Surgical site application of antibiotics: A potential game changer for fracture-related infection care and antibiotic stewardship

1 Systemic prophylactic antibiotics

Prophylactic antibiotics play a pivotal role in the prevention of FRI. Their administration in cases of open fractures significantly reduces the incidence of FRI as shown by a meta-analysis.⁴ The type of antibiotic used often depends on the nature of the fracture and the expected contaminants. British Association of Plastic, Reconstructive and Aesthetic Surgeons (BAPRAS) along with the British Orthopaedic Association (BOA) released updated guidelines in 2020,⁵ for the management of open fractures, recommending a two-phase approach. The initial phase involves administering intravenous antibiotics with similar antimicrobial spectrum (in the UK) to co-amoxiclav or ceftriaxone, which can be adjusted based on patient allergies and risk factors. Consultation with an infection doctor is suggested for cases involving uncommon environmental exposures, and dosages may be adjusted for significant blood loss or prolonged procedures. Treatment continues for 24 h after wound excision. The subsequent phase includes a single intravenous dose of teicoplanin and gentamicin to cover initial contaminating organisms and subsequent nosocomial pathogens during skeletal stabilisation and tissue coverage. Duration of prophylaxis remains controversial, but two recent systematic reviews found no evidence to support prolonged antibiotic exposure, although the authors of both studies highlighted the paucity of high-quality published evidence.^6,7 Another study found that longer durations of antibiotic prophylaxis were more likely to be associated with adverse effects with no improvement in surgical site infection.⁸

2 Empiric and ongoing systemic antibiotics

Empirical antibiotic therapy, initiated before the availability of culture results, aims to provide broad-spectrum coverage against the most common pathogens responsible for FRIs. However, empirical antibiotics should be used judiciously, considering local epidemiology and resistance patterns, to avoid impairing antibiotic stewardship (see later) and promoting antimicrobial resistance.⁹ Early de-escalation of empirical therapy, from broad to narrow spectrum antibiotics and IV to oral, when possible, based on culture results is crucial for minimizing unnecessary broad-spectrum antibiotic use.

While local antibiotic application offers several potential advantages in managing fracture-related infections (FRIs), until the evidence-base is stronger (see later), prolonged systemic antibiotics remain a current global standard of care. The use of systemic antibiotics may be necessary to achieve adequate infection control, especially in cases involving deep or systemic infections, high-risk or resistant pathogens, or significant host factors such as immunosuppression or comorbidities.¹⁰ These antibiotics are generally administered intravenously or orally, depending on infection severity and complexity, and the patient's overall condition.

Systemic antibiotics are typically employed as the initial empirical therapy following surgery for FRIs, given the possibility of polymicrobial infections and the need to cover a broad range of potential pathogens, including any antimicrobial resistances.¹¹ As culture and susceptibility results become available, the antibiotic regimen is tailored to the identified microorganisms and their specific resistance patterns, allowing for more targeted and effective treatment with the narrowest antimicrobial agent possible (see later).

When considering the oral agent to be used, it is generally considered essential to account for the oral and tissue bioavailability of the agent to potentially optimize clinical efficacy and provide confidence for an early IV to oral switch (see later). Examples of agents with high oral bioavailability include, for example, linezolid, doxycycline, rifampicin, co-trimoxazole, fluoroquinolones and clindamycin. The paradigm for using such, often non-beta-lactam agents, has recently been challenged by emerging evidence that suggests patients thought to have penicillin allergy have worse outcomes when treated with non-beta-lactam agents for an infection, including for Clostridium difficile and colonisation with resistant pathogens.¹²

When it comes to paediatric patients, an additional key consideration is the taste of oral antibiotics. Children who are unable to take tablets or capsules may have a strong aversion to liquid medications with unpleasant tastes, such as flucloxacillin, which can lead to non-adherence. In our own unit, we have seen children with recrudescence of orthopaedic infections, which may have been because of this effect. Therefore, prescribing oral antibiotics with a more palatable taste or providing flavouring options can enhance medication acceptance and improve adherence.¹³

3 Duration of systemic antibiotics

The duration of systemic antibiotic therapy depends on the specific clinical situation, including the infection severity and complexity, the patient's immune status, and presence of implantable hardware. In general, a shorter course of therapy (e.g., 1–2 weeks) may be appropriate for superficial infections, while more extended courses (e.g., 4–6 weeks or even more) may be required for deep infections or those involving implantable devices. The OVIVA trial showed that the IV to oral switch can safely be done within 1 week of surgery, with decreased adverse effects and costs, rather than the prior paradigm, which was for prolonged periods of IV therapy.¹⁴

The exact duration of required oral therapy remains controversial however and requires further high-quality research. A recent randomised controlled trial found that a six-week course of systemic antibiotic treatment was not non-inferior to a 12-week regimen in prosthetic joint infections.¹⁵ This difference appeared to be primarily driven by patients undergoing debridement and implant retention (DAIR) procedures, which is analogous to the approach sometimes taken in certain FRIs. However, it is worth noting that the consistent application of local antibiotics was lacking in this study. Therefore, it is possible that with the systematic use of local antibiotics, the duration of required systemic treatment may be safely reduced.

A systematic review of FRIs treated by the DAIR approach suggested that patients with a longer duration of infection prior to surgery (>3 weeks) had poorer outcomes, although the authors highlighted that the evidence was limited. This is analogous to the paradigm in prosthetic joint infections and might influence length of antibiotic prescribing. Our usual local practice after DAIR of FRIs to date, regardless of duration history, is to continue systemic therapy at least until the fracture is clearly radiologically healing or the metal is subsequently removed (whichever occurs first). In our experience, this is rarely less than 12 weeks and even then, recrudescence in patients with ongoing retained metal undoubtedly, but not inevitably, occurs in the years thereafter.

4 Potential advantages and disadvantages of local antibiotic administration

Traditionally, systemic administration has been the primary method of delivery of antimicrobials in orthopaedic infections. However, local antibiotic application, either through antibiotic-impregnated cement, sponges, beads, or other approaches, has gained popularity due to its potential benefits in delivering high concentrations of antibiotics directly to the surgical site while minimizing systemic toxicity.¹⁶ This involves the direct administration of antibiotic agents at the site of infection or operated site, usually as part of a surgical procedure and can be achieved using a myriad of available delivery systems as outlined in Table 1.¹⁷

Local antibiotic administration in FRIs offers several potential advantages. The primary benefit is the achievement of high concentrations of antibiotics at the site of infection, which might be more effective in eradicating infection than systemic administration, particularly in the presence of devitalised tissue, metalware or biofilm formation. This approach is also likely to have a better adverse event profile, as local administration tends to minimize systemic exposure and reduce the risk of systemic side effects.¹⁶ Furthermore, local administration allows prescribers to tailor the choice of antibiotic to the sensitivity of the specific pathogens causing the infection, increasing the probability of successful treatment. In situations where resistance is present, local administration can also provide additional options for treatment that cannot be achieved with oral therapy (i.e. the local administration of an agent otherwise only available in intravenous form).

The published comparative clinical evidence for treatment to date however remains weak. A non-comparative systematic review with only 214 patients, suggested high efficacy of locally administered antibiotic-impregnated calcium sulphate in infected non-unions, with 92.9 % achieving bony union and 95.1 % infection eradication.¹⁸ In another small systematic review of 505 patients,¹⁹ there was no obvious evidence of a difference in outcomes comparing biological (a muscle flap or bone allograft) and non-biological approaches, most of which included local antimicrobials, or outcomes between different approaches within each of those groups, to the management of dead-space during single-stage surgical treatment of chronic osteomyelitis. Another systematic review of 506 patients with infected non-unions treated with antibiotic-coated intra-medullary nails again suggested relatively high efficacy with infection eradication of 90.0 % and bone consolidation of 85.5 %.²⁰ The currently available evidence does not unpick the relative contributions of local or systemic antimicrobials or whether use of local administration can safely reduce the systemic course length.²¹ While encouraging, this evidence is neither practice changing nor defining.

Local administration of antimicrobials could also be employed prophylactically to prevent fracture related infection at the time of initial stabilisation. In a large systematic review of >6000 fractures, that included mostly level 3 evidence studies with a moderate risk of bias, there appeared to be a benefit of local administration, in addition to systemic, versus the latter alone, in reducing deep infections after open, but not closed fractures.^22,23 The results of this systematic review are supported by a systematic review of local antibiotic use in primary hip or knee arthroplasty.²⁴ Whether local antibiotics could be applied instead of systemic antibiotics with good results is unknown, but such an approach would clearly be attractive.

There are some potential theoretical concerns about local antibiotic usage that warrant further investigation. The development of antibiotic resistance in the target pathogen(s) due to local use is theoretically possible, especially as antibiotic elution concentrations decrease over time if the organism is not initially eradicated. Although a risk, this may be mitigated to some extent by the typically very high concentrations achieved initially, usually well above the minimum inhibitory concentration required. There's also the possibility of local toxicity hindering the bone healing process, although current evidence does not support this. Additionally, selective pressure favouring contaminating or colonising organisms resistant to the local antibiotics used could lead to infections subsequently developing from these organisms. The existing understanding in each of these areas remains inadequate, emphasizing the need for further rigorous research.

The SOLARIO trial (NCT03806166) is an ongoing, multicentre, randomized controlled trial comparing short (less than or equal to 7 days) and long (4 weeks or more) courses of oral antibiotics alongside local antibiotics in patients undergoing surgical treatment for orthopaedic infection.²⁵ The primary objective of the study is to ascertain if a short course of systemic antibiotics is non-inferior to a longer course in terms of infection recurrence at one year when local antibiotics are used. Secondary objectives include evaluating the safety and tolerability of the two treatment regimens, as well as assessing patient-reported outcomes and healthcare resource utilization. It may provide valuable insights into the optimal duration of antibiotic therapy for patients with acute orthopaedic infection, which could have implications for antibiotic stewardship and the management of FRIs. However, until the trial's results are available, it is essential to consider the individual patient's clinical scenario, pathogen susceptibility, and risk factors contributing to treatment failure when determining the optimal duration of systemic antibiotic therapy.

5 Antibiotic stewardship

Antibiotic stewardship is a critical component of FRI management. The goal is to improve antibiotic utilization to attain optimal clinical results while reducing the potential for negative effects and antibiotic resistance. It encompasses a range of strategies, mainly comprising of the 5D's, including the judicious selection of drug (antibiotic agent), appropriate dose and tailoring the duration of therapy, de-escalation to narrow spectrum as soon as microbiology results are available and most importantly making an initial correct diagnosis of infection. The accuracy of microbiological diagnosis is facilitated by the sending of multiple operative tissue specimens (5 or 6) using appropriate methods whenever possible, analogous to the approach taken in prosthetic joint infection for many years.²⁶

Antimicrobial stewardship (AMS) is not just an isolated task but an organizational activity that necessitates the active involvement and interest of all individuals engaged in antibiotic prescribing and administration. It is a collaborative effort that requires the commitment of healthcare professionals across various disciplines. Understanding the detrimental effects of antimicrobials on the composition and diversity of the gut and other microbiota niches within the overall human biome is crucial. The use of antimicrobials can result in a reduction of so-called beneficial bacteria and an overgrowth of opportunistic pathogens, potentially leading to dysbiosis. The relationship between the human microbiome and human health is increasingly being recognised with disruption of the gut microbiota having potential notable consequences for immune function, metabolism, cancer risk, response to medications, susceptibility to infections, and even mental health ²⁷. In the future, the integration of local antibiotic application into FRI treatment protocols has the potential to minimize the necessity for extended systemic antibiotic therapy, thereby supporting the goals of antibiotic stewardship and contributing to key hospital-wide antibiotic stewardship initiatives.

6 Conclusion

The surgical site application of antibiotics has emerged as a widely used tool in the management of FRIs, offering the possibility to optimize antibiotic use, reduce the risk of antibiotic resistance, and improve patient outcomes. The OVIVA trial results support the use of short courses of intravenous antibiotics in orthopaedic infections. The evidence-base to support and appropriately deploy the use of local administration of antimicrobials in FRIs remains relatively weak however, but the SOLARIO trial is likely to strengthen this. In the interim, prolonged systemic antibiotics, mostly via the oral route, will continue to play a role in managing FRIs, and the optimal approach to antibiotic therapy should be tailored to the individual patient's clinical scenario and risk factors. Further research is needed to determine the most effective strategies for integrating local and systemic antibiotic use in the context of prophylaxis, therapy, and antibiotic stewardship in FRIs.

Author contributions

Dr Gavin Barlow: Designed the study, guided contributing authors about specific literature search, reviewed the initial draft, reviewed and wrote further draft versions, reviewed and edited the final manuscript, supervised contributing authors.

Dr Fahed Bangash: Literature search, writing the initial and further draft versions, visualisation.

Dr Muhammad Muddassir: Literature search, writing the initial draft and further draft versions.

All three authors have actively contributed to and collaborated throughout the entire process of this review article.

Ethical approval/Patients consent

As our article is a narrative review, it did not involve primary research with human or animal subjects and therefore did not require ethical committee approval or patient consent.

Declaration of generative AI and AI-assisted technologies in the writing process

During the preparation of this work, a co-author used ChatGPT language model and Grammarly in the initial draft version of this project in some sub-topics in order to help with the language. After using this tool/service, all authors reviewed and edited the content several times as needed and take(s) full responsibility for the content of the publication.