Yi Yi-Hu, Wang Jiang-Lin, Yin Wen-Jun, Xu Wei-Hua
Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Pharmacy, Third Xiangya Hospital, Central South University, Changsha, China.
Microb Drug Resist. 2021 Aug;27(8):1044-1056. doi: 10.1089/mdr.2020.0350. Epub 2021 Mar 15.
Several and studies demonstrated that adding a β-lactam to vancomycin (VAN) or daptomycin (DAP) can provide synergy against methicillin-resistant (MRSA). However, the results from clinical studies were controversial. The objective of this systematic review and meta-analysis was to compare the efficacy and safety of using VAN or DAP plus a β-lactam (combination therapy) and using VAN or DAP alone (monotherapy) in MRSA bloodstream infections. We included randomized controlled trials and observational studies evaluating whether combination therapy can improve clinical and microbiological outcomes and safety compared to monotherapy with VAN or DAP in MRSA-related bacteremia. Literature search identified 3 randomized clinical trials and 10 observational studies involving at least 1,796 patients. There were no significant associations between the combination therapy and risk of mortality within 30 days (risk ratios [RRs], 1.10, 95% confidence interval [CI], 0.82-1.46), in-hospital mortality (RR, 0.59, 95% CI, 0.31-1.13) and mortality within 60-90 days (RR, 0.91, 95% CI, 0.64-1.29). There was also no evidence that there was a difference in length of hospital stay between the combination therapy and monotherapy (mean difference, -0.41 days, 95% CI, -3.41 to 2.59). However, compared with monotherapy, combination therapy seemed to have a shorter duration of bacteremia(mean difference, -1.06 days, 95% CI, -1.53 to -0.60), a lower risk of persistent bacteremia (RR, 0.63, 95% CI, 0.51-0.79) and a lower risk of bacteremia recurrence within 60-90 days (RR, 0.61, 95% CI, 0.40-0.92). There were no statistically significant differences in the total number of adverse events, including acute kidney injury (AKI) (RR, 1.52, 95% CI, 0.84-2.73), thrombocytopenia (RR, 1.13, 95% CI, 0.74-1.73), and diarrhea (RR, 1.36, 95% CI, 0.70-2.65), between patients with combination therapy and monotherapy. In subgroup analysis, when the analysis was limited to the studies comparing using DAP plus ceftaroline with monotherapy, we found that the former had a lower risk of mortality within 30 days. In addition, a subgroup analysis limited to randomized clinical trials showed that the combination therapy was associated with a higher risk of AKI compared with using VAN or DAP alone. Although adding a β-lactam to standard therapy seemed to experience a higher clearance compared with monotherapy in patients with MRSA bacteremia, the combination therapy did not increase survival benefits. Based on the available evidence, the combination therapy was not supported as the routine management of MRSA-related bacteremia, and both its harms and benefits should be taken into account.
多项研究表明，在万古霉素（VAN）或达托霉素（DAP）基础上加用β-内酰胺类药物可协同对抗耐甲氧西林金黄色葡萄球菌（MRSA）。然而，临床研究结果存在争议。本系统评价和荟萃分析的目的是比较在MRSA血流感染中，使用VAN或DAP联合β-内酰胺类药物（联合治疗）与单独使用VAN或DAP（单药治疗）的疗效和安全性。我们纳入了随机对照试验和观察性研究，以评估与VAN或DAP单药治疗相比，联合治疗是否能改善MRSA相关菌血症的临床、微生物学结局及安全性。文献检索确定了3项随机临床试验和10项观察性研究，涉及至少1796例患者。联合治疗与30天内死亡风险（风险比[RRs]为1.10，95%置信区间[CI]为0.82 - 1.46）、院内死亡风险（RR为0.59，95% CI为0.31 - 1.13）以及60 - 90天内死亡风险（RR为0.91，95% CI为0.64 - 1.29）之间均无显著关联。也没有证据表明联合治疗与单药治疗在住院时间上存在差异（平均差为 - 0.41天，95% CI为 - 3.41至2.59）。然而，与单药治疗相比，联合治疗的菌血症持续时间似乎更短（平均差为 - 1.06天，95% CI为 - 1.53至 - 0.60），持续性菌血症风险更低（RR为0.63，95% CI为0.51 - 0.79），60 - 90天内菌血症复发风险更低（RR为0.61，95% CI为0.40 - 0.92）。联合治疗组与单药治疗组患者在不良事件总数上无统计学显著差异，包括急性肾损伤（AKI）（RR为1.52，95% CI为0.84 - 2.73）、血小板减少症（RR为1.13，95% CI为0.74 - 1.73）和腹泻（RR为1.36，95% CI为0.70 - 2.65）。在亚组分析中，当分析仅限于比较使用DAP加头孢洛林与单药治疗的研究时，我们发现前者30天内死亡风险更低。此外，仅限于随机临床试验的亚组分析表明，与单独使用VAN或DAP相比，联合治疗与AKI风险更高相关。尽管在MRSA菌血症患者中，与单药治疗相比，在标准治疗基础上加用β-内酰胺类药物似乎清除率更高，但联合治疗并未增加生存获益。基于现有证据，联合治疗不支持作为MRSA相关菌血症的常规治疗方法，应同时考虑其危害和益处。
