Pharmacology of Systemic Antifungal Agents

Mayo Clinic proceedings, 2011

The introduction of new antifungal agents (eg, echinocandins, second-generation triazoles) in the past decade has transformed the management of invasive mycoses to the point that drug toxicity is no longer the major limiting factor in treatment. Yet, many of these newer antifungal agents have important limitations in their spectrum of activity, pharmacokinetics, and unique predisposition for pharmacokinetic drug-drug interactions and unusual toxicities associated with long-term use. This article reviews key pharmacological aspects of systemic antifungal agents as well as evolving strategies, such as pharmacokinetic-pharmacodynamic optimization and therapeutic drug monitoring, to improve the safety and efficacy of systemic antifungal therapy.

Drugs, 2004

including those of a new class and a new generation of an existing class. Caspofungin, the first available echinocandin, has greatly expanded the antifungal armamentarium by providing a cell wall-active agent with candidacidal activity as well as demonstrated clinical efficacy in the therapy of aspergillosis refractory to available therapy. In addition, in clinical trials, caspofungin had comparable efficacy to amphotericin B for candidaemia and invasive Candida infections. Caspofungin and two more recently introduced echinocandins, micafungin and anidulafungin, are available as intravenous formulations only and characterised by potent anti-candidal activity, as well as few adverse events and drug interactions.

Asian journal of pharmaceutical research and development, 2023

Nowadays, the majority of fungal infections, including candidiasis, can cause anything from a minor mucous membrane infection to fatal systemic mycoses. Due to the most rapid increase in populations with impaired hosts, such as those with HIV/AIDS, organ transplant recipients, and chemotherapy patients, candida infections present a serious clinical challenge internationally. In addition, a dramatic rise in the number of elderly people who are vulnerable to fungal infections is anticipated in the next decades. Due to the eukaryotic structure of the cells, developing antifungal medications for these issues is more challenging than developing antibacterial medications. Therefore, there are now only a limited number of antifungal medications available to treat the wide range of fungal infections. Additionally, the antifungal arsenal against fungal diseases has been constrained by the rise in antifungal resistance and unfavourable host effects.

Infectious Disease Clinics of North America, 2003

2000

Invasive fungal infections have emerged as im- portant causes of morbidity and mortality in im- munocompromised patients. In response to this challenge, the field of antifungal chemotherapy has considerably expanded. Fluconazole and itra- conazole, introduced in the late 1980s, were the first durably useful alternatives to amphotericin B deoxycholate. The clinical development of the lipid formulations of amphotericin B, and,

Drugs, 2004

including those of a new class and a new generation of an existing class. Caspofungin, the first available echinocandin, has greatly expanded the antifungal armamentarium by providing a cell wall-active agent with candidacidal activity as well as demonstrated clinical efficacy in the therapy of aspergillosis refractory to available therapy. In addition, in clinical trials, caspofungin had comparable efficacy to amphotericin B for candidaemia and invasive Candida infections. Caspofungin and two more recently introduced echinocandins, micafungin and anidulafungin, are available as intravenous formulations only and characterised by potent anti-candidal activity, as well as few adverse events and drug interactions. Voriconazole, the first available second-generation triazole, available in both intravenous and oral formulations, has added a new and improved therapeutic option for primary therapy of invasive aspergillosis and salvage therapy for yeasts and other moulds. In a randomised trial, voriconazole demonstrated superior efficacy and a survival benefit compared with amphotericin B followed by other licensed antifungal therapy. This and data from a noncomparative study led to voriconazole becoming a new standard of therapy for invasive aspergillosis. Voriconazole has several important safety issues, including visual adverse events, hepatic enzyme elevation and skin reactions, as well as a number of drug interactions. Posaconazole, only available orally and requiring dose administration four times daily, shows encouraging efficacy in difficult to treat infections due to zygomycetes. Ravuconazole, available in both intravenous and oral formulations, has broad-spectrum in vitro potency and in vivo efficacy against a wide range of fungal pathogens. Clinical studies are underway. Despite the advances offered with each of these drugs, the morbidity and mortality associated with invasive fungal infections remains unacceptable, especially for the most at-risk patients. For individuals with severe immunosuppression as a result of chemotherapy, graft-versus-host disease and its therapy, or transplantation, new drugs and strategies are greatly needed. Table I. Systemic antifungal agents Class/compound Mechanism of action Antifungal compounds targeting fungal cell membrane Polyene antifungals Amphotericin B Interaction with ergosterol, formation of aqueous channels, increased membrane Lipid formulations of amphotericin B permeability to univalent and divalent cations, cell death Antifungal triazoles Fluconazole Interaction with cytochrome P450; inhibition of C-14 demethylation of lanosterol, Itraconazole causing ergosterol depletion and accumulation of aberrant and toxic sterols in the Voriconazole cell membrane Posaconazole Ravuconazole Antifungal compounds targeting fungal cell wall Echinocandins Caspofungin Inhibition of fungal β-(1,3) glucan synthase complex, leading to depletion of cell-wall Micafungin glucan and osmotic instability Anidulafungin

Clinical Infectious Diseases, 2006

The incidence of fungal infections has increased globally, and the introduction of the newer triazoles and echinocandin antifungals is a more-than-welcome and long overdue development. In this report, we review the clinical trials evaluating the therapeutic efficacy of these new antifungal agents and examine possible gaps in coverage. Voriconazole has become the primary treatment for most forms of invasive aspergillosis in a number of centers, posaconazole offers a broad antifungal spectrum, and echinocandins are fungicidal against most Candida species. Moreover, the new agents are active against some fungi that are resistant to amphotericin B, may have a role in the management of fever and neutropenia, and provide exciting options for combination antifungal therapy. However, significant questions remain, including the management of breakthrough infections and treatment failures and the efficacy of the new antifungal agents against less common fungi.

Journal of Hospital Medicine, 2009

Recent years have seen the release of multiple new systemic antifungal agents, significantly increasing options for the treatment of most serious fungal infections. Newly available drugs include those in the echinocandin class, including caspofungin, micafungin, and anidulafungin, as well as the newer generation triazoles, voriconazole and posaconazole. Ordering of these agents is variably restricted, depending on a given institution's policies, and all are costly. In this review we examine the available evidence and outline the role of newer antifungal medications in several common and/or important situations, including invasive and mucocutaneous Candida infection, febrile neutropenia, invasive aspergillosis, zygomycosis, and endemic mycoses.

Journal of Antimicrobial Chemotherapy, 2005

For many years, amphotericin B and flucytosine have been the only antifungal agents for invasive fungal infections. Amphotericin B was the standard of care for most of these infections. However, its use was often associated with low efficacy and poor tolerance. 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, caspofungin and micafungin have arrived on the market. Other agents are expected to be licensed shortly (anidulafungin, posaconazole). These various antifungal agents differ in their spectrum, pharmacokinetic profile, route of administration, efficacy in clinical trials, safety profile, drug-drug interactions and, importantly, their cost. There is no longer a unique standard agent for all or nearly all invasive fungal infections but a real choice among several agents. The characteristics of these new agents are reviewed to help clinicians in their decision to select an antifungal agent for their patients.

Indian Journal of Hematology and Blood Transfusion, 2014

The febrile neutropenia episodes of hematological patients and their outcomes were evaluated with respect to fungal pathogens and antifungal therapy in this retrospective study. All patients, who were older than 14 years of age and developed at least one neutropenic episode after chemotherapy due to hematological cancer from November 2010 to November 2012, were included into the study. We retrospectively collected demographic, treatment, and survival data of 126 patients with neutropenia and their 282 febrile episodes. The mean Multinational Association for Supportive Care in Cancer score was 17.18 ± 8.27. Systemic antifungal drugs were initiated in 22 patients with 30 culture-proven invasive fungal infections (IFIs), 25 attacks of 19 patients with probable invasive pulmonary aspergillosis (IPA), 42 attacks of 38 patients with possible IPA, and 31 attacks of 30 patients with suspected IFI. Voriconazole (VOR), caspofungin and liposomal amphotericin B were used to treat 72 episodes of 65 patients, 45 episodes of 37 patients and 34 episodes of 32 patients as a first-line therapy, respectively. Unfavorable conditions of our hematology ward are thought to increase the number of cases with invasive pulmonary aspergillosis and VOR use. It should be taken into consideration that increased systemic and per oral VOR usage predisposes patients to colonization and infection with azole-resistant fungal strains. Catheters should be removed in cases where patients' conditions are convenient to remove it. Acute myeloblastic leukemia cases that are more likely to develop invasive fungal infections should be monitored closely for early diagnosis and timely initiation of antifungal drugs which directly correlates with survival rates.