Developments in the treatment of candidiasis: more choices and new challenges

The incidence of oesophageal candidiasis, candidaemia and disseminated candidiasis has increased dramatically. In addition to the amphotericin B formulations and fluconazole, the echinocandins anidulafungin, caspofungin and micafungin and the newer triazoles posaconazole and voriconazole are in the last stages of development and are becoming available for the management of candidiasis. This review presents these new agents and addresses their role in the treatment of candidiasis. All new antifungal agents exhibit potent activity against Candida spp. and echinocandins are fungicidal against most Candida spp. but appear to be less potent against certain species, such as Candida parapsilosis and C. guilliermondii. Systemic antifungal therapy can now be individualised based on the severity of the infection, comorbid conditions and the Candida spp. causing the infection. Studies are needed to investigate the possible development of resistance and the efficacy of these antifungal agents against the more resistant Candida spp.     

Management of Candida infections in the adult intensive care unit

The epidemiology of Candida infection in intensive care units (ICUs) and the management strategies for such infections in non-neutropenic intensive care patients are discussed in this review. Candida species are one of the leading causes of nosocomial bloodstream infections and a significant cause of morbidity in patients admitted to the ICU. Prophylactic, pre-emptive and empiric treatment strategies for Candida infections have been explored in ICU patients. Routine prophylaxis should not be administered to the whole population of ICU patients, because the concerns about the selection of azole-resistant Candida strains or the induction of resistance are justified. Treatment of fungal infections is now possible with newer antifungal agents, including newer azoles (e.g., voriconazole, posaconazole) and echinocandins (e.g., micafungin, anidulafungin). However, there is a critical need for improvement in diagnosis of invasive Candida infection in order to provide clinicians the opportunity to intervene earlier in the diseases course.     

Antifungal prophylaxis in adult hematopoietic stem cell transplant recipients

Invasive fungal infections (IFIs) are a frequent, costly and potentially life-threatening complication in hematopoietic stem cell transplant (HSCT) recipients. Most prevalent among the causative pathogens are Candida spp. and Aspergillus spp. Risk factors that further increase the risk of IFIs in this patient population include allogeneic transplant and acute graft versus host disease. Among strategies to improve outcomes is the administration of antifungal prophylaxis. However, optimal administration requires the identification of patients who are at the highest risk of developing a fungal infection, thus restricting concerns of drug cost, toxicity and resistance to those most likely to benefit. Currently, there are several antifungal agents recommended by the National Comprehensive Cancer Network for the prophylaxis of IFIs. These include fluconazole, itraconazole, voriconazole, posaconazole and micafungin. Fluconazole was widely considered the standard agent for prophylaxis in patients at lower risk of mold infections. New data support the efficacy of the newer triazole posaconazole and the echinocandin micafungin in this patient population..     

Invasive fungal infections in patients with cancer in the Intensive Care Unit

Invasive fungal infections (IFIs) have emerged as a major cause of morbidity and mortality amongst critically ill patients. Cancer patients admitted to the Intensive Care Unit (ICU) have multiple risk factors for IFIs. The vast majority of IFIs in the ICU are due to Candida spp. The incidence of invasive candidiasis (IC) has increased over recent decades, especially in the ICU. A shift in the distribution of Candida spp. from Candida albicans to non-albicans Candida spp. has been observed both in ICUs and oncology units in the last two decades. Timely diagnosis of IC remains a challenge despite the introduction of new microbiology techniques. Delayed initiation of antifungal therapy is associated with increased mortality. Therefore, prediction rules have been developed and validated prospectively in order to identify those ICU patients at high risk for IC and likely to benefit from early treatment. These rules, however, have not been validated in cancer patients. Similarly, major clinical studies on the efficacy of newer antifungals typically do not include cancer patients. Despite the introduction of more potent and less toxic antifungals, mortality from IFIs amongst cancer patients remains high. In recent years, aspergillosis and mucormycosis have also emerged as significant causes of morbidity and mortality amongst ICU patients with haematological cancer.     

Recent advances in the treatment of life-threatening,invasive fungal infections

Introduction: Invasive fungal infections (IFIs) pose significant morbidity and are often life-threatening to many high-risk patients. Timely diagnosis and treatment of these infections with optimal therapy is imperative.

Areas covered: Advances have been made in diagnostic biomarkers such as peptide nucleic acid fluorescent in situ hybridization, β-D-glucan and galactomannan, although more research is needed in this area to assist with both diagnosis and monitoring for improvement of IFI management. Novel antifungal agents (azole antifungals and echinocandins) are being investigated that have activity against Candida spp. and Aspergillus spp. Optimizing the pharmacodynamics (PD) of our current antifungal therapies through such strategies as continuous infusion of amphotericin B and dose escalation of echinocandins and liposomal formulations of amphotericin B have also been investigated with mixed results. Therapeutic drug monitoring (TDM) shows promise as evident from data with such agents as flucytosine, itraconazole, voriconazole and posaconazole.

Expert opinion: The goal for the future of biomarkers in IFIs will be to have excellent sensitivity and specificity to ideally identify a particular fungus causing the infection or eliminate its existence to prevent unnecessary costs, resistance and antifungal usage. In addition, further developments of new antifungals are needed and judicious use of the current regimens needs to be optimized through antifungal PD properties and TDM.     

Addressing current medical needs in invasive fungal infection prevention and treatment with new antifungal agents,strategies and formulations

Introduction: Morbidity and mortality associated with invasive fungal infections (IFIs) remains unacceptably high. Such diseases represent a substantial burden to the healthcare system. New options are needed to address antifungal resistance in existing and emerging pathogens and improve treatment outcomes while minimizing drug-related toxicities and interactions. Awareness of new and potential future options is of great value for those healthcare professionals who care for patients with IFIs.

Areas covered: A search of PubMed, infectious diseases conference abstracts and reference lists from relevant publications was conducted and relevant information abstracted. This review describes the limitations of existing systemic antifungal therapies (e.g., resistance, drug-drug interactions, drug-related toxicities) and summarizes data regarding several emerging antifungal compounds including (but not limited to) new triazoles (e.g. isavuconazole, ravuconazole), echinocandins (e.g., aminocandin) and nikkomycin Z. Agents in clinical trials such as (but not limited to) new triazoles (e.g., isavuconazole, ravuconazole), echinocandins (e.g., aminocandin) and nikkomycin are included. New formulations of existing drugs including reformulations of miconazole, posaconazole and amphotericin B are also reviewed. Finally, new or novel administration strategies for existing drugs such as combination antifungal therapy, antifungal dose escalation, adjunctive use of iron chelators and preemptive therapy are discussed.

Expert opinion: All present antifungal agents have some deficiencies in antifungal spectra, toxicity, pharmacokinetics and/or drug–drug interactions, making them less than ideal for some fungal infections. Therefore, there remains an urgent need to find safe, effective, rapidly fungicidal, broad-spectrum antifungal agents with excellent pharmacodynamics to effectively eliminate the fungus from the body with short antifungal courses.     

Fungal infections in bone marrow transplant recipients

Invasive fungal infections (IFIs) can cause significant morbidity and mortality in patients after haematopoietic stem cell transplantation. The two most notorious pathogenic fungal species in this group of patients are Candida and Aspergillus. Risk factors for IFIs include: prolonged neutropaenia; fungal overgrowth and conditioning regiment-related mucositis; graft versus host disease; and steroid therapy. Clinical manifestations can be protean, and radiological changes are frequently nonspecific. Diagnostic methods include culture- and nonculture-based techniques. Some experts recommend IFI prophylaxis in the high-risk groups, such as patients with severe graft versus host disease who require prolonged immunosuppressive therapy or patients with a previous history of aspergillosis. Treatment options include therapy with azoles, including the newer agent voriconazole, amphotericin and caspofungin.     

Newer triazole antifungal agents: pharmacology, spectrum, clinical efficacy and limitations

New triazole antifungals (voriconazole, posaconazole, ravuconazole and albaconazole) have been developed to meet the increasing need for new antifungals, and address the rising incidence of invasive fungal infections and the emergence of fungal resistance. This report describes the spectrum of activity of the newer-generation triazoles based on data from in vitro, animal and clinical studies. The authors discuss the use of these agents in combination with other antifungals, the extent of cross-resistance, their toxicity profile and pharmacokinetic properties. A total of two agents are currently available: voriconazole (which is becoming a primary treatment for the management of invasive aspergillosis) and posaconazole (which demonstrates a broad antifungal spectrum). A further two agents, albaconazole and ravuconazole, are undergoing early clinical evaluation and their future is uncertain. For all newer triazoles, concerns about emerging drug-resistant fungi and the incidence and management of breakthrough infections will dictate their role in antifungal prophylaxis and treatment.     

Newer triazole antifungal agents: pharmacology,spectrum, clinical efficacy and limitations

New triazole antifungals (voriconazole, posaconazole, ravuconazole and albaconazole) have been developed to meet the increasing need for new antifungals, and address the rising incidence of invasive fungal infections and the emergence of fungal resistance. This report describes the spectrum of activity of the newer-generation triazoles based on data from in vitro, animal and clinical studies. The authors discuss the use of these agents in combination with other antifungals, the extent of cross-resistance, their toxicity profile and pharmacokinetic properties. A total of two agents are currently available: voriconazole (which is becoming a primary treatment for the management of invasive aspergillosis) and posaconazole (which demonstrates a broad antifungal spectrum). A further two agents, albaconazole and ravuconazole, are undergoing early clinical evaluation and their future is uncertain. For all newer triazoles, concerns about emerging drug-resistant fungi and the incidence and management of breakthrough infections will dictate their role in antifungal prophylaxis and treatment.     

Anidulafungin and voriconazole in invasive fungal disease: pharmacological data and their use in combination

The incidence of invasive fungal infections has been increasing since the 1980s due to a growing population of immunocompromised and critically ill patients with associated risk factors including immunosuppressive chemotherapy, prolonged periods on intensive care units and infection with HIV. Persons who are severely immunocompromised are particularly vulnerable to infection from molds and yeasts that are often found naturally in the environment. In recent years, several new systemic antifungal agents have been released, significantly increasing options for the treatment of the most serious fungal infections. Newly available drugs as those in the echinocandin class include caspofungin, micafungin and anidulafungin, as well as the newer generation triazoles, voriconazole and posaconazole. In this review, the in vitro and in vivo activity of anidulafungin and voriconazole, both new antimycotic substances with a different mode of action, are analyzed.     

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.     

Antifungal drugs: predicting clinical efficacy with pharmacodynamics

Invasive fungal infections are on the rise, particularly in hospitalized patients and immunocompromised hosts. In recent years, several new antifungals have become available at a rapid pace. Data on pharmacokinetics/pharmacodynamics of the newer/older antifungal drugs are accumulating. As with bacterial infections and antibacterial drugs, predicting the clinical efficacy of antifungal drugs based on pharmacodynamic parameters is becoming feasible. For the echinocandin class, a ratio of 10 or more for peak concentration/minimum inhibitory concentration (MIC) predicts efficacy against most Candida organisms. Increasing the currently used doses does not appear to improve efficacy. For the triazole class, a ratio of 25 or more for the pharmacodynamic parameter, AUC/MIC, predicts efficacy of the antifungal drugs against invasive Candida infections. More data are needed for invasive mold infections. The polyene class of drugs exhibit concentration-dependent activity; doses higher than those used conventionally do not show any clinical advantage. Monitoring serum levels of the newer triazoles, voriconazole and posaconazole, appears to be necessary in clinical practice to ensure efficacy and avoid toxicity. Flucytosine levels help to predict toxicity, but not efficacy. Other classes of drugs do not warrant monitoring serum concentrations. As invasive fungal infections usually occur in the setting of compromised immune defenses, clinical success does not depend upon the activity of the drugs alone; host immune factors need consideration to predict clinical outcome.     

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 investigational antifungal agents for treating invasive fungal infections

Systemic fungal infections have been recognised as a major cause of morbidity and mortality during the last two decades. There are only a few therapeutic options for these infections. Severe toxicity, such as impairment of renal function, limits the use of amphotericin B. Flucytosine is associated with side effects and drug resistance. Fluconazole and itraconazole are safer, though emergence of resistance and innate resistance in some fungal pathogens is a concern in their use. Therefore, there is a need for developing novel drugs and/or treatment strategies to combat these infections. In recent years, increased efforts by the pharmaceutical industry and academia have led to the discovery of new re-engineered or reconsidered antifungal agents that are more efficacious, safer and have a broad spectrum of activity. Lipid formulations of polyene antifungal agents, amphotericin B and nystatin, have the advantage of improved therapeutic index. Activity against resistant fungi, high bioavailability, safety and longer half-life are the properties that encourage development of the newer triazoles (e.g., voriconazole, ravuconazole and posaconazole). Echinocandin-like lipopeptide antibiotics are among the antifungal agents with a novel mode of action. In addition to these lead investigational compounds, development of newer antifungal agents is underway.     

Susceptibility to five antifungals of Aspergillus fumigatus strains isolated from chronically colonised cystic fibrosis patients receiving azole therapy

Exposure of Aspergillus fumigatus to stressful antifungal therapies may result in decreased susceptibility. The aim of the present work was to evaluate the susceptibility to azole and non-azole antifungals of 159 isolates of A. fumigatus collected from cystic fibrosis (CF) patients receiving azole antifungal therapy. The genetic diversity of the fungal isolates was assessed using microsatellite genotyping, and some strains were found in patient's sputum samples more than 4 years apart. No resistant isolates [minimal inhibitory concentration (MIC)/minimal effective concentration (MEC) ≥4 μg/mL] were identified to the antifungals amphotericin B, caspofungin, itraconazole and voriconazole. A single A. fumigatus isolate was identified outside of the epidemiological cut-off of 0.25 μg/mL for posaconazole. Susceptibility of the recurrent isolates was in agreement with the susceptibility of the first isolate identified (100% essential agreement). Even after azole exposure, several recurrent A. fumigatus strains were detected in the subsequent sputum samples. Development of resistance in A. fumigatus to antifungals appears to be rare amongst CF patients. However, it remains crucial to evaluate the importance of antifungal agents for allergic fungal diseases.     

Human mycoses and advances in antifungal therapy

The 11th Focus on Fungal Infections meeting was held in Washington, D.C., U.S.A., March 1416, 2001. At the conference, there were well-attended sessions that focused on the pathogenesis and therapy of fungal disease. This report focuses on new information on fungal incidence and pathogenesis as well as on the in vitro and clinical experience of established antifungal drugs (fluconazole, itraconazole, amphotericin B, liposomal formulations of amphotericin B, terbinafine) and the newer antifungal compounds approved for use (e.g., caspofungin) and in development (the new-generation azoles: voriconazole, posaconazole, ravuconazole, and the candins, micafungin and anidulafungin).     

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

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

Combination antifungal therapy for invasive aspergillosis: utilizing new targeting strategies

The optimal therapy for invasive aspergillosis (IA) is unknown, and there is little agreement on the exact antifungal management of IA. The previously stagnant landscape of antifungal choices for IA is rapidly changing with newer antifungals and newer targets. While amphotericin B has historically been the preferred therapy, recent studies support voriconazole as primary therapy or caspofungin as salvage therapy. However, even these newer therapies have only elevated clinical response rates to approximately 50%. Recent in vitro studies, animal models, and limited clinical reports suggest that combination antifungal therapy utilizing novel targeting strategies might offer improved outcome. Until very recently, combination antifungal therapy for IA was of little consequence since there were a limited number of possible permutations available. There has been a great deal of new data published exploring the possibilities of combination therapy, but clinicians need to be aware of the potential advantages and disadvantages of combination antifungal therapy for IA.     

Posaconazole as salvage therapy in a patient with disseminated zygomycosis: case report and review of the literature

Zygomycosis refers to any fungal infection originating from the class Zygomycetes and the order Mucorales. In immunocompromised patients, these fungi produce a relatively rapid, violently destructive, and highly fatal infection. Treatment approaches include both aggressive antifungal pharmacotherapy and surgical intervention. Unfortunately, even with optimal therapy, morbidity and mortality rates remain relatively high. As failure rates are elevated with commercial antifungals, new treatment options are needed. Posaconazole is an orally available, extended-spectrum triazole antifungal being investigated in phase III clinical trials for the treatment and prevention of invasive fungal infections, including zygomycosis. We report the case of a 26-year-old Vietnamese man with a medical history of acute lymphocytic leukemia who had undergone consolidation chemotherapy and had neutropenic fever when he came to the emergency department. The patient was admitted to the hospital and treated with broad-spectrum antibiotics and caspofungin. Two weeks into his admission, however, abscesses in the pelvis, prostate, and musculature surrounding the hip were detected radiographically; these abscesses eventually cultured for Mucor sp. Disseminated zygomycosis was diagnosed. Caspofungin was immediately discontinued, and high-dose liposomal amphotericin B 10 mg/kg/day was begun. Over the next month, infection spread to the right lung, left kidney, middle thoracic spine, and epidural space. As a result, oral posaconazole 200 mg 4 times/day was added to the liposomal amphotericin B. Significant clinical, hematologic, mycologic, and radiologic improvements were demonstrated as early as 10 days after start of posaconazole therapy and continued through 41 days of inpatient treatment. Liposomal amphotericin B was discontinued after 3 weeks of posaconazole, and the patient was discharged on hospital day 92 receiving oral posaconazole, with no major adverse events reported. Five months after discharge, the patient had no evidence of fungal disease recurrence or progression. Posaconazole appears to be a well-tolerated and effective salvage treatment for zygomycosis, including disseminated disease.     

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.