Effect
of Empirical Treatment With Moxifloxacin and Meropenem vs Meropenem on
Sepsis-Related Organ Dysfunction in Patients With Severe Sepsis: A
Randomized TrialTreatment for
Sepsis-Related Organ Dysfunction
JAMA.
2012;():1-10. doi:10.1001/jama.2012.5833
Published
online
背景
patients with neutropenic fever and in patients with
severe sepsisに対して，不適切な抗菌薬による治療は死亡率増加に関係する．
To decrease the
likelihood of inappropriate antimicrobial therapy, recent international sepsis
guidelines suggest empirical combination therapy targeting gram-negative
bacteria, particularly for patients with suspected Pseudomonas infections.
However, the authors of this guideline state
that “no study or meta-analysis has convincingly demonstrated that combination
therapy produces a superior clinical outcome for individual pathogens in a
particular patient group.”
（2008年Surviving
Sepsis Campaign: international guidelines for management of severe sepsis and
septic shock）
目的
sepsis-related
organ dysfunctionに対するMEPM単独治療と，MEPM+MFLX併用治療の効果を比較する．
方法
severe sepsis or
septic shockのクライテリアを満たす600例の患者のうち298例をmonotherapy group，302例をcombination therapy群に割りつけた．
monotherapy: intravenous
MEPM alone (1 g every 8 hours)
combination therapy
MEPM+MFLX (400 mg every 24 hours)
combination therapy MEPM+MFLX (400 mg every 24 hours)
primary study endpoint
mean of the daily total SOFA score（14日間にわたり評価）
secondary endpoints
all-cause mortality at 28 days and 90 days
評価可能であった症例数
monotherapy group 273名，combination therapy group 278名
Mean SOFA score は両群間で有意差なし．
combination群(8.3 points; 95% confidence interval, 7.8 -
8.8 points)
monotherapy群(7.9 points; 95% CI, 7.5 - 8.4 points; P
= .36).
28-day and 90-day
mortality rates, serious adverse events, or major adverse event profilesに有意差なし．
combination群, day 28までの死亡数66名 (23.9%; 95% CI, 19.0% - 29.4%)
monotherapy群,day 28までの死亡数59名(21.9%; 95% CI, 17.1% - 27.4%;). P = .58
combination群, day90までの死亡数96名(35.3%; 95% CI, 29.6% - 41.3%)
monotherapy群,day 90までの死亡数84名(32.1%; 95% CI, 26.5% - 38.1%). P = .43
ICU退室またはday 21までにmonotherapy群はcombination群と比較してcarbapenem-resistant
pathogensの比率が多かったが，症例は少なかった(8
patients vs 1 patient; Table 4).治療期間中にcarbapenem
resistanceを獲得することが報告されており，fluoroquinolonesを初期から併用することは，耐性獲得のリスクの抑制をもたらしているのかもしれない．
考察
To our knowledge, this is the first randomized trial
of the empirical use of combination therapy compared with monotherapy in
patients with severe sepsis or septic shock.
しかしmonotherapyよりcombination therapyの有用性を報告したいくつかの無作為試験がある．
→endocarditis,
gram-negative bacteremia, and neutropenic sepsis,5 ,10 ,21 and
animal models,11 ,22 - 23 ・two separate meta-analyses both.24 - 25
immunocompetent patients with sepsis, gram-negative bacteremia, or bothを対象
β-lactams and aminoglycosidesのbenefitを示した．
・a meta-regression study by Kumar et al26
critically ill patients with septic shockに限ると，combination therapyの有益性が認められる．
・retrospective,
propensity-matched, multicenter cohort study 4662 patients with
culture-positive,
bacterial septic shock , also by Kumar et al,27
combination therapyの有用性
28-day mortality (36.3% vs 29.0%; HR, 0.77 [95% CI, 0.67-0.88]; P <.001) and hospital mortality (47.8% vs 37.4%; odds ratio, 0.69 [95% CI, 0.59-0.81]; P <.001)
ventilator-free day，pressor/inotropic free dayの延長
これらの所見は，β-lactamsにaminoglycosides,
fluoroquinolones, or macrolides/clindamycinを併用した群に限局して認められた．
carbapenems,
extended-spectrum β-lactam or β-lactamase inhibitor combinations, and
antipseudomonal cephalosporinsはcombination therapyに関して有用性なし．
本研究のlimitations
a lack of
generalizability to other antibiotic combinations or patient populations