Abstract
Purpose
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Surgical site infection (SSI) is a rare and serious complication of total knee arthroplasty (TKA), which causes a poor prognosis for patients. The purpose of this study was to explore the effect of intraosseous (IO) antibiotics in preventing infection and complications after TKA compared with intravenous (IV) antibiotics and to provide a certain theoretical basis for clinical treatment.
Methods
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The review process was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched the PubMed, Embase, Ovid, Web of Science, and the Cochrane Central Register of Controlled Trials databases about trials on IO antibiotics (into the proximal tibia before skin incision) to prevent infections in TKA from the respective inception dates to September 30, 2022. The infection occurred within 3 months after surgery. Both researchers individually screened the studies in accordance with the inclusion and exclusion criteria, performed the literature quality evaluation and data extraction, and used Stata 17 software for data analysis.
Results
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Five studies that enrolled 3801 patients were included in this meta-analysis. The results showed that IO antibiotics were effective in reducing the incidence of SSI (OR: 0.25, P = 0.001) and periprosthetic joint infections (OR: 0.16, P = 0.004) relative to IV. Moreover, the percentage of infection due to Gram-positive bacteria (OR: 0.18, P = 0.025) was reduced in the IO group compared with that in IV group, but Gram-negative bacteria levels were not significantly reduced (P = 0.14). There was no difference between the two groups for other systemic adverse effects of the drug.
Conclusions
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IO antibiotics in TKA are safe and effective alternatives to IV antibiotics. Large randomized clinical studies comparing infection rates and related complications with IO and IV antibiotics are required.
Introduction
Surgical site infection (SSI) is a rare and serious complication of total knee arthroplasty (TKA) that can cause a poor prognosis, reduce these patients’ quality of life, and significantly increase the financial burden. Therefore, preventing SSI is of great significance. In addition to strict sterile procedures to control artificial joint infections, the current consensus is to use intravenous (IV) antibiotics during the perioperative period. However, an evaluation of its effectiveness over the past decade has found that tissue concentrations for systemic antibiotic administration do not always meet the minimum inhibitory concentration (MIC) for effective prevention (1).
Intraosseous (IO) techniques were originally used for fluid resuscitation in pediatric patients, and it is currently used widely in adults as an alternative to vascular access in emergency situations. Young et al. pioneered the use of IO antibiotics in 2013, after the tourniquet was inflated and before scratching, and the patient received a local injection of antibiotics at the proximal tibia using injection needles. Using this method, the tissue concentration is significantly higher than the MIC requirements (2). If only one-quarter of the IV amount is used for perioperative IO antibiotics, the effective concentration in the local tissue is still greater than that after IV antibiotic use. Many scholars have also recently confirmed that IO can effectively reduce the incidence of infection after joint replacement surgery (3, 4), but others have found no statistical difference between IO and IV antibiotic administration (5). Because the incidence of SSI is relatively small, clinical research on the topic has shown ambiguous results and has been hampered by small sample sizes. Therefore, the purpose of this paper is to systematically review the literature to determine whether using IO antibiotics in joint replacement reduces the risk of local wound infection. We hypothesized that IO antibiotics would reduce the incidence of infection compared with that in the control group.
Methods
This meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (6). The protocol for this meta-analysis was registered on PROSPERO (registration no.: CRD42022362584).
Inclusion criteria
This study included randomized controlled trials (RCTs), cohort studies, or case–control studies. The study population comprised patients undergoing TKA. The intervention and control were IO antibiotics in the treatment group and IV antibiotics in the control group, respectively. The outcome indicator was a clear report of infection.
Exclusion criteria
The exclusion criteria were as follows: letters, case reports, reviews, animal trials, or republished studies; IO antibiotics were not used; patients with preoperative or pre-existing infection; studies lacking a control group; and a follow-up time of less than 3 months.
Outcomes
The primary outcome was to evaluate the effect of IO vs IV antibiotic prophylaxis against infections (SSI, superficial infection, periprosthetic joint infection (PJI), and infectious bacteria) in TKA. Secondary outcomes were to evaluate systemic complications such as acute renal injury (AKI) (defined for stage I as an increase of serum creatinine ≥0.3 mg/dL or 26.5 mmol/L) and red man syndrome (RMS) (defined as flushing, pruritus, spasm, or hypotension).
Search strategy
One of the authors (HYB) searched PubMed, Embase, Ovid, Web of Science, and the Cochrane Central Register of Controlled Trials databases from their respective inception dates to September 30, 2022. The following keywords were used: ‘topical’ and (’arthroplasty’ or ‘knee joint replacement’ or ‘knee replacement’). No language restrictions were applied during the search.
Study selection
Two researchers (XHL and JX) individually screened the retrieved literature against the inclusion and exclusion criteria. Based on reading the title and abstract, articles that met the inclusion criteria were read in full, and the included articles were identified. If these two researchers did not agree during the literature screening process, the decision was left to the senior researcher (HL).
Data collection process
The following relevant data were extracted from the included studies: author, country, sample size, vancomycin dose, and number of infections and reports of AKI and RMS.
Risk of bias and quality of evidence assessments
Two researchers (HLY and ZZ) independently assessed the quality of all included trials using the Cochrane risk-of-bias criteria (7). The Newcastle–Ottawa scale (NOS) was used to evaluate the literature quality of the retrospective studies (8). We also examined the quality of evidence for outcomes using the GRADE (grading of recommendations assessment, development, and evaluation) approach (9).
Data synthesis
The meta-analysis was performed using Stata (version 17; StataCorp, 2021) software. Heterogeneity was assessed by using the Q test and I2 value calculation. If heterogeneity was not present (P > 0.1 and I2<50%), the data were combined using a fixed-effects model. If heterogeneity was present (P < 0.1 or I2 >50%), the random-effects model was used. The odds ratio (OR) and the associated 95% confidence interval (CI) were used to assess outcomes, and a P value less than 0.05 defined that the difference was statistically significant.
Sensitivity analyses
We performed a sensitivity analysis by excluding the largest trial, excluding cluster randomized or quasi-randomized trials, excluding trials with high risk of bias, and using random-effects models.
Results
There were 766 trials identified (PubMed, 178; Web of Science, 197; Ovid, 198; EBSCO, 161; Cochrane Library, 26; and elsewhere, 6). After merging the various databases and removing duplicates, 457 articles were remained. Among these articles, 445 of them were excluded after reading the titles and abstracts. The remaining 24 articles were read in full, and 19 of them were excluded, among which 4 were short reviews, 5 were clinical trials without outcomes, 1 clinical trial a duplicate of another published article, and 3 were reviews. The other six articles mainly compared the concentrations in the surrounding tissues after IO antibiotics, and although two of the studies mentioned no cases of infection in either group, the article did not specify the follow-up time and the authors may have simply reported that no infection occurred during hospitalization. Thus, five studies were included in the meta-analysis, which were one RCT and four retrospective studies with 3801 patients enrolled among them. The flow diagram is shown in Fig. 1. In the included studies, Klasan et al. reported in the experimental group that a patient developed a joint infection 9 months after surgery (5). Because the patient had sepsis after doing aortic replacement surgery, which resulted in joint infection, we did not include this as an infection that was caused by joint replacement in our study. We did not include the results of Chin et al. with other retrospective studies as different assessments of bias in RCT studies and retrospective studies (10). The sample of Chin et al. was small, and we only explained the findings instead of using subgroup analysis. The study by Chin et al. found that the IO group did not decrease the occurrence of SSI, superficial infection, and PJI compared with the IV group. Information on all included studies is detailed in Table 1. The RCT study used Cochrane's bias evaluation to assess the quality (Fig. 2). Retrospective studies were evaluated using the NOS score and were of high technical quality (≥6 stars) (Table 2).
Flow diagram for search and selection of included studies.
Citation: EFORT Open Reviews 8, 3; 10.1530/EOR-22-0130
Risk of bias summary: review authors’ judgments about each risk of bias item for RCT.
Citation: EFORT Open Reviews 8, 3; 10.1530/EOR-22-0130
Characteristics of included studies.
| Study | Subjects, n | Age, mean ± s.d. | Design | Country | Surgery | Intervention | Definition of PJI | Duration, months | ||
|---|---|---|---|---|---|---|---|---|---|---|
| IO | Control | IO | Control | |||||||
| Chin et al. (10) | 22 | 66 | 63 | RCT | New Zealand | Primary TKA | IO vancomycin (500 mg) + IV cefazolin (2 or 3 g) | IV vancomycin (15 mg/kg dose) + IV cefazolin (2 or 3 g) | – | 6 |
| Harper et al. (11) | 248 | 67 | 67 | RCS | USA | Primary and revision TKA | IO vancomycin (500 mg) | IV vancomycin (15 mg/kg dose) | – | 3 |
| Klasan et al. (5) | 632 | 67.7 ± 8.2 | 68.7 ± 9.2 | RCS | New Zealand | Primary TKA | IO vancomycin (500 mg) + IV cefazolin | IV cefazolin | MSI criteria | 3 |
| Park et al. (3) | 993 | 67.43 ± 8.92 | 66.74 ± 8.87 | RCS | USA | Primary TKA | IO vancomycin (500 mg) + IV cefazolin (1 or 2 g) | IV vancomycin (15 mg/kg dose) + IV cefazolin (1 or 2 g) | MSI criteria | 3 |
| Parkinson et al. (4) | 1906 | 67 ± 9 | 67 ± 8 | RCS | Australia | Primary TKA | IO vancomycin (500 mg) or cefazolin (1 g) + IV or not | IV cefazolin (2 g) | MSI criteria | 12 |
IO, intraosseous; IV; intravenous; MSI, Musculoskeletal Infection Society; PJI, periprosthetic joint infection; RCS, retrospective cohort study; RCT, randomized control trial; TKA, total knee arthroplasty.
New Castle–Ottawa Scale ratings.
| Study | Selection | Comparability | Exposure/outcome |
|---|---|---|---|
| Harper et al. (11) | **** | ** | *** |
| Klasan et al. (5) | **** | ** | *** |
| Park et al. (3) | **** | * | ** |
| Parkinson et al. (4) | **** | ** | *** |
Effectiveness of IO antibiotics in preventing infection
All the five included studies mentioned an infection (3, 4, 5, 10, 11). Klasan et al. mentioned that two cases of superficial infection occurred (5), but the specific distribution in the study group was not specified. The author did not leave an email address, so we could not get in touch with them. Thus, we included this study only in the analysis of PJI but not for the overall infection rate. As Chin et al.'s study was an RCT, the results were not combined with other retrospective studies. The meta-analysis results showed that IO antibiotics were significantly more effective in reducing the incidence of TKA infection compared with IV antibiotics (OR: 0.25; 95% CI: 0.11–0.54; P = 0.001, I 2 = 10.8%, Fig. 3). Two studies mentioned superficial infection (one RCT and one retrospective case series) (10, 11). Due to the different types of studies in the two studies, we were unable to combine the results. The results of both studies showed that IO was not effective for superficial infections compared with IV. A total of five studies reported the occurrence of PJI (3, 4, 5, 10, 11). Since Chin et al.’s study is RCT and the result of PJI in Klasan et al. is double-zero, neither study was included in the calculation of OR. IO antibiotics were significantly more effective in reducing the incidence of PJI (OR: 0.16; 95% CI: 0.05–0.56; P = 0.004, I 2 = 0%, Fig. 4) in TKA patients compared with that in the IV group.
Forest plot of comparison: intraosseous vs intravenous antibiotics in preventing surgical site infection.
Citation: EFORT Open Reviews 8, 3; 10.1530/EOR-22-0130
Forest plot of comparison: intraosseous vs intravenous antibiotics in preventing periprosthetic joint infection.
Citation: EFORT Open Reviews 8, 3; 10.1530/EOR-22-0130
Effectiveness of IO antibiotics on infectious bacteria
Three studies described the types of bacterial infection (3, 4, 10). In Chin et al.'s study, no bacteria were detected between the two groups. When multiple bacteria were detected in the same patient, we divided the detected bacteria into Gram-negative or Gram-positive bacteria. We recorded the count up to one case per category, although sometimes it was possible that the same patient may be infected by multiple Gram-negative or Gram-positive bacteria. IO antibiotics were more effective in reducing the risk of Gram-positive bacterial infection compared with that of the control group (OR: 0.18; 95% CI: 0.04–0.81; P = 0.025; I 2 = 0%, Fig. 5). There was no statistically significant difference between treatment or control groups for the risk of Gram-negative bacterial infection (OR: 0.21; 95% CI: 0.03–1.69; P = 0.14; I 2 = 0%, Fig. 5).
The pooled analysis of infectious bacteria.
Citation: EFORT Open Reviews 8, 3; 10.1530/EOR-22-0130
Other complications
Three studies reported the occurrence of AKI and RMS after vancomycin use (3, 5, 10, 11). Since the result in Harper et al. is double-zero, we did not include in the calculation of OR. There was no statistically significant difference in the incidence of AKI after topical vancomycin use compared with that of the IV antibiotics control group (OR: 0.67; 95% CI: 0.32–1.38; P = 0.28; I 2 = 0%, Fig. 6). No RMS was reported in either group.
The pooled analysis of acute renal injury.
Citation: EFORT Open Reviews 8, 3; 10.1530/EOR-22-0130
Sensitivity analysis
A sensitivity analysis of the included studies was performed on a case-by-case exclusion basis. If any one study was excluded, the remaining studies were combined using the OR values. No study had a significant impact on the results.
Risk of bias
Considering the small sample size (<10 articles) in our meta-analysis, a funnel plot analysis was not applicable to determine the publication bias.
Discussion
Joint arthroplasty is an effective treatment for end-stage osteoarthritis, and it can correct joint deformities, reduce joint pain, restore joint function, and improve the patient’s quality of life. The main causes of survival and efficacy for the joint replacement prosthesis include poor force line of the lower extremities, infection, aseptic loosening of the prosthesis, and anterior pain (12). Among them, prosthetic infection is with an incidence rate of 0.69–2.2% (13, 14). Once infection occurs, it requires surgery and long-term use of antibiotics to be treated, and treatment failure is common. Given the difficulty of treating infections, preventing infections is preferable. Most infections after joint replacement are often caused by Staphylococcus aureus or coagulase-negative staphylococci (15). Therefore, patients undergoing joint arthroplasty require cefazolin for surgery-related antibiotic prophylaxis, and for patients with a history of allergies to penicillin or other β lactams, vancomycin or clindamycin can be used instead of cefazolin (16). However, studies have reported that with IO antibiotics, local antibiotic concentrations around the surgery area do not meet MIC standards and have a high rate of side effects (17). IO antibiotic use is a safe technique in TKA surgery, and the local concentration of antibiotics in bone after IO use is 5–15 times higher than that in the systemic dosing group, and only 1% of tissue samples have antibiotic concentrations of less than 2.0 mg/g, which is the MIC of methicillin-resistant Staphylococcus aureus strains (10, 18).
Previous studies have shown opposing results on whether IO antibiotics can reduce the incidence of PJIs. Klasan et al. retrospectively analyzed the relationship between IO antibiotics and PJIs in 634 TKA patients, and they concluded that IO antibiotics did not reduce the incidence of PJIs (5). Conversely, other scholars showed that IO antibiotics can reduce the incidence of PJIs (3, 4). Five articles were included in this meta-analysis, and the results showed that IO antibiotics can effectively reduce the risk of periprosthetic infection compared with that in the control group, whether for superficial infection or deep infection. Additionally, IO antibiotics are more effective than IV use to inhibit the risk of Gram-positive bacteria. In patients with joint replacement, the incidence of AKI ranges from 1% to 20%, and after IO use, the vancomycin concentration in the serum was lower than that of the venous concentration, and so it has less effect on renal function (19, 20, 21). However, our study found no difference in the incidence of AKI between the two groups. This may be due to the small sample size of the included studies, but it cannot be ruled out that IV and IO use have similar drug side effects. While IO use may reduce systemic adverse effects, it may increase the incidence of other related complications such as drug leakage and osteomyelitis. Local drug leakage appears later because IO antibiotics are applied deeper than IV antibiotics. The most common complication is drug leakage, which occurs in 12% of patients (21). If drug leakage occurs, compartment syndrome may also occur, leading to tissue necrosis or even amputation (22). These complications were not reported in the included articles, and there may be some reporting bias. Topical vancomycin powder application in the joint was reported to reduce the risk of infection, but it will increase local wound complications, such as delayed healing of the incision. The efficacy of topical and IO antibiotic use is an interesting topic that requires in-depth research in the future.
Limitations
Our study had the following limitations: first, some studies also used additional systemic antibiotics after IO antibiotics but others did not, which increased the heterogeneity and potential bias of this analysis. Young et al. (23) showed that IV administration can increase the antibiotic concentration in terminal tissues by less than 10%, and isolating IO and IO + IV cohorts will limit the ability to perform statistical analysis and increase the chance of statistical errors. Thus, all patients receiving IO ± IV prophylactic antibiotics were considered to be one group, and they were compared with a traditional cohort receiving IV prophylactic antibiotics only. Secondly, only one of the included articles used cefazolin IO application, and the rest used vancomycin. Perioperative antibiotic use standards indicate that two generations of cephalosporins are used first. Most patients in this study were treated with vancomycin, which is an unconventional medication that may bias the reported results. A later RCT study on the efficacy of cefazolin compared with that of IO and IV antibiotics should be performed. Third, different studies used different definitions of infection, and some studies did not describe a superficial infection. We counted the total infection rate that included superficial and deep infection, which may lead to measurement bias in the conclusion. Fourth, Klasan et al. mentioned two cases of superficial infection, one of which was a staphylococcal infection, but they did not specify the staphylococcal group (5). Thus, we did not include these data in the pooled analysis of the overall infection rate and bacterial infection. These data from Klasan et al. were included in deep infection, which may lead to a reporting bias in the results (5). Fifth, Park et al. showed that the 3 months follow-up rate was lower in the IO group compared with that in the control group (91.19% vs 95.8%) (3). This could potentially miss more infected knees in the IO group, which would strengthen the case for IV administration. Sixth, although our study included a total of five studies (one RCT and four retrospective studies), the sample of RCT was small, and our findings are based on four retrospective studies. We expect that additional large studies (including RCTs) will further certify our conclusions in the future. Seventh, Klasan et al. and Park et al. used antibiotic-containing bone cement during the TKA, which is a possible confounding factor for the result. Finally, we also look forward to more studies in the later stages to explore the efficiency of antibiotics added to bone cement, topical antibiotics compared with IO antibiotic applications, and different times of antibiotic administration between IV and IO.
Conclusion
Our study shows that the IO regional prophylactic antibiotics in TKA is a safe and effective alternative to IV administration. In addition, we call for additional large studies (including RCTs) to validate our views and expect studies to explore the interesting topic of different antibiotic use to prevent infections. Finally, our analyses shows that the method of IO regional antibiotics is effective in decreasing the risk of infection.
ICMJE Conflict of interest statement
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
Author contribution statement
All the authors contributed to the study conduction and design. H L designed the idea and prepared the first manuscript draft.
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