2.  Abx: antibiotic(s)
 MRSA: methicillin-resistant S. aureus
 SSSI: skin and skin structure infection(s)
 MOA: mechanism of action
 IV: intravenous
 HD: hemodialysis
 Pt: patient(s)
 Tx: treat(s)/treating/treatment(s)

3.  CrCl: creatinine clearance
 TOC: test-of-cure
 PO: oral
 F/u: follow-up
 ADRs: adverse drug reactions
 Rxn: reaction(s)
 Vs: versus
 DDIs: drug-drug interactions

4.  A new abx
› Semi-synthetic lipoglycopeptide
› Marketed as Dalvance
 Properties
› MOA: Disrupts cell wall synthesis
› Half-life: 8.5 days
› Bactericidal activity
 Gram (+), including MRSA

5. http://www.google.com/patents/US8143212

6.  FDA approved for adults
› Acute bacterial skin and skin structure
infections (ABSSSI)
 Staphylococcus aureus
 including MRSA
 Streptococcus pyogenes
 Streptococcus agalactiae
 Streptococcus anginosus

7.  Normal renal function
› 1000 mg IV, then 500 mg IV a week later
› Infuse over 30 minutes
 Prevent infusion rxns
 Renal dosing
› CrCl < 30 (no HD)
 750 mg IV, then 375 mg IV a week later
› If HD, no special dosing required

8.  Resistance
› Novel drug --> Not a concern
 Safety
› No known DDIs
› Few ADRs
› Pregnancy Category C
 Convenience
› Only 2 doses required
› Outpatient tx is an option

9.  Expensive
› Cost comparable to linezolid
› May be offset by the drug's advantages
 IV only
› For pts who insist on PO tx, linezolid would be
a better option

10.  Objective
› Demonstrate safety and efficacy of
dalbavancin vs. linezolid for tx adults with
complicated SSSI
 Rationale
› Growing antimicrobial resistance
 Prevalence of MRSA in SSSI
 Alternative abx needed
› Medication adherence is key to success

11.  Primary
› Clinical success rate of the "clinically
evaluable" pts at TOC
 Success: enough improvement that abx no
longer needed
 Clinically evaluable: tx for 3+ days, attended all
visits, followed directions/met all criteria
 TOC visit within 2 days after completion of tx
› Rate of ADRs in each tx arm
 Secondary: not clearly defined

12.  Adults with complicated SSSI
› Gram(+) etiology
› Systemic infection -> initial IV tx required
 PLUS ≥ 2 of the following
› Drainage/discharge
› Erythema
› Warmth
› Tenderness
› Swelling/induration

13.  Infection involves deeper layers of tissue
(or requires surgery)
› Severe abscess
› Burn
› Wound infection
› Extensive/ulcerating cellulitis
 OR
 Infection where MRSA may be present

14.  Osteomyelitis/septic arthritis
› Require tx >14 days
 Infection requiring 3+ surgeries
› Indicate presence of other complications
 Concomitant abx tx
› Aztreonam/metronidazole permitted for
mixed infections
› D/c when gram (-) coverage no longer
needed

15.  Non-inferiority
› Delta: -12.5%
 Parallel
 Randomized via computer system
 Double-blind
 Duration: 14 days of tx
 Multi-center
› USA, Latvia, Lithuania, Canada, UK, Estonia,
Germany

16.  Dalbavancin
› 1000 mg IV on day 1, then 500 mg IV on day
8
 Linezolid
› 600 mg every 12 hrs for 14 days
› IV to PO after 24 hrs
 Blinding
› IV infusions bid until switch to PO
› IV infusion of medication on day 8

17.  Total enrollment
› 851 individuals
› 571 (dalbavancin) vs. 283 (linezolid)
 Clinically evaluable at TOC
› Analyzed for primary outcome
› 660 individuals
› 434 (dalbavancin) vs. 226 (linezolid)

18.  Efficacy
› Clinical success rate at TOC
 88.9% (dalbavancin) vs. 91.2% (linezolid)
› Lower limit of confidence interval
 -7.28%
 Did not cross delta margin of -12.5%
 Non-inferiority was claimed

19.  Safety
› ADRs similar between tx arms
› Both meds well tolerated
 GI distress most common
› Thrombocytopenia
 0.2% on dalbavancin, 2.5% on linezolid
› Infusion rxns
 2.8% on dalbavancin, 3.9% on linezolid

20.  Methods
› Appropriate dosing regimens
 Per IDSA guidelines
› Adequate blinding/randomization
 Inclusion/exclusion criteria
› Abx with gram (+) activity not permitted
› Pts requiring extended tx were excluded

21.  Tx arms
› Similar baseline characteristics
› Good representation of SSSI types
 Assessments
› Thorough evaluations
 Infection status
 Labs/cultures/vitals
 ADRs
› Excellent f/u with pts

22.  Delta margin (-12.5%)
› 10% is the standard
› Rationale for generous delta not mentioned
 Statistics
› What tests were used?
› Missing p-values/confidence intervals
› Power not addressed
 Med adherence not assessed

23.  Tx arms
› 2x as many subjects on dalbavancin
 Rationale for disparity not explained
 Ancillary meds
› DDIs of linezolid not considered
 Potentially problematic meds permitted
 Serotonin syndrome?
 Increased BP?
 Could explain the higher rate of ADRs

24.  Statistical/clinical significance
 Missing data
 Unable to claim non-inferiority
 Clinical relevance
› High clinical success rate (88.9%)
demonstrates efficacy of dalbavancin
› Alternative to linezolid for complicated SSSI

25.  MRSA concern
› Suspected resistance to other drugs
 Convenience
› Outpatient tx
› Only two IV doses required
 Safety
› When DDIs are a concern
› For elderly, renal/hepatic/pregnant/lactating

26.  Stevens DL, Bisno AL, Chambers HF, et al. IDSA Practice guidelines
for the diagnosis and management of skin and soft-tissue infections.
CID. 2005;41:1373-406.
 Jauregui LE, Babazadeh S, Seltzer E, et al. Randomized, double-blind
comparison of once-weekly dalbavancin versus twice-daily linezolid
therapy for the treatment of complicated skin and skin structure
infections. CID. 2005;41:1407-1415.
 Moran GJ, Abrahamian FM, LoVecchio F, Talan DA. Acute bacterial
skin infections: Developments since the 2005 IDSA guidelines. Journal
Emergency Med. 2013;44:397-412.
 Dalvance package insert. Revised May 2014. Accessed at
www.duratatherapeutics.com on November 14, 2014.