A randomized Phase 2 trial of telavancin versus standard therapy in patients with uncomplicated Staphylococcus aureus bacteremia: the ASSURE study

Martin E Stryjewski, Arnold Lentnek, William O'Riordan, John Pullman, Paul Anantharajah Tambyah, Jose M Miró, Vance G Fowler Jr, Steven L Barriere, Michael M Kitt, G Ralph Corey, Martin E Stryjewski, Arnold Lentnek, William O'Riordan, John Pullman, Paul Anantharajah Tambyah, Jose M Miró, Vance G Fowler Jr, Steven L Barriere, Michael M Kitt, G Ralph Corey

Abstract

Background: Staphylococcus aureus bacteremia is a common infection associated with significant morbidity and mortality. Telavancin is a bactericidal lipoglycopeptide active against Gram-positive pathogens, including methicillin-resistant S. aureus (MRSA). We conducted a randomized, double-blind, Phase 2 trial in patients with uncomplicated S. aureus bacteremia.

Methods: Patients were randomized to either telavancin or standard therapy (vancomycin or anti-staphylococcal penicillin) for 14 days. Continuation criteria were set to avoid complicated S. aureus bacteremia. The primary end point was clinical cure at 84 days.

Results: In total, 60 patients were randomized and 58 received ≥1 study medication dose (all-treated), 31 patients fulfilled inclusion/exclusion and continuation criteria (all-treated target [ATT]) (telavancin 15, standard therapy 16), and 17 patients were clinically evaluable (CE) (telavancin 8, standard therapy 9). Mean age (ATT) was 60 years. Intravenous catheters were the most common source of S. aureus bacteremia and ~50% of patients had MRSA. A similar proportion of CE patients were cured in the telavancin (88%) and standard therapy (89%) groups. All patients with MRSA bacteremia were cured and one patient with MSSA bacteremia failed study treatment in each group. Although adverse events (AEs) were more common in the telavancin ATT group (90% vs. 72%), AEs leading to drug discontinuation were similar (7%) in both treatment arms. Potentially clinically significant increases in serum creatinine (≥1.5 mg/dl and at least 50% greater than baseline) were more common in the telavancin group (20% vs. 7%).

Conclusions: This study suggests that telavancin may have utility for treatment of uncomplicated S. aureus bacteremia; additional studies are warranted. (Telavancin for Treatment of Uncomplicated Staphylococcus Aureus Bacteremia (ASSURE); NCT00062647).

Figures

Figure 1
Figure 1
Patient disposition into the study populations. More than one reason may be present for patients to be excluded from all-treated target and/or clinically evaluable populations. SAB, S. aureus bacteremia; TOC, test of cure.

References

    1. Chu VH, Crosslin DR, Friedman JY, Reed SD, Cabell CH, Griffiths RI, Masselink LE, Kaye KS, Corey GR, Reller LB, Stryjewski ME, Schulman KA, Fowler VG Jr. Staphylococcus aureus bacteremia in patients with prosthetic devices: costs and outcomes. Am J Med. 2005;14(12):1416.
    1. Fowler VG Jr, Olsen MK, Corey GR, Woods CW, Cabell CH, Reller LB, Cheng AC, Dudley T, Oddone EZ. Clinical identifiers of complicated Staphylococcus aureus bacteremia. Arch Intern Med. 2003;14(17):2066–2072. doi: 10.1001/archinte.163.17.2066.
    1. Li Y, Friedman JY, O’Neal BF, Hohenboken MJ, Griffiths RI, Stryjewski ME, Middleton JP, Schulman KA, Inrig JK, Fowler VG Jr, Reed SD. Outcomes of Staphylococcus aureus infection in hemodialysis-dependent patients. Clin J Am Soc Nephrol. 2009;14(2):428–434. doi: 10.2215/CJN.03760708.
    1. Klevens RM, Morrison MA, Nadle J, Petit S, Gershman K, Ray S, Harrison LH, Lynfield R, Dumyati G, Townes JM, Craig AS, Zell ER, Fosheim GE, McDougal LK, Carey RB, Fridkin SK. Active Bacterial Core surveillance (ABCs) MRSA Investigators. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA. 2007;14(15):1763–1771. doi: 10.1001/jama.298.15.1763.
    1. Deresinski S. Counterpoint: vancomycin and Staphylococcus aureus–an antibiotic enters obsolescence. Clin Infect Dis. 2007;14(12):1543–1548. doi: 10.1086/518452.
    1. Sakoulas G, Moise-Broder PA, Schentag J, Forrest A, Moellering RC Jr, Eliopoulos GM. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia. J Clin Microbiol. 2004;14(6):2398–2402. doi: 10.1128/JCM.42.6.2398-2402.2004.
    1. Soriano A, Marco F, Martínez JA, Pisos E, Almela M, Dimova VP, Alamo D, Ortega M, Lopez J, Mensa J. Influence of vancomycin minimum inhibitory concentration on the treatment of methicillin-resistant Staphylococcus aureus bacteremia. Clin Infect Dis. 2008;14(2):193–200. doi: 10.1086/524667.
    1. Deresinski S. Vancomycin heteroresistance and methicillin-resistant Staphylococcus aureus. J Infect Dis. 2009;14(5):605–609. doi: 10.1086/596630.
    1. Tenover FC. Vancomycin-resistant Staphylococcus aureus: a perfect but geographically limited storm? Clin Infect Dis. 2008;14(5):675–677. doi: 10.1086/527393.
    1. Chang FY, Peacock JE Jr, Musher DM, Triplett P, MacDonald BB, Mylotte JM, O’Donnell A, Wagener MM, Yu VL. Staphylococcus aureus bacteremia: recurrence and the impact of antibiotic treatment in a prospective multicenter study. Medicine (Baltimore) 2003;14(5):333–339. doi: 10.1097/01.md.0000091184.93122.09.
    1. Stryjewski ME, Szczech LA, Benjamin DK Jr, Inrig JK, Kanafani ZA, Engemann JJ, Chu VH, Joyce MJ, Reller LB, Corey GR, Fowler VG Jr. Use of vancomycin or first-generation cephalosporins for the treatment of hemodialysis-dependent patients with methicillin-susceptible Staphylococcus aureus bacteremia. Clin Infect Dis. 2007;14(2):190–196. doi: 10.1086/510386.
    1. Fowler VG Jr, Boucher HW, Corey GR, Abrutyn E, Karchmer AW, Rupp ME, Levine DP, Chambers HF, Tally FP, Vigliani GA, Cabell CH, Link AS, De Meyer I, Filler SG, Zervos M, Cook P, Parsonnet J, Bernstein JM, Price CS, Forrest GN, Fätkenheuer G, Gareca M, Rehm SJ, Brodt HR, Tice A, Cosgrove SE. S. aureus Endocarditis and Bacteremia Study Group. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006;14(7):653–665. doi: 10.1056/NEJMoa053783.
    1. Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, Kaplan SL, Karchmer AW, Levine DP, Murray BE, J Rybak M, Talan DA, Chambers HF. Clinical practice guidelines by the infectious diseases society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;14(3):285–292. doi: 10.1093/cid/cir034.
    1. Hegde SS, Reyes N, Wiens T, Vanasse N, Skinner R, McCullough J, Kaniga K, Pace J, Thomas R, Shaw JP, Obedencio G, Judice JK. Pharmacodynamics of telavancin (TD-6424), a novel bactericidal agent, against gram-positive bacteria. Antimicrob Agents Chemother. 2004;14(8):3043–3050. doi: 10.1128/AAC.48.8.3043-3050.2004.
    1. Higgins DL, Chang R, Debabov DV, Leung J, Wu T, Krause KM, Sandvik E, Hubbard JM, Kaniga K, Schmidt DE Jr, Gao Q, Cass RT, Karr DE, Benton BM, Humphrey PP. Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2005;14(3):1127–1134. doi: 10.1128/AAC.49.3.1127-1134.2005.
    1. Lunde CS, Hartouni SR, Janc JW, Mammen M, Humphrey PP, Benton BM. Telavancin disrupts the functional integrity of the bacterial membrane through targeted interaction with the cell wall precursor lipid II. Antimicrob Agents Chemother. 2009;14(8):3375–3383. doi: 10.1128/AAC.01710-08.
    1. Miró JM, García-de-la-Mària C, Armero Y, De-Lazzari E, Soy D, Moreno A, Del Rio A, Almela M, Mestres CA, Gatell JM, Jiménez-de-Anta MT, Marco F. Hospital Clínic Experimental Endocarditis Study Group. Efficacy of telavancin in the treatment of experimental endocarditis due to glycopeptide-intermediate Staphylococcus aureus. Antimicrob Agents Chemother. 2007;14(7):2373–2377. doi: 10.1128/AAC.01266-06.
    1. Leuthner KD, Cheung CM, Rybak MJ. Comparative activity of the new lipoglycopeptide telavancin in the presence and absence of serum against 50 glycopeptide non-susceptible staphylococci and three vancomycin-resistant Staphylococcus aureus. J Antimicrob Chemother. 2006;14(2):338–343. doi: 10.1093/jac/dkl235.
    1. Hegde SS, Skinner R, Lewis SR, Krause KM, Blais J, Benton BM. Activity of telavancin against heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) in vitro and in an in vivo mouse model of bacteraemia. J Antimicrob Chemother. 2010;14(4):725–728. doi: 10.1093/jac/dkq028.
    1. Madrigal AG, Basuino L, Chambers HF. Efficacy of Telavancin in a rabbit model of aortic valve endocarditis due to methicillin-resistant Staphylococcus aureus or vancomycin-intermediate Staphylococcus aureus. Antimicrob Agents Chemother. 2005;14(8):3163–3165. doi: 10.1128/AAC.49.8.3163-3165.2005.
    1. Marcos LA, Camins BC. Successful treatment of vancomycin-intermediate Staphylococcus aureus pacemaker lead infective endocarditis with telavancin. Antimicrob Agents Chemother. 2010;14(12):5376–5378. doi: 10.1128/AAC.00857-10.
    1. Nace H, Lorber B. Successful treatment of methicillin-resistant Staphylococcus aureus endocarditis with telavancin. J Antimicrob Chemother. 2010;14(6):1315–1316. doi: 10.1093/jac/dkq113.
    1. Agresti A, Caffo B. Simple and effective confidence intervals for proportions and differences of proportions result from adding two successes and two failures. Am Stat. 2000;14(4):280–288.
    1. Skinner D, Keefer CS. Significance of bacteremia caused by Staphylococcus aureus: a study of one hundred and twenty-two cases and a review of the literature concerned with experimental infection in animals. Arch Intern Med. 1941;14(5):851–875. doi: 10.1001/archinte.1941.00200110003001.
    1. Hawkins C, Huang J, Jin N, Noskin GA, Zembower TR, Bolon M. Persistent Staphylococcus aureus bacteremia: an analysis of risk factors and outcomes. Arch Intern Med. 2007;14(17):1861–1867. doi: 10.1001/archinte.167.17.1861.
    1. Jensen AG, Wachmann CH, Espersen F, Scheibel J, Skinhoj P, Frimodt-Møller N. Treatment and outcome of Staphylococcus aureus bacteremia: a prospective study of 278 cases. Arch Intern Med. 2002;14(1):25–32. doi: 10.1001/archinte.162.1.25.
    1. Stryjewski ME, Graham DR, Wilson SE, O’Riordan W, Young D, Lentnek A, Ross DP, Fowler VG, Hopkins A, Friedland HD, Barriere SL, Kitt MM, Corey GR. Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by gram-positive organisms. Clin Infect Dis. 2008;14(11):1683–1693. doi: 10.1086/587896.
    1. Bauer KA, West JE, Balada-Llasat JM, Pancholi P, Stevenson KB, Goff DA. An antimicrobial stewardship program’s impact with rapid polymerase chain reaction methicillin-resistant Staphylococcus aureus/S. aureus blood culture test in patients with S. aureus bacteremia. Clin Infect Dis. 2010;14(9):1074–1080. doi: 10.1086/656623.

Source: PubMed

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