Comparison of intraosseous and intravenous Vancomycin in Total Knee Arthroplasty - A Randomised Controlled Trial

Introduction:

When undergoing total joint replacement surgery, antibiotic against methicillin-resistant staph

aureus (MRSA) is vancomycin, which is a frequently used prophylaxis. According to recent

research, intraosseous (10) infusions can deliver systemic levels comparable to subjects where

intravenous (IV) access was used. Thus, many surgeons started to think about intra osseous

infusions as a better option to deliver prophylactic surgical antibiotics. Low-dose intra osseous

vancomycin produced concentrations in tissues that were on par with or better than those of

systemic administration, according to a prospective randomised research conducted in

Australia that compared the local and systemic concentrations of the antibiotic following intra

osseous versus intra venous administration. According to the authors, intra osseous route

maximises the vancomycin delivery duration, and may lessen the possibility of adverse systemic

effects due to the reduced dosage while offering equal or enhanced prophylaxis in total knee

replacement (TKR). Even patients with a higher BMI has similar benefits as shown in literature.

intra osseous infusions have demonstrated good efficacy in improving antibiotic tissue

concentrations at the surgical site with decreased systemic concentrations and reduced

infection rates in primary TKR. Park et al. did a study and stated, patients who received

antibiotics intraoperatively (IO) had significantly reduced incidence of periprosthetic joint

infections (PJI) at 90 days after surgery compared to those subjects who got intra venous

antibiotics. Nevertheless, the use of intra osseous vancomycin in total knee replacement (TKR)

has not been examined in any research. This randomised prospective single-blinded control

study aims to assess the safety and effectiveness of antibiotic distribution during TKR and

determine whether intra osseous methods are a practical option for vancomycin administration

prior to the surgery.

Rationale of the study supported by cited literature:

Rationale of this study is to demonstrate the utility of intra osseous vancomycin over Intra

venous Vancomycin in primary TKR with improved local tissue concentration and decreased

systemic concentrations. With positive findings, intra osseous route may be considered for

alternative procedures for antibiotic delivery.

Hypothesis: decreased serum vancomycin levels is expected when intra osseous vancomycin is

administered at both the start of the procedure and also at the end of the procedure. All local

tissue samples are expected to have higher concentrations of vancomycin when intraosseous

vancomycin is administered.

Research questions: to determine if any difference exists between the concentration of

antibiotic administered by intraosseous or oral route in patients undergoing total knee

replacement

Aims and Objectives:

Aim - To determine the serum and tissue concentration of intra osseous vancomycin and IV

Vancomycin in primary TKA

Objectives -

1. To measure serum vancomycin levels and compare intra osseous to IV vancomycin at both

the start of the procedure and also at the end of the procedure

2. To measure vancomycin levels in local tissue samples and compare intra osseous to IV

vancomycin

Detailed methodology:

After a patient was randomly assigned to one of the two subject groups, the remaining protocol

followed the same steps. During the trial period, both groups receive weight-based

preoperative IV cephazolin in order to ensure adequate preoperative antibiotic compliance in

the event that the intervention group is not successful.

Group 1: Following the incision, the intervention group will get an intra osseous injection of

vancomycin into the femur and tibia’s medial condyles (prior to capsulotomy). Subsequently,

the surgery will proceed according to the operating surgeon’s protocol. All patients will have

the same samples obtained during the operation.

Group 2: Before the procedure, an IV injection of vancomycin will be administered to this

group, and their levels will be evaluated in a similar manner.

Serum vancomycin levels are assessed by drawing blood samples following incision (prior to

capsulotomy) and at the beginning of closure. During the case, soft tissue samples are obtained

from the following areas: the infrapatellar fat pad, the suprapatellar synovium, the medial and

lateral meniscus, and the ACL. Samples of bone are obtained from the distal femur and

proximal tibia cuts, as well as intramedullary bone obtained following the establishment of a

canal. Vancomycin levels are reported in these samples.

Sample Preparation

Samples will be weighted and minced after collection. To digest the materials, 20 mg/ml of

collagenase I in PBS will be employed (overnight at 36 °C).

Phosphate buffered saline (PBS) will be used to prepare the working solution (1 mg/ml) and

stock solution (10 mg/ml) of vancomycin (VANC). The preparation of calibration standard

solutions will involve serial dilution using PBS. The calibration standard solutions will have final

concentrations of 500, 250, 125, 62.5, 31.25, 15.63, and 7.81 mg/L. Ultimately, a homogenizer

is used to homogenise the samples.

In the vial containing the digested sample, caffeine is added as an internal control at a final

concentration of 2 mg/ml. The various samples will be centrifuged for five minutes at 15,000

rpm, and the supernatant will be collected and filtered before being injected into the HPLC

apparatus.

Phosphoric acid is used to alter ph. At room temperature, isocratic separation will be

performed using a flow rate of 0.36 ml/minute and UV detection at 205 nm. Every sample has a

25-minute run time. Vancomycin’s distinctive elution peak occurs at minute 11, whereas the

internal standard, caffeine, has an elution peak at minute 20

Inclusion criteria:

Any subject more than 18 years of age who is undergoing a primary TKR for osteoarthritis and

given consent for the procedure.

Exclusion criteria:

Past knee surgery (including knee scopes), allergy, patients with bleeding disorder and

immunocompromised and/or immunosuppressed patients (HIV, Hepatitis B/C, end stage renal

disease (ESRD), post-transplant, chemotherapy or radiation therapy, medications which are

immunomodulating).

Data analysis plan:

Age, surgery date, date of discharge, sex, side operated, Adverse local and systemic reaction,

30-day and 90 day complication, time from antibiotic administration to incision, and surgery

time were recorded.

Review of literature:

Harper et al demonstrated the efficacy and utility of intraosseous delivery of vancomycin in

patients of primary Total hip replacement with improved local tissue concentration and

reduced systemic concentration[1]

Both increased concentrations in tissues and reduced systemic concentrations of antibiotics are shown in

previous studies performed exclusively within total knee replacement patients [[2], [3], [4]]. Studies have

shown reduced systemic complications and infection rates due to these concentrations [5,6]. Study done by

Young et al demonstrated that deflated torniquet in total knee replacement patients had increased

concentrations within the tissues [3].

Administration of antibiotics 1 hour prior to incision has shown to decrease surgical site infections [7]. In

patients allergic to penicillin, those with MRSA colonisation and those considered high risk for infection,

antibiotic prophylaxis of choice is Vancomycin [7,8]. However, multiple studies has shown that a large

population who receive vancomycin as a preoperative antibiotic are underdosed based on their weight

or the dose received is incomplete [8,9]. Feder et al did a study and showed that patients who were

readmitted for infection concern and diagnosed as PJI recieved vancomycin prophylaxis <30 minutes

from incision time [8]. Incomplete administration of the appropriate dose was the cause in majority.

Kheir et al did a study and concluded that patients had increase risk of developing MRSA PJI who

received a standard 1g of vancomcyin (rather than a weight-based dose) and therefore underdosed [9].

A study by Pai et al showed obese patients are at higher risk for underdosing and thus carry with them

higher baseline infection risk [10].

The delivery of vancomycin using IO infiltration has shown statistically significant increase in tissue

concentrations above IV in all locations including bone, therefore the risk of underdosing patients will

be decreased. [7]

The relevance and expected outcome of the proposed study:

1 Decreased serum vancomycin levels is expected to be seen when comparing intra osseous to

IV vancomycin at both the start of the procedure and also at the end of the procedure. All local

tissue samples are expected to have higher concentrations of vancomycin in the intra osseous

group. A significant increase levels is expected to be present within the bone samples.

Details of funding sought: non funded project

Timelines: data collection - 6 months, data analysis and interpretation - 1.5 years

References

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