New Antibiotics for MRSA

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Lambert Green
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1 New Antibiotics for MRSA

2 Faculty Warren S. Joseph, DPM, FIDSA Consultant, Lower Extremity Infectious Diseases Roxborough Memorial Hospital Philadelphia, Pennsylvania

3 Faculty Disclosure Dr. Joseph: Speaker s Bureau The Medicines Company, Merck

4 MRSA = methicillin-resistant Staphylococcus aureus. Learning Objectives Describe the current role of MRSA in skin and soft tissue infections List available therapies to treat MRSA Appreciate the differences in dosing and effectiveness of the newer antibiotics to treat MRSA

5 What s New in MRSA? Do we even need to concern ourselves? A decrease in patients presenting with MRSA Even if MRSA is present, does it really make a difference? What is wrong with the treatments we have? Changes in the FDA s Guidance for Industry on SSSI A number of new MRSA antibiotics since ceftaroline fosamil (2010) What is in the pipeline? FDA = US Food and Drug Administration; SSSI = skin and skin structure infections. Guidance for industry acute bacterial skin and skin structure infections: developing drugs for treatment Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER); 2013 [cited 2014 April 28]. Available at:

6 2012 IDSA Guidelines Lipsky BA, et al. Clin Infect Dis. 2012;54(12):

7 Lipsky BA, et al. Clin Infect Dis. 2012;54(12): Definitive Therapy and MRSA We recommend that definitive therapy be based on both the results of an appropriately obtained culture and sensitivity testing of a wound specimen and the patient s clinical response to the empirical regimen (Strong, Low) Consider providing empirical therapy directed against MRSA: in a patient with a prior history of MRSA infection; when the local prevalence of MRSA colonization or infection is high; or, if the infection is clinically severe (Weak, Low)

8 Do We Still Have To Be Concerned About MRSA?

9 Do We Still Have To Be Concerned About MRSA? (cont) Dantes R, et al. JAMA Int Med. 2013;173(21):

10 Do We Still Have To Be Concerned About MRSA? (cont) Dantes R, et al. JAMA Int Med. 2013;173(21):

11 Even if It Is MRSA, Is There Concern?

12 Even if It Is MRSA, Is There Concern? (cont) DFI = diabetic foot infection.

13 Even if It Is MRSA, Is There Concern? (cont)

14 MRSA: What Has Been Out There? Mild Later-generation tetracycline (PO) Minocycline Doxycycline TMP/SMX Clindamycin +/- rifampin added to any of the above

15 MRSA: What Has Been Out There? (cont) Moderate/Severe Linezolid (IV/PO) Vancomycin (IV) Daptomycin (IV) Tigecycline (IV) Ceftaroline fosamil (IV) Telavancin (IV)

16 The Hands Give It Away Donskey CJ, et al. N Engl J Med. Jan 2009;360:e3. doi: /NEJMicm

17 Randomized Non-inferiority Trial Harbarth S, et al. J Antimicrob Chemother. September 10, doi: /jac/dku352.

18 What s Wrong with Vancomycin? Deresinski S. Clin Infect Dis. 2007;44(12):

19 How Should We Dose Vancomycin? Zenelaj B, et al. Int J Low Extrem Wounds. 2014;13(4):1-10.

20 IDSA Guidelines for Treatment of MRSA Liu C, et al. Clin Infect Dis. 2011;52:1-38.

21 None of the New MRSA Drugs Are FDA Approved for the Treatment of Diabetic Foot Infection WHY? Subtitle

22 ABSSSI The FDA s latest (October 2013) Guidance for Industry for ABSSSI specifically excludes DFI: This guidance does not address infections needing more complex treatment regimens, such as infections resulting from animal or human bites, necrotizing fasciitis, diabetic foot infection, decubitus ulcer infection, myonecrosis, and ecthyma gangrenosum. Sponsors interested in development of drugs for treatment of skin infections not covered in this guidance should discuss clinical development plans with the FDA. ABSSSI = acute bacterial skin and skin structure infection. Guidance for industry acute bacterial skin and skin structure infections: developing drugs for treatment Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER); 2013 [cited 2014 April 28]. Available at:

23 Your FDA at Work Snodgrass WR, et al. Br Med J. 1937;2(4014):

24 Plan of Investigation Snodgrass WR, et al. Br Med J. 1937;2(4014):

25 Tedizolid Phosphate FDA approved: June 20, mg once daily (PO/IV) x 6 days Non-inferior to linezolid 600 mg (IV to oral) BID x 10 days No SSRI/serotonin syndrome precaution Myelosuppression approximately half that of linezolid MRSA, VRE, vancomycin/daptomycin-resistant S aureus Cost JAMA. 2013;309(6): The ESTABLISH-1 Randomized Trial SSRI = selective serotonin reuptake inhibitor; VRE = vancomycin-resistant Enterococcus species. Sivextro [prescribing information]. Whitby, Ontario: Patheon Inc (tablets)/ferentino, FR Italy: Patheon Italia SpA (injection); Crotty MP, et al. J Clin Microbiol. 2016;54(9): Patel S, et al. Center for drug evaluation and research. Application number: Orig1s000. Medical review(s). Clinical Review: tedizolid phosphate

27 ECCMID 2015 Poster Joseph W. Poster [P1311]. Presented at the 25th ECCMID. April 25, Copenhagen, Denmark.

28 ECCMID 2015 Poster Percentage of lower extremity infections Tedizolid group = 40.7 Linezolid group = 42.2 Joseph W. Poster [P1311]. Presented at the 25th ECCMID. April 25, Copenhagen, Denmark.

29 Lipoglycopeptide Antibiotics Oritavancin Single 1200-mg infusion Dalbavancin Either 1000 mg on day 1 followed by 500 mg on day 7 or a single 1500-mg infusion Orbactiv [prescribing information]. Parsippany, NJ: The Medicines Company; Brade KD, et al. Infect Dis Ther Mar 5(1):1-15. Dalvance [prescribing information]. Parsippany, NJ: Durata

30 Oritavancin FDA approved: August 7, 2014 Lipoglycopeptide Phase 3 SOLO program Single 1200-mg dose of oritavancin was non-inferior to 7 to 10 days of vancomycin in treating ABSSSI caused by Gram-positive pathogens, including MRSA N Engl J Med 2014; 370: Orbactiv [prescribing information]. Parsippany, NJ: The Medicines Company; Brade KD, et al.

31 Oritavancin (cont) 978 patients oritavancin 981 patients vancomycin 405 MRSA subset Primary endpoint ( early clinical response ) 82.3/80.1% (oritavancin) vs 78.9/82.9% (vancomycin) MRSA subset: 81.4% oritavancin vs 80.6% vancomycin Single dose of oritavancin = non-inferior to twice-daily vancomycin for the treatment of acute bacterial skin and skin-structure infections caused by Gram-positive pathogens Corey GR, et al. N Engl J Med. 2014;370: Rubino CM, et al. Antimicrob Agents Chemother.

32 Messina JA, et al. Expert Opin Pharmacother May;16(7): Advantages of Oritavancin No therapeutic drug monitoring No dosage adjustment Mild to moderate renal impairment Mild to moderate hepatic impairment Age, weight, gender, race No peripherally inserted central catheter line No hospitalization

33 Dalbavancin FDA approved: May 23, 2014 MSSA/MRSA/VRE 1000 mg IV followed by a 500-mg second dose 1 week later CrCl <30 ml/min: 750 mg the first week and 375 mg by the second week No dosage reduction for hemodialysis MSSA = methicillin-sensitive Staphylococcus aureus; VRE =

34 Dalbavancin vs Vancomycin/Linezolid: Phase 3 Boucher HW, et al. N Engl J Med. 2014;370(23):

35 Primary and Secondary Efficacy End Points Boucher HW, et al. N Engl J Med. 2014;370(23):

36 Placement of Once-Weekly Injectables? Cost Will hospital pharmacies want to carry it? Will hospitals be okay with losing admission? Which patients would benefit? Patients severe enough for IV but not hospitalization Non-adherence IV drug use Used in what setting? Emergency department In-patient hospital Out-patient or hospital infusion center

37 Conclusions MRSA rates seem to be decreasing Even if MRSA is found, it may not make a difference in outcomes There are now NINE FDA-approved MRSA antibiotics along with effective, unapproved drugs More research on DFI is needed with these new drugs

38 Subtitle Q & A

Antibiotic Updates: Part I

Antibiotic Updates: Part I Fredrick M. Abrahamian, DO, FACEP, FIDSA Health Sciences Clinical Professor of Emergency Medicine David Geffen School of Medicine at UCLA Los Angeles, California Financial Disclosures