found that the time between injury and admission to the definitive trauma treatment center was an independent predictor of the likelihood of infection.

Prodromidis et al. conducted a systematic review and meta-analysis of the infection and non-union rates of patients with open tibial fractures undergoing early (<6 h) vs late (>6 h) I&D.³⁰ Of the included studies, five were retrospective and two prospective, including one trial (LEAP study). Pooled data showed no difference between groups with regards to overall infection rates (RR = 1.32; 95% CI, 0.54–3.23; p = 0.55), deep infection rates (RR = 0.99; 95% CI, 0.48–2.07; p = 0.98), and non-union rates (RR = 1.49; 95% CI, 0.64–3.49; p = 0.36). This study suggested that there is no obvious difference in the overall/deep SSI and non-union rates between open tibial fractures undergoing early (<6 h) vs late (>6 h) I&D.

Johal et al. conducted a propensity score-based analysis of the FLOW trial cohort to assess the effect of time to I&D on the rate of reoperation in open fractures.³¹ Analyzing data from 2,286 patients they observed that after propensity matching, early irrigation was not associated with reoperation (OR 0.71 (95% CI 0.47–1.07); p = 0.73) concluding that when accounting for other variables, late irrigation (>6 h) does not independently increase risk of reoperation. Similarly, Srour et al.^30,32 found that the time to I&D did not affect the development of local infectious complications provided it was performed within 24 h of arrival. Therefore, current evidence supports the fact that performing the I&D in patients with open fracture wounds within 24 h will not increase the risk of FRI.

Surgical débridement: type of solution and irrigation pressure

The use of low pressure normal saline has been shown by the FLOW trial to be the optimal irrigation solution to prevent FRIs when treating open fractures.³³ Bhandari et al. compared in this 2 by 3 factorial multicenter RCT of 2447 patients with open fractures, two different irrigation solutions (saline vs castile soap) and three different irrigation pressures (high vs low vs very low) for the treatment of open fractures. Their results suggested similar reoperation rates regardless of irrigation pressure establishing very low pressure as an acceptable, low-cost alternative in the irrigation of open fractures. However, reoperation occurred in 182 of 1229 patients (14.8%) in the soap group and in 141 of 1218 (11.6%) in the saline group (hazard ratio, 1.32, 95% CI, 1.06 to 1.66; p = 0.01). Thus, saline showed superior to castile soap solution for the routine irrigation of acute open fractures.

Timing and duration of antibiotics (ATBs)

Although the timing and duration of ATBs to prevent FRI in open fracture patients has been the most studied subgroup, it is still a controversial subject. Isaac et al. conducted a systematic review including all clinical trials that evaluated the duration of ATBs in open tibial fractures.³⁴ The primary outcome was SSI after an open tibial fracture, either superficial or deep. The authors included eight studies in total with only one prospective, double-blind randomized study, done by Dellinger et al.³⁵ They concluded that there was a lack of robust evidence regarding the optimal length of ATBs treatment. Dellinger et al.³⁵ Randomized 248 patients with 264 open fractures to receive one of the three following interventions; one or 5 days of a second-generation cephalosporins (cefonicid sodium) therapy administered intravenous (iv), or 5 days of a different second-generation cephalosporin (cefamandole nafate) as part of the initial treatment. Rates of FRI in the three groups were 10 13% (10 out of 79), 12% (10 out of 85), and 13% (11 out of 84), respectively. The author showed that a brief course of ATBs administration is not inferior to a prolonged course of ATBs for the prevention of postoperative FRI in patients with open fractures. No sub analysis by fracture Gustilo-Anderson classification was performed. Similarly, Carsenti-Etesse et al. conducted a multicentre RCT comparing the use of one-day vs 5-day ATBs (pefloxacin single iv dose vs a combination of 2-days iv cefazolin + 3-days of oxacillin) in the prophylaxis of FRI after grade I and II open leg fractures.³⁶ They found no significant differences (6.6% vs 8%, p = 0.51) between groups in FRI up to 3 months.

Whitehouse et al. conducted a systematic review to assess how the timing of ATBs delivery affected infection rates in open fractures.³⁷ Eight studies were included (non-randomized controlled trials) with all studies at substantial risk of bias. The overall deep SSI rate ranged from 5-to-17.5%. One study reported a reduced infection rate with the delivery of ATBs within 66 min of injury and seven studies reported no effect. The authors concluded that no robust evidence is available to determine whether the timing of delivery of iv ATBs has an effect on the risk of deep SSIs, suggesting a need for RCTs in this area.

The idea that administering ATBs within 3 h from the open fracture as the most important intervention to prevent infection comes from the study conducted by Patzakis and Wilkins.³⁸ In a retrospective study, they found an increase in SSIs in the group that received ATBs after 3 h from the injury. However, this study has several limitations including its non-prospective design and the use of 3 different ATBs schemes during the 11-year period evaluated. No clear recommendations can be made with the current evidence regarding the optimal timing and duration of ATBs to prevent FRIs.

Use of local antibiotics (ATBs)

Local ATBs have been recommended in addition to systemic therapy for the management of FRIs^39,40 with gentamicin, tobramycin, vancomycin, and clindamycin being the most used local ATBs in orthopedic surgery.⁴¹

Tubaki et al. conducted an RCT including 907 spinal surgery patients to evaluate whether the addition of local vancomycin was different to the use of systemic prophylaxis only.⁴² They found no differences in infection rates. Morgenstern et al. conducted a recent systematic review and meta-analysis on the use of local ATBs in open fracture patients, including 8 studies (only one was a RCT).⁴³ They found a risk reduction of 11.9% of FRI associated with the use of local ATBs. However, the authors warn that data quality, heterogeneity, and risk of bias warrant caution in the interpretation of this study. The ongoing and unpublished VANCO study aims to compare the proportion of deep SSIs at 6 months in patients undergoing fracture fixation receiving standard of care versus standard of care + vancomycin powder.⁴⁴ Preliminary results available at the clinical trials website (https://clinicaltrials.gov) show a decrease in FRI when adding vancomycin ATBs powder to the site of fracture (6% vs 9.6%).

Despite promising initial evidence on the use of local ATBs in the prevention of FRIs there is scarce high-level evidence available to identify what should be the preferred ATBs, the optimal dosing and carrier.

ATBs coated implants

Antibacterial coatings have been proposed to prevent bacterial adhesion and biofilm formation according to various preclinical studies.^45,46 Malizos et al. conducted a multicentre RCT to assess the effect that an antibiotic-loaded fast-resorbable hydrogel coating (Defensive Antibacterial Coating, DAC®) had in the prevention of SSIs in patients undergoing internal fixation for closed fractures.⁴⁷ They followed 253 patients for at least 1 year. Six SSIs (4.6%) were observed in the control group (without DAC hydrogel) compared to none in the treated group (p < 0.03). No local or systemic side-effects were observed and no interference with bone healing was noted. They concluded that the use of a fast-resorbable antibiotic-loaded hydrogel implant coating reduced the rate of SSIs after internal fixation for closed fractures. However, there are some concerns with the sample size calculation in this study. The authors used a 6% expected prevalence of SSI in the control group (most evidence shows a prevalence of 1-to-2%) and of 0.1% for the treatment group (using data from animal models instead of using data from a pilot study). Although the findings of this trial are promising, the concerns with the sample size calculation methodology raise doubts about the trial being underpowered to detect significant differences. We suggest caution prior to adopt this practice.

Wound care: type of sutures, timing of closure, dressings and need of coverage

Costa et al. in the WOLLF multicentre trial compared the disability, rate of deep SSI, and quality of life in patients with severe open fractures of the lower limb treated with negative pressure wound therapy (NPWT) vs standard wound management after the first surgical débridement of the wound, in patients whose wound could not be closed.⁴⁸ They reported no significant differences in the number of deep SSIs (16 [7.1%] in the NPWT group vs 19 [8.1%] in the standard dressing group; difference, 1.0% [95% CI, −4.2%–6.3%]; p = 0.64).

In addition, Costa et al. in the multicentre WHIST trial compared the rates of deep SSIs of patients undergoing surgery for lower limb fractures related to major trauma (more than 1 body system is injured or an isolated limb subjected to severe trauma) when the wound was treated with incisional NPWT versus standard wound dressing.⁴⁹ Eligible patients were ≥16 years with a lower extremity fracture caused by major trauma that required surgery and, postoperatively, had a wound that could be closed. In this RCT trial, including 1548 patients, they found no significant difference in the rate of deep SSIs at 30 days between incisional NPWT and standard wound dressing (5.8% vs 6.7%, p = 0.52). In addition, no difference in the rate of deep SSIs was observed at 90-days (11.4% vs 13.2%, p = 0.32). Their findings do not support the use of incisional NPWT for surgical wounds associated with lower limb fractures from major trauma.

On the other hand, different types of postoperative wound dressings have been studied. Kadar et al. conducted a RCT to compare silver-coated (SD) versus regular dressings (RD) in patients with hip fractures undergoing surgical treatment (dynamic hip screw, cephalomedullary nail or hemiarthroplasty).⁵⁰ Using a matched group of 55 patients with hip fractures undergoing surgical treatment who were randomized to either SD or RD groups they found no difference in infection amongst groups (SD 6.4% vs RD 8.3%; p = 1.0). Skin colonization was higher but not significantly in the SD group compared to the RD group (63.2% vs 50%, p = 0.67). The authors concluded that the use of SD was associated with higher costs than RD but was not superior in preventing SSIs in elderly patients undergoing surgical treatment of hip fractures. Similar results were reported by Luque-Valenzuela et al. when comparing whether a silver-impregnated occlusive surgical dressing was effective in reducing the rates of wound complications compared to standard dressing after ankle fracture surgery.⁵¹ Current evidence does not support the use of silver dressings to prevent FRIs (Figure 1).

Figure 1.

Prevention of FRIs and practices supported by evidence.

(2) Treatment of fracture-related infections

The body of evidence assessing FRI treatment strategies is more limited compared to the extent of studies assessing prevention strategies. We will discuss the treatment strategies for FRIs that can be supported with high-quality evidence or the lack of thereof.

Surgical débridement

The workhorse of management in patients with FRI is surgical débridement to remove infected tissue and provide adequate soft tissue coverage, ATBs treatment, and implant removal or retention. In a secondary analysis of the FLOW trial, Prada et al. found that 53% of the patients with an open fracture that eventually developed a SSI required operative management within 1 year of follow-up.⁵² Evidence not directly related to FRI treatment but originating from open fractures studies described above suggests meticulous débridement followed by irrigation with normal saline at low pressure may be useful.³³

Implant retention versus implant removal

When dealing with FRIs deciding whether to keep orthopedic implants versus removing them has been controversial. To date there are no high-quality studies comparing implant retention versus removal in FRIs. This can be explained by the fact that this decision depends on multiple factors, including implant type, stability of the construct, consolidation status, anatomical location, soft tissue envelope, the ability to perform an adequate débridement, and the time between fracture fixation and FRI surgery.⁵³ A recent systematic review conducted by Morgenstern et al. analyzed the influence of time between fracture fixation and FRI surgery on success rates after débridement and implant retention.⁵⁴ They included six studies encompassing 276 patients, including one double blinded RCT that did not directly compare the influence of time on success rates, but compared the addition of rifampin to the antibiotic regime of FRI patients.⁵⁵ Follow-up varied between studies, from a minimum of 6 months to a minimum of 2 years. The authors found that in patients with a very short duration of infection (≤3 weeks), implant retention was associated with success rates of 86–100%. This diminished with time, to 82–89% success rates when FRI surgery was performed between weeks 3-to-10, and to 67% after 10 weeks. However, heterogeneity of the data did not allow the authors to compare between early and delayed infections. Furthermore, given the small sample sizes, different definitions of FRI and low-quality studies included, caution is required when interpreting these results.

Antibiotic therapy: duration and route of administration

One of the cornerstones of the treatment of FRIs is ATBs management. Usually, therapy is started with broad spectrum ATBs covering the most common bacteria associated with bone infection and then tailored to the specific ATBs when the organisms and their susceptibilities are identified.⁵³ Rifampin has biofilm activity and, therefore, has been recommended when retaining implants. Zimmerli et al. performed a RCT in two centers, including 33 patients with periprosthetic joint infection or FRI.⁵⁵ They randomized patients to undergo an initial debridement and a two-week iv course of flucloxacillin or vancomycin with either rifampin or placebo, followed by a long-term (3–6 months) combination of ciprofloxacin and rifampin, or ciprofloxacin and placebo. They found that patients allocated to the addition of rifampin had a 100% cure rate, compared to 58% of the patients allocated to placebo. However, 9 of the 33 patients dropped out of the study.

Duration of the ATBs therapy is mostly based on expert opinion, as there are no high-quality studies evaluating duration of systemic ATBs therapy in FRIs.⁵⁶ In case of implant retention, a total treatment period of 12 weeks is recommended, and 6 weeks after implant removal.^39,56 However, multiple strategies exist and there is a lack of evidence to support one over another. In fact, Prada et al. showed in a secondary analysis of the FLOW trial that most patients with a SSI after an open fracture that were managed surgically required 2–3 months at minimum (median of 73 days [IQR 28–165]) to resolve their infection.⁵² Therefore, recent consensus suggests that every patient should receive an individualized treatment plan by a multidisciplinary team.⁵⁶ Future studies are needed to ascertain the optimal treatment strategy and duration.

Regarding the route of administration, there is evidence supporting the use of oral ATBs to be non-inferior in effectiveness than iv ATBs to treat bone or joint infections. In the OVIVA multicenter trial, Li et al. enrolled adults being treated for bone or joint infection (within 7 days after surgery or, if the infection was being managed without surgery, within 7 days after the start of ATBs treatment).⁵⁷ Participants were randomized to receive either iv or oral ATBs to complete the first 6 weeks of therapy. The primary endpoint was definitive treatment failure within 1 year after randomization, defined as the presence of at least one clinical, microbiologic, or histologic criterion of infection. The authors found that oral ATBs therapy was non-inferior to iv ATBs therapy when used during the first 6 weeks for complex orthopedic infection, as assessed by treatment failure at 1 year. Unfortunately, no sub analysis between FRI and PJI patients was performed. A recent systematic review and meta-analysis further evaluated RCTs of blood and bone infections comparing iv to oral ATBs.⁵⁸ They included 8 trials of osteomyelitis, including the OVIVA trial, accounting for 1,321 patients. They found no differences when using iv or oral ATBs to treat osteomyelitis. Therefore, the current recommendation is to limit iv ATBs and use oral ATBs after achieving organism and susceptibility identification, if possible.

Use of local ATBs

Local ATBs have also been often used, but evidence supporting their use for FRIs treatment is scarce. In fact, a 2011 systematic review showed that there are no high-quality well-executed studies investigating the role of ATBs-loaded PMMA beads in orthopaedic infections.⁵⁹ Chan et al. randomized patients with an infected tibial non-union to receive bone grafting or receive bone grafting with ATB impregnated bone.⁶⁰ They included 46 patients in the ATBs impregnated group and 50 in the non-ATBs group. The antibiotic was chosen based on the infecting organisms and tailored for each patient (vancomycin or piperacillin in most patients). They found that, after 4–6 years of follow-up, infection elimination was higher in the ATBs impregnated bone grafting group (95.6% vs. 82% chi2 test, p < 0.05). Contrarily, and as previously mentioned, Tubaki et al. found no differences when using local intrawound Vancomycin in 907 postoperative infection spine patients.⁴² Therefore, with current evidence, there is no consensus on if carriers should be used to treat FRIs, or what carrier is ideal.

ATBs implants, especially intramedullary nails, have been also used with success in FRI patients.⁶¹ Thonse and Conway treated 20 patients with infected tibial non-union using a PMMA coated nail with vancomycin and tobramycin.⁶² They controlled the infection in 19 of the 20 patients and achieved union in 17, while the remaining 3 had a stable non-union. The nail was used as permanent fixation for 16 of the 20 patients. Unfortunately, there is no level I or II evidence to support their use.

Bone defect and grafting

After meticulous I&D, the surgeon may be encountered with a critical bone defect, defined as a bone defect that is not expected to heal in the absence of an intervention and, therefore, requires management. Unfortunately, there is no high-level evidence to guide management when facing bone defects in patients with FRIs. Bezstarosti et al. performed a systematic review including 50 patient series comparing different treatment strategies for bone loss ≥1 cm after débridement in FRI patients, including autologous cancellous grafts, autologous cancellous grafts combined with local ATBs, the induced membrane technique (Masquelet), vascularized grafts, Ilizarov bone transport, and bone transport combined with local ATBs.⁶³ Overall, 1530 patients were treated, with a mean bone defect of 6.6 cm (range 1.0–26.0), of which 1253 (82%) were in the tibia. Mean follow-up was 51 months (range 6–126). Unfortunately, there were no level I or II studies included. Most treatment alternatives resulted in comparable healing and recurrence rates and the authors were not able to draw conclusions due to populations and interventions heterogeneity, and because most studies were retrospective series of patients.

Hohmann et al. performed a systematic review and best evidence synthesis on the optimal timing for bone grafting in infected non-unions of the tibia.⁶⁴ They included 15 studies, 14 of which were rated as low-quality studies. All of them were either level of evidence type III or IV, including 471 patients, of which 353 were infected non-unions of the tibia. For most cases, bone grafting can be performed between 6–8 weeks from the index surgery with union rates over 90%, at a mean of 4.58 months (4.42–4.73). However, the authors warned of the low quality of the evidence to support this recommendation. Thus, even when bone grafting seems to be useful to treat infected non-unions it is unclear which bone grafting technique and what is the optimal timing with the current evidence.

Unfortunately, there is limited high quality evidence to support many practices orthopaedic surgeons perform on a daily basis while managing FRI patients. This is probably explained by the fact that a consensus definition on FRI has been recently achieved, the relatively low frequency of this condition, and because most efforts have been concentrated on preventing them. With FRIs becoming more common and upcoming studies planned to use a standardized definition, future studies will hopefully shed light on common practices not supported by evidence to guide surgeons in their patients' treatment decision-making Figure 2.

Figure 2.

Treatment of FRIs and practices supported by evidence.

Take-home Messages

Despite the importance that FRIs have in orthopedics, there is a paucity of high-quality evidence regarding effective measures to prevent and manage them. Recent efforts to reach a consensus definition are helpful to standardize future trials and increase the external validity of their findings. Challenges to conduct these trials are related to the difficulties of surgical trials enrollment, and the diversity of conditions and patients subpopulations embraced under the FRI definition.

Amongst the few measures that are supported with high-quality evidence we can find:

❖ In patients with open fracture wounds that undergo surgical débridement, irrigation with saline solution at low pressure (5-to-10 psi) is the combination of choice.

❖ Irrigation and débridement of patients with open fracture wounds can be delayed more than 6 h without increasing the risk of FRIs (at least up to 24 h). However, it is unclear to what extent this delay is acceptable.

❖ NPWT use is not associated with a decreased rate of FRI in lower limb fractures.

❖ When treating FRIs, oral antibiotics are non-inferior to IV antibiotics. Therefore, the use of IV antibiotics should be limited and transition to oral antibiotics when possible.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Carlos Prada

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The management of fracture related infections: What practices can be supported by high-level evidence?

Abstract

Keywords

Introduction

Definition

(1) Prevention of fracture-related infections

(a) Preoperative measures

Surgical theaters conditions

Skin preparation solutions

Skin hair management.

(b) Perioperative management

Drapes

Double gloving

Timing of surgical débridement in open fractures

Surgical débridement: type of solution and irrigation pressure

Timing and duration of antibiotics (ATBs)

Use of local antibiotics (ATBs)

ATBs coated implants

Wound care: type of sutures, timing of closure, dressings and need of coverage

(2) Treatment of fracture-related infections

Surgical débridement

Implant retention versus implant removal

Antibiotic therapy: duration and route of administration

Use of local ATBs

Bone defect and grafting

Take-home Messages

Footnotes

Declaration of conflicting interests

Funding

ORCID iD

References