Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario Virgen Macarena, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Seville, Spain.
National Taiwan University Hospital, Zhongzheng District, Taipei City, Taiwan.
Lancet Infect Dis. 2017 Jul;17(7):726-734. doi: 10.1016/S1473-3099(17)30228-1. Epub 2017 Apr 22.
The best available treatment against carbapenemase-producing Enterobacteriaceae (CPE) is unknown. The objective of this study was to investigate the effect of appropriate therapy and of appropriate combination therapy on mortality of patients with bloodstream infections (BSIs) due to CPE.
In this retrospective cohort study, we included patients with clinically significant monomicrobial BSIs due to CPE from the INCREMENT cohort, recruited from 26 tertiary hospitals in ten countries. Exclusion criteria were missing key data, death sooner than 24 h after the index date, therapy with an active antibiotic for at least 2 days when blood cultures were taken, and subsequent episodes in the same patient. We compared 30 day all-cause mortality between patients receiving appropriate (including an active drug against the blood isolate and started in the first 5 days after infection) or inappropriate therapy, and for patients receiving appropriate therapy, between those receiving active monotherapy (only one active drug) or combination therapy (more than one). We used a propensity score for receiving combination therapy and a validated mortality score (INCREMENT-CPE mortality score) to control for confounders in Cox regression analyses. We stratified analyses of combination therapy according to INCREMENT-CPE mortality score (0-7 [low mortality score] vs 8-15 [high mortality score]). INCREMENT is registered with ClinicalTrials.gov, number NCT01764490.
Between Jan 1, 2004, and Dec 31, 2013, 480 patients with BSIs due to CPE were enrolled in the INCREMENT cohort, of whom we included 437 (91%) in this study. 343 (78%) patients received appropriate therapy compared with 94 (22%) who received inappropriate therapy. The most frequent organism was Klebsiella pneumoniae (375 [86%] of 437; 291 [85%] of 343 patients receiving appropriate therapy vs 84 [89%] of 94 receiving inappropriate therapy) and the most frequent carbapenemase was K pneumoniae carbapenemase (329 [75%]; 253 [74%] vs 76 [81%]). Appropriate therapy was associated with lower mortality than was inappropriate therapy (132 [38·5%] of 343 patients died vs 57 [60·6%] of 94; absolute difference 22·1% [95% CI 11·0-33·3]; adjusted hazard ratio [HR] 0·45 [95% CI 0·33-0·62]; p<0·0001). Among those receiving appropriate therapy, 135 (39%) received combination therapy and 208 (61%) received monotherapy. Overall mortality was not different between those receiving combination therapy or monotherapy (47 [35%] of 135 vs 85 [41%] of 208; adjusted HR 1·63 [95% CI 0·67-3·91]; p=0·28). However, combination therapy was associated with lower mortality than was monotherapy in the high-mortality-score stratum (30 [48%] of 63 vs 64 [62%] of 103; adjusted HR 0·56 [0·34-0·91]; p=0·02), but not in the low-mortality-score stratum (17 [24%] of 72 vs 21 [20%] of 105; adjusted odds ratio 1·21 [0·56-2·56]; p=0·62).
Appropriate therapy was associated with a protective effect on mortality among patients with BSIs due to CPE. Combination therapy was associated with improved survival only in patients with a high mortality score. Patients with BSIs due to CPE should receive active therapy as soon as they are diagnosed, and monotherapy should be considered for those in the low-mortality-score stratum.
Spanish Network for Research in Infectious Diseases, European Development Regional Fund, Instituto de Salud Carlos III, and Innovative Medicines Initiative.
针对产碳青霉烯酶肠杆菌科（CPE）的最佳治疗方法尚不清楚。本研究的目的是调查适当治疗和适当联合治疗对产碳青霉烯酶血流感染（BSI）患者死亡率的影响。
在这项回顾性队列研究中，我们纳入了来自 10 个国家的 26 家三级医院的 INCREMENT 队列中患有临床显著的单一致病菌 CPE 引起的 BSI 患者。排除标准为关键数据缺失、指数日期后 24 小时内死亡、在采血时至少接受了 2 天的活性抗生素治疗以及同一患者随后发生的其他感染。我们比较了接受适当治疗（包括针对血液分离株的活性药物和在感染后 5 天内开始治疗）和不适当治疗的患者 30 天全因死亡率，以及接受适当治疗的患者接受活性单药治疗（仅一种活性药物）或联合治疗（多种）的患者死亡率。我们使用了倾向评分来接受联合治疗，并使用了经过验证的死亡率评分（INCREMENT-CPE 死亡率评分）来控制 Cox 回归分析中的混杂因素。我们根据 INCREMENT-CPE 死亡率评分（0-7 [低死亡率评分] 与 8-15 [高死亡率评分]）对联合治疗的分析进行分层。INCREMENT 在 ClinicalTrials.gov 上注册，编号为 NCT01764490。
2004 年 1 月 1 日至 2013 年 12 月 31 日，480 例 CPE 引起的 BSI 患者纳入 INCREMENT 队列，其中 437 例（91%）纳入本研究。343 例患者接受了适当治疗，94 例患者接受了不适当治疗。最常见的病原体是肺炎克雷伯菌（375 例[86%]，437 例中 343 例接受适当治疗与 94 例接受不适当治疗），最常见的碳青霉烯酶是肺炎克雷伯菌碳青霉烯酶（329 例[75%]；253 例[74%]接受适当治疗与 84 例[89%]接受不适当治疗）。适当治疗与死亡率降低相关，不适当治疗的死亡率为 38.5%（343 例患者中 132 例死亡），不适当治疗的死亡率为 60.6%（94 例患者中 57 例死亡）；绝对差异为 22.1%（95%CI 11.0-33.3）；调整后的危险比（HR）为 0.45（95%CI 0.33-0.62）；p<0.0001）。在接受适当治疗的患者中，135 例（39%）接受联合治疗，208 例（61%）接受单药治疗。联合治疗或单药治疗的总体死亡率无差异（135 例患者中 47 例[35%]死亡与 208 例患者中 85 例[41%]死亡；调整后的 HR 为 1.63（95%CI 0.67-3.91）；p=0.28）。然而，在高死亡率评分组中，联合治疗与死亡率降低相关，而在低死亡率评分组中则无相关性（63 例患者中 30 例[48%]死亡与 103 例患者中 64 例[62%]死亡；调整后的 HR 为 0.56（0.34-0.91）；p=0.02），但在低死亡率评分组中则无相关性（72 例患者中 17 例[24%]死亡与 105 例患者中 21 例[20%]死亡；调整后的比值比为 1.21（0.56-2.56）；p=0.62）。
针对产碳青霉烯酶肠杆菌科引起的血流感染患者，适当治疗与死亡率降低相关。联合治疗仅在死亡率高的患者中与生存率提高相关。产碳青霉烯酶血流感染患者应在确诊后尽快接受积极治疗，对于低死亡率评分组的患者应考虑单药治疗。
西班牙传染病研究网络、欧洲发展区域基金、西班牙卡洛斯三世卫生研究所和创新药物倡议。
