Perioperative Antibiotic Prophylaxis in Patients Undergoing Elective Total Knee Arthroplasty: A Prospective, Randomized, Open-label, Controlled Multi-center Trial

Antibiotic Prophylaxis in Patients Undergoing Elective TKA- Multi-center Trial



Sponsors


Source

Duke University

Oversight Info

Is Fda Regulated Drug

Yes

Is Fda Regulated Device

No

Is Us Export

No


Brief Summary

The Antibiotic Prophylaxis in Patients Undergoing Elective Total Knee Arthroplasty (TKA):
Multi-Center Trial is a study that will compare the effectiveness of various perioperative
strategies for antibiotic delivery as prophylaxis for periprosthetic joint infections (PJI)
and surgical site infection in elective primary TKA. The investigators hypothesize that a
single dose of prophylactic antibiotic administered within 60 minutes before the incision is
not an effective way to prevent PJI in elective primary total knee arthroplasty (TKA). The
investigators also hypothesize that the prolonged delivery (24 hours) of antibiotic
prophylaxis after surgery does not further reduce the incidence of PJI in elective primary
TKA.

Detailed Description

Total joint arthroplasty (TJA), is one of the most successful operations in modern medicine;
however, it remains an expensive procedure in an era of constrained health care resources.
Arthritis affects 49.9 million Americans with 21.1 million experiencing
arthritis-attributable activity limitations. As these numbers are expected to increase
significantly by 2030, the demand for primary total knee arthroplasties (TKA) by 673% to 3.48
million procedures/year. Periprosthetic joint infection (PJI), with its disastrous
implications, continues to challenge the orthopaedic community. Practicing orthopaedic
surgeons continue to invest efforts to minimize surgical site infection (SSI). Kamath et al.
evaluated characteristics and resource utilization associated with revision arthroplasty for
PJI using the Nationwide Inpatient Sample. The authors found that PJI was the most common
indication for revision total knee arthroplasty (TKA), and the third most common reason for
revision total hip arthroplasty (THA). Prophylactic antibiotics aim to provide protection
against bacteria most likely to gain access to the surgical site during the procedure and in
the perioperative period. The two most common bacteria causing contamination and subsequent
deep infection in TKA are Staphylococcus aureus and coagulase-negative staphylococci.

While antibiotic regimens for antimicrobial prophylaxis might carry different risks and
side-effect profiles, e.g., hypersensitivity reactions (including anaphylaxis), acute kidney
injury, and Clostridium difficile infection, there are a number of studies which validate the
importance of the preoperative dose of antibiotics in decreasing periprosthetic joint
infection (PJI) and surgical site infection (SSI) in total joint arthroplasty (TJA). However,
there are conflicting opinions as to the optimal timing of this dose and the optimal
duration. The American Academy of Orthopaedic Surgeons (AAOS), the Centers for Disease
Control (CDC), and SCIP guidelines recommend that prophylactic antibiotics be completely
infused within one hour before the surgical incision. The US advisory statement recommends
that antimicrobial prophylaxis be administered within one hour before incision and
discontinued within 24 hours after the end of the operation, while European guidelines
recommend a single dose within 30 minutes before incision.

Antibiotics have been a critical public health tool since the discovery of penicillin in
1928, saving the lives of millions of people around the world. Today, however, the emergence
of drug resistance in bacteria is reversing the miracles of the past eighty years, with drug
choices for the treatment of many bacterial infections becoming increasingly limited,
expensive, and, in some cases, nonexistent. The Centers for Disease Control and Prevention
(CDC) estimates that drug-resistant bacteria cause two million illnesses and approximately
23,000 deaths each year in the United States alone. The Centers for Disease Control and
Prevention (CDC) estimates that drug-resistant bacteria cause two million illnesses and
approximately 23,000 deaths each year in the United States alone
(https://www.cdc.gov/drugresistance/). The National Action Plan for Combating
Antibiotic-resistant Bacteria provides a roadmap to guide the Nation in rising to this
challenge. Developed in response to Executive Order 13676: Combating Antibiotic-Resistant
Bacteria - issued by President Barack Obama on September 18, 2014 - the National Action Plan
outlines steps for implementing the National Strategy for Combating Antibiotic-Resistant
Bacteria and addressing the policy recommendations with regard to antibiotic stewardship as
outlined by the President's Council of Advisors on Science and Technology (PCAST). One of the
goals of the National Action Plan is the implementation of evidence-based infection control
practices can prevent the spread of resistant pathogens and questions the way surgeons use
prophylactic antibiotics in the preoperative period.

The scientific rationale for antibiotic prophylaxis is to inhibit or eliminate contaminating
microorganisms that gain access to the surgical site during the procedure. Thus, the goal of
administering preoperative antibiotics is to allow for adequate tissue (blood, soft tissue,
and bone) concentrations by the time of incision. Thus, these antibiotics should exceed the
minimum inhibitory concentration (MIC) for the organisms most likely to be encountered for
the duration of the operation. While the role of perioperative antibiotic prophylaxis is well
established, controversy exists about best clinical practice guidelines with regard to
antibiotic regimen and route of administration. The results of the proposed study will be
used to establish a clinical practice guidelines for antimicrobial prophylaxis in elective
total joint arthroplasty.

Overall Status

Not yet recruiting

Start Date

2017-10-01

Completion Date

2018-10-01

Primary Completion Date

2018-10-01

Phase

Phase 4

Study Type

Interventional

Primary Outcome

Measure

Time Frame

Rate of periprosthetic infection (PJI) as measured by chart review
90 day post-op

Secondary Outcome

Measure

Time Frame

Costs of antibiotic treatment as measured by costs summed over all patients and divided by group size
up to 1 year

Enrollment

8000

Conditions


Intervention

Intervention Type

Drug

Intervention Name


Description

Cefazolin will be administered intravenously within 30-60 minutes prior to skin incision in elective TKA for Group 1.
Cefazolin will be administered intravenously 30-60 minutes prior to skin incision in elective TKA and will be administered two (every 8 hours) weight based doses for 24 hours postoperatively for Group 2.

Arm Group Label

Study Group 1

Study Group 2


Other Name

Ancef


Eligibility

Criteria

Inclusion Criteria:

- Patient is ≥ 18 years of age

- Patient has no open wounds on operative leg

- Patient is scheduled to undergo elective total knee arthroplasty for posttraumatic,
osteoarthritis, avascular necrosis, and/or inflammatory arthritis

- Patient does not have active infection on the operative leg, the operative joint

- Patient is willing to cooperate and follow study protocol and visit schedule

Exclusion Criteria:

- Patient is ≤ 18 years of age

- Patient is unable to provide written consent

- Patient has psychiatric disorder that precludes safe study participation or that
necessitates confinement in a custodial environment at home or in a chronic care
facility

- Patient has traumatic injury that requires emergent or urgent total knee arthroplasty
(e.g. fracture)

- Patient has active infections in the operative leg/joint

- Patient has severe dementia

- Suspicion of illicit drug abuse by patient

- ASA score of 5 & 6

Gender

All

Minimum Age

18 Years

Maximum Age

N/A

Healthy Volunteers

No


Overall Official

Last Name

Role

Affiliation

Thorsten Seyler
Principal Investigator
Duke University

Overall Contact

Last Name

JaNell Wylie, MPH

Phone

919-660-5077

Email



Verification Date

2017-09-01

Lastchanged Date

2017-09-13

Firstreceived Date

2017-09-13

Responsible Party

Responsible Party Type

Sponsor


Has Expanded Access

No

Number Of Arms

2

Intervention Browse

Mesh Term

Anti-Bacterial Agents

Cefazolin

Antibiotics, Antitubercular



Arm Group

Arm Group Label

Study Group 1

Arm Group Type

Experimental

Description

Patients in Group #1 will receive a single weight-based dose of prophylactic cefazolin antibiotic that is administered intravenously within 30-60 minutes prior to skin incision in elective total knee arthroplasty. No further antibiotic administration will be given.
< 120 kg - patients will receive 2 grams of cefazolin
≥ 120 kg - patient will receive 3 grams of cefazolin
Patients with documented allergy/anaphylactic reaction to penicillin or cephalosporin may receive intravenous monotherapy with vancomycin 15mg/kg monotherapy as an alternative or dual therapy with vancomycin 15 mg/kg and gentamicin 1.5 mg/kg.


Arm Group Label

Study Group 2

Arm Group Type

Experimental

Description

Patients in Group #2 will receive a single weight-based dose of prophylactic cefazolin antibiotic that is administered intravenously within less than 30-60 minutes prior to skin incision in elective total knee arthroplasty. In addition, two (every 8 hours) weight-based doses of cefazolin will be administered for 24 hours postoperatively.
< 120 kg - patients will receive 2 grams of cefazolin
≥ 120 kg - patient will receive 3 grams of cefazolin
Patients with documented allergy/anaphylactic reaction to penicillin or cephalosporin may receive intravenous vancomycin 15 mg/kg monotherapy or dual therapy with vancomycin 15 mg/kg and gentamicin 1.5 mg/kg as an alternative. If allergic, patients will also receive two weight-based doses of vancomycin but not gentamicin postoperatively. Vancomycin schedule: one dose preoperatively, one dose 12 h postoperatively, one dose 24 h postoperatively.



Firstreceived Results Date

N/A

Overall Contact Backup

Last Name

Jennifer Friend

Phone

919-668-4373

Email



Firstreceived Results Disposition Date

N/A

Study Design Info

Allocation

Randomized

Intervention Model

Parallel Assignment

Primary Purpose

Treatment

Masking

None (Open Label)



ClinicalTrials.gov processed this data on September 14, 2017

Conditions

Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In ClinicalTrials.gov, conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions

Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied. Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase

Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions that study is seeking to answer:

In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.

In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.

In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.

These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.



© 2017 ICH GCP