IntrasIte vancomycIn powder as a prophylactIc adjuvant In lumbar fusIon

Objective: To identify whether the use of prophylactic intrasite vancomycin as an adjuvant is a protective factor against deep tissue infection of the surgical site. Methods: Retrospective, descriptive, case-control study evaluating 210 patients, of whom 70 received intrasite vancomycin (case group) and 140 were controls. It was made a follow up for at least one year, reviewing the physical and electronic records. Data were tabulated in spreadsheets (Excel) including all variables and the statistical analysis was made with Epi InfoTM 7 to calculate the odds ratio. Results: Seven cases of deep infection occurred in the control group and none was found in the case group (odds ratio [95% confidence interval]: 0.1262 [0.007–2.24], P = 0.1585). Among the predisposing factors, diabetes and surgical time were the most relevant. Conclusions: Intrasite use of vancomycin has a protective effect against deep infection in patients undergoing lumbar fusion surgery without presenting considerable side effects.


INTRODUCTION
Current indications for lumbar spine fusion include spinal deformity, instability, and pain. 1 Deep tissue infection following spine surgery is a potential and devastating complication.Deep tissue infection from spine surgery is associated with higher morbidity, mortality, and health care costs. 2 Despite increasing knowledge and advances in prophylactic practices, surgical site infections are one of the most common complication in surgery. 3he Center for Disease Control and Prevention (CDC) classifies surgical site infections as either incision or organ/space.Those related to incisions are sub-classified as those involving only the skin and subcutaneous tissue and those involving the deep tissues of the incision (muscle, fascia, for example).Organ/space infections involve any part of the anatomy, other than the incision, that was opened or manipulated during the surgical procedure. 4urgical site infection (SSI) is one of the most common and most devastating complications of spine surgery. 5Its incidence varies depending on several factors, and it is estimated that between 2.8% and 11.9% of patients who undergo spine surgery contract an SSI, despite the implementation of conventional prophylactic strategies.The patients affected by these infections have longer hospitalization times and work disability, diminished quality of life, and their general outcomes compare unfavorably with those of patients who do not suffer these complications. 6he administration of intravenous antibiotics is perhaps the most used strategy for the prevention of SSI.The most recent clinical practice guidelines from the Antibiotic Prophylaxis Work Group of the North American Spine Society recommend the systematic administration of intravenous prophylaxis.However, it has been shown that the magnitude of SSI is relatively low which has led to a search for other alternatives. 7ntibiotics in powder form placed directly in the surgical wound prior to closure has proved to be one of the effective means of reducing postoperative deep tissue infections. 8(Figure 1) In theory, depositing the antibiotic in powder form directly in the site of the operation (intrasite) achieves the highest concentration of the antibiotic in the wound. 7he local use of vancomycin powder has resulted in a significant reduction in postoperative infections in patients with spinal instrumentation. 9No adverse effects attributable to the use of vancomycin in powder form have been reported. 9,10However, the local use of vancomycin powder does not reduce the incidence of postsurgical infection beyond 30 days in patients following spine surgery for deformity. 6he application of vancomycin in powder form in the reconstruction of the surgical wound is an innovative trend for the prevention of surgical site infection and continues to gain the support of spine surgeons for its low cost, availability, ease of application, good safety profile, and apparent effectiveness. 11ven though the pharmokinetic properties of vancomycin applied to the surgical site is a very attractive method of prophylaxis, its adverse effects present a significant inconvenience.Intravenous application has been associated with anaphylactic reactions, arterial hypertension, nephrotoxicity, ototoxicity, and promoting resistance to antibiotics.However, its safety profile when applied topically is not yet totally understood. 12,13n the other hand, several studies have described the mecha-nisms by which vancomycin can interfere with osteoblast maturation and function, which could change the physiological processes involved in bone fusion.For this reason, several authors maintain that high local concentration of vancomycin inside the surgical site can be associated with a higher risk of pseudoarthrosis (or lack of union). 14,15owever, in the meta-analysis by Alcalá-Serra et al. 11 reviewing three studies with 2156 patients regarding the risk of nonunion, they found an incidence of 0.7% in the treated group compared to 0.9% in the control group.They also comment that there are no recorded incidents or complications related to the application of vancomycin in the surgical wound in any of the 1,437 subjects treated from 6 observational studies.Thus, it was not possible to conduct a comparative analysis.
We perform between 850 and 950 surgeries annually.An average of 160 spinal instrumentations are performed per year.The overall infection rate is 1.94% and infection rate amongst lumbar fusions was 6.54% during the year 2013.
Based on this, we believe that the use of intrasite vancomycin as a prophylactic adjuvant will be offer protection against deep tissue infection at the surgical site in at least 50% of cases. 10

MATERIAL AND METHODS
We conducted a retrospective study of cases and controls.Group A (cases) was treated with 1g of vancomycin in powder prior to closure of the surgical wound, in conjunction with first-generation cephalosporin.Group B (controls) was treated exclusively with intravenous first-generation cephalosporin.In both groups, 1g of first-generation cephalosporin was used 1 hour before surgery and three doses of 1g every eight hours following surgery.We used the following inclusion criteria: patients registered with Mexican Social Security (IMSS), adult patients of both sexes who underwent primary lumbar instrumentation.Exclusion criteria were: patients with body mass index > 40 kg/ m 2 , patients with prior lumbar surgeries, patients with histories of allergies to cephalosporin and vancomycin, foreign patients, and patients with rheumatoid arthritis.Patients selected must have had at least one year of postoperative follow-up.
We performed the calculation of the sample size using the Hulley tables for a dichotomous variable (deep tissue infection) considering the following parameters: confidence interval of 95%, expected rate of infection of at least 50% in agreement with the study hypothesis, and an amplitude interval of 25%.With these, we obtained a total number (n) of 61 cases and 122 controls (two controls for each case) with a total number of 183.
The study was reviewed and approved by the Bioethics and Research Committee and was assigned the registration number R-2015-3401-6.

RESULTS
There were 78 patients who had vancomycin applied at the surgical site, 5 of whom were disqualified because of prior lumbar surgeries and 3 because of histories of rheumatoid arthritis.We obtained 70 cases who received intrasite vancomycin and 140 control cases, for a total of 210 patients.The average age was 56 years with 65% of the population between 50 and 70 years of age.(Table 1) The distribution by sex was equal with 48% men and 52% women.70% of the patients had BMI between 26 and 35kg/m 2 .(Figure 2) One gram of vancomycin in powder form was administered intrasite in the 70 cases.There were 7 cases of deep infection in the control group and none in the study group (odds ratio [confidence interval of 95%]: 0.1262 [0.007 -2.24], p=0.1585).In the case group, we found one case of seroma plus dehiscence of the wound with a positive initial culture, however, as a result of the surgical findings reported, a negative postoperative culture, and a favorable evolution.
The microorganisms found were s. aureus 14%, s. epidermidis 14%, e. coli 28%, and MERSA 42%.(Figure 3) One of the cases of MRSA also showed resistance to vancomycin.The case of infection by s. epidermidis was reported as mixed with a. baumanii.The risk of deep infection in the control group was 8.2% in diabetic patients versus 2.31% in patients without diabetes (odds ratio [confidence interval of 95%]: 3.72 [0.79 -17.42], p= 0.0943).Surgical time longer than 4 hours also showed to be a positive factor for the presentation of deep infection (odds ratio [confidence interval of 95%]: 7.6 [0.42 -134.74],p= 0.1676).There was a higher incidence of seromas in the case group (odds ratio [confidence interval of 95%]: 2.0294 [0.27 -14.71], p = 0.4839), only one of which required surgical drainage.When we performed the proportion test to confirm the hypothesis, we found that the rate of deep tissue infection dropped from 6.54% to 0% (p=0.0269).

DISCUSSION
The application of vancomycin in powder form in the reconstruction of surgical wounds is an innovative trend for the prevention of surgical site infections and has gained increasing support among spine surgeons due to its low cost, availability, ease of application, good safety profile, and apparent effectiveness. 11n the study by Strom et al. 10 they reported a reduction in the rate of infection from 10.9% to 2.5% without identifying complications attributable to the administration of vancomycin.In our study, we found a greater reduction in the rate of deep tissue infections, from 6.54% to 0% (p=0.0269).
As has been seen in various publications, we also found a higher incidence of seromas (Figure 4) in the case groups, although not statistically significant.
Despite the fact that the protective factor of the vancomycin was not statistically significant, we found a strong clinical association between the application of vancomycin in the surgical site and a reduced rate of infection, which is statistically significant if the proportion test is performed with p≤0.05.We determined that diabetes and surgical time had an important impact as predisposing factors for infection of the surgical site.
The main limitation of our study was the sample size, even with two years of experience, given that the use of vancomycin in powder form has only been used for a short period of time in the clinical department and few doctors use it routinely in patient prophylaxis.However, little by little its acceptance and use are increasing.
A prospective, controlled, randomized study with more patients is needed to obtain statistically significant results.
In the meta-analysis of Bakhsheshian et al., 16 the use of vancomycin is not advised because of the complications related to its use.However, these reports are related to the systemic use of vancomycin.Meanwhile, in other publications there is no statistically significant difference for these complications.For this reason, we think that there needs to be an adjustment made to consider the means of application in the statistical analysis, as we have done in this study.Regarding the question of an increased incidence of pseudoarthrosis, we cannot address this in this study because of it design and its limitations, and we plan to investigate this in the next study with long-term follow-up.
We think that, for patients at high risk of infection with surgical time longer than 4 hours and with pre-existing diseases like diabetes, it is wise to consider the application of vancomycin in powder to the surgical site and include it in the surgical protocol.
In our study, we suspect that tobacco use has a large impact, taking into account the microvascular damage that it produces and the consequent limitations on penetration of the systemic antibiotic at the surgical site.We think that conducting a study with a greater number of patients in a way focused on defining the patients' tobacco use index could corroborate this suspicion.

Figure 1 .
Figure 1.Photograph of the application of 1g of vancomycin powder to the surgical wound site after cleansing and just prior to closure of the wound.

Figure 3 .
Figure 3. Frequency of the appearance of isolated microorganisms.In one case, both S. epidermidis and Acinetobacter baumanii were present.

Figure 4 .
Figure 4. Incidence of surgical wound complications.Higher incidence was found in the vancomycin group.The case of seroma + wound dehiscence.

Figure 2 .
Figure 2. Distribution of the 210 patients by body mass index.70% of the study population were defined as overweight or grade 1 obese.

Table 1 .
Distribution of the population by age group.