3児の親さん薬剤師のブログ

とある薬剤師です。感染症治療を考える素材をちょこっと提供。noteもあります https://note.com/twin1980

Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal β-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia

JAMAに報告された、MRSA菌血症患者に対し、バンコマイシンまたはダプトマイシン静脈投与による標準治療にβラクタム系抗菌薬を追加投与した研究。

 

主要エンドポイントは、90日時点における死亡、5日時点の持続性菌血症、微生物学的再発、微生物学的治療失敗の複合エンドポイント。

 

https://jamanetwork.com/journals/jama/article-abstract/2760737?widget=personalizedcontent&previousarticle=2760718

 

 感想

 

見事なネガティブ結果。

 

耐性菌との戦い、真の新薬が枯渇する中、コンビネーション検討は今後も進めなければなりません。

 

主要エンドポイントの発生は、βラクタム群59例(35%)、標準治療群68例(39%)だった(絶対群間差:-4.2ポイント、95%CI:-14.3~6.0)

 

 

Key Points

Question  In adults with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, does the addition of 7 days of an antistaphylococcal β-lactam (flucloxacillin, cloxacillin, or cefazolin) to standard antibiotic therapy (vancomycin or daptomycin) lead to improved clinical outcomes at 90 days?

Findings  In this randomized clinical trial that included 352 patients and was stopped early because of increased risk of acute kidney injury in the intervention group, the addition of an antistaphylococcal β-lactam to standard therapy, compared with standard therapy alone, resulted in no significant difference in the primary composite end point of mortality, bacteremia, relapse, or treatment failure (35% vs 39%, respectively).

Meaning  Among patients with MRSA bacteremia, the addition of an antistaphylococcal β-lactam to standard antibiotic therapy did not significantly reduce the primary composite end point.

 

Abstract

Importance  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.

Objective  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.

Interventions  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.

Main Outcomes and Measures  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.

Results  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%).

Conclusions and Relevance  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.

Trial Registration  ClinicalTrials.gov Identifier: NCT02365493