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.     

Therapeutic drug monitoring of voriconazole and posaconazole

Despite the availability of newer antifungal agents, invasive fungal diseases remain a leading cause of morbidity and mortality in immunocompromised patients. Voriconazole and posaconazole are two extended-spectrum triazoles indicated for treatment and prophylaxis of invasive fungal diseases. Recently, there has been increased interest in the utility of therapeutic drug monitoring to optimize safety and efficacy of antifungals in an attempt to improve patient outcomes. We reviewed the pharmacokinetic and pharmacodynamic characteristics of voriconazole and posaconazole in the context of clinical indications for therapeutic drug monitoring. In addition, the most recent evidence examining the relationship between serum concentrations of voriconazole and posaconazole and their efficacy or toxicities was evaluated. This information was then integrated to formulate recommendations for use of therapeutic drug monitoring in clinical settings.     

Triazole antifungal agents in invasive fungal infections: a comparative review

Invasive fungal disease continues to be a problem associated with significant morbidity and high mortality in immunocompromised and, to a lesser extent, immunocompetent individuals. Triazole antifungals have emerged as front-line drugs for the treatment and prophylaxis of many systemic mycoses. Fluconazole plays an excellent role in prophylaxis, empirical therapy, and the treatment of both superficial and invasive yeast fungal infections. Voriconazole is strongly recommended for pulmonary invasive aspergillosis. Posaconazole shows a very wide spectrum of activity and its primary clinical indications are as salvage therapy for patients with invasive aspergillosis and prophylaxis for patients with neutropenia and haematopoietic stem-cell transplant recipients. Itraconazole also has a role in the treatment of fungal skin and nail infections as well as dematiaceous fungi and endemic mycoses. Fluconazole and voriconazole are well absorbed and exhibit high oral bioavailability, whereas the oral bioavailability of itraconazole and posaconazole is lower and more variable. Posaconazole absorption depends on administration with a high-fat meal or nutritional supplements. Itraconazole and voriconazole undergo extensive hepatic metabolism involving the cytochrome P450 system. The therapeutic window for triazoles is narrow, and inattention to their pharmacokinetic properties can lead to drug levels too low for efficacy or too high for good tolerability or safety. This makes these agents prime candidates for therapeutic drug monitoring (TDM). Target drug concentrations for voriconazole and itraconazole should be >1?μg/mL and for posaconazole >1.5?μg/mL for treatment. Blood should be drawn once the patient reaches steady state, which occurs after 5 and 7 days of triazole therapy. Routine TDM of fluconazole is not required given its highly favourable pharmacokinetic profile and wide therapeutic index. The aim of this review is to provide a brief update on the pharmacology, activity, clinical efficacy, safety and cost of triazole agents (itraconazole, fluconazole, voriconazole and posaconazole) and highlight the clinical implications of similarities and differences.     

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.     

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.     

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.     

伊曲康唑在侵袭性真菌感染中的预防作用

由于免疫抑制剂的使用、血液系统恶性肿瘤病人异基因造血干细胞移植等高危人群的不断增多,侵袭性真菌感染的患病率和病死率均呈显著上升趋势。近年来伊曲康唑口服液和注射液相继在欧美及我国批准使用,对于高危病人伊曲康唑的预防性应用能显著降低侵袭性真菌感染的发生率。因此,本文拟从循证医学的角度,对伊曲康唑口服液和注射液在各种危重病病人侵袭性真菌感染中的预防作用作一综述。     

Current management of fungal infections

The management of superficial fungal infections differs significantly from the management of systemic fungal infections. Most superficial infections are treated with topical antifungal agents, the choice of agent being determined by the site and extent of the infection and by the causative organism, which is usually readily identifiable. One exception is onychomycosis, which usually requires treatment with systemically available antifungals; the accumulation of terbinafine and itraconazole in keratinous tissues makes them ideal agents for the treatment of onychomycosis. Oral candidiasis in immunocompromised patients also requires systemic treatment; oral fluconazole and itraconazole oral solution are highly effective in this setting. Systemic fungal infections are difficult to diagnose and are usually managed with prophylaxis or empirical therapy. Fluconazole and itraconazole are widely used in chemoprophylaxis because of their favourable oral bioavailability and safety profiles. In empirical therapy, lipid-associated formulations of amphotericin-B and intravenous itraconazole are safer than, and at least as effective as, conventional amphotericin-B (the former gold standard). The high acquisition costs of the lipid-associated formulations of amphotericin-B have limited their use.     

Posaconazole: a pharmacoeconomic review of its use in the prophylaxis of invasive fungal disease in immunocompromised hosts

Posaconazole (Noxafil?) is an oral, second-generation, extended-spectrum triazole whose approved indications include prophylaxis of invasive fungal disease (IFD) in immunocompromised patients. In pivotal head-to-head trials, posaconazole was significantly more effective in preventing IFD than standard azole therapy (i.e. oral fluconazole or itraconazole) in chemotherapy-induced neutropenic patients with acute myelogenous leukaemia (AML) or myelodysplastic syndromes (MDS) and was noninferior to treatment with fluconazole in patients with graft-versus-host disease (GVHD) who were receiving intensive immunosuppressive therapy following haematopoietic stem cell transplantation. In both indications, prophylactic posaconazole was associated with significantly lower rates of IFD-related mortality. The overall tolerability profile of posaconazole was generally similar to that of the other prophylactic treatments. The large body of modelled cost-effectiveness analyses from a healthcare payer perspective on the use of prophylactic posaconazole suggest that it is a dominant or cost-effective option relative to prophylaxis with standard azole therapy in neutropenic patients with AML/MDS, and fluconazole in patients with GVHD. Based on clinical trial data in these patient groups, antifungal prophylaxis with posaconazole was predicted to be a dominant or cost-effective option relative to prophylaxis with standard oral azoles, with regard to the incremental cost per QALY gained, life-year (LY) gained and/or other outcomes in cost-effectiveness analyses in numerous countries. In those analyses in which posaconazole did not dominate the comparator, posaconazole was considered cost effective, as the incremental cost per QALY or LY gained with posaconazole was lower than assumed willingness-to-pay thresholds. Sensitivity analyses consistently demonstrated that these results were robust to plausible changes in key model assumptions. In conclusion, prophylactic treatment with posaconazole is clinically effective in preventing IFD in neutropenic patients with AML/MDS and patients with GVHD. Available pharmacoeconomic data from several countries, despite some inherent limitations, support the use of posaconazole as a dominant or cost-effective prophylactic antifungal treatment relative to prophylaxis with standard oral azoles in these patient populations at high risk of developing IFD.     

Caspofungin: pharmacology,safety and therapeutic potential in superficial and invasive fungal infections

Invasive fungal infections are important causes of morbidity and mortality in hospitalised patients. Current therapy with amphotericin B and antifungal triazoles has overlapping targets and is limited by toxicity and resistance. The echinocandin lipopeptide caspofungin is the first of a new class of antifungal compounds that inhibit the synthesis of 1,3-β-D-glucan. This homopolysaccharide is a major component of the cell wall of many pathogenic fungi and yet is absent in mammalian cells. It provides osmotic stability and is important for cell growth and cell division. In vitro, caspofungin has broad-spectrum antifungal activity against Candida and Aspergillus spp. without cross-resistance to existing agents. The compound exerts prolonged post-antifungal effects and fungicidal activity against Candida spp. and causes severe damage of Aspergillus fumigatus at the sites of hyphal growth. Animal models have demonstrated efficacy against disseminated candidiasis and disseminated and pulmonary aspergillosis, both in normal and in immunocompromised animals. Caspofungin possesses favourable pharmacokinetic properties and is not metabolised through the cytochrome P450 (CYP) enzyme system. It showed highly promising antifungal efficacy in Phase II and III clinical trials in immunocompromised patients with oesophageal candidiasis. Caspofungin was effective in patients with invasive aspergillosis intolerant or refractory to standard therapies. Based on its documented antifungal efficacy and an excellent safety profile, caspofungin has been approved recently by the US Food and Drug Administration for the treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (i.e., amphotericin B, lipid formulations of amphotericin B, and/or itraconazole). Phase III clinical trials in patients with candidaemia and in persistently febrile neutropenic patients requiring empirical antifungal therapy are ongoing. This paper reviews the preclinical and clinical pharmacology of caspofungin and its potential role for treatment of invasive and superficial fungal infections in patients.     

The cost of treating systemic fungal infections

The increasing incidence of systemic fungal infections and rising medical costs have highlighted the need for an economic appraisal of antifungal agents to determine the most cost-effective therapeutic option. Cost savings derived from the prophylactic or empirical use of antifungal agents have been difficult to estimate because of the lack of information on the costs of systemic fungal infections. Fluconazole is effective in prophylaxis and represents a direct cost saving compared with polyenes. However, itraconazole oral solution, an effective and widely used antifungal prophylactic agent, has not been analysed for cost effectiveness. In empirical therapy, the development of new formulations of existing agents has prompted a number of cost comparisons. In particular, the cost of treatment with conventional amphotericin-B has been compared with the costs of the new lipid-associated formulations of amphotericin-B or the new intravenous (IV) formulation of itraconazole. The acquisition costs of lipid-associated amphotericin-B and IV itraconazole are higher than the cost of conventional amphotericin-B; however, these costs appear to be offset by reductions with both these agents in the cost for increased length of hospital stay and treating adverse events seen with conventional amphotericin-B. In neutropenic patients and bone marrow transplant recipients, IV itraconazole may be the most cost-effective option for empirical therapy.     

卡泊芬净和伊曲康唑治疗侵袭性肺部真菌感染的回顾性分析

目的：比较卡泊芬净和伊曲康唑治疗侵袭性肺部真菌感染（IPFI）的有效性和安全性。方法：回顾性分析本院2010年9月-2011年8月入住呼吸科并诊断为IPFI的患者病例,记录患者一般情况、身体体征和临床表现的变化过程及不良反应,比较临床疗效和不良反应的发生情况,并进行统计分析。结果：卡泊芬净组36例,有效率为58_3％,伊曲康唑组31例,有效率为38．7％,两组有效率比较差异有统计学意义（P〈0．05）;卡泊芬净组和伊曲康唑组不良反应发生率分别为22．2％和54．8％;卡泊芬净组和伊曲康唑组因毒性反应停药的病例数分剐为0例和4例,差异存在统计学意义（P〈0．05）。结论：治疗侵袭性肺部真菌感染时,卡泊芬净比伊曲康唑具有更好的疗效且副作用小,需合理使用以减少耐药菌株的产生。     

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.     

Itraconazole. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in superficial and systemic mycoses

Itraconazole is an orally active triazole antifungal drug which has demonstrated a broad spectrum of activity and a favourable pharmacokinetic profile. It is a potent inhibitor of most human fungal pathogens including Aspergillus sp. In non-comparative clinical trials itraconazole was shown to be extremely effective in a wide range of superficial and more serious 'deep' fungal infections when administered once or twice daily. Generally, greater than 80% of patients with superficial dermatophyte or yeast infections are cured by itraconazole. Similarly, good to excellent response rates (clinical cure or marked improvement) are achieved in paracoccidioidomycosis, histoplasmosis, sporotrichosis, blastomycosis, systemic candidiasis, coccidioidomycosis, chromomycosis, aspergillosis and cryptococcosis. Understandably, given the rare nature of some of these diseases, clinical experience is relatively limited and further evaluation, preferably controlled trials with amphotericin B and ketoconazole, would help clarify the ultimate role itraconazole will have in their management. Preliminary findings also indicate that itraconazole may hold promise for the prophylaxis of opportunistic fungal infections in patients at risk, for example women with chronic recurrent vaginal candidiasis, immunodeficient patients with chronic mucocutaneous candidiasis, AIDS patients and patients receiving immunosuppressant drugs. In studies to date itraconazole has been very well tolerated. Transient changes in indices of liver function occurred in 1 to 2% of patients; however, symptomatic liver dysfunction (as occurs infrequently with ketoconazole) has not been reported. Wider clinical experience is needed to permit clear conclusions as to whether liver dysfunction can result from itraconazole administration. Thus, while several aspects of the drug's profile require further investigation, itraconazole is a promising new oral treatment of fungal disease. The extent to which itraconazole will be employed in preference to ketoconazole will be clarified by wider clinical experience.     

Pharmacokinetic evaluation of oral itraconazole for antifungal prophylaxis in children

Itraconazole is a first‐generation triazole agent with an extended spectrum of activity; it is licensed in adults for superficial and systemic fungal infections; no recommendation has been yet established for use in children patients. Its variable and unpredictable oral bioavailability make it difficult to determine the optimal dosing regimen. Hence, therapeutic drug monitoring, highly available in clinical practice, may improve itraconazole treatment success and safety. The aim of the study was to describe in paediatrics the oral itraconazole pharmacokinetics, used for prophylaxis. Moreover, we evaluated the utility of its therapeutic drug monitoring in this cohort. A fully validated chromatographic method was used to quantify itraconazole concentration in plasma collected from paediatric patients, at the end of dosing interval. Associations between variables were tested using the Pearson test. Mann‐Whitney U test has been used to probe the influence of categorical variables on continuous ones. Any predictive power of the considered variables was finally evaluated through univariate and multivariate linear and logistic regression analyses. A high inter‐individual variability was shown; ethnicity (beta coefficient, β ?0.161 and interval of confidence at 95%, IC ?395.035; ?62.383) and gender (β 0.123 and IC 9.590; 349.395) remained in the final linear regression model with P value of .007 and .038, respectively. This study highlights that therapeutic drug monitoring is required to achieve an adequate target itraconazole serum exposure.     

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.     

Novel triazole antifungal agents

The risk of opportunistic infections is greatly increased in patients who are immunocompromised due to AIDS, cancer chemotherapy and organ or bone marrow transplantation. Candida albicans is often associated with serious systemic fungal infections, however other Candida species such as Candida krusei, Candida tropicalis and Candida glabrata, as well as Cryptococcus neoformans and filamentous fungi such as Aspergillus, have also emerged as clinically significant fungal pathogens. Two triazole antifungal agents, fluconazole and itraconazole, were introduced over a decade ago and since then have been used extensively for the prophylaxis and treatment of a variety of fungal infections. Although both drugs are effective and have their place in therapy, limitations regarding the utility of these agents do exist. For example, fluconazole is not effective for the prophylaxis or treatment of Aspergillus species and has limited activity against C. krusei and C. glabrata. The use of itraconazole has been limited secondary to concerns regarding unpredictable bioavailability. The rising incidence of fungal infections and the reported increase of non-albicans candidal infections noted over the past two decades highlight the need for new antifungal agents with improved spectra of activity. Several new triazole agents are in various phases of preclinical and clinical trials and may be available for human use in the near future. Three such agents voriconazole, posaconazole and ravuconazole are reviewed and compared with existing agents.     

Novel triazole antifungal agents

The risk of opportunistic infections is greatly increased in patients who are immunocompromised due to AIDS, cancer chemotherapy and organ or bone marrow transplantation. Candida albicans is often associated with serious systemic fungal infections, however other Candida species such as Candida krusei, Candida tropicalis and Candida glabrata, as well as Cryptococcus neoformans and filamentous fungi such as Aspergillus, have also emerged as clinically significant fungal pathogens. Two triazole antifungal agents, fluconazole and itraconazole, were introduced over a decade ago and since then have been used extensively for the prophylaxis and treatment of a variety of fungal infections. Although both drugs are effective and have their place in therapy, limitations regarding the utility of these agents do exist. For example, fluconazole is not effective for the prophylaxis or treatment of Aspergillus species and has limited activity against C. krusei and C. glabrata. The use of itraconazole has been limited secondary to concerns regarding unpredictable bioavailability. The rising incidence of fungal infections and the reported increase of non-albicans candidal infections noted over the past two decades highlight the need for new antifungal agents with improved spectra of activity. Several new triazole agents are in various phases of preclinical and clinical trials and may be available for human use in the near future. Three such agents voriconazole, posaconazole and ravuconazole are reviewed and compared with existing agents.     

伊曲康唑注射液治疗深部真菌感染

目的:评价伊曲康唑注射液治疗深部真菌感染的有效性和安全性.方法:采用开放性临床研究,治疗深部真菌感染患者22例.确诊4例、拟诊10例、经验性治疗8例.剂量用法:d1～d2,伊曲康唑注射液200mg,iv,bid;d3～d14,200mg,iv,qd;d15～d42,改用伊曲康唑胶囊200mg,bid.结果:确诊和拟诊的14例患者真菌清除率为6/14,阴转率为6/14;综合疗效评价有效率为8/14,痊愈率为2/14.不良反应发生率为12/28.结论:伊曲康唑注射液治疗重症深部真菌感染安全有效.     

Posaconazole: a new broad-spectrum antifungal agent

The rising incidence of invasive fungal infections and the emergence of broader fungal resistance have led to the need for novel antifungal agents. Posaconazole is a new member of the triazole class of antifungals. It is available as an oral suspension and has a favorable toxicity profile, has demonstrated clinical efficacy in the treatment of oropharyngeal candidiasis and has shown promise as salvage therapy for invasive aspergillosis, zygomycosis, cryptococcal meningitis and a variety of other fungal infections. In addition, data from randomized controlled studies support its efficacy for use in prophylaxis of invasive fungal infections in patients who are severely immunocompromised. The wide spectrum activity of posaconazole in in vitro studies, animal models and preliminary clinical studies suggest that posaconazole represents an important addition to the antifungal armamentarium.