Daptomycin Use for Antimicrobial Prophylaxis in Methicillin Resistant Staphylococcus Aureus (MRSA) Colonized Adult Patients Undergoing Primary Elective Hip, Knee, or Shoulder Arthroplasty

This is a phase 4 randomized open label prospective pilot study comparing the use of
daptomycin versus vancomycin for peri-operative antibiotic prophylaxis in patients
undergoing elective primary knee, hip or shoulder arthroplasty and are at risk for infection
with methicillin resistant Staphylococcus aureus. The study population will include males
and non-pregnant, non-lactating females 18 years of age or older, with history of
methicillin-resistant Staphylococcus aureus infection or colonization, and undergoing
primary elective hip, knee or shoulder arthroplasty. The target enrollment is 100 patients,
who will be randomized to daptomycin or vancomycin in two 50 patient study groups. After
signing the informed consent, patients will undergo pre-enrollment nasal screening for
methicillin resistant Staphylococcus aureus to identify eligible patients. Patients with
positive MRSA nasal screen will proceed with enrollment and get randomized into one of the
two study groups. In one group, patients will receive one dose of daptomycin 6 mg/kg to be
infused over 30 minutes. In this group, the infusion should be started and completed within
60 minutes of surgical incision. In the second group, patients will receive one dose of
vancomycin 15 mg/kg to be infused over 1-2 hours of surgical incision according to the dose
to avoid red man syndrome. In this group, the infusion should be started and completed
within 120 minutes of surgical incision. After surgery, a second similar dose
of vancomycin will be given 12 hours after the first dose to patients with creatinine
clearance (CLcr.) of ≥50 ml/min. All patients in both groups will be asked to shower with
chlorhexidine skin cleanser (HIBICLENS®) once daily from the neck down for 7days before
surgery and apply Mupirocin ointment 2% to their nostrils twice daily for 5 days before
surgery.

The patients will be evaluated on the day of surgery, at 2-3 days postoperatively, on
discharge, at one month and three months follow up visits. During these study evaluations,
patients will be assessed clinically for signs and symptoms of wound, and prosthetic joint
infection (including pain, tenderness, swelling, erythema, poor wound healing and wound
drainage) prior to hospital discharge, and at one, and three months follow up visits. Blood
work including complete blood counts, erythrocytic sedimentation rate, c-reactive protein,
and cultures will be ordered if clinical findings suggest infection. Bacterial isolates
causing infections will be tested locally for antibiotic susceptibilities including
daptomycin and vancomycin and saved for further testing if needed. Adverse effects and
tolerability will be documented with the use of both drugs in the two patient groups. Data
will be collected and analyzed with appropriate testing. The primary endpoint will be the
success in prevention of postoperative SSI and prosthetic joint infection at one month
postoperative follow up visit.

Inclusion Criteria:

- Signed, and dated informed consent as defined by the Institutional Review Board.

- Male and female patients older than 18 years of age undergoing primary elective hip,
knee or shoulder arthroplasty.

- Documented nasal carriage of MRSA.

- If a female of childbearing potential the patient should agree to practice a reliable
contraceptive method (e.g. birth control pills, condoms, or intrauterine device
[IUD]) during treatment and for one month after receiving the study medication.

Exclusion Criteria:

- Concurrent urinary tract infection or colonization unless treated with evidence of
microbiologic cure.

- Evidence of active infection elsewhere other than urinary tract, unless treated with
evidence of microbiologic cure documented by the infectious diseases service.

- Patients undergoing elective secondary arthroplasty.

- Concurrent open wounds

- Pregnant and nursing women (if patient is still of childbearing potential, a negative
serum pregnancy test will be confirmed).

- History of allergy or contraindication to study drugs.

- Weight >150 kg or <50kg

- Patients with creatinine clearance (CLcr) < 30ml/min (calculated using the
Cockcroft-Gault equation using ideal body weight)

- Severe neutropenia (absolute neutrophil count <0.500x103 /µl).

- Patients considered unlikely to comply with study procedures or to return for the
scheduled post treatment evaluation.

- Ongoing antibiotic therapy for active infection that is anticipated to continue until
the day of surgery.

- Any other condition that in the opinion of the investigator, would confound or
interfere with evaluation of safety or efficacy of the investigational medication, or
prevent compliance with the study protocol.