Infected nonunion of long bones is a chronic and debilitating disease with complex pathology. It requires long-term treatment and has an unpredictable outcome, making it challenging for surgeons to manage efficiently in terms of cost and time 1. Infected nonunion has been defined as a state of failure of union and persistence of infection at the fracture site for 6 to 8 months. There are several contributing factors to the development of infected non-unions, such as open fractures, tissue or bone loss, postoperative infections following internal fixation, chronic osteomyelitis leading to pathologic fractures, and surgical removal of infected bone 2. One particularly difficult aspect is dealing with infected bone defects following internal fixation. This is because internal fixation can promote the formation of bacterial biofilms, making treatment more difficult 3, 4, 5. The majority of infections related to orthopaedic trauma are caused by bacteria that can form biofilms 6. A biofilm is comprised of a hydrated matrix composed of polysaccharides and proteins. Once established, it acts as a protective shield for microorganisms, rendering them less susceptible to antimicrobial agents, opsonization, and phagocytosis, thereby playing a significant role in the persistence of infections 7. Cierny and Mader have proposed four principles to address the issue of bacteria that form biofilms. These principles are based on a thorough examination of surgical debridement, fracture stabilization, soft tissue coverage, and analysis of antibiotic levels to effectively eliminate infection 8. Following these principles is important in the clinical evaluation and treatment of biofilm infections 9. Recently, infected non-union tibia cases have been treated using a two-step procedure. The first step involves debridement treatment, where non-antibiotic or antibiotic cemented coated nailing is inserted into a sterile nonunion. The second step involves the restoration of bone stability through internal or external fixations by orthopaedic specialists. However, this approach has undergone a transformation with the advent of antibiotic permeate cement-coated nails. These cement nails soaked in antibiotics have gained attention for their high success rate in stabilizing femur fractures and infected tibia fractures that have not healed properly 5. Studies have shown that using these antibiotic nails for 36 weeks at the site of infection reduces the incidence of side effects from the infection. These cost-effective antibiotic nails have revolutionized the traditional two-step long-term procedures by allowing for a single-stage approach, which increases the likelihood of early mobilization and eliminates the occurrence of infections at the pin sites. Cement coating of orthopaedic implants is supportive and sometimes necessary in various clinical settings 10, 11, 12. Previous studies have documented the use of antibiotic cement-coated internal fixation for managing infected bone defects in long bones 3, 4, 13, 14. The retrospective analysis of potential antibiotic regimens by Baerti et al. indicates that meropenem + vancomycin was the most effective empiric treatment in 95.7% of patients with confirmed susceptibility. Meropenem + vancomycin, gentamicin + vancomycin, and co-amoxiclav + glycopeptide are the best therapeutic options for FRI, regardless of the onset of infection. To avoid multidrug resistance, established antibiotic combinations such as co-amoxiclav with a glycopeptide seem to be reasonable as a systemic antibiotic therapy, while vancomycin + gentamicin could be implemented in local antibiotic therapy to reduce adverse events during treatment 15. In our study, we employed a combination of gentamicin and vancomycin due to their complementary properties that are well-suited for our purpose. The primary objective of our study was to assess the results achieved through the utilization of custom-made antibiotic cement-coated nailing for the treatment of infected nonunion tibia, focusing on its effectiveness in controlling infections and promoting bone union.

This prospective study was conducted in Rome University Hospital, Italy over the course of four years, from 2018 to 2022 involving 52 patients aged between 19 to 59 years, who presented with infected non-union tibia and were treated using antibiotic cement-coated nailing. We included patients who had diaphyseal unhealed fractures of the tibia with bone gaps measuring less than 2 cm and excluded those who were allergic to gentamycin or vancomycin. Out of the 52 patients, 36 had open fractures classified as Gustilo Anderson types I (6 patients), II (7 patients), IIIA (9 patients), and IIIB (14 patients), while the remaining 16 had closed fractures. Following a comprehensive preoperative assessment, surgery was performed after obtaining informed consent. Patients with open fractures were primarily managed with wound debridement, intravenous antibiotics, and intramedullary tibia nail fixation, whereas patients with closed fractures received intramedullary tibia nail fixation with prophylactic antibiotic coverage only. Post operatively, tissue samples were collected from 23 patients who developed draining sinuses for further evaluation. The results of tissue samples indicated the presence of Staphylococcus aureus in all cases. Additionally, in all patients, preoperative investigations of complete blood count (CBC), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) revealed elevated levels.

In all 52 cases, the intraoperative specimens revealed positive cultures. Out of these, 37 samples showed positivity for Staphylococcus aureus, 11 samples showed positivity for multiple bacteria, and 4 samples showed positivity for Klebsiella.

Following a period of 4 to 6 weeks, all infection markers returned to normal levels and complete wound healing was observed. Out of the patient cohort, only seven individuals required flap coverage and bone grafting. In 51 patients, which accounts for 98% of the total, follow-up x-rays revealed successful bone healing within an average duration of 18 months. However, one patient, who had undergone surgery 6 months prior, exhibited elevated inflammatory markers and no radiological evidence of bone union. This patient had suffered a high-energy trauma with an open Grade III B fracture, which also resulted in soft tissue loss due to the trauma. The initial treatment for the open fracture involved debridement, lavage, antibiotics administration, and the use of external fixators to stabilize the fracture temporarily. The patient eventually needed a free flap procedure to cover the tibia during a later stage. This patient was readmitted for the purpose of removing the nail and undergoing a two-stage revision. The tissue sample taken from the wound and the medullary canal showed the presence of Staphylococcus aureus. After the second stage revision, a final evaluation conducted 12 months later revealed that the fracture had healed both clinically and radiologically, with no signs of recurring infection. The remaining patients, on average, achieved bone union at 18 months, and infection control was typically attained within a duration of 4 to 6 weeks. (Fig 1a, 1b, 1c, 1d and 1e)

Figure 1

The study demonstrates the infected nonunion tibia can be effectively treated if the protocol of debridement is correctly followed. The bone stability can be regained within 22 to 48 weeks. Antibiotic-impregnated cemented nail is an ideal procedure to control the postoperative infection and achieve reunion. With the development of bacterial biofilms, the need for prolonged treatment, and the uncertainty of the outcome, orthopaedic physicians and their patients are facing a significant challenge when it comes to infected bone defects due to bacterial resistance to drugs 16. There is currently no universally accepted set of guidelines for managing these types of defects. The conventional approach to managing infected bone defects has involved a multi-stage procedure. This procedure begins with controlling the infection and is followed by reconstructing the bone defect using internal fixation and bone grafting, often with the use of external fixation or antibiotic-impregnated cement beads. While the traditional procedure has demonstrated its effectiveness, it has also exhibited certain disadvantages. Firstly, it requires multiple operation stages and secondly, the utilization of external fixation is linked to a relatively elevated occurrence of infections at the pin sites. In certain instances, the use of external fixation involving a pin can lead to the piercing of soft tissues, resulting in muscle contracture and restricted movement in the joint, especially in the femur fractures 17. Furthermore, certain patients who are obese exhibit inadequate adherence to external fixation procedures, including pin site care. Thirdly, antibiotic-impregnated PMMA cement beads have traditionally been employed to administer antibiotics directly to the site of infection. Nevertheless, this method fails to ensure sustained efficacy for the affected area 18. One effective method to reduce infection rates is to carefully time the initial internal fixation procedure, 18. Timely disinfection and removal of dead tissue are essential for the successful treatment of open wounds caused by war trauma. Proper management of these wounds is critical for a positive outcome. The optimal time for wound treatment is within two hours of the injury. Hence, timely wound treatment can prevent contaminated wounds from progressing into infected wounds, which is of utmost importance in the management of acute open wounds. The same approach is taken when treating patients with open fractures in order to perform early debridement. For individuals with open fractures and soft tissue defects resulting from firearm injuries, the application of corticospongioplastics after completing phase I debridement of wounds smaller than 4 cm has shown positive results. For wounds larger than 4 cm, the Lizarov method has proven advantageous 19, 20. In addition, the Ilizarov technique offers a practical solution for treating open bone defects caused by firearm injuries, with a relatively short surgery time. When dealing with chronic osteomyelitis, controlling the infection is of utmost importance. Once the infection is under control, various methods can be used to repair and reconstruct the bone defects. The Ilizarov method is also a suitable choice for patients who have insufficient soft tissue conditions and are not suitable candidates for flap repair. In appropriate cases, corticospongioplastics should be considered. There is a wide range of literature available that highlights the benefits of using antibiotic-loaded cemented nails in managing infections and achieving bone union through a single-step procedure 14, 21. This involves using antibiotic bone cement-coated internal fixation during the initial stage 22. By using the antibiotic bone cement-coated nail, both infection and stability concerns can be tackled concurrently. It is well-established that intramedullary infections tend to spread throughout the entire canal. Therefore, it is more efficient and versatile to eliminate the dead space through intramedullary contact 21. Furthermore, the antibiotic released locally from the cement-coated nail may exert a bactericidal effect on bacterial biofilms. Additionally, the intramedullary nail can offer a relatively sturdy fixation and stability at the defect site, which can be advantageous for both infection management and bone union 22, 23, 24.

In this research, we utilized vancomycin and gentamicin as antibiotics loaded onto the bone cement. Osteomyelitis usually occurs as a result of various microorganisms, with Staphylococcus aureus being the most commonly reported bacteria in medical literature 25. In about 65% to 70% of cases, Staphylococcus aureus is found alongside other pathogenic bacteria. Local antibiotics like Gentamicin, Tobramycin, Meropenem, and Vancomycin are frequently used due to their wide range of antibacterial activity, stability at high temperatures, and low sensitivity to resistance 26. In earlier studies, vancomycin, and gentamicin, or sometimes tobramycin, were more commonly chosen as antibiotic agents 8, 14, 27. In our study, Staphylococcus aureus was identified in 37 out of 52 cases, multiple bacteria in 11 out of 52 cases, and Klebsiella in 4 out of 52 cases. The choice of local antibiotic was primarily based on the results of bacterial culture and drug sensitivity. The increasing drug resistance patterns indicate that profound pathogenic bacteria, including intramedullary infection, exhibit resistance to gentamicin 28. The current duration of treatment for bone infections is typically over six weeks. However, there is ongoing discussion about whether to administer the treatment intravenously or orally. Some studies suggest that oral antibiotics are just as effective as intravenous antibiotics during the first six weeks of infection. Additionally, using oral antibiotics can shorten hospital stays and reduce the risk of cross-infection while in the hospital 29. It is important to refer to the bacterial culture results and the advice of clinical pharmacists to determine the appropriate duration of intravenous antibiotics. In our study, intravenous antibiotics were administered for a period of six weeks. Notably, infection in all cases was effectively managed in a single phase, underscoring the benefits of utilizing personalized intramedullary nails in controlling infections. Paley and Herzenberg have also recorded successful infection control in nine cases 27. Thonse and Conway have reported a rate of 85% for infection control in their study 5.

Jokhia and their colleagues found that bone union occurred in 80% of cases without requiring any additional procedures 30, Bhatia and their team reported a 95% success rate in eliminating the infection. 11 Comparable findings have demonstrated that the bone cement nail exhibits a satisfactory effect in controlling infections 31. Varying outcomes have been observed across different studies with respect to bone union. Bhatia et al. documented a 60% rate of bone union without the need for supplementary procedures 11. Zheng and Hang have reported a union rate of 22% 32. Thonse and Conway have reported a union rate of 73% 5. In our study, 51 cases (98%) exhibited direct healing in the initial stage, with an average duration of 18 months. It is noteworthy that Shyam et al. have previously reported cases that underwent successful healing in the first stage, provided that the bone defect range was less than 4 cm 33. Owing to the limited number of cases, it is hard to correlate the association between the magnitude of bone defect and the primary healing effect. In our study, we initiated weight bearing partially at postoperative 8 weeks and allowed full weight bearing as tolerated with crutches at 3 months. One patient required readmission for the purpose of nail removal and two-stage revision. Recent research indicates that the combination of teriparatide and the Ilizarov technique in the management of hematogenous osteomyelitis can accelerate the mineralization pace of fresh bone post-bone removal, thereby facilitating the prompt elimination of the external frame 34. Teriparatide is a pharmaceutical agent that facilitates bone formation. It represents a viable approach to expedite bone healing when employed in conjunction with surgical intervention, thereby enhancing the efficacy of the procedure and yielding favourable outcomes. However, most patients currently receiving treatment have limited financial resources. The use of teriparatide further worsens the financial burden on these individuals, which is an important issue that needs to be addressed.

At present, PMMA is commonly employed for the purpose of nail coating. However, PMMA is non-biodegradable and its surgical removal can pose challenges. The major problematic consequence after non-union is nail breakage. Previous removal techniques have been described with satisfactory outcomes 35, 36. Timely removal of nails is recommended once the infection has subsided because theoretically live bacteria are known to persist on antibiotic-impregnated cement under in vitro conditions. Furthermore, concerns persist regarding its thermal reaction, antibiotic release profile, as well as toxicity effects. Anugraha et al. have conducted research on the utilization of a biocomposite consisting of calcium sulphate and hydroxyapatite as a coating for nails. This innovative approach offers promising new possibilities 27. Our study had certain limitations, firstly, it was a prospective study with a relatively small sample size. Secondly, the bone infection site was not localized but rather dispersed. It is important to note that the application of mineral oil on the nail surface could potentially lead to localized inflammatory reactions. Lastly, additional research is required to gain a comprehensive understanding of the biomechanics involved in the use of intramedullary nail bone cement.

The custom-made antibiotic cement-coated intramedullary nail employed in this study demonstrates superior filling properties and represents an ideal approach for postoperative infection control and the successful union of long bones. It boasts a high rate of infection control, with some cases achieving direct bone healing. In contrast to external fixation, it eliminates the need for a complex external fixation frame assembly and is well-received by patients. Moreover, it is a cost-effective option and is particularly suitable for resource-constrained and developing countries where managing infected nonunion of long bones poses significant challenges.