Cost-effectiveness analysis of antifungal treatment for patients on chemotherapy

Invasive fungal infections are fatal complications for patients on chemotherapy, and antifungal prophylactic treatment has been commonly recommended. Because its clinical and economic impact is not well known, we evaluated cost-effectiveness of anti-fungal treatment for patients who were neutropoenic as a result of chemotherapy. We constructed a hypothetical cohort of 40-year-old patients with acute myelogenic leukemia to evaluate years of life survived (YLS), costs (US$), and incremental cost-effectiveness ratio (US$/YLS). The following treatment strategies for fungal infections were compared: (1) prophylactic fluconazole strategy: oral fluconazole administration concurrently with chemotherapy; (2) empirical amphotericin B strategy: empirical intravenous amphotericin B administration at the point where fever is detected; and (3) no prophylaxis strategy: intravenous micafangin administration at the point where fungal infections is diagnosed. Baseline analyses showed that prophylactic fluconazole strategy involved higher costs but also longer YLSs (25,900 US$ and 24.08 YLS). The incremental cost-effectiveness ratio of prophylactic fluconazole strategy was 625 US$/YLS compared to no prophylaxis strategy, and 652 US$/YLS compared to empirical amphotericin B strategy. Baseline result was found to be robust through sensitivity analyses. Our study showed that concurrent administration of oral fluconazole during induction chemotherapy appears to ensure clinical benefits together with acceptable cost-effectiveness.     

氟康唑治疗急性放射性口腔粘膜炎继发的真菌感染

目的 :研究头颈部肿瘤放射治疗中急性放射性口腔粘膜反应与真菌感染的关系及氟康唑治疗的有效性。方法 :71例口腔粘膜受到大面积照射的肿瘤病人 :男性 4 2例 ,女性 2 9例 ;年龄 52a±s 4 1a( 11～ 76a) ,在病人的口腔粘膜反应最严重的时候 ,做口腔粘膜真菌学检查 ,32例有真菌感染的病人 ,用氟康唑胶囊 10 0mg ,po ,qd× 5d或氟康唑注射液 150mg ,iv ,gtt× 3d治疗。结果 :真菌的检出率为 4 5% ,以白念珠菌感染为主。有真菌感染和无真菌感染的 2组病人 ,在急性放射性粘膜反应上差异有显著意义 (P <0 .0 5) ;有真菌感染的病人用氟康唑治疗 ,治疗前后的粘膜反应差异有显著意义 (P<0 .0 5)。结论 :严重的急性放射性粘膜反应与真菌感染有密切的关系 ;有真菌感染的放射性口腔粘膜反应用氟康唑治疗可以明显减轻放射性粘膜反应     

The Design and Validation of a Novel Intravenous Microdialysis Probe: Application to Fluconazole Pharmacokinetics in the Freely-Moving Rat Model

Purpose. The purpose of this study was to design and validate a concentric, flexible intravenous microdialysis probe to determine drug concentrations in blood from the inferior vena cava of a freely-moving animal model. Methods. An intravenous microdialysis probe was constructed using fused-silica tubing and an acrylonitrile/sodium methallyl sulfonate copolymer hollow fiber. The probe was tested in vitro for the recovery of fluconazole and UK-54,373, a fluconazole analog used for probe calibration by retrodialysis. Subsequent in vivo validation was done in rats (n = 7) that had a microdialysis probe inserted into the inferior vena cava via the femoral vein, and the femoral artery was cannulated for simultaneous blood sampling. Comparisons of fluconazole pharmacokinetic parameters resulting from the two sampling methods were performed at 2 and 10 days after probe implantation. Results. There were no statistical differences between the microdialysis sampling and conventional blood sampling methods for the T_1/2, Cl, Vdss, and dose-normalized AUC by paired t-test (p > 0.05) for repeated dosing at day 2 and day 10 after probe placement. The probe recovery, as determined by retrodialysis, significantly decreased over the ten day period. This finding indicates the necessity for frequent recovery determinations during a long-term blood microdialysis experiment. Conclusions. These results show that microdialysis sampling in the inferior vena cava using this unique and robust probe design provides an accurate method of determining blood pharmacokinetics in the freely-moving rat for extended experimental periods. The probe design allows for a simple surgical placement into the inferior vena cava which results in a more stable animal preparation for long-term sampling and repeated-measures experimental designs.     

Synovial fluid levels of fluconazole in a patient with Candida parapsilosis prosthetic joint infection who had an excellent clinical response

A 73-year-old woman presenting with persistent swelling of the right knee 30 months after total joint arthroplasty was found to have a Candida parapsilosis infection. Treatment with fluconazole resulted in full recovery.     

Effects of fluconazole in the prophylaxis of oropharyngeal candidiasis in patients undergoing radiotherapy for head and neck tumour: results from a double-blind placebo-controlled trial

Fluconazole is recommended in the prophylaxis of oropharyngeal candidiasis (OPC) in patients undergoing radiotherapy for head-neck tumours; however, the actual effectiveness of fluconazole in this setting remains unclear. Adult patients with cervico-cephalic carcinoma submitted to radical or adjuvant radiotherapy were randomized to 100 mg fluconazole ( n  = 138) or matched placebo ( n  = 132) oral suspension once daily from the sixth session of radiotherapy up to the end of treatment. The final analysis of the investigation showed a higher rate of the OPC outbreak-free survival in the fluconazole compared with placebo ( P  = 0.008 in the log-rank test). The mean time (95% CI) to OPC outbreak was 56 (53–59) days in the fluconazole group and 47 (43–51) days with placebo. The mean duration of radiotherapy was 43.5 and 39.9 days, respectively in the two groups ( P  = 0.027). Adverse effects were reported in 70.3% of patients in the fluconazole group and in 67.4% with placebo. The results showed prophylaxis with fluconazole given in irradiated patients with head-neck tumours significantly reduces the rate and the time to development of OPC compared with placebo.     

In search of a novel antifungal agent: probing molecular interactions of fluconazole and its analogues with model membranes by NMR and DSC techniques

Objectives In search of a novel antifungal agent with high susceptibility and increased antifungal potency it is necessary to increase the overall lipophilicity of these agents. In view of that, we have synthesized different carboxylic acid ester analogues of fluconazole, such as fluconazole‐benzoate, fluconazole‐p‐nitrobenzoate, fluconazole‐p‐methoxybenzoate and fluconazole‐toluate, with varying degrees of lipophilicity. In order to probe molecular level interactions of these molecules with biomembrane, lipid bilayers prepared from l‐α‐dipalmitoyl phosphatidyl choline (DPPC) as the model membrane were used. Methods Multinuclear and multidimensional nuclear magnetic resonance, differential scanning calorimetry and transmission electron microscopy was used to investigate the changes in the thermotropic properties, organization of the membrane and intermolecular interactions. Key findings Fluconazole and its analogues show varying degrees of changes in the DPPC bilayer's architecture and physico‐chemical characteristics. This might influence important biological features of fungal biomembranes that could be responsible for their respective antifungal effects. Conclusions The study indicates that fluconazole‐p‐methoxybenzoate is the most active among all analogues and therefore could be the most promising antifungal candidate.     

拉曼光谱测定氟康唑晶型的应用研究

 目的 建立了拉曼光谱法测定氟康唑两种晶型方法。方法 选取氟康唑两种晶型原料药,通过X射线粉末衍射,红外光谱,热分析确认其晶型为A、B晶型,采用780 nm色散型拉曼光谱法得到A、B晶型拉曼光谱图,测定了3个不同厂家氟康唑固体口服制剂的晶型类别,并采用拉曼成像技术对含量分布进行初步研究。结果 得到了氟康唑A、B晶型特征拉曼谱图,并确认了3个厂家制剂所含氟康唑晶型类别,其中T1样品除含有A晶型还含有淀粉类辅料,T3样品除含有B晶型还含有乳糖类辅料。结论 本方法可应用于快速鉴别原料及固体口服制剂中氟康唑的不同晶型类别,方法便捷,具有较高的准确度及专属性。     

Australian Dental Research Fund Trebitsch Scholarship* Efficacy of antifungal prophylaxis in bone marrow transplantation

Oral candidal infection is a common problem in bone marrow transplantation. This prospective study compared the effectiveness of antifungal prophylaxis with topical antifungals (nystatin and amphotericin B suspensions) versus oral fluconazole in 196 patients undergoing bone marrow transplantation. Oral candidosis occurred frequently in the group receiving topical antifungals (61/113, 54%), but was rare in the group receiving fluconazole (6/83, 7%). The difference in efficacy between the two groups was highly significant (p<0.00001). There was no difference in the incidence of suspected systemic fungal infection between the two groups. While nausea was a problem with antifungal suspensions, no significant adverse reactions to fluconazole occurred. Because of greater efficacy in preventing oral candidosis and better patient tolerance, oral fluconazole is preferred to antifungal suspensions for prophylactic use in patients undergoing bone marrow transplantation.