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.     

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.     

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.     

Systemic antifungal therapy: new options, new challenges

The frequency of invasive fungal infections has increased dramatically in recent decades because of an expanding population at risk. Until now, treatment options for invasive mycoses have been primarily amphotericin B and the azoles, fluconazole and itraconazole. Traditional agents are limited by an inadequate spectrum of activity, drug resistance, toxicities, and drug-drug interactions. The recent approval of caspofungin and voriconazole clearly has expanded the number of existing antifungal drugs available. However, the enthusiasm that accompanies their availability is counterbalanced by limited clinical experience, high drug acquisition costs, and distinctive toxicities. The pharmacologic characteristics, extent of clinical experience (efficacy and toxicity), and drug acquisition costs among available systemic antifungal agents are compared, with emphasis on the new agents. Also, recommendations on the role of each agent are provided according to the most common indications for systemic antifungal therapy: invasive candidiasis, invasive aspergillosis, and febrile neutropenia.     

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.     

Management of systemic candidal infections in the intensive care unit.

Risk factors and treatment strategies for systemic candidal infections in the intensive care unit (ICU) are discussed. The past two decades have seen a dramatic increase in the frequency of infections caused by Candida species. Risk factors associated with candidemia include treatment with multiple antimicrobials for extended periods, presence of central venous catheters, total parenteral nutrition, colonization by Candida species, abdominal surgery, prolonged stay in the ICU, and compromised immune status. Since the 1960s, conventional amphotericin B has been the primary treatment option for fungal infections. Although effective, amphotericin B has extensive toxicity. Three lipid-based formulations of amphotericin B have been developed in an attempt to decrease nephrotoxicity and improve drug delivery. Practitioners have also been offered alternatives by the introduction of less toxic azole antifungals, such as ketoconazole, fluconazole, and itraconazole; however, their widespread use has resulted in other problems, such as the selection of resistant isolates. There is controversy concerning fluconazole's effectiveness. In the treatment of systemic candidal infections, especially in critically ill patients. Clinical trials do not support the prophylactic or empirical use of fluconazole in the ICU. Treating patients who have no microbiological evidence of infection provides no therapeutic benefit and shifts the fungal flora to noncandidal strains that are more resistant to fluconazole. Patients in ICUs are often susceptible to systemic candidal infection. Preemptive therapy with fluconazole may reduce mortality in high-risk patients. Fluconazole and amphotericin B appear equally effective in treating established systemic candidal infections.     

Antifungal agents in neonates: issues and recommendations

Fungal infections are responsible for considerable morbidity and mortality in the neonatal period, particularly among premature neonates. Four classes of antifungal agents are commonly used in the treatment of fungal infections in pediatric patients: polyene macrolides, fluorinated pyrimidines, triazoles, and echinocandins. Due to the paucity of pediatric data, many recommendations for the use of antifungal agents in this population are derived from the experience in adults. The purpose of this article was to review the published data on fungal infections and antifungal agents, with a focus on neonatal patients, and to provide an overview of the differences in antifungal pharmacology in neonates compared with adults. Pharmacokinetic data suggest dosing differences in children versus adult patients with some antifungals, but not all agents have been fully evaluated. The available pharmacokinetic data on the amphotericin B deoxycholate formulation in neonates exhibit considerable variability; nevertheless, the dosage regimen suggested in the neonatal population is similar to that used in adults. More pharmacokinetic information is available on the liposomal and lipid complex preparations of amphotericin B and fluconazole, and it supports their use in neonates; however, the optimal dosage and duration of therapy is difficult to establish. All amphotericin-B formulations, frequently used in combination with flucytosine, are useful for treating disseminated fungal infections and Candida meningitis in neonates. Fluconazole, with potent in vitro activity against Cryptococcus neoformans and almost all Candida spp., has been used in neonates with invasive candidiasis at dosages of 6 mg/kg/day, and for antifungal prophylaxis in high-risk neonates. There are limited data on itraconazole, voriconazole, and posaconazole use in neonates. Caspofungin, which is active against Candida spp. and Aspergillus spp., requires higher doses in children relative to adults, and dosing is best accomplished based on body surface area. Micafungin shows a clear trend toward lower levels in the smallest patients. There are no data on the use of other new antifungal drugs (ravuconazole and anidulafungin) in neonates. In summary, the initial data suggest dosage differences in neonates for some antifungal agents, although the newer agents have not been fully tested for optimal administration in these patients.     

New developments in chemotherapy for non-invasive fungal infections

Dermatomycosis and subcutaneous mycosis comprise the non-invasive fungal infections commonly encountered in clinical practice around the world. The limited activity of early topical antifungal agents prompted the development of more effective systemic agents. While griseofulvin has been used for more than four decades, the use of early azoles, such as ketoconazole have resulted in better patient compliance and thus greater success. However, poor response and recurrence in dermatomycosis, as well as toxicity associated with ketoconazole therapy, has led to the search for newer antifungal agents and more effective treatment strategies. Terbinafine, itraconazole and fluconazole have the advantage of non-toxicity and a broad spectrum of activity. An overview of non-invasive fungal infections, antifungal agents in clinical use and recent developments in antifungal therapy is reviewed in this article.     

Antifungal use in HIV infection

Systemic fungal infections continue to be a major cause of morbidity and mortality among HIV-infected patients. Mucosal candidiasis remains the most common fungal disease in this population, while cryptococcosis and aspergillosis are associated with significant mortality. Histoplasmosis and penicilliosis are relatively common in some areas. Blastomycosis, coccidioidomycosis and paracoccidioidomycosis have also been described in association with HIV. Over the last decade, a number of clinical trials have evaluated the use of antifungal therapies in this population and shaped our approach to prophylaxis and therapy. This report outlines the state of the art in the management of HIV-associated fungal infections and discusses the unique difficulties and drug-drug interactions associated with managing fungal infections in this population. Deoxycholate or liposomal formulations of amphotericin B and the triazoles fluconazole and itraconazole are the most commonly used antifungal agents. Healthcare providers should be familiar with the appropriate antifungal management and its limitations. Possible interactions with antiretrovirals should be considered when prescribing antifungal treatment. An exciting new decade in antifungal therapy is beginning, in which the second-generation triazoles and echinocandins will hopefully help us to overcome the limitations of the current antifungal arsenal.     

Antifungal use in HIV infection

Systemic fungal infections continue to be a major cause of morbidity and mortality among HIV-infected patients. Mucosal candidiasis remains the most common fungal disease in this population, while cryptococcosis and aspergillosis are associated with significant mortality. Histoplasmosis and penicilliosis are relatively common in some areas. Blastomycosis, coccidioidomycosis and paracoccidioidomycosis have also been described in association with HIV. Over the last decade, a number of clinical trials have evaluated the use of antifungal therapies in this population and shaped our approach to prophylaxis and therapy. This report outlines the state of the art in the management of HIV-associated fungal infections and discusses the unique difficulties and drug-drug interactions associated with managing fungal infections in this population. Deoxycholate or liposomal formulations of amphotericin B and the triazoles fluconazole and itraconazole are the most commonly used antifungal agents. Healthcare providers should be familiar with the appropriate antifungal management and its limitations. Possible interactions with antiretrovirals should be considered when prescribing antifungal treatment. An exciting new decade in antifungal therapy is beginning, in which the second-generation triazoles and echinocandins will hopefully help us to overcome the limitations of the current antifungal arsenal.     

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.     

Pharmacoeconomics of antifungal pharmacotherapy – challenges and future directions

The frequency and severity of invasive fungal infections have been increasingly recognised and new antifungal therapies have expanded the therapeutic armamentarium available to manage such infections. Antifungal agents comprise a significant portion of antibiotic expenditures at major medical centres, prompting adoption of cost-containment measures and treatment guidelines. This paper reviews available data regarding the costs associated with managing fungal infections, including pharmacoeconomic analyses that have been performed in the setting of documented fungal infections, as well as prophylactic and empiric use of antifungal agents. The challenges of performing such studies are discussed, as well as the limitations of published investigations. Finally, recommendations are made regarding the design and implementation of future pharmacoeconomic analyses that can help establish the true costs of managing invasive fungal infections in at-risk patient populations.     

Pharmacoeconomics of antifungal pharmacotherapy--challenges and future directions

The frequency and severity of invasive fungal infections have been increasingly recognised and new antifungal therapies have expanded the therapeutic armamentarium available to manage such infections. Antifungal agents comprise a significant portion of antibiotic expenditures at major medical centres, prompting adoption of cost-containment measures and treatment guidelines. This paper reviews available data regarding the costs associated with managing fungal infections, including pharmacoeconomic analyses that have been performed in the setting of documented fungal infections, as well as prophylactic and empiric use of antifungal agents. The challenges of performing such studies are discussed, as well as the limitations of published investigations. Finally, recommendations are made regarding the design and implementation of future pharmacoeconomic analyses that can help establish the true costs of managing invasive fungal infections in at-risk patient populations.     

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.     

Human mycoses and current antifungal therapy

The Focus on Fungal Infections meeting has become a popular conference for specialists in medical mycology and antifungal chemotherapy. Highlights of the 8th meeting are reported, with a focus on infection and therapy. Although the incidence of mycoses has increased, the identification of these fungal etiologic agents remains difficult. Mucosal candidiasis caused by endogenous Candida albicans and Candida species remains the most common fungal manifestation in HIV-infected patients, while systemic infection by Aspergillus species also has increased in HIV patients. Two presenters at the meeting debated whether fungal infections in AIDS patients are becoming less common and less important. Various strategies for antifungal therapy in AIDS or HIV-positive patients were presented. Most fungal infections in solid organ transplant patients are due to Candida species or Aspergillus species; however, dematiaceous (dark-pigmented) fungi are becoming more common fungal pathogens in these patients. Antifungal therapy remains difficult in this patient group. The meeting included an overview of the current status of diagnosing fungal infections through serodiagnostic techniques. If properly validated, serology can be useful in fungal diagnosis since antigens and antibodies are easier to detect than the invading organism. Premature infants are at high risk for developing invasive fungal infections. Antifungal drugs have not been tested in controlled clinical trials in these patients, thus therapy is accomplished using adult treatment regimens and anecdotal experience. As regards the new lipid-based formulations of amphotericin B, published clinical studies are only now appearing in the literature and these reports suggest that the new formulations have reduced toxicity and comparable efficacy compared to conventional amphotericin B under various clinical conditions. Correlation of minimum inhibitory concentration (MIC) values with clinical response to therapy is beginning to emerge. Two fungal cell wall-active compounds have recently entered clinical trials: an echinocandin and the chitin-synthesis inhibitor nikkomycin Z. Pradimycin and analogues have been studied through experimental animal models with good success; however, phase I clinical trials suggested drug-related toxicities and development was stopped. New molecular targets also are being investigated in antifungal therapy.     

Empiric antifungal therapy in patients with febrile neutropenia

Invasive fungal infections, most commonly candidiasis or aspergillosis, are a major cause of morbidity and mortality among patients with neutropenia. Difficulty in diagnosing invasive fungal infections in these patients complicates decisions regarding pharmacotherapy. Because of the difficult diagnosis and the significant morbidity and mortality of fungal infections in patients with neutropenia, systemic antifungal agents are used as empiric antifungal therapy in patients with febrile neutropenia who are not responding to antibacterial therapy. The pharmacotherapy of invasive fungal infections has evolved rapidly within the past several years as numerous antifungal agents--different formulations of amphotericin B, azoles, and echinocandins--have become available for use as empiric antifungal therapy in patients with febrile neutropenia. Various levels of evidence support the use of these agents for this indication. Their use is limited, however, by drug intolerance, drug interactions, adverse-event profiles, and limited activity with some mold species. Thus, considerations for selecting an antifungal drug for empiric use in patients with febrile neutropenia should include the epidemiology of fungal infections in the individual patient's institution and the specific clinical circumstances of the patient.     

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。     

Lipid-based amphotericin B for the treatment of fungal infections

The frequency of life-threatening fungal infections has increased dramatically over the past few decades. For more than 30 years amphotericin B has been the standard treatment for systemic and deep-seated fungal infections, primarily because of its broad spectrum of activity. Its usefulness is limited by a relatively high frequency of significant adverse events including infusion-related reactions and nephrotoxicity. In an effort to overcome these side effects, a number of lipid-based formulations were developed, each with its own composition and pharmacokinetic behavior. The clinical significance of these differences is unknown. Available clinical data suggest the formulations have a reduced propensity for causing nephrotoxicity. However, considering limited efficacy data, they should be reserved as second-line therapy for patients who cannot tolerate or fail an adequate trial of conventional amphotericin B or cannot benefit from other antifungal 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.