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 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.     

Common fungal infections of the feet in patients with diabetes mellitus

Superficial fungal infections of the foot (tinea pedis and onychomycosis) are common among elderly patients. Although most authorities believe that patients with diabetes mellitus have an increased predisposition to dermatophytic infections, some controversies still remain. Because these infections disrupt the skin integrity and provide an avenue for bacterial superinfection, elderly diabetic patients with dermatophytic infection should be promptly treated with an antifungal agent. For most dermatophytic infections of the foot, topical agents are usually effective and less expensive than oral agents. Laboratory diagnosis of fungal infection prior to institution of therapy is recommended. Proper technique for obtaining the specimen is important to ensure a higher chance of isolating the infecting fungus. Commonly used anti-dermatophytic agents that are also active against the yeasts include the imidazoles, the allylamines-benzylamines and the hydroxypyridones, which are also effective against most of the moulds. Oral therapy for tinea pedis, although not well studied, should be limited to patients with more extensive infections, such as vesicobullous and moccasin type, resistant infections or chronic infections. In addition, oral agents should also be considered in diabetic and immunosuppressed patients. On the other hand, treatment of onychomycosis of the foot usually requires systemic therapy. Griseofulvin is the least effective agent when compared with the newer agents. Terbinafine, itraconazole and fluconazole have been shown to have acceptable cure rates. More recently, topical treatment of the nail with 8% ciclopirox nail lacquer, bifonazole with urea and amorolfine have been reported to be successful. Over the past decade, fungal foot infections of the skin and nail are more effectively treated with the introduction of numerous topical and oral agents.     

Terbinafine. A pharmacoeconomic evaluation of its use in superficial fungal infections

Terbinafine is an orally and topically active allylamine antifungal drug which is an effective and well tolerated therapy for a wide range of superficial dermatophyte infections. In contrast to most other commonly prescribed antifungal agents, terbinafine is fungicidal in vitro and possesses improved pharmacokinetic properties with respect to drug penetration into nail tissue following oral administration. These properties enable terbinafine to achieve high success rates with shortened therapy regimens in the treatment of dermatophyte skin infections and onychomycosis. Pharmacoeconomic analyses have shown that oral terbinafine, with its higher rates of clinical efficacy and lower rates of relapse/reinfection, is less costly and more cost effective than oral griseofulvin, ketoconazole and itraconazole when used as initial therapy in the treatment of onychomycosis. However, some points regarding the clinical efficacy of itraconazole relative to terbinafine and the drug treatment regimens used in these studies need further clarification. In the management of tinea pedis, a cost analysis suggested that initial therapy with terbinafine 1% cream was more costly than initial therapy with miconazole, oxiconazole or clotrimazole. However, in cost-effectiveness studies, terbinafine had a lower cost per disease-free day than ciclopirox, clotrimazole, ketoconazole and miconazole in the treatment of dermatophyte skin infections. In conclusion, available clinical and pharmacoeconomic data support the use of topical terbinafine as first-line treatment of dermatophyte skin infections unless the acquisition cost of terbinafine is markedly greater than that of alternative topical antifungal agents. Oral terbinafine can be recommended as a cost-effective first-line treatment, preferable to oral griseofulvin, ketoconazole and itraconazole, in patients with dermatophyte onychomycosis.     

Management of toenail onychomycosis.

The treatment of toenail onychomycosis is reviewed. Onychomycosis contributes to 40% of all nail disorders and appears to be increasing in frequency. Mycotic nail infections are usually caused by dermatophytes, yeasts, and nondermatophyte molds. Most cases of toenail onychomycosis are caused by dermatophytes. Mycotic nail infections do not always resolve spontaneously and may have a substantial impact on the patient's quality of life. Current treatment modalities for onychomycosis include surgery, topical antifungals, and oral antifungals. Surgery is generally not recommended as first-line therapy. Broad-spectrum topical and oral antifungal agents are the most frequently used treatments. Topical treatment is well tolerated but is usually not effective because of poor patient compliance and inadequate penetration of the nail. Oral antifungals are more successful but carry greater risks. Griseofulvin and ketoconazole have been oral antifungals traditionally used for onychomycosis, but these agents are associated with relatively low cure rates. Itraconazole and terbinafine are both safe and effective first-line agents, with reported overall cure rates of 50-90% for dermatophyte-related onychomycosis. Intermittent oral antifungal therapy may reduce the risk of systemic adverse effects and the cost of therapy; more study of this approach is needed. Oral antifungal agents offer patients with toenail onychomycosis greater likelihood of a cure than topical antifungals, but oral therapy carries greater risks and requires closer monitoring.     

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.     

Onychomycosis in the elderly

Onychomycosis is found more frequently in the elderly, and in more males than females. Onychomycosis of the toes is usually caused by dermatophytes, most commonly Trichophyton rubrum and T. mentagrophytes. The most common clinical presentations are distal and lateral subungual onychomycosis (which usually affects the great/first toe) and white superficial onychomycosis (which generally involves the third/fourth toes). Only about 50% of all abnormal-appearing nails are due to onychomycosis. In the remainder, trauma to the nail, psoriasis and conditions such as lichen planus should be considered in the differential diagnosis. Therefore, the clinical impression of onychomycosis should be confirmed by mycological examination, whenever possible. The management of onychomycosis may include no therapy, palliative treatment with mechanical or chemical debridement, topical antifungal therapy, oral antifungal agents or a combination of treatment modalities. In the US, the only new oral agents approved for treatment of onychomycosis are terbinafine and itraconazole. Fluconazole is approved for onychomycosis in some other countries. Ciclopirox nail lacquer has recently been approved in the US for the treatment of onychomycosis. In some other countries topical agents such as amorolfine are also used. Griseofulvin and ketoconazole are no longer preferred for the treatment of onychomycosis. The new oral antifungal agents are effective and well tolerated in the elderly. Patient selection should be based on the history (including systems review and medication record), examination and baseline monitoring, if indicated. Laboratory monitoring during therapy for onychomycosis varies among physicians. A combination of removal of the diseased nail plate or local measures and oral antifungal therapy may be optimal in certain instances, e.g. when lateral onychomycosis or dermatophytoma are present. For dermatophyte toe onychomycosis the recommended duration of therapy with terbinafine is 250 mg/day for 12 weeks. For itraconazole (pulse) the regimen is 200 mg twice daily for 1 week on, 3 weeks off, repeated for 3 consecutive pulses and with fluconazole the regimen is 150 to 300 mg once weekly given for a usual range of 6 to 12 months or until the nail plate has grown out. In some instances, if extra therapy is required, one suggestion is that 4 weeks of terbinafine or an extra pulse of itraconazole are given between months 6 and 9 from the start of therapy. Once cure has been achieved, it is important to counsel patients on the strategies of reducing recurrence of disease.     

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.     

Pharmacology of itraconazole

Itraconazole is a triazole antifungal agent that has a broad spectrum of activity and is well tolerated. Itraconazole is highly efficacious, particularly because its main metabolite, hydroxy-itraconazole, also has considerable antifungal activity. The original capsule formulation of itraconazole may lead to variability in absorption and the plasma concentration. For the treatment of superficial fungal infections, this is not problematical because itraconazole accumulates at the infection site, making consistently high plasma concentrations unnecessary -- a characteristic that has been exploited in the development of a pulse regimen. Because consistent plasma concentrations are critical for the more serious systemic fungal infections, variable absorption of itraconazole from the capsules limits their application. Moreover, underlying disease processes and medical interventions can reduce absorption from the capsules in some patients with systemic fungal infections. To widen the beneficial application of itraconazole to include such patients, an oral solution and an intravenous formulation were developed. These formulations combine lipophilic itraconazole with hydroxypropyl-beta-cyclodextrin, a ring of substituted glucose molecules, which improves the solubility of itraconazole. The enhanced absorption and bioavailability of itraconazole from these new formulations make them ideal for the treatment of systemic fungal infections in a wide range of patient populations. The additional flexibility offered by the different routes of administration also means that itraconazole can be used in patients at high risk, such as children or those requiring intensive care, for whom the capsule formulation may be impractical.     

Terbinafine. An update of its use in superficial mycoses.

Terbinafine is an allylamine antifungal agent which has fungicidal activity against a wide variety of dermatophytes, moulds and certain dimorphic fungi, and fungistatic activity against Candida albicans. Oral terbinafine 250 mg/day is effective in the treatment of superficial dermatophyte infections such as onychomycosis, tinea pedis and tinea corporis/cruris, generally achieving mycological cure in > 80% of patients. The drug is also effective in children with tinea capitis when administered orally in the dosage range 62.5 to 250 mg/day for 4 weeks. Comparative data indicate that oral terbinafine is more effective than continuous or intermittent intraconazole in dermatophyte onychomycosis, and is as effective as itraconazole 400 mg/day in tinea pedis. The drug has shown greater efficacy than griseofulvin in dermatophyte onychomycosis, tinea pedis and tinea corporis/cruris, and comparable efficacy in children with tinea capitis. Additionally, oral terbinafine is more effective than ketoconazole 200 mg/day in tinea corporis/cruris. Topical terbinafine 1% formulations are effective when applied once or twice daily for up to 2 weeks, achieving mycological cure in > 80% of patients with tinea pedis, tinea corporis/cruris, cutaneous candidiasis and pityriasis versicolor. Its formulations are at least as effective as miconazole 2% cream and naftifine 1% gel in tinea pedis, and more effective than clotrimazole 1% cream, bifonazole 1% cream and oxiconazole 1% lotion. Mycological cure rates achieved with terbinafine generally improve after treatment cessation, reflecting the drug's fungicidal mechanism of action and its residual effect in tissue. Terbinafine is well tolerated after oral or topical administration and has a relatively low potential for drug interactions. Pharmacoeconomic data support the use of terbinafine in dermatophyte infections of the skin or nails. CONCLUSIONS: Evidence suggests that oral terbinafine is the treatment of choice for dermatophyte onychomycosis, as it achieves high rates of mycological and clinical cure, is generally well tolerated and has a relatively low potential for drug interactions. It must also be considered a first-line treatment option, along with itraconazole, in cutaneous mycoses which warrant systemic treatment; topical terbinafine is a treatment of choice in less extensive mycoses. The use of terbinafine in non-dermatophyte or mixed infections has not been fully defined.     

A risk-benefit assessment of the newer oral antifungal agents used to treat onychomycosis.

The newer antifungal agents itraconazole, terbinafine and fluconazole have become available to treat onychomycosis over the last 10 years. During this time period these agents have superseded griseofulvin as the agent of choice for onychomycosis. Unlike griseofulvin, the new agents have a broad spectrum of action that includes dermatophytes, Candida species and nondermatophyte moulds. Each of the 3 oral antifungal agents, terbinafine, itraconazole and fluconazole, is effective against dermatophytes with relatively fewer data being available for the treatment of Candida species and nondermatophyte moulds. Itraconazole is effective against Candida onychomycosis. Terbinafine may be more effective against C. parapsilosis compared with C. albicans; furthermore with Candida species a higher dose of terbinafine or a longer duration of therapy may be required compared with the regimen for dermatophytes. The least amount of experience in treating onychomycosis is with fluconazole. Griseofulvin is not effective against Candida species or the nondermatophyte moulds. The main use of griseo-fulvin currently is to treat tinea capitis. Ketoconazole may be used by some to treat tinea versicolor with the dosage regimens being short and requiring the use of only a few doses. The preferred regimens for the 3 oral antimycotic agents are as follows: itraconazole - pulse therapy with the drug being administered for 1 week with 3 weeks off treatment between successive pulses; terbinafine - continuous once daily therapy; and fluconazole - once weekly treatment. The regimen for the treatment of dermatophyte onychomycosis is: itraconazole - 200mg twice daily for I week per month x 3 pulses; terbinafine - 250 mg/day for 12 weeks; or, fluconazole - 150 mg/wk until the abnormal-appearing nail plate has grown out, typically over a period of 9 to 18 months. For the 3 oral antifungal agents the more common adverse reactions pertain to the following systems, gastrointestinal (for example, nausea, gastrointestinal distress, diarrhoea, abdominal pain), cutaneous eruption, and CNS (for example, headache and malaise). Each of the new antifungal agents is more cost-effective than griseofulvin for the treatment of onychomycosis and is associated with high compliance, in part because of the shorter duration of therapy. The newer antifungal agents are generally well tolerated with drug interactions that are usually predictable.     

伊曲康唑与氟康唑在重症监护室早期经验性治疗真菌感染的疗效比较

目的比较伊曲康唑和氟康唑在重症监护室早期经验性治疗中的有效性和安全性。方法采取随机、对照、开放的临床试验，入选的40例患者具有真菌感染的高危因素，均出现不明原因发热，广谱抗生素治疗3～7 d无效。将入选患者随机分配为伊曲康唑治疗组和氟康唑治疗组各20例。伊曲康唑治疗组给予伊曲康唑注射液200 mg，q12 h，先治疗2 d，随后给予200 mg，qd，共5 d，再改用伊曲康唑口服液口服，每次200 mg，bid，治疗14 d；氟康唑治疗组给予氟康唑注射液400 mg静脉滴注，qd，共治疗21 d。观察患者体温变化、真菌感染情况、药物相关的不良反应和疗效。结果伊曲康唑组总有效率65.0%，不良反应率30.0%；氟康唑组总有效率50.0%，不良反应率5.0%，但两组总有效率和不良反应发生率均差异无显著性（均P＞0.05）。治疗过程中，氟康唑组出现2例深部真菌感染。结论伊曲康唑和氟康唑均可作为现阶段重症监护室早期经验性治疗的一线药物，但伊曲康唑疗效更佳。     

抗真菌药物在皮肤科临床应用新进展

真菌感染在皮肤科较为常见，临床上感染真菌后可引起浅部真菌部和深部真菌病。治疗以抗真菌药物治疗为主。浅部真菌病一般采用外用药治疗，对某些顽固性浅部真菌病及深部真菌病应进行系统的抗真菌治疗。本文简要介绍了近几年抗真菌药物在皮肤科临床应用新进展。     

伊曲康唑间隙冲击疗法治疗甲真菌病120例

目的观察国产伊曲康唑（易启康）冲击疗法治疗甲真菌病的临床疗效,寻求有效而经济的治疗手段。方法120例甲真菌病患者每天口服易启康2次,每次200mg,连用7d,停药21d为1个疗程。指甲真菌病患者用药2个疗程,趾甲真菌病及指趾甲真菌病伴皮肤感染真菌病患者用药3个疗程,分别观察临床疗效和不良反应情况。结果52例指甲真菌病患者临床痊愈率为90．38％,68例趾甲真菌病及指趾甲真菌病伴皮肤感染真菌病患者临床痊愈率为83．82％,伴皮肤真菌感染者真菌清除率分别为96％和95％,不良反应发生率为4．17％。结论易启康短期冲击疗法治疗甲真菌病疗程短、疗效高、副作用小、安全性高而费用低,值得临床推广使用。     

Use of antifungal drugs in pregnancy: a focus on safety.

The use of antifungals in pregnancy requires special consideration for the safety of the developing fetus. Clinicians now have an increased repertoire of both topical and systemic antimycotics available to treat superficial or mucotaneous fungal infections including Candida vaginitis. The ability of many nontopical antifungals to penetrate the placenta and achieve measurable, often therapeutic, concentrations in cord blood, fetal tissue and amniotic fluid means that evidence exists of successful treatment of all varieties of systemic fungal disease in pregnant women, even with placental involvement. However, for the same reasons, safety considerations remain a concern. Although the use of azoles as topical agents for superficial infections is both efficacious and well tolerated, especially when used for short periods, systemic azole therapy is not recommended in pregnancy. Accordingly, amphotericin B remains the drug of choice for systemic, invasive mycotic infections, whether life-threatening or less severe. Unfortunately little if any information is available regarding the safety of the newer lipid formulations of amphotericin B. There is a general reluctance to perform randomised, comparative studies involving antifungal agents in pregnancy, hence cumulative anecdotal reports form much of the available data; animal studies, although useful, have several drawbacks. There is a need for additional safe and effective new antifungal agents for widespread use in pregnant women.     

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.     

Which antifungal agent for onychomycosis? A pharmacoeconomic analysis.

The incidence of fungal nail infections is increasing and this is possibly because of several factors: better methods of detection, a growing population of immunocompromised patients who have a greater susceptibility to such infections, the increased use of immunosuppressive drugs, the increasing number of elderly people, worldwide travel, and the use of communal bathing facilities. Onychomycosis is a fungal infection of the fingernails and toenails that accounts for about 30% of all superficial fungal infections. It is characterised by nail discoloration, thickening and ultimately destruction of the nail plate. Management of this disease has improved significantly and treatment patterns have dramatically changed in recent years as a result of advances in new treatment options (e.g. oral antifungal agents) and changes in treatment regimens (e.g. pulse therapy). Also, newer drugs for onychomycosis have improved tolerability profiles compared with older agents. The overall costs of treating onychomycosis are substantial, and it has been estimated that direct cost for US Medicare patients with the disease is 43 million US dollars per year (year of costing not available). Pharmacoeconomic studies help in the decision-making process when selecting the most cost-effective antifungal agents to treat onychomycosis. To date there have been a number of national and international economic studies aimed at effectively assessing the efficacy and costs of the treatment options available to cure onychomycosis. The objectives of this paper are to (i) review the published findings regarding the epidemiology of onychomycosis; (ii) summarise the original pharmacoeconomic studies that describe the economic impact of the disease; and (iii) address the impact of the disease on patients' health-related quality of life.     

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.     

Treatment of systemic fungal infections in older patients: achieving optimal outcomes

Systemic fungal infections are an increasing problem in older adults. For several of the endemic mycoses, this increase is the result of increased travel and leisure activities in areas endemic for these fungi. Immunosuppressive agents, care in an intensive care unit, and invasive devices all contribute to infection with opportunistic fungi. Treatment of systemic fungal infections is usually with an azole or amphotericin B. The preferred regimen depends on the specific fungal infection, the site and the severity of the infection, the state of immunosuppression of the patient and the possible toxicities of each drug for a specific patient. In older adults, drug-drug interactions between the azoles and drugs commonly prescribed for older persons may lead to serious toxicity, and absorption of itraconazole can be problematic. Amphotericin B is associated with significant nephrotoxicity, especially in older adults with pre-existing renal disease, and infusion-related adverse effects. Newer lipid formulations of amphotericin B can obviate some of these toxicities, but their role in the treatment of systemic fungal infections in older adults has not yet been clarified.