Evidence to improve the treatment of infections caused by carbapenem-resistant Gram-negative bacteria

FedericoPerez, Robert ABonomo

Lancet Infect Dis 2018; 8: 358-360

https://doi.org/10.1016/S1473-3099(18)30112-9

WHO recognises carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Entero-bacteriaceae as pathogens of crucial importance for the development of novel antibiotics.¹ These bacteria manifest resistance to our most trusted therapeutics and, as a result of their increasing prevalence and transmissibility, are becoming an overwhelming health-care burden.² Over the past decade, polymyxins (an old class of cationic antimicrobial peptideantibiotics) became the drugs of last resort to treat carbapenem-resistant Gram-negative bacteria. Although advances have been made in understanding the pharmacology and toxicity of polymyxin B and polymyxin E (ie, colistin) many questions remain; among them, does the use of polymyxins in combination with other antibiotics lead to better clinical outcomes?³

WHO认为，耐碳青霉烯鲍曼不动杆菌、铜绿假单胞菌及肠杆菌科细菌是对新型抗生素产生耐药的重要致病菌。这些细菌对我们最为信赖的治疗药物显示耐药性，由于其罹患率及传播性日益增加，已经成为严峻的公共卫生负担。在过去10年间，多粘菌素成为治疗耐碳青霉烯革兰阴性菌的最后一道屏障。尽管我们对于多粘菌素B和多粘菌素E的药理学及毒性有了深入了解，但仍存在很多问题；例如，多粘菌素与其他抗生素联合使用是否能够改善临床预后？

In The Lancet Infectious Diseases, Mical Paul and colleagues⁴ report on the AIDA trial: a randomised controlled trial, at six sites in Israel, Greece, and Italy, comparing colistin and meropenem with colistin alone for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria. In patients with mostly ventilator-associated pneumonia or hospital-acquired pneumonia and bloodstream infection caused by carbapenem-resistant A baumannii, the combination of colistin and meropenem did not result in fewer clinical failures than colistin alone. These results are in concordance with two randomised controlled trials in patients infected with carbapenem-resistant A baumanniitreated with colistin in combination with rifampicin versus colistin alone,^5,6 and with a smaller trial that randomised patients to receive either colistin plus fosfomycin or colistin alone.⁷ Given the evidence, the authors state that additional antibiotics should not be used in combination with colistin for the treatment of carbapenem-resistant A baumannii, to avoid potential drug-related adverse events, selection of resistant bacteria, and Clostridium difficile infection.

在Lancet Infectious Diseases杂志上，Mical Paul及其同事报告了AIDA试验的结果：这是一项随机对照试验，在以色列、希腊和意大利的6个中心进行，比较了粘菌素联合应用美罗培南及单独使用粘菌素对于耐碳青霉烯革兰阴性菌引起严重感染的疗效。对于耐碳青霉烯鲍曼不动杆菌引起的呼吸机相关肺炎或医院获得性肺炎及血行性感染患者，与单独使用粘菌素相比，联合应用粘菌素和美罗培南不能减少临床治疗失败。这些结果与另外两项随机对照试验一致（这两项研究对于耐碳青霉烯鲍曼不动杆菌感染患者联合使用粘菌素和利福平，或单独使用粘菌素），也与一项较小样本试验结果相似（将患者随机分组，分别使用粘菌素和磷霉素，或单独使用粘菌素）。基于上述证据，作者表示，使用粘菌素治疗耐碳青霉烯鲍曼不动杆菌感染时，不应加用其他抗生素，以避免出现可能的药物相关不良事件、选择耐药细菌或难辨梭状芽孢杆菌感染。

Does the AIDA trial close the door on combination therapy for the treatment of all carbapenem-resistant A baumannii or other Gram-negative bacteria? No. The molecular mechanism of carbapenem resistance in A baumannii was not included in this analysis. Whether certain genotypes or phenotypes differ in their response to combination therapy remains a crucial question in the pharmacotherapy of Acinetobacter spp. Additionally, the pathophysiology of infection by A baumannii is different than other Gram-negative bacteria. The shedding of lipopolysaccharide and bacterial density modulate virulence and might be affected by the type and timing of antibiotic therapy. Even the identification of A baumannii is challenging, because the taxonomy of the genus is quite complex.⁸ In the AIDA trial, were all infections caused by A baumannii, and were all patients infected by the same species of Acinetobacter? We believe these factors do not come into play with P aeruginosa or Enterobacteriaceae.

AIDA试验结果是否意味着联合抗生素治疗所有耐碳青霉烯鲍曼不动杆菌或其他革兰阴性菌的大门已经关闭了？答案是否定的。分析中并未包括鲍曼不动杆菌对碳青霉烯产生耐药的分子学机制。是否存在某些特殊的基因型或表型，其对联合抗生素治疗的反应有所不同，这仍然是药物治疗不动杆菌的重要问题。另外，鲍曼不动杆菌感染的病理生理学与其他革兰阴性菌不同。脂多糖脱落及细菌密度等因素均对毒力产生影响，而且也受到抗生素治疗种类及时机的影响。甚至鲍曼不动杆菌的鉴定也极具挑战性，因为不动杆菌属的分类极为复杂。在AIDA试验中，是否所有感染均由鲍曼不动杆菌引起？是否所有患者的感染均源于不动杆菌的相同菌株？我们相信上述因素并不适用于铜绿假单胞菌或肠杆菌科细菌。

We are awaiting results of a randomised controlled trial,⁹ conducted in the USA, Israel, Taiwan, and Thailand, examining colistin plus meropenem versus colistin alone to treat carbapenem-resistant Gram-negative bacteria (NCT01597973, ClinicalTrials.gov). In the AIDA trial, the number of patients infected with carbapenem-resistant Enterobacteriacea or P aeruginosa was too small to draw conclusions about the benefit of combination therapy. Some outcomes (28-day mortality and clinical failure) were more favourable in the subgroup of patients with infections caused by Enterobacteriaceae treated with colistin–meropenem combination therapy than in patients treated with colistin alone; however, these differences were not statistically significant. An analysis incorporating propensity score matching of a different retrospective cohort of patients with carbapenem-resistant Enterobacteriaceae bloodstream infection found that combination therapy was advantageous in patients who had a high pretreatment probability of death on the basis of a previously validated mortality score.¹⁰

我们正在等待美国、以色列、中华台北及泰国进行的一项随机对照试验的结果，这些研究对粘菌素联合美罗培南与单独应用粘菌素治疗耐碳青霉烯革兰阴性菌进行比较。在AIDA试验中，耐碳青霉烯肠杆菌科细菌或铜绿假单胞菌感染的患者数量太少，无法就联合抗生素治疗的益处得出确切结论。对于肠杆菌科细菌感染的患者亚组，联合使用粘菌素和美罗培南患者的某些预后指标（28天病死率和临床失败率）甚至不如粘菌素单独治疗组；然而，这些差异并没有统计学意义。针对耐碳青霉烯肠杆菌科细菌血行性感染患者的不同回顾队列研究数据进行的倾向性评分匹配分析发现，联合治疗对于那些治疗前死亡概率（基于经过验证的病死率评分）较高的患者有益。

The advent of new antibiotics might preclude the question of how to improve colistin-based therapy: ceftazidime–avibactam offers superior outcomes than colistin-based regimens, as shown in an observational study of patients infected with carbapenem-resistant Enterobacteriaceae, specifically Klebsiella pneumoniae carbapenemase (KPC)-producing K pneumoniae.¹¹ Meropenem–vaborbactam is also active against carbapenem-resistant Enterobacteriaceae if the re-​sistance is mediated by KPC-2 and KPC-3, but not by the oxacillinase OXA-48 or metallo-β-lactamases (eg, New Dehli metallo-β-lactamases and Verona integron-encoded metallo-β-lactamases).¹² Similarly, ceftolozane–tazobactam can be used to treat carbapenem-resistant P aeruginosa in the absence of acquired carbapenemases.¹³ The avoidance of colistin-based regimens can be advantageous because it reduces the risk of kidney injury, which was measured at 30% in the AIDA trial.

新型抗生素的发现可能有助于解决如何改进粘菌素治疗的问题：一项观察性研究表明，对于耐碳青霉烯肠杆菌科细菌感染患者（尤其是产KPC肺炎克雷伯菌），头孢他啶-阿维巴坦治疗患者的预后优于基于粘菌素的抗生素治疗方案。如果耐碳青霉烯肠杆菌科细菌的抗生素耐药系KPC-2或KPC-3引起，美罗培南-vaborbactam也有效，但对苯唑西林酶OXA-48或金属β-内酰胺酶（如新德里金属-β-内酰胺酶及Verona整合子编码金属-β-内酰胺酶）。¹² 与此相似，ceftolozan-他唑巴坦可用于治疗非碳青霉烯酶导致的耐碳青霉烯铜绿假单胞菌。避免使用基于粘菌素的抗生素方案可能有益，因为这样可以降低肾损伤的风险（AIDA试验中这一风险为30%）。

The high patient mortality rate (44% at 28 days) in the AIDA trial is sobering—considering that infection with bacteria susceptibile to colistin was a criterion for inclusion and that colistin dosing was carefully controlled—but is not surprising. Infection with carbapenem-resistant A baumannii is associated with a risk of mortality that is twice that of infection with their carbapenem-susceptible counterparts.¹⁴ Patients in the AIDA trial had relatively low Charlson and SOFA indexes, indicating that underlying comorbidities and severity of illness are unlikely explanations for such high mortality rates. It appears that colistin, either as a monotherapy or combined with a carbapenem, is not that effective. Polymyxin B might have pharmacological characteristics that render it superior to colistin, and it might be advantageous to administer polymyxins directly into the site of infection (eg, inhaled colistin for pneumonia).²

AIDA试验中患者病死率很高（28天病死率44%）— 考虑到感染致病菌对粘菌素敏感是入选标准之一，且粘菌素的剂量经过仔细确定—但如此高的病死率并不意外。耐碳青霉烯鲍曼不动杆菌感染伴随病死率增加，相当于碳青霉烯敏感细菌感染的两倍。AIDA试验中的患者Charlson及SOFA评分较低，提示其基础疾病以及疾病严重程度并不能解释如此高的病死率。可能的原因在于粘菌素（无论是单药治疗抑或联合碳青霉烯）的疗效不佳。多粘菌素B的药理学特性决定其可能优于粘菌素，但将多粘菌素直接应用于感染部位（如吸入粘菌素治疗肺炎）可能更有效。

The AIDA trial underscores the urgent need for new antibiotics with activity against carbapenem-resistant A baumannii, typically producing OXA-23, OXA-24/40, and OXA-58 carbapenemases. Antibiotics that retain stability or inhibitors against these enzymes have proven particularly elusive. Cefiderocol, a novel siderophore cephalosporin, has promising in vitro activity against carbapenem-resistant A baumannii, as well as metallo-β-lactamase-producing organisms, but regulatory approval is still needed and its efficacy in the clinical arena is yet to be shown.¹⁴

AIDA试验的结果表明，我们迫切需要治疗耐碳青霉烯鲍曼不动杆菌（通常产OXA-23、OXA-24及OXA-58碳青霉烯酶）的新型抗生素。对于上述碳青霉烯酶仍保持活性或具有相应抑制剂的抗生素极难发现。Cefiderocol是一种新型头孢菌素，对耐碳青霉烯鲍曼不动杆菌以及产金属-β-内酰胺酶细菌具有良好的体外活性，但仍在等待FDA的批准，其临床疗效也有待验证。

In the AIDA trial, we are concerned that the time to administration of effective antibiotic therapy exceeded 2 days in 50% of patients. This figure highlights that it is imperative to adopt and refine methods to rapidly detect carbapenem resistance in Gram-negative bacteria. In combination with epidemiological studies establishing the prevalence of resistance and clinical studies of outcomes preferred by patients and clinicians, these diagnostic platforms can assist decision making regarding appropriate antibiotic therapy.^15,16 Similarly, the identification of genotypes and phenotypes linked to resistance can lead to the development of rational antibiotic regimens defined by molecular targets, and inform the design of clinical trials. Thus, antimicrobial chemotherapy can advance towards the paradigm of precision medicine.¹⁷ Investments to usher this transformation are urgently needed to offset the staggering global effect of antimicrobial resistance—projected to cost US$100 trillion and result in 10 million deaths per year by 2050¹⁸—and to produce the high-quality evidence necessary to guide therapeutic decisions in our patients with carbapenem-resistant Gram-negative bacteria.

在AIDA试验中，大约50%的患者需要2天时间才接受了有效的抗生素治疗。这一结果表明，很有必要采用或改进方法以快速鉴定革兰阴性菌对碳青霉烯的耐药性。与流行病学研究（验证了细菌耐药的患病率）和临床研究（患者及医生接受的预后指标）相结合，这些诊断平台能够有助于适宜抗生素治疗的临床决策。与此相似，鉴别与抗生素耐药相关联的基因型和表型有助于确定针对分子靶点的合理的抗生素治疗方案，并为临床试验设计提供帮助。因此，抗生素治疗可以迈向精准医学时代。我们迫切需要投入力量加速上述转变，以应对抗生素耐药带来的全球挑战—至2050年，抗生素耐药预计花费10万亿美元，导致1千万人死亡—并得到高质量证据指导耐碳青霉烯革兰阴性菌感染的治疗决策。