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.

Journal ClubAmy Yeh

PharmD CandidateClass of 2015

November 21, 2014

Abbreviations 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)

Abbreviations 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

What is Dalbavancin? 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

Structure

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

Place in Therapy FDA approved for adults

› Acute bacterial skin and skin structure infections (ABSSSI) Staphylococcus aureus

including MRSA Streptococcus pyogenes Streptococcus agalactiae Streptococcus anginosus

Dosing 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

Pros 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

Cons 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

The Study 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

Outcomes 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

Inclusion Criteria Adults with complicated SSSI

› Gram(+) etiology› Systemic infection -> initial IV tx required

PLUS ≥ 2 of the following› Drainage/discharge› Erythema› Warmth› Tenderness› Swelling/induration

Complicated SSSI Infection involves deeper layers of

tissue (or requires surgery)› Severe abscess› Burn › Wound infection› Extensive/ulcerating cellulitis

OR Infection where MRSA may be present

Exclusion Criteria 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

Study Design 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

Tx Arms 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

The Participants Total enrollment

› 851 individuals› 571 (dalbavancin) vs. 283 (linezolid)

Clinically evaluable at TOC› Analyzed for primary outcome› 660 individuals› 434 (dalbavancin) vs. 226 (linezolid)

Statistics/Results 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

Statistics/Results 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

Critique of Strengths 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

Critique of Strengths Tx arms

› Similar baseline characteristics› Good representation of SSSI types

Assessments› Thorough evaluations

Infection status Labs/cultures/vitals ADRs

› Excellent f/u with pts

Limitations/Confounders 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

Limitations/Confounders 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

Relevance of Study 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

When to Use Dalbavancin 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

References 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.