The Treatment and Prophylaxis Usage Prole of Intravenous Vancomycin Medication in Orthopedics

Background: Despite vancomycin has been widely used in orthopedics, the details of vancomycin usage in orthopedics remains unknown. The purpose of the study was to evaluate the usage prole of intravenous vancomycin medication in orthopedics. Methods: The medical records of inpatients receiving intravenous vancomycin medication from January 2015 to December 2019 in a single center of orthopedics department were retrospectively reviewed. The gender, age, diagnosis, surgical information, microbiological data, duration of vancomycin medication were collected. The related data were analyzed and compared between subgroups. Results: A total of 258 cases receiving intravenous vancomycin medication ( ≥ 3 days) were enrolled. The mean age was 57.3 years. There were 141 cases in treatment and 117 in Prophylaxis group. The mean duration of vancomycin medication was 11.2 days. The duration was longer in Treatment than Prophylaxis group (14.8 versus 6.9 days, P<0.05). The main reasons for treatment were PJI after TKA (46.7%) and THA (18.2%) in Joint subgroup and SSI after spine surgery (51.5%) for Spine subgroup. For prophylaxis usage, the main reasons were postoperative clinical suspicious infection. The bacteria responsible for infections in Treatment group were S. epidermidis (34.6%), S. aureus (31.8%), other Staphylococcus (12.1%), MRSA (7.5%), Streptococcus (7.5%), Enterococcus faecalis (3.7%) and Bacillus (2.8%). Conclusion: Taken together, our research rstly revealed the treatment and prophylaxis usage prole of intravenous vancomycin medication in orthopedics. It provides the different purposes, main causes, bacteriological data and medication duration for treatment and prophylaxis vancomycin usage in orthopedics.


Background
Vancomycin is a glycopeptide antibiotic with bacteriostatic activity that has been used since the mid-1950s to treat Gram-positive bacterial infections [1]. Most clinicians use vancomycin for both empiric and de nitive therapy of serious infections as outlined in Infectious Diseases Society of America treatment guidelines [2]. Vancomycin has been regarded as the rst-line antibiotic in the treatment of S. aureus strains that produce penicillinase, especially for methicillin-resistant Staphylococcus aureus (MRSA) [3].
Vancomycin has been widely used in orthopedics because of the high incidence of device-associated infections and surgical site infection (SSI), which are especially di cult to treat since bacteria attach to the implant surface and form so-called bio lm colonies [4]. For the osteoarticular infections, Grampositive bacteria are much more frequently isolated than Gram-negative bacteria, and among Grampositive bacteria the proportion of staphylococcal strains was 74.2% [5], most of which are sensitive to vancomycin.
In order to prevent or treat the infection in orthopedics, vancomycin has often been the priority due to its wide coverage of the microbes most prevalent in SSI following spine and joint surgery [6]. However, the details of vancomycin use related with treatment and prophylaxis in orthopedic remain unknown. To evaluate the usage pro le of intravenous vancomycin medication in orthopedics, including the duration, bacteriological relevance, the current retrospective study was conducted.

Methods
We retrospectively reviewed the records of the inpatient population received intravenous vancomycin medication between January 2015 and December 2019 in orthopedics center.
Patients who received successive intravenous vancomycin medication for at least 3 days in the wards of orthopedic department were included. The following available information was collected retrospectively form medical records: gender, age, diagnosis, surgical information, microbiological data, duration of vancomycin medication. According to the purpose of vancomycin use and microbiological data, the cases was divided into Treatment and Prophylaxis subgroups. Treatment refers to medication for the cases of proven infection with positive bacteria culture or clinical de nite infectious disease without bacteria culture test or with negative bacteria culture. Prophylaxis refers to medication for cases of suspicious infection without bacteria culture test or with negative bacteria culture.
All the cases suffered from either joint or spine diseases in a single orthopedic department. According to the localization and type of the infection and disease, the cases were divided into Joint and Spine subgroups. According to whether there was bacteria (BAC) culture test, the cases were divided into BAC culture (+) and (-) subgroups. If the result of BAC culture was positive, it was de ned as BAC (+), otherwise BAC (-).

Statistical Analysis
Means and standard deviations were calculated for age, duration of vancomycin mediation. Differences between subgroups parameters were determined by the independent-sample T test. P ≤ 0.05 was considered as statistically signi cant. Statistical measures were performed using Statistical Package for Social Science (SPSS, 19.0).

Patients Population
The present study was composed of a group of 258 patients receiving intravenous vancomycin medication in a single orthopedic center (123 male and 135 female). The patients' characteristics are summarized in Table 1. The mean age was 56.3 years. There were 141 cases in Treatment group and 117 cases in Prophylaxis group. The mean age was 58.0 and 54.2 years for Treatment and Prophylaxis subgroups respectively. There were 137 cases in Joint group and 121 cases in Spine group. For all the medication was longer in Treatment than Prophylaxis group (14.8 versus 6.9 days, P < 0.05). The data of vancomycin medication duration for cases of Treatment group were shown in Table 2. For Prophylaxis group, there were 61 and 56 cases in Joint and Spine subgroups. There was no signi cant difference of duration between Joint and Spine subgroups (6.5 versus 7.3 days, P = 0.16). The mean duration of vancomycin medication was longer for cases with BAC culture (+) than BAC culture (-) in both Joint (7.9 versus 5.8 days, P = 0.0011) and Spine subgroups (8.4 versus 6.7 days, P = 0.0332). The data of vancomycin medication duration for cases of Prophylaxis group were shown in Table 3.

Discussion
Sixty years after its introduction into clinical practice, vancomycin continues to be recommended intravenously as a treatment for severe and complicated infections and is the most common antibiotic agent used against perioperative infections when no other antibiotic was available [7]. The implantassociated and SSI are among the most dreaded complications encountered by orthopedic surgeons, which are associated with increased length of hospital stay, decreased patient satisfaction, and increased morbidity and mortality [8]. All these reasons further popularized the usage of vancomycin in orthopedics.
The \infection related with orthopedic surgery cause high medical, economic, and social costs. In one study of 36 patients with SSI after lumbar fusion surgery, treatment of SSI required an average of 2.1 operations per patient, and a total of 1121 days of extra hospitalization [9]. The Gram-positive bacteria, especially Staphylococcus were the most frequent causes of these orthopedic-related infections. In many parts around the world, around 80% of S. epidermidis isolated from hospitalized patients are resistant to methicillin [10]. In addition, the low cost of vancomycin and easy accessibility than other antibiotics also makes it a very attractive option, especially in developing countries [11].
The current study revealed that the main reasons for the orthopedic patients receiving intravenous vancomycin treatment were postoperative SSI for treatment. For the prophylaxis purpose, the most common reasons focus in postoperative suspicious infection with clinical signs, such as incision problem, pyrexia, extreme increase of CRP and ESR. The eradication of infections in orthopedics often requires long-term therapy for a duration of intravenous vancomycin usage [8,12]. The mean duration of vancomycin medication was longer in Treatment than Prophylaxis group in our study.
Most of the spine and joint surgery are involved with biomedical implants, including spinal pedicle screw and joint prosthesis, which eases the development and progression of SSI. The SSI after spine surgery was the most common cause (51.5%) for vancomycin treatment medication in our study. According to a study involve a large group of more than 108,000 patients, super cial and deep SSI after spine surgery were found in 0.8% and 1.3% of patients, respectively [13]. A meta-analysis [14] revealed that the rates of S. aureus, S. epidermidis and methicillin-resistant Staphylococci for SSI after spine surgery were 37.9%, 22.7% and 23.1%, respectively. For genus level, the rates of Staphylococcus, Enterococcus, Streptococcus were 50.2%, 8.2% and 6.9%, respectively. Some authors also reported that the microbiology of SSI in spine surgery is predominantly S. aureus and S. epidermidis [15,16]. In the current study, for the cases in the Spine group, the infection was mostly due to S. epidermidis (37.0%), S. aureus (21.7%), and MRSA (8.7%).
Many reports have revealed that Gram-positive cocci, especially S. aureus and coagulase-negative staphylococci (CNS) were the most common infective organisms for PJI [17][18][19]. Empirical antibiotic treatment of early PJIs include coverage of vancomycin was recommended until de nitive culture results become available [20]. In a prospective cohort study of microbiologic epidemiology of PJI, the results revealed 28.9% of S. aureus, 28.6% of CNS, 14.1% of Enterobacteriaceae and 13.1% of streptococci [21]. In our research, the cases in Joint subgroup receiving vancomycin were mostly PJI after TKA and THA, followed by SSI after other joint surgery. These infections were mostly due to S. aureus (39.3%), S. epidermidis (32.8%) and MRSA (6.6%).
In the current study, S. epidermidis was the main cause for spine cases receiving vancomycin treatment, which was different from S. aureus responsible for joint cases. The microbiological results were consistent with previous reports related with PJI and SSI after spine surgery. In addition, the duration of vancomycin treatment was longer for MRSA than S. epidermidis (P = 0.03) and S. aureus (P = 0.14).
Empirical vancomycin treatment should be stopped when available culture results fail to reveal β-lactamresistant Gram-positive bacterial infections. So, it is regarded as inappropriate that the empirical vancomycin use is continued for a proportion of patients [22]. Misan et al reported that 97% of the patients receiving vancomycin for prophylaxis purposes were classi ed as inappropriate use [23].
No matter treatment or prophylactic medication, vancomycin, as an antibiotic, was used to achieve the ultimate goal of eradicating infection. For the certain infection, vancomycin was used for the purpose of treatment. However, for some clinical suspicious infection, it was also important and urgent to use vancomycin to prevent the infections and avoid serious consequences. Based on the HICPAC criteria, vancomycin use was documented to be treatment and prophylactic in 89.4% and 10.6% patients, respectively [11].
In the current study, 54.6% of the cases were for treatment and 45.4% were for prophylaxis. Prophylaxis medication should target the most common organisms for SSI in orthopedics, including S. aureus and S. epidermidis [24]. However, the bacterial culture may be negative in some infection cases. In 23.2% of patients with PJI, no bacteria were detected despite clinical suspicion of an infection [25]. Given the disastrous consequences of SSI following joint and spine surgery, vancomycin was still continued until the clinical sign of infection was alleviated.
There were also some limitations for the study. First, this was the retrospective study in single center with limited cases number. As for the investigation of drug usage, a large number of cases from multicenter could be more important and convincing. Second, as regard to the prophylaxis mediation of intravenous vancomycin in our study, some controversy maybe exist and need further analysis. A perfect monitor system could be set and maybe a good method to monitor and guide the standardized vancomycin use.

Conclusion
In order to prevent or treat the device-related and SSI, intravenous vancomycin is often used for the purpose of treatment or prophylaxis. Taken together, our research rstly revealed the treatment and prophylaxis usage pro le of intravenous vancomycin medication in orthopedics. It provides the different purposes, main causes, bacteriological data and medication duration for treatment and prophylaxis vancomycin usage in orthopedics. The studies of larger scale from multicenter are needed to better analysis and guide the rational vancomycin use. The main reasons for the cases receiving intravenous vancomycin medication in Treatment group.