Combination Therapy for MRSA Bacteremia: To β or Not to β?
Combination Therapy for MRSA Bacteremia: To β or Not to β?
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MRSA 菌血症的联合治疗：β 还是不β？
DOI：
10.1093/cid/ciz750
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Joshua S. Davis
中科院分区：
文献类型：
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作者：
T. Holland;Joshua S. Davis
耐甲氧西林金黄色葡萄球菌菌血症（MRSAB）是否应该用单药治疗还是联合抗生素治疗几十年来一直是一个不确定的领域。一方面，万古霉素50多年来一直是严重MRSA感染的主要药物;事实上，尽管有关于其过时的传言[1]，但它仍然是全球最常用的MRSA抗生素。另一方面，MRSAB结局仍然很差，死亡率和治疗失败率持续很高[2]。然而，临床医生渴望转向更好的东西，但由于缺乏高质量的试验而感到沮丧[3]。结果是异质性的实践模式[4，5]，大多数临床医生在大多数时间倾向于万古霉素或达托霉素单药治疗MRSA，联合抗生素治疗保留给失败风险较高的患者-例如持续菌血症，万古霉素最低抑菌浓度（MIC）升高，血管内假体材料或MRSA心内膜炎[6]。使用MRSAB联合治疗是有代价的，可以预见的是，以药物不良事件的形式。这是一个教训，我们至少已经学到了两次。添加一种氨基糖苷类抗生素。根据体外数据[7]、证明菌血症清除更快的试验数据[8]和专家意见[9]的组合，金黄色心内膜炎曾一度成为标准治疗，直到人们认识到氨基糖苷类药物的肾毒性超过了血培养快速灭菌的任何益处[10]。最近，利福平看起来很有希望[11]，直到一项大型的、进行良好的试验表明，在标准抗生素治疗中加入利福平对一般人群的S.金黄色葡萄球菌菌血症，但确实导致增加的药物修饰不良事件和药物-药物相互作用[12]。尽管有这些结果，但有理由对具有广泛治疗指数的β-内酰胺类药物联合治疗可能在过去的联合治疗失败的情况下取得成功抱有希望。有充分的证据表明β-内酰胺联合治疗在杀灭沙门氏菌方面具有协同作用。金黄色葡萄球菌[13-15]。观察数据和小型试验令人鼓舞（表1）。最有希望的是，先导性CAMERA 1试验证明，与万古霉素单药治疗相比，万古霉素+氟氯西林联合治疗MRSA的血培养清除更快[16]。在这一期的临床传染病中，Jorgensen及其同事进一步增加了证据基础，报告了72例接受达托霉素加β内酰胺治疗的MRSA菌血症患者的回顾性队列结果，并将其结果与157例接受达托霉素单药治疗的患者进行了比较[23]。该队列占研究期间2家医院所有MRSAB病例的约15%;大多数患者接受万古霉素（非达托霉素）治疗，因此不符合本研究的资格。本文报告的达托霉素治疗患者明显患有急性和慢性疾病（中位APACHE-II评分16，慢性共病患病率高），大多数患者的万古霉素MIC为2 mg/L（61.4%的患者因此从初始万古霉素治疗转为达托霉素治疗），因此这些患者是高度选择的患者组，可能存在治疗失败的重大风险。简而言之，这是一个联合治疗的获益（如果存在）最有可能显现的人群，但也是一个药物相关不良事件风险较高的人群。β-内酰胺联合治疗在少数病例（34.7%）中明确用于MRSA治疗目的;更多情况下，它是MRSA治疗的一部分。
Whether methicillin-resistant Staphy lococcus aureus bacteremia (MRSAB) should be treated with monotherapy versus combination antibiotic therapy has been an area of uncertainty for decades. On the one hand, vancomycin has been the mainstay for serious MRSA infections for more than 50 years; indeed, despite rumors of its obsolescence [1], it endures as the most commonly prescribed antibiotic for MRSAB globally. On the other hand, MRSAB outcomes remain stubbornly poor, with persistently high mortality and treatment failure rates [2]. However, clinicians eager to move on to something better have been frustrated by a dearth of high-quality trials [3]. The result is heterogeneous practice patterns [4, 5], with most clinicians favoring either vancomycin or daptomycin monotherapy for MRSAB most of the time, and combination antibiotic therapy reserved for patients at higher risk of failure—such as persistent bacteremia, elevated vancomycin minimum inhibitory concentration (MIC), endovascular prosthetic material, or MRSA endocarditis [6]. Use of MRSAB combination therapy comes at a cost, predictably, in the form of adverse drug events. This is a lesson we have learned at least twice before. Adding an aminoglycoside for S. aureus endocarditis was for a time the standard of care, based on a combination of in vitro data [7], trial data that demonstrated faster clearance of bacteremia [8], and expert opinion [9], until it was recognized that the nephrotoxicity of aminoglycosides outweighed any benefit of faster sterilization of blood cultures [10]. More recently, rifampin looked promising [11] until a large, well-conducted trial showed that the addition of rifampin to standard antibiotic therapy was not beneficial for a general population of patients with S. aureus bacteremia but did lead to increased antibiotic-modifying adverse events and drug-drug interactions [12]. These results notwithstanding, there is reason to be hopeful that combination therapy with beta-lactams, which have a wide therapeutic index, may succeed where past combinations have failed. There is ample evidence that beta-lactam combination therapy is synergistic in killing S. aureus [13–15]. Observational data and small trials have been encouraging (Table 1). Most promisingly, the pilot CAMERA1 trial demonstrated faster blood culture clearance with a combination of vancomycin plus flucloxacillin for MRSAB, compared to vancomycin monotherapy [16]. In this issue of Clinical Infectious Diseases, Jorgensen and colleagues add further to the evidence base, reporting the outcomes of a retrospective cohort of 72 patients with MRSA bacteremia treated with daptomycin plus a betalactam, and comparing their outcomes to those of 157 patients treated with daptomycin monotherapy [23]. This cohort represents~ 15% of all MRSAB cases at the 2 hospitals during the study period; the majority of patients were treated with vancomycin (not daptomycin) and thus were not eligible for this study. The daptomycin-treated patients reported here were notably both acutely and chronically ill (median APACHE-II score 16, high prevalence of chronic comorbid conditions), and the majority had a vancomycin MIC of 2 mg/L (and 61.4% were switched from initial vancomycin therapy to daptomycin for this reason), so these were a highly selected group of patients likely at substantial risk of treatment failure. In short, this was a population where a benefit of combination therapy, if present, was most likely to be manifest but also a population at high risk of drug-related adverse events. Beta-lactam combination therapy was expressly used for the purposes of MRSA treatment in a minority of cases (34.7%); more often it was part …