Antibiotic strategies in critical care: back to square one?

https://doi.org/10.1016/S1473-3099(18)30057-4

The worth of antibiotics to human health is without bound, but antimicrobial resistance poses a serious threat to this treasured resource.¹ Reduction of the selection pressure on pathogens through the rational use of antimicrobials, and discernment of which antibiotic treatment strategies achieve this goal, are now international priorities. Antibiotic stewardship encompasses different evidence-based measures to improve the appropriate use of antibiotics by promoting selection of optimal drug regimens, including dosing, duration of therapy, and route of administration.^2,3 There have been important recent advances in our understanding of these approaches, but we are still some way from truly knowing how to best use antibiotics in the setting of patients with sepsis in critical care. Although there is a strong consensus that, at the patient level, prescribers need to ensure the right antibiotic, at the right dose, at the right time is used in cases where antibiotics are truly warranted,⁴ treatment strategies at the unit level remain unclear. Among manifold others, two such strategies are cycling and mixing of antibiotics.⁵ Antibiotic cycling refers to prescription of a specific antibiotic drug preferentially as first-line therapy during a prespecified period, with subsequent rotation to another antibiotic drug with different selective properties later on. Antibiotic mixing refers to the changing of antibiotics each time a new patient in need of this drug arrives.

抗生素对人类健康的价值毋庸置疑，但抗生素耐药是对抗生素的严重威胁。通过合理使用抗生素减少对致病菌的选择性压力，确定哪种抗生素治疗策略能够实现上述目标，已经成为国际的热点问题。抗生素的合理使用包括多种循证措施，如选择适当的抗生素方案，包括剂量、疗程及用药途径等。近期，我们对于上述措施的理解有了重要进展，但与真正了解对于ICU的重症感染患者如何才能最佳使用抗生素仍相去甚远。尽管目前的共识是，针对感染患者，必要时医生应当确保正确的抗生素种类、正确的药物剂量以及正确的用药时间，但在病房水平的治疗策略仍不清楚。在众多的治疗策略中，其中2种策略即抗生素的轮替及混用。抗生素轮替指在既定的时间内主要使用一种抗生素作为一线治疗，此后轮换为另一种选择性特征不同的抗生素。抗生素混用指当每一名新的患者需要使用抗生素时均改变抗生素。

Which antibiotic prescription strategy results in the lowest risk of resistance and is therefore preferable is an important, but open, clinical and evolutionary question. Evidence from laboratory studies suggests that drug changes can negatively impact bacterial growth and adaptation.⁶ Theorists have wrestled with this question for decades, and initial enthusiasm for mixing⁷ has waned in light of analyses showing that mixing and cycling are probably hard to distinguish in the clinic,⁵ although cycling has received some theoretical support at times too.⁸

哪种抗生素处方策略导致耐药的风险最低，这是一个重要且开放的临床问题。实验室研究结果提示，改变药物对细菌的生长和适应产生负面影响。理论家对这一问题乐此不疲已历经数十年，研究表明抗生素混用与轮替在临床上难以区分，因此最初对于抗生素混用的热情逐渐消退，尽管抗生素轮替还不断得到理论支持。

To better understand whether antibiotic mixing has more favourable outcomes than cycling for the risk of antibiotic-resistant, Gram-negative bacteria, Pleun Joppe van Duijn and colleagues⁹ report in The Lancet Infectious Diseases the results of a cluster-randomised crossover trial in eight European intensive care units (ICUs). The primary endpoint was the change in unit-wide prevalence of antibiotic-resistant, Gram-negative bacteria, defined as carriage of Enterobacteriaceae harbouring extended-spectrum β-lactamase genes, or phenotypical resistance of Enterobacteriacae to piperacillin–tazobactam or of Acinetobacter spp and Pseudomonas aeruginosa to piperacillin–tazobactam or carbapenems. This endpoint was measured in 745 of 4069 patients present in the ICUs during cycling and 853 of 4707 patients during mixing through monthly point-prevalence screening cultures. Because randomisation was not implemented at a patient level, but rather at an institutional level, the investigators adjusted their analyses for potential patient-related and ICU-related confounders. The trial was pragmatic, whereby treating physicians could deviate from the protocol in case of safety concerns and for the use of combination therapy, including with non-study antibiotics.

为更好理解抗生素混用降低耐药革兰阴性菌风险是否优于抗生素轮替，Pleun Joppe van Duijn及其同事在Lancet Infectious Diseases报告了8个欧洲ICU中进行的一项群组随机交叉试验结果。主要终点为病房中耐药革兰阴性菌（定义为携带ESBL基因阳性肠杆菌科细菌，或肠杆菌科细菌对哌拉西林-他唑巴坦耐药，或不动杆菌属和铜绿假单胞菌对哌拉西林-他唑巴坦或碳青霉烯耐药）罹患率的变化。通过每月时点患病率筛查培养发现，在抗生素轮替阶段4069名患者在ICU期间745名满足主要终点，抗生素混用阶段4707名患者中853名满足主要终点。由于研究并非在患者水平而是在医院水平进行随机分组，研究者对统计分析进行调整，对患者及ICU相关混杂因素进行校正。本研究为实效性试验，主治医生可因安全性考虑决定偏离治疗方案，并决定是否使用联合抗生素治疗，包括非研究抗生素。

The investigators noted no differences in antibiotic use between randomisation groups, and study antibiotics accounted for 42% and 43% of all antibiotics used in the cycling and mixing groups, respectively. For the primary endpoint, investigators did not find a significant difference in the mean prevalence of antibiotic-resistant, Gram-negative bacteria (168 [23%] patients with carriage during cycling vs 184 [22%] during mixing) even when considering the incidence rate ratio derived from a mixed effects analysis adjusted for potential confounders (1·039, 95% CI 0·837–1·291, p=0·73). No difference was observed in several subgroup analyses. These results thus strongly suggest that cycling of antibiotics has no beneficial effect over antibiotic mixing against the emergence of antibiotic resistance for Gram-negative bacteria.

研究者发现，两组患者抗生素使用并无差异，抗生素轮替组与混用组中研究抗生素分别占所有抗生素的42%和43%。至于主要终点，即使通过混合效应分析采用发病率比值对可能的混杂因素进行校正后，研究者仍未发现耐药革兰阴性菌的平均患病率存在显著差异（抗生素轮替阶段携带率168 [23%] 名患者 vs 抗生素混用阶段携带率184 [22%] 名患者）(1·039, 95% CI 0·837–1·291, p=0·73)。各个亚组分析均无显著差异。这些结果强烈提示，与抗生素混用相比，抗生素轮替对于减少耐药革兰阴性菌的出现并无益处。

Where does this trial leave us? This study had a negative outcome, but the findings are consistent with theoretical arguments.⁵ However, a negative study can still be highly informative if the study quality was high, meaning sufficient statistical power to avoid a type II error, high protocol adherence, and a thorough statistical analysis accounting for potential biases. The trial reported by van Duijn and colleagues fulfils these criteria. In their study protocol, the investigators predefined the statistical approach using different sensitivity analyses with sufficient power to detect effects if any were present. High adherence to the study protocol was observed despite two major deviations (one in which data were excluded due to missing point-prevalence information, and another in which the washout period was prolonged due to an outbreak of carbapenem-resistant Klebsiella pneumoniae). There is, therefore, no obvious reason that another trial would contradict these findings. However, reduction of the prevalence of antibiotic-resistant, Gram-negative bacteria in ICUs remains a priority; there is an urgent need to find new institutional strategies that prove beneficial in clinical trials. Until then, we need to reinforce the patient-level tools that are available, including (among others) improved hand hygiene and better selection of patients in need of antibiotics by host-response markers such as procalcitonin and other pathogenic markers.^10,11

这个试验结果究竟告诉我们什么？研究为阴性结果，但研究发现与理论相一致。然而，如果研究质量很高（说明研究有足够的统计学把握度避免II类错误，研究方案依从性很高，并进行了详细的统计分析对可能的偏倚进行校正），那么，即使结果为阴性，研究本身仍然很有意义。van Duijn及其同事报告的试验即符合上述标准。在这项研究的方案中，研究者预先确定了统计分析计划，准备采用具有足够把握度的不同敏感性分析以确定是否存在治疗效应。尽管存在两项主要偏离（一项系由于缺失时点患病率信息导致数据被排除，另一项因耐碳青霉烯肺炎克雷白杆菌暴发流行导致洗脱期延长），但研究方案依从性很高。因此，没有理由相信进行另一项试验会得到不同的结果。然而，降低ICU中耐药革兰阴性菌患病率仍然至关重要；我们迫切需要找到经过临床研究证实有益的新策略。目前，我们仍需强调患者水平的现有措施，包括改进手卫生，通过宿主反应标志物（如降钙素原）及其他致病标志物选择真正需要抗生素治疗的患者。