中国科技论文统计源期刊 中文核心期刊
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
脑卒中具有高发病率、高致残性和高致死性的特点,常见并发症包括肺部感染及尿路感染,可加重患者病情,同时也是患者死亡的主要原因。该类患者的治疗尤为复杂。笔者参与1例脑卒中合并肺部及尿路感染患者会诊,多次调整抗菌药物方案后患者好转,可为临床医师提供用药参考。
患者,男,79岁,58 kg。主诉“行走不稳伴进食呛咳3个月余”,2016年9月4日入院。患者3个月前无明显诱因出现行走不稳,双下肢无力,于2016年5月25日进食发生误吸,并出现呼吸困难、氧饱和度下降至75%,转入呼吸内科治疗。现患者持续右侧肢体无力、间断发热、痰多、尿路感染、低蛋白血症,转入神经内科继续治疗。体检:体温37 ℃,脉搏87次·min-1,呼吸20次·min-1,血压156/70 mmHg(1 mmHg=0.133 kPa);腹部膨隆。入院诊断:①脑卒中后遗症;②肺部感染;③2型糖尿病。
患者以脑卒中后遗症入神经内科,患者既往有心房颤动病史,长期口服华法林抗凝治疗,入院后同时给予降糖、抗感染及对症支持治疗。患者间断发热,最高体温39 ℃,血常规+C-反应蛋白(RP):白细胞11.13×109·L-1、中性粒细胞总数8.00×109·L-1、CRP 128.2 mg·L-1;尿液常规:白细胞中性粒细胞酯酶+++、葡萄糖+-、酵母菌6 393个·μL-1、镜检白细胞定量428.00个·μL-1;肝肾功能均正常,于2016年9月5日痰培养:粘质沙雷菌及铜绿假单胞菌,尿培养:奇异变形杆菌;胸部CT提示:双肺下叶少许不张并炎症,双肺下叶支气管轻度扩张,双侧胸腔少量积液,胸膜轻度增厚。听诊双肺可闻及散在哮鸣音及湿啰音。结合患者病史、临床表现及各项检查指标,肺部感染及尿路感染明确。于2016年9月7日初始抗感染治疗方案给予莫西沙星片400 mg,qd,抗感染治疗及使用氟康唑胶囊400 mg,qd,抗真菌治疗,同时该患者因心房颤动给予华法林片2.5 mg,qd抗凝治疗。患者入院后测血糖15.19 mmol·L-1,糖化血红蛋白7.3%,给予门冬胰岛素注射液10 U,tid(进餐时)+甘精胰岛素针18 U,qd(睡前)皮下注射降糖治疗。
患者持续使用莫西沙星片及氟康唑胶囊11 d后仍间断发热,最高体温38.1 ℃,请临床药师会诊,药师会诊意见:建议选用两性霉素B脂质体(起始剂量为0.1 mg·kg-1·d-1,第2天增加0.25~0.50 mg·kg-1·d-1,剂量逐日递增至维持剂量:1~3 mg·kg-1·d-1)抗真菌治疗;患者已使用莫西沙星片14 d,目前患者少量白色黏痰,血常规及降钙素原均正常,胸部X线片提示肺部感染好转,建议停用莫西沙星片;患者大便隐血阳性,国际标准化比值(INR)6.23,凝血酶原时间72.3 s,建议停用华法林,补充维生素K1;血糖波动于13.9~19.0 mmol·L-1,糖尿病作为脑血管病特别是缺血性卒中/短暂性脑缺血发作的危险因素已经得到公认。越来越多的证据表明,高血糖可以增加卒中发生率,是卒中的独立危险因素[1]。建议调整胰岛素剂量为门冬胰岛素注射液12 U,tid(餐时)+甘精胰岛素针20 U,qd(睡前),控制患者血糖水平。
2016年9月23日患者使用两性霉素B脂质体抗真菌治疗5 d,患者发热好转,但仍有低热,病情相对平稳,使用两性霉素B脂质体期间患者肾功正常。查GM试验(曲霉菌抗原检测)阳性(I值:3.53),请临床药师会诊。药师会诊意见:建议复查GM试验,目前抗真菌治疗有效,继续使用两性霉素B脂质体。患者血糖监测提示以空腹血糖、早餐后及晚餐后血糖增高为主,2016年9月22日晚餐后20:00血糖23.1 mmol·L-1、23日6:00空腹血糖18.5 mmol·L-1、8:30餐后血糖21.7 mmol·L-1,调整胰岛素剂量为门冬胰岛素注射液14 U,tid(进餐时)+甘精胰岛素针24 U·d-1(睡前)。
患者于2016年9月28日复查GM试验阴性(I值:0.36)。患者未见发热,使用两性霉素B脂质体期间肾功能正常,生命体征相对平稳,氧分压及二氧化碳分压在正常范围内波动,复查尿常规正常,尿培养为阴性,已使用两性霉素B脂质体10 d,建议停药。2016年10月4日复查INR为1.67,增加华法林剂量为5 mg。2016年10月11日复查INR为2.51,患者目前INR值控制良好。患者血糖波动于10.2~15.2 mmol·L-1,血糖控制良好,生命体征平稳,出院。出院诊断为:①脑卒中后遗症;②肺部感染,Ⅰ型呼吸衰竭;③尿路感染;④冠状动脉性心脏病;⑤2型糖尿病;⑥前列腺增生。
该患者为79岁的老年男性,基础疾病较多,既往有心房颤动病史,长期口服华法林抗凝治疗,此次入院后给予降糖、抗感染及对症支持治疗。对于该例患者,临床药师首先要了解其诊断,确认患者有无抗菌药物使用指征;其次是评价其抗感染方案的合理性;然后还应结合患者自身临床症状、辅助检查等来辨别痰培养结果所提示的细菌为致病菌还是定植菌;另外,患者长期口服华法林,该药主要在肝脏中由肝微粒体酶代谢,因此在用药期间要注意与其他药物的相互作用。以下分别进行分析和阐述。
患者为老年男性,因脑卒中后遗症入住神经科重症监护室,患者间断发热,最高体温39 ℃,胸部CT提示双肺下叶少许不张并炎症;血常规示白细胞轻度升高;GM试验阳性;尿常规:白细胞中性粒细胞酯酶+++、葡萄糖+-、酵母菌6 393个·μL-1;于2016年9月5日尿培养:奇异变形杆菌;尿涂片:查见中量酵母样真菌孢子;痰培养:粘质沙雷菌及铜绿假单胞菌;血培养阴性;患者肺部感染及尿路感染诊断明确,上诉细菌均非多重耐药菌,患者拒绝静脉给药,经验性选用莫西沙星片及氟康唑胶囊抗感染治疗。
在选用抗菌药物时,应根据不同药物的药动学特点并结合患者感染部位选择抗菌药物。对于下尿路感染,应选择尿中药物能达到有效浓度的抗菌药物,否则即使体外药敏试验显示为敏感,但尿中药物浓度不足,也不能有效清除尿中病原菌[2]。莫西沙星在肺(上皮液、肺泡巨噬细胞、支气管组织),窦(筛窦、上颌窦、鼻息肉)可达到较高浓度,其药物浓度超过血药浓度,另外在腹腔组织和女性生殖道中有较高浓度,而该药在尿路中浓度极低。且该药是经过第二阶段的生物转化后经过肾脏和胆汁/粪便以原形及硫化物和葡萄糖醛酸苷的形式排出,其代谢产物均无微生物学活性。该患者有肺部感染,莫西沙星在肺组织中浓度高。该患者痰培养出粘质沙雷菌及铜绿假单胞菌的药敏结果对左氧氟沙星敏感,但莫西沙星对铜绿假单胞菌效果较差。该患者同时患有尿路感染,尿培养出奇异变形杆菌,而莫西沙星在尿路中浓度极低,莫西沙星说明书中的适应证并没有尿路感染,综合考虑,建议可换用左氧氟沙星、青霉素类或头孢类抗菌药物。
该患者间断发热,GM试验阳性;尿常规:白细胞中性粒细胞酯酶+++、酵母菌6 393个·μL-1;尿涂片:查见中量酵母样真菌孢子。考虑尿路真菌感染,经验性选用氟康唑胶囊合理。
患者持续使用莫西沙星片及氟康唑胶囊11 d后患者仍间断发热,最高38.1 ℃,有少量白色黏痰,仍有尿频、尿急、尿痛症状,复查血常规及降钙素原正常,复查尿常规:白细胞中性粒细胞酯酶+++、酵母菌4 139个·μL-1,送检尿液真菌培养出光滑念珠菌106CFU·mL-1,莫西沙星治疗肺部感染效果良好,但氟康唑抗真菌治疗疗效相对较差。患者于2016年9月18日查血常规正常;患者两次均痰培养出粘质沙雷菌及铜绿假单胞菌,均对喹酮类抗菌药物敏感,患者已使用莫西沙星11 d,且患者目前血常规及CRP均正常,考虑该菌为定植菌可能性大,药师建议停用莫西沙星片合理。
患者有发热、尿急、尿痛症状,有症状念珠菌尿均需要接受治疗[3],尿液真菌培养出光滑念珠菌,氟康唑仅对非光滑、非克柔念珠菌感染效果好,对克柔念珠菌耐药,对光滑念珠菌可能耐药,因此对于光滑念珠菌,最好的选择是棘白菌素类或大剂量多烯类药物[4]。此次培养的光滑念珠菌对氟康唑为中介,对5-氟胞嘧啶、两性霉素B和伏立康唑敏感,患者已使用氟康唑400 mg,qd,抗真菌治疗11 d,尿培养仍然检出大量光滑念珠菌,且尿路症状未有改善,仍有发热,尿标本分离的真菌即使体外药敏试验显示对伏立康唑为敏感,但伏立康唑主要经肝代谢,仅小于2%的药物以原型经尿排出,尿中药物浓度不足,也不能有效清除尿中病原菌。多数光滑念珠菌和克柔念珠菌对氟康唑敏感性低,推荐两性霉素B治疗[5],因我院无两性霉素B,药师建议选用两性霉素B脂质体200 mg,qd,抗真菌治疗合理。
该患者为脑卒中后遗症,同时因既往心房颤动病史长期口服华法林抗凝治疗。华法林是一种合成的香豆素类口服抗凝药物,主要用于预防和治疗血栓相关性疾病,其结构与维生素K相似,作用机制是在体内竞争性抑制维生素K依赖性凝血因子的合成而发挥抗凝血的作用。
华法林和氟康唑联用后INR持续升高,第11天INR上升至6.23,停用华法林同时给予维生素K 1后,INR逐渐下降,停用第3天降至1.52。第5天起再次应用华法林2.5 mg,qd,同时患者因抗感染治疗效果差更改治疗方案,换用两性霉素B脂质体抗真菌治疗,再次使用华法林2.5 mg,qd,4 d后INR为1.76。因此,考虑患者INR升高系华法林与氟康唑联用所致。
华法林是一种外消旋体的混合物,由S型和R型华法林组成。其中约85%的S型华法林通过CYP2C9代谢[10]。R型华法林主要通过CYP1A2和CYP3A4代谢[11]。华法林在体内的代谢主要是通过肝脏细胞色素P450(CYP450)酶系,因此,能够抑制CYP450 酶系活性的药物均可使华法林的代谢减慢,半衰期延长,抗凝作用增强。氟康唑为CYP2C9的强效抑制药和CYP3A4的中效抑制药,可减慢华法林的代谢,增强其抗凝作用[12]。临床同时联用华法林与氟康唑时需及时调整华法林剂量,以避免发生出血风险。
脑卒中患者因长期卧床,入院后易发生肺部及尿路感染,同时该患者长期口服华法林抗凝治疗,华法林是一种双香豆素类的口服抗凝药,治疗窗窄,个体差异大,易受食物、药物及患者疾病状态的影响,若服用不当,易发生出血事件[13]。因此,该类患者的治疗尤为复杂,需临床药师积极参与。抗菌药物中部分品种尤其是唑类抗真菌药氟康唑可与华法林发生明显的具有临床意义的药物相互作用,在使用氟康唑时,应当适当减少华法林剂量,以避免引起出血。临床药师参与临床药物治疗,可借助自身药动学方面的优势,帮助临床更加科学地监测及调整药物的剂量,从而更好地保证临床用药的安全性和有效性。
The authors have declared that no competing interests exist.
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Recent data revealed that patients with myocardial infarction(MI) have a high prevalence of previously unknown diabetes mellitus(DM) and impaired glucose tolerance (IGT). The added prognostic importance of this finding has not been prospectively explored. To investigate whether a newly detected abnormal glucose tolerance (IGT or DM) assessed early after an MI, is related to long-term prognosis. Patients (n=168; age 63.5卤9.3 years) with MI, no previous DM and admission blood glucose 11.0 mmol/l were followed for major cardiovascular events defined as the composite of cardiovascular death, non-fatal MI, non-fatal stroke or severe heart failure (HF). According to an oral glucose tolerance test (OGTT) before hospital discharge, 55 patients had normal and 113 abnormal glucose tolerance (GT). During the follow-up of median 34 months there were eight cardiovascular deaths, 15 patients had a recurrent MI, six had a stroke and ten severe HF. All patients who died from cardiovascular causes had abnormal GT. The composite cardiovascular event occurred in 31(18%) patients. The probability of remaining free from cardiovascular events was significantly higher in patients with normal than abnormal GT(P=0.002). Together with previous MI, abnormal GT was the strongest predictor of future cardiovascular events (hazard ratio 4.18; CI 1.26-13.84; p =0.019). Abnormal glucose tolerance is a strong risk factor for future cardiovascular events after myocardial infarction. Since it is common and possible to detect even during the hospital phase it may be a target for novel secondary preventive efforts.
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DOI:10.1086/380796
URL
[本文引用:1]
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The incidence of disseminated candidiasis has increased dramatically over the past several decades. Fortunately, in recent years, a variety of new antifungal agents have become available to treat these infections. On the basis of efficacy, safety, and cost considerations, fluconazole is the agent of choice for the empirical treatment of disseminated candidiasis in nonneutropenic, hemodynamically stable patients, unless a patient is suspected to be infected with an azole-resistant species (i.e., Candida glabrata or Candida krusei). For hemodynamically unstable or neutropenic patients, agents with broader species coverage, such as polyenes, echinocandins, or, possibly, voriconazole, are preferred for empirical treatment of candidemia. Modification of the initial, empirical regimen depends on the response to therapy and the subsequent identification of the species of the offending pathogen. Echinocandins or high-dose polyenes are preferred for the treatment of infections with C. glabrata or C. krusei. Central venous catheters should be removed from all patients who have disseminated candidiasis, if feasible, and antifungal therapy should be administered to all patients who have candidemia or proven candidiasis.
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A variety of fungi produce the hydrolytic enzyme beta-N-acetylhexosaminidase (HexNAcase), which can be readily detected in assays by using p-nitrophenyl-N-acetyl-beta-D-glucosaminide as a substrate. In the present study we developed a microtiter plate-based HexNAcase assay for distinguishing Candida albicans and Candida dubliniensis strains from other yeast species. HexNAcase activity was detected in 89 of 92 (97%) C. albicans strains and 4 of 4 C. dubliniensis strains but not in 28 strains of eight other Candida species, 4 Saccharomyces cerevisiae strains, or 2 Cryptococcus neoformans strains. The HexNAcase activity in C. albicans and C. dubliniensis was strain specific. All except three clinical C. albicans isolates among the C. albicans strains tested produced enzyme activity within 24 h. These strains did produce enzyme activity, however, after a prolonged incubation period. For two of these atypical strains, genomic DNA at the C. albicans HEX1 gene locus, which encodes HexNAcase, showed nucleotide differences from the sequence of control strains. Among the other Candida species tested, only C. dubliniensis had a DNA sequence that hybridized with the HEX1 probe under low-stringency conditions. The microtiter plate-based assay used in the present study for the detection of HexNAcase activity is a simple, relatively inexpensive method useful for the presumptive identification of C. albicans and C. dubliniensis.
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Primary intestinal invasive aspergillosis is rarely reported in leukaemic patients. We describe a case of jejunal invasive aspergillosis in the setting of aplasia following chemotherapy for acute myeloid leukaemia. The diagnosis was confirmed by biopsy obtained during surgery and our polymerase chain reaction (PCR) test confirmed Aspergillus flavus as the fungus responsible. This patient had high levels of circulating galactomannan, an antigen secreted by Aspergillus sp., in serum. The ELISA test for galactomannan has been developed to improve the diagnosis of invasive aspergillosis but presents a 5-15% false positive rate. We suggest that some false positive results might be due to non-respiratory invasive aspergillosis, the usual localization of invasive aspergillosis. Our PCR test was also positive in serum. In case of positive results in serum with antigen and/or PCR tests without respiratory symptoms, the intestinal localizations should be investigated.
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The antifungal agent fluconazole was found to be a potent inhibitor of cytochrome P450 (P450) 2C9 (Ki = 7-8 microM), the principal enzyme responsible for the clearance (85%) of the more potent anticoagulant (S)-warfarin to the inactive (S)-7- and (S)-6-hydroxywarfarin metabolites in vivo. Fluconazole was also found to be a potent inhibitor of the P4503A4-catalyzed formation of (R)-10-hydroxywarfarin (Ki = 15-18 microM) as well as the low KM P450 enzymes responsible for the formation of (R)-6-, (R)-7-, and (R)-8-hydroxywarfarin (Ki = 2-6 microM). By contrast, experiments with the P4501A2 inhibitor furafylline and cDNA-expressed P4501A2 indicate that fluconazole is a weak inhibitor of this enzyme (Ki > 800 microM), as measured by the inability of fluconazole to significantly suppress the P4501A2-dependent 6-hydroxylation of (R)-warfarin. The prediction generated from these studies, that fluconazole is a potent in vivo inhibitor of warfarin metabolism, , is tested in complementary studies reported in the accompanying article, "Warfarin-Fluconazole II".
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| [12] |
The package insert of the antithrombotic agent warfarin warns users of its interaction with azole antifungals. However, information on the frequency or degree of these interactions is limited. In particular, the time to onset of azole-mediated prothrombin time prolongation, expressed as the international normalized ratio (INR), is poorly characterized. Therefore, we retrospectively examined the INR in 29 patients administered warfarin with fluconazole (FLCZ), voriconazole (VRCZ), or itraconazole (ITCZ). INRs in 18 patients taking FLCZ and in 5 patients taking VRCZ significantly increased from 1.40 to 2.94 and from 1.95 to 2.89, respectively. The warfarin sensitivity index (WSI), calculated as INR/daily warfarin dose, also significantly increased from 1.06 to 1.89 with FLCZ and showed an upward trend from 1.13 to 2.23 with VRCZ. ITCZ had no influence on the INR or WSI in 6 patients. The INRs observed when warfarin was coadministered with azoles (Y) correlated significantly with those observed in the absence of azoles (X): FLCZ, Y=4.94X-3.96, r(2)=0.80; VRCZ, Y=2.13X-1.27, r(2)=0.93. Moreover, in all 8 patients with closely monitored INRs, the WSI increased within 1 week of FLCZ or VRCZ coadministration. In conclusion, FLCZ and VRCZ augmented the anticoagulant activity of warfarin. The INR should be closely monitored within 1 week of initiating FLCZ or VRCZ coadministration with warfarin, especially in patients with high INRs.
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| [13] |
Warfarin is an oral anticoagulant that requires international normalized ratio (INR) monitoring to assess its safety and efficacy and to facilitate dosage adjustments. It is metabolized primarily by CYP2C9 and has a narrow therapeutic index. Warfarin is prone to drug interactions, given its pharmacokinetic and pharmacodynamic properties. Changes in concomitant medications can cause INR fluctuations, particularly if medications are cytochrome P450 inhibitors or inducers. The unpredictability of the extent and duration of an interaction's effect make it challenging to manage, as represented in this case report. Providers are encouraged to adopt strategies to identify potential drug interactions and minimize the risks of adverse outcomes.
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