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