Division of Infectious Diseases, Department of Diagnostic and Public Health, University of Verona, P.Le L.A. Scuro 10, 37134, Verona, Italy.
Global Antibiotic Research & Development Partnership (GARDP), 15 Chemin Louis-Dunant, Geneva, Switzerland.
BMC Infect Dis. 2021 Jun 9;21(1):545. doi: 10.1186/s12879-021-06253-x.
Effective treatment of sepsis due to carbapenem-resistant Gram-negative bacteria (CR-GNB) remains a challenge for clinicians worldwide. In recent years, the combination of antibiotics has become the preferred treatment strategy for CR-GNB infection. However, robust evidence to support this approach is lacking. This systematic review aimed at critically evaluating all available antibiotic options for CR-GNB sepsis with particular focus on combination.
We systematically searched published literature from January 1945 until December 2018 for observational comparative and non-comparative studies and randomized trials examining any antibiotic option for CR-GNB. Studies were included if reporting microbiologically-confirmed infection caused by Acinetobacter baumannii, Enterobacteriaceae/Klebsiella spp., or Pseudomonas aeruginosa, reporting at least one of the study outcomes, and definitive antibiotic treatment. Carbapenem-resistance was defined as phenotypically-detected in vitro resistance to at least one of the following carbapenems: doripenem, ertapenem, imipenem, meropenem. Each antibiotic regimen was classified as "defined" when at least the molecular class(es) composing the regimen was detailed. Primary outcomes were 30-day and attributable mortality. Bayesian network meta-analysis (NMA) approach was selected for quantitative synthesis to explore feasibility of pooling data on antibiotic regimens.
A total of 6306 records were retrieved and 134 studies including 11,546 patients were included: 54 studies were on Acinetobacter, 52 on Enterobacteriaceae/Klebsiella, 21 on mixed Gram-negative, and 7 on Pseudomonas. Nine (7%) were RCTs; 19 prospective cohorts (14%), 89 (66%) retrospective, and 17 (13%) case series. Forty-one studies (31%) were multicentric. Qualitative synthesis showed an heterogeneous and scattered reporting of key-clinical and microbiological variables across studies. Ninety-two distinct antibiotic regimens were identified with 47 of them (51%, 5863 patients) not reporting any details on numbers, type, dosage and in vitro activity of the included antibiotic molecules. The NMAs could not be performed for any of the selected outcome given the presence of too many disconnected components.
The existing evidence is insufficient to allowing for the formulation of any evidence-based therapeutic recommendation for CR-GNB sepsis. Future studies must provide a standardized definition of antibiotic regimen to drive recommendations for using combination of antibiotics that can be reliably applied to clinical practice.
有效治疗碳青霉烯类耐药革兰氏阴性菌（CR-GNB）引起的败血症仍然是全球临床医生面临的挑战。近年来，抗生素联合治疗已成为 CR-GNB 感染的首选治疗策略。然而，缺乏支持这种方法的有力证据。本系统评价旨在批判性地评估所有可用的抗生素治疗 CR-GNB 败血症的方案，特别关注联合治疗。
我们系统地检索了 1945 年 1 月至 2018 年 12 月发表的文献，包括观察性比较和非比较研究以及随机试验，以研究任何针对 CR-GNB 的抗生素选择。如果报告了微生物学证实的由鲍曼不动杆菌、肠杆菌科/克雷伯菌属或铜绿假单胞菌引起的感染，报告了至少一个研究结果，并进行了明确的抗生素治疗，则将研究纳入。碳青霉烯耐药被定义为体外对至少一种以下碳青霉烯类药物表现出的表型耐药：多尼培南、厄他培南、亚胺培南、美罗培南。当至少详细描述了组成方案的分子类别时，将每个抗生素方案分类为“明确”。主要结局为 30 天和归因死亡率。选择贝叶斯网络荟萃分析（NMA）方法进行定量综合，以探索对抗生素方案数据进行合并的可行性。
共检索到 6306 条记录，纳入 134 项研究共 11546 名患者：54 项研究为鲍曼不动杆菌，52 项为肠杆菌科/克雷伯菌属，21 项为混合革兰氏阴性菌，7 项为铜绿假单胞菌。其中 9 项（7%）为 RCT；19 项前瞻性队列研究（14%），89 项回顾性研究（66%）和 17 项病例系列研究（13%）。41 项研究（31%）为多中心研究。定性综合表明，关键临床和微生物学变量在研究之间的报告存在异质性和分散性。确定了 92 种不同的抗生素方案，其中 47 种（51%，5863 名患者）未报告包含的抗生素分子的数量、类型、剂量和体外活性的任何细节。由于存在太多不相关的成分，无法对任何选定的结局进行 NMAs。
目前的证据不足以制定任何基于证据的 CR-GNB 败血症治疗推荐。未来的研究必须提供抗生素方案的标准化定义，以推动联合使用抗生素的建议，这些建议可以可靠地应用于临床实践。
