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
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
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DOI：
10.1093/cid/ciz181
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发表时间：
2019-12-15
影响因子：
11.8
通讯作者：
Ellis-Grosse, Evelyn J.
中科院分区：
文献类型：
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作者：
Kaye, Keith S.;Rice, Louis B.;Ellis-Grosse, Evelyn J.
背景资料。ZTI-01(注射用磷霉素)是一种环氧类抗生素，具有差异化作用机制(MOA)，可抑制细菌细胞壁合成的早期步骤。ZTI-01具有广泛的体外活性谱，包括多药耐药的革兰氏阴性病原菌，正在美国开发用于治疗复杂尿路感染(CUTI)和急性肾盂肾炎(AP)。疑似或微生物确诊为cUTI/AP的住院成年人被随机分为1：1~6g ZTI-01 q8h或4.5g静脉注射哌拉西林-他唑巴坦(PIP-TAZ)q8h，疗程固定为7天(无口服切换)；合并菌血症患者最多可接受14天治疗。在465名随机患者中，分别有233名和231名患者接受了ZTI-01和PIP-TAZ的治疗。在微生物改良意向治疗(m-MITT)人群中，与PIP-TAZ相比，ZTI-01达到了非劣势的主要目标，总成功率分别为64.7%(119/184例患者)和54.5%(97/178例患者)；治疗差异为10.2%(95%可信区间[CI]：-0.4，20.8)。治愈试验(TOC，第19-21天)的临床治愈率很高，治疗之间相似(分别为90.8%[167/184]vs91.6%[163/178])。在使用脉冲场凝胶电泳法分型的独特病原体的事后分析中，ZTI-01的总TOC成功率为69.0%(127/184)，而PIP-TAZ的总成功率为57.3%(102/178)(差异11.7%，95%CI：1.3，22.1)。ZTI-01耐受性良好。大多数治疗中出现的不良反应，包括低钾血症和血清转氨酶升高，都是轻微的和短暂的。ZTI-01对包括AP在内的慢性尿路感染有效，并为严重革兰氏阴性感染患者提供了一种新的静脉治疗选择，具有差异化的MOA。
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.