Use of Topical Vancomycin Powder to Reduce Surgical Site Infections After Deep Brain Stimulation Surgery: UCSF Experience and Meta-analysis

Abstract

Objective

Surgical site infection (SSI) is the most common serious complication of deep brain stimulation (DBS) implantation surgery. Here, we report a single-surgeon experience on the efficacy of topical, intrawound vancomycin powder (VP) in reducing SSI for DBS surgery and present the first systematic review and meta-analysis examining the effect of topical vancomycin on SSI in patients after DBS surgery.

Methods

For the retrospective review, all unique patients undergoing DBS surgery at UCSF for new hardware implantation or internal pulse generator (IPG) replacement by a single surgeon from September 2013 to March 2019, with at least 1 year of follow-up data, were included. For the meta-analysis, we included all primary studies that compared surgical site infections with and without application of topical vancomycin in DBS surgeries.

Results

368 unique patients met inclusion criteria; 195 patients received topical VP (VP group) and 173 did not (control). 99/195 patients in the VP group underwent new DBS implantation and 96/195 had IPG replacement. 71/173 patients in the control group had new DBS implantation and 102/173 had IPG replacement. There were 10 total cases of SSI: 4 patients from the VP group (3 new implants, 1 IPG replacement) and 6 patients from the control group (3 new implants, 3 IPG replacements), resulting in SSI rates of 2.1% and 3.5%, respectively (p-value=0.337). Including our retrospective analysis, 6 studies met inclusion criteria for the systematic review and meta-analysis. In the 4 studies that examined primary DBS implants, 479 total patients received topical VP and 436 did not; mean odds ratio for SSI with topical vancomycin was 0.802 (95% CI 0.175–3.678). Across the 5 studies that examined IPG implantations or replacements, 606 total patients received topical VP while 1173 patients did not; mean odds ratio for SSI with topical vancomycin was 0.492 (95% CI 0.164–1.475). In either case, topical VP application did not significantly decrease risk of SSI.

Conclusion

Surgical infections after DBS surgery are uncommon events, with studies demonstrating mixed results on whether topical vancomycin reduces this risk. Our single-institution retrospective analysis and systematic review of prior studies both demonstrated no significant SSI rate reduction with topical VP. This is likely due to low baseline SSI rates, resulting in a small effect size for prevention. Given the cost-effectiveness, simplicity, and low risk, topical, intrawound VP remains a treatment option to further reduce risk of SSI, particularly in settings with higher baseline infection rates.

INTRODUCTION

Surgical site infections (SSIs) are a major source of morbidity and increased healthcare cost following neurosurgical procedures. Previous studies have indicated that the costs associated with SSIs approximate $3.3 billion spend annually and over $20,000 per-case [1]. The application of topical, intrawound vancomycin powder (VP) as an adjuvant to perioperative intravenous antibiotic use has been extensively studied in spine surgery [2–5]. Multiple studies have reported reductions in SSIs following spine surgeries with instrumentation of hardware [3,6–8]. Studies exploring the use of topical VP following craniotomy procedures have demonstrated mixed effects, with some demonstrating efficacy in reducing SSI [9–12], but others demonstrating no difference in SSI rate [13].

Patients undergoing deep brain stimulation (DBS) surgery represent a special neurosurgical patient population, given implantation of multiple hardware throughout various areas of the body, and the relatively frequent need to undergo repeat surgeries for implantable pulse generator (IPG) replacement. SSI after DBS surgery is one of the most common complications for this procedure, with reported SSI rates of 1%–15% [13,14]. Treatment of SSIs usually necessitates partial or full hardware removal, as well as 4–6 weeks of intravenous antibiotic therapy.

Application of topical VP in DBS surgeries could reduce SSI risk and minimize adverse sequelae. There have been a few reports specifically examining the use of topical VP during DBS surgeries [13,15–18], with infection rate ranging from 1–10% for control groups and 0–5% for topical vancomycin-treated groups. These studies demonstrate mixed results regarding the efficacy of topical vancomycin, ranging from significant reduction in SSIs to increase in SSIs for primary DBS implantations. In our current study, we first evaluated the efficacy of topical VP use in patients undergoing DBS surgery at our institution by comparing a single high-volume surgeon’s experience prior to and after routine application of vancomycin powder during surgery. We then conducted a systematic review of all prior studies examining topical VP use for DBS surgeries. In our study, as seen in reports by other institutions, we find that with low pre-intervention rates of SSI (<5%) we cannot demonstrate a significant benefit to adding topical vancomycin.

METHODS

Retrospective review

Patient selection:

Our retrospective, pre, and post-intervention study included 407 consecutive unique patients who underwent DBS surgery for the treatment of PD, ET, dystonia, tremor, or chronic pain from September 2013 to March 2019 at University of California San Francisco from a single surgeon (PAS). All patients underwent implantation of DBS hardware (brain DBS lead, lead extenders, and/or implantable pulse generator). Inclusion criteria: > 1 year of follow-up, patients receiving new hardware implants – either new DBS systems (including leads) or IPG replacements. Exclusion criteria: pediatric patients (age < 18 years), patients undergoing revision surgery in the setting of chronic infection from remote DBS placement from other institutions, and revision surgery for hardware erosion. If during this time period, a patient underwent multiple DBS surgeries (e.g. primary implantation and multiple replacements) the most recent surgical case was used for analysis.

Antibiotic use during surgery:

All patients were given standard of care for antibiotic prophylaxis during procedures including pre- and postoperative antibiotic prophylaxis of 2–3 g intravenous cefazolin (or 1g IV vancomycin if patient has allergies to cephalosporins) given 30 minutes prior to skin incision. After completion of hardware implantation, all wound sites were irrigated with bacitracin solution at time of closure. Patients in the pre-intervention group would then proceed with standard wound closure (see below). Those in the post-intervention group had 0.1–0.2 g of powdered vancomycin applied in the subgaleal space or subdermal space prior to wound closure. Wounds were closed in a standard multilayer fashion with interrupted 3–0 Vicryl for the galeal or subdermal layer, staples for the scalp or 4–0 absorbable Monocryl subcuticular for the skin. Between June 2016 and December 2016, the use of topical VP prior to wound closure was introduced, after which it was incorporated into standard of care. No other significant procedural changes were made during this time.

Data collection:

Demographic data regarding patients’ age, gender, diagnosis, and previous cranial surgeries were collected from the electronic medical record system. Surgical factors were recorded, including the length of stay and hardware implanted at time of surgery. We also collected various factors associated with increasing surgical morbidities including the following: American Society of Anesthesia (ASA) status, body mass index (BMI), history of coronary artery disease, tobacco use, diabetes mellitus, hypertension, and intra- and perioperative steroid use. Primary outcome was SSI and adverse effects from vancomycin powder. SSI was defined as infection of hardware within 6 months of implantation surgery, requiring partial or complete hardware removal, with a positive culture.

Statistical analysis:

Descriptive statistics were calculated for all variables and summarized as means with standard deviation for continuous variables and frequency of distribution for categorical variables. Univariate analysis with two-proportion z-test or 2-sample 2-tailed t-test was used for all categorical or continuous variables respectively, to compare control vs experimental groups.

Systematic review and meta-analysis

Literature search:

We performed a systematic review using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines [19], towards efforts of standardizing these studies in neurosurgery [20]. A PubMed database search was conducted from inception of the database to May 2021 using the following terms: “powdered vancomycin” or “vancomycin powder” or “topical vancomycin”; and “DBS” or “deep brain stimulation”; and “neurosurgery” or “surgery” or “case.” The question addressed was what the effect of topical vancomycin has on reducing the rate of SSI in DBS surgeries specifically.

Study selection:

Two independent researchers (S.K., J.F.B) screened all titles and abstracts based on inclusion and exclusion criteria. The inclusion criteria were: (1) the study population consists of patients receiving surgery for DBS, with either primary implantation or revision; (2) the study directly compared SSI rate with and without application of topical VP; (3) the study is a randomized control trial (RCT), prospective non-RCT, or retrospective analysis. Exclusion criteria were (1) the study population includes only topical VP treated patients; (2) the study compares the application of topical VP to application of another antibiotic; (3) the study is not specific to DBS (Figure 1).

Figure 1.

PRISMA flow diagram showing flow of study identification for systematic review.

Data extraction:

For the systematic review, one reviewer (S.K.) extracted data on study design, patient population (inclusion and exclusion criteria, surgery type, number of patients, diagnoses), outcomes (SSI rate with and without topical VP), and analytical models. Another reviewer (J.F.B) verified that studies were correctly included or excluded, and that study metrics and outcomes were correctly extracted.

Data synthesis and statistical analysis:

For the outcomes of SSI after DBS implantation and after IPG surgery, a meta-analysis was used to compute a pooled mean odds ratio and 95% confidence interval of SSI with application of topical VP relative to no application. Heterogeneity was assessed using the I² statistic, which describes whether variation in study outcomes is due to heterogeneity rather than chance. Due to heterogeneity present, we used a random effect model to compute the pooled metric.

RESULTS

Effect of topical VP on DBS surgery SSIs – retrospective study

Our retrospective study investigated the incidence of SSIs in 368 consecutive patients who underwent DBS surgery with hardware implantation and met inclusion criteria, of which 173 were in the control group prior to routine application of vancomycin powder and 195 received topical vancomycin powder treatment. Patient demographic data demonstrated that the control and treatment arms were well matched. Significant group differences were found in the following risk factors for SSI: operative time (VP < no VP) and length of hospital stay (VP > no VP for revision surgeries). There were no significant group differences for the following risk factors: gender, age, ASA classification, body mass index (BMI), coronary artery disease (CAD), tobacco use, diabetes, hypertension, perioperative steroid use, and diagnosis (Table 1).

Table 1.

Demographics data of DBS patients from our institution.

	No vancomycin powder (n=173)	Vancomycin powder (n=195)		p-value
Gender	67 female, 106 male	68 female, 127 male		0.441
Age (years)	62.0+/− 15.5	63.5 +/− 13.2		0.616
Operative time (minutes)
Primary*	271.9 +/− 88.1 (n=71)	235.0 +/− 85.1 (n=99)		0.00667
Revision**	28.5 +/− 10.9 (n=102)	30.1 +/− 12.8 (n=96)		0.345
IPG	27.5 +/− 9.6 (n=98)	28.0 +/− 9.7 (n=89)		0.732
LE + IPG	54.0 +/− 10.3 (n=4)	57.4 +/− 15.8 (n=7)		0.709
Length of hospital stay (days)
Primary*	2.2 +/− 1.7	2.3 +/− 1.3		0.750
Revision**	0.0 +/− 0.0	0.1 +/− 0.7		0.0488
ASA Classification	2.3 +/− 0.5	2.3 +/− 0.5		0.930
BMI	25.2 +/− 4.9	25.1 +/− 4.8		0.746
CAD	7 (4.0%)	15 (7.7%)		0.142
Tobacco use	54 (31.2%)	44 (22.6%)		0.0615
Diabetes	11 (6.4%)	17 (8.7%)		0.395
Hypertension	46 (26.6%)	48 (24.6%)		0.667
Perioperative steroid use	37 (21.4%)	50 (25.6%)		0.337
Diagnosis	Cerebral palsy: 1 (0.6%)	Cervical dystonia: 5 (2.6%)
	Chronic pain: 1 (0.6%)	Chronic pain: 3 (1.5%)
	Dystonia: 31 (17.9%)	Dystonia: 33 (16.9%)
	Essential tremor: 14 (8.1%)	Essential tremor: 12 (6.2%)
	Other tremor: 5 (2.9%)	Other tremor: 2 (1.0%)
	Parkinson’s disease: 121 (69.9%)	Parkinson’s disease: 139 (71.3%)
		Tourette’s: 1 (0.5%)
Infections	6 (3.5%)	4 (2.1%)		0.337

^*Primary: lead extender and IPG may be implanted at the same time as DBS lead placement or at a later timepoint.

^**Revision: includes both IPG replacement surgeries and combined lead extender and IPG replacement surgeries.

IPG = internal pulse generator; LE = lead extender.

The primary outcome of the study was incidence of SSIs in the control and vancomycin-treated patients. There were 10 cases of SSIs with an overall incidence of 2.67%. We did not find a significant difference in the number of SSI between the two patient cohorts: 6 in the control group (3.5%), and 4 in the vancomycin-treated group (2.1%; p=0.337). We evaluated the preoperative characteristics of the two cohorts and found that neither diagnosis, preoperative risk factors, nor surgery type is associated with increased risk of infection for the cohorts (Table 2). Surgical site infections in the control group were due to the following organisms: P. acnes (n=4), S. epidermidis (n=3), S. aureus (n=3), E. clocae (n=1), S. marascens (n=1). Of the six infections, three were polymicrobial. Organisms that grew out from SSI culture in the topical VP-treated group were quite similar: P. acnes (n=1), S. epidermidis (n=1), S. aureus (n=1), and Coryneform bacteria (n=1). However, none of the infections in the topical VP-treated group were polymicrobial.

Table 2.

Characteristics of patients with surgical site infections.

	No vancomycin powder (n=6)	Vancomycin powder (n=4)	p-value
Gender	1 female, 5 male	2 female, 2 male	0.258
Age (years)	54.8 +/− 17.0	69.8 +/− 3.8	0.149
Operative time (minutes)	125.0 +/− 147.2	280.5 +/− 141.3	0.135
Length of hospital stay (days)	1.7 +/− 2.3	1.5 +/− 1.0	0.898
ASA status	2.3 +/− 0.5	2.3 +/− 0.5	0.807
BMI	24.5 +/− 6.7	21.8 +/− 2.5	0.532
CAD	0 (0.0%)	0 (0.0%)	~
Tobacco use	2 (33.3%)	0 (0.0%)	0.197
Diabetes	1 (16.7%)	0 (0.0%)	0.390
Hypertension	1 (16.7%)	2 (50.0%)	0.258
Perioperative steroid use	0 (0.0%)	1 (25.0%)	0.197
Diagnosis	Parkinson’s Disease (2), Dystonia (4)	Parkinson’s Disease (4)
Microbes	P. acnes P. acnes/E. clocae S. aureus/S. marascens/P. acnes S. aureus/S. epidermidis/P. acnes S. epidermidis S. epidermidis	Coryneform bacteria P. acnes S. aureus S. epidermidis
Surgery type
Primary * (n=170)	3/71 (4.2%)	3/99 (3.0%)	0.674
Revision** (n=198)	3/102 (2.9%)	1/96 (1.0%)†	0.342

^*Primary: lead extender and IPG may be implanted at the same time as DBS lead placement or at a later timepoint

^**Revision: includes both IPG replacement surgeries and combined lead extender and IPG replacement surgeries.

^†site of infection distant from the surgical site

If the lack of significance is due to insufficient power in this single-institution study, the number of patients needed to treat with vancomycin powder to prevent one SSI was 71.4 for all surgery types combined. The absolute risk reduction of vancomycin on SSI was 1.417%, and the relative risk reduction was 40.0%. There was one documented adverse effect related to topical vancomycin treatment in the treatment cohort, a whole body rash.

When separated by surgery type, there was similarly no difference in SSI rate. For primary DBS implantation surgeries, SSI rate was 3/71 in the control group (4.2%) and 3/99 (3.0%) in the topical VP-treated group (p=0.674). For IPG replacement surgeries, SSI rate was 3/102 (2.9%) in the control group, and 1/96 (1.0%) in the topical VP-treated group (p=0.342). Of note, while 9/10 SSIs were located at the surgical site, the SSI after IPG replacement in the topical VP-treated group was located in the occipital/high cervical area, distant to the surgical site.

Effect of topical VP on DBS surgery SSIs – systematic review

Our systematic review found that three of the five studies demonstrated no significant decrease in SSI risk with application of topical VP in DBS cases (Table 3), with one even demonstrating increased SSI risk with initial implantation (Bernstein, et al., 2019). Notably, studies reporting decreased SSI risk with topical VP had a much higher pre-intervention rate of SSI (7.5–9.5%) as compared to the studies reporting no difference (0.9–2.6%).

Table 3.

Study characteristics of 6 retrospective cohort studies of vancomycin powder in DBS operations.

Authors, Year	Data source (study period)	No. of pts.	Diagnosis	Treatment groups	Control SSI Rate	VP Group SSI Rate	P-value	RRR	ARR	NNT
Kondapavulur*, Burke*, et. al., 2021	UCSF (September 2013–March 2019)	368	PD, ET, dystonia, pain, other	Primary DBS implantation: No VP vs VP	Primary DBS: 4.23%	Primary DBS: 3.03%	Primary DBS: 0.674	28.3%	1.20%	83.7
				IPG replacement: No VP vs VP	IPG: 2.94%	IPG: 1.04%	IPG: 0.342	68.6%	2.14%	46.6
Bernstein, et al., 201918	Single institution (2000–2018)	203	PD, ET, dystonia, OCD, pain	Primary DBS implantation: No VP vs VP	Primary DBS: 0.9%	Primary DBS: 5.3%	Primary DBS: 0.014	−4.9%	−4.4%	~
				IPG replacement: No VP vs VP	IPG: 1.25%	IPG: 0.6%	IPG: 0.61	52%	0.65%	154
Atchley, et al., 201917	University of Alabama, Birmingham (2013–2016)	384	N/I	IPG replacement: No VP vs VP	IPG: 2.6%	IPG: 3.2%	IPG: 0.922	−23%	−0.6%	~
Abode-Iyamah, et al., 201813	University of Iowa (December 2005–September 2015)	242	PD, ET, dystonia, OCD, poststroke	Primary DBS implantation: No VP vs VP	Primary DBS: 9.7%	Primary DBS: 3.3%	Primary DBS: 0.04	66%	6.4%	15.6
Kochanski, et al., 201816	Rush University Medical Center (2015–2017)	419	PD, ET dystonia, OCD, Tourette’s syndrome, epilepsy	Primary DBS implantation: No VP vs VP	Primary DBS: 0.6%	Primary DBS: 0.0%	Primary DBS: 0.162*	100%	0.6%	167
				Connector + IPG placement: No VP vs VP	Conn. + IPG: 1.9%	Conn. + IPG: 0.38%	Conn. + IPG: 0.129*	80%	1.5%	66.7
				IPG replacement: No VP vs VP	IPG: 0.6%	IPG: 0.0%	IPG: 0.222	100%	0.6%	167
Pepper, et al., 201715	NHNN, London (January 2012–December 2014)	171	PD, dystonia, other	IPG replacement: No VP vs VP	IPG: 7.5%	IPG: 0.0%	IPG: 0.02	100%	7.5%	13.3

PD = Parkinson’s disease, ET = essential tremor, OCD = obsessive compulsive disorder, RRR = relative risk reduction, N/I = not indicated.

^*calculated from reported values

In the subsequent pooled meta-analysis consisting of 2,874 patients, there was no difference in SSI rate across all DBS surgery types between control and topical VP-treated groups (Figure 2, pooled odds ratio 0.560, 95% confidence interval: 0.210–1.492, model p=0.246). For primary DBS implantation surgeries, SSI rate was also not reduced with topical VP (Figure 3, pooled odds ratio 0.802, 95% confidence interval: 0.175–3.678, model p=0.776). Similarly, there was no difference in SSI rate for IPG surgeries between control and topical VP-treated groups (Figure 4, pooled odds ratio 0.492, 95% confidence interval: 0.164–1.475, model p=0.205). Of note, variability in the odds ratios of SSI for grouped surgery type and primary DBS implantation was due to heterogeneity across the studies (grouped surgery type: I²=6400, p=0.016; primary DBS implantation: I²=6891, p=0.022).

Figure 2.

Forest plot of SSIs in all DBS surgery types.

Figure 3.

Forest plot of SSIs in primary DBS implantations.

Figure 4.

Forest plot of SSIs in IPG surgeries.

DISCUSSION

Our study presents one of the largest consecutive series of patients undergoing DBS hardware implantation with and without treatment with topical, intrawound vancomycin powder. In our cohort of well-matched patients receiving identical pre- and postoperative care from a single surgeon, we found a non-significant reduction in the rate of SSIs for patients who underwent treatment with topical VP, with absolute SSI risk reduction of 1.417%, and number needed to treat of 70.6. We also observed one adverse event in the topical VP-treated group, a whole-body rash.

Our results regarding efficacy of topical VP in DBS surgeries are congruent with those previously reported in literature [13,16]. We interpret these findings to mean that with low rate of SSI for DBS hardware implantation procedures, it is difficult to demonstrate the benefit of using topical VP without an extremely large number of cases. For example, for IPG replacement surgeries, the number of cases needed to show a significant reduction from 2.9% to 1.0% (the reduction found in our study), with 1:1 enrollment ratio and 80% power, would be 1660 cases. Our systematic review identified four previous studies along with our study for IPG replacement surgery, totaling 1,779 patients; additionally, these studies reported a large range of SSIs without topical VP, from 1–9% [15–18], necessitating a greater number of studies to discern beneficial effects. For both DBS implantation and IPG replacement surgeries, we found that if the pre-intervention SSI was already low (i.e. <5%), there is no difference in SSI risk with use of topical VP. For the two reports that demonstrated topical vancomycin use reduced SSI, the reported SSI rates without VP treatment were 9.7% and 8.5% [13,15].

The most common organisms causing SSI in our series were P. acnes and gram positive cocci (e.g. S. aureus, S. epidermidis). Interestingly, three of the patients with gram positive cocci in the control group had intermediate response to vancomycin based on the minimal inhibitory concentration (MIC) while one of the patients within the VP group had vancomycin-sensitive S. epidermidis. While vancomycin covers a spectrum of gram positive and negative cocci, it did not appear to select for resistant organisms in our study.

Others have reported that concurrent use of vancomycin may increase the risk of side effects such as hypersensitivity reaction, thrombophlebitis, fever, rash, and reversible neutropenia [9], as well as delayed wound healing [21,22]. A recent meta-analysis found that use of prophylactic topical vancomycin may increase the incidence of gram-negative and polymicrobial SSI [23]. Despite these possible side effects of vancomycin, it is a cost-effective and simple prophylactic adjunct therapy. Previous reports have demonstrated the number needed to treat (NNT) with vancomycin to prevent cost related to treating an SSI to be 45 [10]. From our pooled meta-analysis of DBS surgeries specifically, the NNT with vancomycin for primary implants is 173; for IPG surgeries, the NNT is 55. The mean costs related to surgical incision and drainage for hardware salvage is $21,816, that of device explantation and outpatient antibiotics is $12,729, and that of subsequent reimplantation is $40,960 [24]. In contrast, the cost of VP per application is $12 [25–27], thus the total cost for VP to prevent one infection is far less than those related to device removal/revision ($2076 for primary implantation and $660 for IPG replacements). Thus, we recommend that practices weigh the risks and benefits of using topical VP based on prior infection rates and volume of DBS surgeries.

Despite the lack of significant benefit in SSI reduction seen in our study, there are several limitations that should be addressed. First, we reported our experience from a single surgeon, pre/post intervention study; thus for practices that have multiple surgeons performing similar procedures, the effect of topical VP may be greater than we find in this study. Second, the meta-analysis is limited by heterogeneity in the studies included, ranging from differences in underlying diagnoses treated with DBS to comorbidities present in the different study populations (i.e. proportion of patients with diabetes mellitus, mean BMI). Additionally, of the studies included, the treatment groups had different definitions; for example, some studies grouped IPG placements and replacements, whereas others reported the rate of SSI in both groups separately. Thus, with more detailed characterization of specific surgery type, controlling for disease diagnosis, number of prior surgeries, and other factors influencing SSI rate, the meta-analysis would be more accurate and tailored towards determining which surgical patient populations may benefit more or less from the intervention of topical VP.

CONCLUSION

Our study did not show a clear benefit in application of topical, intrawound vancomycin powder intraoperatively towards reducing SSI rate in DBS surgery at our institution, which is likely due to the low pre-intervention rate of infection. Topical vancomycin may be considered as adjunct prophylactic therapy due to the low cost and application simplicity, with practices weighing the risks and benefits of using topical VP based on prior infection rates and volume of DBS surgeries. Further detailed retrospective studies characterizing SSI rates pre- and post-intervention, along with subsequent pooled meta-analyses, will help determine efficacy of topical vancomycin in reducing SSI rates in DBS surgeries.

Data availability:

The datasets supporting the current study have not been deposited in a public repository, but they are available from the corresponding author upon reasonable request.