Review of Epidemiology, Diagnosis, and Treatment of Invasive Mould Infections in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Invasive mould infections are a major cause of morbidity and mortality in hematopoietic stem cell transplant recipients (HSCT). Allogeneic HSCT recipients are at substantially higher risk than autologous HSCT recipients. Although neutropenia following the conditioning regimen remains an important risk factor for opportunistic fungal infections, most cases of invasive mould infection in allogeneic HSCT recipients occur after neutrophil recovery in the setting of potent immunosuppressive therapy for graft-versus-host disease. Invasive aspergillosis is the most common mould infection. However, there has been an increased incidence of less common non-Aspergillus moulds that include zygomycetes, Fusarium sp., and Scedosporium sp. Reflecting a key need, important advances have been made in the antifungal armamentarium. Voriconazole has become a new standard of care as primary therapy for invasive aspergillosis based on superiority over amphotericin B. There is significant interest in combination therapy for invasive aspergillosis pairing voriconazole or an amphotericin B formulation with an echinocandin. There have also been advances in novel diagnostic methods that facilitate early detection of invasive fungal infections that include galactomannan and beta-glucan antigen detection and PCR using fungal specific primers. We review the epidemiology, diagnosis, and management of invasive mould infection in HSCT, with a focus on allogeneic recipients. We also discuss options for prevention and early treatment of invasive mould infections.     

The role of second-generation triazole antifungal agents voriconazole and posaconazole in patients with hematologic malignancies

The second-generation triazoles, voriconazole and posaconazole, have found important roles in the management of invasive fungal infections in high-risk patients. Both agents are more active against Candida albicans and the non-albicans Candida species than the first-generation triazoles. They are active against Aspergillus species, including those species less susceptible to polyenes, and against a variety of non-Aspergillus molds. In contrast to posaconazole, voriconazole has no activity against the zygomycetes, and breakthrough infections have been observed. Both are well absorbed, but considerable intra- and interpatient pharmacokinetic variability has raised the question of therapeutic drug monitoring. Both inhibit hepatic cytochrome P450 isoenzymes, which are important in the metabolism of various drugs coadministered in the management of high-risk patients. Clinical trials have demonstrated the safety and efficacy of both agents for antifungal prophylaxis and treatment in invasive candidiasis, invasive aspergillosis, and in invasive fungal infections caused by a variety of non-Aspergillus molds. Posaconazole is the only triazole approved for use in the treatment of invasive zygomycosis. Voriconazole is the accepted standard first-line therapy for invasive aspergillosis.     

Treatment of Invasive Candida Infections in the Neonatal Intensive Care Unit

Invasive Candida infections are a leading cause of morbidity and mortality in the neonatal intensive care unit (NICU). Extremely preterm and very low birth weight infants are at the highest risk of infection. There are currently no antifungal agents that have FDA-labeling for the treatment of invasive candidiasis in the neonatal population. Based on the current IDSA guidelines, amphotericin and fluconazole are considered first-line options for neonatal candidiasis. The newer antifungal agents (i.e., echinocandins and voriconazole) are currently considered second-line or salvage therapy; however, evidence supporting their use is emerging. This review focuses on the supporting evidence for the selection of antifungal agents for treatment of invasive Candida infections in the NICU.     

Treatment options in emerging mold infections

Although Zygomycetes, Fusarium spp, and Scedosporium spp are far less frequent causes of invasive fungal disease than Aspergillus and Candida, they are emerging. These types of infections in severely immunocompromised patients have a common feature: a poor clinical response to antifungal therapy. Infection is usually airborne, although local infections in cases of skin trauma are also possible. These fungi are resistant to some common antifungal agents; therefore, surgical debridement of the necrotic tissue, when possible, should be combined with specific systemic antifungal treatment in immunocompromised patients. In the absence of randomized clinical trials, most experience in the treatment of these infections is with amphotericin B. Experience with new antifungal agents is still limited, and recovery from neutropenia remains the main predictor of a favorable outcome.     

Is There Still a Place for Conventional Amphotericin B in the Treatment of Neonatal Fungal Infections?

Neonatal invasive fungal infections (IFIs) remain an increasing problem associated with high rates of morbidity and mortality, as well as late-onset neurodevelopmental implications. Invasive candidiasis remains the leading neonatal IFI. Candida albicans is the fungal species most often affecting this population, although a changing epidemiologic incidence to non-albicans Candida species is reported in some neonatal intensive care units. Many treatment recommendations are extrapolated from adult populations, emphasizing the need to establish the optimal antifungal agent, dosage, and duration of therapy in neonates. Historically, conventional amphotericin B has been considered an efficient and safe treatment approach for most neonatal IFIs. More recently, lipid formulations of amphotericin B have been studied, used alone or in combination with other antifungal agents such as azoles or echinocandins. The aim of this article is to review the published experience in the use of amphotericin B formulations to treat neonatal IFIs.     

Antifungal Drug Resistance: Clinical Relevance and Impact of Antifungal Drug Use

Antifungal drug resistance significantly impacts treatment outcomes in patients with invasive fungal infections (IFIs). Although primary (intrinsic) resistance may occur independent of previous therapy, prior concomitant antifungal exposure increases the risk for secondary (acquired) resistance and subsequent colonization or infection with less-susceptible pathogens. Among various pathogen-antifungal combinations, this effect has been best studied clinically with azole exposure and the risk of Candida spp. with reduced susceptibility. The rapid development of secondary resistance to flucytosine in Candida spp. has limited its use as monotherapy. Secondary resistance to amphotericin B is infrequent. In contrast, secondary resistance in Aspergillus spp. is less of a concern. Recent reports of secondary resistance in patients receiving fluconazole for cryptococcal infections may justify susceptibility testing in the setting of prior therapy or treatment failure. Despite numerous patient-focused, drug-focused, and disease-focused strategies to improve treatment outcomes, clinical resistance (manifesting as treatment failures despite adequate antifungal therapy) continues to be problematic in patients with serious IFIs.     

The role of echinocandins, extended-spectrum azoles, and polyenes to treat opportunistic moulds and Candida

Three classes of antifungals—polyenes, extended-spectrum azoles, and echinocandins—are now available for treating systemic fungal infections. Guidance for the appropriate use of this expanded variety of antifungals may come from recent clinical trials. Extended-spectrum azoles have excellent in vitro activity against Aspergillus and have been shown to improve clinical outcomes. For Zygomycetes, along with the lipid formulations of amphotericin, of the new agents, only posaconazole has activity. For Candida, the echinocandins offer a broad spectrum of activity. These new agents offer less toxicity and potentially improved efficacy in these difficult infections.     

Candida Biofilm: Clinical Implications of Recent Advances in Research

Candida spp. are human commensals that can colonize devices and cause diseases associated with host tissue damage. In each lifestyle, Candida forms biofilms – communities of cells living within a protective extracellular matrix comprising proteins, polysaccharides, extracellular nucleic acids, and lipids. In vitro and in vivo models have defined basic steps in Candida biofilm formation as adhesion, initiation, maturation, and dispersal. Biofilms afford Candida cells resistance to antifungal agents, and host defenses and immune responses. In addition to “pathogenic” biofilm, Candida albicans also produces an alternative, permeable “sexual” biofilm that facilitates mating between cells. Treatment of biofilm infections consists of removing the infected device (if feasible) and antifungal therapy. Optimal antifungals are not defined, but echinocandins and lipid formulations of amphotericin B are most consistently active in model systems. Future research will shed light on how biofilm regulation allows Candida to adapt to diverse microenvironments relevant to commensalism and disease.     

Evaluation of Antifungal Susceptibility Testing with Microdilution and Etest Methods of <Emphasis Type="Italic">Candida</Emphasis> Blood Isolates

Candida species that show an increasing number of clinical and/or microbiological resistance to several antifungals and are the most common agents of invasive fungal infections. The aim of this study was to investigate the in vitro susceptibility of Candida blood isolates to antifungal agents (amphotericin B, fluconazole, itraconazole, and voriconazole) by comparative use of the CLSI reference microdilution method and Etest. Four hundred Candida blood isolates (215 Candida albicans, 185 non-albicans Candida strains) were included in the study. The broth microdilution test was performed according to the CLSI M27 A2 document. Etest was carried out according to the manufacturer’s instructions. The MIC results obtained with reference microdilution were compared with those obtained with the Etest by using percent and categorical agreements. According to MIK₉₀ values, voriconazole was the most active and itraconazole was the least active drug in vitro against all Candida species. Other than voriconazole, statistically significant differences were found when the susceptibility of Candida albicans and non-albicans Candida spp. to amphotericin B, fluconazole, and itraconazole were compared. These antifungal agents were found to be more active to C. albicans. Among the non-albicans Candida species, the lowest MIC values were obtained for Candida parapsilosis isolates. When the standard method was compared with Etest, the total agreement was higher for C. albicans than for non-albicans species, especially for fluconazole and voriconazole. In view of the findings, it was concluded that itraconazole showed the lowest activity against all Candida species. Etest could be an alternative method in assessing the in vitro antifungal susceptibility of Candida spp., but it is more convenient to use the microdilution method for studying in vitro susceptibility of non-albicans species, in particular for those possessing high MIC values against azoles.     

Enfermedad fúngica invasora por hongos filamentosos en pacientes hematológicos

Invasive mould infections (IMI) are a persistent problem with high morbidity and mortality rates among patients receiving chemotherapy for hematological malignancies and hematopoietic stem cell transplant recipients. Management of IMI in this setting has become increasingly complex with the advent of new antifungal agents and diagnostic tests, which have resulted in different therapeutic strategies (prophylactic, empirical, pre-emptive, and directed). A proper assessment of the individual risk for IMI appears to be critical in order to use the best prophylactic and therapeutic approach and increase the survival rates. Among the available antifungal drugs, the most frequently used in the hematologic patient are fluconazole, mould-active azoles (itraconazole, posaconazole and voriconazole), candins (anidulafungin, caspofungin and micafungin), and lipid formulations of amphotericin B. Specific recommendations for their use, and criteria for selecting the antifungal agents are discussed in this paper.     

Interaction between Candida agglutinins and antifungal agents

Antifungal agents alter the function and morphology of Candida cell membranes and cell walls. We observed that brief (30 minute) exposure to either amphotericin B or clotrimazole inhibited the agglutination of Candida blastoconidia by murine bronchoalveolar lavage fluid. This inhibition required continuous drug presence. Neither amphotericin nor clotrimazole inhibited Candida agglutination by concanavalin A or pooled human serum. These results demonstrate that antifungal drugs can produce rapid changes in the surface characteristics of some fungi.     

Isavuconazole: A Comprehensive Review of Spectrum of Activity of a New Triazole

Isavuconazole is a new triazole currently undergoing phase III clinical trials. This compound has shown in vitro activity against a large number of clinically important yeasts and moulds including Aspergillus spp., Fusarium spp., Scedosporium spp., Candida spp., the Zygomycetes and Cryptococcus spp. Similar to voriconazole, reduced in vitro activity is seen against Histoplasma capsulatum. In vivo efficacy has been demonstrated in murine models of invasive aspergillosis and candidiasis. Additionally, there are several potential pharmacokinetic and drug–drug interaction advantages of this compound over existing antifungal agents. This review summarizes existing data that has been either published or presented at international symposia.     

In vitro antifungal activities of anidulafungin and micafungin, licensed agents and the investigational triazole posaconazole as determined by NCCLS methods for 12,052 fungal isolates: review of the literature

The echinocandins anidulafungin and micafungin and the triazole posaconazole are currently undergoing phase III clinical trials. Caspofungin and voriconazole have recently been licensed for the treatment of aspergillosis (both agents), other less common mould (voriconazole) and candidal (caspofungin) infections. This review summarizes the published in vitro data obtained by NCCLS or NCCLS modified methods on the in vitro fungistatic and fungicidal activities of these five agents for yeasts and moulds in comparison to the established agents, amphotericin B, fluconazole, itraconazole, and flucytosine. Among the yeasts, the echinocandins have less activity for Candida parapsilosis and Candida guilliermondii, no activity for Cryptococcus neoformans and Trichosporon spp., but good fungistatic and fungicidal activity in vivo and in vitro for most of the other Candida spp.; this fungicidal activity has been reported by minimum fungicidal concentrations (MFCs) or time kill curve results. The new triazoles exhibit good fungistatic activity (but not fungicidal) for most Candida spp., C. neoformans, and Trichosporon spp. For the Aspergillus spp. evaluated, the echinocandins have similar or better fungistatic activity than those of amphotericin B and the triazoles, but fungicidal activity has been demonstrated only with amphotericin B and the triazoles, with the exception of fluconazole. Most studies showed posaconazole and voriconazole minimum inhibitory concentrations (MICs) ranging from 0.25 to 8 microg/ml for non-solani Fusarium spp., while MIC and minimum effective concentration (MEC) endpoints of the echinocandins were >8 microg/ml. The fungistatic activity of the triazoles is also superior to that of the echinocandins for most of the dimorphic fungi and the Zygomycetes. However, micafungin has activity for the mould phase of most dimorphic fungi, but not for the parasitic or yeast phase of Paracoccidioides brasiliensis. The echinocandins appear to have variable and species dependent fungistatic activity for the dematiaceous fungi, but all agents have poor or no activity against most isolates of Scedosporium prolificans. Only amphotericin B exhibit good fungistatic activity against the Zygomycetes. The combination of caspofungin with some triazoles, amphotericin B or liposomal amphotericin B has been synergistic in vitro, in animal models and in patients. Breakpoints are not available for any mould and antifungal agent combination. In vitro/in vivo correlations should aid in the interpretation of these results, but standard testing conditions are needed for the echinocandins, especially for mould testing, to obtain reliable results.     

Aerosolized Delivery of Antifungal Agents

Pulmonary infections caused by Aspergillus species are associated with significant morbidity and mortality in immunocompromised patients. Although the treatment of pulmonary fungal infections requires the use of systemic agents, aerosolized delivery is an attractive option in prevention because the drug can concentrate locally at the site of infection with minimal systemic exposure. Current clinical evidence for the use of aerosolized delivery in preventing fungal infections is limited to amphotericin B products, although itraconazole, voriconazole, and caspofungin are under investigation. Based on conflicting results from clinical trials that evaluated various amphotericin B formulations, the routine use of aerosolized delivery cannot be recommended. Further research with well-designed clinical trials is necessary to elucidate the therapeutic role and risks associated with aerosolized delivery of antifungal agents. This article provides an overview of aerosolized delivery systems, the intrapulmonary pharmacokinetic properties of aerosolized antifungal agents, and key findings from clinical studies.     

In Vitro Antifungal Susceptibility of Oral <Emphasis Type="Italic">Candida</Emphasis> Isolates from Patients Suffering from Caries and Chronic Periodontitis

Caries and chronic periodontitis are common oral diseases where a higher Candida colonization is reported. Antifungal agents could be adjuvant drugs for the therapy of both clinical conditions. The aim of the current study has been to evaluate the in vitro activities of conventional and new antifungal drugs against oral Candida isolates from patients suffering from caries and/or chronic periodontitis. In vitro activities of amphotericin B, fluconazole, itraconazole, miconazole, nystatin, posaconazole and voriconazole against 126 oral Candida isolates (75 Candida albicans, 18 Candida parapsilosis, 11 Candida dubliniensis, six Candida guilliermondii, five Candida lipolytica, five Candida glabrata, four Candida tropicalis and two Candida krusei) from 61 patients were tested by the CLSI M27-A3 method. Most antifungal drugs were highly active, and resistance was observed in less than 5% of tested isolates. Miconazole was the most active antifungal drug, being more than 98% of isolates susceptible. Fluconazole, itraconazole, and the new triazoles, posaconazole and voriconazole, were also very active. Miconazole, fluconazole and voriconazole have excellent in vitro activities against all Candida isolates and could represent suitable treatment for a hypothetically adjunctive therapy of caries and chronic periodontitis.     

The role of adjuvant agents in treating fungal diseases

Invasive fungal infections (IFIs) remain a significant cause of morbidity and mortality despite the recent introduction of new antifungal medications. In this review, the available data on the use of adjuvant agents for the treatment of IFIs are discussed. Cytokines such as interferon-γ, colony-stimulating factors, granulocyte transfusions, and the monoclonal antibody efungumab may have in a role in the management of IFIs through augmentation of the host immune response, whereas pathogen-specific vaccines may help prevent infection. Pentraxin 3, an acute phase protein, may assist in the prevention and treatment of aspergillosis. Deferasirox, an iron chelator, is being investigated as an adjunctive therapy for the treatment of zygomycosis. Lactoferrin, an ironbinding protein, appears to have activity in Candida and Aspergillus infections, and omiganan may help prevent fungal catheter-related infections. Although none of these agents are currently approved for the treatment of IFIs, they may be involved in current and/or future treatment options when used in combination with antifungal drugs.     

Emerging Resistance to Azoles and Echinocandins: Clinical Relevance and Laboratory Detection

Failure to respond to antifungal therapy could be due to in vitro resistance (intrinsic or developed during therapy) or clinical resistance. In vitro resistance is mostly due to genetic mutations (resistance mechanisms), and it is associated with high minimal inhibitory concentrations (MICs), minimal effective concentrations (MECs), and/or clinical failure. Clinical breakpoints (CBPs) and/or epidemiologic cutoff values (ECVs) are useful to detect the in vitro antifungal resistance when isolates are tested by standardized methods. ECVs are available from the Clinical and Laboratory Standards Institute (CLSI) for Candida spp. versus echinocandins (anidulafungin, caspofungin, and micafungin) and triazoles (fluconazole, posaconazole, and voriconazole). Lately, the CLSI has adjusted to species-specific CBPs for Candida spp. versus fluconazole, similar to those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST), and versus echinocandins. However, the available voriconazole EUCAST and CLSI CBPs differ. In the absence of CBPs, EUCAST and CLSI assigned ECVs for various Aspergillus spp. and triazoles. This article reviews emerging resistance, laboratory detection, and clinical relevance as reported in the literature in the past 3 to 4 years.     

Enhanced Topical Delivery of Terbinafine Hydrochloride with Chitosan Hydrogels

Chitosan-based carriers have important potential applications for the administration of drugs. In the present study, topical gel formulations of terbinafine hydrochloride (T-HCl) were prepared using different types of chitosan at different molecular weight, and the antifungal inhibitory activity was evaluated to suggest an effective formulation for the treatment of fungal infections. The characteristics of gel formulations were determined with viscosity measurements and texture profile analysis. Stability studies were performed at different temperatures during 3 months. The ex vivo permeation properties were studied through rat skin by using Franz diffusion cells. The antifungal inhibitory activity of formulations on Candida species and filamentous fungi was also examined with agar-cup method. The microbiological assay was found suitable for determination of in vitro antifungal activity of T-HCl. A marketed product was used to compare the results. The antifungal activity of T-HCl significantly increased when it was introduced into the chitosan gels. A higher drug release and the highest zone of inhibition were obtained from gels prepared with the lowest molecular weight chitosan (Protasan UP CL 213) compared to that of other chitosan gels and marketed product. These results indicated the advantages of the suggested formulations for topical antifungal therapy against Candida species and filamentous fungi.     

Clinical efficacy of new antifungal agents

Several new options are now available for treating serious fungal infections. All three echinocandin agents currently available have been shown in randomized, blinded clinical trials to be efficacious in treating candidemia and invasive candidiasis. By contrast, the demonstrated efficacy of the echinocandins for the treatment of invasive aspergillosis has been based on historically controlled salvage treatment trials in patients failing or intolerant of other therapies. The new triazole agents, voriconazole and posaconazole, have a broad spectrum of antifungal activity. Voriconazole has become the agent of choice for invasive aspergillosis. On the basis of compassionate treatment data, posaconazole appears to be effective for treatment of zygomycosis. These agents have also been shown to be effective in the treatment of non-Aspergillus mould infections, several of the endemic mycoses and serious Candida infections.     

Papel futuro de la micafungina en el tratamiento de las micosis invasoras por hongos filamentosos

BackgroundMicafungin is a echinocandin. It inhibits β-1,3-D-glucan synthesis, thus achieving fungicidal activity against virtually all Candida spp., including those resistant to fluconazole, and fungistatic activity against Aspergillus spp., as well as several but not all pathogenic molds. Results from in vitro studies, animal models, small clinical trials, hint at possible future indications such as invasive aspergillosis and empirical viantifungal therapy, although currently there is little information published.AimsTo describe published data of micafungin as treatment against invasive mold infections, specially analysing its role in the inmunodepressed host and critical care setting.MethodsA sistematic review of literature using the principal medical search engines was performed. Terms such as micafungin, aspergillosis, zygomycosis, invasive fungal infections, emerging fungal infections, antifungal treatment or therapy, antifungal prophylaxis, empiric or pre-emptive therapy were crossed. Febrile neutropenia patients were excluded.ResultsSeveral studies in these setting were identified and were described in this review. Although there were no blinded randomized clinical trials published, treatment or prophylaxis of invasive aspergillosis and other invasive mould infections with micafungin described in open clinical studies were analyzed.ConclusionsMicafungin could play a future important role as a primary or rescue therapy, alone or in combination, in the treatment or prophylaxis of invasive fungal infections caused by moulds. New randomized clinical trials are needed to confirm their efficacy.