## Abstract

BACKGROUND: Intrawound vancomycin powder has been studied extensively in spinal fusion surgeries and been found to reduce rates of surgical site infections (SSIs) significantly. Despite its success in spinal surgeries, topical vancomycin has not been extensively studied with respect to cranial neurosurgery.

OBJECTIVE: To evaluate the efficacy of intrawound topical vancomycin for prevention of SSIs following open craniotomies.

METHODS: We retrospectively analyzed a large series of 350 patients from 2011 to 2015 in a pre/postintervention study of use of topical vancomycin to reduce postoperative craniotomy infection rates. We had a preintervention control group of 225 patients and a postintervention group of 125 patients that received intrawound topical vancomycin.

## RESULTS

This retrospective study investigated the incidence of SSIs in 350 consecutive open craniotomy patients, of which the initial 225 were controls and the following 125 received topical vancomycin treatment. Demographics data were examined and matched in both control and treatment arms. There were no significant differences found in known risk factors for SSI, including age, sex, previous craniotomy, hypertension, or diabetes between these 2 groups (Table 1). There was a statistically significant difference in proportion of patients receiving intraoperative steroids (53.8% in the control group vs 64.8% in the treatment group, risk difference of 11%, P = .03). However, there were more steroids given in the treatment group; thus, steroid administration was not correlated with increased infection rates. Of note, patients receiving topical vancomycin tended to have a shorter mean operative time (168.02 min) compared to patients receiving the standard of care (177.22 min), although the difference was not significant (P = .53).

TABLE 1.

Patient Demographics Organized by Group

Control group Treated patients
Variable (n = 225) (n = 125) P-value
Intraoperative steroids 121 81 .03*
Perioperative steroids 105 64 .15
Age 55.5 ± 18.4 51.69 ± 18.69 .065
Body mass index 26.9 ± 6.5 27.46 ± 5.75 .79
Male sex 133 63 .09
Previous craniotomy 48 37 .15
Coronary artery disease .79
Previous tobacco use 65 46 .13
Current tobacco use 28 13 .53
Diabetes 24 21 .11
Hypertension 78 51 .2
Operation duration 177.22 ± 154.73 168.02 ± 124.89 .52
SSI .046*
Control group Treated patients
Variable (n = 225) (n = 125) P-value
Intraoperative steroids 121 81 .03*
Perioperative steroids 105 64 .15
Age 55.5 ± 18.4 51.69 ± 18.69 .065
Body mass index 26.9 ± 6.5 27.46 ± 5.75 .79
Male sex 133 63 .09
Previous craniotomy 48 37 .15
Coronary artery disease .79
Previous tobacco use 65 46 .13
Current tobacco use 28 13 .53
Diabetes 24 21 .11
Hypertension 78 51 .2
Operation duration 177.22 ± 154.73 168.02 ± 124.89 .52
SSI .046*
*

P < .05

Demographics data were examined and matched in both control and treatment arms. There were no significant differences found in known risk factors for SSI, including age, sex, previous craniotomy, hypertension, or diabetes, between these 2 groups.

The main goal of the study is to determine whether topical vancomycin can reduce the incidence of cranial infections. In our control group, 5 patients in a cohort of 225 experienced SSIs (overall incidence of 2.2%, Table 2) for which they required subsequent readmission and treatment. The time course of these infections was relatively well distributed throughout the initial study period as indicated by operative date in months since the beginning of the study in Table 2. By comparison, no patient receiving vancomycin was infected, a decrease in infection rate that was statistically significant (5% incidence in control group, 0% incidence in experimental group, risk difference of 5%, 95% confidence interval: 0% to 3.84%, P = .046). This corresponded with an odds ratio of 0, a relative risk reduction of 100%, and the number needed to treat of 45 patients to prevent 1 infection. There were also no documented adverse events or side effects related to vancomycin treatment in any of the patients in the treatment cohort.

TABLE 2.

SSI Patients and Pertinent Characteristics

Patient    Body mass Craniotomy Vanco. Op Intraop Periop
no. Diagnosis Age Sex index type use date steroid steroid
Glioblastoma multiforme 67 22.1 Parieto-occipital craniotomy
Glioblastoma multiforme 40 26.49 Parietal craniotomy 8.5
Breast metastasis to brain 73 23.56 Occipital craniotomy 32
Cerebellopontine angle epidermoid 64 73.94 Revision transtemporal craniotomy 32
Hemicraniectomy 79 34.07 Cranioplasty 33
Patient    Body mass Craniotomy Vanco. Op Intraop Periop
no. Diagnosis Age Sex index type use date steroid steroid
Glioblastoma multiforme 67 22.1 Parieto-occipital craniotomy
Glioblastoma multiforme 40 26.49 Parietal craniotomy 8.5
Breast metastasis to brain 73 23.56 Occipital craniotomy 32
Cerebellopontine angle epidermoid 64 73.94 Revision transtemporal craniotomy 32
Hemicraniectomy 79 34.07 Cranioplasty 33

There were a total of 5 patients in the control group cohort of 225 patients that had SSIs. Original operation characteristics, including diagnosis, procedure, and use of vancomycin powder and perioperative steroids, are listed. “Op date” is the date of operation listed in months since initiate of the study.

A secondary aim of this study is to examine the cost-effectiveness of topical vancomycin to determine if it is an economical solution to replace the current standard of care. O'Keeffe et al1 determined that the total cost of a single craniotomy infection amounts to $14 216 per patient. Since 5 patients in our control group presented with an SSI, the cost of not applying vancomycin to every patient amounts to$71 080.

By contrast, 1 g of vancomycin powder costs approximately $49.40 per patient. With 225 patients in our experimental group and no patients experiencing an infection, the treatment group is associated with a cost of$11 115. Therefore, our study estimates a cost savings for the hospital of $59 965 with the experimental vancomycin therapy (Table 3). TABLE 3. Cost Analysis Unit Control Vancomycin Total Treatment cost ($) group group cost ($) Craniotomy infection 14 216 71 080 1 g vancomycin 49.4 125 6175 Unit Control Vancomycin Total Treatment cost ($) group group cost ($) Craniotomy infection 14 216 71 080 1 g vancomycin 49.4 125 6175 We conducted an ad hoc total cost analysis utilizing per unit costs of craniotomy infections from the literature. O'Keeffe et al1 determined that the total cost of a single craniotomy infection amounts to$14 216 per patient. Since 5 patients in our control group presented with an SSI, the cost of not applying vancomycin to every patient amounts to $71 080. By contrast, 1 g of vancomycin powder costs approximately$49.40 per patient and would have amounted to a total cost of $11 115 to cover the entire preintervention cohort of 225 patients. Moreover, the costs associated with SSIs in patients receiving the standard of care may be substantially higher at other institutions and in other studies. According to the literature, SSI rate postcraniotomy can be as low as 2% and high as 5%.3,8,11 In a hypothetical cohort of 200 patients, the SSI costs may range from$56 864 up to $142 160. Therefore, on this spectrum, cost savings from vancomycin therapy could range from$46 984 to a staggering $132 280. ## DISCUSSION In this study, we present a large series of consecutive open craniotomy patients treated with topical vancomycin with the goal of preventing postoperative infection. The key result of the study was evidence of significant reduction in SSIs for patients in the treatment group. The groups were well matched for risk factors that could influence infection rates. Risk factors for SSIs postcraniotomy include gender, age, emergency procedure, longer procedure duration, and postoperative CSF leakage.10 In our study, there were no significant differences in any of these risk factors between our 2 cohorts except for intraoperative steroid administration. However, there were more steroids given in the treatment group; thus, steroid administration was not correlated with increased infection rates. As research in this field expands, new potential risk factors are identified, such as antibiotic dosing and increased body temperature during surgery.10 Combined, these risks predispose craniotomy patients to an SSI incidence of up to 5% in high-risk groups. The current standard of care continues to be inadequate for these patients. Spinal surgeries featuring topical vancomycin in addition to current antibiotic measures demonstrate promise in preventing SSIs.2,4,7,12,16 A recent meta-analysis evaluating 5000 spine surgery patients found that use of intrawound vancomycin powder during open spinal surgery resulted in a 33% reduction of SSI risk with no associated complications.2 The study particularly emphasized the use of topical vancomycin in cases with high baseline infection rate and in high-risk patients. However, there still exists controversy surrounding the routine use of vancomycin powder in spinal surgery. Despite successes seen in high-risk populations and single-level spine surgeries,4,7 the body of literature concerning the use of vancomycin in spine surgery remains inconclusive, with certain groups reporting benefits from the intervention and other groups reporting no difference.2,4,12,16 There also exist concerns about selection of gram-negative, anaerobic, and vancomycin-resistant bacterial SSIs given the broad-spectrum gram-positive coverage vancomycin provides,17 as well concerns regarding systemic vancomycin toxicity with elevated serum concentrations.18 Several studies have demonstrated that with intrawound vancomycin administration, serum levels of vancomycin remain at normal therapeutic or subtherapeutic to undetectable levels whereas local wound concentrations exceed the minimal inhibitory concentration necessary to treat most covered microbes.19,20 A recent meta-analysis of all published studies of intrawound vancomycin use in spinal surgery including over 6700 treated patients found an exceedingly overall adverse event rate of 0.3%, the majority (83%) of which were culture-negative seroma formation and very rarely were there reports of nephrotoxicity (1 patient out of 6701 total included) or ototoxicity resulting in transient hearing loss (2 patients out of 6701 total included).17 In this study, no patients treated with topical vancomycin experienced an SSI postoperatively, whereas 5 patients in our control group had an SSI. Based on the literature and our analysis, cost savings can be tremendous with use of topical vancomycin. In spine surgeries, it is estimated that the treatment helps save approximately$250 000 per 100 thoracolumbar deformity procedures and $438 000 in posterior spinal fusions.5,21 The estimates provided in our results are a bit more conservative at up to$66 140 per 100 craniotomies, and include hospital expenses and patient morbidity, both of which cause strain and financial burden to healthcare systems. In spite of the fiscal costs associated with SSIs, these figures are compounded further when considered in the context of societal productivity.22 Opportunity costs from not being able to work, lower worker productivity leading to decreased gross domestic product, and other factors contribute to broader ramifications.12 Furthermore, SSIs and their resultant hospital readmissions are now tracked quality and outcomes metrics, and may result in lower reimbursements to healthcare institutions from both government and private payers due to poor treatment outcomes.

### Limitations

Despite the strong associations seen in this study, there are limitations to its extrapolations. First and foremost, this is a single-institution, single-surgeon (senior author GL) experience that has a pre/postintervention study design that inherently subject to temporal maturation bias. That is, improvements in infection rates may simply be a result of improvement in aseptic surgical technique secondary to increased experience. However, the rate of infections in the control arm was relatively constant overtime (Table 2), and the there was an abrupt drop-off in SSIs after implementation of vancomycin powder. Second, given that this study was restricted to a single-surgeon experience beginning with the start of his tenure at this institution, the number of patients in both pre/posttreatment cohorts is relatively small, especially given the low rate of infections seen preintervention. However, given that this is a relatively new intervention, this initial study was not able to include a multiple-surgeon, center-wide or multicenter intervention design that would have significantly strengthened the power of this study. Thus, while our study represents some guarded initial evidence of the efficacy of topical vancomycin in open craniotomy, we hope it will generate more interest in topical vancomycin for open craniotomies, which will lead to larger and more definitive studies on its efficacy. As is the case in many other studies, the data were collected from a patient population at a single institution, and may not be representative of populations across the United States. Further studies could implement data collection combining results from several different institutions to reduce this limitation. Also, randomized trials would strengthen the association found in this retrospective study.

Another limitation of these types of retrospective studies is the fact that patients may be admitted to other hospitals adverse events related to vancomycin toxicity or for follow-up procedures. Therefore, there is always a chance of unreported complications that could influence the current data set. However, access to medical record documentation for at least 3 months of follow-up should be more than adequate to capture any infections, adverse events, or complications that would have been relevant for inclusion in this study. Despite the limitations, this study represents some guarded initial evidence of the efficacy of topical vancomycin as SSI prophylaxis in open craniotomy. We sincerely hope that it will lead to more interest and adoption of topical vancomycin so that more definitive studies and evidence may be disseminated.

## CONCLUSION

This study surveys the SSI complications for a large number of postcraniotomy patients, noting a correlation between the use of topical vancomycin and a significant reduction in SSI rate. There were no adverse events or side effects related to topical vancomycin administration. Therefore, topical vancomycin may be considered in all open craniotomy patients given the decrease in SSI rate, safety profile, and associated cost savings found in our study. Future studies with a multiple-surgeon, multiple-center, and, ideally, with a controlled randomized trial design are essential in order to establish definitive efficacy for the use of topical vancomycin in open craniotomies.

### Disclosure

The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

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