1830. Phenotypic Antibiotic Resistance in ZEUS: A Multi-center, Randomized, Double-Blind Phase 2/3 Study of ZTI-01 versus Piperacillin-Tazobactam (P-T) in the Treatment of Patients with Complicated Urinary Tract Infections (cUTI) including Acute Pyelonephritis (AP)
Session: Poster Abstract Session: Clinical Study with New Antibiotics and Antifungals
Saturday, October 7, 2017
Room: Poster Hall CD
Posters
  • Zavante_Poster1830_revCC KS.pdf (99.7 kB)
  • Background: Phenotypic resistance profiles are frequently employed to target appropriate antibiotic treatments. With increasing rates of resistance, antibiotics with a new mechanisms of action are needed. ZTI-01 (fosfomycin for injection) is an injectable epoxide antibiotic with a broad spectrum of activity including multidrug-resistant (MDR) pathogens. ZTI-01 acts at an early step in cell wall synthesis inhibition by covalently binding to MurA, and is being developed for the treatment of complicated urinary tract infections (cUTI) and acute pyelonephritis (AP) in the US.

    Methods: ZEUS study was a multicenter, randomized, double-blind Phase 2/3 trial designed to evaluate safety and efficacy of ZTI-01 in treatment of hospitalized adults with cUTI or acute pyelonephritis versus piperacillin/tazobactam (P-T). Patients received either 6 g ZTI-01 or 4.5 g P-T as 1-hour IV infusions q8h for a fixed 7 days (up to 14 days if concurrent bacteremia). Clinical cure and microbiologic eradication were assessed at the test-of-cure (TOC) visit (Day 19). Using minimum inhibitory concentrations (MICs), blood or urine isolates bearing phenotypic resistance for extended-spectrum beta-lactamases (ESBL: ≥2 µg/mL, aztreonam, ceftazidime or ceftriaxone), carbapenem-resistant Enterobacteriaceae (CRE: ≥4 µg/mL imipenem or meropenem), Amino-R (gentamicin or amikacin resistance), or MDR (nonsusceptibility ≥3 classes) were identified to assess patient and microbiologic outcome.

    Results: In the m-MITT population, 123/362 patients (34%) were infected with a pathogen exhibiting phenotypic resistance: MDR (19%), ESBL (31%), Amino-R (17%), and CRE (6.1%). Clinical cure and microbiologic eradication are presented in Table 1.

    Table 1. Phenotypic Resistance (TOC, m-MITT, % (n))

    ESBL

    Amino-R

    CRE

    MDR

    Cure

    Erad.

    Cure

    Erad.

    Cure

    Erad.

    Cure

    Erad.

    ZTI-01

    93%

    (52/56)

    55%

    (32/58)

    97%

    (29/30)

    67%

    (20/30)

    100%

    (9/9)

    56%

    (5/9)

    92%

    (34/37)

    54%

    (20/37)

    P-T

    93%

    (51/55)

    47%

    (27/58)

    94%

    (29/31)

    38%

    (12/32)

    85%

    (11/13)

    31%

    (4/13)

    90%

    (28/31)

    36%

    (12/33)

    Conclusion: Overall, treatment arms were balanced with number and type of isolates bearing phenotypic resistance and clinical cure rates were high. Eradication rates numerically favored ZTI-01.

    Paul B Eckburg, MD1, David Skarinsky, BS1, Anita Das, PhD2 and Evelyn J. Ellis-Grosse, PhD1, (1)Zavante Therapeutics, Inc., San Diego, CA, (2)Das Statistical Consulting, Guerneville, CA

    Disclosures:

    P. B. Eckburg, Zavante Therapeutics, Inc.: Consultant and Shareholder , Consulting fee

    D. Skarinsky, Zavante Therapeutics, Inc.: Employee and Shareholder , Salary

    A. Das, Zavante Therapeutics, Inc.: Consultant , Consulting fee

    E. J. Ellis-Grosse, Zavante Therapeutics, Inc.: Employee and Shareholder , Salary

    Findings in the abstracts are embargoed until 12:01 a.m. PDT, Wednesday Oct. 4th with the exception of research findings presented at the IDWeek press conferences.