研究背景 革蘭氏陰性菌是加護病房中常見且死亡率高的感染。由於持續上升的抗藥性以及沒有新開發的有效抗生素,colistin(克痢黴素)被視為是最後的治療策略,然而克痢黴素卻會造成一成到七成病人的腎毒性。為了減少因克痢黴素而發生的腎毒性,應該要建立一個全面性完整評估克痢黴素腎毒性的研究,並找出加護病房病人使用克痢黴素後發生急性腎衰竭的危險因子。 研究目的 研究目的為:1. 以統合分析來確立克痢黴素比起其他抗生素以及不同克痢黴素治療策略之間的腎毒性發生率。2. 評估克痢黴素的藥物流行病學,並找出使用克痢黴素發生急性腎衰竭的危險因子。 研究方法 將分別以統合分析及病歷回溯來達成本研究目的。統合分析的文章主要來自2018年4月以前PubMed, EMBase和Cochrane等電子資料庫以及相關文章的參考文獻。納入具有對照組的世代研究以及隨機分派試驗來評估克痢黴素的腎毒性。主要探討的研究結果為比較克痢黴素與其他抗生素以及不同克痢黴素治療策略之間的腎毒性發生率,次要結果則是比較克痢黴素與其他抗生素之間的總體死亡率。 流行病學的部分則是透過高雄醫學大學臨床醫學研究部資料庫以及高醫病歷系統的回溯性研究,探討2012-2017年間高醫附院內科加護病房中使用colistin病人發生急性腎衰竭的流行病學。依照KDIGO的定義,我們將急性腎衰竭定義為開始使用colistin的七天內病人的血清肌肝酸上升至1.5倍或在兩日內上升0.3。另外將是否發生急性腎衰竭作為主要的臨床結果,探討使用克痢黴素發生急性腎衰竭的危險因子。 研究結果 比起其他抗生素,colistin會增加一倍急性腎衰竭的風險,但並不影響死亡率。使用針劑、給予起始劑量以及給予高劑量的colistin也會提高急性腎衰竭的風險。如果colistin併用其他有腎毒性的抗生素會增加發生急性腎衰竭的風險,如果合併carbapenem使用則會降低風險。 在回溯性研究中,colistin相關的急性腎衰竭為輕至中度,發生率為47.6%,這樣的急性腎衰竭是可回復並且不會影響死亡率的。在使用colistin的期間同時也需要使用升壓劑為colistin相關急性腎衰竭的危險因子。另外在回溯性研究中也有看到colistin合併carbapenem使用能降低發生急性腎衰竭的風險。 結論 Colistin的腎毒性比起其他抗生素更加顯著。colistin相關的急性腎衰竭發生率為47.6%,可以回復並且不會影響死亡率。給予更高劑量或是給予起始劑量、併用其他有腎毒性的抗生素以及需要升壓劑來維持血壓都是發生colistin相關急性腎衰竭的危險因子。併用carbapenem可能可以降低colistin相關的急性腎衰竭,然而仍需要更多的研究來證實這個發現。
Background Infections with gram-negative bacteria (GNB) are common in intensive care units (ICUs) and associated with high mortality. Owing to the paucity of new antibiotics and the increasing incidence of multidrug resistance GNB, colistin becomes the last therapeutic option, especially for the infections caused by Pseudomonas aeruginosa and Acinetobacter baumannii. Nonetheless, colistin is associated with acute kidney injury (AKI) with the incidence rate varying from 14 to 74%. In order to minimize the renal toxicity associated with the use of colistin, it is necessary to conduct studies comprehensively to understand the epidemiology and risk factors of the nephrotoxicity associated with colistin. Study Aim 1. To conduct a meta-analysis mainly focusing on the nephrotoxicity between colistin-based versus other antibiotics and different therapeutic strategies of colistin. 2. To evaluate the pharmacoepidemiology of colistin and summarizing the risk factors of colistin-association AKI in hospital at Southern Taiwan. Methods This study composed of two parts. The first, a meta-analysis was performed. Electronic databases of PubMed, EMBase and Cochrane library were searched up to April 2018 and all the reference lists of relevant articles were screened, enrolling all cohort studies and randomized controlled trials (RCT) with two-arm compartments of colistin-based antibiotic treatments for patients with GNB infections. The primary endpoint was the nephrotoxicity between the treatment of colistin-based versus other antibiotics and different therapeutic strategies of colistin (as monotherapy versus combination therapy, whether given high dose, loading dose or adjunctive inhaled colistin). Secondary endpoint was the overall mortality between colistin-based versus other antibiotics. Section of pharmacoepidemiology were conducted as a retrospective cohort study in the medical intensive care unit (MICU) of Kaohsiung Medical University (KMU), a medical center at Southern Taiwan. Patient population was those received the first dose of colistin in MICU or within 48 hours prior to MICU for at least 48 hours. The primary outcome was the development of AKI within 7 days after the initiation of colistin. The secondary outcomes were whether patients need renal replacement therapy and overall mortality. By KDIGO criteria, AKI was defined as serum creatinine increased 1.5 times within 7 days or increased 0.3 mg/dL in 2 days after administration of colistin. The risk factors of colistin-associated AKI were evaluated using univariate and multivariate logistic regressions. Results In meta-analysis, colistin was associated with two times higher incidence rate of AKI than other antibiotics, without significant difference in mortality. IV colistin, higher dose and giving loading dose were the factors that would increase the AKI rate. Colistin co-administrated with nephrotoxins may lead to higher rate of AKI but co-administrated with carbapenem would result in lower incidence rate of AKI. In retrospective cohort study, the incidence rate of colistin-associated AKI was 47.6%, the severity was mild to moderate. Colistin-associated AKI was reversible and was not related to the overall mortality. Vasopressor was an independent factor related to colistin-associated AKI. Colistin co-administrated with carbapenem also showed a trend with lower AKI rate. Conclusion Colistin was related to a higher incidence rate of AKI compared with other antibiotics. The incidence rate of colistin-associated AKI was 47.6%, the severity was mild to moderate. It was reversible and was not related to the overall mortality. Higher dose, giving loading dose, co-administrated with nephrotoxins and required of vasopressor may lead to higher risk of AKI. Co-administrated with carbapenem showed a trend with lower AKI rate. Whether co-administrated carbapenem can lower the AKI rate are necessary to be carryout by other studies.