Treatment Algorithm to Reduce the Use of Vancomycin in Adults With Blood Stream Infection

To demonstrate that the clinical efficacy of algorithm-based therapy of patients with
staphylococcal blood stream infection is noninferior to current standard of care.

PP (per protocol) population: randomized patients EXCLUDING those that: Received a PENS
antibiotic -Did not undergo removal of intravascular catheter suspected to be infected. Note
that patients with simple CoNS bacteremia may retain the catheter; all other patients should
have their catheter(s) removed. -Had blood stream infection with a vancomycin-resistant
staphylococcus; or a staphylococcus resistant to protocol-identified alternative drugs if
these were used -Discontinued study medication prematurely for reasons other than clinical
failure -Did not undergo final TOC assessment -Did not comply with all Patient Inclusion
Criteria -Violated any Patient Exclusion Criteria

- Died within 3 days of randomization

- Were classified as non-evaluable

PPE Population: Patients from the PP population who did not have complicated staphylococcal
infection.

Inclusion Criteria:

1. Provide signed and dated informed consent. The patient's legally authorized
representative (LAR) can provide a signed informed consent for the patient if allowed
by local Institutional Review Board/Ethics Committee (IRB/EC) policy.

2. Is ≥ 18 yrs of age.

3. If the subject has an intravenous catheter in place then the subject and his/her
primary health care provider must agree to have the catheter removed within 5 days of
the initial blood culture draw with the exception of those subjects who meet criteria
for simple CoNS bacteremia as defined in Table 1. The catheter may be retained in
those subjects with simple CoNS bacteremia.

4. Has blood stream infection defined as at least one blood culture positive for S.
aureus or CoNS. In most cases, vancomycin(or other study drug alternative) will have
been started prior to randomization. Enrollment windows depend on speciation and
clinical classification as follows:

1. identification of CoNS and classification as simple per Table 1-must be
randomized within 3 calendar days of the start of treatment effective for the
baseline infecting pathogen

2. identification of CoNS and classification as uncomplicated per Table 1 must be
randomized within 4 calendar days of the start of treatment effective for the
baseline infecting pathogen

3. identification of S. aureus - must be randomized within 12 calendar days of the
start of treatment effective for the baseline infecting pathogen

5. This criterion has been removed

6. Women of child bearing potential must have a negative urine and/or serum pregnancy
test.

7. All patients of reproductive potential must be abstinent or agree to use
double-barrier contraception while receiving study (algorithm based or Standard of
Care) therapy.

Exclusion Criteria:

1. Has known or suspected new complicated staphylococcal infection at the time of
enrollment.

2. Weigh ≥ 200 kg.

3. Has non-removable intravascular foreign material at the time a positive blood culture
was drawn (e.g., intracardiac pacemaker or cardioverter/defibrillator wires,
hemodialysis access grafts, cardiac prosthetic valve, valvular support ring).
Exception: coronary stents, inferior vena cava (IVC) filters in place > 6 weeks,
patients with pacemakers whose baseline infecting pathogen is a CoNS, vascular stents
in place for > 6 weeks, non-hemodialysis grafts in place >90 days and hemodialysis
grafts not used within past 12 months and not previously infected are eligible for
randomization. Arthroplasties and other extravascular devices, e.g. synthetic hernia
repair mesh, and non-arthroplasty orthopedic prostheses including pins or plates, are
acceptable as long as there are no signs or symptoms of foreign material-related
infection at the time of randomization.

4. This criterion has been removed

5. Has a moribund clinical condition such that there is a high likelihood of death or
cardiac surgery during the next three days.

6. Has shock or hypotension (supine systolic blood pressure < 80 mmHg) or oliguria (urine
output < 20 mL/h) unresponsive to fluids or pressors within four hours.

7. Has received an investigational antibacterial agent with anti-staphylococcal activity
within 30 days prior to randomization.

8. Has a documented history of significant allergy or intolerance to all
protocol-approved antibiotics anticipated to be effective for their infection.

9. Has an infecting pathogen with confirmed reduced susceptibility to vancomycin (Minimum
Inhibitory Concentrations (MIC) > 2 µg/mL) if known. Note: If reduced susceptibility
to vancomycin is discovered after enrollment, the patient will be treated with
daptomycin (if pathogen is susceptible). Patient will remain in study as appropriate
and be evaluated in the Intent to Treat (ITT) analysis, but will be excluded from
Protocol Population (PP) analyses.

10. For S. Aureus patients, is severely neutropenic (absolute neutrophil count <
0.100x103/mm3) or is anticipated to develop severe neutropenia (absolute neutrophil
count < 0.100x103/ mm3) during the study treatment period due to prior or planned
chemotherapy. CoNS patients with neutropenia are eligible to be enrolled.

11. This criterion has been removed

12. Has previously known Human Immunodeficiency Virus (HIV) infection with a nadir CD4+
count of <100 cells/mm3 within the past 12 months

13. Is considered unlikely to comply with study procedures or to return for scheduled
post-treatment evaluations.

14. Is pregnant or trying to get pregnant, nursing, or lactating.

15. Has known or suspected septic arthritis, osteomyelitis, pneumonia or other metastatic
focus of infection. CoNS patients with pneumonia and not being treated or anticipated
to start treatment with antibiotics effective for the baseline infecting pathogen can
be included

16. Has polymicrobial blood stream infection including at least one non-staphylococcal
species, except AFTER consultation with the Clinical Medical Monitor at DCRI. Note
that it is possible that a subject may not have a known polymicrobial bloodstream
infection at the time of randomization, but additional pathogen(s) can subsequently be
isolated from the initial blood culture. These patients will be eligible to remain in
the trial. Please also note that patients with S. aureus plus CoNS will follow the
treatment pathway for S. aureus.

17. This criterion has been removed.

18. Is hemodialysis dependent or has end stage renal disease (Creatinine Clearance (CrCl)
< 30 cc/min).

19. Developed Staphylococcus aureus blood stream infection within 72 hours of percutaneous
coronary revascularization

20. Received of any of the following antibiotics for 7 or more of the 10 calendar days
immediately preceding the calendar day that the initial positive blood culture was
drawn:

1. If methicillin susceptibility of the isolate is unknown at the time of
enrollment: vancomycin; daptomycin; telavancin; tigecycline; linezolid (in either
oral or IV administration); quinupristin/dalfopristin; piperacillin/tazobactam;
penicillin; nafcillin; oxacillin; cloxacillin; cefazolin, ceftriaxone,
ceftaroline, dalbavancin, oritavancin, tedizolid, and levofloxacin or equivalent
fluoroquinolone (in either oral or IV administration) Note: ciprofloxacin is not
an exclusion criteria.

2. If the staphylococcal isolate is known to be methicillin resistant: vancomycin;
daptomycin; telavancin; tigecycline; linezolid (in either oral or IV
administration), quinupristin/dalfopristin, dalbavancin, oritavancin, tedizolid,
and ceftaroline.

Note: patients who have developed bacteremia after at least 7 days of prophylaxis with
oral antibiotics have by definition failed prophylaxis and the oral antibiotic can be
deemed non-effective for the index bacteremia. Oral antibiotics that have failed as
prophylaxis in this manner will not be considered exclusionary or count towards the
number of antibiotic days but must be stopped upon randomization

21. Has previously participated in this study.