Program Schedule

265
Hepatic Safety in Acute Bacterial Skin and Skin Structure Infection (ABSSSI) Patients Receiving Tedizolid (TZD) versus Linezolid (LZD)

Session: Poster Abstract Session: Antimicrobial Resistance: Novel Agents and Approaches to Gram-positive Infections
Thursday, October 9, 2014
Room: The Pennsylvania Convention Center: IDExpo Hall BC
Posters
  • 150100334-06 Hepatic Tolerability Poster_L4 10.03.14_FINAL.pdf (760.4 kB)
  • Background: TZD is a novel oxazolidinone with potent antibacterial activity against a wide range of Gram-positive pathogens. In two randomized, double-blind, Phase (Ph) 3 noninferiority trials, ESTABLISH-1 and -2, TZD 200 mg qd for 6 days was noninferior to LZD 600 mg bid in treating ABSSSI. This analysis was conducted to identify any evidence of Drug-Induced Serious Hepatotoxicity (DISH) in a large TZD clinical trial database (Ph 2 and 3) and to assess the effect of TZD in Ph 3 ABSSSI patients (pts) with normal hepatic function, hepatic impairment (HI), or hepatic disease (HD), as measured by incidence of TEAE, TEAE leading to drug discontinuation (D/C), and SAE.

    Methods: Hy's Law (HL) defines DISH as unexplained serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3x upper limit of normal (ULN) + total bilirubin (TBL) >2x ULN without alkaline phosphatase elevation; Temple's corollary (TC) defines it as ALT elevation >3x ULN without TBL elevation. Pts from Ph 2 and 3 trials who received ≥1 TZD or LZD dose with ≥1 on-treatment ALT/TBL value were included. A scatterplot of maximum ALT/AST divided by ULN (/ULN) vs max TBL/ULN was generated on a log10 scale (Figure 1). Safety assessments were performed as described above.

    Results: The DISH population comprised 1024 TZD- and 621 LZD-treated pts who had ALT and TBL values. No TZD pts but 1 LZD pt met HL criteria after the first dose. Thirty-six TZD (3.5%) and 26 LZD (4.1%) pts met TC criteria. TZD pts had no evidence of DISH following medical review. The incidence of TEAE, TEAE leading to D/C, and SAE were similar in both arms in Ph 3 trials (Table).

    Conclusion: There was no DISH signal in a safety database from Ph 2 and Ph 3 clinical trials in ABSSSI. TEAE profiles were similar for Ph 3 TZD- and LZD-treated patients with HI/HD, and those with normal hepatic function, suggesting no worsening of hepatic function.

     

    Figure 1. Drug-Induced Serious Hepatotoxicity

    Table 1. Incidence of TEAE, TEAE leading to drug discontinuation (D/C), and serious AE (SAE)

    Pts

    TZD

    (N = 662)

    LZD

    (N = 662)

    n

    %

    n

    %

    Normal

    n = 474

    n = 443

    ≥1 TEAE

    202

    42.6

    183

    41.3

    TEAE → D/C

    1

    0.2

    3

    0.7

    ≥1 SAE

    9

    1.9

    7

    1.6

    HI

    n = 14

    n = 12

    ≥1 TEAE

    3

    21.4

    5

    41.7

    TEAE → D/C

    0

    0

    0

    0

    ≥1 SAE

    1

    7.1

    2

    16.7

    HD

    n = 175

    n = 209

    ≥1 TEAE

    78

    44.6

    98

    46.9

    TEAE → D/C

    2

    1.1

    3

    1.4

    ≥1 SAE

    2

    1.1

    4

    1.9

    HI: Child-Pugh score ≥7; HD: Baseline ALT/AST >2 ULN or hepatitis C seropositivity.

     

    Catherine Hardalo, Edward Fang, Carisa De Anda, Sonia Minassian and Philippe Prokocimer, Cubist, San Diego, CA

    Disclosures:

    C. Hardalo, Cubist: Consultant, Consulting fee

    E. Fang, Trius/Cubist: Employee, Salary

    C. De Anda, Cubit: Employee and Shareholder, Salary

    S. Minassian, Cubist: Consultant, Consulting fee

    P. Prokocimer, Cubist: Employee and Shareholder, Salary

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