High- versus low-dose fluconazole therapy for empiric treatment of suspected invasive candidiasis among high-risk patients in the intensive care unit: a cost-effectiveness analysis

ABSTRACT

Background: High-dose fluconazole is an alternative for patients with candidemia caused by Candida glabrata or other Candida species with decreased fluconazole susceptibility. However, empiric high-dose fluconazole is not currently recommended and may result in higher drug costs and toxicity.

Objective: To determine the cost-effectiveness of using empiric high-dose fluconazole in intensive care unit (ICU) with suspected invasive candidiasis.

Design: Decision analytic model. Target population: ICU patients with suspected invasive candidiasis. Time horizon: Lifetime. Perspective: Societal.

Interventions: Low-dose fluconazole (loading dose of 800?mg followed by 400?mg daily) vs. high-dose fluconazole (loading dose of 1600?mg followed by 800?mg daily). Generic fluconazole costs were used for the analysis. Outcome measures: Incremental life expectancy and incremental cost per discounted life year (DLY) saved.

Result of base-case analysis: Based on current national levels of fluconazole resistance and ability to correctly identify patients with candidemia, high-dose fluconazole was the more effective but more expensive treatment strategy. Empiric high-dose fluconazole therapy decreased the mortality rate by 0.15% compared to low-dose strategy with a cost-effectiveness rate of $55 526 per DLY saved.

Results of sensitivity analysis: Empirical high-dose fluconazole was an acceptable treatment strategy (using $100?000 per DLY saved as threshold) unless the physical age of an ICU survivor was 66 years or older. Empirical high-dose fluconazole was an acceptable treatment strategy using $50?000 per DLY saved with minor changes in parameters estimates.

Limitations: The estimates of our model may not be applicable to all ICU patients. Other hospitals with differences in fluconazole resistance, prevalence of invasive candidiasis, or duration of fluconazole therapy may produce different results.

Conclusion: These results suggest that empiric high-dose fluconazole therapy should reduce the mortality associated with invasive candidiasis at an acceptable cost.     

大剂量达克宁联合氟康唑片短期治疗念珠菌性阴道炎临床观察

目的：探讨氟康唑与大剂量达克宁栓剂联合短期治疗念珠菌性阴道炎的疗效。方法：将90例念珠菌性阴道炎患者随机分为3组．氟康唑组、大剂量达克宁组和联合治疗组。治疗3天后观察疗效,并作阴道分泌物检查。结果：氟康唑组有效率为76．6％,大剂量达克宁组有效率为80．0％,两组间差异无显著性;联合治疗组有效率为93.3％,与前两组比较差异有显著性。3组均未出现严重不良反应。结论：氟康唑与大剂量达克宁栓剂联合使用可有效治疗念珠菌性阴道炎,疗效高,治疗时间短,患者依从性好。     

氟康唑联合制霉素阴道栓治疗外阴阴道假丝酵母菌病临床观察

目的：观察氟康唑联合制霉素阴道栓治疗外阴阴道假丝酵母菌病的临床疗效。方法：将200例外阴阴道假丝酵母菌病患者随机分为两组,观察组112例,采用氟康唑＋制霉素阴道栓治疗,对照组88例,单用制霉素阴道栓治疗。结果：观察组短期疗效与对照组基本相同（P〉0.05）,但复发率却远远低于对照组（P〈0.01）。结论：氟康唑联合制霉素阴道栓治疗外阴阴道假丝酵母菌病方法简单,价格低廉,疗效好,易被患者接受。     

氟康唑与伏立康唑治疗念珠菌肺炎的疗效比较

目的 比较伏立康唑与氟康唑治疗肺部念珠菌感染的疗效与安全性.方法 79例肺念珠菌感染患者按照住院号顺序分为伏立康唑组与氟康唑组,观察患者症状和体征变化,评价感染治愈率及治疗安全性.结果 伏立康唑组总体有效率为93.1％,明显高于氟康唑组的65.9％(x2=7.51,P＜0.01),痊愈率分别为65.1％和36.1％,差异均有统计学意义(x2 =6.60,P＜0.05).伏立康唑组不良反应发生率为14.0％,氟康唑组不良反应发生率为16.7％,两组差异无统计学意义(P＞0.05).结论 伏立康唑治疗肺部念珠菌感染效果优于氟康唑,两者安全性均较高.     

氟康唑预防早产儿侵袭性念珠菌病的研究进展

随着我国计划生育政策的变化,新生儿早产率持续上升,因早产儿免疫功能低下,侵袭性念珠菌病（IC）是导致早产儿致残、致死的重要原因。近年来临床尝试小剂量使用氟康唑预防早产儿IC,但在给药方案及安全性方面存在争议。本文就念珠菌的耐药现状,氟康唑的抗菌活性、PK/PD特点及预防IC的有效性、安全性研究进行综述,为临床用药提供参考。     

制霉菌素与凯妮汀治疗妊娠期念珠菌性阴道炎效果的对比分析

目的对比制霉菌素与凯妮汀治疗妊娠期念珠菌性阴道炎疗效,评价药物效果。方法通过对我院门诊2004年3月至2008年10月妊娠期念珠菌性道炎的277例患者进行分组治疗,A组患者行制霉菌素治疗,B组行凯妮汀治疗,观察症状改善情况及体征和镜下复查结果,记录并对比分析病情变化和结果。结果凯妮汀治愈84例,占60.87%,制霉菌素治愈70例,占50.36%,统计分析示χ2=10.380,P〈0.05,差异具有统计学意义。结论凯妮汀治疗妊娠期念珠菌性阴道炎效果优于制霉菌素组,其用药简单,对胎儿影响小,是临床可以选择的治疗药物。     

氟康唑治疗复发性外阴阴道念珠菌病的疗效及安全性评价

目的 探讨氟康唑用于治疗复发性外阴阴道念珠菌病的临床疗效及安全性.方法 选取2012年8月-2013年8月我院就诊的复发性外阴阴道念珠菌病患者150例,随机分为观察组和对照组.对照组给予克霉唑阴道片治疗,观察组给予克霉唑阴道片联合氟康唑治疗.结果 治疗1个月后,观察组总有效率（90.67%）高于对照组总有效率（78.67%）,差异有统计学意义（P＜0.05）.治疗2个月后,观察组总有效率（93.33%）高于对照组总有效率（81.33%）,差异有统计学意义（P＜0.05）.两组患者均未出现明显药物不良反应病例.结论 氟康唑用于治疗复发性外阴阴道念珠菌病疗效可靠,具有良好的安全性.     

氟康唑联合达克宁栓治疗复发性念珠菌性阴道炎的临床疗效

目的:探讨氟康唑联合达克宁栓治疗复发性念珠菌性阴道炎的临床效果。方法:回顾性分析我院收治的120例复发性念珠菌性阴道炎患者的临床资料,根据治疗方法将患者分成治疗组和对照组各60例,对照组患者单用达克宁栓治疗,治疗组在对照组的基础上加用氟康唑治疗,比较两组患者的临床有效率和治疗前后的临床体征情况。结果:治疗两周后,治疗组的总有效率高达93.33%,对照组患者的总有效率为73.33%,两组患者比较具有显著性差异,P<0.05,治疗组显效率51.67%,显著高于对照组38.33%,P<0.05;治疗前两组患者白带增多、黏膜充血、疼痛、涂片结果阳性等临床体征均无显著性差异,P>0.05,治疗后治疗组的临床体征例数均显著低于对照组,P<0.05。结论:采用氟康唑联合达克宁栓治疗复发性念珠菌性阴道炎能显著改善患者的临床体征,临床效果明显,为复发性念珠菌性阴道炎的治疗用药提供了指导。     

保妇康栓联合氟康唑治疗复发性外阴阴道假丝酵母菌病临床观察

目的:探讨保妇康栓联合氟康唑治疗复发性外阴阴道假丝酵母菌病(VCC)的疗效.方法:将60例复发性外阴阴道假丝酵母菌病患者随机分为两组.观察组30例,阴道放置保妇康栓,同时口服氟康唑;对照组30例,单纯保妇康栓阴道放置.结果:观察组3个月治疗结束后治愈率为90.00%,对照组为66.67%,两组比较差异有显著性(χ2=4.81,P<0.05);治疗后3个月总复发率观察组3.70%,对照组25.00%,两组比较差异有显著性(χ2=4.68,P<0.05).结论:保妇康栓联合氟康唑治疗复发性外阴阴道VCC较单纯应用保妇康栓局部治疗疗效确切,并能降低其复发率,值得临床推广.     

Successful treatment of chronic disseminated candidiasis with high-dose fluconazole in a child with acute myelo-monocytic leukemia

A 6-year-old boy with acute myelo-monocytic leukemia [French-American-British classification, M4 (Bennett et al., Br J Haematol 1976; 33: 451-458)] developed chronic disseminated candidiasis (CDC) in a phase of remission induction chemotherapy. The diagnosis was made based on the histological examination of the biopsy specimen of the liver that showed invasion of Candida. High-dose fluconazole (FCZ) therapy (up to 23.5 mg/kg/day) was given effectively and without significant side effect over a period of 15 months. Pharmacokinetic analysis revealed that FCZ showed one or two compartment model. Administration of 12 mg/kg/day of the drug showed that t (1 2 ) were 11.5 and 16.1 h, respectively. We would suggest that if lesser doses are ineffective in eradicating invasive fungal infection, dose escalation of FCZ was possible up to a single administration of 20 mg/kg daily in children.     

痰热清联合氟康唑治疗白色念珠菌肺炎疗效观察

目的观察痰热清联合氟康唑治疗白色念珠菌肺炎的临床疗效。方法将86例白色念珠菌肺炎患者随机分为治疗组和对照组各43例。对照组予氟康唑治疗,治疗组予痰热清联合氟康唑治疗。观察2组临床疗效和不良反应情况。结果治疗组总有效率为93．O％高于对照组的69．8％,差异有统计学意义（P〈0．01）;治疗组未见明显不良反应。结论痰热清联合氟康唑治疗白色念珠菌肺炎临床疗效显著,安全性好,值得临床推广应用。     

制霉菌素溶液漱口与氟康唑口服治疗念珠菌口咽炎的效果比较

目的 比较制霉菌素溶液漱口与氟康唑口服治疗念珠菌口咽炎的疗效.方法 采用随机数字表法将40例患者分为两组:制霉菌素组20例,用制霉菌素溶液漱口.氟康唑组20例,口服氟康唑胶囊150 mg/d.治疗3d后评估疗效.停药1周后评估是否复发.结果 两组有效率分别为80％、85％,复发率分别为18.8％、11.8％,差异均无统计学意义(均P＞0.05).结论 制霉菌素漱口可有效治疗念珠菌口咽炎,且复发率低,可作为临床治疗的一线用药.     

氟康唑脂质体凝胶的制备及体外透皮实验（英文）

目的制备氟康唑脂质体凝胶,并研究其性质。方法以薄膜分散法制备氟康唑脂质体,透射电镜观察脂质体的形态,粒度分布仪测定粒径,透皮吸收扩散池测定脂质体凝胶的透皮吸收。结果氟康唑脂质体的包封率为47.68%。脂质体粒径均匀,平均粒径为250±8nm。氟康唑脂质体凝胶的累积透过量（25.27%）低于非脂质体凝胶（36.72%）,而脂质体凝胶的药物皮内滞留量（162±15μg·cm^-2于非脂质体凝胶（48±6μg·cm^-2结论氟康唑脂质体凝胶剂可显著提高药物的皮内滞留量,有望成为氟康唑的一种外用新剂型。     

Role of chitosan on controlling the characteristics and antifungal activity of bioadhesive fluconazole vaginal tablets

Vaginal fluconazole (FLZ) prolonged release tablets containing chitosan in physical blends with other bioadhesive polymers were designed. Chitosan was mixed with hydroxypropyl methylcellulose (HPMC), guar gum or sodium carboxymethyl cellulose (NaCMC) at different ratios and directly compressed into tablets. In-vitro release profiles of FLZ were monitored at pH 4.8. Compressing chitosan with HPMC at different ratios slowed FLZ release, however, time for 80% drug release (T₈₀) did not exceed 4.3?h for the slowest formulation (F11). Adding of chitosan to guar gum at 1:2 ratio (F3) showed delayed release with T₈₀ 17.4?h while, in presence of PVP at 1:2:1 ratio (F5), T₈₀ was 8.8?h. A blend of chitosan and NaCMC at 1:2 ratio (F15) showed prolonged drug release with T₈₀ 11.16?h. Formulations F5 and F15 showed fair physical characteristics for the powder and tablets and were subjected to further studies. Fast swelling was observed for F15 that reached 1160.53?±?13.02% in 4?h with 2?h bioadhesion time to mouse peritoneum membrane compared with 458.83?±?7.09% swelling with bioadhesion time exceeding 24?h for F5. Extensive swelling of F15 could indicate possible dehydration effect on vaginal mucosa. Meanwhile, antifungal activity against C. albicans was significantly high for F5.     

Drugs currently under investigation for the treatment of invasive candidiasis

Introduction: The widespread implementation of immunosuppressants, immunomodulators, hematopoietic stem cell transplantation and solid organ transplantation in clinical practice has led to an expanding population of patients who are at risk for invasive candidiasis, which is the most common form of fungal disease among hospitalized patients in the developed world. The emergence of drug-resistant Candida spp. has added to the morbidity associated with invasive candidiasis and novel therapeutic strategies are urgently needed.

Areas covered: In this paper, we explore investigational agents for the treatment of invasive candidiasis, with particular attention paid to compounds that have recently entered phase I or phase II clinical trials.

Expert opinion: The antifungal drug development pipeline has been severely limited due to regulatory hurdles and a systemic lack of investment in novel compounds. However, several promising drug development strategies have recently emerged, including chemical screens involving Pathogen Box compounds, combination antifungal therapy, and repurposing of existing agents that were initially developed to treat other conditions, all of which have the potential to redefine the treatment of invasive candidiasis.     

Fluconazole Review and situation among antifungal drugs in the treatment of opportunistic mycoses of human immuno-deficiency virus infections

Fluconazole is a novel triazole antifungal drug chiefly used in the treatment of opportunistic mycoses in immuno-compromised patients, particularly those with the acquired immuno-deficiency syndrome (AIDS). In comparison with other antifungal drugs, fluconazole has outstanding physical and pharmacokinetic properties, such as an excellent aqueous solubility allowing a parenteral formulation, high bioavailability by the oral route, even distribution throughout the tissues, including the central nervous system and the cerebro-spinal fluid, a long half-life (permitting once daily administration), and low binding to plasma proteins. It is excreted mainly as unchanged drug in the urine. Fluconazole is a broad-spectrum antifungal agent, especially effective againstCandida spp.,Cryptococcus neoformans and dermatophytes. Its antifungal efficacy was mainly proved by testing in animal models, since there is no relationship betweenin vitro andin vivo activities. It possesses a low toxicity and it is well-tolerated. Fluconazole is currently marketed for the treatment of oropharyngeal candidiasis in immuno-compromised patients and of atrophic oral candidiasis. Its place in the treatment of opportunistic mycoses in human immuno-deficiency virus-positive patients, in particular cryptococcal meningitis, is still under investigation but is promising.