Pharmacokinetics of oral posaconazole in neutropenic patients receiving chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome

STUDY OBJECTIVE: To analyze the pharmacokinetics of posaconazole administered as prophylaxis for invasive fungal infection (IFI) in neutropenic patients receiving chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). DESIGN: Pharmacokinetic subanalysis of a phase III, prospective, randomized, multicenter, evaluator-blinded trial comparing posaconazole with standard azoles (fluconazole and itraconazole). PATIENTS: One hundred ninety-four patients with AML or MDS who received posaconazole oral suspension 200 mg 3 times/day with meals or a nutritional supplement for a minimum of 7 days to achieve steady state and for a maximum of 12 weeks. INTERVENTION: For the first 20 patients, blood samples were collected before the first dose on day 8 and at 2, 4, 6, and 24 hours after that first dose; for all other patients, blood samples were collected at 1 and 3 hours after the first dose on day 8 and during the first episode of evaluation for a possible IFI. MEASUREMENTS AND MAIN RESULTS: The effects of the following covariates on average (Cav) and maximum (Cmax) posaconazole plasma concentrations at steady state were explored: age, sex, and race-ethnicity; proven or probable IFI; baseline body weight and body surface area; and baseline (on or before day 7) increases in liver enzyme levels, mucositis, neutropenia, diarrhea, vomiting, or use of an H2-receptor antagonist or proton pump inhibitor. Diarrhea, proton pump inhibitor use, gamma-glutamyl transferase level of 2 or more times the upper limit of normal, and race-ethnicity reduced Cav. Although statistically significant, these results were not considered clinically significant and did not necessitate posaconazole dosage adjustments. Mean Cav and Cmax values did not appear different in the six patients with IFIs (three with proven IFIs, three with probable IFIs) compared with the entire sample of 194 patients; however, a definitive conclusion cannot be made due to the small sample size of patients with IFI. No factor found to affect posaconazole concentrations predominated in patients with IFIs. CONCLUSION: Oral posaconazole 200 mg 3 times/day provided plasma concentrations adequate for preventing IFIs. No dosage adjustments are recommended based on any covariate tested.     

Posaconazole : a review of its use in the prophylaxis of invasive fungal infections

Posaconazole is a second-generation triazole antifungal agent with a broad spectrum of activity that includes Aspergillus spp., Candida spp. and the Zygomycetes. In the US, posaconazole oral suspension administered three times daily is indicated for prophylaxis against invasive Aspergillus and Candida infections in patients aged > or =13 years who are at high risk of developing these infections because of immunosuppression, such as haematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD), or those with haematological malignancies with prolonged neutropenia as a result of chemotherapy. EU-approved prophylactic indications for posaconazole are similar to those in the US.Posaconazole provided effective prophylaxis against invasive fungal infections and was generally well tolerated in two large, well designed trials in HSCT recipients with GVHD, or patients receiving induction-remission chemotherapy for acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) that was expected to result in prolonged neutropenia. It offers coverage of clinically relevant pathogens and is potentially associated with fewer drug-drug interactions than other licensed triazole antifungal agents. Its usefulness in some patients may be limited by the lack of an intravenous formulation, although one is currently being developed. As with other antifungal agents, concerns remain regarding the potential emergence of resistance to broad-spectrum antifungal prophylaxis with posaconazole. Despite this, posaconazole is a valuable emerging option for use as prophylaxis against invasive fungal infections in immunocompromized patients who are at high risk of developing these infections.     

氟康唑预防性治疗急性再生障碍性贫血患者侵袭性真菌病的临床分析

目的观察氟康唑预防性治疗急性再生障碍性贫血患者合并侵袭性真菌病(invasive fungal disease,IFD)的临床疗效及安全性。方法选择急性再生障碍性贫血合并存在IFD高危临床因素的病例作为观察对象,回顾性总结氟康唑针剂(大扶康)在预防性临床使用中的临床疗效、安全性分析、严重不良事件发生率;确立未预防治疗及预防治疗病例组,通过2组间的感染发生率、药物不良反应、治疗转归(包括粒细胞减少恢复的时间及调节性T细胞水平的纠正)、疾病预后等进行两两对照。结果及结论使用氟康唑作为预防性抗真菌治疗的策略对于减少深部真菌感染的发生、减少患者住院周期及费用、改善患者疾病预后等有着显著意义;在用药期间,未发现氟康唑针剂相关的不良反应,具有良好的安全性。可以作为预防性用药的优先推荐药物。     

Pharmacokinetics of oral posaconazole in allogeneic hematopoietic stem cell transplant recipients with graft-versus-host disease

STUDY OBJECTIVE: To analyze the pharmacokinetics of posaconazole administered as prophylaxis for invasive fungal infections in recipients of hematopoietic stem cell transplants (HSCTs) who have graft-versus-host disease (GVHD). DESIGN: Pharmacokinetic analysis in a subset of posaconazole-treated patients from a large, multicenter, phase III, randomized, double-blind, double-dummy, parallel-group trial that compared posaconazole with fluconazole. SETTING: Ninety international medical centers. PATIENTS: The subset of patients comprised 246 HSCT recipients for whom pharmacokinetic data were available. INTERVENTION: All patients received posaconazole 200 mg oral suspension 3 times/day for a maximum of 16 weeks. MEASUREMENTS AND MAIN RESULTS: Blood samples were collected after dosing on day 2; at weeks 2, 4, 8, and 12; and on the last day of oral treatment. After patients had received posaconazole for at least 7 days (i.e., after achieving steady state), both maximum observed posaconazole concentration (C(max)) and average posaconazole concentration (C(av)) were determined. Five patients developed invasive fungal infections while receiving treatment. Median C(av) and C(max) were 611 and 635 ng/ml, respectively, in these five patients and were 922 and 1360 ng/ml, respectively, in the 241 patients without invasive fungal infection. In patients without invasive fungal infection, posaconazole concentrations were not clinically affected by race, body weight, or age. Median plasma posaconazole concentrations were higher in patients with chronic GVHD than in those with acute GVHD. In 18 patients without invasive fungal infection who experienced diarrhea on the day of sampling, posaconazole concentrations were lower than the concentrations in patients without diarrhea. No relationship was observed between alanine aminotransferase, aspartate aminotransferase, or bilirubin levels and posaconazole concentrations. CONCLUSION: Posaconazole 200 mg 3 times/day resulted in median plasma drug concentrations sufficiently high to prevent invasive fungal infections in HSCT recipients with GVHD, without compromising patient safety. Plasma posaconazole concentrations are generally unaffected by demographic variables, including race, sex, body weight, and age.     

氟康唑在恶性血液病化疗后粒细胞减少期预防真菌感染的应用

目的：评价氟康唑预防血液病患者化疗后粒细胞减少期并发真菌感染的疗效.方法：采用随机对照试验方法,把60例化疗后中性粒细胞减少的血液病患者分为真菌感染预防用药组和对照组.其中预防用药组患者预防性的服用氟康唑,而对照组患者未接受任何预防性抗真菌药物治疗.观察并比较2组患者真菌感染的发生率和严重程度.结果：用药组30例服用氟康唑口服液患者中.发生真菌感染的仅2例.真菌感染率为6.7%.而对照组30例中.并发真菌感染7例,包括3例深部真菌感染.真菌感染率为23.3%.明显高于预防用药组（P〈0.01）.结论：在血液病患者中性粒细胞减少期及早给予氟康唑进行预防,能有效降低真菌感染的发生率.     

Pregnancy outcomes after maternal exposure to fluconazole

We evaluated pregnancy outcomes in 234 women exposed to fluconazole, 492 exposed to a topically administered azole preparation, 88 exposed to an oral azole preparation other than fluconazole, and 1629 not exposed to any of these agents during the first trimester of pregnancy Relative risks of having a baby with a congenital disorder for women exposed to fluconazole, oral azoles, and topical azoles in the first trimester of pregnancy compared with those who were unexposed were 1.1 (95% CI 0.4-3.3), 2.1 (95% CI 0.7-6.8), and 0.6 (95% CI 0.2-1.6), respectively These results provide reassurance that fluconazole exposure in the first trimester of pregnancy does not materially increase the risk of congenital disorders in infants.     

Effects of azoles on human acute myelogenous leukemia blasts and T lymphocytes derived from acute leukemia patients with chemotherapy-induced cytopenia

The effects of azoles (fluconazole, ketoconazole, miconazole, itraconazole) on human acute myelogenous leukemia (AML) blasts and T lymphocytes were studied in vitro. All the azoles altered spontaneous proliferation, cytokine-dependent proliferation and constitutive cytokine secretion by native AML blasts for a subset of patients, and all the drugs then had divergent effects. All four drugs also affected the responsiveness (cytokine-dependent and mitogen-stimulated proliferation, cytokine release) of clonogenic CD4+ and CD8+ T cells derived from acute leukemia patients with chemotherapy-induced cytopenia. However, the T cell effects were also divergent and dependent on differences between various azoles, AML accessory cells and mitogenic activation signals. These drug effects may have a clinical relevance in acute leukemia patients receiving intensive chemotherapy together with azoles as prophylaxis or treatment for fungal infections: (i) effects on AML blasts may influence their susceptibility to drug-induced apoptosis; and (ii) effects on T cells may alter effector functions that mediate additional antileukemic effects in patients receiving intensive chemotherapy.     

Factors influencing the pharmacokinetics of prophylactic posaconazole oral suspension in patients with acute myeloid leukemia or myelodysplastic syndrome

Objectives

To estimate the pharmacokinetic (PK) properties of posaconazole in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing chemotherapy in a clinical setting.

Methods

Posaconazole concentrations in patients with AML/MDS receiving prophylactic posaconazole were determined by high-performance liquid chromatography. A population PK model with nonlinear mixed effect modeling was developed. The list of tested covariates included age, weight, height, gender, posaconazole dose, ethnicity, co-administration of antineoplastic chemotherapy, ranitidine or pantoprazole, coincident fever, diarrhea, leukocyte counts, and γ-glutamyltransterase plasma activity.

Results

A total of 643 serum concentrations of posaconazole from 84 patients were obtained. A one-compartment model with first order absorption and elimination as the basic structural model appropriately described the data, with an apparent clearance of 56.8?L/h [95% confidence interval (CI) 52.8–60.8?L/h] and an apparent volume of distribution of 2,130 L (95% CI 1,646–2,614?L). Significant effects on apparent clearance (CL/F) were found for presence of diarrhea and for co-medication with proton-pump inhibitors (1.5- and 1.6-fold increase in CL/F, respectively), weight (33.4?L larger apparent volume of distribution per kilogram), and co-administration of chemotherapy (0.6-fold lower apparent volume of distribution).

Conclusion

We developed a prediction basis for mean posaconazole concentrations in AML/MDS patients. Patient weight, presence of diarrhea, and concomitant medication (chemotherapy and pantoprazole) showed significant effects on posaconazole exposure. Corresponding adjustments of the starting dose according to the presence of diarrhea and during the co-administration of chemotherapy or proton-pump inhibitors appear justified before therapeutic drug monitoring results are available. Further investigation of the interaction between different chemotherapeutic regimens and posaconazole is warranted.     

Fluconazole for antifungal prophylaxis in chemotherapy-induced neutropenia.

Fluconazole is compared with other agents for antifungal prophylaxis in patients with chemotherapy-induced neutropenia. Fluconazole is an attractive alternative for antifungal prophylaxis because of its activity against many Candida species, long half-life, good patient tolerability, and minimal associated toxicity. The results of clinical trials suggest that fluconazole is superior to placebo and oral polyenes in preventing superficial fungal infection in neutropenic patients; however, its efficacy against systemic infection is not as strongly supported. Fluconazole use may increase emergence of resistant yeasts, particularly Candida krusei and Torulopsis glabrata. The cost of fluconazole 50 mg/day is similar to the costs of other antifungals used for prophylaxis; however, fluconazole 400 mg/day (the most frequently studied dose in neutropenic patients) is considerably more expensive. Comparative clinical trials between fluconazole and other antifungals are needed to determine which is superior for prophylaxis. Fluconazole is effective for prophylaxis against superficial fungal infection and may be an attractive alternative therapeutic regimen in patients undergoing bone marrow transplantation. In other neutropenic patients, such as those with leukemia, the superiority of fluconazole has not been substantiated; therefore, it is not recommended over other agents, such as clotrimazole and ketoconazole, at this time.     

Impact of patient education on plasma concentrations and effectiveness of posaconazole oral suspension under clinical conditions

Posaconazole prophylaxis is recommended for patients with acute myeloid leukaemia during induction chemotherapy. Although a tablet formulation with better oral bioavailability is available, some patients have to rely on the oral suspension in clinical routine. Therefore, effectiveness of posaconazole oral suspension under real‐life clinical conditions and impact of patient education about the correct intake on its plasma concentrations were assessed in this study. Altogether 96 patients receiving 160 cycles of induction chemotherapy were retrospectively (40 patients) and prospectively (56 patients) analysed. Patients were assigned into two groups for each chemotherapy cycle according to the application of antifungal prophylaxis (A: posaconazole oral suspension, 200 mg three times a day ≥7 days; B: intake <7 days, fluconazole or no prophylaxis). Antifungal prophylaxis and therapy were analysed for each cycle. Additionally, plasma concentrations were determined from prospectively included subjects of group A who were intensively educated to perform a correct drug intake. Systemic antifungal therapy was statistically started less often in group A (26% vs 53%; P = 0.002). Posaconazole prophylaxis was associated with a lower risk of proven invasive fungal infection (P = 0.003). Median plasma concentration apparently increased between the first and second time of determination effected by an initial intensive on‐site patient education. The clinical effectiveness of posaconazole oral suspension was confirmed. A detailed patient education at the beginning of the treatment with posaconazole oral suspensions seems to be of primary importance for efficient plasma concentrations.     

Itraconazole vs. posaconazole for antifungal prophylaxis in patients with acute myeloid leukemia undergoing intensive chemotherapy: A retrospective study

ObjectiveThe objective of this study was to compare itraconazole with posaconazole for antifungal prophylaxis in acute myeloid leukemia (AML) patients undergoing intensive chemotherapy.MethodsAdult patients with AML received either itraconazole or posaconazole for antifungal prophylaxis while undergoing intensive chemotherapy. The primary endpoint was incidence of prophylaxis failure (change in antifungal agent due to suspected invasive fungal infection [IFI], drug intolerance, drug interaction, or adverse event).ResultsFrom February 2016 to January 2018, 90 patients were included in the itraconazole group and 45 patients in the posaconazole group. Prophylaxis failure occurred in 88% of itraconazole recipients compared with 33% of posaconazole recipients (P<0.001). The primary reason for prophylaxis failure with itraconazole was suspected IFI (58%) whereas for posaconazole, failure predominantly related to drug interaction (60%). An antifungal regimen was continued upon discharge in 47% of itraconazole recipients compared with 9% of posaconazole recipients (P<0.001). The use of breakthrough IFI diagnostic tests was not significantly different in the two groups. A larger proportion of drug concentrations were collected in the posaconazole group.ConclusionsIn AML patients undergoing intensive chemotherapy, posaconazole was associated with significantly lower rates of prophylaxis failure and less need for continued antifungal therapy on discharge compared with itraconazole.     

泊沙康唑与伊曲康唑预防骨髓增生异常综合征/急性髓系白血病患者侵袭性真菌病的成本-效果分析

目的：开展泊沙康唑对比伊曲康唑用于预防骨髓增生异常综合征/急性髓系白血病患者发生侵袭性真菌病的成本-效果分析,为临床合理用药、药品费用不合理增长及医保药品目录的遴选提供决策依据。方法：基于医疗卫生体系角度,构建决策树模型及Markov模型,比较泊沙康唑和伊曲康唑用于预防侵袭性真菌病的短期和长期的经济性;短期健康产出为侵袭性真菌病的发生率,长期健康产出为患者所获得的生命年和质量调整生命年,成本数据来源于2019年中国真实医疗环境价格及文献研究。进行敏感性分析以验证基础分析结果的稳健性。结果：与伊曲康唑相比,泊沙康唑在短期模拟的100 d成本更高（10 992元vs. 8 038元）,但预防效果更好（侵袭性真菌病发生率4.6%vs. 11.1%）。在长期的患者全生命周期模拟中获得的生命年和质量调整生命年更多（2.949 LYs vs. 2.719 LYs,2.096 QALYs vs. 1.932 QALYs）,其增量成本-效果比为18 030元/QALY,远低于2019年中国社会意愿支付阈值（212 676元/QALY）。敏感性分析结果与基础分析结果一致。结论：在中国,泊沙康唑相比伊曲康唑用于预防骨髓增生异常综合征/急性髓系白血病患者发生侵袭性真菌病的经济性更好。     

Cost-utility analysis of treatment with olanzapine compared with other antipsychotic treatments in patients with schizophrenia in the pan-European SOHO study

OBJECTIVE: To determine the cost utility of treating schizophrenic patients with olanzapine compared with other antipsychotics in a naturalistic outpatient setting. METHODS: The pan-European SOHO study is a 3-year, prospective, outpatient, observational study of outcomes associated with antipsychotic treatment, focusing on olanzapine, in ten European countries. For the cost-utility analysis, healthcare resource use (inpatient care, day care, outpatient psychiatric consultations and antipsychotic and concomitant medication use) and EQ-5D data were collected at baseline and at 3, 6 and 12 months. The perspective was that of the health service payer. UK healthcare unit costs (year 2004 values) were applied to the resource use data for the ten countries. UK population tariffs were applied to the EQ-5D data to determine utility values.An Epoch analysis was used to analyze the longitudinal data. Multivariate regression analyses that adjusted for baseline covariates were used to estimate the incremental cost and utility gains for patients treated with olanzapine compared with each of the other antipsychotics (risperidone, quetiapine, amisulpride, clozapine and oral or depot typical antipsychotics). RESULTS: A total of 10 972 patients were enrolled at baseline, of which 9107 completed the 12-month study period. Treatment with olanzapine was more effective in terms of QALYs gained than all of the other antipsychotic treatments. Treatment with olanzapine dominated quetiapine and amisulpride. The incremental cost for olanzapine compared with risperidone was pound sterling 226 per patient over 12 months and the incremental cost per QALY gained was pound 5156, with bootstrap analyses showing 100% of the replications falling below a pound sterling 30 000 per QALY gained threshold. Compared with treatment with clozapine, olanzapine was found to be marginally more effective, at an additional cost of pound sterling 13 per patient over 12 months and to have an incremental cost per QALY gained of pound sterling 775. Bootstrap analyses showed that 81% of replications fell below a pound sterling 30 000 per QALY gained threshold. Comparing olanzapine with oral and depot typical antipsychotics, the incremental cost was pound sterling 849 and pound sterling 1106 per patient over 12 months and the incremental cost per QALY gained was pound sterling 15 696 and pound sterling 23 331, respectively. Bootstrap analyses showed that 98% of the replications fell below a pound sterling 30 000 per QALY gained threshold for the comparison with oral typical antipsychotics, and 79% of replications for the comparison with depot preparations. CONCLUSIONS: Among SOHO patients, if a funding threshold of pound sterling 30 000 per QALY gained is assumed, this analysis suggests that olanzapine has a high probability of being the most cost-effective treatment compared with other antipsychotic treatments. However, comparison of olanzapine with clozapine and typical depot antipsychotics should be viewed with caution because clozapine is a second-line treatment and depot treatment is used for patients who do not adhere to their oral medication.     

Clinical experience with itraconazole in systemic fungal infections

The broad spectrum antifungal itraconazole is an effective and well tolerated agent for the prophylaxis and treatment of systemic fungal infections. The recent development of an itraconazole oral solution and an intravenous itraconazole solution has increased the options for the use of this drug and increased the oral bioavailability in a variety of at-risk patients. Reliable absorption of the itraconazole oral solution has been demonstrated in patients with HIV infection, neutropenic patients with haematological malignancy, bone marrow transplant recipients and neutropenic children. In clinical trials, itraconazole oral solution (5 mg/kg/day) was more effective at preventing systemic fungal infection in patients with haematological malignancy than placebo, fluconazole suspension (100 mg/day) or oral amphotericin-B (2 g/kg/day) and was highly effective at preventing fungal infections in liver transplant recipients. There were no unexpected adverse events with the itraconazole oral solution in any of these trials. In addition, intravenous itraconazole solution is at least as effective as intravenous amphotericin-B in the empirical treatment of neutropenic patients with systemic fungal infections, and drug-related adverse events are more frequent in patients treated with amphotericin-B. A large proportion of patients with confirmed aspergillosis also respond to treatment with intravenous itraconazole followed by oral itraconazole. The new formulations of itraconazole are therefore effective agents for prophylaxis and treatment of most systemic fungal infections in patients with haematological malignancy.     

The prophylactic effectiveness of various antifungal agents against the progression of trichosporonosis fungemia to disseminated disease in a neutropenic mouse model

Neutropenic mice with latent trichosporonemia were given various antifungal agents (amphotericin B, fluconazole, itraconazole) or saline to determine which antifungal agent could be useful for prophylaxis. The 3-week-survival rate was 80% in the fluconazole group, 50% in the amphotericin B group, 45% in the itraconazole group, and 30% in the saline group. Compared with the other antifungal agents, fluconazole offered superior prophylaxis against the progression of trichosporonosis fungemia to disseminated disease (P<0.05). These results suggest that clinical studies are warranted to investigate fluconazole prophylaxis of trichosporonosis progression in neutropenic patients, such as people receiving chemotherapy and patients who have received solid organ transplants.     

Patients at high risk of invasive fungal infections: when and how to treat

When and how to treat invasive fungal infections (IFIs) is discussed in this review, with a focus on the two most prevalent non-endemic IFIs, namely invasive aspergillosis and invasive candidiasis. Early treatment initiation in patients with IFIs has a profound impact on mortality rates, but reliable diagnostic measures are lacking. This situation has led to the parallel use of different treatment strategies, e.g. prophylaxis, empirical and pre-emptive treatment, as well as targeted treatment in response to a definite diagnosis of IFI. Identifying high-risk patients is the first step in reducing IFI-related mortality. Patients at risk of invasive aspergillosis comprise (i) those with acute myelogenous leukaemia (AML) or myelodysplastic syndrome (MDS) during remission induction chemotherapy; (ii) patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT); (iii) recipients of solid organ transplants; and (iv) those with other conditions of severe and prolonged immunosuppression. Patients at high risk of invasive candidiasis are less well defined. Risk factors are diverse and include haematological malignancy, neutropenia, age <1 month or >65 years, and recent abdominal surgery. The individual risk further depends on the presence of a variety of other risk factors, including central venous catheters, use of broad spectrum antibacterials, prolonged intensive care unit (ICU) stay, total parenteral nutrition, mucosal Candida spp. colonization and renal failure.Extensive research has been conducted to facilitate the best possible treatment strategies for these severe infections. Optimal timing and choice of antifungal agents largely remain a matter of controversy. After having reviewed the major clinical trials, we conclude that comparisons between different treatment strategies cannot be made, neither at present nor in the near future. The complexity of the clinical problem leads to an eclectic treatment approach to reduce morbidity and mortality from IFIs without compromising tolerability. We recommend prophylaxis with posaconazole for allogeneic HSCT recipients, patients receiving induction chemotherapy for AML or MDS, and those undergoing immunosuppressive therapy for graft-versus-host disease after allogeneic HSCT. For the empirical treatment of persistently febrile neutropenia, caspofungin is our first- and liposomal amphotericin B deoxycholate (LAmB) our second-line choice. Once a diagnosis of invasive aspergillosis has been established, voriconazole should be the preferred treatment option, with LAmB being an alternative. Fluconazole prophylaxis for invasive candidiasis should remain restricted to high-risk ICU patients. Once a diagnosis has been established, the drug of choice for adequate treatment depends largely on neutrophil count and haemodynamic stability. In non-neutropenic patients, an echinocandin should be considered the first-line treatment option, while patients with susceptible Candida spp. may be switched to fluconazole. In neutropenic patients, caspofungin or micafungin might be preferred to anidulafungin as first-line treatment. LAmB is a second-line treatment option in both settings.Early diagnosis of IFIs is imperative to facilitate treatment success. In all patients at risk for IFIs, blood cultures, galactomannan antigen and diagnostic imaging should be rigorously enforced.     

Cost effectiveness of itraconazole in the prophylaxis of invasive fungal infections

BACKGROUND: Invasive fungal infections in neutropenic patients treated for haematological malignancies are associated with a high mortality rate and, therefore, require early treatment. As the diagnosis of invasive fungal infections is difficult, effective antifungal prophylaxis is desirable. So far, fluconazole has been the most commonly used. OBJECTIVE: To assess the cost effectiveness of itraconazole compared with both fluconazole and no prophylaxis for the prevention of invasive fungal infections in haematological patients, mean age 51 years, in Germany and The Netherlands. STUDY DESIGN: We designed a probabilistic decision model to fully incorporate the uncertainty associated with the risk estimates of acquiring an invasive fungal infection. These risk estimates were extracted from two meta-analyses, evaluating the effectiveness of fluconazole and itraconazole and no prophylaxis. The perspective of the analysis was that of the healthcare sector; only medical costs were taken into account. All costs were reported in euro, year 2004 values.Cost effectiveness was expressed as net costs per invasive fungal infection averted. No discounting was performed, as the model followed patients during their neutropenic period, which was assumed to be less than 1 year. RESULTS: According to our probabilistic decision model, the monetary benefits of averted healthcare exceed the costs of itraconazole prophylaxis under baseline assumptions (95% CI: from cost-saving to euro 5000 per invasive fungal infection averted). Compared with fluconazole, itraconazole is estimated to be both more effective and more economically favourable, with a probability of almost 98%. CONCLUSIONS: In specific groups of neutropenic patients treated for haematological malignancies, itraconazole prophylaxis could potentially reduce overall healthcare expenditure, without harming effectiveness, in settings where fluconazole is common practice in the prophylaxis of invasive fungal infections.     

Candidemia in children

Abstract

Seriously ill or immunocompromised children are at increased risk of invasive fungal infections, particularly candidemia. Candida albicans and Candida parapsilosis are the two most frequent causes of candidemia in pediatric patients. Candidemia in children is associated with high morbidity and mortality, increased length of hospital stays, and higher healthcare costs. Early effective antifungal therapy is the key to improved outcomes. Risk factors for candidemia may be used to identify patients suitable for empiric therapy. Such risk factors include prolonged stay in an intensive care unit, immunosuppression, prior bacterial infection, and recent surgery, as well as the use of a central venous catheter, mechanical ventilation, and/or total parenteral nutrition. Recent guidelines from the Infectious Diseases Society of America recommend consideration of fluconazole or an echinocandin for empiric therapy in suitable candidates, with a preference for an echinocandin in patients with moderate-to-severe disease, recent azole exposure, or high risk of Candida glabrata or Candida krusei infection. Fluconazole or an echinocandin is also preferred initial therapy for non-neutropenic candidemia, depending on disease severity and other characteristics. The guidelines recommend treatment with an echinocandin or lipid formulation of amphotericin B for most patients with neutropenic candidemia, although fluconazole is identified as an alternative for less critically ill patients without recent azole exposure. Risk factors for candidemia – and, hence, criteria for prophylaxis – are less well established in older children than in neonates. Further research is needed to better establish criteria for antifungal prophylaxis in children at high risk for candidemia.     

Fluconazole versus amphotericin B for the prevention of fungal infection in neutropenic patients with hematologic malignancy.

Effective prophylaxis against fungal infection is important in neutropenic patients with hematologic malignancies, but the best method remains unclear. We investigated the effectiveness of fungal prophylaxis with amphotericin B or fluconazole. We reviewed the data on fungal isolates, plasma (1-->3)-beta-D glucan (beta-D glucan) levels, febrile periods (the number of days with an axillary temperature > 38 degrees C), and the duration of an axillary temperature > 38 degrees C when the neutrophil count was < 500/microliter. Of the 124 patients studied, 57 had acute myelogenous leukemia, 19 had acute lymphoblastic leukemia, 18 had non-Hodgkin's lymphoma, six had chronic myeloid leukemia, three had adult T-cell leukemia, and five had chronic lymphocytic leukemia. There were no significant differences in clinical characteristics between the 70 patients treated with amphotericin B and the 54 patients given fluconazole. There was a significant decrease of fungal isolates (chi 2-test, p < 0.001), the plasma beta-D glucan level (Wilcoxon test, p = 0.0001), and the febrile period (t-test, p < 0.05) in the patients given fluconazole compared with those given amphotericin B. In neutropenic patients with hematologic malignancies, prophylaxis with fluconazole significantly decreased fungal isolation and other indicators of fungal infection when compared with amphotericin B. Fluconazole may therefore be more effective for fungal prophylaxis in these patients.     

Fluconazole. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses

Fluconazole is a bis-triazole antifungal drug with novel pharmacokinetic properties (metabolic stability, relatively high water solubility) which contribute to its therapeutic activity. Clinical experience is limited to a relatively small number of mycoses and, as might be expected at this early stage of development, optimal dosage and duration of treatment for some serious mycoses is not yet established. Further study to evaluate higher dosages and to establish the efficacy of fluconazole relative to more established antifungal agents is required. In patients with oropharyngeal or oesophageal candidiasis, fluconazole produces rapid relief and eradicates the yeast in 50 to 90% of patients. Relapse of oral infection is common in chronically immunocompromised patients regardless of the antifungal used, and adequate primary therapy plus long term prophylaxis appears necessary in patients with AIDS. A single oral dose of fluconazole was comparable to standard topical azole therapy in women with acute vaginal candidiasis. Preliminary reports of success against deep-seated candidiasis are encouraging; moreover, experience in noncomparative clinical trials suggests that fluconazole 200 to 400mg once daily resolves infection in the majority of seriously ill patients. Clinical improvement has been reported in a few cases of pulmonary Aspergillus infection but the overall efficacy of conventional dosages of fluconazole in this mycosis has not been as impressive. Early experience in coccidioidosis, predominantly meningitis, suggests a beneficial clinical effect with oral fluconazole in this difficult to treat mycosis but relapse remains a problem. Fluconazole is a promising treatment of cryptococcal meningitis. The rate of clinical resolution and eradication of Cryptococcus neoformans from cerebrospinal fluid has been similar between fluconazole and amphotericin B treatment groups in comparative trials. Comparative trials of maintenance therapy indicate a similar low rate of relapse among patients given oral fluconazole once daily and intravenous amphotericin B once weekly. However, these results are preliminary and further study is required. Fluconazole has been well tolerated to date but wider clinical experience is needed, especially with regard to the rate occurrence of hepatotoxicity and exfoliative skin reactions. The promising clinical response of patients with various forms of candidiasis or cryptococcosis--together with convenient administration regimens--recommends fluconazole as a useful addition to currently available systemic antifungal therapies, in particular for the treatment of mycoses in patients with AIDS.