Clinical trial NCT03928522
Conditions: Total Knee Replacement
Sponsor: Washington University School of Medicine
Start date: 2019-01-28; Completion date: 2019-09-30
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to characterize and quantify the level of antibiotics eluted from antibiotic laden cement after primary cemented total knee arthroplasty.

Patients will be identified by medical record review to make sure they meet inclusion and exclusion criteria.

Patients that qualify and sign consent will be randomized to 1 of 4 antibiotic cement groups which are pre-mixed tobramycin, hand-mixed tobramycin, hand mixed vancomycin, and hand-mixed tobramycin and hand mixed vancomycin. Study patients will be blinded to their study group. Intraoperative fluid from the knee prior to surgery and postoperative drain fluid from the knee postoperatively will be collected as well.

Detailed description:
Patients will be identified by medical record review to make sure they meet inclusion and exclusion criteria.

Patients that qualify and sign consent will be randomized to 1 of 4 antibiotic cement groups which are pre-mixed tobramycin, hand-mixed tobramycin, hand mixed vancomycin, and hand-mixed tobramycin and hand mixed vancomycin. Study patients will be blinded to their study group. Intraoperative fluid from the knee prior to surgery and postoperative drain fluid from the knee postoperatively will be collected as well.

Arms: arm 1: patients will receive pre-mixed tobramycin cement arm 2: patients will receive hand mixed tobramycin cement arm 3: patients will receive hand mixed vancomycin cement arm 4: patients will receive hand mixed vancomycin and tobramycin
Interventions: intervention 1: hand mixed vancomycin intervention 2: hand mixed tobramycin intervention 3: pre-mixed tobramycin
Intervention descriptions: intervention 1: hand mixed vancomycin powder into cement intervention 2: hand mixed tobramycin into cement intervention 3: this cement is already pre-mixed with tobramycin

Protocol documents:
Prot_SAP_001.pdf: 
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Human Research Protection Office  
Box 8089 
(314)633-7400 
Fax (314)367-3041 
 
Prospective randomized study investigating the characterization of elution of antibiotics from 
antibiotic impregnated cement after total knee arthroplasty 
Principal Investigator:  
Charles Lawrie, MD 
 
 
Co-Investigators:  
Robert L. Barrack, MD  
Rick Wright, MD 
 
Study team members 
Venessa Riegler, BS 
Rondek Salih, MPH 
Toby Barrack, BS 
 
OVERVIEW 
 
Background information:  
Antibiotic cement is commonly used in primary total knee arthroplasty. It has mixed evidence for 
reducing infection rates after total knee arthroplasty. Some surgeons utilize pre-mixed antibiotic 
cement, while others hand mix the same dose of antibiotic into plain cement. The difference in 
antibiotic elution of pre-mixed versus hand-mixed antibiotic bone cement is unknown. The cost of 
hand-mixed cement is significantly less than that of pre-mixed cement. Therefore, investigating 
any difference between the two types of cement could potentially lead to enormous cost savings 
for the healthcare system. For cementless knees surgeons typically add an antibiotic to the knee 
prior to closing the incision to reduce infection.  
 
Additionally, prior studies have shown the majority of organisms causing infection after primary 
total knee arthroplasty are resistant to aminoglycosides, the major antibiotic class present in 
pre-mixed antibiotic cement. Vancomycin is an ideal antibiotic to use in antibiotic cement as it is 
heat stable and effective against the Staphylococcal species that commonly cause prosthetic joint 
infection after total knee arthroplasty. In-vitro analyses have shown vancomycin elution to be 
unpredictable from antibiotic bone cement. However, the addition of an aminoglycoside in similar 
studies have shown it to improve vancomycin elution in a synergistic manner. Therefore, we also 
seek to investigate the synergistic effect, if any, of vancomycin and tobramycin together on 
vancomycin elution rates after primary total knee arthroplasty with antibiotic laden cement. 


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Primary Hypothesis:  
The antibiotic elution profile will be the same for hand-mixed and pre-mixed antibiotic in 
polymethylmethacrylate bone cement. Tobramycin and vancomycin together will synergistically 
improve elution profiles of each other. The elution levels of vancomycin drained from the knee 
will be very minimal and is an effective way to reduce joint infections.  
Aim(s): 
1. Determine any difference in elution of antibiotic from pre-mixed and hand-mixed antibiotic 
cements with tobramycin 
2. Determine the synergistic effect, if any, of vancomycin and tobramycin together in 
antibiotic cement 
3. Determine the elution level of antibiotic from the knee in a cementless total knee 
arthroplasty 
 
Potential Contribution:  
The findings of this study will provide evidence for optimal antibiotic choice in antibiotic cement 
used in total knee arthroplasty, as well as determine the effect of using surgeon-mixed versus 
pre-mixed antibiotic cement on elution of antibiotics from the cement. The findings will also 
determine the effect of using antibiotic powder in the wound prior to closure in a cementless total 
knee arthroplasty. 
 
METHODS 
Timeline: 1 year 6 months (1 year of prospective enrollment and 6 months of data analysis.)   
 
Data analysis will begin after this study has received approval. Anticipated end date is January 
2020. 
 
Inclusion/Exclusion Criteria:   
1. Age over 18 
2. Total knee arthroplasty for primary osteoarthritis performed by Dr. Rick Wright and Dr. Charles 
Lawrie and Dr. Robert Barrack.  Primary diagnosis of knee osteoarthritis 
 
Exclusion criteria: 
1. Diminished mental capacity 
2. Vancomycin allergy 
3. Tobramycin allergy 
4. Chronic kidney disease stage III and stage IV 
 
Recruitment:  
We will be identifying patients from the clinical practice of Dr. Rick Wright and Dr. Charles 


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Lawrie and Dr. Robert Barrack.  
 
Design:  
This study is a prospective, randomized, study designed to characterize and quantify the level of 
antibiotics eluted from antibiotic laden cement after primary cemented total knee arthroplasty and 
the level of antibiotics eluted from the knee after cementless total knee arthroplasty 
The study will collect intraoperative fluid postoperative intraarticular drain fluid from the total 
knee arthroplasty the day after surgery. The fluid being used for the study is fluid that is drained 
after surgery and discarded. Data collected will permit clinical evaluation of antibiotic cement 
types as they pertain to total knee arthroplasty knee pre-operative and postoperative. This study 
will collect implant-related or possibly implant-related adverse events. Data collected will include 
the following: Patient demographics (age, gender, BMI), implant and surgical information, 
medical comorbidities and intraarticular findings. Each eligible participant will be required to 
execute written informed consent and covers the provisions of this study.  
Number of participants: We propose to enroll 58 participants. A randomization schedule will be 
determined at the initiation of the study for assigning the first 24 patients to one of four antibiotic 
cement study groups, we will then review and proceed with a randomization schedule for the next 
24 patients to one of four antibiotic cement study groups: 
Pre-mixed tobramycin 
Hand-mixed tobramycin 
Hand-mixed vancomycin 
Hand-mixed vancomycin and hand-mixed tobramycin 
 
Enrollment will provide 1:1:1:1 study group ratios 
The study patients will be blinded to their study group. The surgeons and study personnel will not 
be blinded to study group. 
10 patients will be in the cementless group. 
Data collection: 
Data collection for prospective patients will occur preoperatively and postoperatively.  
 
Data analysis: 


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A student t-test will be used to compare means and standard deviations between study groups for 
the variable which this test methodology is appropriate. Descriptive statistics will be used to 
analyze the subjective data points such as AEs. Analysis methods will be further discussed during 
data and publication review meetings. We will be doing analysis at pre-operative, intraoperative 
and postoperative. An independent statistician, independent of the study team and the orthopedics 
department will analyze the data.  
 
Procedures:  
The study will collect intraarticular drain fluid from the total knee arthroplasty the day after 
surgery. There will also be a chart review. 
 
INFORMED CONSENT 
Enrollment and consent will begin in the clinics of Dr. Rick Wright and Dr. Charles Lawrie The 
treating surgeon will identify patients who are determined to be candidates for primary TKA, and 
who generally meet the study requirements.  
 
The consent process will occur by one of the following means:  
 
1) The study coordinator will meet with each potentially eligible participant to review the study 
requirements (including additional screening for eligibility) and answer any questions the patient 
may have.  
 
If the patient has any clinical questions that cannot be answered by the study coordinator they will 
be answered by the physician or the physician's nurse. The patient will have the opportunity to 
review the consent form, discuss with family/friends, and do his/her own research on the subject if 
desired. Qualified patients who agree to participate in the study will be required to sign an 
Informed Consent Document. Valid enrollment is not granted until after surgery, once it has been 
verified that the participant has had total knee surgery. 
 
2) The consent discussion and review of the Informed Consent Document may occur over the 
phone. In this case, the study coordinator will call the patient to present the study to the participant 
and gauge interest in participation. If the patient expresses interest in participation, the study 
coordinator will e-mail, mail or fax the Informed Consent Document to the participant. The patient 
will be given the opportunity to ask questions. If the patient has any research questions beyond the 
scope of the study coordinator, arrangements will be made for the participant to speak with the 
applicable member of the research team, including the PI. After review of the Informed Consent 
Document, the participant will sign the applicable sections of the Informed Consent Document and 
mail or fax the consent for back to the study coordinator. The Informed Consent Document will be 
signed by the consenting study coordinator upon receipt. Valid enrollment is not granted until after 
surgery, once it has been verified that the participant applicable member of the research team, 
including the PI. After review of the Informed Consent Document, the participant will sign the 
applicable sections of the Informed Consent Document and email, mail or fax the consent for back 
to the study coordinator. 
 


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PROCEDURES FOR MAINTAINING CONFIDENTIALITY 
Data Security:  
Protection of confidentiality by the Washington University Coordinating Center will be maximized 
by use of (a) protected and secured data collection, (b) password protected access to data storage, 
and (c) access to patient data limited to the study coordinator or his designate.  
 
ASSESSMENT OF RISKS AND BENEFITS 
Risks 
A potential risk of accidentally disclosing information regarding Washington University patients is 
possible though unlikely. 
Benefits 
The findings of the study will identify areas for improvement in antibiotic choice used for total 
knee arthroplasty and comparing different types of antibiotic cement used in total knee 
arthroplasty.   
 
 
REFERENCES 
 
1. Murray J. Penner MD, BSc, Bassam A. Masri, MD, FRCS(C), Clive P. Duncan, 
MD, MSc, FRCS ( C) (1996) Elution characteristics of vancomycin and 
tobramycin combined in acrylic bone-cement The Journal of Arthroplasty 1996 
Dec;11(8):939-44 
2. Konstantinos Anagnostakos, Jens Kelm (2009) Enhancement of antibiotic elution 
form acrylic bone cement Journal of Biomedical Materials Research Part B: 
Applied Biomaterials 2009 Jul;90(1):467-75, doi:10.1002/jbm.b.31281 
3. Brien WW, Salvati EA, Klein R, Brause B, Stern S(1993) Antiobiotic impregnated 
bone cement in total hip arthroplasty. An in vivo comparison of the elution 
properties of tobramycin and vancomycin Clinical Orthopedics and Related 
Research Nov;(296):242-8 
4. Gonzalez Della Valle A, Bostrom M, Brause B, Harney C, Salvati EA (2001) 
Effective bactericidal activity of tobramycin and vancomycin eluted from acrylic 
bone cement Acta Orthopaedica Scandinavica 2001 Jun;72(3):237-40 
5. Paloma Anguita-Alonso MD, Arlen D Hanssen MD, Douglas R. Osmon MD, 
Andrej Trampuz MD, James M. Steckelberg MD, Robin Patel MD (2005) High rate 
of aminoglycoside resistance among staphylococci causing prosthetic joint 
infection Clinical Orthopaedics and Related Research 2005 Oct;439:43-7 
6. Gregory Vrabec MD, FRCS, Willis Stevenson MD, Sameh Elguizaoui MD, 
Matthew Kirsch MD, John Pinkowski MD (2016) What is the intraarticular 
concentration of tobramycin using low dose tobramycin bone cement in TKA: An 
in vivo analysis  Clinical Orthopaedics and Related Research 2016 
474:2441-2447 doi 10.1007/s11999-016-5006-x