The Medical Letter. on Drugs and Therapeutics. Objective Drug Reviews Since Volume 56 August 18, 2014

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1 The Medical Letter on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 56 ISSUE ISSUE No Volume 56 IN THIS ISSUE Two New Drugs for Skin and Skin Structure Infections...p 73 Important Copyright Message FORWARDING OR COPYING IS A VIOLATION OF U.S. AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter, Inc. publications are protected by U.S. and international copyright laws. Forwarding, copying or any distribution of this material is prohibited. Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited. By accessing and reading the attached content I agree to comply with U.S. and international copyright laws and these terms and conditions of The Medical Letter, Inc. For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: Published by The Medical Letter, Inc. A Nonprofit Organization

2 The Medical Letter publications are protected by US and international copyright laws. Forwarding, copying or any other distribution of this material is strictly prohibited. For further information call: The Medical Letter on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 56 Take CME exams Two New Drugs for Skin and Skin Structure Infections The FDA has approved two new drugs for treatment of adults with acute bacterial skin and skin structure infections caused by susceptible gram-positive bacteria. Dalbavancin (Dalvance Durata) is a longacting intravenous (IV) lipoglycopeptide antibiotic similar to telavancin (Vibativ). 1 Tedizolid phosphate (Sivextro Cubist) is an IV and oral oxazolidinone antibacterial drug similar to linezolid (Zyvox). 2 A third IV antibiotic, oritavancin (Orbactiv), recently approved by the FDA for the same indication, will be reviewed in a future issue. STANDARD TREATMENT Patients hospitalized for non-purulent skin and soft-tissue infections, which are often caused by streptococci, can usually be treated empirically with IV penicillin, cefazolin, ceftriaxone, or clindamycin. 3 Purulent skin infections are now caused predominantly by methicillin-resistant Staphylococcus aureus (MRSA) in many parts of the US. Patients hospitalized for complicated MRSA skin and soft-tissue infections are usually treated with IV vancomycin. Alternatives include linezolid, daptomycin, clindamycin, telavancin, and ceftaroline fosamil. For less serious MRSA infections, incision and drainage alone or with oral trimethoprim/sulfamethoxazole (TMP/SMX) or doxycycline is usually effective. 4 DALBAVANCIN ACTIVITY Dalbavancin inhibits cell wall synthesis in gram-positive bacteria. In vitro, it is bactericidal against Streptococcus pyogenes and S. aureus, including MRSA, in concentrations readily achieved in blood with recommended doses of the drug. It has Table 1. Some IV Drugs for MRSA Skin and Skin Structure Infections Some Available Usual Adult FDA-Approved Drug Formulations Dosage 1 Duration Cost 2 Ceftaroline fosamil 3 400, 600 mg vials 600 mg q12h 5-14 days Teflaro (Forest) $ Dalbavancin mg vials 1000 mg x 1, then 14 days (2 doses Dalvance (Durata) 500 mg 1 wk later 1 week apart) Daptomycin mg vials 4 mg/kg q24h 7-14 days Cubicin (Cubist) Linezolid 200, 400, 600 mg infusion bags mg q12h days Zyvox (Pfizer) Tedizolid mg single-use vials mg once/d 6 days Sivextro (Cubist) Telavancin 3 250, 750 mg vials 10 mg/kg q24h 7-14 days Vibativ (Theravance) Vancomycin 500, 750 mg, 1, 5, 10 g vials 15 mg/kg (max 2 g) generic q12h Dosage adjustment may be needed for renal or hepatic impairment. 2. Approximate wholesale acquisition cost (WAC) for 1 day s treatment of a 70-kg patient with the lowest usual dosage. Source: Analy$ource Monthly (Selected from FDB MedKnowledge ) August 5, Reprinted with permission by FDB, Inc. All rights reserved Actual retail prices may be higher. 3. Not FDA-approved for use in children. 4. Cost for one 500-mg vial. 5. Also available for oral administration in 600-mg tabs and a 100 mg/5 ml oral suspension. 6. Dosage for children <12 years old is 10 mg/kg q8h. 7. Also available for oral administration in 200-mg tabs. 8. Dose may be too low to achieve adequate trough concentions in many patients with normal renal function. Some experts recommend mg/kg q8-12 hours (M Rybak et al. Am J Health Syst Pharm 2009; 66:82). Initial pediatric dosage is mg/kg q6h. Published by The Medical Letter, Inc. A Nonprofit Organization 73

3 been shown to be active clinically and in vitro against S. aureus (including MRSA), S. pyogenes, Streptococcus agalactiae and Streptococcus anginosus group. It is also active in vitro against vancomycin-susceptible Enterococcus faecium and Enterococcus faecalis, and against vancomycin-intermediate S. aureus. 5 PHARMACOLOGY After IV injection of a single mg dose, serum concentrations of dalbavancin remain above the minimum inhibitory concentration for MRSA for about 8 days. The terminal half-life of dalbavancin is about 14 days, but when given once a week for 8 weeks to healthy adults with normal renal function, the drug did not accumulate. Table 2. Pharmacology of Dalbavancin Class Lipoglycopeptide antibiotic Route IV Formulation 500 mg single-use vials Distribution 93% protein bound Metabolism Minimal; not a substrate, inhibitor, or inducer of CYP450 enzymes Excretion Very slow; urine (33% unchanged, 12% metabolite) in 42 days; feces (20%) in 70 days Half-life (terminal) ~14 days CLINICAL STUDIES FDA approval of dalbavancin was based on the results of 2 double-blind non-inferiority trials (DISCOVER 1 and DISCOVER 2) comparing it to IV vancomycin followed by oral linezolid in a total of 1312 adult patients with acute bacterial skin and skin structure infections. Patients treated with dalbavancin received 1000 mg once on day 1 and 500 mg on day 8; those randomized to vancomycin received 1 g or 15 mg/ kg every 12 hours for at least 3 days, after which they could be switched to oral linezolid to complete a 10- to 14-day course. The primary endpoint in both studies was no increase from baseline in the size of the infected area hours after starting treatment and a temperature 37.6 C. 6 The results are summarized in Table 3. Clinical success rates were maintained at follow-up (day 26-30). ADVERSE EFFECTS In phase 2 and 3 clinical trials that included a total of 1778 patients treated with dalbavancin, the most common adverse effects of the drug were nausea, diarrhea, and headache, each of which occurred in about 5% of patients. Rapid IV infusion of the drug could cause infusionrelated reactions (red-man syndrome). Serious hypersensitivity reactions, including anaphylaxis, have been reported with dalbavancin; the long halflife of the drug can further complicate these reactions. Patients with a history of a hypersensitivity reaction Table 3. Dalbavancin Clinical Trials Cessation of Reduction Study Drug Lesion Spread 1 in Lesion Area 2 DISCOVER 1 Dalbavancin 83% (240/288) 90% (259/288) (n=573) Vancomycin/ 82% (233/285) 91% (259/285) linezolid DISCOVER 2 Dalbavancin 77% (285/371) 88% (325/371) (n=739) Vancomycin/ 78% (288/368) 86% (316/368) linezolid) 1. No increase from baseline in lesion surface area and temperature <37.6 C hrs after the first dose. 2. Reduction from baseline of >20% in lesion surface area hrs after the first dose. to another glycopeptide (vancomycin or telavancin) may be at increased risk. Unlike telavancin, dalbavancin does not prolong the QT interval. Use of telavancin has been limited by its adverse effects, which include taste disturbances, nausea, vomiting, and nephrotoxicity. Pregnancy Dalbavancin is classified as category C (some fetal toxicity in animals; no adequate human studies) for use during pregnancy. DOSAGE The recommended dosage of dalbavancin is 1000 mg infused over 30 minutes, followed one week later by 500 mg. Patients with creatinine clearance <30 ml/min should receive 750 mg for the first dose and 375 mg for the second. TEDIZOLID ACTIVITY Tedizolid, the active moiety of the prodrug tedizolid phosphate, inhibits bacterial protein synthesis. 7 In vitro and in clinical studies, it has shown activity against S. aureus (including MRSA), S. pyogenes, S. agalactiae, S. anginosus group, and E. faecalis. Tedizolid is active in vitro against other gram-positive pathogens, including coagulase-negative staphylococci and E. faecium. It also appears to have activity in vitro against some staphylococcal and enterococcal strains that are non-susceptible to vancomycin and against some strains of gram-positive cocci that are non-susceptible to linezolid. 8,9 Tedizolid is also active in vitro against Mycobacterium tuberculosis strains resistant to isoniazid, rifampin, or both. 10 PHARMACOLOGY The pharmacokinetics of tedizolid are similar after IV or oral administration. Steady-state concentrations are achieved within 3 days. CLINICAL STUDIES FDA approval of tedizolid was based on 2 double-blind non-inferiority trials (ESTABLISH-1 and ESTABLISH-2) comparing tedizolid 200 mg once daily for 6 days with linezolid 600 mg 74

4 Table 4. Pharmacology of Tedizolid Class Oxazolidinone antibiotic Route Oral and IV Formulations 200 mg tabs and single-use vials Tmax (single-dose) 2.5 hrs (oral); 1.1 hrs (IV) Distribution 70-90% protein bound Metabolism The prodrug tedizolid phosphate is rapidly converted to tedizolid by endogenous phosphatases; it is not a substrate, inhibitor, or inducer of CYP450 enzymes Excretion 82% (feces), 18% (urine) as inactive metabolite Half-life (terminal) 12 hrs twice daily for 10 days. Patients in the first trial received oral therapy and those in the second trial started with IV treatment for at least 1 day before being given the option to switch to the oral formulation. The primary endpoint in both trials was clinical response hours after the first dose, which was defined as no increase from baseline in lesion size and an oral temperature of 37.6 C in ESTABLISH-1 and as a 20% reduction from baseline in lesion size in ESTABLISH-2. 11,12 The results are summarized in Table 5. Clinical response rates were maintained 7-14 days after the end of therapy. tonergic drugs or adrenergic agents such as tyramine and pseudoephedrine. 13 DOSAGE The recommended oral or IV dosage of tedizolid for skin and skin structure infections is 200 mg once daily for 6 days. CONCLUSION Dalbavancin (Dalvance) and tedizolid phosphate (Sivextro) are effective for treatment of acute bacterial skin and skin structure infections, including those caused by MRSA. Use of dalbavancin in 2 doses one week apart may permit outpatient treatment of some infections that previously required hospitalization. Once-daily tedizolid may be more convenient than twice-daily linezolid (Zyvox). The efficacy of these drugs for more invasive infections, including pneumonia and bacteremia, is unknown and their long-term safety has not been established. Older, less expensive antibiotics are generally preferred. Table 5. Tedizolid Clinical Trials Cessation of Reduction Study Drug Lesion Spread 1 in Lesion Area 2 ESTABLISH-1 Tedizolid 79% (256/323) 78% (252/323) (n=649) Linezolid 79% (258/326) 76% (246/326) ESTABLISH-2 Tedizolid 86% (286/332) 85% (283/332) (n=666) Linezolid 84% (281/334) 83% (276/334) 1. No increase from baseline in lesion surface area and temperature <37.6 C hrs after the first dose. 2. Reduction from baseline of >20% in lesion surface area hrs after the first dose. ADVERSE EFFECTS The most common adverse effects of tedizolid reported in clinical trials were nausea (8%), headache (6%), diarrhea (4%), vomiting (3%), and dizziness (2%); similar reactions have occurred in patients taking linezolid. Potentially clinically significant decreases in platelet counts occurred in 2.3% of patients taking tedizolid in clinical trials, compared to 4.9% of those who received linezolid. Higher doses and/ or longer treatment durations might increase the risk of hematologic abnormalities with tedizolid. Peripheral and optic neuropathy have been reported with both tedizolid and linezolid. Pregnancy Tedizolid is classified as category C (fetal toxicity in animals; no adequate human studies) for use during pregnancy. DRUG INTERACTIONS In vitro, tedizolid is a weak, reversible inhibitor of monoamine oxidase (MAO), but it may be less likely than linezolid to interact with sero- 1. Telavancin (Vibativ) for gram-positive skin infections. Med Lett Drugs Ther 2010; 52:1. 2. Linezolid (Zyvox). Med Lett Drugs Ther 2000; 42: DL Stevens et al. Executive summary: practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infec Dis 2014; 59: Drugs for MRSA skin and soft-tissue infections. Med Lett Drugs Ther 2014; 56: HF Chambers. Pharmacology and the treatment of complicated skin and skin-structure infections. N Engl J Med 2014; 370: HW Boucher et al. Once-weekly dalbavancin versus daily conventional therapy for skin infection. N Engl J Med 2014; 370: O Urbina et al. Potential role of tedizolid phosphate in the treatment of acute bacterial skin infections. Drug Des Devel Ther 2013; 7: RN Jones et al. TR-700 in vitro activity against and resistance mutation frequencies among Gram-positive pathogens. J Antimicrob Chemother 2009; 63: SD Brown and MM Traczewski. Comparative in vitro antimicrobial activities of torezolid (TR-700), the active moiety of a new oxazolidinone, torezolid phosphate (TR-701), determination of tentative disk diffusion interpretive criteria, and quality control ranges. Antimicrob Agents Chemother 2010; 54: L Vera-Cabrera et al. In vitro activities of DA-7157 and DA-7218 against Mycobacterium tuberculosis and Nocardia brasiliensis. Antimicrob Agents Chemother 2006; 50: P Prokocimer et al. Tedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin structure infections: the ESTABLISH-1 randomized trial. JAMA 2013; 309: GJ Moran et al. Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTAB- LISH-2): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis 2014; 14: S Flanagan et al. In vitro, in vivo, and clinical studies of tedizolid to assess the potential for peripheral or central monoamine oxidase interactions. Antimicrob Agents Chemother 2013; 57:

5 EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.; ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D., Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M. Shah, Pharm.D., F. Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard CONTRIBUTING EDITORS: Carl W. Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K. Dalton, M.D., M.P.H., University of Michigan Medical School; Eric J. Epstein, M.D., Albert Einstein College of Medicine; Jane P. Gagliardi, M.D., M.H.S., F.A.C.P, Duke University School of Medicine; Jules Hirsch, M.D., Rockefeller University; David N. Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B. Kim, M.D., University of Western Ontario; Hans Meinertz, M.D., University Hospital, Copenhagen; Sandip K. Mukherjee, M.D., F.A.C.C., Yale School of Medicine; Dan M. Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K. Schaefer, M.D., M.P.H., Harvard Medical School; F. Estelle R. Simons, M.D., University of Manitoba; Neal H. Steigbigel, M.D., New York University School of Medicine; Arthur M. F. Yee, M.D., Ph.D., F.A.C.R., Weill Medical College of Cornell University MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown EXECUTIVE DIRECTOR OF SALES: Gene Carbona; FULFILLMENT & SYSTEMS MANAGER: Cristine Romatowski; DIRECTOR OF MARKETING COMMUNICATIONS: Joanne F. Valentino; VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy Founded in 1959 by Arthur Kallet and Harold Aaron, M.D. Copyright and Disclaimer: The Medical Letter, Inc. is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations. The editorial process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants. The Medical Letter, Inc. is supported solely by subscription fees and accepts no advertising, grants, or donations. No part of the material may be reproduced or transmitted by any process in whole or in part without prior permission in writing. The editors do not warrant that all the material in this publication is accurate and complete in every respect. The editors shall not be held responsible for any damage resulting from any error, inaccuracy, or omission. Subscription Services Address: Customer Service: Permissions: Subscriptions (US): Site License Inquiries: The Medical Letter, Inc. Call: or To reproduce any portion of this issue, 1 year - $98; 2 years - $189; info@medicalletter.org 145 Huguenot St. Ste. 312 Fax: please your request to: 3 years - $279. $49 per year Call: New Rochelle, NY custserv@medicalletter.org permissions@medicalletter.org for students, interns, residents, and Special rates available for bulk fellows in the US and Canada. subscriptions. Reprints $12 each. Copyright ISSN

New Antibiotics for MRSA

New Antibiotics for MRSA Faculty Warren S. Joseph, DPM, FIDSA Consultant, Lower Extremity Infectious Diseases Roxborough Memorial Hospital Philadelphia, Pennsylvania Faculty Disclosure Dr. Joseph: Speaker