Invasive fungal infections in critically ill patients: different therapeutic options and a uniform strategy

The high morbidity, mortality, and healthcare costs associated with the invasive fungal infections, especially in the critical care setting, is of importance since the prophylactic, empiric, and pre-emptive therapy interventions, based on early identification of risk factors, is of common occurrence. In the last years alone there have been important developments in antifungal pharmacotherapy. Evidence-based studies using new antifungal agents are now emerging as important players in the pharmacotherapy of invasive fungal infections in seriously ill and difficult patients. However, data on critically ill patients are more limited and usually recovered from general studies. This study shows the benefits obtained by the new antifungal agents on different clinical situations in critical care units. The increasing number of non-C. albicans species and the high mortality rates in these settings suggest that the application of early de-escalation therapy in critically ill patients with fungal infection should be mandatory. The possibility of using antifungal combination therapy in these types of patients should be considered.     

Antifungal Distribution Into Cerebrospinal Fluid,Vitreous Humor,Bone, and Other Difficult Sites

The incidence of invasive fungal infections continues to increase, especially in patients with immune dysfunction. Fungal infections are often difficult to treat, requiring therapy for weeks or months to eradicate infection. Although fungal infections of the central nervous system, eye, and bones occur less frequently than infections at other sites, it is necessary to assess the utility of the currently available antifungal agents in treating these infections. Unfortunately, information regarding drug distribution to these sites is often scarce and limited to a few animal studies or case reports. This review summarizes information about commonly used antifungal agents and their penetration into the central nervous system, eye, and bone.     

Opciones terapéuticas para el tratamiento antifúngico en el paciente crítico

Invasive fungal infections, especially in the critical care setting, have become an excellent target for prophylactic, empiric, and pre-emptive therapy interventions due to their associated high morbidity, mortality rate, increased incidence, and healthcare costs. For these reasons, new studies and laboratory tests have been developed over the last few years in order to formulate an early therapeutic intervention strategy in an attempt to reduce the high mortality rate associated with these infections. In recent years, evidencebased studies have shown the roles that the new antifungal drugs play in the treatment of invasive mycosis in seriously ill and complex patients, although data from critically ill patients are more limited. New antifungal agents have been analyzed in different clinical situations in critical care units, and the increasing number of non-Candida albicans species suggest that the application of early echinocandin therapy in critically ill patients with invasive candidiasis is a good option. Voriconazole should be recommended for invasive aspergillosis as a first line option.     

AmBisome,tres retos: infección por Candida auris,infección del sistema nervioso central e infección asociada a biopelículas

The treatment of invasive fungal infections remains a challenge, both for the diagnosis and for the need of providing the appropriate antifungal therapy. Candida auris is a pathogenic yeast that is responsible for hospital outbreaks, especially in intensive care units; it is characterized by a high resistance to the antifungal agents and can become multidrug-resistant. At present, the recommended antifungal agents for the invasive infections with this pathogen are echinocandins, always after carrying out an antifungal susceptibility testing. In case of no clinical response or persistent candidemia, the addition of liposomal amphotericin B or isavuconazole may be considered. Both fungal infection of the central nervous system and that associated with biomedical devices remain rare entities affecting mainly immunocompromised patients. However, an increase in their incidence in recent years, along with high morbidity and mortality, has been shown. The treatment of these infections is conditioned by the limited knowledge of the pharmacokinetic properties of antifungals. A better understanding of the pharmacokinetic and pharmacodynamic parameters of the different antifungals is essential to determine the efficacy of the antifungal agents in the treatment of these infections.     

Farmacoeconomía del tratamiento de las candidiasis invasoras

BackgroundInvasive candidiasis episodes have increased during last years and they have been related with high rates of crude mortality. Invasive candidiasis-related deaths have not diminished significantly with the introduction of antifungals in the past decade. Finantial managers are worried about extra costs from acquisition of new antifungal agents.AimThis review includes the main studies age-stratified to assess different variables related to the economic burden of invasive candidiasis.MethodsSystematic review of biomedic databases including Medline, PubMed and EMBASE.ResultsThe studies show hospital stay as the main variable related with higher impact in the increase of invasive candidiasis costs. Acquisition costs of antifungals have a very low impact in the invasive candidiasis costs.ConclusionsPharmacoeconomics applied in candidiasis invasive therapy must avoid assessing acquisition costs of antifungals exclusively, needing to include both direct and indirect costs associated with this fungal infection. The cost of antifungal acquisition represents a low impact in the overall economic burden of this fungal infection. Further pharmacoeconomics evaluations should be performed including similar definitions to decrease the possible bias in results interpretation.     

Update on Antifungal Drug Dosing and Therapeutic Drug Monitoring

The prevention and treatment of invasive fungal infections can be compromised by antifungal agents that display unpredictable pharmacokinetics and significant drug interactions and which demonstrate a strong relationship between drug exposure and efficacy and toxicity. Clinical studies have shown that maintaining antifungal drug levels within a targeted range decreases the risk for treatment failure and drug toxicity and thus have established a role for therapeutic drug monitoring with the use of various agents. Evidence from experimental and clinical studies supporting the role of therapeutic drug monitoring and practical applications for attaining targeted levels are reviewed.     

Pros and Cons of Extrapolating Animal Data on Antifungal Pharmacodynamics to Humans

Both the incidence of invasive fungal infections and the number of antifungal agents available to clinicians have expanded significantly over the past two decades. Successes with pharmacokinetic and pharmacodynamic evaluations of other antimicrobial agents in animal models and their clinical correlations with patient outcomes have led to an increased number of studies evaluating both old and new antifungal agents. Recently, animal models have successfully defined target pharmacodynamic indices for many antifungal agents and fungal infections, but validation of these targets in human studies is frequently lacking. This article evaluates the potential pros and cons of extrapolating to humans the animal data on antifungal pharmacodynamics.     

Repurposing benzimidazoles to fight Cryptococcus

The human diseases caused by the fungal pathogens Cryptococcus neoformans and Cryptococcus gattii are associated with high rates of mortality and toxic or cost-prohibitive therapeutic protocols. The need for affordable antifungals to combat cryptococcal disease is unquestionable. Benzimidazoles are potentially attractive antifungal compounds that were introduced in clinical practice nearly 60 years ago to treat helminthic infections. In addition to being safe, their cost of treatment is extraordinarily low. Several studies suggested benzimidazoles as promising anticryptococcal agents combining low-cost and high antifungal efficacy. So far, anti-cryptococcal activities were demonstrated for 16 different benzimidazoles. In particular, albendazole, mebendazole, flubendazole, and fenbendazole have potent in vitro antifungal activity against C. neoformans and C. gattii. Mice lethally infected with C. neoformans and treated with fenbendazole had 100 % survival when the drug was administered intranasally. In this review, we discuss the potential of benzimidazoles as potential anti-cryptococcal agents, including a general literature overview, most recent findings, mechanism of antifungal action, costs, toxicity, and antifungal potential in vivo.     

Harnessing calcineurin as a novel anti-infective agent against invasive fungal infections

The number of immunocompromised patients with invasive fungal infections continues to increase and new antifungal therapies are not keeping pace with the growing incidence of these infections and their associated mortality. Calcineurin inhibition is currently used to exert effective immunosuppression following organ transplantation and in treating various other conditions. However, the calcineurin pathway is also intricately involved in the growth and pathogenesis of the three major fungal pathogens of humans, Cryptococcus neoformans, Candida albicans and Aspergillus fumigatus, and the exploitation of fungal calcineurin pathways holds great promise for the future development of novel antifungal agents. This Review summarizes our current understanding of calcineurin biology in these fungal species, and its exciting potential role in treating invasive fungal infections.     

Antifungal Dosing in Dialysis and Continuous Renal Replacement Therapy

Appropriate dosing of antifungal drugs is crucial to achieving favorable outcomes in patients with invasive fungal infections. The use of various types of renal replacement therapy (RRT) in patients with severe acute or chronic renal insufficiency adds another level of complexity to the already challenging use of these drugs. The medical literature provides only a limited number of studies specifically addressing the use of antifungal agents in patients receiving RRT, and there are a number of inherent difficulties in interpreting and applying these studies of drug dosing during RRT to individual patients. This article briefly reviews recent studies examining the dosing of antifungal agents during RRT, and also briefly reviews device-related and drug-related factors that determine the removal of drugs during RRT. Finally, this article summarizes current recommendations for dosing of antifungal agents in patients receiving RRT and highlights areas for future study.     

Primary and Secondary Antifungal Prophylaxis in the Immunocompromised Child: Where do we Stand?

Invasive opportunistic fungal infections are important causes of morbidity and mortality in immunocompromised children undergoing chemotherapy or haematopoietic stem cell transplantation (HSCT). Primary and secondary chemoprophylaxis of invasive fungal infections targets high risk disease-related patients with acute myeloid leukaemia, high risk acute lymphoblastic leukaemias, recurrent leukaemias and those following allogeneic HSCT. The rationale for antifungal prophylaxis in high risk patients comes from two different aspects. On the one hand, is the difficulty of instant diagnosis and, on the other hand, the consequences of morbidity and mortality by invasive infectious diseases. Although we have limited pediatric data concerning antifungal prophylaxis, it has become part of infectious disease supportive care schemes in most of paediatric leukaemia and HSCT centres. This review has insights on the evidence concerning primary and secondary antifungal prophylaxis in immunocompromised children. Although our knowledge comes from large adult studies concerning antifungal agents, there is a great need for evidence of primary or secondary antifungal prophylaxis in large pediatric clinical trials in order to have a consensus in primary and secondary antifungal prophylaxis in immunocompromised children.     

Antifungal activity of nontraditional antifungal agents

Invasive fungal infections are becoming increasingly important in the management of critically ill and immunocompromised patients. As organ and stem cell transplantation becomes more prominent and immune therapies are employed for diseases such as rheumatoid arthritis and plaque psoriasis, the population of patients at risk continues to grow. Many invasive fungal infections are associated with extremely high mortality rates. Antifungal options are limited and novel therapies are intriguing as we attempt to improve patient outcomes and preserve the antifungal armamentarium. Many other classes of pharmaceuticals typically seen as non-antifungal do in fact have significant antifungal activity. Prominent among these are calcineurin inhibitors, antiarrhythmics, antidepressants, antibacterials, and others. Some have activity alone and some augment the activity of conventional antifungals. Unfortunately, clinical data are lacking for most of these agents and their role in therapy remains undefined. This review focuses on several representative non-antifungal agents with antifungal activity.     

Recent Studies on Invasive Fungal Diseases in Children and Adolescents: an Update

The improved survival of fragile pediatric hosts such as those afflicted with primary or acquired immune deficiencies, prematurity, and surgical pathology – mainly gastrointestinal and trauma – has resulted in an increased number of children susceptible to invasive fungal infections. These infections are associated with significant morbidity and mortality. Newer, safer antifungal agents allow for preventive and empiric strategies in the management of patients at risk, such as premature infants, patients receiving chemotherapy, and bone marrow or solid-organ transplant recipients. Improved radiological and molecular techniques result in earlier diagnosis of fungal infections, allowing for preemptive therapy in these patients, minimizing exposure to antifungal agents and the risk of emergence of resistant fungal strains. A better understanding of the differences in pharmacokinetics between children and adults will allow for better utilization of existing antifungal agents and improved outcomes.     

Candidiasis invasora en el paciente crítico quemado

BackgroundThe advances in burn care therapy have extended considerably the survival of seriously burned patients, exposing them to infectious complications, notably fungal infections. Due to the difficulty in the diagnosis of invasive mycoses and their high associated mortality rates, approaches to prophylactic or pre-emptive antifungal therapy in high-risk burned patients have been proposed, although these guidelines remain controversial. On the other hand, the management of these conditions is a serious problem, especially in critically ill patients with multiorgan failure, including severely ill burn patients due to the shortage of available antifungal agents. However, in the last several years, the range of antifungal agents has been significantly extended, which have led to an improvement in the treatment of invasive fungal infection in this population.Clinical caseWe report a case of invasive candidiasis in a severelly ill burns patient successfully treated with an echinocandin. In this case report, current treatment options are discussed, and a review of the literature of previously published cases is made.ConclusionsThere are still significant gaps in our knowledge of the optimal diagnostic and management approach for invasive candidiasis in burn patients. Prospective studies are needed in this population to optimise management and improve outcomes in this state of high morbidity and mortality.     

The fungal cell wall as a target for the development of new antifungal therapies

In the past three decades invasive mycoses have globally emerged as a persistent source of healthcare-associated infections. The cell wall surrounding the fungal cell opposes the turgor pressure that otherwise could produce cell lysis. Thus, the cell wall is essential for maintaining fungal cell shape and integrity. Given that this structure is absent in host mammalian cells, it stands as an important target when developing selective compounds for the treatment of fungal infections. Consequently, treatment with echinocandins, a family of antifungal agents that specifically inhibits the biosynthesis of cell wall (1-3)β-D-glucan, has been established as an alternative and effective antifungal therapy. However, the existence of many pathogenic fungi resistant to single or multiple antifungal families, together with the limited arsenal of available antifungal compounds, critically affects the effectiveness of treatments against these life-threatening infections. Thus, new antifungal therapies are required. Here we review the fungal cell wall and its relevance in biotechnology as a target for the development of new antifungal compounds, disclosing the most promising cell wall inhibitors that are currently in experimental or clinical development for the treatment of some invasive mycoses.     

Molecular targeted treatments for fungal infections: the role of drug combinations

Invasive mycoses are associated with a high mortality rate, and their incidence is increased in immunologically deficient patients. From a diagnostic and therapeutic perspective, these infections represent a significant challenge to medicine. In addition to new antifungal agents, drug combinations are an important therapeutic resource, which might be exploited clinically, owing to the multiplicity of fungal targets against which currently available agents are active. In this review, we examine the experimental data regarding the combination of conventional antifungal agents with cytokines, antibacterial agents, calcineurin inhibitors and drugs under development characterized by novel mechanisms of action.     

几种新型抗真菌药物简介

脂质型二性霉素B,新型唑类药物如伏立康唑,以及作用于真菌细胞壁的药物如卡泊芬净和米卡芬净的问世,反映了抗真菌药物研究向高效、广谱、低毒的方向发展的一个特点,无疑为各种类型真菌感染的药物治疗提供了新型的有力的手段;与传统的抗真菌药物如脱氧胆酸二性霉素B和氟康唑等相比,这些药物临床疗效好,毒副作用低,对于系统性真菌感染的防治具有重大意义,文中就这方面的信息做了简介。     

Using Antifungal Pharmacodynamics to Improve Patient Outcomes

In vitro and in vivo studies of available and investigational antifungals have broadened our understanding of the pharmacodynamics of these agents as well as the pharmacokinetic/pharmacodynamic characteristics that are associated with efficacy. These data are increasingly being used as surrogate means to answer questions about dosing and administration of antimicrobial agents in order to improve outcomes in patients with invasive fungal infections, as these questions are difficult to answer in clinical trials. The objective of this article is to review the pharmacodynamic activity of widely used classes of antifungal agents, including the azoles, amphotericin B, and the echinocandins, discuss the pharmacokinetic/pharmacodynamic parameters associated with efficacy of these agents in preclinical studies, and describe how this information is being translated into the clinical arena to optimize patient outcomes.     

Aerosolized Antifungals for the Prevention and Treatment of Invasive Fungal Infections

Invasive fungal infections result in significant morbidity and mortality, most notably in immunosuppressed patients. Aerosolized antifungal agents have been utilized primarily as prophylaxis (either alone or in combination with systemic antifungals) in patients at highest risk of invasive infections in attempts to optimize drug delivery while minimizing the potential for systemic toxicity and/or drug interactions. Published clinical experience with aerosolized antifungals most frequently involves various formulations of the polyene amphotericin B in patients undergoing lung transplantation and/or select patients with hematologic malignancy. Adverse events are infrequent and generally limited to dyspnea, dysgeusia, and cough. Existing data suggests lipid-based amphotericin B formulations may be better tolerated than amphotericin B deoxycholate. Published clinical experience with aerosolized antifungals as adjunctive treatment of invasive fungal infections is limited to case reports. Currently, there is insufficient evidence to support use of aerosolized echinocandins and azoles in clinical practice. Outstanding questions regarding comparative efficacy, optimal dose, duration and drug delivery present a continuing challenge when utilizing these agents in clinical practice.