Echinocandins in antifungal pharmacotherapy

Recent Patents on Anti-Infective Drug Discovery, 2010

Echinocandins are an interesting group of antifungals that were originally discovered in the early 1970s. They are a group of lipopeptides produced by fungi which consists of a large number of structural analogs of echinocandin B, the first echinocandin to be structurally characterized. All clinically used echinocandins are produced semi-synthetically. The cyclic peptide nuclear core is retained while the acyl chain is replaced to minimize toxicity and expand their spectrum of activity. It was not until 2002 with the introduction of caspofungin (Cancidas) into the clinics that their true worth was realized. Since the introduction of caspofungin, two other echinocandins, micafungin (Mycamine) and anidulafungin (Eraxis) have been introduced. They all function by inhibiting an enzyme unique for fungal cell wall production, which presumably accounts for their minimal side-effects. In this review, topics pertaining to their production, structural diversity, and use in the clinic along with the recent patents are discussed.

Therapeutics and Clinical …, 2007

The incidence of invasive fungal infections, especially those due to Aspergillus spp. and Candida spp., continues to increase. Despite advances in medical practice, the associated mortality from these infections continues to be substantial. The echinocandin ...

Current Fungal Infection Reports, 2012

Caspofungin, micafungin and anidulafungin are antifungal drugs with excellent safety profiles. Dosing regimens and treatment durations must be appropriate for optimal patient outcomes. Overall, factors that affect dosing of all three drugs are similar. Drug-specific properties, including in vitro concentration-dependent antifungal activity, activity against fungal biofilms, and pharmacokinetic and pharmacodynamic parameters influence dose selection and duration of therapy. Dosing strategies that provide "unbound" plasma drug concentrations exceeding the minimum inhibitory concentration (or minimum effective concentration) of the fungus are essential. Patient weight, age and illness severity are also important considerations for adequate exposure to drug: individuals >66 kg, pediatric patients and the critically-ill clear drug at higher rates although drug product information guidelines do not recommend for these populations to receive doses higher than those currently used. Clinical studies of treatment of, and prophylaxis against, Candida and Aspergillus infection indicate that currently recommended dosing regimens are adequate in most instances.

Asian Journal of Pharmaceutical and Clinical Research

Scientific and clinical reports globally demonstrated that the opportunistic mycotic infections are at major risk to the human fitness. In past few decades, development of resistance in microbes to existing antifungals, has emphasized on the search of new antimycotic drugs. As a matter of fact "echinocandins" are new categories of broad-spectrum antifungal enlighten a hope in this direction. Echinocandins are bulky lipopeptides that inhibits the production of β-[1,3]-glucan "a major constituent of fungal cell wall" which ultimately leads to the death of fungal pathogens. In vitro as well as in vivo published reports have demonstrated that the echinocandins exhibit fungicidal activity against most Candida spp while fungistatic against Aspergillus spp and exclusively found to be more effective when tested in combination with polyenes/azoles. Present article is an expert views on the recent and historical literature available on the antifungal therapies with accessi...

Clinical Infectious Diseases, 2006

Until recently, the treatment available for serious fungal infections was composed of amphotericin B and azoles, and each class demonstrated significant limitations. Echinocandins are a new class of drugs that have shown promising results in treating a variety of fungal infections. Of these, anidulafungin is a novel echinocandin that appears to have several advantages over existing antifungals. It is unique because it slowly degrades in humans, undergoing a process of biotransformation rather than being metabolized. It has potent in vitro activity against Aspergillus and Candida species, including those resistant to fluconazole or amphotericin B. Results of several clinical trials indicate that anidulafungin is effective in treating esophageal candidiasis, including azole-refractory disease. The results of a recent study comparing fluconazole versus anidulafungin demonstrated the superiority of anidulafungin in the treatment of candidemia and invasive candidiasis (IC). Studies evaluating the concomitant use of anidulafungin and either amphotericin B, voriconazole, or cyclosporine did not demonstrate significant drug-drug interactions or adverse events. To date, anidulafungin appears to have an excellent safety profile. On the basis of early clinical experience, it appears that anidulafungin will be a valuable asset in the management of serious and difficultto-treat fungal infections. Invasive fungal infections are a major and growing cause of morbidity and mortality in immunocompromised patients. In the past 20 years, the incidence of invasive fungal infections has markedly increased . Oropharyngeal candidiasis (OPC) and esophageal candidiasis (EC) are the most common opportunistic infections in patients infected with HIV [2, 3]. In addition, 10%-50% of HIV-infected patients will experience an episode of EC at some time during the course of their disease . Individuals at high risk for serious fungal infections include patients in the medical or surgical intensive care unit, surgical patients, patients with HIV infection/AIDS, and those with hematologic malignancies, such as leukemia and lymphoma, as well as patients with a solid tumor . Patients undergoing solid organ transplantation or hematopoietic stem-cell transplantation (HSCT), particularly those who develop graft-versus-host disease or Cytomegalovirus infection or who are exposed to high-dose steroid therapy, are similarly at high risk. In recent years, the epidemiology of invasive fungal infections

Antimicrobial Agents and Chemotherapy, 2007

Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.

Enfermedades Infecciosas y Microbiología Clínica, 2011

Journal of Antimicrobial Chemotherapy, 2002

Antimicrobial Agents and Chemotherapy, 2011

Candida glabrata is a leading cause of disseminated candidiasis. The echinocandins are increasingly used as first-line agents for the treatment of patients with this syndrome, although the optimal regimen for the treatment of invasive Candida glabrata infections in neutropenic patients is not known. We studied the pharmacokinetics (PK) and pharmacodynamics (PD) of micafungin, anidulafungin, and caspofungin in a neutropenic murine model of disseminated Candida glabrata infection to gain further insight into optimal therapeutic options for patients with this syndrome. A mathematical model was fitted to the data and used to bridge the experimental results to humans. The intravenous inoculation of Candida glabrata in mice was followed by logarithmic growth throughout the experimental period (101 h). A dose-dependent decline in fungal burden was observed following the administration of 0.1 to 20 mg/kg of body weight every 24 h for all three agents. The exposure-response relationships for each drug partitioned into distinct fungistatic and fungicidal components of activity. Surprisingly, the average human drug exposures following currently licensed regimens were predicted to result in a fungistatic antifungal effect. Higher human dosages of all three echinocandins are required to induce fungicidal effects in neutropenic hosts.

Seminars in Pediatric Infectious Diseases, 2001

Invasive fungal infections are increasing in prevalence because of modern support for immunocompromised patients allowing longer survivial times. The risk of fungal infection has also increased because of the use of broad spectrum of antibiotics in this patient population, and the intensity and duration of immunosuppression. The list of antifungal options has expanded with renewed interest in these infections with high morbidity and mortality. Amphotericin B deoxycholate has been and continues to be the mainstay of antifungal agents. Lipid formulations of amphotericin that improve the serum and the tissue level of amphotericin B while decreasing toxicity are being increasingly used. Imidazoles, including fluconazole and itraconazole, have reduced toxicities in comparison with amphotericin B deoxycholate, but their spectrum activity is limited. Echinocandins, including caspofungin and new investigational agents with unique mechanisms of action, offer great promise as antifungal agents either alone or in a combination agent with amphotericin B. Antifungal strategies and antifungal resistance in relationship to clinical outcomes are also discussed.