Dalbavancin For The Treatment of Gram Positive Osteoarticular Infections
Condition: Bone Infection; Osteomyelitis; Septic Arthritis; Joint Infection; Prosthetic Joint Infection
MeSH terms: Infections; Communicable Diseases; Arthritis, Infectious; Osteomyelitis
Study type: Interventional
Phase: Phase 4

Summary: 
      Because of its prolonged terminal half-life, dalbavancin is an extremely attractive option in
      treating Gram-positive infections caused by S. aureus including MRSA, and streptococcal
      species. Systemic bacterial infections due to Staphylococci such as osteomyelitis and septic
      arthritis, are conditions which require prolonged IV therapy, typically for at least 3-6
      weeks, though sometimes more. Due to dalbavancin's prolonged terminal half-life, it may offer
      the opportunity to substantially reduce costs and morbidity in native joint and prosthetic
      joint infections with one infusion every fourteen days until completion of therapy.
    

Detailed description: 
      Dalbavancin, currently FDA approved for the treatment of skin and soft tissue infections
      (SSTI), is a lipoglycopedptide with bactericidal activity in vitro against Staphylococcus
      aureus, including MRSA and VISA strains, and Streptococcus pyogenes. Its bactericidal action
      results primarily from inhibition of cell-wall biosynthesis, specifically the prevention of
      N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG)-peptide subunits incorporation into
      the peptidoglycan matrix. Dalbavancin alters bacterial-cell-membrane permeability and RNA
      synthesis. It is highly protein bound, primarily to albumin, with a half-life of 346 hours.
      Approximately 33% of unchanged drug is excreted in the urine, 20% via feces and 12% as the
      minor metabolite, hydroxyl-dalbavancin. There is minimal potential for drug-drug
      interactions; it is not a substrate, inducer or inhibitor of hepatic CYP450 isoenzymes and
      the administration of CYP450 substrates, inhibitors or inducers does not affect its clearance
      rate. In SSTI trials, Dalbavancin was demonstrated to be non-inferior to vancomycin and
      linezolid.

      Prosthetic joint infections (PJI) are an emerging health problem. Although the incidence of
      these infections is historically low (approximately 0.5%-1.0of implants), because of the
      rapid increase in the number of hip, knee and other joint implants, the absolute number of
      cases of infection is increasing. In 2010, 332,000 hip joints and 719,000 knee joints were
      implanted. This alone conservatively translates to 5,000-10,000 cases, with an economic
      impact of $1 billion. Management of PJI is particularly challenging because long term
      antibiotic therapy in most cases is accompanied by removal of the prosthesis and
      re-implantation.

      For long term antimicrobial administration, current standard of care requires a peripherally
      inserted central catheter (PICC) or other indwelling intravascular catheter, and
      daily/multiple daily infusions. There is substantial cost of maintaining the intravascular
      access, drugs, home health care and monitoring, as well as the infection risk of the chronic
      indwelling line which is being accessed frequently. There is a clear need for alternative
      care models to the current approach. Dalbavancin, because of its activity profile against
      Gram-positive organisms and its pharmacokinetics which would allow weekly or every other week
      dosing, is a favorable option. This option would eliminate the need for long term IV access,
      because at most, weekly IV infusions would be performed.

      In terms of bone infection, dalbavancin has favorable pharmacokinetic properties. A PK study
      performed in subjects undergoing elective orthopedic surgery found that dalbavancin (dosed at
      1000mg IV at enrollment and then 500mg weekly for up to 7 weeks) maintained levels in
      cortical bone at bactericidal levels , at >50X the MIC of typical staphylococcal organism
      (including MRSA). Animal studies in a rat osteomyelitis model also found that dalvabancin was
      comparable to vancomycin. Because of these same PK properties, dalbavancin offers the
      opportunity to substantially reduce costs and morbidity in native joint and prosthetic joint
      infections.

      This is a two-center, randomized, open label trial of dalbavancin versus standard intravenous
      therapy control comparator in the treatment of subjects with gram positive native joint or
      prosthetic joint infections. The primary outcome variable is clinical cure at day 42 after
      start of treatment in all randomized patients. Safety and tolerability will also be assessed
      throughout the study period via laboratory measurements and AE monitoring. Additionally,
      clinical response will be measured by patient reported outcomes with change from baseline
      symptoms and by Quality of Life questionnaire.

      Eligible subjects with confirmed gram positive joint infections, will be randomized in a
      ratio of 2:1 to receive open label dalbavancin or standard IV therapy. Standard IV therapy
      will depend on the antibiotic susceptibility of the causative pathogen. Subjects randomized
      to dalbavancin may have received standard of care therapy for no more than 120 hours prior to
      first dalbavancin dose. Subjects randomized to standard of care can continue with treatment
      course if already started, or receive the first dose at the baseline visit.
    

Intervention name(s): Dalbavancin; Vancomycin
Intervention type(s): Drug; Drug
Intervention description(s): Dalbavancin 1,500mg intravenously every fourteen days for two to four infusions; Examples of standard of care arm; infusions one to three times per day depending on the antibiotic for a total of three to eight weeks
Other intervention name(s): Dalvance; Xydalba; Zevan; Daptomycin; Nafcillin; Cefazolin
Intervention MeSH terms: Vancomycin; Cefazolin; Daptomycin; Dalbavancin; Nafcillin
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: Since it's a pilot study, the sample size is fixed (n = 50). The sample size were not selected based on statistical criteria. However, we would need to know what would be the detectable effect size.
∆^2=((z_(α/2)+z_β )^2 (σ_1^2+σ_2^2 ))/n
Masking: None (Open Label)
Primary purpose: Treatment