翻译：左文婷  单位：北京协和医学院/中日友好医院

校对：徐九洋 单位：中日友好医院 呼吸与危重症医学科

摘要

重症肺炎与高死亡率（短期和长期）以及肺部和肺外并发症有关。对重症肺炎患者的恰当诊断和早期开始充分的抗微生物治疗是提高危重症患者生存率的关键。鉴定潜在致病病原体对于抗菌药物的管理也至关重要。然而，对大多数患者确定病因诊断具有挑战性，尤其是那些有慢性基础疾病的患者、既往接受过抗生素治疗的患者以及接受机械通气治疗的患者。此外，由于抗菌治疗必须是经验性的，国内和国际指南建议根据所在地区的流行病学进行初始抗微生物治疗；对于入住重症监护室的患者有相应关于疾病管理的具体建议。遵循肺炎指南进行临床管理可为重症肺炎患者带来更好的临床结局。然而，重症肺炎相关的研究内容十分广泛，在宿主免疫反应、疾病严重程度评估、微生物病因、多重耐药病原体的危险因素、诊断试验和治疗选择等方面有许多不同观点。

引言

肺炎是一个主要的健康问题，与高发病率和短期和长期死亡率有关。它也是全世界各年龄段人群死亡的主要传染病病因【1，2】。重症肺炎表现为社区获得性肺炎（CAP）、医院获得性肺炎（HAP），、与机械通气相关的肺炎（呼吸机相关性肺炎，VAP）。重症肺炎患者表现出较高的短期及长期死亡率，幸存者常伴有严重后遗症，如肺功能改变、精神和认知功能减退、运动功能减退以及功能自主性降低【3，4】。重症肺炎的正确诊断对于提高危重症患者的生存率至关重要，鉴定病原体对于重症肺炎患者的抗菌药物管理也至关重要。然而，在大多数患者中，病因诊断具有挑战性，尤其是那些有慢性基础疾病的患者、既往接受过抗生素治疗的患者以及接受机械通气治疗的患者。及时和充分的抗生素治疗对于重症肺炎危重症患者的最佳临床结局至关重要，也是国际肺炎指南管理的重点【5-7】。

在这篇文章中，我们回顾了当前关于重症肺炎患者的管理相关知识，包括CAP和HAP，重点是流行病学、微生物病因、发病机制、治疗和预防。

入选来源及标准

我们检索的数据库包括 PubMed、Medline、Cochrane 系统评价数据库和中央对照试验登记册 (clinicaltrials.gov)， 检索年限为2000年至2021年。 我们使用了关键词和关键词组合，包括“肺炎”、“严重呼吸道感染”、“重症肺炎”、“危重症肺炎”、“社区获得性肺炎”、“重症监护肺炎”、“医院获得性肺炎”、“ 呼吸机相关性肺炎”、“肺炎管理”、“肺炎诊断”和“肺炎治疗”。我们回顾了这些研究的相关标题和摘要并优先选择英文研究，此外还考虑了Meta分析、系统性综述、国际指南、随机对照试验 (RCT) 以及大型描述性和观察性研究，我们还收录了2000年之前发表的一些其他相关文章。

重症肺炎的定义及其流行病学

重症社区获得性肺炎（SCAP）

早期识别SCAP患者对提供快速、明确的治疗及避免延误提供重症监护，从而降低死亡率至关重要【8，9】。多种评分系统可为确定治疗地点提供依据，但其中大多数可被用来预测死亡风险，而不是专门用于预测是否需要入院接受重症监护治疗。恰当的初始治疗地点很重要，因为对于先入住普通病房、再转入重症监护病房（ICU）的患者，其住院时间和死亡率都高于直接入住ICU的患者【10，11】。

重症CAP最广泛接受的定义标准来自2007年美国传染病学会/美国胸科学会（ATS/IDSA）关于成人CAP管理的共识指南【12】（表1）。进入ICU治疗的标准包括：需要机械通气，或需要升压药物治疗的休克，或满足九项次要标准中的三项。几项关于次要标准的验证研究【13-17】发现，这些标准对于预测ICU入院需求是准确的。

伴随着高龄、免疫功能低下或有潜在重症并发症的患者数量增加，需要重症监护治疗的患者数量也在增加。2018年，一项横断面研究【18】显示，2003-2015年间，因急性呼吸道感染住院的人数大幅增加，老年患者尤为明显：据报道，85-89岁的患者入住ICU的人数是年轻人群的3.3倍，90岁及以上的患者入住ICU的认识是年轻人群的5.8 倍。

一项针对美国CAP住院患者的前瞻性、基于人群的队列研究的二次分析发现，23%的患者需要入住ICU，其中24%需要有创机械通气，20%需要无创机械通气。作者报道，在ICU每年每10万成人患者中有145例发生CAP【19】。

CAP也是脓毒症的主要原因。2016年，第三届国际共识定义（Sepsis-3）将脓毒症定义为序贯性器官衰竭评估（SOFA）得分增加2分或以上，并建议在疑似感染患者（如CAP）中【20】,使用快速序贯性器官衰竭评估（qSOFA）进行评分，从而识别具有高死亡风险和延长ICU住院时间的患者。一些研究评估了CAP人群中qSOFA的效果，结果表明，在预测死亡率和ICU入住率方面，qSOFA比其他评分更准确，如CRB（意识模糊、呼吸频率、血压)和SOFA。尽管SCAP能得到早期识别和治疗，但短期和长期死亡率仍然很高（27-50%）【19】。

表格 1 重症CAP的ATS/IDSA标准

次要标准

l  呼吸频率≥30次/分

l  PaO2/FiO2≤250

l  多肺叶浸润

l  意识模糊/定向障碍

l  尿毒症（血尿素氮水平≥20 mg/dL）

l  白细胞减少(白细胞计数90%可能的革兰氏阴性病原体+/- MRSA(如果> 25%的金黄色葡萄球菌分离物是MRSA)

脓毒症休克:联合治疗，抗假单胞菌抗方案+/- MRSA(如果> 25%的金黄色葡萄球菌分离物是MRSA)

这两份指南都同意根据耐多药病原体的个人和当地社区危险因素对患者进行分层

表格 2 HAP/VAP中出现多耐药致病菌的危险因素

欧洲指南（2017）

美国指南(2016)

既往抗生素治疗

既往抗生素治疗

住院≥5天

住院≥5天

脓毒症休克

脓毒症休克

多重耐药菌感染率高(> 25%)的医院

VAP之前有ARDS

MDR病原体先前定植

VAP之前有急性肾脏替代治疗

死亡风险>   15%

VAP——MRSA与耐药革兰氏阴性病原体

在过去的十年中，来自美国和欧洲的研究报告称，VAP中耐多药病原体患病率率有所增加【143-145】。最常见的耐多药革兰氏阴性病原体是铜绿假单胞菌、不动杆菌属和产生广谱β-内酰胺酶的肠杆菌科。此外，MRSA是最常见耐多药革兰氏阳性病原体。这些病原体组与不良的临床结局有关，尤其是因为初始抗菌治疗不适当或延迟【146-148】。

目前来自ATS/IDSA和欧洲呼吸学会、欧洲重症医学学会、欧洲临床微生物学和传染病学会和拉丁美洲胸腔协会的指南【7】强调了根据患者对耐多药病原体的风险分层以及当地微生物学和抗生素耐药性数据进行及时和充分的经验性治疗的重要性(表2)。

美国指南【5】确定了与耐多药病原体相关的5个风险因素:既往90天内接受过静脉注射抗生素治疗;VAP发生前住院≥5天;VAP时发生脓毒性休克;VAP前出现ARDS;VAP发病前需要进行肾脏替代治疗。一项前瞻性队列研究发现【149】，在使用这些风险因素对耐多药病原体进行治疗时，敏感性很高，但特异性很低，整体表现较差，这可能导致过度的广谱经验性抗菌治疗。在5个危险因素中，只有过去90天内使用抗生素(阴性预测值为79%)和肺炎前≥5天住院(阴性预测值为80%)与多药耐药有密切关系。VAP前存在ARDS对MDR病原体的存在具有71%的阴性预测值。欧洲指南【7】未将肾替代治疗或ARDS纳入耐多药微生物高危患者的定义中。因此，除了患者个体的风险因素外，欧洲指南还包括将耐多药微生物高发的医院环境(≥25%的ICU病原体是耐多药的)、局部耐药模式以及耐多药微生物先前定植作为此类病原体风险的决定因素。

治疗

CAP指南建议

ATS/IDSA CAP指南于2019年【6】发布，对之前的建议进行了修改【12】。最值得注意的是，指南建议取消医疗相关性肺炎(HCAP)类别，以避免过度使用经验性广谱治疗。即使是在那些重症CAP的患者中，耐药病原体的发生率也很低，对所有患有HCAP的患者实施广谱治疗会导致其过度使用。具有高CAP死亡率的HCAP患者通常伴有影响生存的临床特征和多种合并症，而不仅仅是存在耐药病原体的危险因素。此外，有关不良结果的报告，如艰难梭菌相关感染的增加，与广谱抗生素的过度使用有关【135，150，151】。

初始抗生素的选择

对于大多数重症CAP患者，初始治疗包括β-内酰胺加大环内酯或氟喹诺酮类药物的组合。对于没有MRSA和假单胞菌危险因素的患者，β-内酰胺可以是头孢噻肟、头孢曲松、氨苄西林-舒巴坦或头孢洛林【6】。对于那些有假单胞菌危险因素的患者，可以使用β-内酰胺类药物，如哌拉西林/他唑巴坦、头孢吡肟、头孢他啶、亚胺培南或美罗培南来覆盖病原体。在有β-内酰胺过敏的患者中，氨曲南是一种选择。针对更耐药的革兰氏阴性病原菌具有活性的较新的β-内酰胺类药物讨论见下。

如何选择广谱抗生素

   在重症CAP中，有证据表明，与非大环内酯方案相比，β-内酰胺联合大环内酯可显著改善患者的预后【152-155】。一项回顾性观察性研究报告，与联合氟喹诺酮类药物相比，β-内酰胺+大环内酯类药物联合治疗重症肺炎患者14天死亡率(8%v27%，P=0.02)和30天死亡率(18%v37%，P=0.05)较低【154】。同样【153】，一项前瞻性多中心观察性研究评估了257例插管重症CAP患者，其中20%的患者接受单药治疗，其余80%接受联合治疗。在作者调整严重程度后，与氟喹诺酮类药物患者相比，大环内酯类药物的使用与较低的ICU死亡率相关(危险比0.48,CI95% 0.23-0.97,P=0.04)。作者推荐联合大环内酯类药物治疗重症CAP患者。一项包括9850例CAP危重患者的meta分析观察到，与其他治疗方案相比，大环内酯类药物联合β-内酰胺治疗(21%vs24%;风险比0.82;95%CI0.70-0.97;P=0.02)与较低的死亡率有关。一项包括1131例CAP【152】患者的前瞻性队列研究发现，基于肺炎严重程度指数(PSI)和CURB-65评分【12，22，23】的联合治疗并没有显著降低两组患者的30天死亡率。然而，基于ATS/IDSA标准的联合治疗显著降低了重症肺炎患者的30天死亡率(OR 0.12, 95% CI 0.007-0.57)，尽管在非重症肺炎患者中没有降低(OR 1.85, 95% CI 0.51-5.40)。

联合治疗的一个优势是其能够覆盖非典型病原体，以及利用大环内酯的免疫调节作用有助于减弱细菌毒力因子和过度的全身炎症反应。一项实验研究发现【156】，大环内酯可抑制肺炎球菌溶血素的产生，并且对耐大环内酯药物的肺炎球菌也有抑制作用。肺炎球菌溶血素会促进肺炎球菌的肺外传播，从而导致心脏损伤【57】。此外，当作为联合治疗的一部分使用时【157】，大环内酯类药物可降低重症CAP患者的死亡率，尤其是肺炎球菌菌血症患者【158，159】。一项前瞻性、多中心和国际研究分析了844例肺炎球菌菌血症患者【159】，发现联合治疗14天死亡率较低(23%v55%，P=0.015)。

MRSA的最佳治疗方法

与院内MRSA不同，CA-MRSA对克林霉素、TMP-SMX和多西环素敏感【160】。克林霉素和利奈唑胺可以抑制毒素的产生，从而阻止细菌蛋白质的合成。根据ATS/IDSA指南的建议【6】，只有当患者存在MRSA的危险因素(此前从呼吸道标本中分离出MRSA;最近住院[近90天]，使用肠外抗生素[近90天]，以及当地证实的MRSA风险因素)。临床医生还应获取培养样本，并进行鼻PCR检测，以指导决定降阶梯治疗还是继续治疗【161，162】。

MRSA的经验性治疗选择包括万古霉素15 mg/kg/12小时(根据水平调整)或利奈唑胺600 mg/12小时。对于重症坏死性CAP患者，可能需要添加抗毒素治疗。例如在万古霉素中加入克林霉素或单独使用利奈唑胺(它也有抗毒素活性)。利奈唑胺穿透肺部的能力优于万古霉素，但临床医生更常在HAP和VAP中使用利奈唑胺，而非CAP。

抗病毒药物

病毒性肺炎被认为是重症CAP的常见病因，许多患者有病毒和细菌混合感染。ATS/ISDA指南建议对所有重症流感患者使用抗流感治疗(奥司他韦)，无论症状持续时间长短，但如果在最初48小时内给予【6】，效果最好。此外，由于细菌合并感染的发病率很高，建议在确诊的流感感染中使用抗生素治疗，尤其是覆盖肺炎球菌和金黄色葡萄球菌。然而，对于无细菌合并感染迹象且抗生素治疗48-72小时后临床表现稳定的患者，建议将抗生素降级【6】。

在COVID-19患者中，有时会观察到细菌性肺炎与病毒性肺炎并存【163，164】。大多数肺部浸润的患者最初接受抗生素治疗，根据临床评估和生物标志物 (如降钙素原) 的系列测量，终止此类治疗【165，166】。对于COVID-19住院患者，抗病毒药物瑞德西韦显示出一些好处，特别是在疾病的早期过程中，单克隆抗体也是如此(特别是在疾病的早期和门诊患者中)【167】。关于瑞德西韦用于COVID-19的两项大型随机对照试验的数据显示了不同的结果。ACT-1试验【168】发现，瑞德西韦在缩短COVID-19住院成人患者的康复时间方面优于安慰剂，而SOLIDARITY 试验【169】报告称，对死亡没有益处。目前，瑞德西韦被推荐用于需要氧疗的重症COVID-19患者，不包括机械通气或体外膜氧合【170】。

对于免疫功能正常的宿主中的其他病毒性肺炎，不常规给予抗病毒药物。

糖皮质激素

糖皮质激素具有免疫调节的特性，由于其抗炎作用，常被用作重症肺炎的辅助治疗。关于糖皮质激素的使用仍存在争议，但一些研究数据显示，糖皮质激素的使用降低了重症CAP患者的死亡率，尤其是那些全身炎症水平较高的患者【171，172】。然而，这种效果尚未在非重症肺炎患者中出现。

在一个多中心、随机、双盲和安慰剂对照试验中，调查了皮质类固醇对120例重症CAP治疗失败(61例使用甲强龙和59例对照组)和高炎症反应(初始水平的C反应蛋白(CRP)＞15 mg/dL)患者的影响。与安慰剂组(31%)相比，接受皮质激素组(13%)治疗失败的频率较低(P=0.02)。然而，两组之间的住院死亡率相似(10% v15%;P=0.37)。该研究的结论是，与安慰剂相比，使用低剂量皮质类固醇(0.5 mg/kg，每12小时服用一次，持续5天)可以减少重症CAP和高炎症反应患者的治疗失败【171】。

另一项系统回顾和meta分析【172】,包括六个试验共1506例患者的数据(748名患者被随机分入皮质类固醇组，758例安慰剂组)报道,皮质类固醇的使用缩短了住院患者的临床稳定时间(调整差异,-1.03天;95% CI -1.62- -0.43天;P=0.001)和住院时间(-1.15天;95% CI -1.75至-0.55天；P＜0.001);对死亡率无任何影响(OR, 0.75;95% CI 0.46-1.21;P=0.24)。然而，作者也报告了CAP相关再次住院的风险增加(OR 1.85, 95% CI 1.03 - 3.32, P=0.04)和高血糖(OR 2.15;95% CI 1.60-2.90, P＜0.001)。

来自两项随机临床试验的数据【173，174】支持使用氢化可的松作为脓毒性休克患者的辅助治疗。一项在危重症患者中随机辅助使用皮质类固醇治疗的试验【173】包括3658例接受机械通气的脓毒性休克患者(1832例随机分为氢化可的松组，1826例随机分为安慰剂组)。参与者接受每日200mg氢化可的松或安慰剂，持续7天或直到死亡或ICU出院。作者报告，与接受安慰剂的患者相比，在这一人群中使用氢化可的松并没有导致90天死亡率的降低(OR 0.95;95%CI 0.82-1.10;P=0.50)。一项多中心、双盲和随机试验【174】对1241例脓毒性休克患者评估了氢化可的松加氟氢化可的松治疗与安慰剂治疗的疗效(614例随机接受氢化可的松加氟氢化可的松治疗，627例随机接受安慰剂治疗)进行了研究，发现接受氢化可的松联合氟氢化可的松治疗的患者的90天全因死亡率较低(43%vs49%，P=0.03)。

相反，几项研究发现，在流感中使用皮质类固醇可能与由重叠感染导致的死亡率升高有关【175-177】。尽管存在这些担忧，但最近关于重症COVID-19合并呼吸衰竭的研究，特别是在对照、开放标签的COVID-19治疗试验随机评估显示，死亡率有所好转。该试验包括对接受氧气或机械通气的患者每天给予6mg地塞米松，持续10天【178】。

ESCAPe试验(NCT01283009)调查了583例成年危重CAP患者使用甲基强的松龙(20天的治疗: 7天(40毫克/天) ，7天(20毫克/天) ，6天(12毫克/天和4毫克/天))与安慰剂的使用情况，主要研究终点为60天的死亡率。患者的平均年龄为68.8岁，平均PSI为124。这些患者中96%为男性，33%接受通气治疗。关于60天死亡率，结果显示甲基强的松龙和安慰剂之间无差异(OR 0.90;95% CI 0.58-1.40, P=0.635)【179】。

目前，国际指南中关于使用糖皮质激素作为辅助治疗的建议是，无论是非重症CAP患者还是重症流感肺炎患者，都不常规使用糖皮质激素。然而，在伴有难治性脓毒性休克或高度全身炎症反应的重症肺炎患者以及肺炎球菌性CAP合并脑膜炎患者中，皮质类固醇可能是有价值的【6】。

免疫球蛋白治疗

一些研究表明，与非ICU患者相比，重症肺炎ICU患者的循环免疫球蛋白水平较低，而且这些低水平的免疫球蛋白水平与死亡率升高之间存在关联【180，181】。这些数据提示免疫球蛋白可能在重症CAP患者的辅助治疗中发挥作用。

在一项单中心观察性研究【182】中，362例CAP患者(172例在病房和190例在ICU)的免疫球蛋白水平(IgG、IgA、IgM)的作用及其对预后的影响，IgG2＜301 mg/dL与较差的预后相关。此外，较低的IgG2水平是进入ICU和死亡的独立标志物。同样的,另一项独立的单中心观察性【181】研究报道，IgM浓度与严重程度呈负相关，而且在重症流感病例中，IgM浓度是死亡的一个保护因素。

在机械通气的重症CAP和脓毒症休克患者【183】中，研究了免疫球蛋白作为辅助治疗的疗效。在一项对1324名接受免疫球蛋白辅助治疗的患者和6940名对照组的观察研究中，辅助治疗和死亡率之间没有明显的关联。同样,对另一项回顾性队列研究（包括 960 名脓毒症和感染性休克患者）的数据进行亚组分析发现，使用低剂量 IgG 免疫球蛋白作为辅助治疗与 ICU住院率 （21% 对 18%，P=0.185） 或住院死亡率（34% 对 31%，P=0.066）减少之间没有关联【184】。

此外，一项双盲II期研究【185】公布了160例需要有创机械通气的重症肺炎患者的数据，这些患者连续5天被随机分为三联蛋白组(一种含有IgM、IgA和IgG的多克隆抗体制剂)或安慰剂组。与安慰剂组患者相比，使用三联蛋白治疗并没有增加无呼吸机天数(中位数11天vs 8天，P=0.173)。有趣的是，作者观察到，使用三联蛋白治疗后，CRP升高和/或IgM水平降低的患者死亡率降低，并且不使用呼吸机的天数增加。

VAP指南建议

在过去十年中，VAP中报告的耐多药病原体（MDR）的发生率增加，管理复杂，由这些微生物引起的感染与不良结局有关【147，148】。当地流行病学和易感性信息应被用于指导VAP的经验性治疗，同时仔细评估患者耐多药病原体的危险因素【5】。MDR病原体的危险因素在美国【5】和欧洲指南【7】之间存在差异;然而，在考虑经验性治疗时，当地的细菌学和细菌耐药模式仍然很重要，之前的抗生素治疗也是如此(表2)。

联合治疗的原因和时间

一般来说，当地的微生物对抗生素敏感谱，以及耐多药、革兰氏阴性或革兰氏阳性和革兰氏阴性菌混合感染的可能性指导选择单药治疗还是联合治疗。

根据美国指南【5】，如果患者没有特定的MDR病原体(如铜绿假单胞菌或MRSA)危险因素，并在MDR微生物流行率低(＜10%)的ICU接受治疗，则推荐使用单一的、对非耐药革兰氏阴性微生物有活性的窄谱抗生素(弱推荐，低质量证据)。根据欧洲指南，对于在MDR微生物发病率低(＜25%)的ICU接受治疗的患者，如果MDR危险因素少且死亡风险较低，推荐使用对非耐药革兰氏阴性微生物有效的窄谱抗生素(弱推荐，证据质量非常低)【7】。

对于MDR高危的患者，建议使用双重抗生素治疗。针对VAP患者的经验性治疗，一项系统回顾和meta分析【186】对单一疗法和联合疗法进行了比较。该研究包括41项试验和7015名患者的数据。作者报道，头孢他啶-氨基糖苷联合用药在治疗失败风险方面劣于美罗培南(相对风险(RR)0.70;95%CI 0.53-0.93)。但总体而言，单药治疗和联合治疗的死亡率和治疗失败率相似(单药治疗的死亡率RR 0.94;95% CI 0.76-1.16;单药治疗失败的RR 0.88;95%CI 0.72-1.07)。作者强调，VAP病例中由耐多药病原体引起的比例很小，这可能解释了联合治疗缺乏益处的原因。一项随机对照试验【187】比较经验性单用美罗培南与环丙沙星联合美罗培南治疗疑似VAP患者的28天死亡率，两组比较无显著性差异。(RR 1.05, 95%CI 0.78-1.42,P=0.74)。此外，在ICU住院时间和总住院时间、治疗反应和抗生素耐药菌的出现方面没有发现差异。然而，该研究排除了已知定植或感染假单胞菌或MRSA的患者。有趣的是，作者分析了56例由假单胞菌、不动杆菌和耐多药革兰阴性杆菌引起的感染病例。他们观察到，与单药治疗相比，美罗培南+环丙沙星联合治疗耐药菌组获得充分的初始治疗(84.2% v 18.8% P=0.001)和微生物清除(64.1% v 29.4%，P=0.05)的可能性更高。类似地，一个系统性综述【188】，包括来自12个随机对照试验的3571例VAP患者，发现单一治疗和联合治疗在全因死亡率(OR 0.97, 95% CI 0.73-1.30)、临床康复率(OR 0.88, 95% CI 0.56-1.36)和ICU住院时间(平均差异0.65，95% CI 0.007-1.23)方面没有显著差异。然而，作者承认，这些数据可能不适用于所有患者群体，因为该研究并没有识别出耐多药细菌风险增加的患者。此外，在由耐多药细菌引起的病例中，观察性研究【189-192】的结果显示，与单一治疗或β-内酰胺和氟喹诺酮联合治疗相比，包括广谱β-内酰胺和氨基糖苷的联合治疗方案可增加恰当治疗病例的比例。

美国指南建议对耐多药微生物高风险的患者使用针对革兰氏阴性微生物的双重抗生素治疗：患有肺部疾病者;以及在ICU接受治疗的耐多药病原体流行率未知或较高(＞10%)的患者(弱推荐，低质量证据)。如果患者也有感染MRSA的风险，就会增加对这种病原体的治疗。相反，如果患者在ICU中耐多药微生物患病率高(＞25%)和/或耐多药微生物和死亡风险高，欧洲指南建议在经验性抗生素治疗中采用更广泛的方法。然后根据患者的血流动力学状态进行具体选择。对于诊断时无脓毒性休克的患者，单一疗法是足够的，只要该药物对ICU环境中90%的常见革兰氏阴性菌有效。广谱、多药物治疗被推荐用于脓毒性休克患者。然而，这种治疗应该覆盖铜绿假单胞杆菌、具有广谱β-内酰胺酶的肠杆菌科和鲍曼不动杆菌(如果在ICU中非常普遍)(强烈推荐，低质量证据)。联合治疗的基本原理是提供足够广泛的覆盖范围，使适当的治疗比单一治疗更有可能。此外，与单一疗法相比，联合治疗可以更快清除病原体，从而对于感染性休克和死亡风险> 25%的患者而言具有生存优势【7，193】。

MDR病原体的治疗:MRSA，假单胞菌，不动杆菌

应根据流行病学数据决定是否使用经验性抗MRSA抗生素。ATS/ISDA指南【5】建议在>10-20%的金黄色葡萄球菌分离物是MRSA时使用，而欧洲指南【7】建议在>25%的金黄色葡萄球菌分离物是MRSA时使用。对于耐多药病原体风险高的患者或在ICU环境中接受治疗的患者，若革兰氏阴性病原体超过10%对最佳单药治疗方案耐药，欧洲指南建议使用两种不同类别的抗假单胞菌药物。

美国指南【5】将高危患者分为两大类:(1)具有耐多药病原体高风险且无感染性休克的患者，他们可以接受单一广谱药物，该药物对90%以上的革兰氏阴性微生物有效，（2）具有耐多药病原体和感染性休克高风险的患者，他们应接受双重抗假单胞菌方案，如果不动杆菌属和产ESBL的肠杆菌科的病原体在当地抗菌谱中普遍存在，则应覆盖这些病原体。

近年来，HAP/VAP有了新的治疗方法，特别是针对耐多药病原体的治疗:

1.   头孢他啶-阿维巴坦(CEF/AVI)是第三代头孢菌素与非β-内酰胺类β-内酰胺酶抑制剂的组合。CEF/AVI对多种β-内酰胺酶有活性，包括Ambler A类(肺炎克雷伯菌碳青霉烯酶和ESBL型酶)，Ambler C类和一些Ambler D类丝氨酸酶(如苯唑青霉素酶 oxa-48)。然而，它对金属β-内酰胺酶或不动杆菌oxa样碳青霉烯酶没有活性。头孢他啶-阿维巴坦已获得美国食品和药物管理局(FDA)和欧洲药品管理局(EMA)批准用于HAP/VAP。在一项随机对照试验中，针对耐碳青霉烯类非肠杆菌科肺炎的联合方案被证明不劣于美罗培南【194】。

2.   头孢洛芬他唑巴坦（Ceftolozane-tazobactam，CEF/TAZ)是一种头孢菌素和β-内酰胺酶抑制剂，具有体外抗耐多药铜绿假单胞菌和产ESBL肠杆菌科的作用。一项随机对照双盲、非劣效性试验的结果包括726名机械通气的革兰氏阴性医院获得性肺炎患者【195】，比较了CEF/TAZ(每8小时输注1小时2g头孢洛芬加1g他唑巴坦)(362名受试者在头孢洛芬-他唑巴坦组)与美罗培南(每8小时输注1g，持续1小时)(美罗培南组364名受试者)。在这项研究中，两种药物在机械通气的革兰氏阴性医院肺炎患者中是等效的并且耐受性良好。然而，在死亡率方面，CEF/TAZ在那些有通气性HAP和那些以前对当前的院内肺炎进行抗生素治疗失败的患者中具有优势。这种新型抗生素已获得FDA和EMA批准用于HAP治疗【196，197】。

3.   美罗培南-瓦博巴坦是一种联合制剂，含有现有的β-内酰胺抗生素(美罗培南)和环硼酸非β-内酰胺酶抑制剂(瓦博巴坦)，对革兰氏阴性微生物(包括那些具有广谱β-内酰胺酶和肺炎克雷伯菌碳青霉烯酶)有效。但对产金属-β-内酰胺酶和苯唑西林酶的菌株无活性。在一项包括耐碳青霉烯类肠杆菌科机械通气患者的试验中，尽管美罗培南-瓦博巴坦未获批准用于VAP，但与现有的最佳治疗方法(通常是粘菌素)相比，美罗培南-瓦博巴坦在临床恢复方面具有优势【198】。

4.   亚胺培南-瑞巴坦(IR)是一种含现有β-内酰胺类抗生素(亚胺培南-西司他丁)和非β-内酰胺类β-内酰胺酶抑制剂(瑞巴坦)的复方药物，对革兰氏阴性微生物有活性，包括Ambler C类、产广谱β-内酰胺酶和肺炎克雷伯菌碳青霉烯酶的菌株。但对产金属-β-内酰胺酶和苯唑西林酶的菌株无活性。在一项III期试验中，在 537 名医院获得性肺炎患者中比较了 IR 与哌拉西林-他唑巴坦，其中一半患者接受了机械通气，两种治疗在临床恢复和死亡率方面相当。然而，在基线时机械通气的亚组接受IR时生存率较高【199】。

5.   头孢地尔是一种铁载体头孢菌素，它与铁结合，通过铁运输系统进入细菌细胞。它抑制广泛的碳青霉烯耐药病原体，包括肠杆菌科，铜绿假单胞菌和鲍曼不动杆菌。对嗜麦芽寡养单胞菌也有抑制作用。头孢地尔被批准用于包括VAP在内的院内肺炎，但与美罗培南相比，没有显示出生存优势或更高的治愈率。在另一项研究中，VAP患者的生存期低于最佳可用疗法【200，201】。

利用药代动力学/药效学原理优化给药剂量

应用药代动力学/药效学(PK/PD)原则给药可改善肺炎患者的预后。以浓度依赖性方式杀灭细菌的药物(氨基糖苷类药物)，其效力的最大化与其在血清和感染部位达到的峰值浓度与目标病原体的最低抑制浓度(MIC)比值高低有关。当整个24小时剂量作为单次输注给药时，治疗效果可以被优化【185，194】。相反，β-内酰胺类药物(青霉素类、头孢菌素类、碳青霉烯类)的最佳杀菌效果取决于其浓度维持在目标病原体MIC以上的时间，这可以通过延长输注时间或持续输注来优化【131，195】。例如，持续输注万古霉素可改善预后【202，203】，而较高剂量和持续输注利奈唑胺可改善预后，特别是在ARDS患者和耐药病原体引起的感染患者中【204，205】。

雾化抗生素

雾化抗生素可以在肺实质中达到更高的抗生素浓度，比静脉治疗具有更少的全身毒性，但未将其作为VAP的常规辅助治疗。三项随机试验调查了VAP患者使用辅助雾化抗生素的情况【206-209】:IASIS试验(雾化吸入辅助阿米卡星和磷霉素对VAP和疑似MDR、革兰氏阴性菌患者的影响);INHALE试验(吸入阿米卡星作为VAP和疑似MDR、革兰氏阴性菌患者的辅助治疗);和VAPORISE试验(吸入妥布霉素作为VAP患者的辅助治疗)。这三项研究在改善临床结局或死亡率方面均显示为阴性结果。

2019年，ATS/IDSA HAP指南委员会的一项meta分析结果(包括9项用于VAP治疗的吸入性抗生素研究)显示【210】，使用吸入性抗生素对治疗难以治疗的微生物引起的VAP是有益的。因此，ATS/IDSA指南【5】建议在耐多药微生物引起的革兰氏阴性肺炎病例中，将吸入抗生素添加到全身抗生素治疗方案中，使用吸入性粘菌素代替多粘菌素B。对于治疗无反应的VAP和敏感或耐药微生物患者，也建议将吸入性抗生素作为最后的手段。在获得更多数据之前，欧洲指南不建议使用吸入式抗生素。

CAP和HAP的治疗持续时间

来自两项meta分析的数据显示，短期抗生素治疗(5 - 7天)对CAP患者可能足够【211，212】。在包含4861例患者数据的19个随机对照试验的首次meta分析中，不论肺炎的严重程度,作者没有发现短疗程(≤6天)和长疗程(≥7天)的临床治愈率有任何差异【211】。此外，短疗程治疗与更少的严重不良事件相关(RR=0.73;95%CI 0.55-0.97)，死亡率可能低于长期疗程治疗(RR=0.52;95% CI 0.33-0.82)。第二项meta分析分析了来自7个随机对照试验(包括3021名患者【212】的数据)，表明对细菌性CAP患者进行短期抗生素治疗(5天)获得的临床效果与接受长期抗生素治疗(7至14天)的患者观察到的临床效果相似。作者还报道，全因死亡率与抗生素治疗时间无关，并且短疗程的抗生素治疗与较低的不良反应率相关。

根据ATS/IDSA指南【6】，应使用患者的临床稳定性指导抗生素治疗的持续时间，且不少于5天。指南还指出，在肺炎并发脑膜炎、心内膜炎和其他深部感染的情况下，建议使用较长的抗生素疗程。在其他不太常见的病原体感染的情况下，指南没有规定治疗时间【6】。

对于VAP患者，美国指南【5】建议进行7天疗程的抗生素治疗。视临床、影像学和实验室参数的改善速度而定;然而，有些病人可能需要较短或较长的抗生素治疗时间。欧洲指南【7】建议对无免疫缺陷、无囊性纤维化或其他肺部并发症(脓胸、肺脓肿、空洞或坏死性肺炎);初期接受适当治疗;没有高耐药病原体(铜绿假单胞菌、耐碳青霉烯不动杆菌属、耐碳青霉烯肠杆菌科);并且对抗生素治疗反应良好的患者进行7-8天疗程的抗生素治疗。

生物标记物

生物标记物提供关于宿主对感染和药物干预的反应信息;然而，肺炎患者的异质免疫和炎症反应使其普遍使用具有挑战性【213，214】。现已研究的生物标志物包括CRP、降钙素原(PCT)、淋巴细胞计数、红细胞分布宽度、白细胞介素-6，肾上腺髓质素原，N-末端B型利钠肽前体、髓系细胞上表达的可溶性触发受体-1、共肽素、尿激酶型纤溶酶原激活物受体的可溶性形式【214-222】。

在临床实践中，CRP、PCT以及近来的淋巴细胞计数是指导肺炎抗生素治疗时间和预后的最常用的生物标志物。

C-反应蛋白（CRP）是巨噬细胞在应对任何类型的炎症(包括细菌和病毒感染)时产生的主要急性期蛋白。它会在急性损伤后的4-6小时内释放，在36-48小时左右达到峰值。然而，CRP在肺炎诊断中的特异性较低，因为其他临床原因（如肿瘤或自身免疫性疾病）也可能导致c -反应蛋白水平升高【223】。

PCT是在甲状腺中合成的降钙素激素的肽前体。它在炎症和感染性疾病期间增加，主要作为肝脏产生的急性期反应物。在健康个体中，血浆PCT浓度非常低(＜0.1 ng/mL);然而，细菌感染会使其升高【223】。

虽然没有发现可以区分CAP住院患者【224】的病毒感染和细菌感染的PCT阈值，但PCT水平较高表明细菌感染的可能性增加。

有趣的是,对来自两个前瞻性纵向队列【225】的数据进行二次分析,发现从肺炎症状发作到初次就诊的时间可能影响CRP和PCT水平。该研究包括541例CAP,基于出现症状的时间分为两组:早期就诊者(症状出现＜3天)和晚期就诊者(症状出现＞3天)。在本研究中，CRP和PCT在早期就诊者中水平较低，这表明症状出现的时间可能会影响这些生物标志物。作者还建议，对于症状持续时间较长的患者，CRP可能是一个更有用的生物标志物;对于症状持续≤48小时的患者，PCT可能有更好的效用。

在CAP患者中，PCT已成为减少抗生素治疗时间的辅助工具。一些随机对照试验使用了一系列的PCT测量来确定抗生素治疗的持续时间，显示治疗时间缩短。然而，接受标准治疗的对照组参与者的抗生素治疗疗程超过了7天【226-229】，并且超过了指南的建议。目前的国际指南建议，在影像学确诊的CAP中，应基于临床怀疑而不是基于PCT水平开始抗菌治疗。有趣的是，研究报告了CRP和PCT水平的升高与并发症、ICU住院和短期死亡风险的增加之间的相关性【216，230-232】。

一项对26项关于呼吸道感染(CAP、HAP、VAP、COPD加重和支气管炎)【223】抗生素治疗时间的大型meta分析发现，PCT指导的治疗可使治疗时间减少2.4天(5.7 v 8.1天，P＜0.001)。此外，在PCT指导抗生素治疗的组中观察到较低的死亡率(OR 0.83, 95% CI 0.70 to 0.99, P=0.037)。这也适用于ICU中CAP和VAP的患者。欧洲HAP/VAP【7】指南中提出的建议是，在需要较长疗程的肺炎病例中，使用连续PCT测量与临床评估相结合，以缩短抗生素治疗时间。

最近，一项研究【213】调查了淋巴细胞计数作为疾病严重程度的生物标志物的价值，发现淋巴细胞减少会增加CAP患者严重程度的风险，并且在CURB-65评分中增加淋巴细胞计数可以改善30天死亡率的预测。另一项来自中国的研究【234】报道，PO2/FiO2和淋巴细胞计数联合能预测流感肺炎住院患者的死亡率和ICU住院时间。作者发现PO2/FiO2 ≤250或外周血淋巴细胞计数＜0.8×109 /L的患者发生重症流感肺炎的可能性较高。淋巴细胞计数作为ICU获得性肺炎(ICU-AP)的生物标志物也被研究。西班牙一项对473名患者的研究报告，淋巴细胞减少是非免疫功能低下患者90天死亡率的独立预测因子【235】。淋巴细胞计数是一种简单且不昂贵的生物标志物，被证明是有用的，特别是在其他生物标志物无法获得的医院;该生物标志物在重症CAP和ICU-AP免疫缺陷患者中的应用已经得到证实。

尽管CRP和PCT有很好的应用价值，但在日常实践的使用中仍存在局限性。在临床评估和决策过程中，生物标记物应被视为与治疗地点和治疗时间相关的辅助工具。

肺炎的预防

CAP预防的重点是疫苗接种，而不是那些有重症肺炎风险的人。本讨论将集中于VAP和旨在减少感染发生率和改善临床病程的措施，重点是阻断疾病的发病机制。目前，预防致病菌定植和吸入仍是VAP预防措施的前沿研究热点。研究最多的VAP预防措施包括抬高床头、缩短或避免机械通气时间、早期活动、气管插管袖套设计、声门下分泌物抽吸、口腔护理和使用益生菌。

与半卧位(床头抬高30°- 45°)患者相比【236-238】，仰卧位通气患者(头抬高0°- 10°)吸入胃内容物的风险增加。2016年，一项综述和meta分析【238】(包括8项RCT，共759例患者)对仰卧位和半卧位进行了比较。作者发现，与仰卧位相比，半卧位显著降低了疑似VAP的风险(14%v40%，RR 0.36;95% CI 0.25-0.50)。但微生物证实的VAP的发生无显著差异。一项包括5539名接受至少3天机械通气【239】的患者的回顾性队列研究称，床头抬高以及诸如镇静输液中断、自发呼吸试验和血栓预防等措施与缩短拔管时间有关。一项RCT【240】中395例患者(其中194例为侧卧特伦德伦伯格卧位[侧卧头低脚高位]，201例为半卧位)比较了侧卧特伦德伦伯格卧位和半卧位。研究表明，半卧位与侧卧特伦德伦伯格卧位相比，VAP发生率更高(4% v 0.5%;RR 0.13;95% CI 0.02-1.03;P = 0.04)。微生物学证实的VAP和死亡率无差异。然而，由于随机分配的侧卧特伦德伦伯格卧位的患者出现不良事件，该试验被提前终止。

床头抬高到半卧位是一种常见预防VAP的干预措施【241，242】。

有创机械通气引起的口咽分泌物微量吸入是VAP发生的主要危险因素【243，245】。避免机械通气【246-249】，减少插管时间和自主呼吸试验【251，252】是预防VAP的有效措施。不同的研究人员已经评估了改变气管插管袖套的形状和材料的好处，因为这与减少液体通过袖套泄漏到肺部和预防 VAP 有关。由聚氨酯等材料制成的袖套经过测试，证明与气管的形状更吻合，从而减少液体流向肺部。与传统的圆柱形袖套不同，新型袖套呈圆锥形，在最大直径处均匀地接近气管壁。尽管如此，RCT和meta分析的结果并不支持这些创新比传统材料和形式更好地防止VAP的结论【253，256】。

抽吸聚集在气管插管套上方的声门下分泌物与较低的VAP率相关;但其在减少机械通气时间、ICU住院时间和呼吸机相关事件方面的价值存在争议【257-262】。最近的一项系统评价和meta分析，包括20项研究(9项系统回顾和meta分析和20项随机对照试验)，发现声门下分泌物引流显著降低了VAP的发生率(RR 0.56;95% CI 0.48-0.63, I2 =0%， P=0.841)和死亡率(RR 0.88;95% CI 0.80- 0.97, I2 =0%，P=0.888)。需要更多高质量的研究来阐明这种干预在通气患者中的潜在作用。有趣的是，一项meta分析研究了声门下分泌物引流对VAP致病微生物的影响,发现声门下分泌物引流与革兰氏阳性球菌和流感嗜血杆菌引起的VAP降低之间存在显著关联(OR 0.29, 95% CI 0.18-0.48;P＜0.001)。而由非发酵菌和肠杆菌引起的VAP无显著差异【264】。

选择性消化道去污(SDD)是一种预防性抗生素使用策略，用于控制肠道内病原体的过度生长，特别是那些革兰氏阴性和多药耐药的病原体，使用局部口服和胃部抗生素，如妥布霉素、多粘菌素和两性霉素B，以及初始静脉注射抗生素。先前的研究【265，266】在低水平抗生素耐药性的ICU环境中观察到，SDD和选择性口咽去污(SOD)与改善临床结局相关。一项研究【267】报道，SDD在预防感染方面比SOD更有效。

关于使用SDD的主要担忧是增加了抗生素耐药性的风险【268】，以及使用抗生素可能对没有细菌感染的患者产生的影响。一项研究【269】表明，SDD诱导了4个抗性基因的选择。结论是，在抗生素抗药性中发生SDD的风险有限。此外，在存在中等至高耐药性病原体流行率的ICU环境中，未观察到SDD的使用与感染率下降有关【270】。在一项针对ICU机械通气患者去污染策略的随机临床试验中，在抗生素耐药微生物高流行的ICU环境中，SDD策略并不比标准护理增加更多的益处【270】。

在抗生素耐药微生物低流行的ICU环境中，SDD策略与较少的抗生素耐药和改善的临床结局相关。需要在耐药微生物流行率较高的ICU环境中进行更多的研究。此外，有报道称，在机械通气患者中，使用洗必泰治疗口腔卫生可降低VAP的风险【271-274】。一项RCT【275】发现，与0.2%的洗必泰相比，使用2%的洗必泰作为VAP的预防措施和减少口咽定植更有效。一项Cochrane系统综述和meta分析报告称，需要更多的证据来证明洗必泰的使用及其与降低感染、死亡率和ICU住院时间的关系【274】。来自观察性研究和随机对照试验的meta分析的结果显示，使用洗必泰与死亡风险增加之间存在关联【239，276-278】。洗必泰微量吸入可引起急性呼吸窘迫综合征【273-279】。洗必泰的使用也被报道与不良反应相关，如口腔黏膜损伤(如糜烂性口腔病变、溃疡、白色或黄色斑块、粘膜出血)【280】和过敏反应【281，282】。此外，据报道洗必泰敏感性降低，这令人担忧【283】。

最后，作为SDD的一部分，短期预防性的全身抗生素治疗可能对心脏骤停或神经损伤后紧急插管的患者有效。使用24-48小时的全身抗生素治疗可以根除插管过程中吸入的微生物，并防止随后48小时内发生VAP【284，285】。

新兴的管理方法

基于下一代测序(NGS)的宏基因组学研究可能显著改善肺炎的诊断和治疗，特别是重症病例【286-288】。NGS允许在单一检测中更准确和快速地检测多种病原体。血浆microRNA特征也成为一种能够预测疾病严重程度的工具，最近有报道称，它是COVID-19重症监护室患者严重程度和病情恶化的良好标志物【289】。事实上，这项技术可以帮助临床医生为重症肺炎患者提供更加个性化的治疗【290】。此外，越来越多的证据表明检测技术的价值，如Filmarray肺炎检测。这是一种多重PCR检测方法，可以检测肺炎中最常见的病原体及其耐药性模式。关于病原体耐药性的数据最近发表在PROGRESS试验(一项前瞻性多中心随机试验)的一项子研究中【291】。该研究包括56例无MDR病原体危险因素的CAP患者和34例有MDR病原体危险因素的CAP患者。具体来说，肺炎检测的检出率为72%，而常规微生物试验的检出率为10% (P＜0.001)。这些结果支持了这种新的诊断测试的价值及其在未来临床实践中的潜在应用。

指南

在形成本综述时，我们考虑了美国传染病学会和美国胸科学会【5，6】、欧洲呼吸学会、欧洲重症监护医学学会、欧洲临床微生物学和传染病学会、和拉丁美洲协会关于CAP、HAP、VAP的建议【5-7，12】。主要建议总结如上，包括可能的病原体、推荐的诊断检测、初始抗菌治疗的选择、治疗持续时间、辅助治疗的使用和肺炎的预防。

对于重症CAP患者，最初的治疗是大环内酯类药物或氟喹诺酮类药物与β-内酰胺类药物联合使用。β-内酰胺的选择是基于假单胞菌危险因素的存在，MRSA的附加覆盖范围也基于特定危险因素的存在而决定。有流感记录的患者应服用奥司他韦加上抗生素。治疗至少5-7天，持续时间可由降钙素原等生物标志物指导。糖皮质激素辅助治疗并不推荐，但可能对某些患者有益。预防的重点是高危人群的疫苗接种。

HAP/VAP的诊断仍然是一个难题，现有指南对支气管镜标本定量培养的价值认可存在差异。对于所有铜绿假单胞菌和其他革兰氏阴性病原体的患者，包括MDR病原体和MRSA的治疗建议，基于个体危险因素和这些病原体在ICU的出现频率。较新的药物和吸入的抗生素可能对一些高耐药病原体有作用。大多数患者将需要联合治疗，如果初始治疗准确，病原体不具有高度耐药性，而且患者对治疗反应良好，治疗时间可短至7天。预防主要集中在可用的干预措施上，如抬高床头、预防误吸、减少机械通气持续时间或避免机械通气、早期活动和气管插管袖套设计。

结论

尽管在诊断、管理、抗菌治疗和预防方面取得了进展，但肺炎仍对全球卫生保健系统产生重大影响。多药耐药病原体的出现、人口年龄的增长、多重合并症患者数量的增加和多种药物治疗是临床医生在治疗重症肺炎患者时面临的一些挑战。尽管CAP和HAP/VAP管理的国际指南存在一些差异，但遵循这些建议将确保因肺炎住进ICU的患者有更好的预后。

表格 3 未来研究的问题

l  在重症肺炎患者中，分子诊断检测在明确病原微生物诊断中的价值是什么?它在抗菌素降阶梯治疗中的作用是什么?

l  如何在病程早期识别重症肺炎病例?

l  我们如何将生物标志物和严重程度评分与临床判断相结合，以提高重症肺炎的鉴别能力？

l  皮质类固醇或其他抗炎治疗可使具有什么特征的重症CAP患者获益？

l  新型抗菌剂能否帮助我们更有效地管理感染耐多药病原体的患者？

l  重症病毒性肺炎患者是否需要短期抗生素治疗?

参考文献

1.      GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet2020; 396: 1204-22.doi:10.1016/S0140-6736(20)30925-9 pmid:33069326

2.      Torres A, Cilloniz C, Niederman MS, et al. Pneumonia. Nat Rev Dis Primers 2021; 7:25. doi:10.1038/s41572-021-00259-0. pmid:33833230.

3.      Bein T, Weber-Carstens S, Apfelbacher C. Long-term outcome after the acute respiratory distress syndrome: different from general critical illness? Curr Opin Crit Care2018;24:35-40.doi:10.1097/MCC.0000000000000476. pmid:29189296.

4.      Sangla F, Legouis D, Marti P-E, et al. One year after ICU admission for severe community-acquired pneumonia of bacterial, viral or unidentified etiology. What are the outcomes? PLoS One2020;15: e0243762. doi:10.1371/journal.pone.0243762. pmid:33315946.

5.      Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis2016;63:e61-111. doi:10.1093/cid/ciw353. pmid:27418577.

6.      Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med2019;200: e45-67. doi:10.1164/rccm.201908-1581ST. pmid:31573350.

7.      Torres A, Niederman MS, Chastre J, et al. International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: Guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociación Latinoamericana del Tórax (ALAT). Eur Respir J2017; 50:1700582. doi:10.1183/13993003.00582-2017. pmid:28890434.

8.      Woodhead M, Welch CA, Harrison DA, Bellingan G, Ayres JG. Community-acquired pneumonia on the intensive care unit: secondary analysis of 17 869 cases in the ICNARC Case Mix Programme Database. Crit Care2006;10(Suppl 2): S1. doi:10.1186/cc4927.

9.      Phua J, Ngerng WJ, Lim TK. The impact of a delay in intensive care unit admission for community-acquired pneumonia. Eur Respir J2010; 36:826-33. doi:10.1183/09031936.00154209. pmid:20185424.

10.   Renaud B, Santin A, Coma E, et al. Association between timing of intensive care unit admission and outcomes for emergency department patients with community-acquired pneumonia. Crit Care Med2009;37:2867-74. doi:10.1097/CCM.0b013e3181b02dbb. pmid:19770748.

11.   Restrepo MI, Mortensen EM, Rello J, Brody J, Anzueto A. Late admission to the ICU in patients with community-acquired pneumonia is associated with higher mortality. Chest 2010; 137:552-7. doi:10.1378/chest.09-1547.pmid:19880910.

12.   Mandell LA, Wunderink RG, Anzueto A, et al., Infectious Diseases Society of America, American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis2007;44(Suppl 2): S27-72. doi:10.1086/511159. pmid:17278083.

13.   Phua J, See KC, Chan YH, et al. Validation and clinical implications of the ATS/IDSA minor criteria for severe community-acquired pneumonia. Thorax2009; 64:598-603. doi:10.1136/thx.2009.113795. pmid:19386583.

14.   Liapikou A, Ferrer M, Polverino E, et al. Severe community-acquired pneumonia: validation of the Infectious Diseases Society of America/American Thoracic Society guidelines to predict an intensive care unit admission. Clin Infect Dis2009; 48:377-85. doi:10.1086/596307. pmid:19140759.

15.   Kontou P, Kuti JL, Nicolau DP. Validation of the Infectious Diseases Society of America/American Thoracic Society criteria to predict severe community-acquired pneumonia caused by Streptococcus pneumoniae. Am J Emerg Med2009; 27:968-74. doi:10.1016/j.ajem. 2008.07.037.pmid:19857416.

16.   Brown SM, Jones BE, Jephson AR, Dean NC, Infectious Disease Society of America/American Thoracic Society 2007. Validation of the Infectious Disease Society of America/American Thoracic Society 2007 guidelines for severe community-acquired pneumonia. Crit Care Med2009; 37:3010-6. doi:10.1097/CCM.0b013e3181b030d9. pmid:19789456.

17.   Chalmers JD, Taylor JK, Mandal P, et al. Validation of the Infectious Diseases Society of America/American Thoratic Society minor criteria for intensive care unit admission in community-acquired pneumonia patients without major criteria or contraindications to intensive care unit care. Clin Infect Dis2011;53:503-11. doi:10.1093/cid/cir463.pmid:21865188.

18.   Laporte L, Hermetet C, Jouan Y, et al. Ten-year trends in intensive care admissions for respiratory infections in the elderly. Ann Intensive Care2018; 8:84. doi:10.1186/s13613-018-0430-6. pmid:30112650.

19.   Cavallazzi R, Furmanek S, Arnold FW, et al. The burden of community-acquired pneumonia requiring admission to ICU in the United States. Chest 2020; 158:1008-16. doi:10.1016/j.chest.2020.03.051. pmid:32298730.

20.   Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus definitions for sepsis and septic shock (Sepsis-3). JAMA2016; 315:801-10. doi:10.1001/jama.2016.0287. pmid:26903338.

21.   Ranzani OT, Prina E, Menéndez R, et al. New sepsis definition (Sepsis-3) and community-acquired pneumonia mortality. A validation and clinical decision-making study. Am J Respir Crit Care Med 2017; 196:1287-97. doi:10.1164/rccm.201611-2262OC. pmid:28613918.

22.   Chen Y-X, Wang J-Y, Guo S-B. Use of CRB-65 and quick Sepsis-related Organ Failure Assessment to predict site of care and mortality in pneumonia patients in the emergency department: a retrospective study. Crit Care 2016; 20:167. doi:10.1186/s13054-016-1351-0. pmid:27250351.

23.   Kolditz M, Scherag A, Rohde G, Ewig S, Welte T, Pletz M, CAPNETZ Study Group. Comparison of the qSOFA and CRB-65 for risk prediction in patients with community-acquired pneumonia. Intensive Care Med 2016; 42:2108-10. doi:10.1007/s00134-016-4517-y. pmid:27647332.

24.   Tokioka F, Okamoto H, Yamazaki A, Itou A, Ishida T. The prognostic performance of qSOFA for community-acquired pneumonia. J Intensive Care 2018; 6:46. doi:10.1186/s40560-018-0307-7. pmid:30116532.

25.   Müller M, Guignard V, Schefold JC, Leichtle AB, Exadaktylos AK, Pfortmueller CA. Utility of quick sepsis-related organ failure assessment (qSOFA) to predict outcome in patients with pneumonia. PLoS One2017;12: e0188913. doi:10.1371/journal.pone.0188913. pmid:29267291.

26.   Kim MW, Lim JY, Oh SH. Mortality prediction using serum biomarkers and various clinical risk scales in community-acquired pneumonia. Scand J Clin Lab Invest 2017; 77:486-92. doi:10.1080/00365513.2017.1344298. pmid:28678546.

27.   Zhou H, Lan T, Guo S. Prognostic prediction value of qSOFA, SOFA, and admission lactate in septic patients with community-acquired pneumonia in emergency department. Emerg Med Int2020;2020:7979353. doi:10.1155/2020/7979353.pmid:32322422.

28.   Melsen WG, Rovers MM, Groenwold RHH, et al. Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies. Lancet Infect Dis 2013; 13:665-71. doi:10.1016/S1473-3099(13)70081-1. pmid:23622939.

29.   Forel J-M, Voillet F, Pulina D, et al. Ventilator-associated pneumonia and ICU mortality in severe ARDS patients ventilated according to a lung-protective strategy. Crit Care2012;16: R65. doi:10.1186/cc11312. pmid:22524447.

30.   Burja S, Belec T, Bizjak N, Mori J, Markota A, Sinkovič A. Efficacy of a bundle approach in preventing the incidence of ventilator associated pneumonia (VAP). Bosn J Basic Med Sci 2018; 18:105-9. pmid:28976870.

31.   Su K-C, Kou YR, Lin F-C, et al. A simplified prevention bundle with dual hand hygiene audit reduces early-onset ventilator-associated pneumonia in cardiovascular surgery units: An interrupted time-series analysis. PLoS One 2017;12: e0182252. doi:10.1371/journal.pone.0182252. pmid:28767690.

32.   Dudeck MA, Edwards JR, Allen-Bridson K, et al. National Healthcare Safety Network report, data summary for 2013, device-associated module. Am J Infect Control 2015; 43:206-21. doi:10.1016/j.ajic.2014.11.014. pmid:25575913.

33.   Metersky ML, Wang Y, Klompas M, Eckenrode S, Bakullari A, Eldridge N. Trend in ventilator-associated pneumonia rates between 2005 and 2013. JAMA 2016; 316:2427-9. doi:10.1001/jama.2016.16226. pmid:27835709.

34.   Giuliano KK, Baker D, Quinn B. The epidemiology of nonventilator hospital-acquired pneumonia in the United States. Am J Infect Control 2018; 46:322-7. doi:10.1016/j.ajic.2017.09.005. pmid:29050905.

35.   Healthcare-associated infections in intensive care units—Annual Epidemiological Report for 2017. 2017; https://www.ecdc.europa.eu/en/publications-data/healthcare-associated-infections-intensive-care-units-annual-epidemiological-1

36.   Álvarez-Lerma F, Palomar-Martínez M, Sánchez-García M, et al. Prevention of ventilator-associated pneumonia: the multimodal approach of the Spanish ICU “Pneumonia Zero” program. Crit Care Med 2018; 46:181-8. doi:10.1097/CCM.0000000000002736. pmid:29023261.

37.   Pileggi C, Mascaro V, Bianco A, Nobile CGA, Pavia M. Ventilator bundle and its effects on mortality among ICU patients: a meta-analysis. Crit Care Med 2018; 46:1167-74. doi:10.1097/CCM.0000000000003136. pmid:29629985.

38.   Álvarez Lerma F, Sánchez García M, Lorente L, et al., Sociedad Española de Medicina Intensiva, Sociedad Española de Enfermería Intensiva. Guidelines for the prevention of ventilator-associated pneumonia and their implementation. The Spanish “Zero-VAP” bundle. Med Intensiva 2014; 38:226-36. doi:10.1016/j.medin.2013.12.007. pmid:24594437.

39.   Colombo SM, Palomeque AC, Li Bassi G. The zero-VAP sophistry and controversies surrounding prevention of ventilator-associated pneumonia. Intensive Care Med2020;46:368-71. doi:10.1007/s00134-019-05882-w. pmid:31844907.

40.   Magill SS, Edwards JR, Bamberg W, et al., Emerging Infections Program Healthcare-Associated Infections and Antimicrobial Use Prevalence Survey Team. Multistate point-prevalence survey of health care-associated infections. N Engl J Med 2014; 370:1198-208. doi:10.1056/NEJMoa1306801. pmid:24670166.

41.   Micek ST, Chew B, Hampton N, Kollef MH. A case-control study assessing the impact of nonventilated hospital-acquired pneumonia on patient outcomes. Chest 2016;150:1008-14. doi:10.1016/j.chest.2016.04.009. pmid:27102181.

42.   Herkel T, Uvizl R, Doubravska L, et al. Epidemiology of hospital-acquired pneumonia: Results of a Central European multicenter, prospective, observational study compared with data from the European region. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub2016s6;160:448-55. doi:10.5507/bp.2016.014. pmid:27003315.

43.   Ibn Saied W, Mourvillier B, Cohen Y, et al., OUTCOMEREA Study Group. A comparison of the mortality risk associated with ventilator-acquired bacterial pneumonia and nonventilator ICU-acquired bacterial pneumonia. Crit Care Med 2019; 47:345-52. doi:10.1097/CCM.0000000000003553. pmid:30407949.

44.   Talbot GH, Das A, Cush S, et al., Foundation for the National Institutes of Health Biomarkers Consortium HABP/VABP Project Team. Evidence-based study design for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. J Infect Dis 2019; 219:1536-44. doi:10.1093/infdis/jiy578. pmid:30649434.

45.   Esperatti M, Ferrer M, Giunta V, et al. Validation of predictors of adverse outcomes in hospital-acquired pneumonia in the ICU. Crit Care Med 2013; 41:2151-61. doi:10.1097/CCM.0b013e31828a674a. pmid:23760154.

46.   Vincent J-L, Sakr Y, Singer M, et al., EPIC III Investigators. Prevalence and outcomes of infection among patients in intensive care units in 2017. JAMA 2020; 323:1478-87. doi:10.1001/jama.2020.2717. pmid:32207816.

47.   Restrepo MI, Reyes LF, Anzueto A. Complication of community-acquired pneumonia (including cardiac complications). Semin Respir Crit Care Med 2016; 37:897-904. doi:10.1055/s-0036-1593754. pmid:27960213.

48.   Corrales-Medina VF, Musher DM, Wells GA, Chirinos JA, Chen L, Fine MJ. Cardiac complications in patients with community-acquired pneumonia: incidence, timing, risk factors, and association with short-term mortality. Circulation 2012; 125:773-81. doi:10.1161/CIRCULATIONAHA.111.040766. pmid:22219349.

49.   Musher DM, Rueda AM, Kaka AS, Mapara SM. The association between pneumococcal pneumonia and acute cardiac events. Clin Infect Dis 2007; 45:158-65. doi:10.1086/518849. pmid:17578773.

50.   Viasus D, Garcia-Vidal C, Manresa F, Dorca J, Gudiol F, Carratalà J. Risk stratification and prognosis of acute cardiac events in hospitalized adults with community-acquired pneumonia. J Infect 2013; 66:27-33. doi:10.1016/j.jinf.2012.09.003. pmid:22981899.

51.   Aldás I, Menéndez R, Méndez R, et al., Grupo NEUMONAC, Anexo. Grupo NEUMONAC. Early and late cardiovascular events in patients hospitalized for community-acquired pneumonia. Arch Bronconeumol (Engl Ed) 2020; 56:551-8. doi:10.1016/j.arbr.2020.07.003. pmid:31791646.

52.   Tralhão A, Póvoa P. Cardiovascular events after community-acquired pneumonia: a global perspective with systematic review and meta-analysis of observational studies. J Clin Med 2020;9:414. doi:10.3390/jcm9020414. pmid:32028660.

53.   Violi F, Cangemi R, Falcone M, et al., SIXTUS (Thrombosis-Related Extrapulmonary Outcomes in Pneumonia) Study Group. Cardiovascular complications and short-term mortality risk in community-acquired pneumonia. Clin Infect Dis 2017; 64:1486-93. doi:10.1093/cid/cix164. pmid:28205683.

54.   Aliberti S, Ramirez JA. Cardiac diseases complicating community-acquired pneumonia. Curr Opin Infect Dis 2014; 27:295-301. doi:10.1097/QCO.0000000000000055. pmid:24685550.

55.   Musher DM, Abers MS, Corrales-Medina VF. Acute infection and myocardial infarction. N Engl J Med 2019; 380:171-6. doi:10.1056/NEJMra1808137. pmid:30625066.

56.   Corrales-Medina VF, Taljaard M, Yende S, et al. Intermediate and long-term risk of new-onset heart failure after hospitalization for pneumonia in elderly adults. Am Heart J 2015; 170:306-12. doi:10.1016/j.ahj.2015.04.028. pmid:26299228.

57.   Anderson R, Nel JG, Feldman C. Multifaceted role of pneumolysin in the pathogenesis of myocardial injury in community-acquired pneumonia. Int J Mol Sci 2018; 19:1147. doi:10.3390/ijms19041147. pmid:29641429.

58.   Postma DF, Spitoni C, van Werkhoven CH, van Elden LJR, Oosterheert JJ, Bonten MJM. Cardiac events after macrolides or fluoroquinolones in patients hospitalized for community-acquired pneumonia: post-hoc analysis of a cluster-randomized trial. BMC Infect Dis 2019; 19:17. doi:10.1186/s12879-018-3630-7. pmid:30612559.

59.   Cillóniz C, Polverino E, Ewig S, et al. Impact of age and comorbidity on cause and outcome in community-acquired pneumonia. Chest 2013; 144:999-1007. doi:10.1378/chest.13-0062. pmid:23670047.

60.   Cillóniz C, Dominedò C, Ielpo A, et al. Risk and prognostic factors in very old patients with sepsis secondary to community-acquired pneumonia. J Clin Med 2019; 8:961. doi:10.3390/jcm8070961. pmid:31269766.

61.   Bermejo-Martin JF, Martín-Fernandez M, López-Mestanza C, Duque P, Almansa R. Shared features of endothelial dysfunction between sepsis and its preceding risk factors (aging and chronic disease). J Clin Med 2018; 7:400. doi:10.3390/jcm7110400. pmid:30380785.

62.   Corrales-Medina VF, Musher DM, Shachkina S, Chirinos JA. Acute pneumonia and the cardiovascular system. Lancet 2013; 381:496-505. doi:10.1016/S0140-6736(12)61266-5. pmid:23332146.

63.   Brown AO, Millett ERC, Quint JK, Orihuela CJ. Cardiotoxicity during invasive pneumococcal disease. Am J Respir Crit Care Med 2015; 191:739-45. doi:10.1164/rccm.201411-1951PP. pmid:25629643.

64.   Pasparakis M, Vandenabeele P. Necroptosis and its role in inflammation. Nature 2015; 517:311-20. doi:10.1038/nature14191. pmid:25592536.

65.   Beno SM, Riegler AN, Gilley RP, et al. Inhibition of necroptosis to prevent long-term cardiac damage during pneumococcal pneumonia and invasive disease. J Infect Dis 2020; 222:1882-93. doi:10.1093/infdis/jiaa295. pmid:32492702.

66.   Eurich DT, Marrie TJ, Minhas-Sandhu JK, Majumdar SR. Risk of heart failure after community acquired pneumonia: prospective controlled study with 10 years of follow-up. BMJ 2017; 356:j413. doi:10.1136/bmj.j413. pmid:28193610.

67.   Shenoy AT, Beno SM, Brissac T, Bell JW, Novak L, Orihuela CJ. Severity and properties of cardiac damage caused by Streptococcus pneumoniae are strain dependent. PLoS One 2018; 13:e0204032. doi:10.1371/journal.pone.0204032. pmid:30216364.

68.   Kwong JC, Schwartz KL, Campitelli MA, et al. Acute myocardial infarction after laboratory-confirmed influenza infection. N Engl J Med 2018; 378:345-53. doi:10.1056/NEJMoa1702090. pmid:29365305.

69.   Blackburn R, Zhao H, Pebody R, Hayward A, Warren-Gash C. Laboratory-confirmed respiratory infections as predictors of hospital admission for myocardial infarction and stroke: time-series analysis of English data for 2004-2015. Clin Infect Dis 2018; 67:8-17. doi:10.1093/cid/cix1144. pmid:29324996.

70.   Sellers SA, Hagan RS, Hayden FG, Fischer WA 2nd.The hidden burden of influenza: A review of the extra-pulmonary complications of influenza infection. Influenza Other Respir Viruses 2017; 11:372-93. doi:10.1111/irv.12470. pmid:28745014.

71.   Naghavi M, Wyde P, Litovsky S, et al. Influenza infection exerts prominent inflammatory and thrombotic effects on the atherosclerotic plaques of apolipoprotein E-deficient mice. Circulation 2003; 107:762-8. doi:10.1161/01.CIR.0000048190.68071.2B. pmid:12578882.

72.   Sommerstein R, Merz TM, Berger S, Kraemer JG, Marschall J, Hilty M. Patterns in the longitudinal oropharyngeal microbiome evolution related to ventilator-associated pneumonia. Antimicrob Resist Infect Control 2019; 8:81. doi:10.1186/s13756-019-0530-6. pmid:31139364.

73.   Ciofu O, Tolker-Nielsen T. Tolerance and resistance of Pseudomonas aeruginosa biofilms to antimicrobial agents—How P aeruginosa can escape antibiotics. Front Microbiol 2019; 10:913. doi:10.3389/fmicb.2019.00913. pmid:31130925.

74.   Souza LCD, Mota VBRD, Carvalho AVDSZ, Corrêa RDGCF, Libério SA, Lopes FF. Association between pathogens from tracheal aspirate and oral biofilm of patients on mechanical ventilation. Braz Oral Res 2017; 31: e38. doi:10.1590/1807-3107bor-2017.vol31.0038. pmid:28591237.

75.   Fernández-Barat L, Motos A, Panigada M, et al. Comparative efficacy of linezolid and vancomycin for endotracheal tube MRSA biofilms from ICU patients. Crit Care 2019; 23:251. doi:10.1186/s13054-019-2523-5. pmid:31291978.

76.   Feldman C, Kassel M, Cantrell J, et al. The presence and sequence of endotracheal tube colonization in patients undergoing mechanical ventilation. Eur Respir J 1999; 13:546-51. doi:10.1183/09031936.99.13354699. pmid:10232424.

77.   Danin P-E, Girou E, Legrand P, et al. Description and microbiology of endotracheal tube biofilm in mechanically ventilated subjects. Respir Care 2015; 60:21-9. doi:10.4187/respcare.02722. pmid:25371399.

78.   Fernández-Barat L, Torres A. Biofilms in ventilator-associated pneumonia. Future Microbiol 2016; 11:1599-610. doi:10.2217/fmb-2016-0040. pmid:27831764.

79.   Thorarinsdottir HR, Kander T, Holmberg A, Petronis S, Klarin B. Biofilm formation on three different endotracheal tubes: a prospective clinical trial. Crit Care 2020; 24:382. doi:10.1186/s13054-020-03092-1. pmid:32600373.

80.   Man WH, de Steenhuijsen Piters WAA, Bogaert D. The microbiota of the respiratory tract: gatekeeper to respiratory health. Nat Rev Microbiol 2017; 15:259-70. doi:10.1038/nrmicro.2017.14. pmid:28316330.

81.   Woo TE, Lim R, Heirali AA, et al. A longitudinal characterization of the Non-Cystic Fibrosis Bronchiectasis airway microbiome. Sci Rep 2019; 9:6871. doi:10.1038/s41598-019-42862-y. pmid:31053725.

82.   Wang Z, Maschera B, Lea S, et al. Airway host-microbiome interactions in chronic obstructive pulmonary disease. Respir Res 2019; 20:113. doi:10.1186/s12931-019-1085-z. pmid:31170986.

83.   Sharma A, Laxman B, Naureckas ET, et al. Associations between fungal and bacterial microbiota of airways and asthma endotypes. J Allergy Clin Immunol 2019; 144:1214-1227.e7. doi:10.1016/j.jaci.2019.06.025. pmid:31279011.

84.   Martin-Loeches I, Dickson R, Torres A, et al. The importance of airway and lung microbiome in the critically ill. Crit Care 2020; 24:537. doi:10.1186/s13054-020-03219-4. pmid:32867808.

85.   Wu BG, Segal LN. The lung microbiome and its role in pneumonia. Clin Chest Med 2018; 39:677-89. doi:10.1016/j.ccm.2018.07.003. pmid:30390741.

86.   Kelly BJ, Imai I, Bittinger K, et al. Composition and dynamics of the respiratory tract microbiome in intubated patients. Microbiome 2016; 4:7. doi:10.1186/s40168-016-0151-8. pmid:26865050.

87.   Zakharkina T, Martin-Loeches I, Matamoros S, et al. The dynamics of the pulmonary microbiome during mechanical ventilation in the intensive care unit and the association with occurrence of pneumonia. Thorax 2017; 72:803-10. doi:10.1136/thoraxjnl-2016-209158. pmid:28100714.

88.   Roquilly A, Torres A, Villadangos JA, et al. Pathophysiological role of respiratory dysbiosis in hospital-acquired pneumonia. Lancet Respir Med 2019; 7:710-20. doi:10.1016/S2213-2600(19)30140-7. pmid:31182406.

89.   Segal LN, Clemente JC, Tsay J-CJ, et al. Enrichment of the lung microbiome with oral taxa is associated with lung inflammation of a Th17 phenotype. Nat Microbiol 2016; 1:16031. doi:10.1038/nmicrobiol.2016.31. pmid:27572644.

90.   Antoni Torres CC. Clinical Management of Bacterial Pneumonia | Antoni Torres | Springer.1st ed. Springer, 2015, https://www.springer.com/gp/book/9783319220611. doi:10.1007/978-3-319-22062-8.

91.   Cilloniz C, Ceccato A, San Jose A, Torres A. Clinical management of community acquired pneumonia in the elderly patient. Expert Rev Respir Med 2016; 10:1211-20. doi:10.1080/17476348.2016.1240037. pmid:27690702.

92.   Prina E, Ranzani OT, Torres A. Community-acquired pneumonia. Lancet 2015; 386:1097-108. doi:10.1016/S0140-6736(15)60733-4. pmid:26277247.

93.   Black AD. Non-infectious mimics of community-acquired pneumonia. Pneumonia (Nathan) 2016; 8:2. doi:10.1186/s41479-016-0002-1. pmid:28702282.

94.   Fernando SM, Tran A, Cheng W, et al. Diagnosis of ventilator-associated pneumonia in critically ill adult patients-a systematic review and meta-analysis. Intensive Care Med 2020; 46:1170-9. doi:10.1007/s00134-020-06036-z. pmid:32306086.

95.   Laursen CB, Sloth E, Lambrechtsen J, et al. Diagnostic performance of chest Radiograph for the diagnosis of community acquired pneumonia in acute admitted patients with respiratory symptoms. Scand J Trauma Resusc Emerg Med 2013; 21:A21doi:10.1186/1757-7241-21-S2-A21.

96.   Claessens Y-E, Debray M-P, Tubach F, et al. Early chest computed tomography scan to assist diagnosis and guide treatment decision for suspected community-acquired pneumonia. Am J Respir Crit Care Med 2015; 192:974-82. doi:10.1164/rccm.201501-0017OC. pmid:26168322.

97.   Franquet T. Imaging of community-acquired pneumonia. J Thorac Imaging 2018; 33:282-94. doi:10.1097/RTI.0000000000000347. pmid:30036297.

98.   Ferreira-Coimbra J, Ardanuy C, Diaz E, et al. Ventilator-associated pneumonia diagnosis: a prioritization exercise based on multi-criteria decision analysis. Eur J Clin Microbiol Infect Dis 2020; 39:281-6. doi:10.1007/s10096-019-03720-x. pmid:31654147.

99.   Klompas M. Does this patient have ventilator-associated pneumonia? JAMA 2007; 297:1583-93. doi:10.1001/jama.297.14.1583. pmid:17426278.

100. Chastre J, Luyt C-E. Does this patient have VAP? Intensive Care Med 2016; 42:1159-63. doi:10.1007/s00134-016-4239-1. pmid:26846513.

101. Long L, Zhao H-T, Zhang Z-Y, Wang G-Y, Zhao H-L. Lung ultrasound for the diagnosis of pneumonia in adults: A meta-analysis. Medicine (Baltimore) 2017; 96:e5713. doi:10.1097/MD.0000000000005713. pmid:28099332.

102. Staub LJ, Biscaro RRM, Maurici R. Emergence of alveolar consolidations in serial lung ultrasound and diagnosis of ventilator-associated pneumonia. J Intensive Care Med 2021; 36:304-12. doi:10.1177/0885066619894279. pmid:31818178.

103. Torres A, Lee N, Cilloniz C, Vila J, Van der Eerden M. Laboratory diagnosis of pneumonia in the molecular age. Eur Respir J 2016; 48:1764-78. doi:10.1183/13993003.01144-2016. pmid:27811073.

104. Musher DM, Montoya R, Wanahita A. Diagnostic value of microscopic examination of Gram-stained sputum and sputum cultures in patients with bacteremic pneumococcal pneumonia. Clin Infect Dis 2004; 39:165-9. doi:10.1086/421497. pmid:15307023.

105. Fukuyama H, Yamashiro S, Kinjo K, Tamaki H, Kishaba T. Validation of sputum Gram stain for treatment of community-acquired pneumonia and healthcare-associated pneumonia: a prospective observational study. BMC Infect Dis 2014; 14:534. doi:10.1186/1471-2334-14-534. pmid:25326650.

106. Paonessa JR, Shah RD, Pickens CI, et al. Rapid detection of methicillin-resistant Staphylococcus aureus in BAL: a pilot randomized controlled trial. Chest 2019; 155:999-1007. doi:10.1016/j.chest.2019.02.007. pmid:30776365.

107. Said MA, Johnson HL, Nonyane BAS, et al., AGEDD Adult Pneumococcal Burden Study Team. Estimating the burden of pneumococcal pneumonia among adults: a systematic review and meta-analysis of diagnostic techniques. PLoS One 2013; 8:e60273. doi:10.1371/journal.pone.0060273. pmid:23565216.

108. Walden AP, Clarke GM, McKechnie S, et al., ESICM/ECCRN GenOSept Investigators. Patients with community acquired pneumonia admitted to European intensive care units: an epidemiological survey of the GenOSept cohort. Crit Care 2014; 18:R58. doi:10.1186/cc13812. pmid:24690444.

109. Vallés J, Diaz E, Martín-Loeches I, et al. Evolution over a 15-year period of the clinical characteristics and outcomes of critically ill patients with severe community-acquired pneumonia. Med Intensiva 2016; 40:238-45. doi:10.1016/j.medin.2015.07.005. pmid:26391738.

110. Jain S, Self WH, Wunderink RG, et al., CDC EPIC Study Team. Community-acquired pneumonia requiring hospitalization among US adults. N Engl J Med 2015; 373:415-27. doi:10.1056/NEJMoa1500245. pmid:26172429.

111. Zhou F, Wang Y, Liu Y, et al., CAP-China Network. Disease severity and clinical outcomes of community-acquired pneumonia caused by non-influenza respiratory viruses in adults: a multicentre prospective registry study from the CAP-China Network. Eur Respir J 2019; 54:1802406. doi:10.1183/13993003.02406-2018. pmid:31164430.

112. Kuypers J. Impact of rapid molecular detection of respiratory viruses on clinical outcomes and patient management. J Clin Microbiol 2019; 57:e01890. doi:10.1128/JCM.01890-18. pmid:30651392.

113. Cillóniz C, Dominedò C, Magdaleno D, Ferrer M, Gabarrús A, Torres A. Pure viral sepsis secondary to community-acquired pneumonia in adults: risk and prognostic factors. J Infect Dis 2019; 220:1166-71. doi:10.1093/infdis/jiz257. pmid:31115456.

114. Cavallazzi R, Ramirez JA. Influenza and viral pneumonia. Clin Chest Med 2018; 39:703-21. doi:10.1016/j.ccm.2018.07.005. pmid:30390743.

115. Alimi Y, Lim WS, Lansbury L, Leonardi-Bee J, Nguyen-Van-Tam JS. Systematic review of respiratory viral pathogens identified in adults with community-acquired pneumonia in Europe. J Clin Virol 2017; 95:26-35. doi:10.1016/j.jcv.2017.07.019. pmid:28837859.

116. Burk M, El-Kersh K, Saad M, Wiemken T, Ramirez J, Cavallazzi R. Viral infection in community-acquired pneumonia: a systematic review and meta-analysis. Eur Respir Rev 2016; 25:178-88. doi:10.1183/16000617.0076-2015. pmid:27246595.

117. Abelenda-Alonso G, Rombauts A, Gudiol C, et al.Influenza and bacterial coinfection in adults with community-acquired pneumonia admitted to conventional wards: risk factors, clinical features, and outcomes. Open Forum Infect Dis 2020; 27:ofaa066. doi:10.1093/ofid/ofaa066.

118. Karhu J, Ala-Kokko TI, Vuorinen T, Ohtonen P, Syrjälä H. Lower respiratory tract virus findings in mechanically ventilated patients with severe community-acquired pneumonia. Clin Infect Dis 2014; 59:62-70. doi:10.1093/cid/ciu237. pmid:24729498.

119. Short KR, Kroeze EJBV, Fouchier RAM, Kuiken T. Pathogenesis of influenza-induced acute respiratory distress syndrome. Lancet Infect Dis 2014; 14:57-69. doi:10.1016/S1473-3099(13)70286-X. pmid:24239327.

120. Cilloniz C, Ferrer M, Liapikou A, et al. Acute respiratory distress syndrome in mechanically ventilated patients with community-acquired pneumonia. Eur Respir J 2018; 51:1702215. doi:10.1183/13993003.02215-2017. pmid:29545274.

121. Piralla A, Mariani B, Rovida F, Baldanti F. Frequency of respiratory viruses among patients admitted to 26 Intensive Care Units in seven consecutive winter-spring seasons (2009-2016) in Northern Italy. J Clin Virol 2017; 92:48-51. doi:10.1016/j.jcv.2017.05.004. pmid:28527970.

122. Burrell A, Huckson S, Pilcher DV, ANZICS. ANZICS. ICU admissions for sepsis or pneumonia in Australia and New Zealand in 2017. N Engl J Med 2018; 378:2138-9. doi:10.1056/NEJMc1717178. pmid:29847767.

123. Cillóniz C, Civljak R, Nicolini A, Torres A. Polymicrobial community-acquired pneumonia: An emerging entity. Respirology 2016; 21:65-75. doi:10.1111/resp.12663. pmid:26494527.

124. Almeida ST, Paulo AC, Froes F, de Lencastre H, Sá-Leão R. Dynamics of pneumococcal carriage in adults: a new look at an old paradigm. J Infect Dis 2021; 223:1590-600. doi:10.1093/infdis/jiaa558. pmid:32877517.

125. Palacios G, Hornig M, Cisterna D, et al. Streptococcus pneumoniae coinfection is correlated with the severity of H1N1 pandemic influenza. PLoS One 2009; 4:e8540. doi:10.1371/journal.pone.0008540. pmid:20046873.

126. Centers for Disease Control and Prevention (CDC). Severe methicillin-resistant Staphylococcus aureus community-acquired pneumonia associated with influenza--Louisiana and Georgia, December 2006-January 2007. MMWR Morb Mortal Wkly Rep 2007; 56:325-9.pmid:17431376.

127. Siegel SJ, Roche AM, Weiser JN. Influenza promotes pneumococcal growth during coinfection by providing host sialylated substrates as a nutrient source. Cell Host Microbe 2014; 16:55-67. doi:10.1016/j.chom.2014.06.005. pmid:25011108.

128. Wilden JJ, Jacob JC, Ehrhardt C, Ludwig S, Boergeling Y. Altered signal transduction in the immune response to influenza virus and S. pneumoniae or S. aureus co-infections. Int J Mol Sci 2021; 22:5486. doi:10.3390/ijms22115486. pmid:34067487.

129. Aguilera ER, Lenz LL. Inflammation as a modulator of host susceptibility to pulmonary influenza, pneumococcal, and co-infections. Front Immunol 2020; 11:105. doi:10.3389/fimmu.2020.00105. pmid:32117259.

130. Vardakas KZ, Matthaiou DK, Falagas ME. Incidence, characteristics and outcomes of patients with severe community acquired-MRSA pneumonia. Eur Respir J 2009; 34:1148-58. doi:10.1183/09031936.00041009. pmid:19541719.

131. He H, Wunderink RG. Staphylococcus aureus pneumonia in the community. Semin Respir Crit Care Med 2020; 41:470-9. doi:10.1055/s-0040-1709992. pmid:32521547.

132. Prina E, Ranzani OT, Polverino E, et al. Risk factors associated with potentially antibiotic-resistant pathogens in community-acquired pneumonia. Ann Am Thorac Soc 2015; 12:153-60. doi:10.1513/AnnalsATS.201407-305OC. pmid:25521229.

133. Cilloniz C, Dominedo C, Peroni HJ, et al. Difficult to treat microorganisms in patients aged over 80 years with community-acquired pneumonia: the prevalence of PES pathogens. Eur Respir J 2020; 56:2000773. doi:10.1183/13993003.00773-2020. pmid:32430413.

134. Shorr AF, Zilberberg MD, Micek ST, Kollef MH. Prediction of infection due to antibiotic-resistant bacteria by select risk factors for health care-associated pneumonia. Arch Intern Med 2008; 168:2205-10. doi:10.1001/archinte.168.20.2205. pmid:19001196.

135. Aliberti S, Di Pasquale M, Zanaboni AM, et al. Stratifying risk factors for multidrug-resistant pathogens in hospitalized patients coming from the community with pneumonia. Clin Infect Dis 2012; 54:470-8. doi:10.1093/cid/cir840. pmid:22109954.

136. Park SC, Kim EY, Kang YA, et al. Validation of a scoring tool to predict drug-resistant pathogens in hospitalised pneumonia patients. Int J Tuberc Lung Dis 2013; 17:704-9. doi:10.5588/ijtld.12.0723. pmid:23575340.

137. Shindo Y, Ito R, Kobayashi D, et al. Risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia. Am J Respir Crit Care Med 2013; 188:985-95. doi:10.1164/rccm.201301-0079OC. pmid:23855620.

138. Maruyama T, Fujisawa T, Ishida T, et al. A therapeutic strategy for all pneumonia patients: a 3-year prospective multicenter-cohort study using risk factors for multidrug resistant pathogens to select initial empiric therapy. Clin Infect Dis 2019; 68:1080-8. doi:10.1093/cid/ciy631. pmid:30084884.

139. Aliberti S, Cilloniz C, Chalmers JD, et al. Multidrug-resistant pathogens in hospitalised patients coming from the community with pneumonia: a European perspective. Thorax 2013; 68:997-9. doi:10.1136/thoraxjnl-2013-203384. pmid:23774884.

140. Cillóniz C, Dominedò C, Nicolini A, Torres A. PES pathogens in severe community-acquired pneumonia. Microorganisms 2019; 7:49. doi:10.3390/microorganisms7020049. pmid:30759805.

141. Ishida T, Ito A, Washio Y, et al. Risk factors for drug-resistant pathogens in immunocompetent patients with pneumonia: Evaluation of PES pathogens. J Infect Chemother 2017; 23:23-8. doi:10.1016/j.jiac.2016.09.002. pmid:27729192.

142. Kobayashi D, Shindo Y, Ito R, et al. Validation of the prediction rules identifying drug-resistant pathogens in community-onset pneumonia. Infect Drug Resist 2018; 11:1703-13. doi:10.2147/IDR.S165669. pmid:30349327.

143. Micek ST, Wunderink RG, Kollef MH, et al. An international multicenter retrospective study of Pseudomonas aeruginosa nosocomial pneumonia: impact of multidrug resistance. Crit Care 2015; 19:219. doi:10.1186/s13054-015-0926-5. pmid:25944081.

144. Cillóniz C, Dominedò C, Torres A. An overview of guidelines for the management of hospital-acquired and ventilator-associated pneumonia caused by multidrug-resistant Gram-negative bacteria. Curr Opin Infect Dis 2019; 32:656-62. doi:10.1097/QCO.0000000000000596. pmid:31567412.

145. Cerceo E, Deitelzweig SB, Sherman BM, Amin AN. Multidrug-resistant Gram negative bacterial infections in the hospital setting: overview, implications for clinical practice, and emerging treatment options. Microb Drug Resist 2016; 22:412-31. doi:10.1089/mdr.2015.0220. pmid:26866778.

146. Watkins RR, Van Duin D. Current trends in the treatment of pneumonia due to multidrug-resistant Gram negative bacteria. F1000Res. 2019 Jan 30; 8:F1000 Faculty Rev-121.

147. Magiorakos A-P, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012; 18:268-81. doi:10.1111/j.1469-0691.2011.03570.x. pmid:21793988.

148. Bassetti M, Righi E, Vena A, Graziano E, Russo A, Peghin M. Risk stratification and treatment of ICU-acquired pneumonia caused by multidrug- resistant/extensively drug-resistant/pandrug-resistant bacteria. Curr Opin Crit Care 2018; 24:385-93. doi:10.1097/MCC.0000000000000534. pmid:30156569.

149. Ekren PK, Ranzani OT, Ceccato A, et al. Evaluation of the 2016 Infectious Diseases Society of America/American Thoracic Society guideline criteria for risk of multidrug-resistant pathogens in patients with hospital-acquired and ventilator-associated pneumonia in the ICU. Am J Respir Crit Care Med 2018; 197:826-30. doi:10.1164/rccm.201708-1717LE. pmid:28902529.

150. Webb BJ, Sorensen J, Jephson A, Mecham I, Dean NC. Broad-spectrum antibiotic use and poor outcomes in community-onset pneumonia: a cohort study. Eur Respir J 2019; 54:1900057. doi:10.1183/13993003.00057-2019. pmid:31023851.

151. Ewig S, Kolditz M, Pletz MW, Chalmers J. Healthcare-associated pneumonia: is there any reason to continue to utilize this label in 2019? Clin Microbiol Infect 2019;25:1173-9. doi:10.1016/j.cmi.2019.02.022. pmid:30825674.

152. Ito A, Ishida T, Tachibana H, Tokumasu H, Yamazaki A, Washio Y. Azithromycin combination therapy for community-acquired pneumonia: propensity score analysis. Sci Rep 2019; 9:18406. doi:10.1038/s41598-019-54922-4. pmid:31804572.

153. Martin-Loeches I, Lisboa T, Rodriguez A, et al. Combination antibiotic therapy with macrolides improves survival in intubated patients with community-acquired pneumonia. Intensive Care Med 2010; 36:612-20. doi:10.1007/s00134-009-1730-y. pmid:19953222.

154. Lodise TP, Kwa A, Cosler L, Gupta R, Smith RP. Comparison of beta-lactam and macrolide combination therapy versus fluoroquinolone monotherapy in hospitalized Veterans Affairs patients with community-acquired pneumonia. Antimicrob Agents Chemother 2007; 51:3977-82. doi:10.1128/AAC.00006-07. pmid:17709460.

155. Sligl WI, Asadi L, Eurich DT, Tjosvold L, Marrie TJ, Majumdar SR. Macrolides and mortality in critically ill patients with community-acquired pneumonia: a systematic review and meta-analysis. Crit Care Med 2014; 42:420-32. doi:10.1097/CCM.0b013e3182a66b9b. pmid:24158175.

156. Anderson R, Steel HC, Cockeran R, et al. Comparison of the effects of macrolides, amoxicillin, ceftriaxone, doxycycline, tobramycin and fluoroquinolones, on the production of pneumolysin by Streptococcus pneumoniae in vitro. J Antimicrob Chemother 2007; 60:1155-8. doi:10.1093/jac/dkm338. pmid:17848373.

157. Sligl WI, Asadi L, Eurich DT, Tjosvold L, Marrie TJ, Majumdar SR. Macrolides and mortality in critically ill patients with community-acquired pneumonia: a systematic review and meta-analysis. Crit Care Med 2014; 42:420-32. doi:10.1097/CCM.0b013e3182a66b9b. pmid:24158175.

158. Waterer GW. Monotherapy versus combination antimicrobial therapy for pneumococcal pneumonia. Curr Opin Infect Dis 2005; 18:157-63. doi:10.1097/01.qco.0000160906.02308.3c. pmid:15735421.

159. Baddour LM, Yu VL, Klugman KP, et al., International Pneumococcal Study Group. Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia. Am J Respir Crit Care Med 2004; 170:440-4. doi:10.1164/rccm.200311-1578OC. pmid:15184200.

160. Siddiqui AH, Koirala J. Methicillin Resistant Staphylococcus Aureus. In: StatPearls.StatPearls Publishing, 2021, https://www.ncbi.nlm.nih.gov/books/NBK482221/.

161. Baby N, Faust AC, Smith T, Sheperd LA, Knoll L, Goodman EL. Nasal methicillin-resistant Staphylococcus aureus (MRSA) PCR testing reduces the duration of MRSA-targeted therapy in patients with suspected MRSA pneumonia. Antimicrob Agents Chemother 2017; 61:e02432. doi:10.1128/AAC.02432-16. pmid:28137813.

162. Woolever NL, Schomberg RJ, Cai S, Dierkhising RA, Dababneh AS, Kujak RC. Pharmacist-driven MRSA nasal PCR screening and the duration of empirical cancomycin therapy for suspected MRSA respiratory tract infections. Mayo Clin Proc Innov Qual Outcomes 2020; 4:550-6. doi:10.1016/j.mayocpiqo.2020.05.002. pmid:33083704.

163. Musuuza JS, Watson L, Parmasad V, Putman-Buehler N, Christensen L, Safdar N. Prevalence and outcomes of co-infection and superinfection with SARS-CoV-2 and other pathogens: A systematic review and meta-analysis. PLoS One 2021; 16:e0251170. doi:10.1371/journal.pone.0251170. pmid:33956882.

164. Feldman C, Anderson R. The role of co-infections and secondary infections in patients with COVID-19. Pneumonia (Nathan) 2021; 13:5. doi:10.1186/s41479-021-00083-w. pmid:33894790.

165. Han J, Gatheral T, Williams C. Procalcitonin for patient stratification and identification of bacterial co-infection in COVID-19. Clin Med (Lond) 2020; 20:e47. doi:10.7861/clinmed.Let.20.3.3. pmid:32414743.

166. Drewett GP, Smibert OC, Holmes NE, Trubiano JA. The use of procalcitonin as an antimicrobial stewardship tool and a predictor of disease severity in coronavirus disease 2019 (COVID-19). Infect Control Hosp Epidemiol 2021;1-3doi:10.1017/ice.2021.28.

167. National Institutes of Health. Information on covid-19 treatment, prevention and research. Covid-19 treatment guidelines. https://www.covid19treatmentguidelines.nih.gov/

168. Beigel JH, Tomashek KM, Dodd LE, et al., ACTT-1 Study Group Members. Remdesivir for the treatment of covid-19—final report. N Engl J Med 2020; 383:1813-26. doi:10.1056/NEJMoa2007764 pmid:32445440CrossRefPubMedGoogle Scholar

169. Pan H, Peto R, Henao-Restrepo AM, et al., WHO Solidarity Trial Consortium. Repurposed antiviral drugs for covid-19—interim WHO Solidarity Trial results. N Engl J Med 2021; 384:497-511. doi:10.1056/NEJMoa2023184. pmid:33264556.

170. Remdesivir. https://www.idsociety.org/covid-19-real-time-learning-network/therapeutics-and-interventions/remdesivir/

171. Torres A, Sibila O, Ferrer M, et al. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. JAMA 2015; .313:677-86. doi:10.1001/jama.2015.88 pmid:25688779.

172. Briel M, Spoorenberg SMC, Snijders D, et al., Ovidius Study Group, Capisce Study Group, STEP Study Group. Corticosteroids in patients hospitalized with community-acquired pneumonia: systematic review and individual patient data meta-analysis. Clin Infect Dis 2018; 66:346-54. doi:10.1093/cid/cix801. pmid:29020323.

173. Venkatesh B, Finfer S, Cohen J, et al., ADRENAL Trial Investigators and the Australian–New Zealand Intensive Care Society Clinical Trials Group. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med 2018; 378:797-808. doi:10.1056/NEJMoa1705835. pmid:29347874.

174. Annane D, Renault A, Brun-Buisson C, et al., CRICS-TRIGGERSEP Network. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med 2018; 378:809-18. doi:10.1056/NEJMoa1705716. pmid:29490185.

175. Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Lim WS. Corticosteroids as adjunctive therapy in the treatment of influenza. Cochrane Database Syst Rev 2016;3:CD010406. doi:10.1002/14651858.CD010406.pub2. pmid:26950335.

176. Moreno G, Rodríguez A, Reyes LF, et al., GETGAG Study Group. Corticosteroid treatment in critically ill patients with severe influenza pneumonia: a propensity score matching study. Intensive Care Med 2018; 44:1470-82. doi:10.1007/s00134-018-5332-4. pmid:30074052.

177. Cao B, Gao H, Zhou B, et al. Adjuvant corticosteroid treatment in adults with influenza A (H7N9) viral pneumonia. Crit Care Med 2016; 44:e318-28. doi:10.1097/CCM.0000000000001616. pmid:26934144.

178. Horby P, Lim WS, Emberson JR, et al., RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with covid-19—preliminary report. N Engl J Med 2021; 384:693-704. doi:10.1056/NEJMoa2021436. pmid:32678530.

179. VA Office of Research and Development. CSP #574 - Evaluate the safety and efficacy of methylprednisolone in hospitalized veterans with severe community-acquired pneumonia. clinicaltrials.gov; 2020. https://clinicaltrials.gov/ct2/show/results/NCT01283009

180. de la Torre MC, Torán P, Serra-Prat M, et al. Serum levels of immunoglobulins and severity of community-acquired pneumonia. BMJ Open Respir Res 2016; 3:e000152. doi:10.1136/bmjresp-2016-000152. pmid:27933180.

181. Justel M, Socias L, Almansa R, et al. IgM levels in plasma predict outcome in severe pandemic influenza. J Clin Virol 2013; 58:564-7. doi:10.1016/j.jcv.2013.09.006. pmid:24076102.

182. de la Torre MC, Palomera E, Serra-Prat M, et al. IgG2 as an independent risk factor for mortality in patients with community-acquired pneumonia. J Crit Care 2016; 35:115-9. doi:10.1016/j.jcrc.2016.05.005. pmid:27481745.

183. Tagami T, Matsui H, Fushimi K, Yasunaga H. Intravenous immunoglobulin use in septic shock patients after emergency laparotomy. J Infect 2015; 71:158-66. doi:10.1016/j.jinf.2015.04.003. pmid:25869539.

184. Iizuka Y, Sanui M, Sasabuchi Y, et al. Low-dose immunoglobulin G is not associated with mortality in patients with sepsis and septic shock. Crit Care 2017; 21:181. doi:10.1186/s13054-017-1764-4. pmid:28701223.

185. Welte T, Dellinger RP, Ebelt H, et al. Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study). Intensive Care Med 2018; 44:438-48. doi:10.1007/s00134-018-5143-7. pmid:29632995.

186. Aarts M-AW, Hancock JN, Heyland D, McLeod RS, Marshall JC. Empiric antibiotic therapy for suspected ventilator-associated pneumonia: a systematic review and meta-analysis of randomized trials. Crit Care Med 2008; 36:108-17. doi:10.1097/01.CCM.0000297956.27474.9D. pmid:18007262.

187. Heyland DK, Dodek P, Muscedere J, Day A, Cook D, Canadian Critical Care Trials Group. Randomized trial of combination versus monotherapy for the empiric treatment of suspected ventilator-associated pneumonia. Crit Care Med 2008; 36:737-44. doi:10.1097/01.CCM.0B013E31816203D6. pmid:18091545.

188. Arthur LE, Kizor RS, Selim AG, van Driel ML, Seoane L. Antibiotics for ventilator-associated pneumonia. Cochrane Database Syst Rev 2016; 10:CD004267.pmid:27763732.

189. Chamot E, Boffi El Amari E, Rohner P, Van Delden C. Effectiveness of combination antimicrobial therapy for Pseudomonas aeruginosa bacteremia. Antimicrob Agents Chemother 2003; 47:2756-64. doi:10.1128/AAC.47.9.2756-2764.2003. pmid:12936970.

190. Garnacho-Montero J, Sa-Borges M, Sole-Violan J, et al. Optimal management therapy for Pseudomonas aeruginosa ventilator-associated pneumonia: an observational, multicenter study comparing monotherapy with combination antibiotic therapy. Crit Care Med 2007; 35:1888-95. doi:10.1097/01.CCM.0000275389.31974.22. pmid:17581492.

191. Martínez JA, Cobos-Trigueros N, Soriano A, et al. Influence of empiric therapy with a beta-lactam alone or combined with an aminoglycoside on prognosis of bacteremia due to gram-negative microorganisms. Antimicrob Agents Chemother 2010; 54:3590-6. doi:10.1128/AAC.00115-10. pmid:20585123.

192. Micek ST, Welch EC, Khan J, et al. Empiric combination antibiotic therapy is associated with improved outcome against sepsis due to Gram-negative bacteria: a retrospective analysis. Antimicrob Agents Chemother 2010; 54:1742-8. doi:10.1128/AAC.01365-09. pmid:20160050.

193. Kumar A, Safdar N, Kethireddy S, Chateau D. A survival benefit of combination antibiotic therapy for serious infections associated with sepsis and septic shock is contingent only on the risk of death: a meta-analytic/meta-regression study. Crit Care Med 2010; 38:1651-64. doi:10.1097/CCM.0b013e3181e96b91. pmid:20562695.

194. Torres A, Rank D, Melnick D, et al. Randomized trial of ceftazidime-avibactam vs meropenem for treatment of hospital-acquired and ventilator-associated bacterial pneumonia (REPROVE): analyses per US FDA-specified end points. Open Forum Infect Dis 2019; 6:ofz149. doi:10.1093/ofid/ofz149. pmid:31041348.

195. Kollef MH, Nováček M, Kivistik Ü, et al. Ceftolozane-tazobactam versus meropenem for treatment of nosocomial pneumonia (ASPECT-NP): a randomised, controlled, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis 2019; 19:1299-311. doi:10.1016/S1473-3099(19)30403-7. pmid:31563344.

196. Approval Letter ZERBAXA. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2019/206829Orig1s008ltr.pdf

197. Approval letter ZERBAXA. https://www.ema.europa.eu/en/documents/variation-report/zerbaxa-h-c-3772-ii-0020-epar-assessment-report-variation_en.pdf

198. Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G, et al. Effect and safety of meropenem-vaborbactam versus best-available therapy in patients with carbapenem-resistant enterobacteriaceae infections: the TANGO II randomized clinical trial. Infect Dis Ther 2018; 7:439-55. doi:10.1007/s40121-018-0214-1. pmid:30270406.

199. Titov I, Wunderink RG, Roquilly A, et al. A randomized, double-blind, multicenter trial comparing efficacy and safety of imipenem/cilastatin/relebactam versus piperacillin/tazobactam in adults with hospital-acquired or ventilator-associated bacterial pneumonia (RESTORE-IMI 2 Study). Clin Infect Dis 2020 Aug 12: ciaa803 doi:10.1093/cid/ciaa803.

200. Wunderink RG, Matsunaga Y, Ariyasu M, et al. Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis 2021; 21:213-25. doi:10.1016/S1473-3099(20)30731-3. pmid:33058798.

201. Bassetti M, Echols R, Matsunaga Y, et al. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis 2021; 21:226-40. doi:10.1016/S1473-3099(20)30796-9. pmid:33058795.

202. Flannery AH, Bissell BD, Bastin MT, Morris PE, Neyra JA. Continuous versus intermittent infusion of vancomycin and the risk of acute kidney injury in critically ill adults: a systematic review and meta-Analysis. Crit Care Med 2020; 48:912-8. doi:10.1097/CCM.0000000000004326. pmid:32317590.

203. Hao J-J, Chen H, Zhou J-X. Continuous versus intermittent infusion of vancomycin in adult patients: A systematic review and meta-analysis. Int J Antimicrob Agents 2016; 47:28-35. doi:10.1016/j.ijantimicag.2015.10.019. pmid:26655032.

204. Soraluce A, Barrasa H, Asín-Prieto E, et al. Novel population pharmacokinetic model for linezolid in critically ill patients and evaluation of the adequacy of the current dosing recommendation. Pharmaceutics 2020; 12:54. doi:10.3390/pharmaceutics12010054. pmid:31936614.

205. Taubert M, Zoller M, Maier B, et al. Predictors of inadequate linezolid concentrations after standard dosing in critically ill patients. Antimicrob Agents Chemother 2016; 60:5254-61. doi:10.1128/AAC.00356-16. pmid:27324768.

206. Kollef MH, Ricard J-D, Roux D, et al. A randomized trial of the amikacin fosfomycin inhalation system for the adjunctive therapy of Gram negative ventilator-associated pneumonia: IASIS trial. Chest 2017; 151:1239-46. doi:10.1016/j.chest.2016.11.026. pmid:27890714.

207. Niederman MS, Chastre J, Corkery K, Fink JB, Luyt C-E, García MS. BAY41-6551 achieves bactericidal tracheal aspirate amikacin concentrations in mechanically ventilated patients with Gram-negative pneumonia. Intensive Care Med 2012; 38:263-71. doi:10.1007/s00134-011-2420-0. pmid:22147112.

208. Stokker J, Karami M, Hoek R, Gommers D, van der Eerden M. Effect of adjunctive tobramycin inhalation versus placebo on early clinical response in the treatment of ventilator-associated pneumonia: the VAPORISE randomized-controlled trial. Intensive Care Med 2020; 46:546-8. doi:10.1007/s00134-019-05914-5. pmid:31974920.

209. Niederman MS, Alder J, Bassetti M, et al. Inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with Gram-negative pneumonia (INHALE): a double-blind, randomised, placebo-controlled, phase 3, superiority trial. Lancet Infect Dis 2020; 20:330-40. doi:10.1016/S1473-3099(19)30574-2. pmid:31866328.

210. Sweeney DA, Kalil AC. Why don’t we have more inhaled antibiotics to treat ventilator-associated pneumonia? Clin Microbiol Infect 2019;25:1195-9. doi:10.1016/j.cmi.2019.04.018. pmid:31035015.

211. Tansarli GS, Mylonakis E. Systematic review and meta-analysis of the efficacy of short-course antibiotic treatments for community-acquired pneumonia in adults. Antimicrob Agents Chemother 2018; 62:e00635. doi:10.1128/AAC.00635-18. pmid:29987137.

212. Lan S-H, Lai C-C, Chang S-P, Lu L-C, Hung S-H, Lin W-T. Five-day antibiotic treatment for community-acquired bacterial pneumonia: A systematic review and meta-analysis of randomized controlled trials. J Glob Antimicrob Resist 2020; 23:94-9. doi:10.1016/j.jgar.2020.08.005. pmid:32866643.

213. Bermejo-Martin JF, Cilloniz C, Mendez R, et al., NEUMONAC group. Lymphopenic community acquired pneumonia (L-CAP), an immunological phenotype associated with higher risk of mortality. EBioMedicine 2017; 24:231-6. doi:10.1016/j.ebiom.2017.09.023. pmid:28958655.

214. Bermejo-Martin JF, Almansa R, Martin-Fernandez M, Menendez R, Torres A. Immunological profiling to assess disease severity and prognosis in community-acquired pneumonia. Lancet Respir Med 2017; 5:e35-6. doi:10.1016/S2213-2600(17)30444-7. pmid:29185421.

215. Luo Q, Ning P, Zheng Y, Shang Y, Zhou B, Gao Z. Serum suPAR and syndecan-4 levels predict severity of community-acquired pneumonia: a prospective, multi-centre study. Crit Care 2018; 22:15. doi:10.1186/s13054-018-1943-y. pmid:29368632.

216. Zhou H, Guo S, Lan T, Ma S, Zhang F, Zhao Z. Risk stratification and prediction value of procalcitonin and clinical severity scores for community-acquired pneumonia in ED. Am J Emerg Med 2018; 36:2155-60. doi:10.1016/j.ajem.2018.03.050. pmid:29691103.

217. Legramante JM, Mastropasqua M, Susi B, et al. Prognostic performance of MR-pro-adrenomedullin in patients with community acquired pneumonia in the Emergency Department compared to clinical severity scores PSI and CURB. PLoS One 2017; 12:e0187702. doi:10.1371/journal.pone.0187702. pmid:29161297.

218. Gilbert DN. Role of procalcitonin in the management of infected patients in the intensive care unit. Infect Dis Clin North Am 2017; 31:435-53. doi:10.1016/j.idc.2017.05.003. pmid:28779830.

219. Julián-Jiménez A, González Del Castillo J, Candel FJ. Usefulness and prognostic value of biomarkers in patients with community-acquired pneumonia in the emergency department. Med Clin (Barc) 2017; 148:501-10.pmid:28391994.

220. Keramat F, Ghasemi Basir HR, Abdoli E, Shafiei Aghdam A, Poorolajal J. Association of serum procalcitonin and C-reactive protein levels with CURB-65 criteria among patients with community-acquired pneumonia. Int J Gen Med 2018; 11:217-23. doi:10.2147/IJGM.S165190. pmid:29942144.

221. Spoorenberg SMC, Vestjens SMT, Voorn GP, et al., Ovidius study group. Course of SP-D, YKL-40, CCL18 and CA 15-3 in adult patients hospitalised with community-acquired pneumonia and their association with disease severity and aetiology: A post-hoc analysis. PLoS One 2018; 13:e0190575. doi:10.1371/journal.pone.0190575. pmid:29324810.

222. Menéndez R, Méndez R, Aldás I, et al. Community-acquired pneumonia patients at risk for early and long-term cardiovascular events are identified by cardiac biomarkers. Chest 2019; 156:1080-91. doi:10.1016/j.chest.2019.06.040. pmid:31381883.

223. Khan F, Owens MB, Restrepo M, Povoa P, Martin-Loeches I. Tools for outcome prediction in patients with community acquired pneumonia. Expert Rev Clin Pharmacol 2017; 10:201-11. doi:10.1080/17512433.2017.1268051. pmid:27911103.

224. Self WH, Balk RA, Grijalva CG, et al. Procalcitonin as a marker of etiology in adults hospitalized with community-acquired pneumonia. Clin Infect Dis 2017; 65:183-90. doi:10.1093/cid/cix317. pmid:28407054.

225. Méndez R, Menéndez R, Cillóniz C, et al. Initial inflammatory profile in community-acquired pneumonia depends on time since onset of symptoms. Am J Respir Crit Care Med 2018; 198:370-8. doi:10.1164/rccm.201709-1908OC. pmid:29509439.

226. Christ-Crain M, Stolz D, Bingisser R, et al. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med 2006; 174:84-93. doi:10.1164/rccm.200512-1922OC. pmid:16603606.

227. Schuetz P, Christ-Crain M, Thomann R, et al., ProHOSP Study Group. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009; 302:1059-66. doi:10.1001/jama.2009.1297. pmid:19738090.

228. Akagi T, Nagata N, Wakamatsu K, et al. Procalcitonin-guided antibiotic discontinuation might shorten the duration of antibiotic treatment without increasing pneumonia recurrence. Am J Med Sci 2019; 358:33-44. doi:10.1016/j.amjms.2019.04.005. pmid:31084909.

229. Ito A, Ishida T, Tokumasu H, et al. Impact of procalcitonin-guided therapy for hospitalized community-acquired pneumonia on reducing antibiotic consumption and costs in Japan. J Infect Chemother 2017; 23:142-7. doi:10.1016/j.jiac.2016.11.006. pmid:28024740.

230. Chalmers JD, Singanayagam A, Hill AT. C-reactive protein is an independent predictor of severity in community-acquired pneumonia. Am J Med 2008; 121:219-25. doi:10.1016/j.amjmed.2007.10.033. pmid:18328306.

231. Menéndez R, Cavalcanti M, Reyes S, et al. Markers of treatment failure in hospitalised community acquired pneumonia. Thorax 2008; 63:447-52doi:10.1136/thx.2007.086785.

232. McCluskey SM, Schuetz P, Abers MS, et al. Serial Procalcitonin as a Predictor of Bacteremia and Need for Intensive Care Unit Care in Adults With Pneumonia, Including Those With Highest Severity: A Prospective Cohort Study. Open Forum Infect Dis 2017; 4:ofw238. doi:10.1093/ofid/ofw238. pmid:28480236.

233. Schuetz P, Wirz Y, Sager R, et al. Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis. Lancet Infect Dis 2018; 18:95-107. doi:10.1016/S1473-3099(17)30592-3. pmid:29037960.

234. Shi SJ, Li H, Liu M, et al. Mortality prediction to hospitalized patients with influenza pneumonia: PO2 /FiO2 combined lymphocyte count is the answer. Clin Respir J 2017; 11:352-60. doi:10.1111/crj.12346. pmid:26148709.

235. Ceccato A, Panagiotarakou M, Ranzani OT, et al. Lymphocytopenia as a predictor of mortality in patients with ICU-acquired pneumonia. J Clin Med 2019; 8:843. doi:10.3390/jcm8060843. pmid:31200458.

236. Torres A, Serra-Batlles J, Ros E, et al. Pulmonary aspiration of gastric contents in patients receiving mechanical ventilation: the effect of body position. Ann Intern Med 1992; 116:540-3. doi:10.7326/0003-4819-116-7-540. pmid:1543307.

237. Drakulovic MB, Torres A, Bauer TT, Nicolas JM, Nogué S, Ferrer M. Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial. Lancet 1999; 354:1851-8. doi:10.1016/S0140-6736(98)12251-1. pmid:10584721.

238. Wang L, Li X, Yang Z, et al. Semi-recumbent position versus supine position for the prevention of ventilator-associated pneumonia in adults requiring mechanical ventilation. Cochrane Database Syst Rev 2016;(1):CD009946. doi:10.1002/14651858.CD009946.pub2. pmid:26743945.

239. Klompas M, Li L, Kleinman K, Szumita PM, Massaro AF. Associations between ventilator bundle components and outcomes. JAMA Intern Med 2016; 176:1277-83. doi:10.1001/jamainternmed.2016.2427. pmid:27428482.

240. Li Bassi G, Panigada M, Ranzani OT, et al., Gravity-VAP Network. Randomized, multicenter trial of lateral Trendelenburg versus semirecumbent body position for the prevention of ventilator-associated pneumonia. Intensive Care Med 2017; 43:1572-84. doi:10.1007/s00134-017-4858-1. pmid:29149418.

241. Krein SL, Greene MT, Apisarnthanarak A, et al. Infection prevention practices in Japan, Thailand, and the United States: results from national surveys. Clin Infect Dis 2017;64(suppl_2):S105-11. doi:10.1093/cid/cix073. pmid:28475786.

242. Saint S, Greene MT, Fowler KE, et al. What US hospitals are currently doing to prevent common device-associated infections: results from a national survey. BMJ Qual Saf 2019; 28:741-9. doi:10.1136/bmjqs-2018-009111. pmid:31015378.

243. Blot S, Koulenti D, Dimopoulos G, et al., EU-VAP Study Investigators. Prevalence, risk factors, and mortality for ventilator-associated pneumonia in middle-aged, old, and very old critically ill patients*. Crit Care Med 2014; 42:601-9. doi:10.1097/01.ccm.0000435665.07446.50. pmid:24158167.

244. Liu Y, Di Y, Fu S. Risk factors for ventilator-associated pneumonia among patients undergoing major oncological surgery for head and neck cancer. Front Med 2017; 11:239-46. doi:10.1007/s11684-017-0509-8. pmid:28493197.

245. Ding C, Zhang Y, Yang Z, et al. Incidence, temporal trend and factors associated with ventilator-associated pneumonia in mainland China: a systematic review and meta-analysis. BMC Infect Dis 2017; 17:468. doi:10.1186/s12879-017-2566-7. pmid:28676087.

246. Frat J-P, Thille AW, Mercat A, et al., FLORALI Study Group, REVA Network. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med 2015; 372:2185-96. doi:10.1056/NEJMoa1503326. pmid:25981908.

247. Monro-Somerville T, Sim M, Ruddy J, Vilas M, Gillies MA. The effect of high-flow nasal cannula oxygen therapy on mortality and intubation rate in acute respiratory failure: a systematic review and meta-analysis. Crit Care Med 2017; 45:e449-56. doi:10.1097/CCM.0000000000002091. pmid:27611978.

248. Burns KEA, Meade MO, Premji A, Adhikari NKJ. Noninvasive positive-pressure ventilation as a weaning strategy for intubated adults with respiratory failure. Cochrane Database Syst Rev 2013;(12):CD004127. doi:10.1002/14651858.CD004127.pub3. pmid:24323843.

249. Vaschetto R, Longhini F, Persona P, et al. Early extubation followed by immediate noninvasive ventilation vs. standard extubation in hypoxemic patients: a randomized clinical trial. Intensive Care Med 2019; 45:62-71. doi:10.1007/s00134-018-5478-0. pmid:30535516.

250. Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000; 342:1471-7. doi:10.1056/NEJM200005183422002. pmid:10816184.

251. Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet 2008; 371:126-34. doi:10.1016/S0140-6736(08)60105-1. pmid:18191684.

252. Klompas M. Potential strategies to prevent ventilator-associated events. Am J Respir Crit Care Med 2015; 192:1420-30. doi:10.1164/rccm.201506-1161CI. pmid:26398835.

253. Philippart F, Gaudry S, Quinquis L, et al., TOP-Cuff Study Group. Randomized intubation with polyurethane or conical cuffs to prevent pneumonia in ventilated patients. Am J Respir Crit Care Med 2015; 191:637-45. doi:10.1164/rccm.201408-1398OC. pmid:25584431.

254. Saito M, Maruyama K, Mihara T, Hoshijima H, Hirabayashi G, Andoh T. Comparison of polyurethane tracheal tube cuffs and conventional polyvinyl chloride tube cuff for prevention of ventilator-associated pneumonia: A systematic review with meta-analysis. Medicine (Baltimore) 2021; 100:e24906. doi:10.1097/MD.0000000000024906. pmid:33655952.

255. Jaillette E, Girault C, Brunin G, et al., BestCuff Study Group and the BoRéal Network. Impact of tapered-cuff tracheal tube on microaspiration of gastric contents in intubated critically ill patients: a multicenter cluster-randomized cross-over controlled trial. Intensive Care Med 2017; 43:1562-71. doi:10.1007/s00134-017-4736-x. pmid:28303301.

256. Maertens B, Blot K, Blot S. Prevention of ventilator-associated and early postoperative pneumonia through tapered endotracheal tube cuffs: a systematic review and meta-analysis of randomized controlled trials. Crit Care Med 2018; 46:316-23. doi:10.1097/CCM.0000000000002889. pmid:29206767.

257. Caroff DA, Li L, Muscedere J, Klompas M. Subglottic secretion drainage and objective outcomes: a systematic review and meta-analysis. Crit Care Med 2016; 44:830-40. doi:10.1097/CCM.0000000000001414. pmid:26646454.

258. Muscedere J, Rewa O, McKechnie K, Jiang X, Laporta D, Heyland DK. Subglottic secretion drainage for the prevention of ventilator-associated pneumonia: a systematic review and meta-analysis. Crit Care Med 2011; 39:1985-91. doi:10.1097/CCM.0b013e318218a4d9. pmid:21478738.

259. Bouza E, Pérez MJ, Muñoz P, Rincón C, Barrio JM, Hortal J. Continuous aspiration of subglottic secretions in the prevention of ventilator-associated pneumonia in the postoperative period of major heart surgery. Chest 2008; 134:938-46. doi:10.1378/chest.08-0103. pmid:18641114.

260. Dezfulian C, Shojania K, Collard HR, Kim HM, Matthay MA, Saint S. Subglottic secretion drainage for preventing ventilator-associated pneumonia: a meta-analysis. Am J Med 2005; 118:11-8. doi:10.1016/j.amjmed.2004.07.051. pmid:15639202.

261. Frost SA, Azeem A, Alexandrou E, et al. Subglottic secretion drainage for preventing ventilator associated pneumonia: a meta-analysis. Aust Crit Care 2013; 26:180-8. doi:10.1016/j.aucc.2013.03.003. pmid:23583261.

262. Mao Z, Gao L, Wang G, et al. Subglottic secretion suction for preventing ventilator-associated pneumonia: an updated meta-analysis and trial sequential analysis. Crit Care 2016; 20:353. doi:10.1186/s13054-016-1527-7. pmid:27788682.

263. Pozuelo-Carrascosa DP, Herráiz-Adillo Á, Alvarez-Bueno C, Añón JM, Martínez-Vizcaíno V, Cavero-Redondo I. Subglottic secretion drainage for preventing ventilator-associated pneumonia: an overview of systematic reviews and an updated meta-analysis. Eur Respir Rev 2020; 29:190107. doi:10.1183/16000617.0107-2019. pmid:32051169.

264. Huang XA, Du YP, Fu BB, Li LX. Influence of subglottic secretion drainage on the microorganisms of ventilator associated pneumonia: A meta-analysis for subglottic secretion drainage. Medicine (Baltimore) 2018; 97:e11223. doi:10.1097/MD.0000000000011223. pmid:29995754.

265. de Jonge E, Schultz MJ, Spanjaard L, et al. Effects of selective decontamination of digestive tract on mortality and acquisition of resistant bacteria in intensive care: a randomised controlled trial. Lancet 2003; 362:1011-6. doi:10.1016/S0140-6736(03)14409-1. pmid:14522530.

266. de Smet AMGA, Kluytmans JAJW, Cooper BS, et al. Decontamination of the digestive tract and oropharynx in ICU patients. N Engl J Med 2009; 360:20-31. doi:10.1056/NEJMoa0800394. pmid:19118302.

267. Plantinga NL, de Smet AMGA, Oostdijk EAN, et al. Selective digestive and oropharyngeal decontamination in medical and surgical ICU patients: individual patient data meta-analysis. Clin Microbiol Infect 2018; 24:505-13. doi:10.1016/j.cmi.2017.08.019. pmid:28870727.

268. Bhalodi AA, van Engelen TSR, Virk HS, Wiersinga WJ. Impact of antimicrobial therapy on the gut microbiome. J Antimicrob Chemother 2019;74(Suppl 1):i6-15. doi:10.1093/jac/dky530. pmid:30690540.

269. Buelow E, Bello González TDJ, Fuentes S, et al. Comparative gut microbiota and resistome profiling of intensive care patients receiving selective digestive tract decontamination and healthy subjects. Microbiome 2017; 5:88. doi:10.1186/s40168-017-0309-z. pmid:28803549.

270. Wittekamp BH, Plantinga NL, Cooper BS, et al. Decontamination strategies and bloodstream infections with antibiotic-resistant microorganisms in ventilated patients: a randomized clinical trial. JAMA 2018; 320:2087-98. doi:10.1001/jama.2018.13765. pmid:30347072.

271. Zhao T, Wu X, Zhang Q, Li C, Worthington HV, Hua F. Oral hygiene care for critically ill patients to prevent ventilator-associated pneumonia. Cochrane Database Syst Rev 2020; 12:CD008367.pmid:33368159.

272. Labeau SO, Van de Vyver K, Brusselaers N, Vogelaers D, Blot SI. Prevention of ventilator-associated pneumonia with oral antiseptics: a systematic review and meta-analysis. Lancet Infect Dis 2011; 11:845-54. doi:10.1016/S1473-3099(11)70127-X. pmid:21798809.

273. Klompas M. Oropharyngeal decontamination with antiseptics to prevent ventilator-associated pneumonia: rethinking the benefits of chlorhexidine. Semin Respir Crit Care Med 2017; 38:381-90. doi:10.1055/s-0037-1602584. pmid:28578560.

274. Hua F, Xie H, Worthington HV, Furness S, Zhang Q, Li C. Oral hygiene care for critically ill patients to prevent ventilator-associated pneumonia. Cochrane Database Syst Rev 2016;10:CD008367. doi:10.1002/14651858.CD008367.pub3. pmid:27778318.

275. Zand F, Zahed L, Mansouri P, Dehghanrad F, Bahrani M, Ghorbani M. The effects of oral rinse with 0.2% and 2% chlorhexidine on oropharyngeal colonization and ventilator associated pneumonia in adults’ intensive care units. J Crit Care 2017; 40:318-22. doi:10.1016/j.jcrc.2017.02.029. pmid:28320561.

276. Deschepper M, Waegeman W, Eeckloo K, Vogelaers D, Blot S. Effects of chlorhexidine gluconate oral care on hospital mortality: a hospital-wide, observational cohort study. Intensive Care Med 2018; 44:1017-26. doi:10.1007/s00134-018-5171-3. pmid:29744564.

277. Klompas M, Speck K, Howell MD, Greene LR, Berenholtz SM. Reappraisal of routine oral care with chlorhexidine gluconate for patients receiving mechanical ventilation: systematic review and meta-analysis. JAMA Intern Med 2014; 174:751-61. doi:10.1001/jamainternmed.2014.359. pmid:24663255.

278. Price R, MacLennan G, Glen J, SuDDICU Collaboration. Selective digestive or oropharyngeal decontamination and topical oropharyngeal chlorhexidine for prevention of death in general intensive care: systematic review and network meta-analysis. BMJ 2014; 348:g2197. doi:10.1136/bmj.g2197. pmid:24687313.

279. Hirata K, Kurokawa A. Chlorhexidine gluconate ingestion resulting in fatal respiratory distress syndrome. Vet Hum Toxicol 2002; 44:89-91.pmid:11931511.

280. Plantinga NL, Wittekamp BHJ, Leleu K, et al. Oral mucosal adverse events with chlorhexidine 2% mouthwash in ICU. Intensive Care Med 2016;42:620-1. doi:10.1007/s00134-016-4217-7. pmid:26850333.

281. Chiewchalermsri C, Sompornrattanaphan M, Wongsa C, Thongngarm T. Chlorhexidine allergy: current challenges and future prospects. J Asthma Allergy 2020; 13:127-33. doi:10.2147/JAA.S207980. pmid:32210588.

282. Odedra KM, Farooque S. Chlorhexidine: an unrecognised cause of anaphylaxis. Postgrad Med J 2014; 90:709-14. doi:10.1136/postgradmedj-2013-132291. pmid:25352674.

283. La Combe B, Bleibtreu A, Messika J, et al. Decreased susceptibility to chlorhexidine affects a quarter of Escherichia coli isolates responsible for pneumonia in ICU patients. Intensive Care Med 2018; 44:531-3. doi:10.1007/s00134-018-5061-8. pmid:29379992.

284. Righy C, do Brasil PEA, Vallés J, Bozza FA, Martin-Loeches I. Systemic antibiotics for preventing ventilator-associated pneumonia in comatose patients: a systematic review and meta-analysis. Ann Intensive Care 2017; 7:67. doi:10.1186/s13613-017-0291-4. pmid:28620893.

285. Leone M, Bouadma L, Bouhemad B, et al. Hospital-acquired pneumonia in ICU. Anaesth Crit Care Pain Med 2018; 37:83-98. doi:10.1016/j.accpm.2017.11.006. pmid:29155054.

286. Chiu CY, Miller SA. Clinical metagenomics. Nat Rev Genet 2019; 20:341-55. doi:10.1038/s41576-019-0113-7. pmid:30918369.

287. Xie F, Duan Z, Zeng W, et al. Clinical metagenomics assessments improve diagnosis and outcomes in community-acquired pneumonia. BMC Infect Dis 2021; 21:352. doi:10.1186/s12879-021-06039-1. pmid:33858378.

288. Chen J, Zhao Y, Shang Y, et al. The clinical significance of simultaneous detection of pathogens from bronchoalveolar lavage fluid and blood samples by metagenomic next-generation sequencing in patients with severe pneumonia. J Med Microbiol 2021; 70:001259. doi:10.1099/jmm.0.001259. pmid:33231537.

289. Gonzalo-Calvo D, de, Benítez ID, Pinilla L, et al.Circulating microRNA profiles predict the severity of COVID-19 in hospitalized patients. Transl Res 2021; 236:147-59. doi:10.1016/j.trsl.2021.05.004.

290. Bonneau E, Neveu B, Kostantin E, Tsongalis GJ, De Guire V. How close are miRNAs from clinical practice? A perspective on the diagnostic and therapeutic market. EJIFCC 2019; 30:114-27.pmid:31263388.

291. Kyriazopoulou E, Karageorgos A, Liaskou-Antoniou L, et al. BioFire® FilmArray® pneumonia panel for severe lower respiratory tract infections: subgroup analysis of a randomized clinical trial. Infect Dis Ther 2021; 10:1437-49. doi:10.1007/s40121-021-00459-x. pmid:34120316.

 [JX1]建议将方框中的“p”换成“分”

中文的“点”也都统一成“分”

第二个框中“抗菌治疗小于90天”，应理解为“90天内使用抗菌药物治疗”

第三个框中“非流动状态”应理解为“卧床状态”