Does topical vancomycin prevent fracture-related infections in closed fractures undergoing open reduction and internal fixation? A randomised controlled trial

Abstract

Purpose

The role of topical vancomycin in fracture-related infection (FRI) is debatable. Very few studies have reported their efficacy in open and high-risk extremity fractures. This study aimed to assess topical vancomycin's role in reducing FRI in closed fractures undergoing open surgical intervention with an implant.

Methods

This prospective randomized cohort study was carried out between February 2021 to January 2022. Patients with isolated closed fractures, who were planned for open reduction and internal fixation within 2 weeks from the time of injury were included for this study. The data collected included age, gender, socioeconomic status, mechanism of injury, diagnosis, Tscherne classification, and time interval to take up for surgery. Patients were randomized into the intervention and control groups using the block randomization technique. The control group received only systemic antibiotic prophylaxis, whereas the intervention group received topical application of vancomycin powder in the surgical wound alongside systemic antibiotic prophylaxis. The primary outcome measure was the incidence of FRI among these individuals. Clinical and radiological findings and culture reports (in cases with infection) were recorded during the post-operative period and at 6 weeks of follow-up. All relevant statistical calculations were done using STATA statistical/data analysis-parallel edition version 16.0 (StataCorp LLC). The quantitative variables like age and duration of the surgery were assessed for normalcy by Shapiro-Wilk W test. An independent samples t-test with equal variances was applied to the age data. Fisher's exact test was used for the analysis of the primary outcome measure (presence of FRI following surgery), and “Risk of FRI” and “Risk difference” between the 2 groups was calculated. The strength of the association between qualitative variables was assessed using the Fisher's exact and Chi-square tests, respectively.

Results

There were 88 patients included in this study. No statistical significance was found about FRI between both groups (p = 0.494). At 6 weeks following surgery, no incidence of infection was observed in the intervention group. Two infections (4.5%) were found in the control group, with positive cultures reported in one of them but none in the treatment group. Radiologically, 15.9% of patients in the control group showed lysis around the implant compared to 2.3% in the intervention group. Impaired fracture healing was observed in 22.7% of patients in the intervention group compared to 15.9% in the control group.

Conclusion

Applying topical vancomycin in closed fractures undergoing open reduction and internal fixation does not significantly reduce the incidence of FRI until the end of 6 weeks following surgery.

1. Introduction

Post-operative infection following fracture fixation has been a cause of worry for orthopaedic surgeons despite advancements in sterilization, antisepsis, and other infection control techniques over the years. Orthopaedic surgery is commonly associated with metal implants but amplifying post-operative infection risk. The cost of infection in the orthopaedic setting is enormous. There has been a recent consensus on a separate entity of musculoskeletal infection in the presence of an implant for primary fracture treatment. Previously, the term “orthopaedic device related infection or orthopaedic implant related infection” has been used to describe infection in the presence of an implant. This term includes infection with joint prosthesis and other orthopaedic implants. Recently, a specific separate entity called fracture-related infection (FRI) has been introduced, which describes the infection in the presence of a fracture fixation implant. These unlike prosthetic joint infection have been classified as FRI.1, 2, 3, 4

The incidence of infection in closed fractures is approximately 1% – 2%.¹ The consequences of FRI are severe, causing extensive morbidity and occasionally leading to amputation and death. Multiple strategies are employed simultaneously to decrease the incidence of post-operative infection.² Prophylactic systemic antibiotics given at predetermined intervals during the peri-operative period have been proved to help certain control the infection rate, especially for high-risk cases. Antibiotics are typically given intravenously just before the surgery. Despite using prophylactic intravenous antibiotics, the incidence of post-operative infection has plateaued and further reduction has proven elusive.

In addition, intravenous antibiotics have some limitations, such as the limitation of low doses, less penetration of antibiotics to fracture sites due to local hematomas, hematomas and tissue ischaemia, and systemic toxicity with increasing intravenous doses. Another route of administration is topical antibiotics at the fracture site, which provides a high concentration of antibiotics at the operative site in synergy with intravenous administration. Local delivery has better penetration into surrounding tissue and is not limited by vascular compromise at the fracture site. The dose of intravenous antibiotic can be kept at a minimum, avoiding systemic toxicity. Antibiotics currently available for local application in orthopaedic clinical practice are clindamycin, tobramycin, gentamycin, and vancomycin.³ Consequent to a large amount of drug delivered locally, the activity spectrum against different pathogens is enhanced.

Broad pathogen spectrum, drug resistance, and toxicity profile favour vancomycin, which can be used for local application to prevent FRI. Intrawound application of vancomycin and related antibiotics can be made through a delivery vehicle or in nascent powder/aqueous form; however, which incur a high cost to the patient, are not easily accessible in peripheral centres, and require removal sometimes. On the other hand, nascent antibiotics (to be applied to the fracture site) are economical and easily accessible to surgeons in most centres. Although the efficacy of topical vancomycin has been proven in spine surgery, its role in orthopaedic trauma has not been studied in detail.5, 6, 7, 8, 9 Very few studies are available in the literature, mainly focusing on lower extremity fractures.10, 11, 12, 13, 14 This study aims at extending the limits of preventing infection using topical vancomycin in specific patients with closed fractures treated with an implant. Additionally, the other goal of the study is to explore the possibility of an inexpensive and low-cost adjunct to the existing management algorithm for better prevention of FRI in trauma surgery patients.

2. Methods

This prospective randomized controlled trial was carried out from February 2021 to January 2022 after obtaining approval from the Institutional Ethics Committee (Project no: JIP/IEC/2020/102). The detailed selection criteria for patients are mentioned in Table 1. Patients who met the inclusion and exclusion criteria were enrolled in the study. The nature and course of the study were explained, and the written informed consent for participation in the study was obtained from all patients.

Table 1.

Table showing the eligibility criteria for the study.

Inclusion criteria

Exclusion criteria

Patients presenting to our emergency department with isolated closed fractures, who are planned for open reduction and internal fixation within 2 weeks from the time of injury.

1.Patients' acceptance of immunosuppressive therapy 2.Patients with previous history of infection at the surgical site 3.Allergic to vancomycin 4.Pathological fractures, peri-prosthetic fractures 5.Polytrauma patients 6.Known remote foci of infections like pulmonary tuberculosis, infected non unions etc. 7.Platelet count < 150,000/mL 8.Total lymphocyte count < 1500/mm3 9.Those with known metabolic bone disease.

Patients were randomized into the intervention and control groups using the block randomization technique. Baseline blood investigations and pre-operative workup was done for all patients. Patients in both groups received standard systemic antibiotic prophylaxis consisting of 1 g ceftriaxone intravenously at the time of surgical incision, followed by 1 g ceftriaxone intravenously every 8 h for a day post-operatively or until drain removal, as per the institutional protocol. Standard surgical approaches were used in all cases. Irrigation was done with 1 L of warm normal saline before starting closure as a routine for all cases. For the patients in the intervention group, 2 g of vancomycin powder was applied locally to the fracture site, on the muscle, fascia, and subcutaneous tissue intra-operatively after wound wash and before wound closure (Fig. 1). No additional intra-operative intervention was done for the patients in the control group.

Fig. 1.

Image showing the technique of topical application of vancomycin powder.

Sub-fascial drains were used wherever necessary, and wounds were closed with absorbable Vicryl sutures in the deep fascia and subcutaneous layers. Skin closure was done with skin staples/Prolene sutures. Following skin closure, surgical wounds were cleaned again with alcohol-based preparations, and sterile dressings were applied.

Following surgery, patients in both groups were followed up for 6 weeks to look for any signs of FRI, in accordance with the consensus definition, and the findings were recorded for statistical analysis. The primary outcome was to assess the incidence of FRI. Clinical and radiological findings and culture reports (in cases with infection) were recorded during the post-operative period and follow-up. The flowchart of the entire study methodology is shown in Fig. 2.

Fig. 2.

Flowchart showing the study methodology.

2.1. Statistical analysis

All relevant statistical calculations were done using STATA statistical/data analysis-parallel edition version 16.0 (StataCorp LLC). The quantitative variables like age and duration of the surgery were assessed for normalcy by Shapiro-Wilk W test. The age of the patients was summarised as mean ± SD. An independent samples t-test with equal variances was applied to the age data to compare the 2 groups. Data for the duration of surgery pertaining to both the groups was summarised as median with interquartile range. A 2-sample Wilcoxon Rank sum test (Mann-Whitney test) was used to compare the 2 groups with respect to the duration of surgery. All the other variables were categorized and treated as categorical variables and summarised as proportions. The Chi-square test and Fisher's exact test were used respectively to test for association among the 2 groups pertaining to these variables. The primary outcome measure (presence of FRI following surgery) was analysed using Fisher's exact test, and “Risk of FRI” and “Risk difference” between the 2 groups was calculated. The strength of the association between qualitative variables was assessed using the Fisher's exact and Chi-square tests, respectively. The significance level was kept at 5%, and a p value less than 0.05 was considered significant.

3. Results

A total of 96 patients were included in the study, among whom 4 lost to follow-up. One patient expired due to pulmonary embolism. Three patients were withdrawn from the study, of whom 2 patients had to undergo revision surgery during the immediate post-operative period due to poor reduction, and 1 was due to a change of surgical plan to closed reduction as per the surgeon's opinion. At the end, 88 patients were available in this study. The control group (without vancomycin) and the intervention group (with vancomycin) comprised of 44 patients each. Both groups were found to be comparable with regard to patient demographic characteristics (Table 2).

Table 2.

The baseline information of the patients included in this study.

Parameters	The intervention group (n = 44)	The control group (n = 44)
Age (year)	40.38 ± 14.15	40.90 ± 15.63
Sex
Male	36	29
Female	8	15
Socioeconomic status
Lower	37	36
Middle	7	8
Upper	0	0
Comorbidities
DM	1	4
CKD	1	1
HTN, DM	1	1
Mechanism of Injury
RTA	22	24
Fall from a height	11	6
Fall of other objects	2	3
Others	9	11
Diagnosis
Upper limb fractures	21	14
Lower limb fractures	16	20
Spine injuries	6	5
Pelvic injuries	1	5
Multiple fractures	8	10
Tscherne classification
0	37	39
1	5	4
2	2	1
Time taken to take for surgery
< 24 h	2	0
1 day to 1 week	29	30
≥ 1 week	12	14
Duration of surgery (h)	4	4
FRI	0	2

Data present as mean ± SD or n.

DM: diabetes mellitus; CKD: chronic kidney disease; HTN: hypertension; RTA: road traffic accident; FRI: fracture-related infection.

According to the consensus definition, the presence or absence of FRI was used in our study to evaluate the outcome of participants following surgery.¹ Two patients in the control group developed infection according to the criteria, while none in the topical vancomycin group developed infection. Fisher's exact test was applied to the outcome data, and no statistically significant association was found between the 2 groups (p = 0.494). There was no statistical difference in the incidence of infection between the 2 groups. One of them patients showed culture positivity with pseudomonas aeruginosa and acinetobacter baumannii organisms.

The risk of FRI in the group of patients “exposed to intrawound vancomycin” was calculated to be 0 according to the results of this study, as compared to the group of patients “not exposed to vancomycin”, which was found to be 0.04545 (45 per 1000 cases). The risk difference between the group of patients “Exposed to vancomycin” vs. “Not exposed to vancomycin” was -0.04545 (Table 3).

Table 3.

The risk of FRIs.

Parameters	Exposed to vancomycin	Unexposed to vancomycin	Total
FRI present	0	2	2
FRI absent	44	42	86
Total	44	44	88
Risk	0	0.04545	0.22727

FRI: fracture-related infections.

A set of clinical and radiological outcomes contributing to the international consensus definition of FRI were recorded at 6 weeks following surgery and used to compare the 2 groups (Table 4). None of the patients developed any vancomycin-related side effects.

Table 4.

The comparison of secondary outcomes, n.

Parameters	The intervention group	The control group
Fistula/sinus/wound breakdown	0	1
Local erythema	0	2
Local swelling	0	2
Local rise of temperature	0	2
Fever	0	1
Pus drainage	0	2
Pain without weight bearing	0	3
Bone lysis around the implant	1	7
Implant loosening	0	2
Impaired fracture healing	10	7

4. Discussion

This study aimed to assess the decrease in the incidence of FRI after using topical vancomycin to the fracture site intra-operatively in patients with only closed fractures. The incidence rate of FRI was 4.54% (2 out of 44 patients) in the control group, while there was no FRI in the intervention group, and the difference was not statistically significant. A relatively higher proportion of patients in the control group had developed bone lysis around the implant. At the end of 6-week follow-up, the number of patients in the intervention group with no signs of fracture union was slightly higher than in the control group.

We found that with a baseline rate of FRI as low as 4.54% (2 out of 44 patients) in the control group, it would be difficult to demonstrate any statistically significant benefit by using vancomycin powder. Even if it was present, there would be a question of cost-effectiveness with such a low baseline rate of infection in the study sample. A randomized control trial done by Tubaki et al.¹⁴ (restricted to spine patients) demonstrated no significant benefit of the intervention. Few other studies also reported no additional advantage of using topical vancomycin to prevent FRI.15, 16, 17 Vaida et al.¹⁵ reported that there was no significant decrease on FRI with the use of intrawound vancomycin in open fractures of the lower extremity. Similarly, in their study on periarticular fractures treated with intrawound vancomycin, Singh et al.¹⁶ did not notice any significant reduction in infection. Cichos et al.¹⁷ studied the patients undergoing open reduction and internal fixation in acetabular fracture and also found no significant decrease on FRI. Our observation in this study is in line with these studies.

On the contrary, few studies on spine surgery have shown a lower infection rate with topical vancomycin. Peng et al.¹⁸ have reported a decreased surgical site infection with topical vancomycin in patients who underwent hip and knee arthroplasty. In a retrospective study of the fracture population, Qadir et al.¹⁰ showed that topical vancomycin efficiently lowered infection rates in high-risk cases. Morgenstern et al.¹¹ found a reduction rate (11.9%) of FRI in open extremity fractures with the use of topical antibiotics. O'Toole et al.¹² did a randomized trial on tibial articular fractures who underwent surgery and reported a decrease in gram-positive surgical infection with topical vancomycin. In the study of Marchand et al.,¹⁹ it was reported that the use of topical vancomycin remains controversial and there was wide variability between different institutions and treating surgeons.

The infection rate in our study was low, probably because of our patients sustaining Tscherne grade 0 and 1 injuries. Among the 2 patients with infection, one of them had Tscherne grade 2 injury, and the other one had grade 0 injury. Generally, a longer duration of surgery is associated with a higher infection rate. The duration of surgery in the infected patients was 3 h and 5 h in this study, respectively. One of them who developed FRI showed positive cultures from the deep tissue samples (Fig. 3, Fig. 4). The identified organisms in this case were pseudomonas aeruginosa and acinetobacter baumannii.

Fig. 3.

(A & B) The patient in the control group underwent open reduction and internal fixation with a plate and developed infection. (C) Intra-operative image during debridement. (D) Clinical photograph showing the healed wound at the end of 6 weeks.

Fig. 4.

(A) The second patient who developed infection in the control group showing left closed comminuted bicolumnar acetabular fracture with neck of femur fracture and left iliac blade fracture. (B) Post-operative day 7 wound showing wound dehiscence and pus discharge. (C) Radiograph in follow-up showing implant failure. (D) Radiograph at the end of 6 weeks after implant removal and excision arthroplasty.

When administered intravenously, there are several known adverse effects of vancomycin, such as hypotension, tachycardia, nephrotoxicity, ototoxicity, cutaneous rashes, urticaria, and red man syndrome, which can occur either due to drug-related hypersensitivity or supra-therapeutic dose administration.²⁰ But, there were no reported adverse effects of vancomycin when applied locally.²¹ It is also worth noting that the systemic absorption of vancomycin when given through the topical route is negligible.²² As a concern for local skeletal toxicity, delayed/non-union would be the side effect of locally applied vancomycin.²³ A study to this effect conducted by Rathbone et al.²⁴ found that amikacin, vancomycin, and tobramycin were least cytotoxic locally and did not interfere with fracture healing until abnormally high concentrations were used, whereas antibiotics like doxycycline, penicillin, nafcillin, colistin, ciprofloxacin caused the greatest cytotoxic activity. In our study, around 7 patients in the control group had developed lysis of bone around the implant. From a statistical point of view, this finding nearly achieved significance, whereas, from a critical point of view, it was considered to be due to chance. Ten patients in the treatment group had no signs of fracture union at the endpoint follow-up of the study compared to the control group. Although it was found to be statistically insignificant in this study, similar findings with variable significance have been reported in previous studies, which can be attributed to the local cytotoxic effects of supra-therapeutic doses of local antibiotics.^25,26 We would like to imply from the observations in our study that prophylactic topical vancomycin may not benefit significantly in closed fractures. With the increase in antimicrobial resistance, vancomycin must be ideally utilized only in culture-proven cases.

From our analysis of previous literature, the studies which reported a higher baseline rate of infections in the control group also showed a statistically significant reduction in the addition of supplemental topical antibiotics, in contrast to the studies where the incidence of infection was relatively low. However, the use in institutions where the baseline infection rate is higher, as well as in a subset of patients with fractures at high risk of infection, with multiple risk factors involved is questionable.

Both the intervention and control groups were comparable, and no statistical difference were found among them with respect to the demographic data and baseline characteristics. Since we have taken a sample of all trauma patients and are not restricted to either spine or pelvic injuries, our results are more generalizable to the entire population.

From the conclusions drawn in multiple studies, although many studies support topical vancomycin use, most were retrospective studies and there was heterogeneity in the study population. Similarly, other retrospective studies have demonstrated no significant difference between the vancomycin group and control group in cases with high-risk lower limb fractures. However, there is a scarcity of concrete evidence. High-quality randomized control trials with adequate sample sizes are required to shed further light on this area. The main strength of this study is that it is a prospective randomized trial in a set of patients with only closed fractures who underwent open reduction and internal fixation. Both the groups were almost homogenous, and hence selection bias was avoided. The small sample size was one of the limitations of our study. Further randomized studies with a larger sample size would be able to better predict the effectiveness of this intervention in closed fractures due to the low incidence, as reported in this study.

Topical application of vancomycin in closed fractures undergoing open reduction and internal fixation did not significantly reduce the incidence of FRIs until the end of 6 weeks following surgery. It implies that a routine use of topical vancomycin as an adjunct may not be effective in closed fractures, particularly in institutions/groups where the expected baseline infection incidence is relatively low.

Funding

Nil.

Ethical statement

This study was approved by the Institute Ethics Committee. Written informed consent was obtained from all participants.

Declaration of competing interest

The authors have no relevant financial or non-financial interests to disclose. The authors have no competing interests to declare that are relevant to the content of this article.

Author contributions

Mohit Gandhi: Literature search, manuscript writing, statistical analysis, manuscript review. Gopisankar Balaji: Idea conceptualization, study design, data collection, manuscript writing, and editing. Jagdish Menon: Idea conceptualization, intellectual content, data acquisition, manuscript writing, and editing. Ruben Raj Thomas: Statistical analysis, intellectual content, manuscript editing.