Treatment Algorithm to Reduce the Use of Vancomycin in Adults With Blood Stream Infection
Condition: Bacteremia
MeSH terms: Bacteremia; Sepsis
Intervention: Vancomycin; Vancomycin
Intervention description: Duration; Duration
Intervention MeSH terms: Vancomycin; Cefazolin; Daptomycin; Cloxacillin; Oxacillin; Nafcillin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 509.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: staphylococci

Summary:

      The purpose of this study is to accurately determine the length of appropriate drug treatment
      for staphylococcal blood stream infection. The study seeks to address important information
      about the management of staphylococcal blood stream infections.
    

Eligibility criteria:

        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.