Fracture-Related Infection Epidemiology, Etiology, Diagnosis, Prevention, and Treatment.

Background: Fracture-related infection (FRI) is a challenge to physicians and other workers in health care. In 2018, there were 7253 listed cases of FRI in Germany, corresponding to an incidence of 10.7 cases per 100 000 persons per year.

Methods: This review is based on pertinent publications retrieved from a search in PubMed with the search terms "fracture," "infection," "guideline," and "consensus." Aside from the primary literature, international guidelines and consensus recommendations were evaluated as well.

Results: FRI arise mainly from bacterial contamination of the fracture site. Staphylococcus aureus is the most commonly detected pathogen. The treatment is based on surgery and antibiotics and should be agreed upon by an interdisciplinary team; it is often difficult because of biofilm formation. Treatment options include implant -preserving procedures and single-stage, two-stage, or multi-stage implant replacement. Treatment failure occurs in 10.3% to 21.4% of cases. The available evidence on the efficacy of various treatment approaches is derived mainly from retrospective cohort studies (level III evidence). Therefore, periprosthetic joint infections and FRI are often discussed together.

Conclusion: FRI presents an increasing challenge. Preventive measures should be optimized, and the treatment should always be decided upon by an interdisciplinary team. Only low-level evidence is available to date to guide diagnostic and treatment decisions. High-quality studies are therefore needed to help us meet this challenge more effectively.

Review article

Periprosthetic joint infections and fracture-related infections (FRI) are becoming increasingly important in the field of orthopedic trauma surgery, with 16 174 and 7253 inpatient cases, respectively, treated in 2018 (1). The rising number of surgical fracture treatments that are needed and that involve the implantation of osteosynthesis materials, combined with the growing proportion of older people represent a challenge for the current and future care of patients (2). Periprosthetic joint infections and FRI are often dealt with together. The complication posed by infections in the fracture region was only recognized in the international literature in 2018 with the introduction and definition of the specific term 'fracture-related infection' (3).

This review is based on a selective literature search in PubMed with the search terms "fracture AND infection AND guidelines," as well as "fracture AND infection AND consensus." In addition to international guidelines and consensus recommendations, the primary literature was also evaluated. The aim of this study was to formulate current standards in diagnosis and treatment in the form of practical recommendations and to familiarize the reader with key aspects of epidemiology, etiology, and prevention.

In 2018, 1.23% of all fractures treated in Germany on aninpatient basis resulted in an FRI (1). Between 2008 and 2018, a slight increase in administrative incidence from 5556 cases (8.4/100 000 persons) to 7253 cases (10.7/100 000 persons) was observed in Germany (1). One can assume that the worldwide incidence of FRI will continue to rise (e1). FRI poses a particular challenge in countries with medium and low average incomes, since here not only is the incidence higher due to the greater number of open fractures but resources for surgical or antibiotic treatment is also limited (e2).

FRI arise mainly from bacterial contamination of the fracture site. In the case of open fractures, this can occur as a result of the trauma itself, while in the case of closed fractures, this may also result from inoculation of pathogens into the wound area during surgery. Overall, the risk of FRI increases with the severity of soft tissue damage. Whereas an infection rate of 1-2% is assumed for closed tibial-shaft fractures, this rate rises to 42.9% for open fractures with extensive soft tissue injury (Gustilo -Anderson type III) (4, 5). Hematogenous infection--the colonization of pathogens originating in the skin, oral cavity, and respiratory or urinary tract via the blood to the fracture region--is less common (5). Biofilm formation of the infection-causing pathogen poses a challenge. Biofilm refers to the aggregation of freely moving (= planktonic) bacterial cells on surfaces. Once there, they become sessile cells forming an extracellular polysaccharide matrix (e3). Bacteria in the planktonic phase are considered to be responsible for a more acute infection process, but are on the whole readily treatable, while the sessile form is associated with a slower infection process and less favorable treatment options.

As in other musculoskeletal infections, Staphylococcus aureus (31.4-37.4%) and Staphylococcus epidermidis (16.9 -25.8%) are the most common FRI-causing pathogens. Other staphylococci (8.4-18%), streptococci (7.2%), enterococci (2.4%), and Cutibacterium species (2.4%) represent additional gram-positive pathogens, whereas gram-negative bacteria, in particular Enterobacteriaceae and Pseudomonas species, account for approximately one fifth of all pathogens (20.5-23%) (6, 7, 8). The rate of polymicrobial infections varies (8.6-36%), with these occurring more frequently in acute infections (7, 8, 9). The pathogen spectrum does not appear to be influenced by whether the FRI is an acute or chronic infection (9). Antibiotic -resistant pathogens play an important role worldwide. Although methicillin-resistant Staphylococcus aureus (MRSA) is only a marginal occurrence in FRI in Germany (~ 1%), it is of greater relevance in the USA (44.1%) and China (25.3%) (e4, e5, e6). Therefore, periods abroad should be taken into account when taking a patient's history of MRSA risk.

As a result of the previous lack of a definition, diagnostic criteria for periprosthetic infections were often extrapolated (e7). A consensus definition for FRI, including both confirmatory and suggestive diagnostic criteria, was finally published in 2018 (Table 1) (3).

Diagnosis is to a great extent clinical routine. In addition to FRI itself, consideration should also be given to systemic diseases, and these should be discussed and treated with specialist colleagues in an interdisciplinary exchange (Figure 1). In order to optimize microbiological diagnosis, it is recommended to take between three and five tissue specimens instead of the usual intraoperative swabs. These should each be taken with a separate sterile instrument from the infected region and not from the area of the skin or fistula. A possible complementary diagnostic measure is to additionally send the implant for sonication (e8). Here, the foreign material as a whole is subjected to ultrasound treatment in order to dislodge any bacteria from the surface of the material and from the biofilm.

In addition to general measures recommended by the World Health Organization (WHO) and the Centers for Disease Control and Prevention (10, 11), such as hand disinfection, use of sterile instruments, and repeated sterile cleansing of the surgical site, recent studies show that alcohol -based antiseptic solutions such as chlorhexidine for skin disinfection are superior in terms of minimizing the risk of postoperative infections (11, 12).

The co-treatment of comorbidities such as underlying cardiac disease, peripheral arterial occlusive disease (PAOD), and type II diabetes mellitus is an important factor (13, 14). Moreover, perioperative antibiotic prophylaxis is essential in orthopedic and trauma surgical procedures. In the case of closed fractures and elective procedures, a single dose of a first-generation cephalosporin, for example, cefazolin, 15-60 min before the start of surgery is recommended. If surgery time exceeds 2 -3 h, re-dosing should take place, as has been shown in retrospective cohort studies (15, 16). With regard to open fractures, the evidence on type and duration of antibiotic prophylaxis is less consistent (15). In these cases, intravenously administered antibiotic prophylaxis should be carried out as early as possible (e9). In the case of grade I and II open fractures according to Gustilo-Anderson, first- and second-generation cephalosporins or aminopenicillins plus beta lactamase inhibitors are recommended, although their administration beyond 24 h is not recommended (17). For grade III open fractures, the microbial spectrum of gram-negative bacteria needs to be more broadly covered, hence piperacillin/tazobactam are the drugs of choice. Antibiotic prophylaxis for more than 72 h was not superior in terms of reducing the rate of fracture -related infections in grade III open fractures (18). In complex and high-grade open fractures, a beneficial effect has been demonstrated for the local application of antibiotics. This can take the form of polymethyl methacrylate (PMMA) beads, collagen fleeces, or bone regeneration materials in combination with various antibiotics (19). In open fractures with severe Gustilo -Anderson type IIIB soft tissue defects, soft tissue coverage should ideally be carried out within 72 h, since this can significantly reduce infection rates as well as flap failure compared to delayed free-flap reconstruction after 72 h, as shown in a meta-analysis based on data from 35 case series and eight case reports (20).

In surgical treatment, particularly in the case of open fractures, adequate debridement involving the removal of heavily contaminated and necrotic tissue is essential. In addition, thorough wound irrigation with saline solution should be performed in the case of open fractures (21). For the primary treatment of high-grade open fractures, temporary external fixation by means of fixators is also recommended (22). Preclinical studies have shown a benefit in terms of reducing infection for the antimicrobial coating of osteosynthesis material with antibiotics or silver compared with standard uncoated implants (e10, e11). Coated implants are also already in clinical use. However, the evidence for their benefits is currently still based on case series and reports (evidence level IV) (23, e12, e13, e14).

For postoperative wound care, the general measures such as the use of sterile dressing material and strict adherence to hand hygiene apply. A meta-analysis based on data from three randomized controlled trials was unable to show a difference in infection rates between dressing changes carried out early (< 48 h postoperatively) and in a delayed manner (> 48 h postoperatively) (24). Nevertheless, it is recommended that the first dressing change does not take place in the first 24 h postoperatively, assuming the dressing is dry and sits properly (15).

General aspects

The aim of FRI treatment is infection-free consolidation of the fracture. This is based on a combination of surgical treatment and antibiotic therapy and should be carried out in an interdisciplinary manner. Numerous facets--from soft tissue status, local blood circulation, and underlying diseases to the advanced age of the patient, their psychological processing of the trauma, and antibiotic therapy lasting several weeks--can fall outside the expertise of orthopedic and trauma surgeons. In such cases, a number of different specialties should be involved. Joint medical rounds or boards are a proven means of closely and efficiently coordinating diagnosis and treatment in the interests of the patient and reducing revision and amputation rates, as shown in a recently published retrospective cohort study (25) (Table 2).

Surgical measures

Antibiotic treatment alone is not usually sufficient for complete infection resolution due to the pathogens living in the biofilm on the implants (Figure 2). A number of criteria play a role in the decision-making process regarding surgical treatment. In addition to the importance of intact soft tissue conditions, which are considered essential for infection resolution, an assessment of potential for further bone healing in terms of the reduction conditions and the stability of the osteosynthesis is important. Furthermore, there must be the possibility for sufficient debridement in order to reduce the bacterial load.

In the simplest case, fracture healing has progressed to the point where the fracture has healed. Therefore, the implant can be removed without problem and the infection can be brought under control by thorough surgical debridement of the former implant site, soft tissue, and healed bone.

In the case of acute infections involving an immature biofilm and unhealed fractures, the debridement, antibiotics, and implant retention (DAIR) approach may be considered (e15). Here, the existing osteosynthesis material is left in place, adequate surgical debridement and irrigation are performed, and antibiotic therapy, ideally local as well as systemic, is administered. The prerequisites of DAIR include sufficient soft tissue coverage, the presence of a stable implant with good reduction, and a surgically accessible implant site. For this reason, DAIR should be avoided if intramedullary interlocking nails are present, since these preclude the possibility of sufficient debridement. Moreover, leaving intramedullary nails in place is associated with a significantly higher reinfection rate (e16) (Table 2). A meta-analysis based on six studies (randomized controlled trials as well as prospective and retrospective cohort studies) with a total of 276 patients showed that the DAIR procedure has the best chance of success primarily within the first 3 weeks following fracture treatment, with success rates of 86-100% (26).

In the case of implant loosening, the implant must always be removed and reosteosynthesis performed, since stability in the fracture area is a basic precondition not only for infection management but also for fracture consolidation (e17). Similarly, leaving the implant in place is no longer indicated in the case of established infection of a nonunion (e18). Therefore, in such situations, a one-stage implant replacement, a two-stage or multi-stage surgical procedure, and--in extreme cases--amputation of the affected limb represent options. If there is no bony defect and the soft tissue status is good, single-stage implant replacement with direct re-osteosynthesis can be performed following adequate debridement. This is possible even if the infection has not yet been eradicated, since antibiotic therapy protects the newly inserted implant from renewed bacterial colonization. Even if plastic surgical coverage with bony defect reconstruction is required, the literature reports excellent long-term results for single-stage procedures, with 94% freedom from infection at more than 6 years (evidence level IV) (27, 28). Although it appears possible to achieve excellent results of this kind in highly specialized centers with an appropriate multidisciplinary treatment approach for limited bone defects, one must sometimes consider a two-stage or multi -stage procedure as the standard of care for soft tissue and bone defects. The aim of the treatment is to control the existing infection in the first step and to reconstruct the bony defect in the second step once the infection has eased. Programmed revisions with multiple wound irrigation procedures should be a thing of the past in view of the anesthetic burden on the patient and the risk of secondary contamination of the wound with other bacteria (e19). Depending on the clinical findings, it may be necessary in exceptional cases to repeat the debridement several times to eradicate the infection if it does not resolve, in which case this is referred to as a multi-stage procedure (evidence level III, Table 2).

In addition to adequate surgical debridement, the key to treatment success lies in dead space management following bone resection with antibiotic-loaded carriers as well as soft tissue management (29, 30). If there is a soft tissue defect, it is essential to achieve early soft tissue closure, as stated above. In the short term, that is, limited to a few days, vacuum assisted closure (VAC) or antibiotic bead pouches can be used (e20). Bacterial colonization of the VAC system can potentially be considered as causal in poorer treatment outcomes (30, 31, 32). If plastic surgical expertise is not available on site, prompt transfer of the patient to an appropriate center is advised.

For the reconstruction of bony defects, various reconstruction methods are available depending on the localization, size, and shape of the defect. In this context, what is referred to as the Masquelet technique has become increasingly established in recent years as a two -stage procedure. Here, the infection is initially eradicated during the first surgical procedure using spacers coated with antibiotic-containing PMMA bone cement and a well-vascularized neomembrane is formed around the bony defect zone. In a second surgery, the spacer is removed after approximately 6 weeks and the defect is filled with autologous or allogenic bone (e21). In addition, numerous bone replacement materials are available (e22). For segmental bone defects, callus distraction procedures, such as segment transport according to the Ilizarov technique, have proven their worth (e23). In 3% of cases, amputation must be taken into consideration as the best treatment option (33). This may be necessary particularly in elderly and multimorbid patients in the case of severe infection (Table 2).

Antibiotic treatment should be initiated immediately upon completion of intraoperative specimen collection for microbiological analysis and if there is clinical suspicion of infection. An exception is made in the case of septic patients, in whom treatment should begin once blood cultures have been taken. Here, the calculated treatment should ideally cover the local spectrum of pathogens; for example, a glycopeptide antibiotic (vancomycin) can be combined with a beta-lactam (ceftriaxone or alternatively amoxicillin/clavulanic acid) to cover both the gram -positive and gram-negative spectrum. Of course, antibiotic treatment needs to be adjusted as soon as the pathogen has been detected (13).

According to current knowledge, the additive use of rifampicin is only beneficial in staphylococcal infections if foreign material is still present. In general, one waits for wound healing before adding rifampicin. Due to its high oral bioavailability, rifampicin can be administered orally from the outset. However, it is important to bear in mind that rifampicin can interact strongly with other drugs. Therefore, a review for possible interactions with the patient's concomitant medication, particularly with new oral anticoagulants (NOACs) and phenprocoumon, should be mandatory (13).

Particularly for linezolid, oral administration for longer than 4 weeks is not possible due to the bone marrow toxicity that frequently occurs. In such cases, the only remaining option is outpatient parenteral antibiotic therapy (OPAT).

No specific studies are available on the duration of treatment for FRI; the recommendations for prosthetic infections are often used as a guide, meaning that the duration of treatment is usually 12 weeks (Table 3).

Fracture-related infection presents an increasing challenge in clinical routine. Against this backdrop, preventive measures should be optimized and treatment should always be carefully decided upon by an interdisciplinary team. The evidence for the various treatment approaches is largely based on retrospective cohort studies.

The authors declare that no conflict of interests exists.

Manuscript received on 11 June 2023, revised version accepted on 23

October 2023.

Translated from the original German by Christine Rye.