每日 1 次普拉唑米星治疗复杂性尿路感染。

Once-Daily Plazomicin for Complicated Urinary Tract Infections.

机构信息

From the Justus Liebig University, Giessen, Germany (F.M.E.W.); Achaogen, South San Francisco (D.J.C., A.S.K., D.S.C., K.M.K., T.R.K., L.E.C., I.F.), the David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles (L.G.M.), and Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance (L.G.M.) - all in California; and Vanderbilt University Medical Center, Nashville (J.P.D.).

出版信息

N Engl J Med. 2019 Feb 21;380(8):729-740. doi: 10.1056/NEJMoa1801467.

DOI:10.1056/NEJMoa1801467

PMID:30786187

Abstract

BACKGROUND

The increasing multidrug resistance among gram-negative uropathogens necessitates new treatments for serious infections. Plazomicin is an aminoglycoside with bactericidal activity against multidrug-resistant (including carbapenem-resistant) Enterobacteriaceae.

METHODS

We randomly assigned 609 patients with complicated urinary tract infections (UTIs), including acute pyelonephritis, in a 1:1 ratio to receive intravenous plazomicin (15 mg per kilogram of body weight once daily) or meropenem (1 g every 8 hours), with optional oral step-down therapy after at least 4 days of intravenous therapy, for a total of 7 to 10 days of therapy. The primary objective was to show the noninferiority of plazomicin to meropenem in the treatment of complicated UTIs, including acute pyelonephritis, with a noninferiority margin of 15 percentage points. The primary end points were composite cure (clinical cure and microbiologic eradication) at day 5 and at the test-of-cure visit (15 to 19 days after initiation of therapy) in the microbiologic modified intention-to-treat population.

RESULTS

Plazomicin was noninferior to meropenem with respect to the primary efficacy end points. At day 5, composite cure was observed in 88.0% of the patients (168 of 191 patients) in the plazomicin group and in 91.4% (180 of 197 patients) in the meropenem group (difference, -3.4 percentage points; 95% confidence interval [CI], -10.0 to 3.1). At the test-of-cure visit, composite cure was observed in 81.7% (156 of 191 patients) and 70.1% (138 of 197 patients), respectively (difference, 11.6 percentage points; 95% CI, 2.7 to 20.3). At the test-of-cure visit, a higher percentage of patients in the plazomicin group than in the meropenem group were found to have microbiologic eradication, including eradication of Enterobacteriaceae that were not susceptible to aminoglycosides (78.8% vs. 68.6%) and Enterobacteriaceae that produce extended-spectrum β-lactamases (82.4% vs. 75.0%). At late follow-up (24 to 32 days after initiation of therapy), fewer patients in the plazomicin group than in the meropenem group had microbiologic recurrence (3.7% vs. 8.1%) or clinical relapse (1.6% vs. 7.1%). Increases in serum creatinine levels of 0.5 mg or more per deciliter (≥40 μmol per liter) above baseline occurred in 7.0% of patients in the plazomicin group and in 4.0% in the meropenem group.

CONCLUSIONS

Once-daily plazomicin was noninferior to meropenem for the treatment of complicated UTIs and acute pyelonephritis caused by Enterobacteriaceae, including multidrug-resistant strains. (Funded by Achaogen and the Biomedical Advanced Research and Development Authority; EPIC ClinicalTrials.gov number, NCT02486627.).

摘要

背景

革兰氏阴性尿路病原体的耐药性不断增加，需要新的治疗方法来治疗严重感染。普拉佐米星是一种氨基糖苷类药物，对包括耐碳青霉烯类肠杆菌科在内的多种耐药菌具有杀菌作用。

方法

我们将 609 例复杂性尿路感染（UTI）患者（包括急性肾盂肾炎）随机分为 1:1 组，分别接受静脉注射普拉佐米星（15mg/公斤体重，每日 1 次）或美罗培南（1g/8 小时）治疗，至少 4 天的静脉治疗后可选择口服降阶梯治疗，总疗程为 7 至 10 天。主要目的是证明普拉佐米星在治疗复杂性 UTI（包括急性肾盂肾炎）方面不劣于美罗培南，非劣效性边界为 15 个百分点。主要终点是在微生物学改良意向治疗人群中第 5 天和治疗后评估（开始治疗后 15 至 19 天）的复合治愈率（临床治愈和微生物学清除）。

结果

普拉佐米星在主要疗效终点方面不劣于美罗培南。第 5 天，普拉佐米星组 191 例患者中有 88.0%（168 例）和美罗培南组 197 例患者中有 91.4%（180 例）达到复合治愈（差异为-3.4 个百分点；95%置信区间为-10.0 至 3.1）。在治疗后评估时，普拉佐米星组和美罗培南组分别有 81.7%（156 例）和 70.1%（138 例）的患者达到复合治愈（差异为 11.6 个百分点；95%置信区间为 2.7 至 20.3）。在治疗后评估时，普拉佐米星组比美罗培南组有更高比例的患者达到微生物学清除，包括对氨基糖苷类药物不敏感的肠杆菌科（78.8%比 68.6%）和产超广谱β-内酰胺酶的肠杆菌科（82.4%比 75.0%）的清除。在晚期随访（开始治疗后 24 至 32 天）中，普拉佐米星组比美罗培南组的微生物学复发（3.7%比 8.1%）和临床复发（1.6%比 7.1%）患者更少。普拉佐米星组有 7.0%的患者血清肌酐水平较基线升高 0.5mg/dL 或以上（≥40μmol/L），美罗培南组有 4.0%的患者出现这种情况。