米卡芬净与伏立康唑联合治疗侵袭性真菌感染的临床研究

目的评价米卡芬净静脉注射后口服伏立康唑治疗ICU侵袭性真菌感染(IFI)疗效及安全性。方法将侵袭性真菌感染患者,根据不同抗真菌治疗方法分成两组,A组(16例)采用米卡芬净静注后伏立康唑口服联合疗法;B组(16例),米卡芬净组静脉滴注米卡芬净(100 mg/d),观察两组患者的疗效和不良反应。结果 A组的总有效率为87.5%(14/16),药物相关的不良反应发生率6.3%(1/16);B组的总有效率56.3%(9/16),药物相关的不良反应发生率为25%(4/16)。两组总有效率较高,但有显著性差异(P0.05),A组不良反应率显著低于B组。结论两种方案对侵袭性真菌感染的患者均有效,米卡芬净联合伏立康唑疗法比单独应用米卡芬净更具有疗效优势,且安全性好,不良反应少,有显著性差异(P0.05)。     

Clinical outcomes of lung-transplant recipients treated by voriconazole and caspofungin combination in aspergillosis

Background and objective: Invasive pulmonary aspergillosis (IPA) is a serious cause of death among immune‐compromised patients such as organ‐transplant recipients. Recently, voriconazole has been approved for first‐line therapy in IPA. Theoretically, optimal voriconazole blood level (superior to 1 mg/L according to recent studies) should be reached within 24 h. In practice, a significantly longer time seems to be needed in lung‐transplant recipients. Therefore, caspofungin is now used in combination with voriconazole to provide cover against Aspergillus spp. infection during this gap. The first aim of this study was to investigate Aspergillus spp. infection treated with this combination and the atter’s tolerability. The median time for attainment of apparently active blood levels in lung transplant recipients were compared between those with cystic fibrosis and those without. Methods: Lung‐transplant recipients who received a combination of voriconazole and caspofungin between 2002 and 2008 as primary therapy were identified retrospectively. The median number of days to reach active voriconazole blood levels was compared between cystic fibrosis and other patients by Student’s t‐test. Statistical significance was defined by P‐value <0·05. Results: Four patients were treated for Aspergillus colonization before transplantation and their culture were negative at 90 days. Eleven patients were treated for proven or probable invasive aspergillosis and 14 of them had a complete response. Hallucinations (n = 2) and significant hepatic toxicity (n = 2) were reported. Among the 15 studied transplant recipients, a median of 12·3 days was observed for active voriconazole blood levels to be reached. With cystic fibrosis patients, time tended to be longer than with other recipients (14·9 days vs. 8·3 days). Tacrolimus blood levels (between 5 and 15 ng/mL) may have been increased by voriconazole. Conclusion: This retrospective study describes practical experience in the management of this rare and severe disease in a referral centre for cystic fibrosis lung transplantation. Voriconazole and caspofungin combination was acceptably safe and was associated with good clinical outcomes in almost all patients. We showed that in 15 lung‐transplant recipients a median of 12·3 days was required for voriconazole to reach high enough blood levels. Caspofungin in combination with voriconazole provides cover against Aspergillus infection during the period when voriconazole may be at subtherapeutic levels with good tolerability.     

伏立康唑治疗老年白血病合并侵袭性肺部真菌感染的临床效果

目的 探讨伏立康唑治疗老年白血病合并侵袭性肺部真菌感染的临床效果.方法 选择2014年3月至2018年12月在我院住院治疗的68例老年白血病合并侵袭性肺部真菌感染患者作为研究对象,按照入院顺序将其分为对照组和观察组,各34例.对照组给予两性霉素B治疗,观察组给予伏立康唑治疗.比较两组临床疗效、不良反应发生情况、血清炎症...     

Management of fungal infections following allogeneic stem cell transplantation

Fungal infection remains an important complication in allogeneic stem cell transplantation (allo-SCT). Since the prognosis of fungal infection is poor, prophylaxis is critical for its management; owing to recent progression in allo-SCT management and widespread use of reduced-intensity regimens, the strategy of infectious prophylaxis has also changed. Various antifungals have recently been developed and applied to clinical use. A major change in antifungal management will probably occur in the next few years.     

Pharmacodynamic studies of voriconazole: informing the clinical management of invasive fungal infections

Introduction: Voriconazole is a broad-spectrum antifungal agent commonly used to treat invasive fungal infections (IFI), including aspergillosis, candidiasis, Scedosporium infection, and Fusarium infection. IFI often occur in immunocompromised patients, leading to increased morbidity and mortality.

Areas covered: The objective of this review is to summarize the pharmacodynamic properties of voriconazole and to provide considerations for potential optimal dosing strategies. Studies have demonstrated superior clinical response when an AUC/MIC >25 or C_min/MIC >1 is attained in adult patients, correlating to a trough concentration range as narrow as 2–4.5 mg/L; however, these targets are poorly established in the pediatric population. Topics in this discussion include voriconazole use in multiple age groups, predisposing patient factors for IFI, and considerations for clinicians managing IFI.

Expert commentary: The relationship between voriconazole dosing and exposure is not well defined due to the large inter- and intra-subject variability. Development of comprehensive decision support tools for individualizing dosing, particularly in children who require higher dosing, will help to increase the probability of achieving therapeutic efficacy and decrease sub-therapeutic dosing and adverse events.     

Optimization of voriconazole dosage regimen to improve the efficacy in patients with invasive fungal disease by pharmacokinetic/pharmacodynamic analysis

Invasive fungal disease (IFD) is a significant cause of morbidity and mortality in hospitalized patients. To maximize the efficacy of voriconazole treatment, the study established the relationship between voriconazole pharmacokinetic/pharmacodynamic (PK/PD) and probability of response and optimized voriconazole dosage regimen in patients with IFD based on Monte Carlo simulation. Forty‐four patients proven with IFD were involved in this study. Among them, the overall cure rate was 75% (33/44) and there was a significant difference between C_min/MIC values in patients with lack of response (n = 11) and those with successful response (n = 33) (mean value: 1.91 vs. 11.33; P < 0.05). Logistic regression model showed a high correlation between voriconazole C_min/MIC ratio and clinical response (P = 0.044, OR = 1.349). According to Monte Carlo simulation results under different voriconazole dosing regimens, we could draw a conclusion that 200 mg voriconazole administered intravenously or orally twice daily for Candida infections and 300 mg administered orally or with 200 mg administered intravenously twice daily for Aspergillus infections were rational, which could achieve a value of the cumulative fraction of response >90%. This study built the relationship between voriconazole PK/PD and clinical response and obtained the reasonable empirical dosage regimen, which can be used to customize individual dosage regimen and improve the efficacy of voriconazole treatment.     

Voriconazole for prophylaxis of invasive fungal infections after allogeneic hematopoietic stem cell transplantation

Introduction: Invasive fungal infections (IFIs) following allogeneic hematopoietic stem cell transplantation (alloHSCT) are associated with a high mortality, and accordingly most alloHSCT recipients receive prophylaxis with antifungal agents. Despite some improvement in outcomes of IFIs over time, they continue to represent substantial clinical risk, mortality, and financial burden.

Areas covered: We review the main pathogens responsible for IFIs in recipients of alloHSCT, current treatment recommendations, and discuss clinical and economic considerations associated with voriconazole prophylaxis of IFIs in these patients.

Expert commentary: The clinical efficacy of voriconazole appears to be at least equivalent to other antifungal treatments, and generally well tolerated. Overall, benefit-risk balance is favorable, and findings from cost-effectiveness analyses support the use of voriconazole prophylaxis of IFIs in recipients of alloHSCT.     

Distribution of micafungin in the tissue fluids of patients with invasive fungal infections

The distribution of micafungin (MCFG) in tissue fluids, such as cerebrospinal fluid (CSF), pleural effusions, ascites, and wound tissue fluids, was examined in seven patients with invasive fungal infections. MCFG (100–300 mg) was administered once daily over a 1-h intravenous infusion. Blood and tissue fluid samples were collected from 1 to 24 h after infusion. Although two patients had similar MCFG concentrations in their plasma, the concentrations in the CSF differed between these two patients. The concentration in the CSF of one patient was much higher than the MIC₉₀ for Candida albicans, Candida glabrata, and Aspergillus fumigatus, whereas the MCFG concentration in the CSF of the other patient was comparable to the MIC₉₀. By contrast, MCFG concentrations in pleural effusions, ascites, and wound tissue fluids were above the MIC₉₀ . These results suggest that intravenous MCFG may be effective to treat invasive fungal infections that invade the organs and tissues.     

Antifungal prophylaxis in solid organ transplant recipients

Solid organ transplantation is life saving for thousands of patients worldwide with end-stage organ failure, but post-transplantation invasive fungal infections (IFIs) remain a significant cause of morbidity and mortality. To improve patient outcomes, investigators have explored various strategies of prevention, including the use of antifungal prophylaxis with both systemic and topical nonabsorbable agents. Often, the strategy is to identify those patients at highest risk for IFIs who would be expected to derive the most benefit from antifungal prophylaxis. Currently, data support the use of antifungal prophylaxis in liver, lung, small bowel and pancreas transplant recipients. By understanding the epidemiology of post-transplant IFIs and antifungal adverse effects, clinicians may target antifungal prophylaxis more optimally. Herein, we review antifungal prophylaxis with systemic agents among solid organ transplant recipients.     

无菌部位侵袭性真菌感染的病原学特点及预后不良危险因素分析

目的 探讨患者无菌部位侵袭性真菌感染(IFI)的菌种分布、药物敏感性、临床特征及预后不良危险因素。方法 收集2019年7月至2023年6月于承德医学院附属医院从血液、胸腔、腹腔等无菌部位培养物分离出的真菌菌株,通过基质辅助激光解吸电离飞行时间质谱(MALDI-TOF MS)等方法进行鉴定。酵母菌采用ATB Fungus 3酵母样真菌药敏试剂盒检测抗真菌药物敏感性。利用东华医院信息管理系统收集患者的临床和实验室资料,并进行统计分析。结果 175株真菌菌株主要由酵母菌(169/175,96.57%)和丝状真菌(6/175,3.43%)构成,白念珠菌是IFI最常见致病菌(91/175,52.00%)。单因素分析显示,入住ICU、中心静脉置管、机械通气、连续性肾脏替代治疗(CRRT)、感染性休克及感染热带念珠菌是患者预后的影响因素(P<0.05)。多因素Logistic回归分析发现机械通气与感染热带念珠菌是患者预后不良的独立危险因素。降钙素原(PCT)是IFI患者预后不良的可靠预测指标。药敏结果显示多数光滑念珠菌和热带念珠菌的耐药株出现唑类交叉耐药的现象。结论 临床需重视非白念珠菌,尤其...     

米卡芬净单药及联合两性霉素B对小鼠侵袭性肺曲霉病的治疗作用

目的评价米卡芬净单药及联合两性霉素B对小鼠侵袭性肺曲霉病(IPA)的治疗作用。方法采用环磷酰胺骨髓抑制、烟曲霉孢子滴鼻接种构建中性粒细胞减少小鼠IPA模型。实验动物随机分为为4组:模型对照组(NS+5%GS,A组)、米卡芬净治疗组[5 mg/(kg.d),B组]、两性霉素B治疗组[1 mg/(kg.d),C组]和米卡芬净[5 mg/(kg.d)]加两性霉素B[1mg/(kg.d)]治疗组(D组),治疗从接种第2天开始,每天1次,共7 d。①动物生存期观察:每组15~16只小鼠,接种后每天观察1次至第21天。共进行2批次实验,分别给予2×105和6×106个孢子/小鼠。②肺的真菌负荷:每组9只小鼠,给予1.5×104个孢子/小鼠。治疗结束后取肺,匀浆后梯度稀释培养,记取菌落数并计算肺的真菌负荷量。结果①生存分析:第1批次,米卡芬净、两性霉素B单药及联合用药治疗均能延长小鼠生存期,但3种治疗方案在延长生存期方面差异无显著性(B组、C组分别与A组比较均有P<0.05,D组与A组比较P<0.01)。第2批次,联合用药组生存期长于其它各组,米卡芬净及两性霉素B单药治疗组与模型组比较差异无显著性(D组与A组比较P<0.01;D组分别与B组及C组比较均有P<0.05)。②肺的真菌负荷:两性霉素B单药及联合用药均能降低肺的真菌负荷,米卡芬净单药不降低肺的真菌负荷(C组与A组比较P<0.01;D组与A组比较P<0.05;B组与C组比较P<0.05;B组与D组比较P<0.01)。结论单独应用米卡芬净或两性霉素B及联合用药均能够延长中性粒细胞减少IPA小鼠生存期,当孢子接种量为6×106/小鼠时,联合用药优于单独应用米卡芬净或两性霉素B。单独应用米卡芬净不降低肺的真菌负荷,联合用药或两性霉素B单药在降低肺的真菌负荷方面均优于对照组及米卡芬净组。     

Fungal infections of the skin and nail: new treatment options

Knowledge of the currently available antifungal agents, along with clinical, microbiologic and histopathologic methods, can help the medical professional optimally manage skin and nail fungal infections. With regards to treatment of fungal disease of the skin or nail, there are a variety of systemic antifungal agents, including several newer agents that have different formulations, tolerability, adverse effect profiles and spectrum of activity. This review will highlight the clinically important fungal infections of the skin and nail and describe the activity and role of antifungal treatment.     

Micafungin for the prophylaxis and treatment of Candida infections

Invasive fungal infection is a significant cause of morbidity and mortality worldwide. The incidence of these infections is steadily increasing. In addition, strains resistant to many commonly used antifungal agents are becoming more prevalent. Many new antifungals have become commercially available in recent years, which have vastly improved the ability to treat these infections effectively. Micafungin is one of three commercially available echinocandins available for use in the USA. This class of agents possess a unique mechanism of action that helps to reduce toxicity while maintaining potent antifungal activity. Micafungin is currently approved for the treatment of esophageal candidiasis in adults and is the only in its class approved for the prophylaxis of Candida infection in patients who have undergone hematopoietic stem cell transplantation. It was also recently approved in the USA for the treatment of candidemia and other forms of invasive candiaisis (acute disseminated candiaisis, Candida peritonitis and abscess). In general, micafungin is well tolerated and has favorable safety and drug-interaction profiles.     

血清1,3-β-D-葡聚糖检测用于造血干细胞移植后患者侵袭性真菌感染诊断的界值初探

目的 评价血清1,3-β-D-葡聚糖(BG)浓度检测对我国造血干细胞移植(HSCT)后患者侵袭性真菌感染(IFI)早期诊断的意义并确定其界值.方法 按我国IFI的诊断标准,采用Glucatell试剂盒对HSCT后拟诊IFI的36例患者m清标本(每周采血2次)进行BG浓度的检测(G实验).根据临床回顾性诊断标准定义阳性和阴性病例,按不同G试验阳性标准计算其灵敏度、特异度,最终确定G试验在我国HSCT后患者IFI诊断的界值.结果 按试验中所得的单次结果≥80 ng/L或连续两次结果≥60ng/L作为界值,得出G试验的灵敏度、特异度、阳性和阴性预测值结果分别为81.0%、81.8%、89.5%和69.2%(P=0.002),并以此作为G试验在我国HSCT后IFI诊断的界值.结论 G试验在我国HSCT患者IFI诊断的界值与国外基本相同,是一种早期诊断IFI的快速、灵敏的检测.方法 ,值得临床推广.     

米卡芬净在儿童恶性血液病患者合并肺部真菌感染中的临床应用

目的 探讨米卡芬净治疗儿童恶性血液病并侵袭性肺部真菌感染的疗效及安全性.方法 选取柘城县人民医院血液/肿瘤病区治疗恶性血液病合并肺部真菌感染患儿51例,随机分为两组,分别给予米卡芬净与伏立康唑治疗,比较两组的治疗有效率、痊愈率和不良反应发生率.结果 两组患儿在有效率和痊愈率方面比较差异无统计学意义（P〉0.05）,但在不良反应发生率方面,米卡芬净组患儿低于伏立康唑组患儿,差异有统计学意义（P〈0.05）.结论 米卡芬净与伏立康唑对儿童恶性血液病侵袭性肺部真菌感染均具有良好的疗效,但米卡芬净具有更好的安全性.     

恶性血液病合并侵袭性真菌感染63例临床分析

本研究的目的是了解恶性血液病患者罹患侵袭性真菌感染的临床现状,探讨易感因素和防治措施。收集本院血液内科2008年1月至2011年12月541例恶性血液病患者的临床资料,进行回顾性统计分析。结果表明,541例患者中合并侵袭性真菌感染患者63例,感染部位以呼吸道为主(62.34%),其次为肠道(19.48%);致病菌株以白色念珠菌(66.67%)、光滑念珠菌(12.82%)为主。结论:本院恶性血液病并发侵袭性真菌感染的危险因素主要包括原发病、化疗、糖皮质激素、化疗后粒细胞缺乏、使用广谱抗生素及老龄化等。应根据危险因素进行危险度分级来指导侵袭性真菌感染的防治。     

肝移植ICU下呼吸道侵袭性真菌感染的特点及护理探索

目的 探讨肝移植ICU病房患者下呼吸道侵袭性真菌的感染特点,及相关护理干预措施对控制侵袭性真菌感染的作用。方法 总结和分析肝移植重症监护病房2010年1月-2012年8月我院27例下呼吸道侵袭性真菌感染者的临床资料和护理记录,总结相应的护理干预措施。结果 27例共分离出36株菌株,其中酵母菌占92 %(33/ 36 株) ,以白色念珠菌为主(25株),其余为热带酵母菌(2株)、近平滑酵母菌(1株)及耐氟康唑酵母菌光滑酵母菌(4株)、克柔酵母菌(1株)。非酵母菌有黄曲霉菌(2 株) 、烟曲霉菌(1 株) 。通过临床资料分析显示,侵袭性真菌感染的肝移植受体术后死亡率高,肝癌合并肝硬化患者,术前应用广谱抗生素(碳青霉烯类为主)、术中失血量大(≥3000ml)、呼吸机支持时间长(≥72h)、ICU滞留时间长、中心静脉置管时间长、术后长期使用免疫抑制剂等都是造成感染死亡率高的危险因素。结论 下呼吸道侵袭性真菌感染是肝移植ICU常见的并发症,给病人的预后带来极大危害。因此在使用敏感抗菌药物治疗的同时,必须对患者采取相应护理措施,加强医院感染管理力度,做好隔离措施,以促进患者恢复,避免引发交叉感染,保护其他易感患者。     

国产两性霉素B治疗侵袭性真菌感染121例临床分析

目的 观察静脉用国产两性霉素B对血液病患者侵袭性真菌感染(IFI)的临床疗效及其安全性.方法 选择121例血液病患者静脉使用两性霉素B,剂量为5～50 mg/d,用药时间5～101d,中位数为19 d,并对用药前后患者肝、肾功能及电解质进行监测.结果 静脉使用两性霉素B临床总有效率为67.3%,真菌清除率为66.7%.不良反应包括寒战、高热、低钾血症、肝肾功能损害、胃肠道反应、静脉炎和皮疹.结论 只要合理应用,对其不良反应进行积极防治,两性霉素B仍是较为安全有效的一线抗真菌药物.     

Current status of diagnosis and treatment of invasive fungal infections in Japan: the influence of the new Japanese guidelines

One year after the release of the Japanese “Guidelines for the Diagnosis and Treatment of Deep-Seated Mycosis” we conducted a survey of clinicians to determine the extent to which the new guidelines had penetrated clinical practice, and compared these results with those of a previous survey. The responses to the current survey regarding the diagnosis and treatment had changed from those of the previous survey to reflect the new recommendations, showing that the guidelines have had an effect on clinical practice. However, the current survey highlights a need to provide more practical information in the guidelines for use in the clinical settings. In particular, physicians expect the guidelines to proactively provide more information about the features of both current and new drugs. In addition, an effective drug against the genus Aspergillus is eagerly awaited. However, because it is difficult to differentiate among filamentous fungi, there is a need for a drug with broad-spectrum coverage against filamentous fungi. Investigation of combination therapy consequently becomes necessary. Definitive diagnoses of invasive fungal infection are too scarce at the national level. The cooperation of clinicians for organizing more definitive diagnoses would be appreciated when the guidelines are revised.