2024, Vol. 31
2. 复旦大学附属中山医院药剂科，上海 200032;
3. 复旦大学附属中山医院检验科，上海 200032;
4. 复旦大学附属中山医院感染管理科，上海 200032
2. Department of Pharmacology, Zhongshan Hospital, Fudan University, Shanghai 200032, China;
3. Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China;
4. Department of Infection Control and Management, Zhongshan Hospital, Fudan University, Shanghai 200032, China
耐药的革兰阴性菌（Gram-negative bacteria, GNB）感染给公共卫生带来极大挑战。世界卫生组织的高优先级病原体名单中，耐碳青霉烯鲍曼不动杆菌（carbapenem-resistant Acinetobacter baumannii, CRAB）、耐碳青霉烯铜绿假单胞菌（carbapenem-resistant Pseudomonas aeruginosa, CRPA）和耐碳青霉烯肠杆菌科细菌（carbapenem-resistant Enterobacteriaceae, CRE）被列为最高级别[1]。β-内酰胺类抗生素可被β-内酰胺酶灭活，是GNB最重要的耐药机制。在产超广谱β-内酰胺酶（extended-spectrum β-lactamase, ESBL）和产AmpC β-内酰胺酶（AmpC β-lactamase, AmpC）菌株高度流行的环境中，碳青霉烯类药物常是严重感染的首选药物。耐药监测显示，我国的ESBL菌株流行率很高，鲍曼不动杆菌耐药严重，耐碳青霉烯类肺炎克雷伯菌的流行率持续升高[2]；CRE菌株中，携带碳青霉烯酶的菌株数量逐渐增加[3]。
本文总结近年的新型抗GNB抗生素及其进展，包括窄谱青霉素类抗生素替莫西林（temocillin），新型含氟四环素类依拉环素（eravacycline），新一代半合成氨基糖苷类普拉佐米星（plazomicin），新型铁载体头孢菌素类头孢地尔（cefiderocol），头孢菌素与β-内酰胺酶抑制剂（β-lactamase inhibitor, BLI）组合的头孢洛扎/他唑巴坦（ceftolozone/tazobactam, C/T）、头孢他啶/阿维巴坦（ceftazidime/avibactam, CZA）、头孢吡肟（cefepime）/enmetazobactam，碳青霉烯类与新型BLI组合的美罗培南/韦博巴坦（meropenem/vaborbactam, MEV）和亚胺培南-西司他丁/雷巴坦（imipenem-cilastatin/relebactam, I/R），以及单环内酰胺类与BLI组合的氨曲南/阿维巴坦（aztreonam/avibactam, AZA）。目前，CZA已在我国批准上市。新型抗GNB抗生素以及基于耐药机制的应用详见表 1。
| Novel antibiotics | ESBL/AmpC | KPC | OXA-48 | MBL | CRAB | CRPA |
| Temocillin | ++ | ++ | － | － | － | － |
| Cefiderocol | ++ | ++ | ++ | ++ | ++ | ++ |
| Ceftolozone/Tazobactam | ++ | － | － | － | － | +/－ |
| Ceftazidime/Avibactam | ++ | ++ | ++ | － | － | +/－ |
| Cefepime/Enmetazobactam | ++ | ++ | +/－ | － | － | +/－ |
| Meropenem/Vaborbactam | ++ | ++ | － | － | ||
| Imipenem-Cilastatin/Relebactam | ++ | ++ | － | － | － | +/－ |
| Aztreonam/Avibactam | ++ | ++ | ++ | ++ | － | － |
| Eravacycline | ++ | ++ | ++ | + | ++ | － |
| Plazomicin | ++ | ++ | ++ | +/－ | － | － |
| ESBL: extended-spectrum β-lactamase; AmpC: AmpC β-lactamase; KPC: Klebsiella pneumoniae carbapenemase; OXA-48: OXA-48 carbapenemase; MBL: Metallo-β-lactamase; CRAB: carbapenem-resistant Acinetobacter baumannii; CRPA: carbapenem-resistant Pseudomonas aeruginosa.++: active against＞90% of isolates; +: active against 70%-90% of isolates; +/－: active against about 50% of isolates; －: inactive; blank: lack of data. | ||||||
替莫西林对产ESBL和AmpC的肠杆菌科细菌有很强的杀菌活性[4]，对流感嗜血杆菌、卡他莫拉菌、奈瑟菌属和洋葱伯克霍尔德菌具有活性，但对革兰阳性球菌、厌氧菌和非发酵菌无活性。替莫西林对CRE菌株的最低抑菌浓度（minimum inhibitory concentration, MIC）较高，＜10%的产OXA-48型碳青霉烯酶（OXA-48）和（或）金属β-内酰胺酶（MBL）的菌株对替莫西林敏感，而大于85%的产KPC型碳青霉烯酶（KPC）的菌株对替莫西林敏感[5-6]。该药耐受性好，且对肠道微生物菌群的影响小。
一项随机对照试验（radomized controlled trial, RCT）[7]比较了替莫西林间断静脉滴注（2 g，每8 h 1次）和持续静脉滴注（6 g）在腹腔感染（intra-abdominal infection, IAI）和下呼吸道感染中的疗效，病原体主要为大肠埃希菌、肺炎克雷伯菌和其他肠杆菌属。结果显示，间断给药、持续输注和同时持续血液滤过的临床治愈率分别为79%、93%和75%。对于重症患者，建议延长输注时间或持续输注以提高疗效。另一项RCT研究[8]评估了替莫西林在泌尿道感染（urinary tract infection, UTI）中的疗效以及对肠道菌群的影响。患者分为替莫西林组（2 g，每8 h 1次，静脉注射）和头孢噻肟组（1~2 g，每8 h 1次，静脉注射），治疗7~10 d；若存在血流感染（bloodstream infection, BSI），治疗14 d，并检测对三代头孢菌素敏感性降低的肠杆菌科细菌和（或）产毒素艰难梭菌的定植率。结果显示，替莫西林治疗组临床治愈率94%，对肠道菌群影响更小（定植率26% vs 48%）。替莫西林可用于门诊患者，是治疗产ESBL肠杆菌科细菌感染和KPC菌株引起非复杂性UTI的优良选择。菌血症、肺部感染也可考虑选择，但该药不适用于脑膜炎。
2 头孢地尔头孢地尔利用铁转运系统通过细菌外膜，从而不受外膜通透性降低的影响[9]。该药抗菌谱广，包括产ESBL、KPC、OXA和MBL肠杆菌科细菌、假单胞菌属、窄食单胞菌属和伯克霍尔德菌属。对90%以上的肠杆菌分离株、不动杆菌属和铜绿假单胞菌分离株具有活性[10]，但对厌氧菌、葡萄球菌或肠球菌覆盖不足。头孢地尔已获得美国食品和药品监督管理局（FDA）批准，用于治疗复杂性泌尿道感染（complicated UTI, cUTI）和医院获得性肺炎/呼吸机相关性肺炎（hospital-acquired pneumonia/ventilator-associated pneumonia, HAP/VAP）。
一项cUTI的临床试验[11]显示，头孢地尔治疗的临床和微生物学应答均显著高于亚胺培南-西司他丁（73% vs 55%）。Falcone等研究[12]纳入了既往治疗失败的BSI和VAP患者10例，病原体为CRAB、耐碳青霉烯类嗜麦芽窄食单胞菌和产新德里金属β-内酰胺酶（NDM）的肺炎克雷伯菌，头孢地尔的临床治疗成功率为70%。一项RCT研究（APEKS-NP）[13]比较了头孢地尔与高剂量美罗培南（均2 g，每天3次，静脉滴注）在HAP或VAP中的疗效。结果显示，两组患者14 d死亡率、微生物治愈率和不良反应差异无统计学意义。CREDIBLE-CR研究[14]评估了头孢地尔与最佳治疗（best available therapy）对耐碳青霉烯类GNB所致cUTI、HAP、VAP、医疗保健相关性肺炎（healthcare-associated pneunomia, HCAP）和BSI的疗效，结果显示两组的治愈率接近。值得注意的是，肺炎和BSI患者中，头孢地尔组全因死亡率高于对照组（34% vs 18%），其中不动杆菌感染者死亡率达50%，导致该药被列入FDA警告。一项观察性研究[15]比较了CRAB感染中头孢地尔和黏菌素的疗效与安全性，结果显示患者30 d死亡率在黏菌素组与头孢地尔组中分别为55.8%和34%，两组BSI患者的死亡率差异有统计学意义，但未在VAP中得到证实。
3 C/T头孢洛扎对产ESBL肠杆菌科细菌和碳青霉烯类不敏感的铜绿假单胞菌具有活性。C/T对产AmpC菌株的覆盖力不同，对碳青霉烯类不敏感的不动杆菌和肠杆菌科细菌的活性有限，不能很好覆盖革兰阳性菌或厌氧菌[16-17]。C/T在2014年获得美国FDA批准用于cUTI和复杂性腹腔感染（complicated IAI, cIAI），后适应证扩展至HAP/VAP。C/T常见不良反应包括恶心、腹泻、头痛和发热；罕见但严重的不良反应包括粒细胞缺乏症，使用药物时应当进行相应指标监测[18]。
一项比较C/T与黏菌素的回顾性临床研究[19]显示，接受C/T与感染广泛耐药假单胞菌VAP的临床治疗成功率增加相关。ASPECT-NP研究[20]共纳入726例HAP/VAP患者，比较了C/T（3 g，每8 h 1次，静脉注射）与美罗培南（1 g，每8 h 1次，静脉注射）的疗效与安全性，结果显示，C/T组的28 d死亡率及临床治愈率不劣于美罗培南组。Paterson等[21]进行回顾性亚组分析，比较了C/T与美罗培南在产ESBL和（或）AmpC肠杆菌科细菌所致HAP/VAP中的疗效。结果显示，C/T组的28 d死亡率低于美罗培南组（6.7% vs 32.3%），而临床治愈率更高（73.3% vs 61.3%）。Kollef等[22]的多因素回顾性分析进一步证实，与C/T组相比，美罗培南组的28 d全因死亡率更高。一项在我国IAI病例中开展的RCT研究[23]显示，C/T联合甲硝唑的临床治愈率不劣于美罗培南，两组的微生物学应答与安全性相当。
4 CZACZA对ESBL、AmpC、KPC和OXA-48具有活性，但对MBL无效[24-26]，对厌氧菌无活性，对不动杆菌敏感性的数据有限。2015年美国FDA批准CZA用于治疗cUTI，CZA联合甲硝唑治疗cIAI，2018年适应证扩展至HAP/VAP。
多项研究显示，在治疗铜绿假单胞菌所致的cUTI、cIAI和HAP中，CZA非劣效于碳青霉烯类（主要是美罗培南）。一项meta分析[27]显示，相比其他药物，接受CZA治疗的CRE感染患者临床治愈率较高而死亡率降低。CAVICOR研究[28]比较了CZA与最佳治疗（庆大霉素、替加环素、磷霉素和黏菌素）对KPC和OXA-48阳性CRE的疗效，结果显示CZA组的30 d死亡率更低。在一项纳入577例产碳青霉烯酶类肺炎克雷伯菌感染患者的回顾性研究[29]中，CZA单药和联合其他药物治疗BSI、UTI、下呼吸道感染和IAI的临床疗效与死亡率差异无统计学意义，但在下呼吸道感染者中CZA治疗后的死亡率更高。CZA是严重感染患者有多重耐药（multidrug-resistant, MDR）GNB感染风险时经验性治疗的合理选择，但结合上述观察，对于合并休克的VAP和HAP病例，应当谨慎使用。此外，若已知有不动杆菌或产MBL菌株感染病史者，应当选择其他抗生素。针对产MBL肠杆菌科细菌所致BSI的前瞻性观察性研究[30]显示，与其他方案相比，接受CZA联合氨曲南的治疗组30 d死亡率更低（19.2% vs 44%）。然而，CZA联合氨曲南的治疗优势值得进一步研究。
5 头孢吡肟/enmetazobactam头孢吡肟/enmetazobactam是第4代头孢菌素头孢吡肟与新型青霉烷酸砜超广谱β-内酰胺酶抑制剂enmetazobactam的组合。体外实验[31]中，在8 μg/mL浓度下，enmetazobactam可使头孢吡肟对大肠杆菌（16 μg/mL降至0.12 μg/mL）、肺炎克雷伯菌（＞64 μg/mL降至0.5 μg/mL）、阴沟肠杆菌（16 μg/mL降至1 μg/mL）的MIC90明显降低，但不能增强头孢吡肟对铜绿假单胞菌的活性。采用8 μg/mL的折点时，所有肠杆菌科细菌的抑制率为98.1%，铜绿假单胞菌抑制率为82.8%。另一项体外研究[32]中，头孢吡肟/enmetazobactam能够抑制84%的碳青霉烯类不敏感铜绿假单胞菌分离株，但对CRAB无效。欧洲药品管理局基于enmetazobactam与头孢吡肟联合在上皮衬液中的研究结果，允许该药无需经过Ⅲ期临床试验即可申请肺炎中的应用许可。
一项多中心RCT研究（ALLIUM）[33]共入组1 034例cUTI或急性肾盂肾炎患者，其中8%~11%合并BSI。患者随机接受头孢吡肟/enmetazobactam（2 g/0.5 g）或哌拉西林/他唑巴坦（4 g/0.5 g）治疗（每8 h 1次，静脉滴注2 h），疗程7 d（BSI治疗14 d）。结果显示，头孢吡肟/enmetazobactam组的总成功率为79.1%，而对照组仅58.9%。此外，头孢吡肟/enmetazobactam耐受良好，不良事件发生率与对照组相当，分别有0.2%与0.6%的严重不良事件直接与药物相关。然而，研究中仅21%的患者感染产ESBL的细菌。头孢吡肟/enmetazobactam在耐药GNB患者中的治疗价值仍需进一步研究。
6 MEV韦博巴坦能够抑制ESBL、AmpC和KPC，但不能抑制OXA或MBL。联合韦博巴坦可使美罗培南的MIC值降低至原来的1/1 024~1/2，显著提高其对大多数肠杆菌科细菌的活性，但并不能提高对鲍曼不动杆菌或铜绿假单胞菌的活性[34]。比较C/T、CZA、MEV、头孢地尔和对照药物在BSI的GNB分离株的活性发现，对于产KPC的肠杆菌科细菌，MEV最为敏感（敏感率92.9%），其次是CZA、头孢地尔和黏菌素，敏感率分别为89.3%、87.5%和83.9%[35]。目前，MEV已被批准用于治疗cUTI。
各类CRE感染的多项回顾性研究[36-37]显示，MEV的临床治愈率为60%~80%，复发率约10%。一项碳青霉烯不敏感病原体所致cUTI、HAP/VAP、BSI等多种感染的研究[38]中，与最佳治疗相比，MEV的28 d临床治愈率更高（65.6% vs 33.3%）。然而，此研究的对照组中查尔森合并症指数＞6分的患者比例较高，或许对治愈率有影响。一项约半数为重症监护室（intensive care unit, ICU）患者的观察性研究[39]比较了MEV（中位治疗12 d）和CZA（中位治疗11 d）对CRE所致UTI和IAI的疗效，其中部分患者联合其他抗生素治疗（MEV组15.4%，CZA组51%）。结果显示，MEV组的临床成功率高于CZA组（69.2% vs 61.9%）。一项RCT研究（TANGOⅠ）[40]显示，MEV（2 g/2 g，每8 h 1次，持续输注3 h）和哌拉西林/他唑巴坦（4 g/0.5 g，每8 h 1次，输注30 min）对cUTI患者的治疗成功率分别为98.4%和94.0%。该研究中，最常见致病菌为大肠埃希菌与肺炎克雷伯菌。
7 I/R雷巴坦在结构上与阿维巴坦相似，对ESBL、AmpC、KPC和OXA-48具有活性，但对MBL无效。与亚胺培南相比，亚胺培南联合雷巴坦对产KPC的肺炎克雷伯菌等大多数肠杆菌科细菌（MIC＞32 mg/L降至≤0.5 mg/L）和铜绿假单胞菌（MIC90 16 mg/L降至2 mg/L）的活性显著提高，但并不能恢复亚胺培南对产MBL的肠杆菌和CRAB的活性[40-41]。体外实验[42-43]显示，I/R与氨曲南对产MBL的菌株可产生协同作用，但联合治疗的临床疗效需进一步的临床研究确认。I/R于2019年获得美国FDA批准用于治疗cUTI和cIAI（亚胺培南500 mg、西司他丁500 mg、雷巴坦250 mg，每日4次，静脉注射）。2020年，适应证扩展至HAP/VAP。
一项RCT研究[44]比较了I/R和哌拉西林/他唑巴坦（4 g/500 mg，每日4次，静脉滴注）治疗VAP患者（共治疗7~14 d）的全因死亡率与临床反应，纳入病例中最常见病原体是肠杆菌科细菌（41.1%）、铜绿假单胞菌（18.9%）和不动杆菌（15.7%）。结果显示，I/R组28 d全因死亡率更低（15.9% vs 21.3%）。另一项RCT研究[45]比较了I/R联合安慰剂与亚胺培南-西司他丁（500 mg/500 mg，每日4次，静脉滴注）联合黏菌素治疗各类亚胺培南耐药的GNB感染（约半数为UTI）的效果。在微生物改良意向治疗组中，I/R治疗组的28 d临床应答率更高（71.4% vs 40.0%）。
8 AZAAZA是唯一的单环内酰胺类药物氨曲南与新型BLI的复合制剂。绝大多数产MBL细菌也表达丝氨酸β-内酰胺酶，可灭活氨曲南；氨曲南本身虽然不被MBL灭活，其单一制剂效力有限。当结合阿维巴坦以抑制多种丝氨酸β-内酰胺酶时，氨曲南对产MBL和丝氨酸酶细菌的活性恢复。体外药敏实验[46-47]显示，AZA对产MBL革兰阴性细菌具有活性，对耐碳青霉烯类大肠埃希菌和肺炎克雷伯菌的体外活性优于CZA，对CRPA的作用不及CZA。2019年，美国FDA授予AZA合格传染病产品和快速通道资格认定，用于治疗cIAI、cUTI、细菌性HAP/VAP。除病例报告和药物安全性研究外，其相关临床研究数据相对较少，所观察到的不良事件与氨曲南单药治疗一致，目前Ⅲ期研究正在进行中。
除以上介绍的6种新型β-内酰胺/β-内酰胺酶抑制剂（β-lactam/β-lactamase inhibitors, BLBLI）外，正在研究中的其他具有抗GNB潜力的BLBLI组合包括头孢吡肟/taniborbactam、头孢吡肟/zidebactam、美罗培南/nacubactam等，但目前尚未确定其临床折点，且缺少人类临床试验，有待进一步研究。
9 依拉环素依拉环素对耐甲氧西林金黄色葡萄球菌（methicillin-resistant Staphylococcus aureus, MRSA）、耐万古霉素肠球菌、厌氧菌、ESBL株、部分CRE分离株（包括产OXA和KPC菌株）和不动杆菌属均有活性，但对假单胞菌属或伯克霍尔德菌属无效。依拉环素的MIC与替加环素有很好的相关性，但效力更高[48-49]。2018年，美国FDA批准其用于治疗复杂性IAI。该药不良反应与其他四环素类药物相同，包括过敏和永久性牙齿变色等[50]。
一项RCT研究[51]显示，依拉环素对cIAI的疗效不劣于碳青霉烯类药物（＞80%的患者接受了手术治疗）；研究中＞70%的病原体为GNB，依拉环素和美罗培南对ESBL株的临床治愈率分别为87%和84.6%；不足10%的患者由铜绿假单胞菌感染引起，治愈率＞90%，可见手术清创对cIAI的重要性；此外，BSI亚组中，依拉环素的微生物学治愈率与碳青霉烯类接近，均超过97%。对于cUTI，其疗效小于左氧氟沙星和厄他培南[52-53]。值得注意的是，一项小规模回顾性研究[54]比较了依拉环素与最佳治疗对感染耐药鲍曼不动杆菌患者的疗效，结果发现依拉环素组患者的30 d死亡率更高，尤其是合并BSI者。依拉环素同时对革兰阴性菌和革兰阳性菌有活性，在cIAI的经验性治疗中具有一定价值。但考虑到回顾性研究中患者的死亡率更高，在不动杆菌感染中的使用需谨慎。
10 普拉佐米星普拉佐米星通过抑制细菌蛋白质合成呈剂量依赖性杀灭细菌[55-56]。体外实验[57-58]中，普拉佐米星对超过95%的肠杆菌科细菌有活性，对ESBL菌株有活性，对84.6%~97.6%的耐碳青霉烯类菌株有活性。与传统氨基糖苷类相比，普拉佐米星对耐药铜绿假单胞菌和鲍曼不动杆菌的活性并无提高，仅对30%~40%的分离株具有活性[59]。该药对KPC阳性分离株具有良好活性（药物浓度小于等于2 mg/L时对92.9%的分离株敏感），对OXA-48阳性株活性稍弱（87%），而对MBL阳性株活性有限（40.5%）。全球收集的CRE菌株中，36%的产NDM分离株以及50%的产OXA-48分离株对普拉佐米星敏感[60]。其对多数氨基糖苷类修饰酶稳定，不能被灭活[61]。对其他3种氨基糖苷类（阿米卡星、庆大霉素与妥布霉素）均耐药的分离株中，仍有52.2%对该药敏感[57]。此外，该药对包括MRSA在内的金黄色葡萄球菌也有活性，但对厌氧菌和肠球菌属抗菌活性弱。美国FDA批准其用于cUTI和急性肾盂肾炎。普拉佐米星（15 mg/kg，每日1次，静脉注射）在cUTI中的疗效不劣于左氧氟沙星[62]和美罗培南[63]。一项纳入39例CRE所致BSI和细菌性肺炎患者的RCT研究（CARE）[64]中，普拉佐米星组（治疗7~14 d）的28 d全因死亡率或疾病相关重要并发症为24%，而黏菌素联合美罗培南或替加环素治疗组为50%。但是，该研究因入组缓慢而提前终止。该药的联合治疗在抗耐药GNB中的价值有待进一步研究。
综上所述，对于产KPC肠杆菌科细菌所致的HAP/VAP、cIAI和cUTI，表 1中除C/T外的其他药物均有效。对于产OXA-48的菌株引起的HAP/VAP，可使用头孢地尔和CZA，cIAI可使用CZA和依拉环素。产MBL肠杆菌科细菌所致HAP/VAP的选择有限，仅推荐头孢地尔和AZA。对于CRAB感染，若感染类型为HAP/VAP可选择头孢地尔；若感染类型为cIAI可选择依拉环素。对因外排增多、产AmpC或外膜蛋白OprD缺失而非产MBL的CRPA感染，可选择CZA或C/T。尽管多种新药较老药更具活性，但不代表其可作为临床上常规使用的药物；临床医师应当利用好现有的药物，积极推动抗生素应用管理以避免耐药菌扩散和新耐药机制产生。除新型抗生素外，针对耐药菌感染的其他研究方向还包括新药与老药的联合方案、抗微生物肽、金属纳米粒子、正电荷聚合物装置[65]、内毒素中和治疗[66]、CRISPR/Cas策略、噬菌体[67]和疫苗[68]等。
耐药GNB的抗生素治疗是细菌感染领域的重点[69]。本文介绍了10种新型抗生素，这些药物均在治疗耐碳青霉烯类细菌方面具有价值，将在今后临床耐药GNB的治疗中发挥重要作用，尤其是新型BLBLI组合，其合理应用值得进一步探讨。
伦理声明 无。
利益冲突 所有作者声明不存在利益冲突。
作者贡献 姚雨濛：文章选题、文章设计、资料收集、资料分析、起草论文与修改；陈璋璋：文章选题、资料分析与论文修改；单玉璋：资料收集、资料分析与论文修改；潘珏：选题、资料分析、论文修改与行政支持；胡必杰：文章设计、资料分析、论文修改与行政支持。
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