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
CIDから報告された、ZEUS trial
RCT 非劣勢 Phase 2/3
ZTI-01
6 g ZTI-01 (IV fosfomycin) intravenously administered every 8 hours (18g total daily dose for 7-14 calendar days)
piperacillin tazobactam
4.5 g piperacillin/tazobactam (4 g piperacillin/0.5 g tazobactam) intravenously administered every 8 hours (13.5g total daily dose for 7-14 calendar days)
Primary Outcome Measures
Number of Patients With an Overall Success [ Time Frame: TOC Visit (Day 19) ]
Clinical cure (resolution or significant improvement in signs and symptoms) and microbiologic eradication (baseline pathogen) in m-MITT population
感想
ZTI-01 は、PIP/TAZと非劣勢でした。
スペクトル超拡大路線でなく、Fosfomycinの活用はいい流れですね。
安全性も統計的に同等ですが、ZTI-01の方が高い傾向であったことはちょっと意外でしたね。
それにしても、ZEUS というネーミングセンスは震えます。
ホスミ神、ゾ神の神対決ということでしょうか
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
