Fosfomycin for Injection (ZTI-01) Versus Piperacillin-tazobactam for the Treatment of Complicated Urinary Tract Infection Including Acute Pyelonephritis: ZEUS, A Phase 2/3 Randomized Trial

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 intravenous (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% confidence interval [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 m-MITT were 69.0% (127/184) for ZTI-01 versus 57.3% (102/178) for PIP-TAZ (difference 11.7% 95% CI: 1.3, 22.1). ZTI-01 was well tolerated. Most treatment-emergent adverse events, 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 Gram-negative infections.

Clinical trial registration: NCT02753946.

Keywords: ZTI-01; acute pyelonephritis; complicated urinary tract infection; fosfomycin.

Figure 1.

Study design. N: Number of patients in the ITT population. Percentages were calculated using the number of patients in the ITT population as the denominator. A, Completed study drug was defined as completing 7 to 14 days of treatment. B, Only included patients who received study drug. Patient 1401–16 had an adverse event and did not receive study drug. Abbreviations: ITT, intent-to-treat; LFU, late follow-up; PIP-TAZ, piperacillin-tazobactam; TOC, test of cure; ZTI-01, fosfomycin for injection.

Figure 2.

Analysis population disposition. Percentages were calculated using the number of patients in the ITT population as the denominator. Abbreviations: CE, clinical evaluable; CFU, colony-forming unit; EOT, end of treatment; I/E, inclusion/exclusion; ITT, intent-to-treat; LFU, late follow-up; ME, microbiologic evaluable; MITT, modified intent to treat; m-MITT, microbiologic modified intent to treat; PIP-TAZ, piperacillin-tazobactam; TOC, test of cure; ZTI-01, fosfomycin for injection.