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Clin Infect Dis. 2019 Mar 6. pii: ciz181. doi: 10.1093/cid/ciz181. [Epub ahead of print]

Fosfomycin for injection (ZTI-01) vs Piperacillin-Tazobactam (PIP-TAZ) for the Treatment of Complicated Urinary Tract Infection (cUTI) Including Acute Pyelonephritis (AP): ZEUS, A Phase 2/3 Randomized Trial.

Author information

1
Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, MI.
2
Department of Medicine, Warren Alpert Medical School of Brown University and Rhode Island Hospital and The Miriam Hospital, Providence, RI.
3
DaneStat Consulting, Alderly Edge, UK.
4
Municipal Institution Dnipropetrovsk Medical Academy of MOH of Ukraine, Dnipro, Ukraine.
5
Municipal Institution Zaporizhzhia Regional Clinical Hospital of Zaporizhzhia, Regional Council Department of Urology, State Institution Zaporizhzhia Medical Academy of Postgraduate Education under the Ministry of Health of Ukraine.
6
Brest Regional Hospital, Brest, Belarus.
7
Das Statistical Consulting, Guerneville, CA.
8
Clinical Operations, Zavante Therapeutics, Inc., San Diego, CA.
9
Chief Medical Officer, Zavante Therapeutics, Inc., San Diego, CA.
10
Chief Scientific Officer, Zavante Therapeutics, Inc., San Diego, CA.

Abstract

BACKGROUND:

ZTI-01 (fosfomycin for injection) is an epoxide antibiotic with a differentiated mechanism of action (MOA) inhibiting an early step in bacterial cell wall synthesis. ZTI-01 has broad in vitro spectrum of activity, including multidrug-resistant Gram-negative pathogens, and is being developed for treatment of complicated urinary tract infection (cUTI) and acute pyelonephritis (AP) in the United States.

METHODS:

Hospitalized adults with suspected or microbiologically confirmed cUTI/AP were randomized 1:1 to 6 g ZTI-01 q8h or 4.5 g IV piperacillin-tazobactam (PIP-TAZ) q8h for a fixed 7-day course (no oral switch); patients with concomitant bacteremia could receive up to 14 days.

RESULTS:

Of 465 randomized patients, 233 and 231 were treated with ZTI-01 and PIP-TAZ, respectively. In the microbiologic Modified Intent-to-Treat (m-MITT) population, ZTI-01 met the primary objective of noninferiority compared with PIP-TAZ with overall success rates of 64.7% (119/184 patients) vs 54.5% (97/178 patients), respectively; treatment difference was 10.2% (95% CI: 0.4, 20.8). Clinical cure rates at test-of-cure (TOC, Day 19-21) were high and similar between treatments (90.8% [167/184] vs 91.6% [163/178], respectively). In post-hoc analysis using unique pathogens typed by pulsed-field gel electrophoresis, overall success rates at TOC in mMITT were 69.0% (127/184) for ZTI-01 vs 57.3% (102/178) for PIP-TAZ (difference 11.7% 95% CI: 1.3, 22.1). ZTI-01 was well tolerated. Most TEAEs, including hypokalemia and elevated serum aminotransferases, were mild and transient.

CONCLUSIONS:

ZTI-01 was effective for treatment of cUTI including AP, and offers a new IV therapeutic option with a differentiated MOA for patients with serious Gramnegative infections.

CLINICAL TRIAL REGISTRATION:

NCT02753946.

KEYWORDS:

ZTI-01; acute pyelonephritis; complicated urinary tract infection; fosfomycin

PMID:
30861061
DOI:
10.1093/cid/ciz181

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