Dalvance (Dalbavancin) A new once-weekly Lipoglycopeptide Antibiotic Prepared by: Kamaldeep Kainth, PharmD 2015

Objectives: To define what is MRSA To explain current medications for MRSA infection To introduce Dalbavancin To describe the dosage, storage, Administration, ADRs of Dalbavancin To evaluate ABSSSI Trials: Results To describe treatment Comparison To review prevention of Staph. infection.

Patient Case: CA is a 33 y/o male football player admitted to the ER with complaints of fever, inability to walk, Erythema, local swelling and pain on the left leg for about 5 days. His medical history was unremarkable. Physical examination: Wt 180lb, Ht 6ft, T 101.5F, Pain 6/10, local tenderness, restricted leg movement. Labs: SCr 0.9, Glu 101, Hg 12.1, WBC 20, CRP 60. Other labs: WNL Needle Aspiration: GP cocci The patient was initially treated with Cefazolin 3gm/day

Patient Case: 2 Days Later... There was no improvement after 2 days of treatment. CA still have fever of 102 and his WBCs are now 25000. Both the needle aspirate and bone culture grew MRSA. How would you treat this patient???

What is MRSA??

MRSA is…. Methicillin Resistant Staphylococcus Aureus. Staphylococcus Aureus, or simply referred as Staph. are bacteria commonly carried on skin or in the nose of healthy person. When staph becomes resistant to Methicillin or Oxacillin antibiotic then its called MRSA...

Infections caused by MRSA: Skin and soft tissue infection (most common) Wound (Traumatic) Urinary Tract Infection Osteomyelitis Bacteremia Pneumonia (Less common)

Risk Factors: Recurrent skin disease or open wound Long term illness or patients on dialysis Illicit drug use (Injectables) Surgery Recent hospitalization. Recent Antibiotic use Living in crowded settings

Diagnosis: ...To make a definitive diagnosis and confirm that Staph is the bacteria causing the infection, culture is usually done… ...In the past, most serious Staph bacterial infections were treated with penicillin type antibiotics or a cephalosporins.. Over the past 50 years, treatment of these infections has become more difficult because staph bacteria have become resistant to various antimicrobial agents, including the commonly used penicillin class antibiotics.

What is common among these?? Vancomycin Daptomycin Linezolid Clindamycin Tigecycline Synercid (Quinupristin/Dalfopristin) Telavancin Rifampin Ceftaroline

What’s New??

Dalbavancin for injection.. Now Approved for Treatment for Acute bacterial skin and skin structure infections… May 2014….

Introduction: ...Dalbavancin is second-generation semisynthetic lipoglycopeptide antibiotic. ...Because of its longer half-life (t1/2 of 6 - 10 days) it is dosed once weekly. A complete course of therapy consist of 2 single weekly doses administered on Day 1 and Day 8….

Spectrum of Activity: GRAM POSITIVE ORGANISMS: Staphylococcus Aureus (MSSA and MRSA) Streptococcus pyogenes Streptococcus agalactiae Streptococcus anginosus group (S. anginosus, S. intermedius, S. Constellatus) Enterococcus faecium (Only vanco susceptible strains) Enterococcus faecalis (Only vanco susceptible strains) Also effective against some resistant strains of Streptococcus, Peptostreptococcus species, Clostridium species and Actiniomyces species.

Mechanism of Action: Bactericidal ..Dalbavancin interferes with the transpeptidation and transglycosylation step in cell wall synthesis mediated by binding to D-ala D-ala terminus. Binding to this substrate inhibits the cross-linking reactions that strengthen the bacterial cell wall…..

Dosage and Administration: Acute Bacterial Skin and Skin structure Infection in Adults 500mg vial available as sterile powder. 1000 mg given IV over 30 minutes on day 1 500 mg given IV over 30 minutes on day 8 Must be reconstituted with sterile water for injection and diluted only with 5% dextrose. Renal Impaired: CrCl <30ml/L→ Administer 750 mg on day 1, followed one week later 375 mg

Reconstitution and Storage: Each 500 mg vial must be reconstituted with 25 ml of sterile water for injection, USP. The reconstituted solution can then be diluted or transferred to iv bag of 5% Dextrose solution to a final concentration between 1mg/ml to 5mg/ml. Storage: Refrigerated→ 2 - 8 C (36-46 F) Controlled Room temperature→ 20-25 C (68-77F) DO NOT FREEZE **Total time from reconstitution to dilution to administration should not exceed 48 hours.**

Adverse Effects: Common AEs: Serious AEs: Pregnancy Category: C Constipation (18.2%) Diarrhea (4.4%) Nausea (5.5%) Headache (4.7%) Serious AEs: C. Diff Colitis (<2%) GI Hemorrhage (<2%) Infusion reaction (<2%) Hepatotoxicity (<2%) Pregnancy Category: C

Drug Interactions: Dalbavancin is not affected by co-administration of known CYP450 substrates, inducers or inhibitors….

Clinical Studies: ABSSSI Trials → 2 Trials performed with total of 1312 randomized patients. The specific infections in these trials were Cellulitis (50%), Major abscess (30%) and wound infections (20%). → Baseline signs and symptoms of infection included: Temperature 38C or higher, WBC 12000 or higher or 10% or more bands. → The mean age was 50 years and mean BMI was 29.1 kg/m2 → Primary endpoint was clinical response rate defined as no increase from baseline in lesion area after 48 to 72 hours and T at or <37.6C

Clinical studies: Clinical Response rate in the trials at 48 to 72 hours after initiation of therapy Dalavance Group: 1000 mg followed 1 week later 500mg. (Dose adjusted for CrCl) Vanco/Linezolid: iv vanco 1000 mg or 15 mg/kg q 12 h. with option to switch to oral linezolid after 3days. Dalavancin n/N(%) Vancomycin/Linezolid n/N (%) Difference 95% CI TRIAL 1 240/288 (83.3%) 233/285 (81.8%) 1.5% (-4.6, 7.9) TRIAL 2 285/371 (76.8%) 288/368 (78.3%) -1.5% (-7.4, 4.6) There were 7 patients who did not receive treatment and were counted as non-responders: 6 dalbavancin patients (3 in each trial) and one vancomycin/linezolid patient in Trial 2. 2 Patients who died or used non-study antibacterial therapy or had missing measurements were classified as non-responders. 3 The 95% Confidence Interval (CI) is computed using the Miettinen and Nurminen approach, stratified by baseline fever status.

Clinical Studies: Secondary end point: → Patients who had reduction in lesions by 20% or greater in 48 to 72 hours after initiation of therapy Dalavance n/N (%) Vanco/Linezolid n/N(%) Difference (95% CI) TRIAL 1 259/288 (89.9%) 259/285 (90.9%) -1.0% (-5.7, 4.0) TRIAL 2 325/371 (87.6%) 316/368 (85.9%) 1.7% (-3.2, 6.7)

ADRs: ..In the Clinical trials, the treatment related ADRs for Dalbavancin was 12.3% and for Vanco/Linezolid was 18.3%. **ADRs in > or =3% of patients in Dalbavancin included: Nausea, Diarrhea, Headache, Pruritus. Discontinuations: D → 1.8% V/L → 2.1%

Results: → The study results concluded that Dalbavancin is non-inferior when compared to standard drug therapy (Vancomycin/Linezolid) in Acute Bacterial skin and skin structure infection….

Back to our Patient: CA is a 33 y/o male football player admitted to the ER with complaints of fever, inability to walk, Erythema, local swelling and pain on the left leg for about 5 days. His medical history was unremarkable. There was no improvement after 2 days of treatment with Cefazolin. CA still have fever of 102 and his WBCs are now 25000. Both the needle aspirate and bone culture grew MRSA… What would be the treatment therapy???

Treatment Options: Vancomycin <<< Daptomycin Linezolid Clindamycin** Tigecycline Synercid (Quinupristin/Dalfopristin) Telavancin Rifampin Ceftaroline Dalbavancin <<< **CA MRSA only

CO$T>>>> Vancomycin >>> (750mg/150ml IV $86.98) Daptomycin >>>(500mg IV $403) Linezolid >>> (600mg/300ml IV $167.35) Clindamycin>> (900mg/50ml IV $9.62)*** Tigecycline>> (500mg/100ml IV $1216) Synercid (Quinupristin/Dalfopristin) >>>(350/150mg per vial $307.30) Telavancin >>>>(750mg IV $358.80) Rifampin >>> (600mg IV $136.35) Ceftaroline >>> (600mg IV $758) Dalbavancin<< (750mg vial $1000-$3000)# ***CA-MRSA only

to prevent Staph. Infection... Precautions to prevent Staph. Infection...

Can I protect myself from becoming infected? WASH YOUR HANDS If no visible dirt, use alcohol-based hand sanitizer Keep cuts and abrasions covered Avoid contact with other people’s wounds Avoid skin-to-skin contact with infected persons Do not share personal items Clean objects and other shared surfaces before you use them

How to keep it from spreading to others? Keep infected areas covered Follow doctor’s instructions Wash hands Put disposable waste in a separate trash bag and close tightly before throwing it out Wear gloves Do not share personal items Avoid participating in contact sports

Conclusion: Dalbavancin Vancomycin → 2 Dose Regimen for SSTI → Dosed more frequently (qd to q 8 h) → Safety not established in Pediatrics → Established use in neonates, infants and children. → Headache, GI SEs, Hepatic and infusion related SEs (>30min) → Nephrotoxicity, Ototoxicity, Neutropenia, infusion related (>60mins) → Pregnancy Category : C → Half-life : 6 to 10 days → Half-life 4 to 6 hours. → Monitoring: Improvement, Diarrhea, Hypersensitivity reaction → Culture, CBS, Improvement, Trough levels, Renal function, Dose adjustments** → Cost: $$$$ → Cost: $$

References: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM390793.pdf http://www.webmd.com/skin-problems-and-treatments/understanding-mrsa-detection-treatment http://www.cdc.gov/mrsa/ http://www.webmd.com/a-to-z-guides/video/truth-about-mrsa http://www.medscape.org/viewarticle/518862_16 http://content.stockpr.com/duratatherapeutics/files/docs/Dalvance+APPROVED+USPI.PDF http://www.duratatherapeutics.com/news-media/press-releases/detail/333/durata-therapeutics-announces-phase-3-clinical-trial http://www-micromedexsolutions-com.proxy.westernu.edu/micromedex2/librarian/PFDefaultActionId/evidencexpert.ShowDrugCompareResults