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

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.

Recently, the Center for Disease Control (CDC) published its updated guidelines for
prevention of SSI prevention that included a recommendation regarding peri-operative
antibiotic prophylaxis. Based on their evaluation of the available literature, the CDC
recommended that a single dose of peri-operative antibiotics be utilized for patients
undergoing clean-contaminated surgical interventions, advocating for no prophylaxis after the
incision is closed in the operating room. This guideline encompasses surgeries where implants
are utilized, including arthroplasty, spine fusion, and fracture fixation. Furthermore, it
was classified as a category IA-strong recommendation with high quality evidence. However,
much of the literature cited for this recommendation is based on cardiothoracic, vascular,
and general surgeries, where few or no implants are utilized. It is important to recognize
that these surgical cohort may behave differently from the orthopaedic patient population in
terms of infection risk and severity of infection outcomes.

This clinical research protocol seeks to address the lack of knowledge and Level I data
around the optimal antimicrobial prophylaxis and to address the question if a single
preoperative dose is enough compared to additional postoperative prophylaxis. Several smaller
clinical studies have used pre- and post-intervention periods to assess the effect of
antibiotic duration for surgical prophylaxis. Tang et al launched a surgical wound infection
surveillance program to monitor all orthopaedic surgeries and changed the prophylactic
antibiotic regimen from intravenous cefuroxime (one preoperative and 2 postoperative doses
every 8 hours) to one single preoperative dose of intravenous cefazolin for all clean
orthopaedic surgeries. The authors of this study found no significant difference in the
superficial and deep wound infection rates in 1,367 primary arthroplasties performed with a
single preoperative dose of cefazolin versus 3 doses of cefuroxime. The deep wound infection
rate for THA was 1.1% (95% CI, 0%-3.3%) in the cefuroxime group and 1.1% (95% CI, 0%-2.2%) in
the cefazolin group (p=1.0). The deep wound infection rate of TKA was 1.6% (95% CI, 0%-3.8%)
in the cefuroxime group and 1.0% (95% CI, 0.3%-1.7%) in the cefazolin group (p=0.63).121 In a
retrospective review of 1,341 TJAs, Williams and Gustilo found no difference in deep
infection rates between a 3 day and 1 day course of prophylactic antibiotics, but emphasized
the importance of the preoperative dose, which was 2g of cefazolin. Mauerhan compared the
efficacy of a one-day regimen of cefuroxime with a 3-day regimen of cefazolin in a
prospective, double-blinded, multicenter study of 1,354 patients treated with arthroplasty
and concluded that there was no significant difference in the prevalence of wound infections
between the two groups.[34] In the group treated with primary THA, the prevalence of deep
wound infection was 0.5% (1/187) for those treated with cefuroxime compared with 1.2% (2/168)
for those who had received cefazolin. In the group treated with a primary TKA, the rate of
deep wound infection was 0.6% (1/178) for those treated with cefuroxime compared with 1.4%
(3/207) for those who had received cefazolin. Heydemann and Nelson, in a study of hip and
knee arthroplasty procedures, initially compared a 24-hour regimen of either nafcillin or
cefazolin with a 7-day regimen of the same and found no difference in the prevalence of
infection. They then compared a single preoperative dose with a 48-hour regimen and again
found no difference in infection prevalence. A total of 466 procedures was performed during
the 4-year study. No deep infections developed in either the one-dose or 48-hour antibiotic
protocol group. A deep infection developed in one (0.8%) of the 127 patients in the 24-hour
protocol group and in two (1.6%) of the 128 patients in the 7-day protocol group for an
overall infection rate of 0.6% (3/466). The authors recognized that as a result of the small
sample sizes, the study lacked the power to compare the one dose and the more than one dose
categories. In two trials, a total of 1609 patients were randomly assigned to receive 1.5 g
of cefuroxime intravenously every 8 hours for a total of 16 hours (n = 1511) or 24 hours (n =
98) postoperatively versus 1600 patients given no postoperative prophylaxis. Both studies
showed no difference between treatment groups suggesting that current available evidence may
not support the efficacy of postoperative antibiotic prophylaxis for the prevention of
surgical-site infections.

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.

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 pregnant

- 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

- No application of topical antibiotic powder such as vancomycin in surgical wound

- Intra-operative re-dosing other than specified re-dosing intervals or without
excessive blood loss (<1500mL)

- History of prior native septic knee arthritis

- No planned procedure within 90 days of surgery