Is there information on intrawound/topical vancomycin powder in craniotomy?
Introduction
Background
A craniotomy is a surgery that involves removing a small piece of the skull to access the brain for a neurologic procedure and then returning the bone flap to its original placement, sometimes using metal plates to keep the bone in place.1 Complications following these procedures are common, with infection rates ranging from 2.2% to 19.8% and causing significant morbidity and mortality. Risk factors for development of surgical site infection (SSI) after craniotomy are not completely understood, but may include pre-operative length of stay, post-operative complications, patient demographic factors, history of previous brain surgery, concurrent chemotherapy treatment, preoperative glucose levels and steroid use, and the American Society of Anesthesiologists (ASA) score.1,2 In a retrospective study looking at 5723 patients with brain tumors who underwent craniotomy in Beijing Tiantan Hospital, cerebrospinal fluid was analyzed to determine which pathogens were causing postoperative infections.3 Eight-two percent of infections were caused by Gram-positive organisms (coagulase-negative Staphylococcus, Staphylococcus aureus, Enterococcus species, and Streptococcus species), 16.8% were caused by Gram-negative organisms (Acinetobacter species, Klebsiella pneumoniae, Enterobacter species, Pseudomonas aeruginosa, and Escherichia coli) and Candida species were found to cause 1.2% of infections. A case-control study conducted at the University of Iowa Hospitals and Clinics looked at SSIs in patients following craniotomy or craniectomy.2 Of the patients that developed an SSI, 51.9% of them had organ/space infections (in the subgaleal space, subdural space, cranial bone, or brain), 36.5% had deep incisional infections, and 11.5% had superficial incisional infections. These studies demonstrate the importance of using antibiotics that will cover Gram-positive organisms and targeting the subgaleal and subdural spaces for preventing infection in patients undergoing a craniotomy procedure.
Clinical practice guidelines published in 2013 (currently archived) by the American Society of Health System Pharmacists, Infectious Diseases Society of America, Surgical Infection Society, and Society for Healthcare Epidemiology of America for antimicrobial prophylaxis in surgery recommend intravenous (IV) cefazolin as the preferred prophylactic agent in neurologic surgeries, including craniotomies, and IV vancomycin or clindamycin for patients with a β-lactam antibiotic allergy.4 Cefazolin 2 g IV (can use 3 g IV if the patient weighs more than 120 kg) should be given within 1 hour prior to surgery; a single pre-operative dose is recommended for clean neurosurgical procedures. The Centers for Disease Control and Prevention specifically recommend against using formulations including ointments, solutions, and powders in the surgical incision for preventing SSIs because of an overall lack of evidence showing efficacy and safety with this practice.5 Even with the administration of prophylactic IV antibiotics prior to surgery, the rate of SSIs remain high following neurosurgeries. There are issues associated with using IV antibiotics, namely the inability of these agents to concentrate at the surgical site and their associated systemic side effects (eg, renal failure, hypersensitivity, ototoxicity).6 There is also an increasing prevalence of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) colonizing the skin in surgical patients, with estimates of nearly half of SSIs being due to this organism. Vancomycin powder, used topically and within surgical wounds, is an agent that is becoming increasingly popular to use in surgical infection prophylaxis. This agent can be concentrated at surgical sites, the risk of systemic absorption is minimal, and several studies have shown clinical efficacy and cost-savings associated with use of topical vancomycin in various surgeries. In spinal surgeries, vancomycin powder has been shown to decrease the incidence of SSIs from 4.7% to 0.7%, with similar benefits seen in cardiothoracic surgeries.
Spectrum of Activity and Additional Considerations for Use of Topical Vancomycin
The way that vancomycin exerts its bactericidal action is by inhibiting bacterial cell wall synthesis, altering cell membrane permeability, and modifying ribonucleic acid synthesis.7 Vancomycin has no activity against gram-negative species but is active against several gram-positive organisms such as Enterococcus species (including Enterococcus faecalis), Staphylococcus aureus (including MRSA), and Streptococcus species. Vancomycin powder is a crystalized form of vancomycin hydrochloride that is supplied in sterile vials.6 Administration of the powder varies depending on the site of surgery; for craniotomies this usually involves applying the powder directly to the bone flap in the subgaleal space. The pharmacokinetic parameters of topical vancomycin powder vary widely depending on the dose used, the site of the surgery, and the method of placement in the wound.8 Doses of topical vancomycin used in clinical studies of patients undergoing neurosurgical procedures that do not involve the spine have ranged from 0.5 to 2 grams. Patients in these studies are also frequently treated with pre- and post-operative intravenous (IV) antibiotics (usually cefazolin or ceftriaxone) in addition to topical vancomycin. Based on the benefits associated with localized application of vancomycin, high rate of SSIs attributed to MRSA, and efficacy of topical vancomycin for SSI prophylaxis in other types of surgical procedures, the purpose of this review is to summarize existing literature on the use of topical vancomycin in craniotomy in adults, which may help to inform its use for infection prophylaxis in these surgeries.
Summary of Evidence
Meta-analysis
In a meta-analysis published by Bokhari et al., literature assessing localized application of powdered vancomycin for SSI prophylaxis in non-spinal neurosurgical procedures was assessed and compiled.6 The authors identified 3 studies involving topical vancomycin in craniotomy specifically. The pooled data from these studies showed a lower risk for SSI among patients treated with topical vancomycin (odds ratio, 0.12; 95% confidence interval [CI] 0.03 to 0.45; p=0.002) compared to standard of care. The overall conclusion of this review was that although most of these studies showed a favorable effect on SSI incidence in patients treated with vancomycin powder in addition to standard of care, the evidence is not of high-quality and further randomized controlled studies need to be conducted to strengthen this body of evidence. The 3 individual studies included in this meta-analysis, Abdullah 20158, Ravikumar 20179, and Mallela 201810, and an additional study that has been published more recently, Jimenez-Martinez 202011, are described in detail in Table 1.
Prospective and Retrospective Studies
Three retrospective studies and 1 prospective study have been published looking at the use of intrawound vancomycin powder following craniotomy as infection prophylaxis.8-11 Demographics of patients were similar across studies, with the average age between 50 and 55 years. Standards of care were also similar across studies with all studies using IV cefazolin as the antibiotic of choice and all studies involving pre-operative skin preparation with an antiseptic. A dose of 1 g topical vancomycin powder was used in each study for the treatment group, with administration of the powder into the subgaleal space. Most studies showed a statistically significant decrease in the rate of SSI following craniotomy for patients that were treated with intrawound vancomycin powder as compared to patients only treated with the standard of care for infection prophylaxis. The study by Jimenez-Martinez11 also found significant improvements in the incidence of SSI among patients who received treatment which included topical vancomycin, but the study’s main intervention involved an entire care package and not just topical vancomycin compared to standard of care. Methicillin-susceptible Staphylococcus aureus was the infecting organism in all cases of SSI in the vancomycin group across studies and Streptococcus spp. and Propionibacterium acnes were the most common organisms causing infection in the control group across studies.8-11 The majority of these infections occurred in the post-hospitalization period following discharge. Patients were followed for a minimum of 3 months across all studies, with longer follow-up times used in Mallela 201810 and Jimenez-Martinez 2020.11 Limitations of these studies were similar in that they were not randomized or blinded, they were conducted at single hospital sites, and they included relatively small sample sizes, with only a few patients in each study developing SSI.
| Table 1. Overview of studies examining the use of vancomycin powder to reduce SSIs in craniotomy.8-11 | ||||
|---|---|---|---|---|
| Study design and duration | Subjects | Interventions | Results | Conclusions |
| Prospective studies |
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| Mallela 201810 Single center, prospective cohort study Patients were followed for a mean of 658 ± 29 days | N = 355 adult patients who underwent open craniotomy with a “clean” wound designation at the Hospital of the University of Pennsylvania between June 2013 and December 2015 | Control group (n=150): Standard of carea Vancomycin group (n=205): Standard of care plus 1 gram of vancomycin powder administered evenly in the subgaleal flap over the bone flap after the final wound irrigation prior to closure | SSI within 120 days of surgery significantly reduced with vancomycin (1 patient; 0.49%) vs control (9 patients; 6%); p=0.002 Sensitivity analysis: Difference in infection rates due to treatment cohort (p=0.016) and not the surgeon assigned to the patient (p=0.4829) No adverse events relating to the use of vancomycin occurred in any patient | The use of vancomycin powder in addition to the standard of care for infection prophylaxis in craniotomy reduces the incidence of postoperative SSIs. Limitations: Numerically variable baseline demographic differences (more patients with HTN, DM, and steroid use in control group; more patients with previous brain surgery in vancomycin group) |
| Retrospective studies |
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| Jimenez-Martinez 202011 Single center pre- and post-intervention study with a historical control 2-year follow-up | N=1017 adult patients who underwent a clean open craniotomy in a university hospital for adults in Barcelona, Spain Pre-intervention period: January 2013 to December 2015 Intervention period: January 2016 to December 2017 | Pre-intervention period (n=595): preoperative showering with chlorhexidine and hair removal; intraoperative skin prep with povidone iodine and IV cefuroxime prophylaxis prior to incision and every 3 hours thereafter; postoperative surgical wound drape and head washing/wound care Intervention period (n=422): Same as the pre-intervention period with the addition of intraoperative bone graft care, adding 1 gram of vancomycin powder to the subgaleal space prior to scalp closure, and more frequent and aseptic head washing and wound care techniques to the care bundle | Primary Incidence of SSI within 1 year after craniotomy was significantly reduced in the intervention period (3.5%) vs the pre-intervention period (15.3%); p<0.001 Majority of infections were at the organ-space in both treatment groups (73.6% in pre-intervention and 66.7% in intervention) Secondary Re-intervention rates were higher in the pre-intervention period (26.6%) vs the intervention period (19.2%); p=0.008 Readmission rates were significantly higher in the pre-intervention period (6.9%) vs the intervention period (2.1%); p=0.004 No difference in 30-day mortality or median length of hospital stay Full compliance rates with care bundles: 56.4% | The use of vancomycin powder as part of a care bundle intervention to prevent infection in craniotomy surgery significantly decreased the number of SSIs caused by Gram-positive organisms. These benefits were seen despite differences in preoperative wound care bundle compliance. Limitations: Pre-/post-intervention study design Multiple interventions added to the care bundle in the intervention period, thus making the true effect of topical vancomycin alone less clear |
| Ravikumar 20179 Retrospective, single center, pre- and post-intervention study Minimum of 3 month follow-up | N=350 adult patients who underwent open craniotomy at Stanford Hospital from 2011 to 2015 | Control group (n=225): Standard of careb Vancomycin group (n=125): Standard of care plus 1 g of powdered vancomycin applied following replacement of the bone flap or bone flap substitute | The development of SSI was significantly higher in the control group (5 patients) vs the vancomycin group (0 patients); risk difference of 5% (95% CI, 0% to 3.84%); p=0.046 No documented adverse events from the vancomycin treatment were seen in any of the patients | Topical vancomycin decreases SSI rate in patients undergoing craniotomy without increasing the risk for adverse events. Limitations: Pre-/post-intervention study design Short follow-up time |
| Abdullah 20158 Single center, retrospective cohort analysis Average follow-up duration: Control group: 287 ± 187 days Treatment group: 212 ± 143 days | N = 150 adult patients who underwent open craniotomy with a “clean” wound designation at the Hospital of the University of Pennsylvania between August 2011 and October 2013 | Control group (n=75): Standard of carec Vancomycin group (n=75): Standard of care plus 1 gram of vancomycin powder applied to the bone flap prior to wound closure | Primary The development of SSI was significantly higher in the control group (5 patients) vs the treatment group (1 patient); OR, 0.189 (95% CI, 0.02 to 1.67); NNT, 19; RRR, 81% Secondary Average vancomycin concentration from the wound drain: 499 µg/mL Serum concentrations: undetectable Average postoperative pH: Fluid from drain: 7.7 Fluid from sera: 7.45 | Subgaleal vancomycin powder reduces the incidence of SSIs in craniotomy. Serum and wound drain concentrations of vancomycin give evidence to the localized action of this agent with topical use. Limitations: Numerically variable baseline demographic differences (more patients with previous brain surgery and HTN in the control group) |
| aPreoperative skin preparation with topical chlorhexidine followed by Chloraprep and IV cefazolin 1 to 2 grams prior to surgery, then given every 8 hours for 2 doses post-surgery bPre- and post-operative IV ceftriaxone or cefazolin 1 g given 30 min before the incision. Patients with a penicillin allergy were instead treated with 1 g vancomycin IV cIV cefazolin 1 to 2 grams given within 30 min prior to surgery and then every 8 hours for 2 doses post-surgery (1 gram of IV vancomycin given before and after surgery for patients with a penicillin allergy) plus skin preparation with topical chlorhexidine followed by ChloraPrep Abbreviations: CI=confidence interval; DM=diabetes mellitus; HTN=hypertension; IV=intravenous; NNT=number needed to treat; OR=odds ratio; RRR=relative risk-reduction; SSI=surgical site infection |
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Cost-Analysis
In addition to decreasing SSI incidence, potential cost savings to the healthcare system is another important consideration. Two of the aforementioned studies also included a cost-benefit analysis of using intrawound vancomycin to prevent infections following craniotomy. The results of these cost analyses are summarized in Table 2 below. Both the prospective study by Mallela et al.10 and the retrospective study by Ravikumar et al.9 show an overall cost savings per patient in those treated with intrawound vancomycin prior to craniotomy versus those only treated with standard of care. These results take into account the predicted incidence of infection rate among treatment groups and estimated costs associated with SSI and vancomycin use.
| Table 2. Cost-benefit analysis for use of topical vancomycin to prevent SSI in patients undergoing craniotomy 9,10 | |||
|---|---|---|---|
| Study | Cost of 1 g topical vancomycin | Cost of SSI per patient | Estimated total cost savings |
| Ravikumar 20179 | $49.50 | $14,216 | $59,965 |
| Mallela 201810 | $2 to $12.00 | $24,853 | $1,357,400 (per 1000 patients) |
| Abbreviations: SSI=surgical site infection |
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Conclusion
Current guidelines regarding surgical infection prophylaxis from the Centers for Disease Control and Prevention do not recommend using topical/intrawound vancomycin because of a lack of strong evidence suggesting the safety and benefit of this practice. The existing literature, consisting of 1 meta-analysis, 1 prospective study, and 3 retrospective studies, suggest both a reduction and a cost benefit in SSI when using topical vancomycin as infection prophylaxis following craniotomy procedures. None of these studies were randomized, they were conducted at single centers, and sample sizes were relatively small, so larger, randomized controlled trials would lend better evidence to further support the use of topical vancomycin for SSI prevention in craniotomies. However, no adverse events were seen in these studies, which can most likely be attributed to the low systemic absorption of intrawound vancomycin. Based on the existing evidence, the addition of topical vancomycin powder to standard infection prophylaxis procedures for craniotomies may be associated with lower rates of SSIs, without additional associated adverse effects.
References
- Jiménez-Martínez E, Cuervo G, Hornero A, et al. Risk factors for surgical site infection after craniotomy: a prospective cohort study. Antimicrob Resist Infect Control. 2019;8:69. Published online May 2, 2019. doi:10.1186/s13756-019-0525-3
- Chiang HY, Kamath AS, Pottinger JM, et al. Risk factors and outcomes associated with surgical site infections after craniotomy or craniectomy. J Neurosurg. 2014;120(2):509-521. doi:10.3171/2013.9.JNS13843
- Shi ZH, Xu M, Wang YZ, et al. Post-craniotomy intracranial infection in patients with brain tumors: a retrospective analysis of 5723 consecutive patients. Br J Neurosurg. 2017;31(1):5-9. doi:10.1080/02688697.2016.1253827
- Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70(3):195-283. doi:10.2146/ajhp120568
- Berríos-Torres SI, Umscheid CA, Bratzler DW, et al. Centers for Disease Control and Prevention guideline for the prevention of surgical site infection, 2017. JAMA Surg. 2017;152(8):784-791. doi:10.1001/jamasurg.2017.0904
- Bokhari R, You E, Zeiler FA, et al. Effect of intrawound vancomycin on surgical site infections in nonspinal neurosurgical procedures: a systematic review and meta-analysis. World Neurosurg. 2019;123:409-417.e7. doi:10.1016/j.wneu.2018.10.168
- Micromedex Solutions. Truven Health Analytics, Inc; 2020. Accessed October 29, 2020. http://www.micromedexsolutions.com/
- Abdullah KG, Attiah MA, Olsen AS, Richardson A, Lucas TH. Reducing surgical site infections following craniotomy: examination of the use of topical vancomycin. J Neurosurg. 2015;123(6):1600-1604. doi:10.3171/2014.12.JNS142092
- Ravikumar V, Ho AL, Pendhakar AV, Sussman ES, Kwong-Hon Chow K, Li G. The use of vancomycin powder for surgical prophylaxis following craniotomy. J Neurosurg. 2017;80(5):754-758. doi:10.1093/neuros/nyw127
- Mallela AN, Abdullah KG, Brandon C, Richardson AG, Lucas TH. Topical vancomycin reduces surgical-site infections after craniotomy: A prospective, controlled study. J Neurosurg. 2018;83(4):761-767. doi:10.1093/neuros/nyx559
- Jiménez-Martínez E, Cuervo G, Carratalà J, et al. A care bundle intervention to prevent surgical site infections after a craniotomy. Clin Infect Dis. Published online June 28, 2020. doi:10.1093/cid/ciaa884
Prepared by:
Samantha Socco, PharmD
UIC PGY1 Pharmacy Practice Resident
December 2020
The information presented is current as of October 29, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.