Preferable assessed after debridement , the FRI classification is a useful tool for guiding clinicians to make a personalized treatment plan after sampling and debridement, based on the three major elements: Fracture (F), Related patient factors (R) and Impairment of soft tissues (I).

Fracture (F) treatment

Fracture stabilization is essential for successful treatment.

An unstable fracture is at higher risk of mal- or nonunion, and it disrupts healing of the soft tissue due to continuous trauma. This leads to inflammation, impaired immune response, disrupted neovascularization and reduced penetration of antibiotics. The result is an increased chance of infection, leading to lysis of bone and/or implant loosening. Surgery is often required to break this cycle.

The F element does not specifically analyze the configuration of the fracture, but rather the healing potential. However, it considers three aspects of the fracture:

• The viability of the bone ends (biological ability to heal).
• The stability of the fracture construct (biomechanical ability to heal).
• The quality of reduction (bone contact and mechanical alignment).

F1 cases

The fracture has already healed but there is an infection, often of the implant. In most cases, debridement and removal of the implant, if present, will effectively treat the FRI. In most cases, six weeks of antibiotics, based on the culture results, is recommended.

F2 cases

There is non-/malunion. The bone is considered to be of good quality, with good fracture reduction and fixation, stability and viable bone ends. (debridement, antibiotics, and implant retention) may be possible, depending on the type of implant and duration of infection. In cases with a longer duration and/or more severe infection, consider implant exchange, if feasible.

F3 cases

There is also a non-/malunion and there is poor healing potential due to unacceptable reduction, instability in fixation or devascularized bone ends. DAIR is generally not possible and intraoperatively the surgeon may find small, non-critical bone defects after debridement. A new reduction and/or fixation is recommended.

There are two main options for new fixation:

• Internal fixation (exchange if already material in situ)
• External fixation

Both options can be combined, for example internal fixation can follow after a period of external fixation that allows the soft tissues to heal.

Internal fixation

Traditionally, infection has been a contraindication for internal fixation. However, recent studies have shown it can be a viable option. The principle is that due to direct bone healing, sequestration is avoided and a potential source for biofilm formation eliminated. Therefore, debridement is a vital part of treatment. Furthermore, in the case of intramedullary nailing, patients may quickly regain the ability to walk, which can be essential in low-resource settings, preventing catastrophic healthcare expenditure.

For more detailed information, see Internal fixation in open fractures.

External fixation

External fixation is a good and reliable fixation option for FRI. It allows for fracture stabilization without any foreign materials in the infection site, reducing the chance of biofilm formation. Pins and bars are also reusable, which makes it suitable for low-resource settings.

External fixation can be a bridging option, to achieve temporary stabilization before final internal fixation, or a final treatment. In a high-resource setting, temporary external fixation and exchange of implants have comparable treatment and functionality outcomes in healthy patients with small bone defects, healthy bone and soft tissues without multi-resistant microorganisms. Both modular and circular external fixators can be used for final treatment.

For more detailed information, see Definitive fixation with an external fixator.

In F3 cases, to adress the small bone defects, you may apply:

• Very limited bone shortening
• Bone substitutes
• Obliteration with healthy soft tissues

Managing non-critical cavitary defects in the bone

Cavitary defects are created by dead space left after surgical debridement and must be managed accordingly. As a rule of thumb, these cavities must be filled to treat the infection. Depending on the type of defect, treatment strategies may vary.

F4 cases

Bone reconstruction is required to treat the bone defect, and shortening is not an option due to loss of function. A critical bone defect is defined as: Any defect that will not heal without further surgical intervention. treatment of critical bone defects is complex and mostly based on expert opinion. Large defects of over 5cm in the lower limb are especially difficult to treat. Treatment options include:

• The Masquelet technique using non-vascularized grafts
• A vascularized bone graft such as a fibula graft
• Bone transport techniques

Managing 'death space' and segmental bone defects

Once you have decided the tissue and/or dead bone needs to be excised, you must be prepared to manage the resulting death space. This can be achieved with a vascularized soft tissue flap if there is no critical size bone defect. Critical size bone defects are defined by bone loss that will not heal spontaneously and when this leads to impaired function, proper management is needed.

Using a spacer that contains local antibiotics inside the bone (mixed into a suitable carrier) is recommended. It is generally safe to add about the same amount of antibiotic as a normal daily IV or oral dose to the carrier.

There are two types of carriers:

• Non-absorbable carriers (such as PMMA) that must be removed later, and
• Absorbable carriers, which do not need removal and can allow a single-stage procedure.

Polymethylmethacrylate (PMMA) is the most commonly used carrier for local antibiotic delivery.
It is easy to obtain and affordable in many African settings. PMMA can be used as a spacer, beads, or to coat an implant. However, PMMA has important disadvantages:

• it may become colonized by antibiotic-resistant bacteria.

• it usually requires two surgeries,

• it has poor antibiotic release

The absorbable local antibiotic carriers (e.g. Stimulan and Cerament) are not yet widely available in LMICs. They offer multiple advantages like a single stage surgical strategy, osteoconductive properties and prolonged local action of the antibiotics compared with the PMMA spacers.

There are publications providing alternatives for these expensive absorbable antibiotic carriers (example) but a proven cheap and effective alternative is not yet widely available.

Other local antibiotic options include bone grafts mixed with antibiotics during surgery.
These can be useful for treating infected bone defects in settings with limited resources.

Using antibiotic powder directly in the wound (without a carrier) is not recommended for managing fracture-related infections.

Debridement in very late presentation and chronic FRI in LMICs

Late presentation of FRI, sometimes months or even years after the injury, is relatively common in resource-limited settings. In these cases, the debridement of soft tissues and death bone is often a big challenge.

In complex situations, with necrosis of the bone, a sequester may have formed. A sequester is a fragment of dead bone. This situation is also common in hematogenous osteomyelitis. In this specific situation the treatment strategy for hematogenous osteomyelitis and FRI have broad overlap.

If the patient is lucky, the body may have encapsulated the sequester with new cortical bone, so the fracture itself may have healed. The formation of new bone around a sequestrum is called an involucrum. It has a very specific radiological appearance on plain X-ray, as seen in the figure below: it appears as a cortical thickening with a central radiolucency. Cloaca of sinuses may be present. Intraoperatively, a sequester may seem very obvious. However, the exact border between vital and dead bone may also be less obvious if the formation of involucrum is still progressing and the demarcation between sequester and involucrum has not finished.

In the presence of fracture healing and a stable involucrum the excision of the sequester is relatively simple. If the involucrum has not yet formed or it provides not enough stabilization to the fracture, excision of a sequester may be postponed until enough involucrum has formed that no critical bone defect will occur when operating. This may seem counterintuitive, as medicine rarely allows for retention of a foreign body (death bone in this case), but if the area of affected bone is very big, and the borders are not clear, the patient may end with a non-functional limb if all the affected bone is resected and it can not be reconstructed. In these situations it is wise to wait as long as the the patient conditions allows until the involucrum has formed. Optimizing the patients conditions is key to success. Often these patients receive antibiotics for a long time, but this is probably of limited value in patients without generalized infection signs, since resistance will occur within a few weeks, especially when there is a discharging wound or sinus which is almost the case. Long term AB treatment in chronic bone infections with open wounds is not useful.

After a sequestrectomy, use large volumes of normal saline to irrigate the excision site, to reduce bacterial load. If excision of the sequester has left the bone fragile, consider fixation using either an external fixator or plaster of Paris cast with a window for wound inspection. In case there will be a bone defect.

Management of segmental bone defects

The management of larger segmental defects is extremely challenging. It should only be performed by a multidisciplinary team of experienced clinicians on a patient with a reasonable chance of recovery. The size of the defect determines what treatment options are available, as shown in the figure below.

Alternatives in specific situations are:

• Arthrodesis (in some specific peri-articular FRI)
• A (custom-made) prosthesis, in very selective cases

F5 cases

If a segmental defect or severe infection is not treatable with available expertise, refer the patient. If referral is impossible, consider amputation. Involve your rehabilitation physician and possible prosthesis maker at an early stage. They can provide the patient with information and offer you advice on the most functional level of amputation.

The stigma of amputation

In many places, amputation carries a stigma, and patients may resent the physician for proposing it. Discuss the sociocultural and economic consequences of performing or refusing an amputation with the patient and their family.

In some cases, antibiotic suppression may be an option if patients refuse amputation, but outcome is poor and if the leg heals, it will take a very long time.

Relevant patient factors (R)

This element is about the patient and includes systemic and local factors influencing healing and resistance to infections. Systemic factors are subdivided into comorbidities with or without end organ damage. However, if possible, risk factors should be modified to the benefit of the patient and treatment strategy.

Optimizing a patient before surgery is crucial to maximize their chances of a successful outcome, especially in FRI patients.

Factors such as smoking, arterial insufficiency, cardiovascular and pulmonary conditions, and endocrine disorders can compromise a patient's general and local limb status, increasing the risk of postoperative complications. Therefore, identify modifiable risk factors and address them appropriately.

• Smoking cessation prior to surgery and for the duration of healing.
• Correcting severe arterial insufficiency.
• Managing reversible cardiovascular, pulmonary, and fluid imbalance conditions for better tissue oxygenation and perfusion, are essential steps.
• Correct anemia.
• Manage metabolic factors like diet (including micronutrients) and diabetes.
• Mobility: involve physiotherapy early.

In FRI cases, commence empiric broad-spectrum antibiotic therapy after tissue sampling, and adapt the therapy based on culture results.

Compliance with general infection prevention measures, such as preoperative washing, decontamination, and appropriate surgical skin antisepsis, is important.

Given the long-term disability often associated with FRI, it is essential to provide patients with comprehensive information about treatment options, benefits, risks, and potential outcomes to ensure psychological preparedness and compliance.

What if the patient is not fit for surgery?

CSAT

If a patient is not fit for surgery due to chronic diseases and/or constitutional factors, consider chronic suppressive antibiotic therapy (CSAT). This involves antibiotic treatment for a longer period of time, usually a maximum of three months. CSAT may help in improving a patient’s quality of life.

The antibiotics most often used in CSAT:

• Beta-lactams
• Fluoroquinolones
• Clindamycin
• Co-trimoxazole

Needle aspiration

If a fluid collection is clinically suspected or seen on imaging, perform needle aspiration. This may help reduce the bacterial load, and aspirated fluid can be used for culturing, allowing for smaller spectrum antibiotics.

Impairment of the soft tissues (I)

Adequate debridement of bone and soft tissue is a fundamental component of modern fracture-related infection (FRI) treatment. While thorough surgical removal of all non-viable tissue is essential, it can result in significant soft tissue defects that require reconstruction. Managing these defects is complex and requires consideration of multiple factors. Up to 40% of FRIs require local, pedicled or free flaps to address the defects. Selecting the best treatment strategy can be challenging.

Timing of closure

For a long time, two-stage treatment was the norm even for non-infected open fractures: fractures would be fixed in the acute phase, and final closure was achieved within one week. However, since the concept of ‘fix and flap’ has been introduced, with closure achieved immediately after fracture fixation. This has reduced infection rates dramatically.

In FRI, historically, culture negative wounds were required before closure was performed. However, even in DAIR procedures (i.e., debridement, antibiotics, and implant retention) single stage revisions show that this is not a necessity. Implant stability, effective debridement and immediate healthy soft tissue coverage are a prerequisite for DAIR.

We experienced in many settings with limited availability of experienced and skilled plastic surgeons that soft tissue reconstruction is delayed because the wound is 'not ready yet' for soft tissue reconstruction. That means often that a more aggressive debridement is needed immediately followed with a more challenging local flap or free flap. Only when the damage of the debridement cannot be solved by the reconstruction, a more conservative approach is understandable. Because FRI patients confront surgeons with very complex technical challenges, it requires dedicated orthoplastic teamwork with from both specialties superspecialists to achieve the best outcomes. Plastic and orthopedic surgeons should be more specifically trained for these challenges globally.

Type of flap

In FRI cases, the reconstruction ladder applies the same as in normal open fractures.

Historically, free and pedicled muscle flaps have been the preferred choice for wound coverage, due to their rich vascularization. Another benefit is that a muscle flap can reduce dead space resulting from the debridement. However, a study pooling both acute trauma and chronic post-trauma compared free muscle flaps and free fasciocutaneous free flaps and found no differences in limb salvage, functional outcomes and flap complications.

Overall, muscle and fasciocutaneous flaps appear to show similar results. When considering a free or local flap, research shows widely variable outcomes. One does not appear to be clearly superior to the other, and flap selection should be based on local soft tissue status and patient-related factors. Furthermore, free flaps require specialized equipment and high technical skills. This limits their application in a low-resource setting.

Soft tissue coverage of a large part of exposed bone or bone defect may simply not be possible. In those cases, acute compression or shortening of the long bone has been described to allow for adequate coverage with the remaining tissues.

Vascularity of tissue is very important for successful flap surgery. For example, high-energy trauma can damage vessels, and local infection can compromise venous outflow. These factors should be taken into account when making a treatment plan.

For more detailed information on surgical techniques in soft tissue reconstruction, see Methods of soft tissue reconstruction.

Describing or categorizing the soft tissue defect – the I element of the FRI Classification – may help and guide in developing a treatment plan.

I1 cases

The tissues over the fracture are well-vascularized, soft, and can be closed easily without tension. Direct closure provides strong coverage of the fracture and implant, creating an effective barrier against bacterial ingress.

I2 cases

Direct closure is possible, but the tissue quality is compromised due to fragility, scarring, vascular insufficiency, or cellulitis. While direct closure is generally successful, the failure rate is higher compared to I1 cases.

I3 cases

and : Direct closure is not feasible, and tissue transfer is always required. The reconstruction approach depends on the FRI location and local tissue condition. For example, a proximal tibia FRI may be covered with a local gastrocnemius muscle flap

I4 cases

A more extensive defect in the mid-tibia often necessitates a free muscle or a more challenging fasciocutaneous flap or muscle flap when free flaps are not available. When a free flap is not possible a cross leg flap can be a last option to consider with your patient.

I5 cases

Complex soft tissue reconstruction is not feasible due to severe vascular compromise, such as major vessel disruption from high-energy trauma, chronic infection affecting venous outflow, or inadequate recipient vessels in patients with atherosclerosis. In these cases, the only limb preserving treatment optios may be prolonged conservative wound care. In situations where amputation is not accepted by the patients and/or when prosthesis are not available, we experienced that very challenging F5I5 cases healed with acceptable functional outcome, although it took many months to years of conservative wound management. However, as surgeons we should not see an amputation as a failure.

Amputation is one of the options to reconstruct function and to bring the patient back into the society with good quality of life.

If FRI is suspected, do not start antibiotic treatment before a diagnostic workup, unless the patient is systemically ill, or in situations when a diagnostic workup is not possible. Providing antibiotics to patients with FRI without cultures and antibiograms will lead to inadequate treatment and antibiotic resistance development.

Which pathogens cause FRI?

The most common organism that causes FRI is Staphylococcus aureus.

Skin flora, such as coagulase-negative Staphylococci, Cutibacterium acnes and Streptococci can also cause infections. However, in general they possess fewer virulence factors than S. aureus. Other bacteria, such as Enterobacter, Enterococcus, Stenotrophomonas and Pseudomonas, are found quite frequently in FRI.

Polymicrobial infections or growth of environmental bacteria, like Clostridium, Aeromonas, anaerobes and mycobacteria, can also cause FRI, especially in open fractures. Environmental molds like Aspergillus, Fusarium and Mucorales can occur depending on geographical areas and injury type or extent, and they usually grow slower than bacteria. Candida is rare in fracture-related infections, but it is difficult to treat.

Microbiological and antibiotica resistance profiles of FRI varies between regions and countries.

This means that empirical antibiotic therapy is dependend on local guidelines and resistance profiles. Furthermore, it underlines the importance of taking samples for cultures.

How do pathogens cause FRI?

Different microorganisms have different mechanisms of infection, some of which are not completely understood. Microorganisms are introduced in a planktonic state – they are ‘free’ to explore the environment looking for nutrients that will allow them to multiply and cause an infection.

When bacteria are introduced to an open fracture and not treated promptly, or if they express surface components that promote adhesion, they can form biofilms on implants or bone tissue. This makes the infection much harder to eradicate.

Some bacteria express surface proteins that facilitate intracellular infections. Some bacteria secrete toxins that cause cell death. S. aureus can form micro-abscesses, which contribute to bacterial persistence and sustain inflammatory response. It can also colonize the osteocyte lacunocannicular network which promotes osteocyte cell death.

Classifying infections by timeline can give useful insights into the progression of infection, although the relevance of classifying FRI by time since injury is not crucial for the definition or microbiology.

FRI antibiotic treatment

Antibiotic treatment of FRI is an important part of a treatment plan, but is not a replacement for surgical debridement partly because of the formation of biofilm mentioned in the previous paragraph. It is an adjunct and its use should be clearly planned and documented. Antiiotic treatment can be:

• Systemic: Orally, intramuscularly or intravenously.
• Local: Either ‘naked’ by direct local administration, or by using a ‘carrier’.

Systemic, empiric IV broad-spectrum antibiotics should be initiated immediately after surgical sampling, based on local microbiological profile. Empirical antibiotic treatment (EAT) should consist of at least TWO systemic antibiotics with one being a lipo/glycopeptide (for example gentamicine or vancomycine) and one providing gram negative coverage.

A recent large scale randomized control trial has shown that long term oral antibiotics are not inferior to intravenous antibiotics when treating FRI. Therefore, an early switch to oral antibiotics is preferred whenever feasible. When planning oral antibiotic treatment consider oral bioavailability and likelihood of therapy adherence together with susceptibility of the cultures. In case of early FRI, 6 weeks of antibiotics is generally accepted, while in chronic FRI or following implant retention 12 weeks of therapy is still advised. Definitive antimicrobial therapy should be culture-specific and preferably guided by microbiology or infectious disease expertise.

Local antibiotic delivery (e.g., antibiotic-loaded bone cement or beads) is advisable when available. The local dose should be equivalent to a standard IV dose for optimal efficacy. Carriers can be absorbable or non-absorbable and the choice of carrier directly affects treatment strategy.

In culture-negative FRI, an agreed policy should define the empiric antimicrobial regimen, ensuring adherence to antimicrobial stewardship principles.

Systemic antibiotics in FRI

Infection management with systemic antibiotics is composed of two essential parts:

1. First, cultures and antibiograms allow for diagnosis and analysis of causative pathogens.
2. Second, expert advice allows for targeted treatment and dedicated microbiological advice has a positive effect on outcomes. This not only relates to a microbiologist, but preferably one with a background in musculoskeletal infections. While a specialist may not be available in a low-resource setting, consultation of a regional, national or international expert may be advisable if such systems are in place.

For more details on sample taking, see Diagnosing FRIs.

Time does not influence the choice of antibiotic.

Despite persistent beliefs, time since injury does NOT directly influence the type of causative microorganism. It was hypothesized that early infections were mostly caused by rapidly growing organisms like S. aureus, while chronic infections were caused by low-grade bacteria. However, recent research has shown that the microorganisms that are being cultured are not affected by time from injury.

Preoperative antibiotics should NOT be given unless in the case of sepsis, as this may influence cultures. Intraoperative antibiotics should be given in the form of local antibiotics.

Postoperative antibiotics should be given in the form of systemic therapy. FRI should be treated with six weeks of antibiotics, with the exception of certain cases with very active biofilm, where 12 weeks is recommended.

Short or Long Antibiotic Regimes in Orthopaedics (SOLARIO) is an ongoing clinical trial that compares one week or less of antibiotic therapy after surgery with the normal regimen of six weeks in cases where local antibiotics were applied. The initial results show that this may be as effective, showing huge potential in antimicrobial stewardship.

Rules of thumb for postoperative antibiotics:

• Stop gram-negative coverage if nothing has grown after 48 hours. An exception may be extensive and persistent open fractures.
• Use two different types of antibiotics.
• Operative findings may be relevant to antibiotic choice. Good operative notes are essential!

Local antibiotics in FRI

The use of local antibiotics is becoming more and more popular and evidence for their effectiveness is growing. They serve a dual purpose: They can be applied as filler materials in voids left by debridement and sometimes are used as a structural component in segmental bone defect. They are generally available in the form of beads or maleable to fit a specific viod.

There are three types of carriers:

• Polymers
• Synthetic bone graft substitutes
• Natural bone grafts

Polymers

Acrylic carriers like PMMA can simultaneously be used as dead space fillers (beads or bone cement) or as structural components in segmental bone defects. Generally, these carriers are loaded with gentamicin, tobramycin or vancomycin. However they have disadvantages because multi stage surgeries are needed to remove the carriers and the local antibiotic effect is very limited. Furthermore, heat produced from the exothermic hardening reaction limits the options of antibiotics

Synthetic bone graft substitutes

These carriers are made of biodegradable materials —such as calcium sulphate or combinations of calcium sulphate with hydroxyapatite— used to deliver antibiotics locally, support bone healing and release antimicrobial drugs in a more effective way. Because these carriers create very high antibiotic levels at the site of infection, a single locally applied aminoglycoside may sometimes be adequate, especially for difficult Gram-negative infections, where systemic antibiotics are often costly and associated with significant toxicity. These modern bioabsorbable products are, however, expensive and rarely available in most African countries.

Natural Bone grafts

Bone grafts can be sourced from the patient themselves(Autologous) of from a bone donor(Allogenic). In settings with limited resources, a practical alternative is to use these bone grafts during surgery and soak them in antibiotics. However, autologous bone grafting is limited by the direct availability of bone from the donor site, while allogenic bone grafting requires either a direct donor or a centralized donor bank/

Applying loose antibiotic powder directly into the wound is not recommended for managing fracture-related infection.

Emerging evidence suggests that when a local antibiotic carrier is used, a short systemic antibiotic course of around seven days may be just as effective as prolonged treatment. If similar results can be achieved in low-resource environments, this could shorten hospital stays, reduce overall costs, and improve adherence to therapy. For now, the limited availability of these carriers means that such benefits are mostly confined to high-income settings.

What to do in case of culture negative infection or lack of microbiological diagnosis?

Consider histology to diagnose infection in case of culture negative chronic fractures or non-unions.

• Range >5 polymorphous neutrophil per high powered field
• Lower: 98% Positive predictive value for aseptic
• Higher: 100% Positive predictive value for septic

This test is very reliable and accurate. Moreover, it can be performed in a resource-limited setting. If clear microscopic images can be produced, these can be sent to an experienced microbiologist to help make a diagnosis when local experience is lacking.

Histopathology can give additional information about inflammation depth or stage (acute/chronic), can look for micro-abscesses, do a gram stain or PAS stain, and can look for underlying malignant processes.

Follow-up and monitoring

Chronic FRI remains a long-term risk, requiring prolonged follow-up and possible additional intervention.

FRI patients should be followed up for a minimum of 12 months, preferably by clinicians with experience in FRI treatment and who have been involved with the current treatment. They should be closely monitored for signs of recurrent infection, non-union, or implant failure.

A surgical site infection and antimicrobial surveillance systems should be in place, allowing auditing of complication rates, types of microorganisms and antimicrobial resistance.

Multidisciplinary rehabilitation, including physical therapy and nutritional support, is essential for optimal functional recovery.

During treatment and follow up, patients should be discussed in MDT meetings concerning progress and outcomes. Recommended outcome measures include:

• Re-operation rates
• Non-union
• Infection recurrence
• Amputation
• Death

Understanding the basic principles for the treatment of FRI will help you develop a structured approach.

FRI treatment principles

Before treating a patient with FRI, consider the following elements:

• Early identification and intervention are key to optimizing patient outcomes. However, in non-septic patients there is time to get the patient at the right place for the best possible diagnostics and interventions. Refer complex cases to specialized centers for advanced multidisciplinary care.

• If you suspect FRI, do not start antibiotic treatment before a diagnostic workup (unless the patient is systemically ill).

• Inform patients about their condition, treatment plan, follow-up, and expected outcome.

• Prioritize the most cost-effective treatments.

• Patients should undergo host optimization (e.g., nutritional support, glycemic control) before and during definitive FRI management.

• Effective surgical debridement is the most important and probably also the most difficult step of surgical treatment. Remove dead tissue carefully to avoid creating large bone defects. Combine this procedure with diagnostic sampling taking deep cultures only.
  • Paprika sign: During excision, be alert for bleeding from small blood vessels in the cortex that occurs when drilling or sawing bone. This is called the ‘paprika sign’, and it indicates vital bone.

• Irrigation: Use plenty of saline; avoid additives.

• Start antibiotic treatment according to local protocols or previous cultures. If those are not available, treat for the most likely pathogens.

• After debridement and diagnostic sampling, perform:
  • Appropriate fracture stabilization
  • Adequate management of bone and/or soft tissue defects

Adjust targeted antimicrobial therapy based on culture results.

While the focus tends to be on the technical aspects of the treatment and specific antibiotic regimens, you must take patient factors into account when devising a treatment plan. You are treating a patient, not a disease. Shared decision making is recommended in any complex surgical condition with different treatment options that have specific risks and benefits.

Read more about surgical management in: “The surgical management of fracture-related infection. Surgical strategy selection and the need for early surgical intervention,” Marais et al. (2024).

Putting the actions into a flow chart makes the process more practical:

Emergency management

Patients with life-threatening sepsis must receive IV fluids and broad-spectrum antibiotics within two hours of presentation. In such cases, take blood cultures before antibiotic administration to guide targeted therapy. Urgent surgical intervention may be required in unstable or rapidly progressing cases. Consider amputation if sepsis is severe (‘life over limb’).

Timing of surgery

While it may be tempting to send a patient to the operation room straight away to prevent further infection, this might not be the preferred choice for the best outcomes, except for the life-threatening infections. Host optimization, soft tissue assessment and multidisciplinary consultation should be performed if the situation allows for it.

The flowchart below may help you decide when to perform surgery.

Host optimization and the multidisciplinary approach

The general health of the patient is both a predictor for the development of an FRI and a pillar of treatment. As one of the treatment principles, it is a form of tertiary prevention.

Improving the general health of a patient to improve treatment outcomes is called host optimization.

Effective host optimization is best done by a team of specialists:

• Trauma/orthopedic surgeon
• Plastic surgeon
• Microbiologist/infectious disease specialist
• Radiologist
• Nutritionist/endocrinologist
• Rehabilitation specialist
• Physiotherapist
• Consider: internal medicine specialist, geriatric specialist, anesthesiologist

Such a team is known as a multidisciplinary team (MDT). When therapy-focused decision making is performed by an MDT, patient outcomes improve significantly, showing fewer amputations, fewer revisions, and more use of local antibiotics. Furthermore, there was a trend in the reduction of recurrent infection and treatment failures.

Read more about MDT care in Rupp et al. (2023), “Multidisciplinary Treatment of Fracture-Related Infection Has a Positive Impact on Clinical Outcome—A Retrospective Case Control Study at a Tertiary Referral Center.”

Early FRI management vs late FRI management

Early FRI (<6 weeks) can often be managed at any facility that provides operative fracture care, especially when using internal fixation techniques. In early FRI, early intervention is improtant to ensure good outcomes.

In late/chronic FRI, host-optimization and a multidiciplinary approach should be priority.

Surgery is usually required to effectively diagnose and manage FRI. If surgery is not feasible, suppressive antibiotics may control symptoms but rarely eradicate the infection, this approach is not recommended. This decision must be documented, including the planned duration of therapy.

Key steps include:

• Diagnostic sampling: Obtain microbiological samples before starting antibiotics during surgery.
• Debridement: Remove all non-viable tissue and thoroughly irrigate the wound.
• Fracture stabilization:
  • Unstable FRI require external or internal fixation.
  • Stable prior fixation with satisfactory reduction may be retained in early FRI (DAIR)
  • In case of chronic/late FRI consider debridement antibiotics and implant exchache(DAIEX) or removal if the fracture is stable.
  • In resource limited setting, implants may be sterilized instead of exchanged.
  • Always consider exchange of infected intramedullary nails as debridement of a nail is challenging.
  • Inadequate prior fixation should be removed and replaced.
• Soft tissue management: Definitive good-quality soft tissue closure is required. If complex defects are present, involve plastic surgical expertise where available.

In late presentation, especially with prolonged presence of wounds (>6 weeks) the implant retention is less likely to be successful and if possible it should be exchanged for a new fixation is the fracture is still unstable.

Single versus multi-stage

If the debridement can be performed adequately leaving only healthy tissue and a direct sore tissue reconstruction is possible singe stage surgery is recommended. Multi-stage procedures are preferred if there are signs of systemic sepsis, or uncontrollable local infection with for example, a large accumulation of pus. If these factors are not present, make an orthoplastic collaborative decision: Quality of the remaining bone, soft tissues and host status all influence the choice of single or multi-stage strategies.

Follow-up and Outcomes

• Minimum 12-month follow-up is recommended.
• Monitor wound healing, fracture union, antibiotic side effects, and infection recurrence.
• Track outcomes: re-operation, non-union, recurrence, amputation, death.
• Hospitals should maintain a surgical site infection surveillance system.

FRI classification is helpful to compare patients for research and to guide clinicians in decision-making when treating patients with a standardized treatment strategy. There are several classifications (Cierny-Mader, BACH) that can help to understand FRI. However, these classification systems were developed before the destinction between FRI and oestomyelitis was made, limiting their usefullness in clinical practice especially in a low-resource setting.

A new FRI classification system was published in 2024 and is according to our experts most useful to guide personalized decision-making. This new system was based on simplicity, reproducibility and distinctness. It has been specifically created to be applicable in all clinical settings, as the highest prevalence of fracture-related infections is in LMICs.

This FRI classification system has three major elements and is easy to remember:

• Fracture
• Related patient factors
• Impairment of soft tissues

Complexity in each element is graded from 1 to 5, and this grading helps you consider possible treatment options.

It’s important to realize that the situation for a patient may change before a definitive treatment plan is made. For example, related patient factors can be optimized, or impairment of soft tissues can become more extensive following a primary surgical debridement.

Ideally, use this classification after surgical debridement in the OR when you can assess the situation adequately.

The Chapter 'Managing FRI' uses this classificatin system in the decision making when making an FRI treatment plan.

Why is time not a factor in FRI classification?

Historically, bone infection classification and treatment plans have been influenced by time to presentation, specifically the decisions to treat with debridement, antibiotics and implant retention (DAIR). However, there is very little evidence to support this choice, and more recent research has classified time from injury as an independent factor on treatment outcomes. In expert opinion, time from injury impacts the patient as a whole, but no cutoff is possible.

The passage of time may have a positive influence on FRI, as some bone healing may occur. For example, an F2 can become an F1, leading to better outcomes. On the other hand, it may create bigger issues, for example bone loss.

FRI should be suspected in cases of poor bone healing, poor soft tissue coverage, sinus formation, or persistent pain. The diagnosis of FRI can be challenging in certain situations without clear signs of infection.There are a few things to keep in mind before assessing a patient with suspected FRI:

Firstly, patients with signs of systemic sepsis are an emergency and require an immediate assessment and urgent sepsis management. This condition is relatively rare in FRI patients, especially when there are discharging wounds.

Secondly, the differentiation between early and late or chronic FRI is important to make from the start. For suspected early FRI (within 6 weeks after the injury or the surgery), early intervention is more important to ensure good outcomes. In chronic FRI, treatment can be scheduled and there is time to optimize the patient condition and to refer to a dedicated multidisciplinary team in an expert centre, even when this takes a few weeks time.

The diagnosis of FRI is made when a patients’ condition meets certain criteria, as proposed and published by an international expert group. The criteria have been subdivided into pre-operative criteria and post-operative criteria. In both situations confirmatory signs or suggestive criteria have been defined.

The following flowchart outlines the diagnostic process of FRIs.

Pre-operative criteria

FRI diagnosis is easy if there is pus draining from a wound or sinus from the fracture side (with or without an exposed fracture or implant). In low-resources settings this is the easiest and the most common presentation of FRI.

Additional suggestive preoperative criteria:

• Local redness and fever
• New onset joint effusion
• Persistent, increasing or new-onset wound drainage

If only suggestive criteria are found, we recommended diagnostic sampling [link to subsection], if resources to get reliable cultures are available. Avoid sinus tract or wound swabs; instead, take intra-operative samples.

In situations where resources are limited, consider referring the patient to a better equipped center, if feasible. If not, try to do the best you can with the resources available, but be aware of the risks: do no further harm.

Post-operative criteria (after sampling in the OR)

Post-operatively, diagnostic criteria are based on the results of the deep cultures that are taken surgically in a sterile environment in the operating theatre.

Diagnostic sampling is a crucial step in the treatment of FRI. It is essential that it is performed correctly as it provides the only opportunity to obtain uncontaminated culture samples. It is the foundation of the antibiotic regimen that follows.

How to perform accurate diagnostic sampling

Stop antibiotics 2 weeks before sampling if the patient is stable, especially in chronic FRI.

• “No Touch Technique” – While it is tempting to feel the consistency of the tissues during sampling, this is not the time. Only touch tissues with instruments and avoid cross contamination by touching. This may seem irrelevant as everything seems to be infected, but it can provide the microbiologist with essential information.
• Take five samples for culture and sensitivity and label them clearly – This may seem excessive, but it provides redundancy while allowing for a double check of the causative pathogen. If fungal culture is required, discuss this with the lab.
• Use five dedicated sets of clean instruments – Avoid cross contamination of specimens at all costs. Consider using disposable scalpels and forceps if resources are limited.
• If possible, send implants for sonication – This technique aims to break the biofilm of the implant with ultrasonic waves. The explanted implant is in a box with fluid; after sonication, this fluid is cultured.
• What to sample:
  • Abscess wall/pus
  • Tissue around implant/interface tissue (between plate and bone)
  • Dead bone
  • Loose implants
  • Non-union tissue/callus
  • Take deep samples: NEVER skin or sinus tract
  • Possible: Joint fluid, synovial biopsy and joint capsule; bodily fluids may be collected in blood culture bottles
  • In patients unable to undergo surgery, only fluid aspiration may be used.

The diagnosis of FRI is confirmed by identifying two or more indistinguishable microorganisms in the intra-operative samples. The diagnostic accuracy of sampling is 84% when 3 samples are taken, increasing to 97% for 5 samples taken in high-income setting. Increasing the number of samples therefore is the best way of ensureing a diagnosis.

KEEP YOUR HANDS CLEAN - Clean hands and gloves are a sign of proper sampling, as this reduces the chance of cross contamination.

Additional value of histology: In patients that do not have clinical confirmative criteria of FRI, two or more bone/soft tissue samples are recommended. In resource-limited settings, a single sample may be acceptable. The presence of micro-organisms or more than 5 polymorphonuclair neutrophils per field is confirmative for FRI.

FRI diagnostics: Imaging and lab tests

Additional investigative modalities are available to search for other suggestive criteria when diagnosing FRI.

Clinical chemistry: CRP, WBC, ESR

Blood tests are of limited diagnostic value. While elevated levels of CRP, WBC and ESR are suggestive of FRI, normal values do not exclude an infection. Additional blood tests are important to check general health and identify treatable problems (anaemia, vitamin D deficiency, diabetes, HIV) that help with host optimization.

Plain X-rays

X-rays should be the first imaging you perform. They can show bone lysis, implant loosening, sequestration, non-union or malunion, or when taken over a span of time show changes in the fracture site that can aid in diagnosis. However, there is no evidence of the diagnostic reliability of a plain radiograph. More advanced imaging is recommended for specific indications, if available, but is of relatively limited value, even in settings where these resources are available.

CT

Shows fracture configuration more clearly and can be used in surgical planning for fracture management. Relatively low diagnostic performance for FRI (sensitivity 47% and specificity 60%) but can be useful to detect abscesses and sequesters.

MRI

Very useful in mapping the extent of tissue inflammation. Cannot distinguish between inflammation of normally healing bones and tissue or inflammation due to infection. The sensitivity is 82–100%, specificity 43–60%. MRI may not be appropriate when a patient has metal implants

FDG-PET

Useful scan for diagnosing FRI, specifically if presentation is more than one month after surgery. Sensitivity is 65–94%, specificity 76–100%.

3-phase bone scan

High sensitivity (89–100%), low specificity (0–10%). Not recommended in the workup of FRI.

WBC scintigraphy

The sensitivity 79–100% and sensitivity 89–97%. A major advantage of WBC scintigraphy is that its accuracy is not influenced by recent surgery. This technique is laborious, constly and time consuming and it is less accurate in the axial skeleton.

Ultrasonography

While this modality of imaging may be used for fracture diagnosis, in the case of FRI its use is limited. However, it may identify massive abscesses and provides the possibility of USS guided aspiration of fluid collections to culture. In patients who are unfit for surgery, this can allow targeted antibiotic treatment.

Open fractures have a increased risk of developing FRI, with rates between 12–52% of all open fractures in low resource setting. Effective initial management is critical in reducing this risk by removing as much primary contamination as possible while at the same time preventing iatrogenic introduction of pathogens. Prompt washout and early administration of antibiotics are vital steps that need to be taken as early as possible.

While generally less at risk than open fractures, closed fractures can also become infected (10–25%). If surgical treatment of these fractures is required, again preventing iatrogenic introduction of pathogens is essential. Minimally invasive surgery techniques, surgical safety checklists, proper operating room hygiene, adequate antibiotic prophylaxis, shorter hospitals stays and operative times all contribute in keeping the infection rate as low as possible. All healthcare workers who treat fractures should be aware of these risk factors to reduce the chances of infection.

To effectively prevent FRI, the clinician must understand how an open fracture can lead to FRI: At the moment of initial injury, microbes are introduced into the zone of injury. While the bodies own immune sytem will try to attack and destroy these microbes, its ability to do so is hampered by the presence of foreign materials and devascularized tisses. In these conditions, microorganisms have the ability to create a biofilm upon these foreign materials and devascularized tissues and help them to survive and thrive. Bacteria in biofilms are difficult to eradicate with only conventional antibiotic therapy. The concentration required to penetrate the microorganisms in a biofilm is simply too high. Therefore, systemic antibiotic therapy is rarely a cure by itself. Surgical debridement is required to remove any tissues or materials that contain or can develop biofilm. Surical debridement can lead to deadspace formation due to bone or tissue loss. It is of vital improtance that this deadspace is managed to prevent recurrent infection. There is increasing evidence that applying local antibiotics in this deadspace have an important additional value in preventing and treating FRI.

Risk factors

The risk of developing FRI is multifactorial and most easily categorized as:

• Injury-related risk factors
• Patient-related risk factors
• Treatment-related risk factors

Injury-related risk factors include the Gustilo Anderson-classification, level and type of wound contamination, and vascular injury.

Patient-related risk factors include smoking,  age, malnutrition, HIV status, and tuberculosis.

Treatment-related risk factors concern the timing and the quality of care provided. Examples include a lack of appropriate antibiotic prophylaxis for an open fracture; a prolonged preoperative hospital stay and prolonged operation time (with increased risk of colonization with a resistant hospital-acquired bacterial strain); inadequate immobilization or fixation techniques; lack of a sterile environment during a surgical procedure; poor initial debridement, increasing the risk of biofilm formation.

Many risk factors are modifiable and avoiding them will lead to better outcomes when treating patients with open fractures.

Preventive measures

Healthcare workers who treat fractures should adhere to guidelines on (open) fractures management. The principles to follow are those of infection prevention and control (IPC). Not only healthcare workers but also patients and caretakers should be informed about the symptoms and signs of FRI to facilitate timely treatment.

A fracture-related infection (FRI) is a serious complication of a fracture. They can occur in open or closed fractures, particularly in fractures that were treated with open reduction and internal fixation.

^{Presentation of Fracture-Related Infection (FRI) across Mild, Moderate, and Severe Stages}

Around 1.8 Around 1.8 million FRIs occur globally each year. Rates are expected to rise due to more road accidents, better fracture care, and increasing rates of diseases like diabetes. FRI accounts for a high morbidity and mortality rate and can have a substantial socioeconomic impact on patients and those around them. FRI requires timely diagnosis and appropriate management. An unsuccessful or ineffective treated FRI may result in permanent functional loss or even amputation in otherwise healthy patients.

The management of FRI is resource intensive and a succesful treatment plan is adapted in the available resources. Governments, clinicians, industries and NGOs should collaborate to improve availability of these resources, while simultaneously training clinicians in orthopedic and plastic surgical skills to create multidiciplinary units specialized in treating FRI. More research is needed to improve evidence-based care in low-resource settings.

Definition of an FRI

An infection of the bone or osteosynthesis material secondary to a fracture is defined  as a fracture-related infection (FRI). The criteria for diagnosing FRI were defined in 2018 after a consensus meeting with input from 2,000 surgeons. For the criteria we refer to the chapter: 'How to diagnose FRI'.

In the past, different terms have been used in the literature, including a fracture with osteomyelitis or osteitis. However, today it is recommended to use these terms to describe infections in bone without a fracture. These bone infections without a fracture form a heterogeneous group often related to another medical condition, like diabetes mellitus, vascular insufficiency, dissemination of hematogenous infection, trauma without a fracture or sickle cell disease, among others.

FRI in resource-limited settings

Fracture-related infection (FRI) puts a heavy burden on health systems, especially in low-resource settings. Evidence and guidelines for FRI come from high-income countries. They may not fit low-resource settings because of differences in for example access to surgery, implants, imaging, microbiology, patient health, and funding.

In resource-limited settings, an FRI is often already present when the patient comes to the hospital for the first time with an open fracture. This is because patients in these settings are more likely to have delays in seeking or receiving hospital care.

(Hematogenous) osteomyelitis leading to a fracture is also classified as an FRI. This condition is uncommon in high-income settings, but it can be seen more often in LMICs settings, mainly in children. It is often related to poor nutritional status and/or sickle cell disease. Proper recognition of this specific condition is important as it will affect treatment choices and prognosis. 

Pathophysiology of FRI

FRI is caused by the introduction of a pathogen to the fracture site. This can be through:

• Introduction during injury, i.e. penetrating trauma or an open fracture.
• Introduction during treatment, i.e. intraoperatively.

Introduction during injury

How - Direct introduction of micro-organisms from the environment.

Microorganisms involved - Mainly bacteria (predominantly skin flora and environmental bacteria), sometimes fungi.

What happens - Tissue devitalization (death of soft tissue and bone due to trauma) creates a good medium for bacterial growth. Hematoma and dead bone fragments act as nutrients and surfaces for bacterial colonization, while simultaniously local immune defenses are impaired due to vascular damage. Abscess formation can develop as neutrophils respond, leading to pus collection and further necrosis.

Impact - The risk of fracture-related infection increases with the severity of soft tissue damage and can be up to more than 40% in open fractures with extensive soft tissue injury.

Introduction during treatment

How - Infection can occur intraoperatively during fracture fixation or debridement.

Microorganisms involved - S. aureus is an important organism associated with infection after surgery because of its virulence factors.

What happens - Common contamination sources include non-sterile instruments, implants, inadequate skin preparation, or airborne particles in the operating room. Additionally, orthopedic materials (plates, screws, nails) facilitate bacterial adhesion, which begins within minutes. If not cleared, bacteria form a biofilm, a protective matrix that resists microorganisms from the immune system and antibiotics.

Impact - Even minimal contamination can result in chronic infection due to the biofilm.

Postoperative or late-onset infection

How - Infections can develop later due to poor wound healing, delayed soft tissue coverage, or biofilm formation in dead spaces or on fixation materials.

Microorganisms involved - Bacteria in biofilms may be few in number or slow-growing, which makes detection and treatment difficult. However, time since injury does not directly influence the type of causative microorganism.

What happens - Biofilms commonly form on necrotic bone and implants, and resist treatment through blocking immune cells, limiting antibiotic penetration, and resisting mechanical debridement/removal. Their microbial composition varies with oxygen and nutrient levels, complicating eradication.