Antifungal Therapy in Pediatric Patients

Invasive fungal infections still play a major role in morbidity and mortality in pediatric patients, especially in children undergoing therapy for an underlying malignancy and in preterm infants. Relative to the adult population, pediatric age groups display important differences not only in host biology, predisposing conditions, epidemiology, and presentation of fungal infections, but also in the disposition and clearance of antifungal compounds. During the past decade, several new antifungal agents have been developed. Although not all of these agents are yet approved for children, the pediatric development of antifungal agents has moved forward in an exemplary manner, which is essential for the successful management of the individual patient. This article reviews the current data on pharmacokinetics, safety, and dosing of antifungal agents in pediatric patients.     

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.     

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.     

Systemic antifungals. Pharmacodynamics and pharmacokinetics

Invasive fungal infections are important causes of morbidity and mortality in critically ill non neutropenic patients. For many years, amphotericin B and flucytosine have been the only available antifungal agents for invasive fungal infections. Fortunately, the antifungal armamentarium has increased during the past two decades with the addition of several new agents. In addition to itraconazole and fluconazole, lipid formulations of amphotericin B, voriconazole, and caspofungin have been recently licensed. These various antifungal agents differ in their pharmacokinetic and pharmacodynamic profile.     

An update on the pharmacoeconomics of antifungal pharmacotherapy

The incidence and severity of invasive fungal infections are on the rise and they pose a risk of significant morbidity and mortality. The cost burden of fungal infections in the United States is high. There are many newer, less toxic antifungal agents to manage these challenging infections; however, these agents also carry a high cost of their own. When considering an antifungal agent for a specific patient, it is important to consider safety, efficacy, and cost, thus making it essential to continually evaluate the antifungal pharmacoeconomic literature to assist in the therapeutic decision-making process for patients with invasive fungal infections. Unfortunately, there is a lack of pharmacoeconomic studies addressing the costs associated with the treatment and prevention of fungal infections. Future large-scale clinical studies should include pharmacoeconomic analyses and end points that encompass all costs associated with antifungal drug use, not solely drug acquisition costs.     

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.     

Antifúngicos disponibles para el tratamiento de las micosis ungueales

Nail fungal infections are considered one of the major dermatological problems due to their high rate of therapeutic failure, management and treatment difficulties. Long-term treatments, inadequate therapies, mycological misdiagnosis and follow-up, secondary alterations of the nail, and resistant microorganisms, are some of the causes of these complications. Although the discovery of new antifungal agents has provided some effective molecules, none of the current available drugs are totally effective. It is important to continue researching in this field to provide new antifungal agents and combined therapies.     

Recommendations for fungal opportunistic infections prevention in persons infected with human immunodeficiency virus

Fungal infections have become important causes of morbidity and mortality in immunocompromised hosts, including those with the acquired immune deficiency syndrome (AIDS). Although significant therapeutic advances are being made in the field of antiretroviral therapy, parallel advances must be attained in the management of secondary infections, including those due to fungi. As increasing numbers of people with HIV infection come in to medical attention, the problem of fungal infections will also increase, requiring innovative approaches toward understanding the pathogenesis of these infections and developing new diagnostic and therapeutic modalities. A better understanding is required for the immunopathogenesis of fungal infections. Improved understanding of new and established antifungal agents in conjunction with ART agents as well as immune modulators, should yield important advances in prevention, control and treatment of fungal infections of HIV infected people.     

Antifungal Prophylaxis in the Pediatric Intensive Care Unit

Invasive fungal infections in children have shown a dramatic increase over the last two decades. Their importance and clinical implications are more prominent in selected groups of patients such as critically ill children in the pediatric intensive care unit (PICU). This population constitutes an important target for prophylactic antifungal interventions. While antifungal agents have been studied in various clinical settings, knowledge in this particular setting is rather scant. The current data suggest that antifungal prophylaxis in the PICU setting should be tailored to the needs of each patient guided by the individual’s risk factors and local epidemiology.

     

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.     

Systemic fungal infections: A pharmacist/researcher perspective

Systemic fungal infections are increasing in prevalence, especially in immunocompromised patients and post-surgical patients. The rise in systemic fungal infections has resulted in increased utilization of antifungal agents which, in turn, has contributed to escalating resistance rates as seen by the increasing number of fungal pathogens added to the Centers for Disease Control and Prevention Antimicrobial Resistance Threats Report in 2019. Unfortunately, there are few novel antifungal agents coming to market to combat these ever-increasing resistance rates. In this review, we cover the current climate of antifungal agents and explore agents coming through the pipeline and potentially to market. We also discuss the indicated uses for empiric and targeted antifungal therapies as well as the need to include antifungal agents as a part of antimicrobial stewardship programs that focus heavily on antibacterial agents.     

Antifungal activity of immunosuppressants used alone or in combination with fluconazole

Fungal infections remain a challenge to clinicians due to the limited available antifungals. With the increasing use of antifungals in clinical practice, drug resistance has been emerging continuously, especially to fluconazole (FLC). Thus, a search for new antifungals and approaches to overcome antifungal resistance is needed. However, the development of new antifungals is usually costly and time consuming; discovering the antifungal activity of non-antifungal agents is one way to address these problems. Interestingly, some researchers have demonstrated that several classes of immunosuppressants (calcineurin inhibitors, glucocorticoids, etc) also displayed potent antifungal activity when used alone or in combination with antifungals, especially with FLC. Some of them could increase FLC's susceptibility against resistant Candida albicans significantly reversing fungal resistance to FLC. This article reviews the antifungal activities of immunosuppressants used alone or in combination with antifungals and their potential antifungal mechanisms that have been discovered so far. Although immunosuppressive agents have been identified as risk factors for fungal infection, we believe these findings are very important for overcoming drug resistance and developing new antifungals.     

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.     

Antifungals discovery: an insight into new strategies to combat antifungal resistance

Undeniably, new antifungal treatments are necessary against pathogenic fungi. Fungal infections have significantly increased in recent decades, being highlighted as important causes of morbidity and mortality, particularly in immunocompromised patients. Five main antifungal classes are used: (i) azoles, (ii) echinocandins, (iii) polyenes, (iv) allylamines and (v) pyrimidine analogues. Moreover, the treatment of mycoses has several limitations, such as undesirable side effects, narrow activity spectrum, a small number of targets and fungal resistance, which are still of major concern in clinical practice. The discovery of new antifungals is mostly achieved by the screening of natural or synthetic/semisynthetic chemical compounds. The most recent discoveries in drug resistance mechanism and their avoidance were explored in a review, focusing on different antifungal targets, as well as new agents or strategies, such as combination therapy, that could improve antifungal therapy.

Significance and Impact of the Study

The failure to respond to antifungal therapy is complex and is associated with microbiological resistance and increased expression of virulence in fungal pathogens. Thus, this review offers an overview of current challenges in the treatment of fungal infections associated with increased antifungal drug resistance and the formation of biofilms in these opportunistic pathogens. Furthermore, the most recent and potential strategies to combat fungal pathogens are explored here, focusing on new agents as well as innovative approaches, such as combination therapy between antifungal drugs or with natural compounds.     

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.     

Antifungal agents: mechanisms of action

Clinical needs for novel antifungal agents have altered steadily with the rise and fall of AIDS-related mycoses, and the change in spectrum of fatal disseminated fungal infections that has accompanied changes in therapeutic immunosuppressive therapies. The search for new molecular targets for antifungals has generated considerable research using modern genomic approaches, so far without generating new agents for clinical use. Meanwhile, six new antifungal agents have just reached, or are approaching, the clinic. Three are new triazoles, with extremely broad antifungal spectra, and three are echinocandins, which inhibit synthesis of fungal cell wall polysaccharides--a new mode of action. In addition, the sordarins represent a novel class of agents that inhibit fungal protein synthesis. This review describes the targets and mechanisms of action of all classes of antifungal agents in clinical use or with clinical potential.     

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.     

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.     

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.