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Department of Orthopedic Surgery, Beijing Chaoyang Hospital, Capital Medical University, 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing 100020, PR China
Department of Orthopedic Surgery, Beijing Chaoyang Hospital, Capital Medical University, 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing 100020, PR China
Department of Orthopedic Surgery, Beijing Chaoyang Hospital, Capital Medical University, 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing 100020, PR China
Department of Orthopedic Surgery, Beijing Chaoyang Hospital, Capital Medical University, 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing 100020, PR China
Department of Orthopedic Surgery, Beijing Chaoyang Hospital, Capital Medical University, 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing 100020, PR China
Department of Orthopedic Surgery, Beijing Chaoyang Hospital, Capital Medical University, 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing 100020, PR China
Department of Orthopedic Surgery, Beijing Chaoyang Hospital, Capital Medical University, 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing 100020, PR China
Department of Orthopedic Surgery, Beijing Chaoyang Hospital, Capital Medical University, 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing 100020, PR China
Despite the improvements in surgical techniques and the use of prophylactic intravenous antibiotics, the fracture-related infection (FRI) incidence after high-risk tibial plateau fractures remains high. This study aimed to evaluate the clinical effect of the intrawound application of vancomycin on the FRI after high-risk tibial plateau fracture surgery.
Methods
A total of 243 patients who underwent high-risk tibial plateau fracture surgery from May 2013 to June 2021 were retrospectively reviewed. Of these, 233 cases were enrolled. Considering the preoperative patient condition, surgeons applied vancomycin powder directly into the surgical site before wound closure in 105 cases (intrawound application of vancomycin powder with preoperative intravenous cephalosporin). The remaining 128 cases served as the control group (preoperative intravenous cephalosporin alone). Clinical data and surgical details were recorded. The Cox proportional hazards regression analysis was used to assess risk factors for FRI. The Kaplan-Meier method and the log rank test illustrated the infection status of patients based on the application of intrawound vancomycin. The primary outcome was an FRI within one year. Secondary outcomes included bacterial culture and vancomycin-related complications.
Results
Our study demonstrated a significant difference in the incidence of FRI between the vancomycin group and the control group (3.8% versus 10.9%; p=0.041). Multivariable Cox regression showed the intrawound application of vancomycin powder decreased the rate of FRI. There were no complications related to intrawound vancomycin observed during follow-up. The presence of Gram-positive FRI was higher in the control group compared with the vancomycin group.
Conclusions
Intrawound application of vancomycin was associated with a significant lower rate of FRI after high-risk tibial plateau fracture surgery compared to the control group.
Fracture-related infection (FRI) is becoming increasingly challenging as orthopedic surgery increases. The incidence of FRI in lower extremity fractures was reported to reach 23.2–30% [
]. Notably, an impaired immune system causes superoxide formation and microbial clearance dysfunction among patients treated with high-energy fracture surgery.
Vancomycin is an attractive antibiotic in spinal and trauma surgery, particularly useful for common pathogens (especially Methicillin-Resistant Staphylococcus Aureus and other Gram-positive bacteria). In the previous study, systemic application of vancomycin was reported to be low absorbable at the surgical site, the concentration of which was insufficient to restrain bacteria [
]. Therefore, the intrawound application of vancomycin has become widely accepted to maintain therapeutic concentrations. Furthermore, high doses of intravenous vancomycin are associated with nephrotoxicity and hypotension. In an in-vitro trial, intrawound application of vancomycin had a very slight and transient effect on osteoblastic proliferation and was unrelated to osteoblastic metabolism or bone nodular mineralization [
Measures to reduce end-of-case wound contamination: the impact of intra-wound vancomycin powder and betadine irrigation on surgical site infections in posterior spinal fusion.
Reduction in surgical site infection with suprafascial intrawound application of vancomycin powder in instrumented posterior spinal fusion: a retrospective case-control study.
]. Moreover, there is a large amount of meta-analysis on spine and arthroplasty, further recommending the application of intrawound vancomycin powder before wound closure [
Is use of topical vancomycin in pediatric spine surgeries a safe option in the prevention of surgical site infections? A meta-analysis and systematic review of the literature.
The application of topical vancomycin powder for the prevention of surgical site infections in primary total hip and knee arthroplasty: a meta-analysis.
]. However, few studies examined the clinical effect of intrawound application of vancomycin in reducing infection after open reduction internal fixation surgery [
]. Therefore, this study aimed to evaluate the efficacy of intrawound vancomycin to prevent FRI after high-risk tibial plateau fracture surgery.
Patients & methods
Cohort identification
With the approval of the institutional review committee, a retrospective study was performed on patients who underwent open reduction internal fixation for high-risk tibial plateau fractures in XXX from May 2013 to June 2021.
Our study referred to the previous literature and defined the “high-risk fracture” as an open fracture or a fracture requiring planned surgical delay or staged fracture fixation because of soft-tissue concerns [
]. Inclusion criteria were as follows (1) patients over 18 years old treated with a high-risk tibial plateau fracture surgery, (2) preoperative x-ray and CT showed AO classification B or C, (3) received internal fixation more than three days after injury because of wound swelling or had a Gustilo-Anderson classification type I, II or III-A open fracture. Exclusion criteria included (1) previous history of traumatic surgery at the surgical site, (2) previous history of tumor in the injured limb, (3) allergic history to vancomycin, (4) surgical procedure including irrigation and debridement performed at an outside facility prior to arrival at our institution; (5) Gustilo-Anderson classification type III-B or III-C open fracture.
Patient demographics (age and gender), tobacco use, polytraumas, open fractures, and comorbidities (diabetes mellitus, hypertension, and coronary heart disease) were obtained from medical records. In addition, surgical details, including the number of surgical approaches and locking plates, operative time, time to surgery, and blood loss, were recorded. All patients were assessed by AO classification using X-ray and 3D CT imaging. Two resident physicians performed the fracture type clarification, and a senior physician was invited to evaluate when divergence appeared.
Perioperative antibiotic administration
Preoperative and postoperative intravenous antibiotics were administrated by the anesthetist and ward nurse. After admission, patients with severe infection or open trauma were treated instantly using intravenous cefuroxime (clindamycin if allergic to penicillin). All patients received intravenous antibiotics within 2 h preoperatively. Routine intravenous antibiotics were administered until three days postoperatively (antibiotics were constantly applied if blood tests or wound conditions indicated evidence of infection).
During the operation, the decision of 1g vancomycin powder was based on the patient's condition, which included Gustilo-Anderson classification type I or II or III-A open fracture, malnutrition and poor preoperative evaluation of surgical incision healing (swelling or aseptic exudation of the affected limb). At the discretion of the treating surgeon, sterile vancomycin powder was directly applied to the locking plate and bones before wound closure.
Surgical procedures
Patients with open fractures were immediately given intravenous antibiotics and were urgently taken to the operating room. Initial treatment included attempted closed reduction, irrigation and debridement. Laboratory tests and blood cultures around the wound were also required.
After perioperative preparation, the tibial plateau fractures underwent an open reduction and internal fixation. The posteromedial and anterolateral approaches (including the modified anterolateral approach, used to expose the anterolateral and posterolateral fragments simultaneously) were available for tibial plateau fracture surgery.
The incision was cut layer by layer. The fracture block was separated, exposed, and temporarily fixed using Kirschner wires. The bone collapse of the articular surface was restored using multiple Kirschner wires for a temporary reduction. The fracture reduction was determined under C-arm fluoroscopy, then anterolateral and posteromedial internal fixations were placed in the appropriate position, and several screws were fixed. The joint surface was also examined and satisfactory. 1-2 L pulse lavage with saline was performed on the surgical site. One or two drainages were placed superficially on both sides. After skin closure, the incisions were cleaned again with alcohol and betadine solution, and a sterile dressing was applied. Sterile dressings and drainage remained in place until a daily drainage volume was less than 50 mL without bloody or purulent fluid.
FRI details and follow-up evaluation
In our study, the primary outcome was FRI within one year. The secondary outcomes included bacterial culture results and vancomycin-related complications.
According to a consensus from an international expert group, the enrolled patients were separated into two groups, based on the presence or absence of confirmatory FRI signs [
]. The FRI was defined as postoperative infections within one year that met at least 1 of the following conditions: (1) clinical signs including presence of a fistula, sinus, wound breakdown or purulent exudation, (2) confirmed pathogens by culture results from at least two separate deep tissue/implant specimens during paracentesis or operations.
As a result, enrolled patients evaluated for clinical outcomes underwent a year of regular follow-up by the same trauma team. The FRI group were recorded including culture results, the time between FRI and surgery, duration of infection and subsequent treatments.
Vancomycin-related complications included nephrotoxicity, hepatotoxicity, urticaria medicamentosa, ototoxicity, and red man syndrome. At the 1-year follow-up, knee activity and patient functional outcomes were analyzed using the Rasmussen functional score. Two independent and blinded orthopedic surgeons assessed function scores and averaged their measurements.
Statistical analysis
Descriptive statistics were used for the clinical characteristics of the two groups. A Student t-test was performed to analyze continuous variables. A Chi-square test with Yates continuity correction was used for analyzing categorical variables. Fisher's exact test was used to generate p values whenever the anticipated numbers of cell entries were less than 5. Categorical variables were summarized as count (%), and continuous variables were summarized as median (interquartile range). Patients who failed to have a full twelve months follow-up were included in analysis up to the time when lost to follow-up (3 in the vancomycin group and 16 in the control group). To assess whether a significant difference exists between the vancomycin group and the control group in terms of the occurrence of FRI, a log rank test was performed using Kaplan-Meier survival analysis. Univariate Cox regression was also used to determine risk factors for FRI. A multivariable Cox regression was performed in which vancomycin use and other significant risk factors were evaluated.
A p < 0.05 was considered statistically significant. The analysis was conducted using statistics software version 21.0 (SPSS, Chicago, IL).
Results
Patients
A total of 243 patients were included to receive intrawound vancomycin powder (107 patients) or be in the control group (136 patients). The final follow-up assessments were completed in July 2022. Among these 243 patients, 233 (95.9%) were eligible for inclusion in this study (105 vancomycin and 128 control patients). Further details on the patient flow are stated in Fig. 1.
Fig. 1CONSORT (Consolidated Standards of Reporting Trials) flowchart demonstrating patient eligibility, allocation, and follow-up.
The vancomycin group and the control group were statistically similar in gender ratio (vancomycin group 53%, control group 59%; p=0.36) and age (vancomycin group 53.4 years, control group 53 years; p=0.81) (Table 1). The clinical data also showed no statically significant difference in hypertension, diabetes mellitus, coronary heart disease, tobacco use, AO classification, polytrauma, postoperative intravenous antibiotics duration and Rasmussen scores between these two groups (p>0.05). The surgical details are also shown in Table 1. No statistically significant differences were found in the number of surgical approaches and locking plates, operative time, time to surgery and blood loss (p>0.05).
Table 1Patient characteristics according to the presence of vancomycin use.
Chi-squared analysis and student t-test were performed to analyze categorical and continuous variables comparisons, retrospectively. *Denotes statistical significance with p<0.05.
‡ Chi-squared analysis and student t-test were performed to analyze categorical and continuous variables comparisons, retrospectively. *Denotes statistical significance with p<0.05.
Intrawound vancomycin and open fracture in relation to FRI
The univariate and multivariable Cox regression analyses were used to identify the statistically significant clinical factors responsible for FRI. The clinical factors included gender, age, comorbidities, tobacco use, AO classification, polytrauma, postoperative intravenous antibiotics duration, open fracture, number of surgical approaches and locking plates, operative time, time to surgery, blood loss and vancomycin use.
Open fracture (HR 4.01, p=0.014) was revealed as a significant univariate risk factor for FRI after tibial plateau fracture surgery (Table 2). The application of intrawound vancomycin was at the borderline of conventional statistical significance in the univariate Cox model (HR 0.33, p=0.052) but was statistically significant using the log rank test (p=0.041) (Fig. 2). The cumulative chance of FRI was 3.8% and 10.9% for the vancomycin and control group respectively. A multivariable Cox model demonstrated that the application of intrawound vancomycin increased its significance (HR 0.31, 95% confidence interval 0.10–0.94, p=0.038) in the presence of open fracture in the model (Table 3).
Table 2Univariate Cox regression analysis with time to FRI as clinical outcome.
Table 4 presented an FRI detail among the vancomycin and control groups. Of note, the presence of Gram-positive FRI was higher in the control group compared with the vancomycin group (12/128 versus 1/105). In addition, vancomycin-related complications were not observed among these 233 patients during follow-ups.
Table 4Comparison of patients diagnosed as FRI with or without vancomycin powder.
There was no polymicrobial infection observed in our study. The most common organism was Methicillin-Sensitive Staphylococcus Aureus (MSSA) (8/14) in the control group. Two types of microbes, Escherichia coli (E. coli) and MSSA, were found in FRI patients in the vancomycin group (Fig. 3). In addition, no FRIs with vancomycin-resistant bacteria were observed in both groups.
Fig. 3Cultural results of FRI patients in both groups. MSSA: Methicillin-Sensitive Staphylococcus Aureus; MRSE: Methicillin-Resistant Staphylococcus Epidermidis; MRSA: Methicillin-Resistant Staphylococcus Aureus; E. coli: Escherichia coli.
In this retrospective study, among patients with operatively treated tibial plateau fractures, intrawound vancomycin reduced the incidence of FRI by 10.9% to 3.8%, which attributed to pharmacological effects on gram-positive bacterial infections. However, our result did not prove the association between vancomycin powder and gram-negative infection.
A previous study reported E. coli and Staphylococcus Aureus were major microbes attributing to lower limb fracture infections [
]. A multicenter randomized control trial involving 980 tibial plateau or pilon fracture operations found the protective effect of intrawound vancomycin powder on gram-positive deep surgical site infection, which was consistent with the activity of vancomycin [
]. Several potential factors contributed to latent fracture-related infections, including the use of tourniquets, metal implants with biofilm formation, and differing bacterial pathogens. Therefore, this study observed postoperative infections within 182 days and performed an additional follow-up a year following surgical fracture fixation.
Intrawound vancomycin has minimal clinical evaluation among the orthopedic trauma patient population. Sombat et al. proposed that vancomycin powder dose was not associated with the incidence of FRI [
Comparison between 1 g and 2 g of intrawound vancomycin powder application for prophylaxis in posterior instrumented thoracic or lumbosacral spine surgery: a preliminary report.
]. However, antibiotic abuse is attributed to the development of antibiotic-resistant bacteria. Khanna et al. found that the incidence of Gram-negative bacterial infection seemed to increase after the intrawound application of vancomycin [
]. In our study, none of the patients were diagnosed with vancomycin-resistant bacteria infection after 12 months of follow-up. The incidence of Gram-positive bacteria in the intrawound vancomycin group was lower than that in the control group, which was similar to previous literature [
Topical vancomycin powder decreases the proportion of staphylococcus aureus found in culture of surgical site infections in operatively treated fractures.
Recently, some studies on spine and joint replacement surgery demonstrated a strong association between the intrawound application of vancomycin and the incidence of deep surgical site infection [
This study presented that vancomycin use had a protective effect (HR 0.31) compared with open fractures, which were associated with significant risk (HR 6.37). Some similar studies evaluated the association between open fractures and infectious complications [
No vancomycin-related complications were observed during follow-ups, such as renal insufficiency (glomerular filtration rate ≤ 60ml/min or serum creatinine ≥ 133μmol/L), urticaria medicamentosa and ototoxicity. Due to technical limitations and cost-effectiveness, the laboratory result of osteoblast-like cell replication was not acquired. Despite limited literature on the increased concern of inhibitory effects on bone marrow-derived mesenchymal stem cells viability at higher vancomycin doses, a recent animal study stated these cells decreased by 40-60% after four days with 4 mg/mL vancomycin [
]. For reference, in a retrospective cohort study measuring vancomycin dosage from the drainage tube, vancomycin diminished by half per day and peaked on the postoperative day 0 with an average of 1475 μg/mL (range to 263–2938 μg/mL) [
In addition, we included the Rasmussen score for evaluating knee function and clinical outcomes. Our results suggested that the vancomycin group seemed to get a higher score, but there was no statistically significant difference between these two groups. Other trauma clinical works also did not support that vancomycin could contribute to the recovery of the affected limbs [
There are several limitations worth mentioning in this study. Firstly, this was a single-center, retrospective cohort study. The conclusions from our study might not extrapolate to other medical centers or other areas of orthopedics. Our sample size was relatively small, limiting the power to identify all influences on the occurrence of FRI. Therefore, our findings must be interpreted cautiously. Secondly, due to incomplete medical records, some risk factors for FRI were not included (such as duration of drainage tube application and length of the surgical incision). Thirdly, because a single group in our institutions performed all surgeries, it is unlikely to exclude surgeon bias from our results. Moreover, we initiated the application of vancomycin powder during operation in 2013, and the usage rate could vary over time. Finally, some patients might have been treated for FRI at another trauma center, of which we were unaware. However, these patients’ data were recorded until they were lost to follow-up.
Conclusion
Compared to a control group treated with single intravenous antibiotics, intrawound application of vancomycin is associated with the lower incidence of FRI in high-risk tibial plateau fractures. Despite some conclusions we have drawn, our trauma center is continuing to devote itself to identifying the effect of vancomycin powder on high-risk fractures.
Declaration of Competing Interest
The authors declare that they have no competing interests.
Acknowledgements
I would like to appreciate my co-authors for their contributions to this study and the writing of this manuscript.
References
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Complications following limb-threatening lower extremity trauma.
Measures to reduce end-of-case wound contamination: the impact of intra-wound vancomycin powder and betadine irrigation on surgical site infections in posterior spinal fusion.
Reduction in surgical site infection with suprafascial intrawound application of vancomycin powder in instrumented posterior spinal fusion: a retrospective case-control study.
Is use of topical vancomycin in pediatric spine surgeries a safe option in the prevention of surgical site infections? A meta-analysis and systematic review of the literature.
The application of topical vancomycin powder for the prevention of surgical site infections in primary total hip and knee arthroplasty: a meta-analysis.
Comparison between 1 g and 2 g of intrawound vancomycin powder application for prophylaxis in posterior instrumented thoracic or lumbosacral spine surgery: a preliminary report.
Topical vancomycin powder decreases the proportion of staphylococcus aureus found in culture of surgical site infections in operatively treated fractures.
Denotes variables with p < 0.1 were included in the multivariable model.
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