Victorian Infectious Disease Service, Royal Melbourne Hospital, and University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
Menzies School of Health Research, Charles Darwin University, Casuarina, Northern Territory, Australia.
JAMA. 2020 Feb 11;323(6):527-537. doi: 10.1001/jama.2020.0103.
Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a β-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted.
To determine whether combining an antistaphylococcal β-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia.
DESIGN, SETTING, AND PARTICIPANTS: Open-label, randomized clinical trial conducted at 27 hospital sites in 4 countries from August 2015 to July 2018 among 352 hospitalized adults with MRSA bacteremia. Follow-up was complete on October 23, 2018.
Participants were randomized to standard therapy (intravenous vancomycin or daptomycin) plus an antistaphylococcal β-lactam (intravenous flucloxacillin, cloxacillin, or cefazolin) (n = 174) or standard therapy alone (n = 178). Total duration of therapy was determined by treating clinicians and the β-lactam was administered for 7 days.
The primary end point was a 90-day composite of mortality, persistent bacteremia at day 5, microbiological relapse, and microbiological treatment failure. Secondary outcomes included mortality at days 14, 42, and 90; persistent bacteremia at days 2 and 5; acute kidney injury (AKI); microbiological relapse; microbiological treatment failure; and duration of intravenous antibiotics.
The data and safety monitoring board recommended early termination of the study prior to enrollment of 440 patients because of safety. Among 352 patients randomized (mean age, 62.2 [SD, 17.7] years; 121 women [34.4%]), 345 (98%) completed the trial. The primary end point was met by 59 (35%) with combination therapy and 68 (39%) with standard therapy (absolute difference, -4.2%; 95% CI, -14.3% to 6.0%). Seven of 9 prespecified secondary end points showed no significant difference. For the combination therapy vs standard therapy groups, all-cause 90-day mortality occurred in 35 (21%) vs 28 (16%) (difference, 4.5%; 95% CI, -3.7% to 12.7%); persistent bacteremia at day 5 was observed in 19 of 166 (11%) vs 35 of 172 (20%) (difference, -8.9%; 95% CI, -16.6% to -1.2%); and, excluding patients receiving dialysis at baseline, AKI occurred in 34 of 145 (23%) vs 9 of 145 (6%) (difference, 17.2%; 95% CI, 9.3%-25.2%).
Among patients with MRSA bacteremia, addition of an antistaphylococcal β-lactam to standard antibiotic therapy with vancomycin or daptomycin did not result in significant improvement in the primary composite end point of mortality, persistent bacteremia, relapse, or treatment failure. Early trial termination for safety concerns and the possibility that the study was underpowered to detect clinically important differences in favor of the intervention should be considered when interpreting the findings.
ClinicalTrials.gov Identifier: NCT02365493.
重要性：耐甲氧西林金黄色葡萄球菌（MRSA）菌血症的死亡率超过 20%。尽管尚未进行充分的随机临床试验来评估这种干预措施的效果，但联合使用标准治疗和β-内酰胺类抗生素已经被证明可以降低死亡率。
目的：确定与标准治疗相比，联合使用抗葡萄球菌β-内酰胺类抗生素是否比标准治疗更有效治疗 MRSA 菌血症患者。
设计、地点和参与者：这是一项在 2015 年 8 月至 2018 年 7 月期间在 4 个国家的 27 家医院进行的、开放性标签、随机临床试验，纳入了 352 例 MRSA 菌血症住院成人患者。2018 年 10 月 23 日完成了随访。
干预措施：参与者被随机分为标准治疗（静脉万古霉素或达托霉素）加抗葡萄球菌β-内酰胺类抗生素（静脉氟氯西林、氯唑西林或头孢唑林）（n=174）或标准治疗（n=178）。总治疗时间由治疗医生确定，β-内酰胺类抗生素治疗持续 7 天。
主要终点和次要终点：主要终点为 90 天死亡率、第 5 天持续菌血症、微生物学复发和微生物学治疗失败的复合终点。次要终点包括第 14、42 和 90 天死亡率；第 2 和 5 天持续菌血症；急性肾损伤（AKI）；微生物学复发；微生物学治疗失败；以及静脉抗生素的使用时间。
结果：由于安全性问题，数据和安全监测委员会建议在招募 440 名患者之前提前终止试验。在随机分组的 352 名患者（平均年龄 62.2[SD，17.7]岁；121 名女性[34.4%]）中，345 名（98%）完成了试验。联合治疗组有 59 名（35%）达到主要终点，标准治疗组有 68 名（39%）（绝对差异，-4.2%；95%CI，-14.3%至 6.0%）。7 个预先指定的次要终点未显示显著差异。对于联合治疗组与标准治疗组，所有原因 90 天死亡率分别为 35 名（21%）和 28 名（16%）（差异，4.5%；95%CI，-3.7%至 12.7%）；第 5 天持续菌血症分别为 19 名（11%）和 35 名（20%）（差异，-8.9%；95%CI，-16.6%至-1.2%）；排除基线接受透析的患者，AKI 分别为 34 名（23%）和 9 名（6%）（差异，17.2%；95%CI，9.3%至 25.2%）。
结论：在 MRSA 菌血症患者中，与标准抗生素治疗（万古霉素或达托霉素）联合使用抗葡萄球菌β-内酰胺类抗生素并没有显著改善死亡率、持续菌血症、复发或治疗失败的主要复合终点。由于安全性问题提前终止试验以及该研究可能没有足够的效力来检测有利于干预措施的临床重要差异，在解释研究结果时应予以考虑。
试验注册：ClinicalTrials.gov 标识符：NCT02365493。
