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医药导报, 2019, 38(3): 287-293
doi: 10.3870/j.issn.1004-0781.2019.03.001
三唑类抗真菌药物肺组织渗透性研究进展
Research Progress of Permeability of Triazole Antifungal Drugs in Lung Tissue
阎鸿焰1,2,, 黄银1,2, 陈诚1,2, 秦博1,2, 张灵1,2, 杨勇1,2,

摘要:

肺部真菌感染患者在使用三唑类抗真菌药物后,肺组织感染/定植部位的药物浓度能够更准确地反映临床疗效。该文总结了肺部真菌感染患者使用三唑类抗真菌药物后肺组织药物浓度的相关研究进展,并综述肺泡上皮衬液中药物浓度测定方法和不同药物渗透特点。

关键词: 抗真菌药物 ; 三唑类 ; 真菌感染 ; 肺部 ; 肺泡上皮衬液 ; 肺组织浓度

Abstract:

In patients with pulmonary fungal infection, the concentration of the drug in the lung tissue infection/colonization site more accurately reflects the clinical efficacy after the use of triazole antifungal drugs.This paper summarized the research progress about triazole antifungal drug concentration in lung tissue of patients with pulmonary fungal infection after administration, and summarized the determination of drug concentration in alveolar epithelial lining fluid and the permeation characteristics of different drugs.

Key words: Antifungal drugs ; triazole ; Fungal infections ; pulmonary ; Epithelial lining fluid ; Lung tissue concentration

足够的药物渗透到微生物感染/定植部位对于抗微生物治疗结局至关重要,肺泡上皮衬液(epithelial lining fluid,ELF)是细胞外肺部微生物感染/定植的重要部位[1,2]。临床治疗中都是以抗菌药物的血药浓度与最低抑菌浓度(minimum inhibitory concentration,MIC)或最低杀菌浓度(minimum bactericidal concentration,MBC)之间的关系来评估抗菌药物的疗效,而感染/定植部位的抗菌药物浓度更能准确抗菌药物疗效。笔者在本文介绍三唑类抗真菌药物在肺组织渗透性的相关研究,总结肺组织感染部位药物浓度的测定方法,并对三唑类抗真菌药物在肺部感染部位的相关数据进行分析和总结。

1 三唑类抗真菌药

曲霉属、接合菌属、镰刀菌属和丝孢菌属等菌种正成为侵袭性肺部真菌病的常见病原体,尤其是免疫功能低下且患有癌症或接受器官移植的患者[2,3]。三唑类和其他类抗真菌药是用于治疗侵袭性肺部真菌病的主要抗真菌药物[1,2]。目前常用的三唑类抗真菌药物主要包括氟康唑、伊曲康唑、伏立康唑和泊沙康唑等。

氟康唑具有较高水溶性,轻微亲脂性。临床广泛用于多种深部真菌感染,主要对芽生菌、念珠菌、球孢子菌、隐球菌、组织胞浆菌和曲霉菌具有活性[4]

伊曲康唑主要应用于深部真菌所致系统感染,对曲霉病、念珠菌病、球孢子菌病、芽生菌病、隐球菌病和组织胞浆菌病等均有较好疗效[5]

伏立康唑是一种广谱三唑类抗真菌药物,对临床上各种主要酵母菌和曲霉菌具有抗菌活性。目前被认为是治疗侵入性曲霉病、念珠菌病、隐球菌病和由病原性酵母菌、丝孢菌属、尖端足分支霉菌和镰刀菌属引起的严重真菌感染的首选药物,也用于其他抗真菌药物治疗无效或不耐受者[6,7,8]

泊沙康唑用于治疗难治性真菌感染性疾病或其他耐药性真菌感染,如对曲霉菌、镰刀菌、隐球菌、念珠菌、组织胞浆菌和芽孢杆菌属都有良好活性,这些感染一般发生在严重免疫抑制人群,如器官移植或化学治疗(化疗)患者[9,10]

2 肺组织与ELF

肺部感染时,达到有效抗菌药物效应位点浓度对于成功治疗和防止耐药必不可少。对于大多数肺部感染患者,感染部位是ELF。ELF是病原体引起肺部感染的细胞外抗微生物活性的部位[1]。为达到ELF有效抗菌浓度,抗菌药物需要从肺毛细血管进入肺间质间隙,然后穿过肺泡壁上皮到达ELF和肺泡细胞(alveolar cell,AC)[11]。由于存在紧密连接和药物转运蛋白,肺泡和毛细血管之间存在一个屏障——气血屏障[12],只有一些小分子物质、血浆蛋白结合率低或脂溶性较高的抗菌药物才能有效透过这个紧密结合的细胞屏障,使其在AC、肺组织等位置达到较高浓度。肺部真菌感染时,药物透过屏障进入AC和ELF的药物浓度决定了临床治疗的效果。因此确定抗菌药物在肺部感染时的渗透性和在肺部不同部位的药物浓度,以及微生物的感染部位,可以更好地设计感染患者个体化治疗方案,提高临床治愈率。

3 肺组织药物浓度测定

近年来,已有多种测量抗菌药物渗透进入肺内模式和肺组织药物浓度的方法。根据测量样本的来源不同,常用方法包括全肺组织匀浆、痰、呼吸道分泌物、支气管黏膜、胸膜液、支气管肺泡灌洗、ELF、微透析、正电子发射断层扫描(positron emission tomography,PET)和磁共振波谱等[1]。但尚无实验证明哪种方法和技术最适合。例如,早期通过手术获得肺组织样本来测定抗菌药物浓度,但这种方法具有一定局限性,且会对人体造成相应损伤[5]。也不推荐检测全肺组织药物浓度,因为细胞内外抗菌药物浓度不一致。而对于痰液、唾液这些操作简单、取样方便的方法来说,由于取样过程中容易被稀释且可能是各部位混合后的平均浓度,结果差异也较大[9]。事实上,每种测量方法都有其优点和局限性。

当前,支气管镜检查与支气管肺泡灌洗结合已成为从下呼吸道支气管肺泡表面获取ELF中AC和组织中各种标本的安全有效方法[1,3]。给予患者利多卡因局麻后,将纤维支气管镜插入右中肺或下肺叶,通过将三或四等分试样0.9%氯化钠溶液滴入肺叶,立即将每个等分试样抽吸出,并置于冰上;支气管镜检查的平均持续时间约4 min;第一次因含有临近气道的细胞等杂质应丢弃。将第二次、第三次和第四次的支气管肺泡灌洗液(bronchoalveolar lavage fluid,BALF)合并汇集,测量并记录其体积;将收集的BALF过滤去除杂质,立即离心5 min,分离上清液和肺泡细胞,并将上清液保存在约-70 ℃环境下,直至测定抗菌药物和尿素的浓度[1,5,9,13]。支气管肺泡灌洗操作的同时留取血浆样本,以测定血浆中药物和尿素的浓度。血浆和BALF中抗菌药物浓度可以采用高效液相色谱(HPLC)法[14]、反相高效液相色谱(RP-HPLC)法[5]、液相色谱-串联质谱法(liquid chromatography -tandem mass spectrometry,LC-MS/MS)[10]等方法进行检测。此外,可以通过酶耦联法[10]、比色法[7]等测定血浆和BALF中尿素浓度。

3.1 ELF中抗菌药物浓度的计算

由于回收的BALF中包含灌洗用0.9%氯化钠溶液、ELF和其他细胞组分混合物。测定ELF中抗菌药物实际浓度有很大难度。为确定抗菌药物浓度,必须估算ELF表观体积。RENNARD等[15]采用尿素稀释法间接计算抗菌药物浓度。由于尿素是小分子非极性物质,可以自由透过气血屏障[12],并迅速在血和肺组织达到平衡,所以可以认为血中尿素浓度与ELF中尿素浓度相等。通过测定血液和BALF 中尿素浓度,从而计算ELF中药物实际浓度。公式如下:

VELF=VBALF× Ure a BALF Ure a plasma

其中VELF为ELF体积,VBALF为BALF 体积,UreaBALF为BALF 中尿素浓度,Ureaplasma为血浆尿素浓度。

使用计算的ELF体积值,可以计算ELF中药物浓度(CELF),公式如下:

CELF= V BALF V ELF ×CBALF

其中CBALF为BALF 中药物浓度,将等式①和等式②整理得出:

CELF= Ure a plasma Ure a BALF ×CBALF

因此,测定肺泡灌洗时血浆中尿素浓度和回收BALF中尿素浓度,以及BALF中药物浓度即可根据上述公式计算ELF中药物实际浓度。

通过得出的CELF和测定的Cplasma计算肺组织渗透率:

肺组织渗透率= C ELF C plasma

3.2 AC中抗菌药物浓度的计算

测量细胞悬液中AC的体积,可以通过BALF细胞计数实现[14]。在最低检测限为106·L-1的血细胞计数器中计数细胞。1.0 mL细胞悬液中细胞数量等于30倍1.0 mL BALF中的细胞数量。由于离心过程中有细胞损失,实际回收的细胞数量可能低于计数数量,实际抗菌药物浓度可能比计算的高出约20%[16]。细胞悬液中AC的体积为BALF细胞计数乘以肺泡巨噬细胞平均体积之积,肺泡巨噬细胞平均体积约2.42 μL·1 0 - 6 [ 13 ]

AC中抗菌药物浓度的计算可根据下列公式[14]:

CAC= C PELLET V AC

其中,CAC是肺泡细胞中抗菌药物浓度,CPELLET是在1 mL细胞悬液中测得的抗菌药物浓度,VAC是在1 mL细胞悬液中的AC体积。

通过得出的CAC和测定的Cplasma计算肺组织渗透率:

肺组织渗透率= C AC C plasma

4 三唑类抗真菌药物的肺组织渗透性
4.1 氟康唑

笔者仅检索到一项关于氟康唑渗透性的动物研究,VADEN等[4]采用交叉研究设计,将6只猫随机分配到两组,分别接受氟康唑50 mg口服或者静脉注射,均50 mg·d-1,8 d后采用HPLC法[14]测定药物浓度,尿素稀释法[15]间接计算抗菌药物在ELF的浓度,测得猫体内氟康唑平均浓度为:ELF=(26.0±5.2) μg·mL-1,液体药物浓度平均比率:ELF/血浆=1.20。静脉和口服氟康唑后,药动学参数差异无统计学意义。由于氟康唑相对分子质量小,水溶性及血浆蛋白结合率低,药物可分布于全身,包括进入特定感染部位。ELF中氟康唑浓度超过氟康唑对病原真菌的最小抑制浓度。结果显示,氟康唑在猫体内ELF中有高度渗透性,表明氟康唑可以有效治疗由新型隐球菌和其他对氟康唑敏感的微生物引起的下呼吸道感染。上述结论需要进一步证实氟康唑在人体内也具有相同的高渗透性。

4.2 伊曲康唑

一项26例健康受试者使用伊曲康唑(ITRA)的试验,受试者给予伊曲康唑200 mg,bid,空腹口服,共10次[5]。26例受试者被随机分为5组,最后一次给药后4,8,12,16和24 h,进行支气管镜检查和支气管肺泡灌洗,收集样本并以RP-HPLC测量血浆和BALF中药物浓度[5],酶耦联法测定尿素浓度[10],尿素稀释法计算抗菌药物浓度[15]。结果显示,血浆、ELF和AC中ITRA药物最大浓度(Cmax)分别为(2.1±0.8),(3.3±1.0)和(0.5±0.7) μg·mL-1;代谢产物14-羟基伊曲康唑(OH-ITRA)Cmax分别为(1.0±0.9),(5.5±2.9)和(6.6±3.1) μg ·mL-1。血浆、ELF和AC中ITRA的AUC分别为34.4,7.4,101 μg·h·mL-1,OH-ITRA的AUC分别为60.2,18.9,134 μg·h·mL-1。AC中ITRA的Cmax/MIC90比值、AUC/MIC90比值分别为1.1和3.2,OH-ITRA的比值分别为51和67。ELF中ITRA和OH-ITRA的渗透率为0.22和0.31;AC中ITRA和OH-ITRA的渗透率为2.94和2.23。由此可知,ITRA和OH-ITRA能有效渗透到肺组织,但到达AC中的药物居多,研究结论认为ITRA口服给药方案(200 mg,bid)使AC中ITRA和OH-ITRA浓度显著大于血浆或ELF。ITRA亲脂性和高血浆蛋白结合率有利于其进入AC。肺内ITRA和OH-ITRA药物浓度达到了有利于治疗真菌性呼吸道感染的浓度。

4.3 伏立康唑

PASSLER等[6]在评估正常马第7天和第14天伏立康唑体液浓度的安全性研究中,6匹成年马中有5匹马接受伏立康唑粉剂,1匹马给予伏立康唑片剂。6匹马均每天给药一次,4 mg·kg-1,均给药14 d。收集血浆、BALF样本,RP-HPLC法[5]测定血浆和BALF中药物浓度,酶耦联法[10]测定尿素浓度,尿素稀释法[15]计算其结果。第7天,血浆、ELF和尿中伏立康唑平均浓度分别为(1.47±0.63),(79.45±69.4)和(1.83±0.44) μg·mL-1。第14天,血浆、ELF和尿中伏立康的唑平均浓度分别为(1.60±0.37),(47.76±45.4)和(3.34±2.17) μg·mL-1。第7天,ELF中平均伏立康唑浓度为平均血浆浓度的54倍。第14天,ELF中伏立康唑平均浓度是血浆浓度的29倍。该研究结果表明,正常马通过每天一次口服4 mg·kg-1可以实现高于血浆、尿液和ELF中伏立康唑浓度0.5 μg·mL-1的治疗目标。马体内ELF中伏立康唑浓度显著超过血浆浓度,伏立康唑浓度在ELF中高于血浆29~54倍,ELF中伏立康唑浓度远高于导致马真菌性肺炎的真菌生物体的MIC90

WANG等[8]评价了伏立康唑对肺泡基底上皮细胞(A549细胞)中烟曲霉菌的动力学和活性,伏立康唑对A549细胞有浓度依赖性毒性作用,经细胞外分别为2,8和16 mg·L-1伏立康唑作用2 h后穿透到A549细胞,分别达到(1.14±0.64),(3.72±1.38)和(6.36±0.95) μg·mL-1。当细胞外伏立康唑浓度分别为8和16 mg·L-1时,分别杀死75.6%和80.5%细胞内烟曲霉菌。ELF在肺上皮细胞表面[8,11],药物穿透到A549细胞需先经过ELF,所以ELF与上皮细胞浓度相当甚至更高。因此间接得出ELF中较高浓度伏立康唑保持较高的细胞内抗菌活性,从而有效抵抗烟曲霉菌。该研究结果发现,伏立康唑可以减少体外分生孢子侵入肺上皮细胞的数量,并有效抑制细胞内分生孢子生长,证实了伏立康唑能预防和早期治疗免疫功能低下患者侵入性肺曲霉菌病。

CAPITANO等[17]进行的一项前瞻性研究中,12例患者在肺移植后立即开始伏立康唑治疗,6 mg·kg-1,每12 h静脉注射2次,随后口服200 mg,bid。所有患者在伏立康唑预防期间,在移植后2,4和8周进行支气管肺泡灌洗,样本处理后采用HPLC法测定伏立康唑浓度,比色法测定尿素浓度[7],尿素稀释法计算相关液体中药物浓度[15]。成功收集11例患者的BALF和血液样本,其ELF和血浆浓度分别为1.98和0.19,13.28和1.35,7.85和1.34,1.58和0.76,44和2.66,57.9和2.10,83.32和4.56,0.29和0.05,13.27和1.16,0.73和0.15,2.16和0.43 μg·mL-1,ELF中伏立康唑总浓度超过血浆总伏立康唑浓度,平均ELF/血药浓度为11±8,伏立康唑具有显著的肺穿透力。观察到血浆和ELF浓度之间的强关联(R2=0.95,P<0.0001)。HENG等[18,19]的前瞻性观察性试验研究中,12例肺移植患者接受口服伏立康唑进行预先治疗,并在肺移植后接受定期支气管镜检查和支气管肺泡灌洗检查,每例患者在口服伏立康唑治疗至少1周后预先取样测定,样本用HPLC测定药物浓度,酶耦联法测定尿素浓度,并采用尿素稀释法[15]进行计算。由于血液严重污染或伏立康唑浓度分析测量的干扰,3例患者BALF样本被排除分析。结果显示,9例患者ELF中伏立康唑浓度高于所有患者中大部分曲霉菌和酵母菌分离株报道的MIC90。其ELF和血浆浓度分别为42.3和1.67,37.9和3.18,1.56和0.15,5.75和0.57,59.5和3.87,2.98和0.67,2.92和0.48,27.4和0.56,7.66和0.70 μg·mL-1,伏立康唑中平均ELF/血浆浓度比例为12.5±6.3。结果显示ELF和血浆浓度之间存在很强的正相关线性关系(R2=0.868,P<0.001),且波谷血浆浓度与ELF中伏立康唑浓度之间存在密切关系,表明波谷血浆伏立康唑浓度可以作为ELF浓度的潜在替代指标。此研究的预防性治疗方案中伏立康唑ELF浓度超过了曲霉菌的MI C 90 [ 20 ]

CRANDON等[13]联合伏立康唑和阿尼芬净治疗肺曲霉菌病,20例健康受试者接受静脉内伏立康唑(第1天,6 mg·kg-1,q12 h,然后4 mg·kg-1,q12h)和阿尼芬净[第1天200 mg,然后100 mg·(24 h)-1]3 d。随机选择每5例受试者分别抽取4,8,12和24 h支气管肺泡灌洗样本,处理后LC-MS/MS测定伏立康唑浓度,比色法测定尿素浓度,尿素稀释法[15]计算药物ELF和AC浓度。药物渗透性通过ELF和肺泡巨噬细胞给药间隔期间浓度-时间曲线下总药物面积与总药物AUC 0-t比例来确定。伏立康唑在4,8和12 h的ELF中穿透率平均值分别为9.5±2.3,4.9±2.8和7.7±3.4;同一时间点AC中渗透水平分别为3.9±0.6,5.6±1.9和5.9±4.5。血浆中伏立康唑半衰期和AUC0-t分别是(6.9±2.1)h和(39.5±19.8)μg·h·mL-1。在ELF和AC中,伏立康唑AUC0-t分别为282和178 μg·h·mL-1。伏立康唑在ELF和AC中肺组织渗透率分别为7.1和4.5。药物在4,8,12和24 h的ELF和AC中的总平均浓度高于大多数曲霉菌种的MIC90。结果显示,在健康成年志愿者,伏立康唑在ELF和AC中都达到高水平暴露。伏立康唑很好地渗透到ELF和AC,其中每个区室在大多数时间点浓度均超过血浆浓度。

ANDERSEN等[7]纳入6例患者接受40 mg伏立康唑吸入,bid,共2 d;另有6例患者接受口服伏立康唑片,第1天400 mg,bid,第2天200 mg,bid。最后一次给予伏立康唑给12 h,进行支气管镜检查和支气管肺泡灌洗,采用HPLC测定药物浓度,比色法测定样本中尿素浓度,尿素稀释法[15]计算药物浓度。最后一次给药后12 h,吸入组中位数血浆伏立康唑浓度为8(4~26) ng·mL-1,口服组为1224(535~2341) ng·mL-1。吸入组中位数ELF浓度为190(55~318) ng·mL-1,口服组为8827(4369~35 172) ng·mL-1。吸入组中位ELF/血浆浓度比为21(6~63),口服组为8(3~20)。BALF中,吸入组伏立康唑浓度范围为0.7~4.6 ng·mL-1,口服组范围为10~90 ng·mL-1。口服伏立康唑标准负荷剂量方案组给药2 d后,血浆和ELF浓度分别比接受较低吸入剂量的患者组高约150和50倍。在单一测定点,吸入伏立康唑患者ELF/血浆浓度比约为口服治疗的2.5倍。吸入给药和口服给药伏立康唑后在ELF中的浓度都高于血浆中的浓度。吸入伏立康唑比口服给药能更有效地渗透到肺组织,但需要更多研究来解释吸入给药后ELF/血浆比是否更有利。

4.4 泊沙康唑

SEYEDMOUSAVI等[21]将96只小鼠分别给予4,8,16或32 mg·kg-1泊沙康唑口服溶液,qd,然后使小鼠感染烟曲霉菌。感染后8个预定时间点(0,0.5,1,2,4,8,12和24 h,每个时间点3只小鼠)抽取血液和BALF样品,超荧光液相色谱(UPLC)法荧光检测血浆和BALF泊沙康唑浓度,酶耦联法测定尿素浓度,尿素稀释法计算药物浓度[15]。结果显示4,8,16或32 mg·kg-1给药方案后血浆和ELF中总AUC0-24分别为72.69和14.69,149.80和42.14,198.90和62.23,290.50和78.78 mg·h·L-1。所有给药剂量的血浆中药物浓度包括泊沙康唑的Cmax均高于ELF中的药物浓度。线性回归分析显示,血浆和ELF平均泊沙康唑浓度之间存在显著相关性(R2=0.61,P<0.000 1)。ELF中泊沙康唑暴露量(AUC0-24)为总药物血浆中浓度的20.21%~31.39%,且血浆和ELF中泊沙康唑和AUC0-24之间也存在显著线性关系。泊沙康唑亲脂性和高细胞内浓度有助于分布在感染/定植部位ELF。泊沙康唑表现出暴露依赖的药效学特征,其中游离AUC0-24/MIC范围为1.67~1.78,是预测与半最大效力相关的成功的值。泊洛康唑在ELF中渗透性较高,这与亲脂特性和其细胞内通透性增加一致。泊沙康唑高肺内渗透率表明该药是预防由于唑类敏感和(或)唑类烟曲霉所致真菌感染的最佳治疗选择。

CONTE等[9]对25例健康成人以400 mg·(12 h)-1口服悬液给药和高脂饮食8 d,共接受14个剂量泊沙康唑。最后一次给药后3,5,8,12和24 h进行支气管镜检查和支气管肺泡灌洗,最后一次给药后24 h收集血液样品,采用LC-MS/MS测定泊沙康唑浓度和酶耦联法测定尿素浓度,并用尿素稀释法计算其组织浓度[15]。结果显示,血浆、ELF和AC最大浓度(Cmax)分别为(2.08±0.93),(1.86±1.30)和(87.7±65.0) μg·mL-1。ELF/血浆和AC/血浆0~12 h曲线下面积(AUC 0-12)为0.84和33。ELF/血浆和AC/血浆范围为0.589~1.08和27.3~44.3。血浆、ELF和AC中AUC0-24/MIC 90分别为87.6,73.2和2860。ELF、血浆和AC中AUC0-12值分别为18.3,21.9和715 μg·h·mL-1,相当于总药物86%的ELF/血浆渗透率。血浆、ELF和AC中泊沙康唑浓度无显著降低,表明多次给药达稳态后缓慢消除。血浆、ELF和AC中泊沙康唑平均浓度高于曲霉菌MIC90(0.5 μg·mL-1)。

另一项前瞻性研究[10]纳入20例成人肺移植患者,每天两次服用泊沙康唑口服混悬剂400 mg加高脂肪餐,共14剂。最后一次给予泊沙康唑后约3,5,8,12或24 h进行支气管镜检查和支气管肺泡灌洗,收集样本,采用LC-MS/MS测定泊沙康唑浓度,酶耦联法测定尿素浓度,尿素稀释法计算组织浓度[15]。血浆、ELF和AC中最大浓度(Cmax)为1.3±0.4,1.3±1.7和55.4±44.0 μg·mL-1。血浆游离和总Cmax/MIC90分别为0.04和2.5。游离AUC0-12和AUC0-24分别为0.16和0.30 μg·h·mL-1。游离AUC0-12/MIC90为0.33,游离AUC0-24/MIC90为0.60。血浆、ELF和AC中泊沙康唑浓度未显著降低,表明多次给药后缓慢消除。在12 h给药间隔期间,以及最后一次给药后24 h血浆、ELF和AC中泊沙康唑的平均浓度都在曲霉菌中MIC90(0.5 μg·mL-1)以上。泊沙康唑对念珠菌属具有浓度依赖性活性,且治疗效力与AUC/MIC最佳相关。结果表明,每12 h口服给药方案泊沙康唑(400 mg)在整个12 h的给药间隔内的血浆、ELF和AC浓度都维持在曲霉菌的MIC90以上。在该研究中观察到,高肺内AUC0-12/MIC90有利于治疗或预防曲霉病;口服泊沙康唑在健康成人中和肺移植患者中耐受均良好。

5 讨论

三唑类抗真菌药物在肺部组织的渗透性不同,具体见表1。

表1 三唑类抗真菌药物在不同研究对象肺部组织的渗透率
Tab.1 Permeability of triazole antifungal drugs in lung tissues of different study subjects
药物与研究对象 渗透率(ELF/血浆浓度)
氟康唑
1.20
伊曲康唑
健康受试者 0.22
伏立康唑
41 ±12
肺移植患者 11 ± 8[17]
肺移植患者 12.5± 6.3[18]
健康受试者 7.1[15]
健康受试者 21(吸入组)/8(口服组)[7]
泊沙康唑
1.73
健康成年人 0.84
肺移植患者 0.33

渗透率均为平均值或均数±标准差

Permeability is expressed as mean or mean±standard deviation

表1 三唑类抗真菌药物在不同研究对象肺部组织的渗透率

Tab.1 Permeability of triazole antifungal drugs in lung tissues of different study subjects

仅一项动物研究显示,氟康唑能够在猫体内渗透到ELF,渗透率>1,还需进一步人体实验证实氟康唑在人体内也具有相同的高渗透率;伊曲康唑及其代谢产物能够有效渗透到健康受试者ELF,但渗透率<1,仍需更多研究确定其渗透性;伏立康唑在马、肺移植患者和健康受试者的研究显示ELF中药物浓度均高于血浆,且渗透率远远超过1,在三唑类抗真菌药物中效果最好;泊沙康唑在鼠ELF中的浓度高于血浆,渗透率>1。然而泊沙康唑在健康成年人和肺移植患者ELF的浓度低于血浆,渗透率<1,但浓度始终高于病原体MIC90,有利于治疗或预防曲霉病。所有药物浓度均达到有利于治疗真菌性呼吸道感染的浓度。每种药物肺组织渗透率不同的原因可能与三唑类药物相对分子质量大小、血浆蛋白结合率、亲脂性或亲水性等多种因素有关,而药物在ELF 或AC中的浓度与血浆浓度的关系可以为临床制定合理个体化给药方案提供可靠依据。临床医师可根据患者感染部位、病情严重程度、血药浓度和组织浓度以及药物肺组织渗透率,考虑病原菌的特点及MIC(或AUC)值,调整患者给药剂量和给药方法,使药物在感染部位的浓度超过或维持在敏感菌的MIC90以达到有效治疗效果。

上述研究都是针对特定的研究对象,如动物(猫、马、鼠)、离体细胞、健康受试者和肺移植患者,但各研究对象的病理生理状态均有所不同,肺部感染导致的其他炎症并发症也不相同,还需根据患者实际情况制定抗菌药物给药方案。以上研究证明,伏立康唑在健康受试者和肺移植患者肺组织渗透性最好,是目前治疗深部真菌感染的最好选择,雾化吸入伏立康唑渗透性效果好,可作为临床新的给药方式。同时可以考虑采取治疗药物监测(therapeutic drug monitoring,TDM)和建立群体药动学/药效学模型(pharmacokinetics/pharmacodynamics,PK/PD)等相关辅助手段,使临床医师更加了解药物在体内的代谢过程和渗透部位,从而制定个体化给药方案,降低患者不良反应以及细菌耐药突变,从而提高临床抗真菌感染的治愈率。

The authors have declared that no competing interests exist.

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The pharmacokinetics of fluconazole following intravenous (i.v.) and oral (p.o.) administration and the penetration of fluconazole into cerebrospinal fluid, aqueous humour and epithelial lining fluid (ELF) of the lungs were evaluated in adult male cats. Pharmacokinetic parameters were calculated from serum concentration-time data obtained following i.v. and p.o. administration of 50 mg per cat using a cross-over study design. Fluconazole concentrations were measured using a high-performance liquid chromatography assay. Mean total body clearance of fluconazole was 37.7 mL/h.kg, mean volume of distribution at steady state was 1.14 L/kg, mean residence time was 31.0 h and mean half-life of elimination was 25 h as derived by non-compartmental analysis of data. Absorption was complete. Mean ratios of fluid:serum fluconazole concentrations following administration of 50 mg fluconazole per day for 8 days were as follows: cerebrospinal fluid, 0.88; aqueous humour 0.79; ELF, 1.20. Fluconazole concentrations in cerebrospinal fluid, aqueous humour and ELF exceeded reported minimum inhibitory concentrations of fluconazole for pathogenic fungi. Results of this study suggest fluconazole can effectively be administered to cats at 50 mg per cat per day.
DOI:10.1111/j.1365-2885.1997.tb00093.x      PMID:9185083      URL    
[本文引用:2]
[5] CONTE J J,GOLDEN J A,KIPPS J,et al.Intrapulmonary pharmacokinetics and pharmacodynamics of itraconazole and 14-hydroxyitraconazole at steady state[J].Antimicrob Agents Chemother,2004,48(10):3823-3827.
Abstract We determined the steady-state intrapulmonary pharmacokinetic and pharmacodynamic parameters of orally administered itraconazole (ITRA), 200 mg every 12 h (twice a day [b.i.d.]), on an empty stomach, for a total of 10 doses, in 26 healthy volunteers. Five subgroups each underwent standardized bronchoscopy and bronchoalveolar lavage (BAL) at 4, 8, 12, 16, and 24 h after administration of the last dose. ITRA and its main metabolite, 14-hydroxyitraconazole (OH-IT), were measured in plasma, BAL fluid, and alveolar cells (AC) using high-pressure liquid chromatography. Half-life and area under the concentration-time curves (AUC) in plasma, epithelial lining fluid (ELF), and AC were derived using noncompartmental analysis. ITRA and OH-IT maximum concentrations of drug (C(max)) (mean +/- standard deviation) in plasma, ELF, and AC were 2.1 +/- 0.8 and 3.3 +/- 1.0, 0.5 +/- 0.7 and 1.0 +/- 0.9, and 5.5 +/- 2.9 and 6.6 +/- 3.1 microg/ml, respectively. The ITRA and OH-IT AUC for plasma, ELF, and AC were 34.4 and 60.2, 7.4 and 18.9, and 101 and 134 microg. hr/ml. The ratio of the C(max) and the MIC at which 90% of the isolates were inhibited (MIC(90)), the AUC/MIC(90) ratio, and the percent dosing interval above MIC(90) for ITRA and OH-IT concentrations in AC were 1.1 and 3.2, 51 and 67, and 100 and 100%, respectively. Plasma, ELF, and AC concentrations of ITRA and OH-IT declined monoexponentially with half-lives of 23.1 and 37.2, 33.2 and 48.3, and 15.7 and 45.6 h, respectively. An oral dosing regimen of ITRA at 200 mg b.i.d. results in concentrations of ITRA and OH-ITRA in AC that are significantly greater than those in plasma or ELF and intrapulmonary pharmacodynamics that are favorable for the treatment of fungal respiratory infection.
DOI:10.1128/AAC.48.10.3823-3827.2004      PMID:15388441      URL    
[本文引用:7]
[6] PASSLER N H,CHAN H M,STEWART A J,et al.Distribution of voriconazole in seven body fluids of adult horses after repeated oral dosing[J].J Vet Pharmacol Ther,2010,33(1):35-41.
Passler, N. H., Chan, H.-M., Stewart, A. J., Duran, S. H., Welles, E. G., Lin, H.-C., Ravis, W. R. Distribution of voriconazole in seven body fluids of adult horses after repeated oral dosing. J. vet. Pharmacol. Therap. 33, 35–41.The purpose of this study was to assess safety and alterations in body fluid concentrations of voriconazole in normal horses on days 7 and 14 following once daily dose of 4 mg/kg of voriconazole orally for 14 days. Body fluid drug concentrations were determined by the use of high performance liquid chromatography (HPLC). On day 7, mean voriconazole concentrations of plasma, peritoneal, synovial and cerebrospinal fluids, aqueous humor, epithelial lining fluid (ELF), and urine were 1.47 ± 0.63, 0.61 ± 0.22, 0.70 ± 0.20, 0.62 ± 0.26, 0.55 ± 0.32, 79.45 ± 69.4, and 1.83 ± 0.44 μg/mL respectively. Mean voriconazole concentrations in the plasma, peritoneal, synovial and cerebrospinal fluids, aqueous humor, ELF and urine on day 14 were 1.60 ± 0.37, 1.02 ± 0.27, 0.86 ± 0.25, 0.64 ± 0.21, 0.68 ± 0.13, 47.76 ± 45.4 and 3.34 ± 2.17 respectively. Voriconazole concentrations in the bronchoalveolar cell pellet were below the limit of detection. There was no statistically significant difference between voriconazole concentrations of body fluids when comparing days 7 and 14. Results indicated that voriconazole distributes widely into body fluids.
DOI:10.1111/j.1365-2885.2009.01099.x      PMID:20444023      URL    
[本文引用:2]
[7] ANDERSEN C U,SONDERSKOV L D,BENDSTRUP E,et al.Voriconazole concentrations in plasma and epithelial lining fluid after inhalation and oral treatment[J].Basic Clin Pharmacol Toxicol,2017,121(5):430-434.
Abstract Adverse effects can compromise oral voriconazole treatment of pulmonary aspergillosis. Inhaled low-dose voriconazole may be an alternative treatment. In this study, six patients inhaled 40 mg voriconazole b.i.d. for two days, and six patients ingested 400 and 200 mg orally b.i.d. on day one and two, respectively. Blood samples were collected after the first inhalation, and bronchial alveolar lavage fluids and blood samples were collected for measurements of voriconazole 12 hr after the last administration. The concentration of voriconazole in epithelial lining fluid (ELF) was calculated by the urea dilution method. Voriconazole concentrations were detectable in plasma 15 min. after inhalation, and declined at 30 and 60 min. Twelve hours after the last dose, median (95%CI) plasma voriconazole concentration was 8 (4-26) ng/mL in the inhalation group, and 1224 (535-2341) ng/mL in the oral group (p<0.0001). In ELF, median concentration was 190 (55-318) ng/mL, and 8827 (4369-35172) ng/mL, respectively (p<0.0001). Median ELF/plasma concentration ratio was 21 (6-63) in the inhalation group, and 8 (3-20) in the oral group (p=0.2). In conclusion, voriconazole is rapidly absorbed into the systemic circulation after inhalation. There was a non-significant trend towards a higher ELF/plasma concentration ratio in the inhalation group compared to the oral group. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
DOI:10.1111/bcpt.12820      PMID:28609608      URL    
[本文引用:4]
[8] WANG T,YANG Q,CHEN L,et al.Uptake and efflux kinetics,and intracellular activity of voriconazole against Aspergillus fumigatus in human pulmonary epithelial cells: a new application for the prophylaxis and early treatment of invasive pulmonary aspergillosis[J].Fundam Clin Pharmacol,2017,31(3):311-318.
[本文引用:3]
[9] CONTE J J,GOLDEN J A,KRISHNA G,et al.Intrapulmonary pharmacokinetics and pharmacodynamics of posaconazole at steady state in healthy subjects[J].Antimicrob Agents Chemother,2009,53(2):703-707.
【Key Words】:
DOI:10.1128/AAC.00663-08      PMID:19029316      URL    
[本文引用:4]
[10] CONTE J J,DEVOE C,LITTLE E,et al.Steady-state intrapulmonary pharmacokinetics and pharmacodynamics of posaconazole in lung transplant recipients[J].Antimicrob Agents Chemother,2010,54(9):3609-3613.
This prospective study evaluated the plasma and intrapulmonary pharmacokinetics and pharmacodynamics (PKPD) of posaconazole (POS) in lung transplant recipients. Twenty adult lung transplant patients were instructed to take a 400-mg POS oral suspension twice daily (BID) with a high-fat meal for a total of 14 doses. Pulmonary epithelial lining fluid (ELF) and alveolar cell (AC) samples were obtai...
DOI:10.1128/AAC.01396-09      PMID:2934990      URL    
[本文引用:6]
[11] VALITALO P A,GRIFFIOEN K,RIZK M L,et al.Structure-based prediction of anti-infective drug concentrations in the human lung epithelial lining fluid[J].Pharm Res,2016,33(4):856-867.
Abstract PURPOSE: Obtaining pharmacologically relevant exposure levels of antibiotics in the epithelial lining fluid (ELF) is of critical importance to ensure optimal treatment of lung infections. Our objectives were to develop a model for the prediction of the ELF-plasma concentration ratio (EPR) of antibiotics based on their chemical structure descriptors (CSDs). METHODS: EPR data was obtained by aggregating ELF and plasma concentrations from historical clinical studies investigating antibiotics and associated agents. An elastic net regularized regression model was used to predict EPRs based on a large number of CSDs. The model was tuned using leave-one-drug-out cross validation, and the predictions were further evaluated using a test dataset. RESULTS: EPR data of 56 unique compounds was included. A high degree of variability in EPRs both between- and within drugs was apparent. No trends related to study design or pharmacokinetic factors could be identified. The model predicted 80% of the within-drug variability (R(2) WDV) and 78.6% of drugs were within 3-fold difference from the observations. Key CSDs were related to molecular size and lipophilicity. When predicting EPRs for a test dataset the R(2) WDV was 75%. CONCLUSIONS: This model is of relevance to inform dose selection and optimization during antibiotic drug development of agents targeting lung infections.
DOI:10.1007/s11095-015-1832-x      PMID:26626793      URL    
[本文引用:2]
[12] KASPER J Y,HERMANNS M I,UNGER R E,et al.A responsive human triple-culture model of the air-blood barrier:incorporation of different macrophage phenotypes[J].J Tissue Eng Regen Med,2017,11(4):1285-1297.
Abstract Top of page Abstract 1Introduction 2Materials and methods 3Results 4Discussion 5Conclusion Conflict of interest Acknowledgements References Current pulmonary research underlines the relevance of the alveolar macrophage (AM) integrated in multicellular co-culture-systems of the respiratory tract to unravel, for example, the mechanisms of tissue regeneration. AMs demonstrate a specific functionality, as they inhabit a unique microenvironment with high oxygen levels and exposure to external hazards. Healthy AMs display an anti-inflammatory phenotype, prevent hypersensitivity to normally innocuous contaminants and maintain tissue homeostasis in the alveolus. To mirror the actual physiological function of the AM, we developed three different polarized [classically activated (M1) and alternatively activated (M2 wh , wound-healing; M2 reg , regulatory)] macrophage models using a mixture of differentiation mediators, as described in the current literature. To test their immunological impact, these distinct macrophage phenotypes were seeded on to the epithelial layer of an established in vitro air–blood barrier co-culture, consisting of alveolar epithelial cells A549 or H441 and microvascular endothelial cells ISO-HAS-1 on the opposite side of a Transwell filter-membrane. IL-8 and sICAM release were measured as functionality parameters after LPS challenge. The M1 model itself already provoked a severe inflammatory-like response of the air–blood barrier co-culture, thus demonstrating its potential as a useful in vitro model for inflammatory lung diseases. The two M2 models represent a ‘non-inflammatory’ phenotype but still showed the ability to trigger inflammation following LPS challenge. Hence, the latter could be used to establish a quiescent, physiological in vitro air–blood model. Thus, the more complex differentiation protocol developed in the present study provides a responsive in vitro triple-culture model of the air–blood-barrier that mimics AM features as they occur in vivo . 08 2015 The Authors Journal of Tissue Engineering and Regenerative Medicine Published by John Wiley & Sons, Ltd.
DOI:10.1002/term.2032      PMID:26078119      URL    
[本文引用:2]
[13] CRANDON J L,BANEVICIUS M A,FANG A F,et al.Bronchopulmonary disposition of intravenous voriconazole and anidulafungin given in combination to healthy adults[J].Antimicrob Agents Chemother,2009,53(12):5102-5107.
Voriconazole and anidulafungin in combination are being investigated for use for the treatment of pulmonary aspergillosis. We determined the pulmonary disposition of these agents. Twenty healthy participants received intravenous voriconazole (at 6 mg/kg of body weight every 12 h [q12h] on day 1 and then at 4 mg/kg q12h) and anidulafungin (200 mg on day 1 and then 100 mg every 24 h) for 3 days. Five participants each were randomized for collection of bronchoalveolar lavage samples at times of 4, 8, 12, and 24 h. Drug penetration was determined by the ratio of the total drug area under the concentration-time curve during the dosing interval (AUC(0-tau)) for epithelial lining fluid (ELF) and alveolar macrophages (AM) to the total drug AUC(0-tau) in plasma. The mean (standard deviation) half-life and AUC(0-tau) were 6.9 (2.1) h and 39.5 (19.8) microg h/ml, respectively, for voriconazole and 20.8 (3.1) h and 101 (21.8) microg h/ml, respectively, for anidulafungin. The AUC(0-tau) values for ELF and AM were 282 and 178 microg h/ml, respectively, for voriconazole, and 21.9 and 1,430 microg h/ml, respectively, for anidulafungin. This resulted in penetration ratios into ELF and AM of 7.1 and 4.5, respectively, for voriconazole and 0.22 and 14.2, respectively, for anidulafungin. The mean total concentrations of both drugs in ELF and AM at 4, 8, 12, and 24 h remained above the MIC(90)/90% minimum effective concentration for most Aspergillus species. In healthy adult volunteers, voriconazole achieved high levels of exposure in both ELF and AM, while anidulafungin predominantly concentrated in AM.
DOI:10.1128/AAC.01042-09      PMID:2786330      URL    
[本文引用:2]
[14] RODVOLD K A,DANZIGER L H,GOTFRIED M H.Steady-state plasma and bronchopulmonary concentrations of intravenous levofloxacin and azithromycin in healthy adults[J].Antimicrob Agents Chemother,2003,47(8):2450-2457.
The purpose of this study was to compare the concentrations of levofloxacin and azithromycin in steady-state plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) after intravenous administration. Thirty-six healthy, nonsmoking adult subjects were randomized to either intravenous levofloxacin (500 or 750 mg) or azithromycin (500 mg) once daily for five doses. Venipuncture and bronchoscopy with bronchoalveolar lavage were performed in each subject at either 4, 12, or 24 h after the start of the last antibiotic infusion. The mean concentrations of levofloxacin and azithromycin in plasma were similar to those previously published. The dosing regimens of levofloxacin achieved significantly (P < 0.05) higher concentrations in steady-state plasma than azithromycin during the 24 h after drug administration. The respective mean (+/- standard deviation) concentrations at 4, 12, and 24 h in ELF for 500 mg of levofloxacin were 11.01 +/- 4.52, 2.50 +/- 0.97, and 1.24 +/- 0.55 micro g/ml; those for 750 mg of levofloxacin were 12.94 +/- 1.21, 6.04 +/- 0.39, and 1.73 +/- 0.78 micro g/ml; and those for azithromycin were 1.70 +/- 0.74, 1.27 +/- 0.47, and 2.86 +/- 1.75 micro g/ml. The differences in concentrations in ELF among the two levofloxacin groups and azithromycin were significantly (P < 0.05) higher at the 4- and 12-h sampling times. The respective concentrations in AM for 500 mg of levofloxacin were 83.9 +/- 53.2, 18.3 +/- 6.7, and 5.6 +/- 3.2 micro g/ml; those for 750 mg of levofloxacin were 81.7 +/- 37.0, 78.2 +/- 55.4, and 13.3 +/- 6.5 micro g/ml; and those for azithromycin were 650 +/- 259, 669 +/- 311, and 734 +/- 770 micro g/ml. Azithromycin achieved significantly (P < 0.05) higher concentrations in AM than levofloxacin at all sampling times. The concentrations in ELF and AM following intravenous administration of levofloxacin and azithromycin were higher than concentrations in plasma. Further studies are needed to determine the clinical significance of such high intrapulmonary concentrations in patients with respiratory tract infections.
DOI:10.1128/AAC.47.8.2450-2457.2003      PMID:166098      URL    
[本文引用:4]
[15] RENNARD S I,BASSET G,LECOSSIER D,et al.Estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution[J].J Appl Physiol (1985),1986,60(2):532-538.
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[16] WILLCOX M,KERVITSKY A,WATTERS L C,et al.Quantification of cells recovered by bronchoalveolar lavage.Comparison of cytocentrifuge preparations with the filter method[J].Am Rev Respir Dis,1988,138(1):74-80.
Controversy exists as to the appropriate methods to use in the processing of bronchoalveolar lavage (BAL) fluid for total cell numbers and cellular differential analysis. It has been shown that cell losses (primarily lymphocytes) occur by the most commonly employed methods. Therefore, we examined the total cell and differential counts obtained by several methods of cytocentrifuge preparation and by the filter preparation in 46 consecutive patients with interstitial lung disease and 29 healthy volunteers undergoing bronchoalveolar lavage. The retrieved lavage fluid was pooled, and an aliquot was used to determine the total cell count, cell viability, and the differential cell count by the filter and cytocentrifuge techniques. The remaining fluid was centrifuged (800 for 10 min), and the cell pellet was resuspended in Hank's balanced salt solution without Caand Mg. An aliquot of these centrifuged and resuspended cells was used for repeat determination of the cell viability, total cell count, and cellular differential by cytocentrifuge technique. Autologous serum was added to another aliquot of these centrifuged and resuspended cells to arrive at a 10% protein solution, and the cellular differential obtained by cytocentrifuged preparation. We found that () measurement of the total cells recovered by lavage is most accurate if determined on the original uncentrifuged, pooled lavage fluid, () the centrifugation and resuspension of lavage cells causes a generalized loss of total cells with a decrease in cell viability, () the addition of serum to the cell suspension prior to preparation of the cytoprep slides results in a selective loss of lymphocytes, and () the use of uncentrifuged, pooled lavage fluid for the cytopreparation yields identical cell differential counts compared with those of the filter technique. Thus, quantification of the total cells recovered by BAL is most accurate when counted on an aliquot of the original cell suspension. Further, cytopreparations yield accurate quantification of lavage cellular constituents if serum is not added to the solution.
DOI:10.1164/ajrccm/138.1.74      PMID:3059868      URL    
[本文引用:1]
[17] CAPITANO B,POTOSKI B A,HUSAIN S,et al.Intrapulmonary penetration of voriconazole in patients receiving an oral prophylactic regimen[J].Antimicrob Agents Chemother,2006,50(5):1878-1880.
Abstract Voriconazole penetrated well into the pulmonary epithelial lining fluid (ELF) in lung transplant patients receiving oral prophylaxis. The ELF concentrations exceeded those of the plasma, with an average ELF-to-plasma ratio of 11 (+/-8). A strong association between plasma and ELF concentrations (r(2) = 0.95) was noted.
DOI:10.1128/AAC.50.5.1878-1880.2006      PMID:1472209      URL    
[本文引用:1]
[18] HENG S C,SNELL G I,LEVVEY B,et al.Relationship between trough plasma and epithelial lining fluid concentrations of voriconazole in lung transplant recipients[J].Antimicrob Agents Chemother,2013,57(9):4581-4583.
Abstract Trough (predose) voriconazole concentrations in plasma and pulmonary epithelial lining fluid (ELF) of lung transplant recipients receiving oral voriconazole preemptive treatment were determined. The mean (± standard deviation [SD]) ELF/plasma ratio was 12.5 ± 6.3. A strong positive linear relationship was noted between trough plasma and ELF voriconazole concentrations (r(2) = 0.87), suggesting the feasibility of using trough plasma voriconazole concentration as a surrogate to estimate the corresponding concentration in ELF of lung transplant recipients.
DOI:10.1128/AAC.00942-13      PMID:3754345      URL    
[本文引用:1]
[19] HENG S C,NATION R L,LEVVEY B,et al.Quantification of voriconazole in human bronchoalveolar lavage fluid using high-performance liquid chromatography with fluorescence detection[J].J Chromatogr B Analyt Technol Biomed Life Sci,2013,913-914:171-175.
The quantification of voriconazole concentration in lung epithelial lining fluid to facilitate the management of pulmonary fungal colonisation or aspergillosis is of increasing interest. An accurate and reproducible high-performance liquid chromatography method to quantify voriconazole in human bronchoalveolar lavage (BAL) fluid was developed and validated. BAL samples were concentrated by freeze-drying and reconstituted with water prior to deproteinisation. Separation was achieved with a C18 column employing fluorescence detection (excitation: 260nm, emission: 370nm). The calibration curves were linear from 2.5 to 500ng/mL. The intra- and inter-day precisions were within 7%. Accuracies ranged from 102% to 107%. The clinical applicability was established by successful measurement of voriconazole concentrations in lung transplant recipients. The assay provides an alternative approach for those with negligible access to liquid chromatography andem mass spectrometry instrumentation.
DOI:10.1016/j.jchromb.2012.11.030      PMID:23314356      URL    
[本文引用:1]
[20] PFALLER M A,MESSER S A,HOLLIS R J,et al.Antifungal activities of posaconazole,ravuconazole,and voriconazole compared to those of itraconazole and amphotericin B against 239 clinical isolates of Aspergillus spp.and other filamentous fungi: report from SENTRY Antimicrobial Surveillance Program,2000[J].Antimicrob Agents Chemother,2002,46(4):1032-1037.
Posaconazole, ravuconazole, and voriconazole are new triazole derivatives that possess potent, broad-spectrum antifungal activity. We evaluated the in vitro activity of these investigational triazoles compared with that of itraconazole and amphotericin B against 239 clinical isolates of filamentous fungi from the SENTRY Program, including Aspergillus spp. (198 isolates), Fusarium spp. (7 isolates), Penicillium spp. (19 isolates), Rhizopus spp. (4 isolates), Mucor spp. (2 isolates), and miscellaneous species (9 isolates). The isolates were obtained from 16 different medical centers in the United States and Canada between January and December 2000. In vitro susceptibility testing was performed using the microdilution broth method outlined in the National Committee for Clinical Laboratory Standards M38-P document. Overall, posaconazole was the most active compound, inhibiting 94% of isolates at a MIC of 8 microg/ml) or Mucor spp. (MIC(50), >8 microg/ml). Posaconazole and ravuconazole were more active than voriconazole against Rhizopus spp. (MIC(50), 1 to 2 microg/ml versus >8 microg/ml, respectively). Based on these results, all three new triazoles exhibited promising activity against Aspergillus spp. and other less commonly encountered isolates of filamentous fungi. The clinical value of these in vitro data remains to be seen, and in vitro-in vivo correlation is needed for both new and established antifungal agents. Surveillance efforts should be expanded in order to monitor the spectrum of filamentous fungal pathogens and their in vitro susceptibility as these new antifungal agents are introduced into clinical use.
DOI:10.1002/stem.146      PMID:11897586      URL    
[本文引用:0]
[21] SEYEDMOUSAVI S,BRUGGEMANN R J,MELCHERS W J,et al.Intrapulmonary posaconazole penetration at the infection site in an immunosuppressed murine model of invasive pulmonary aspergillosis receiving oral prophylactic regimens[J].Antimicrob Agents Chemother,2014,58(5):2964-2967.
Adequate penetration to the infection/colonization site is crucial to attain optimal efficacy of posaconazole against Aspergillus fumigatus diseases. We evaluated posaconazole exposure in pulmonary epithelial lining fluid (ELF) in a murine model of invasive pulmonary aspergillosis. The posaconazole exposure (area under the plasma concentration-time curve from time zero to 24 h postinfusion [AUC0-24]) in ELF was 20% to 31% of that in plasma for total drug after the third dose, and the relationship between plasma and ELF exposure was linear (r(2) = 0.97, P = 0.016).
DOI:10.1128/AAC.00053-14      PMID:24566183      URL    
[本文引用:1]
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关键词(key words)
抗真菌药物
三唑类
真菌感染
肺部
肺泡上皮衬液
肺组织浓度

Antifungal drugs
triazole
Fungal infections
pulmonary
Epithelial lining fluid
Lung tissue concentration

作者
阎鸿焰
黄银
陈诚
秦博
张灵
杨勇

YAN Hongyan
HUANG Yin
CHEN Cheng
QIN Bo
ZHANG Ling
YANG Yong