Prophylaxis and treatment of fungal infections associated with haematological malignancies

Patients with haematological malignancies form one of the most susceptible host groups for microbial infection, especially during neutropenia. The incidence of invasive fungal infections has increased in recent years, highlighting the need for better diagnosis and more effective antifungal therapies. Amphotericin B is the drug of choice for many fungal infections, although toxicity and the need for intravenous infusion restrict its use. When possible, oral administration of antifungal agents is preferable but intravenous administration is often needed and current oral agents have their limitations: fluconazole because of a narrow spectrum of activity; itraconazole capsules because of erratic absorption. In this review, prophylactic and treatment options for systemic fungal infections are discussed. The specific needs of patients with different types of leukaemia and the benefits of new amphotericin B and itraconazole formulations are examined.     

Itraconazole: pharmacology, clinical experience and future development

Itraconazole is an orally active, broad-spectrum, triazole antifungal agent which has a higher affinity for fungal cytochrome P-450 than ketoconazole but a low affinity for mammalian cytochrome P-450. Itraconazole has a broader spectrum of activity than other azole antifungals and shows interesting pharmacokinetic features in terms of its tissue distribution. These properties have resulted in reduced treatment times for a number of diseases such as vaginal candidiasis, as well as effective oral treatment of several deep mycoses, including aspergillosis and candidiasis. Currently itraconazole is registered in 42 countries for the treatment of systemic fungal infections. Further development is concentrating on antifungal prophylaxis as well as on an oral solution and an intravenous formulation.     

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.     

Clinical pharmacokinetic monitoring of itraconazole is warranted in only a subset of patients

Itraconazole is a synthetic triazole antifungal agent that is commonly used in the prophylaxis and treatment of fungal infection. A role for itraconazole drug monitoring has been suggested previously; however, the advent of new formulations and increased clinical evidence may aid in further defining this role. Consequently, we have used a previously published decision-making algorithm to determine whether clinical pharmacokinetic monitoring of itraconazole is warranted. First, itraconazole has proven efficacy for the prophylaxis and treatment of fungal infection in immunocompromised individuals such as neutropenic cancer, human immunodeficiency virus (HIV), and solid organ transplant patients. Several assays have been developed to quantify itraconazole and its main metabolite in patient plasma. Measurement of these plasma drug levels in many clinical studies has resulted in no clear definition of a relationship between concentration and efficacy. However, limited evidence suggests a correlation between itraconazole levels greater than 250 or 500 ng/mL and increased efficacy. Clinical monitoring of efficacy is difficult because of the challenges in diagnosis of fungal infections and nonspecific clinical symptoms associated with fungal infections. Pharmacokinetic studies of itraconazole indicate that significant inter- and intrapatient variability exists in both healthy and immunocompromised patient populations, although subpopulations such as neutropenic cancer and HIV patients appear to require more drug than their healthy counterparts to attain similar drug levels. A therapeutic range has not been defined for itraconazole, but because of its relatively minimal side effects, a narrow range is unlikely. Drug interactions can occur with itraconazole because it is both an inhibitor and substrate of the cytochrome P450 3A4 (CYP3A4) enzyme and P-glycoprotein transporter systems. Protein binding alterations could also lead to differences in drug effect. Last, the duration of treatment of prophylaxis is significantly long to propose a potential benefit from drug monitoring. From weighing the available evidence, it appears that itraconazole drug level monitoring would provide more information on efficacy than clinical judgment alone in a subset of patients. Immunosuppressed patients requiring preventative therapy who have suspected poor absorption, are on concomitant enzyme inducers, or are suspected to be noncompliant would have the greatest benefit from itraconazole drug monitoring.     

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.     

Itraconazole

Itraconazole is a broad spectrum triazole antifungal agent. It has favourable pharmacodynamic and pharmacokinetic profiles and is available as both oral and iv. formulations. Over the last two decades, clinical and animal infection studies have demonstrated the efficacy of itraconazole in a wide range of superficial fungal infections including difficult-to-treat dermatophytoses and onychomycoses. Furthermore, shortened treatment regimens have proven to be effective, ranging from 1-day treatment for vaginal candidosis to 1-week pulse therapy per month, for 2 - 4 months, in onychomycosis and follicular dermatophytosis. Clinical experience with itraconazole in the treatment of deep mycoses is less comprehensive. However, results in systemic candidosis, sporotrichosis, blastomycosis, paracoccidioiodomycosis, certain types of histoplasmosis and aspergillosis are extremely encouraging. Itraconazole is less effective in the treatment of chromomycosis and coccidioidomycosis. Nevertheless, considering the refractory nature of these diseases, itraconazole has proven to be a valuable addition to the antifungal drugs currently available for treatment. Itraconazole has been well-tolerated with doses of up to 400 mg/day being generally free of serious adverse effects. However, a potential for drug interactions exists, mediated through the cytochrome P450 enzyme 3A4 system, which should be considered when itraconazole is used as part of a multi-drug regimen.     

Itraconazole

Itraconazole is a broad spectrum triazole antifungal agent. It has favourable pharmacodynamic and pharmacokinetic profiles and is available as both oral and i.v. formulations. Over the last two decades, clinical and animal infection studies have demonstrated the efficacy of itraconazole in a wide range of superficial fungal infections including difficult-to-treat dermatophytoses and onychomycoses. Furthermore, shortened treatment regimens have proven to be effective, ranging from 1-day treatment for vaginal candidosis to 1-week pulse therapy per month, for 2-4 months, in onychomycosis and follicular dermatophytosis. Clinical experience with itraconazole in the treatment of deep mycoses is less comprehensive. However, results in systemic candidosis, sporotrichosis, blastomycosis, paracoccidioiodomycosis, certain types of histoplasmosis and aspergillosis are extremely encouraging. Itraconazole is less effective in the treatment of chromomycosis and coccidioidomycosis. Nevertheless, considering the refractory nature of these diseases, itraconazole has proven to be a valuable addition to the antifungal drugs currently available for treatment. Itraconazole has been well-tolerated with doses of up to 400 mg/day being generally free of serious adverse effects. However, a potential for drug interactions exists, mediated through the cytochrome P450 enzyme 3A4 system, which should be considered when itraconazole is used as part of a multi-drug regimen.     

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.     

Population pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole in paediatric cystic fibrosis and bone marrow transplant patients

OBJECTIVE: The objective of the study was to characterise the population pharmacokinetic properties of itraconazole and its active metabolite hydroxy-itraconazole in a representative paediatric population of cystic fibrosis and bone marrow transplant (BMT) patients and to identify patient characteristics influencing the pharmacokinetics of itraconazole. The ultimate goals were to determine the relative bioavailability between the two oral formulations (capsules vs oral solution) and to optimise dosing regimens in these patients. METHODS: All paediatric patients with cystic fibrosis or patients undergoing BMT at The Royal Children's Hospital, Brisbane, QLD, Australia, who were prescribed oral itraconazole for the treatment of allergic bronchopulmonary aspergillosis (cystic fibrosis patients) or for prophylaxis of any fungal infection (BMT patients) were eligible for the study. Blood samples were taken from the recruited patients as per an empirical sampling design either during hospitalisation or during outpatient clinic visits. Itraconazole and hydroxy-itraconazole plasma concentrations were determined by a validated high-performance liquid chromatography assay with fluorometric detection. A nonlinear mixed-effect modelling approach using the NONMEM software to simultaneously describe the pharmacokinetics of itraconazole and its metabolite. RESULTS: A one-compartment model with first-order absorption described the itraconazole data, and the metabolism of the parent drug to hydroxy-itraconazole was described by a first-order rate constant. The metabolite data also showed one-compartment characteristics with linear elimination. For itraconazole the apparent clearance (CL(itraconazole)) was 35.5 L/hour, the apparent volume of distribution (V(d(itraconazole)) was 672 L, the absorption rate constant for the capsule formulation was 0.0901 h(-)(1) and for the oral solution formulation was 0.96 h(-1). The lag time was estimated to be 19.1 minutes and the relative bioavailability between capsules and oral solution (F(rel)) was 0.55. For the metabolite, volume of distribution, V(m)/(F . f(m)), and clearance, CL/(F . f(m)), were 10.6L and 5.28 L/h, respectively. The influence of total bodyweight was significant, added as a covariate on CL(itraconazole)/F and V(d(itraconazole))/F (standardised to a 70 kg person) using allometric three-quarter power scaling on CL(itraconazole)/F, which therefore reflected adult values. The unexplained between-subject variability (coefficient of variation %) was 68.7%, 75.8%, 73.4% and 61.1% for CL(itraconazole)/F, V(d)((itraconazole)())/F, CL(m)/(F . f(m)) and F(rel), respectively. The correlation between random effects of CL(itraconazole) and V(d(itraconazole)) was 0.69. CONCLUSION: The developed population pharmacokinetic model adequately described the pharmacokinetics of itraconazole and its active metabolite, hydroxy-itraconazole, in paediatric patients with either cystic fibrosis or undergoing BMT. More appropriate dosing schedules have been developed for the oral solution and the capsules to secure a minimum therapeutic trough plasma concentration of 0.5 mg/L for these patients.     

Reduced food-effect and enhanced bioavailability of a self-microemulsifying formulation of itraconazole in healthy volunteers.

Self-microemulsifying drug delivery systems (SMEDDS) represent a possible alternative to traditional oral formulations of lipophilic compounds. This study was designed to compare the oral bioavailability and food-effect of SMEDDS of itraconazole (ITRA-GSMP capsule containing 50mg itraconazole) to that of the currently marketed formulation (Sporanox capsule containing 100mg itraconazole). Eight healthy volunteers received Sporanox or ITRA-GSMP capsule in the fasted state or after a high-fat diet on four separate dosing occasions with a 2-week washout period. Blood samples were collected and analyzed. After administration of the ITRA-GSMP capsule, AUC0-24 and Cmax were 1.9- and 2.5-fold higher in the fasted state and 1.5- and 1.3-fold higher in the fed state, respectively, than those of the Sporanox capsule. Moreover, ITRA-GSMP capsules yielded more reproducible blood-time profiles than Sporanox capsules. Food had a marked effect on itraconazole absorption from the Sporanox capsule, whereas the influence was less pronounced for the ITRA-GSMP capsule. Collectively, our data suggest that a new self-microemulsifying formulation may provide an alternative oral formulation for itraconazole with improved oral bioavailability and reduced food-effect.     

Standard antifungal therapy in neutropenic patients

Fungal infections are life-threatening complications in patients with prolonged neutropenia. Amphotericin B, which is fungicidal and has a broad spectrum of antifungal activity, remains the current gold standard agent. However, because of its low therapeutic index, new lipid formulations of amphotericin B have been developed with better tolerance and less toxicity. The use of 5-fluorocytosine is waning because of the medullar toxicity of this agent. Fluconazole and itraconazole are both fungistatic and are more convenient for the treatment of fungal infections in haemodynamically stable patients.     

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.     

Impact of Absolute Stereochemistry on the Antiangiogenic and Antifungal Activities of Itraconazole

Itraconazole is used clinically as an antifungal agent and has recently been shown to possess antiangiogenic acitivity. Itraconazole has three chiral centers that give rise to eight stereoisomers. The complete role of stereochemistry in the two activities of itraconazole, however, has not been addressed adequately. For the first time, all eight stereoisomers of itraconazole (1a-1h) have been synthesized and evaluated for activity against human endothelial cell proliferation and for antifungal activity against five fungal strains. Distinct antiangiogenic and antifungal activity profiles of the trans- stereoisomers, especially 1e and 1f, suggest different molecular mechanisms underlying the anti-angiogenic and anti-fungal activities of itraconazole.     

Effect of food on the absorption and pharmacokinetics of prednisolone from enteric-coated tablets

Summary We have studied the influence of food and dose (50, 100, 200 mg) on the oral systemic availability of the broad spectrum antifungal itraconazole and the pharmacokinetics after repeated dosing of 100 mg in six healthy volunteers.The relative systemic availability of itraconazole capsules compared with solution averaged 39.8% in the fasting state but 102% in the post-prandial state. Food did not significantly affect the t_max of the capsules. Itraconazole AUC at single doses of 50, 100, and 200 mg had a ratio of 0.3:1:2.7, and the steady-state AUC (0–24) after 15 days of 100 mg was five times the single-dose AUC.These findings suggest non-linear itraconazole pharmacokinetics in the range of therapeutically used doses. Furthermore, capsules should be given shortly after a meal to ensure optimal oral systemic availability.     

Pharmacokinetics of antifungal agents in onychomycoses

Onychomycosis is caused by infection by fungi, mainly dermatophytes and nondermatophyte yeasts or moulds; it affects the fingernails and, more frequently, the toenails. Dermatophytes are responsible for about 90 to 95% of fungal infections. Trichophyton rubrum is the most common dermatophyte; Candida albicans is the major nondermatophyte yeast. Although topical therapy of onchomycosis does not lead to systemic adverse effects or interactions with concomitantly taken drugs, it does not provide high cure rates and requires complete compliance from the patient. At present there are 3 oral antifungal medications that are generally used for the short term treatment of onychomycosis: itraconazole, terbinafine and fluconazole. The persistence of these active drugs in nails allows weekly administration, reduced treatment or a pulse regimen. Good clinical and mycological efficacies are obtained with itraconazole 100 to 200 mg daily, terbinafine 250mg daily for 3 months, or fluconazole 150 mg weekly for at least 6 months. Itraconazole is a synthetic triazole with a broad spectrum of action. It is well absorbed when administered orally and can be detected in nails 1 to 2 weeks after the start of therapy. The nail : plasma ratio stabilises at around 1 by week 18 of treatment. Itraconazole is still detectable in nails 27 weeks after stopping administration. Nail concentrations are higher than the minimum inhibitory concentration (MIC) for most dermatophytes and Candida species from the first month of treatment. The elimination half-life of itraconazole from nails is long, ranging from 32 to 147 days. Terbinafine is a synthetic allylamine that is effective against dermatophytes. Terbinafine is well absorbed from the gastrointestinal tract, and the time to reach effective concentrations in nail is 1 to 2 weeks. The half-life is from 24 to 156 days, explaining the observed persistence of terbinafine in nails for longer than 252 days. Fluconazole is a bis-triazole broad spectrum antifungal with high oral bioavailability. The uptake of fluconazole by nail increases with the length of treatment, and nail : plasma ratios are generally 1.5 to 2 at steady state. Fluconazole concentrations exceed the MIC for Candida species soon after the start of treatment. Fluconazole concentrations fall slowly after the drug is stopped, with a half-life of 50 to 87 days, and fluconazole is still detectable in nails 5 months after the end of treatment. All these drugs are potent inhibitors of cytochrome P450 (CYP) enzymes and may increase the plasma concentrations of concomitantly used drugs. Itraconazole inhibits CYP3A4. Fluconazole inhibits CYP3A4, but to a lesser degree than itraconazole, CYP2C9 and CYP2C19. Terbinafine inhibits CYP2D6.     

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.     

抗真菌药伊曲康唑的药代动力学研究概况

伊曲康唑为三唑类广谱抗真菌药,对浅表真菌、深部真菌感染均有显著疗效,且耐受性良好,临床应用广泛。本文对伊曲康唑在体内的吸收、分布、代谢、排泄的药代动力学特征和影响研究,以及不同患者群体中的药动学作一综述,促进临床合理使用。     

A mucoadhesive, cyclodextrin-based vaginal cream formulation of itraconazole

The development of vaginal medications, especially antifungal medications, requires that the drug is solubilized as well as retained at or near the mucosa for sufficient periods of time to ensure adequate bioavailability. Itraconazole is a broad-spectrum antifungal agent, which has been used for some time orally and intravenously but for which a vaginal formulation has not yet been developed. We present here a novel itraconazole formulation intended for vaginal use based on hydroxypropyl-β-cyclodextrin (HPβCD), a functional excipient that increases drug solubility and generates a mucoadhesive system in the presence of other ingredients. An aqueous phase was prepared by solubilizing itraconazole with HCl in the presence of propylene glycol and then adding an aqueous solution of HPβCD. After pH adjustment, the itraconazole/HPβCD solution was added to the oil phase (paraffin oil, trihydroxystearate, and cetyl dimethicon copolyol) and the desired cream containing 1%, 2%, and 2.5% drug obtained by homogenization. Primary irritation studies and subchronic toxicity studies using a rabbit vaginal model indicated that the formulation was safe, well tolerated, and retained in the vaginal space. Clinical investigations indicated that application of 5 g of a 2% cream was very well tolerated and itraconazole was not systemically absorbed. Additional studies in women found that the itraconazole cream was highly effective in reducing or eliminating fungal cultures with few adverse effects. These studies suggested that an HPβCD-based, emulsified wax cream formulation was a useful and effective dosage form for treating vaginal candidiasis.     

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。     

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.