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Hayashi K, Hashimoto C, Ueda K, Nakaya Y, Suzuki A, Hayashi M, Sato M, Kobayashi Y. Improved Sixty-Day Mortality in Candidemia with Antifungal Treatment Within 72 Hours of Fever Onset: A Single-Center Retrospective Study in Rural Japan. Infect Dis Rep 2025; 17:36. [PMID: 40277963 PMCID: PMC12027375 DOI: 10.3390/idr17020036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 04/14/2025] [Accepted: 04/16/2025] [Indexed: 04/26/2025] Open
Abstract
Introduction: Prognostic factor investigations for candidemia have been conducted in large-scale facilities, leading to significant evidence, including early administration of echinocandin antifungal agents and removal of central venous catheters (CVCs). In departments that provide aggressive chemotherapy or transplantation, candidiasis markers are regularly evaluated, and preemptive treatments may be initiated. However, in resource-limited facilities, candidemia detection largely relies on vital signs like fever and blood cultures. This study assessed whether evidence from large-scale facilities applies to such settings. Additionally, while prior studies indicate that early antifungal treatment is based on positive blood cultures, no established criteria exist for early administration based on fever as an indicator. Methods: This study analyzed cases of candidemia from blood cultures at Fukui General Hospital (2014-2024). Patients aged 18 or older with at least one positive blood culture for Candida species and clinical signs of infection were included, while contamination cases were excluded. The patients were categorized into survival and death groups based on 60-day survival from fever onset. The variables collected included age, gender, duration from admission to fever onset, time from fever onset to blood culture collection and antifungal treatment initiation, antifungal treatment within 72 h, serum albumin levels, history of cancer, diabetes, empiric echinocandin treatment, CVC insertion, duration of CVC insertion until fever onset, use of total parenteral nutrition, broad-spectrum antibiotic use, and sequential organ failure assessment (SOFA) score. Fever was defined as a body temperature of 38.0 °C or higher, guiding blood culture collection. Results: Of 30 candidemia cases, 29 were analyzed. Survival was significantly associated with younger age (average 73.3 ± 13.3 vs. 83.1 ± 9.1 years, p = 0.038) and antifungal treatment within 72 h of fever onset (9 vs. 3, p = 0.025). CVC use was of marginal significance (8 vs. 13, p = 0.108). There was a significant difference in the duration (in days) of CVC insertion until fever onset (median [IQR]: 15.5 [11.75-19.5] vs. 30.0 [19.0-39.0], p = 0.027). Logistic regression identified early antifungal treatment (OR = 0.065, p = 0.035) and CVC use (OR = 21.8, p = 0.024) as independent predictors of mortality. Conclusions: Early antifungal treatment within 72 h of fever onset and CVC use were independent predictors of mortality in candidemia. The importance of early antifungal treatment was reaffirmed even in smaller facilities. The impact of CVC insertion on 60-day survival cannot be readily generalized due to the limited sample size. Further research is needed to clarify the impact of fever-based antifungal initiation and CVC use on 60-day survival.
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Affiliation(s)
- Koji Hayashi
- Department of Rehabilitation Medicine, Fukui General Hospital, 55-16-1 Egami, Fukui City 910-8561, Fukui, Japan
- Department of Infection Control Team, Fukui General Hospital, 55-16-1 Egami, Fukui City 910-8561, Fukui, Japan
| | - Chizuru Hashimoto
- Department of Infection Control Team, Fukui General Hospital, 55-16-1 Egami, Fukui City 910-8561, Fukui, Japan
| | - Kohei Ueda
- Department of Infection Control Team, Fukui General Hospital, 55-16-1 Egami, Fukui City 910-8561, Fukui, Japan
- Department of Internal Medicine, Fukui General Hospital, 55-16-1 Egami, Fukui City 910-8561, Fukui, Japan
| | - Yuka Nakaya
- Department of Rehabilitation Medicine, Fukui General Hospital, 55-16-1 Egami, Fukui City 910-8561, Fukui, Japan
| | - Asuka Suzuki
- Department of Rehabilitation Medicine, Fukui General Hospital, 55-16-1 Egami, Fukui City 910-8561, Fukui, Japan
| | - Maho Hayashi
- Department of Internal Medicine, Fukui General Hospital, 55-16-1 Egami, Fukui City 910-8561, Fukui, Japan
| | - Mamiko Sato
- Department of Rehabilitation Medicine, Fukui General Hospital, 55-16-1 Egami, Fukui City 910-8561, Fukui, Japan
- Graduate School of Health Science, Fukui Health Science University, 55-13-1 Egami, Fukui City 910-3190, Fukui, Japan
| | - Yasutaka Kobayashi
- Graduate School of Health Science, Fukui Health Science University, 55-13-1 Egami, Fukui City 910-3190, Fukui, Japan
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Li S, Mei Y, Jiang L, Yang X, Zeng W, Du Y. Oxazole and isoxazole-containing pharmaceuticals: targets, pharmacological activities, and their SAR studies. RSC Med Chem 2025:d4md00777h. [PMID: 40008190 PMCID: PMC11848632 DOI: 10.1039/d4md00777h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 02/18/2025] [Indexed: 02/27/2025] Open
Abstract
Oxazole, a five-membered aromatic heterocycle featuring a nitrogen and an oxygen atom separated by a carbon atom, and its isomer isoxazole, with directly attached oxygen and nitrogen atoms, have been pivotal in medicinal chemistry. Over the past few decades, the U.S. Food and Drug Administration (FDA) has approved more than 20 drugs containing these nuclei for various clinical conditions, including Tafamidis and Oxaprozin. Due to their unique physicochemical properties, these drugs often exhibit superior pharmacokinetic profiles and pharmacological effects compared to those with similar heterocycles. This review provides a comprehensive overview of all FDA-approved drugs containing oxazole and isoxazole nuclei, focusing on their pharmacological activities and structure-activity relationships.
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Affiliation(s)
- Shanshan Li
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University Tianjin 300072 China +86 22 27406121
| | - Yiou Mei
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University Tianjin 300072 China +86 22 27406121
| | - Luchen Jiang
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University Tianjin 300072 China +86 22 27406121
| | - Xueyan Yang
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University Tianjin 300072 China +86 22 27406121
| | - Wei Zeng
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University Tianjin 300072 China +86 22 27406121
| | - Yunfei Du
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University Tianjin 300072 China +86 22 27406121
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McMahon CL, Esqueda M, Yu JJ, Wall G, Romo JA, Vila T, Chaturvedi A, Lopez-Ribot JL, Wormley F, Hung CY. Development of an Imaging Flow Cytometry Method for Fungal Cytological Profiling and Its Potential Application in Antifungal Drug Development. J Fungi (Basel) 2023; 9:722. [PMID: 37504711 PMCID: PMC10381375 DOI: 10.3390/jof9070722] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 06/27/2023] [Accepted: 06/29/2023] [Indexed: 07/29/2023] Open
Abstract
Automated imaging techniques have been in increasing demand for the more advanced analysis and efficient characterization of cellular phenotypes. The success of the image-based profiling method hinges on assays that can rapidly and simultaneously capture a wide range of phenotypic features. We have developed an automated image acquisition method for fungal cytological profiling (FCP) using an imaging flow cytometer that can objectively measure over 250 features of a single fungal cell. Fungal cells were labeled with calcofluor white and FM4-64FX, which bind to the cell wall and lipophilic membrane, respectively. Images of single cells were analyzed using IDEAS® software. We first acquired FCPs of fungal cells treated with fluconazole, amphotericin B, and caspofungin, each with a distinct mode of action, to establish FCP databases of profiles associated with specific antifungal treatment. Once fully established, we investigated the potential application of this technique as a screening methodology to identify compounds with novel antifungal activity against Candida albicans and Cryptococcus neoformans. Altogether, we have developed a rapid, powerful, and novel image-profiling method for the phenotypic characterization of fungal cells, also with potential applications in antifungal drug development.
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Affiliation(s)
- Courtney L McMahon
- Department of Molecular Microbiology and Immunology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX 78249, USA
| | - Marisol Esqueda
- Department of Molecular Microbiology and Immunology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX 78249, USA
| | - Jieh-Juen Yu
- Department of Molecular Microbiology and Immunology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX 78249, USA
| | - Gina Wall
- Department of Molecular Microbiology and Immunology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX 78249, USA
| | - Jesus A Romo
- Department of Molecular Microbiology and Immunology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX 78249, USA
| | - Taissa Vila
- Department of Molecular Microbiology and Immunology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX 78249, USA
| | - Ashok Chaturvedi
- Department of Molecular Microbiology and Immunology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX 78249, USA
| | - Jose L Lopez-Ribot
- Department of Molecular Microbiology and Immunology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX 78249, USA
| | - Floyd Wormley
- Department of Molecular Microbiology and Immunology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX 78249, USA
| | - Chiung-Yu Hung
- Department of Molecular Microbiology and Immunology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX 78249, USA
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Mishra A, Juneja D. Fungal arthritis: A challenging clinical entity. World J Orthop 2023; 14:55-63. [PMID: 36844378 PMCID: PMC9945246 DOI: 10.5312/wjo.v14.i2.55] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/22/2022] [Accepted: 01/19/2023] [Indexed: 02/17/2023] Open
Abstract
There has been an increasing incidence of fungal infections in recent years. Rarely joints are also affected by fungal infections. Mainly, these infections develop in prosthetic joints, but sometimes native joints are also involved. Candida infections are mostly reported, but patients may also develop infections secondary to non-Candida fungi, especially Aspergillus. Diagnosis and management of these infections is challenging and may involve multiple surgical interventions and prolonged antifungal therapy. Despite this, these infections are associated with high morbidity and mortality. This review described the clinical features, risk factors, and therapeutic interventions required to manage fungal arthritis.
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Affiliation(s)
- Anjali Mishra
- Department of Critical Care Medicine, Holy Family Hospital, New Delhi 110025, India
| | - Deven Juneja
- Institute of Critical Care Medicine, Max Super Specialty Hospital, Saket, New Delhi 110017, India
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Polat HK, Kurt N, Aytekin E, Bozdağ Pehlivan S, Çalış S. Novel Drug Delivery Systems to Improve the Treatment of Keratitis. J Ocul Pharmacol Ther 2022; 38:376-395. [PMID: 35763406 DOI: 10.1089/jop.2021.0127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Keratitis is a disease characterized by inflammation of the cornea caused by different pathogens. It can cause serious visual morbidity if not treated quickly. Depending on the pathogen causing keratitis, eye drops containing antibacterial, antifungal, or antiviral agents such as besiloxacin, moxifloxacin, ofloxacin, voriconazol, econazole, fluconazole, and acyclovir are used, and these drops need to be applied frequently due to their low bioavailability. Studies are carried out on formulations with extended residence time in the cornea and increased permeability. These formulations include various new drug delivery systems such as inserts, nanoparticles, liposomes, niosomes, cubosomes, microemulsions, in situ gels, contact lenses, nanostructured lipid carriers, carbon quantum dots, and microneedles. Ex vivo and in vivo studies with these formulations have shown that the residence time of the active substances in the cornea is prolonged, and their ocular bioavailability is increased. In addition, in vivo studies have shown that these formulations successfully treat keratitis. However, it has been observed that fluoroquinolones are used in most of the studies; similar drug delivery systems are generally preferred for antifungal drugs, and studies for viral and acanthameba keratitis are limited. There is a need for new studies on different types of keratitis and different drug active substances. At the same time, proving the efficacy of drug delivery systems, which give promising results in in vivo animal models, with clinical studies is of great importance for progress in the treatment of keratitis.
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Affiliation(s)
- Heybet Kerem Polat
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey.,Department of Pharmaceutical Technology, Faculty of Pharmacy, Erzincan Binali Yıldırım University, Erzincan, Turkey
| | - Nihat Kurt
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey.,Department of Pharmaceutical Technology, Faculty of Pharmacy, Tokat Gaziosmanpaşa University, Tokat, Turkey
| | - Eren Aytekin
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey
| | - Sibel Bozdağ Pehlivan
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey
| | - Sema Çalış
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey
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Boahen A, Than LTL, Loke YL, Chew SY. The Antibiofilm Role of Biotics Family in Vaginal Fungal Infections. Front Microbiol 2022; 13:787119. [PMID: 35694318 PMCID: PMC9179178 DOI: 10.3389/fmicb.2022.787119] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 04/25/2022] [Indexed: 11/15/2022] Open
Abstract
“Unity in strength” is a notion that can be exploited to characterize biofilms as they bestow microbes with protection to live freely, escalate their virulence, confer high resistance to therapeutic agents, and provide active grounds for the production of biofilms after dispersal. Naturally, fungal biofilms are inherently resistant to many conventional antifungals, possibly owing to virulence factors as their ammunitions that persistently express amid planktonic transition to matured biofilm state. These ammunitions include the ability to form polymicrobial biofilms, emergence of persister cells post-antifungal treatment and acquisition of resistance genes. One of the major disorders affecting vaginal health is vulvovaginal candidiasis (VVC) and its reoccurrence is termed recurrent VVC (RVVC). It is caused by the Candida species which include Candida albicans and Candida glabrata. The aforementioned Candida species, notably C. albicans is a biofilm producing pathogen and habitually forms part of the vaginal microbiota of healthy women. Latest research has implicated the role of fungal biofilms in VVC, particularly in the setting of treatment failure and RVVC. Consequently, a plethora of studies have advocated the utilization of probiotics in addressing these infections. Specifically, the excreted or released compounds of probiotics which are also known as postbiotics are being actively researched with vast potential to be used as therapeutic options for the treatment and prevention of VVC and RVVC. These potential sources of postbiotics are harnessed due to their proven antifungal and antibiofilm. Hence, this review discusses the role of Candida biofilm formation in VVC and RVVC. In addition, we discuss the application of pro-, pre-, post-, and synbiotics either individually or in combined regimen to counteract the abovementioned problems. A clear understanding of the role of biofilms in VVC and RVVC will provide proper footing for further research in devising novel remedies for prevention and treatment of vaginal fungal infections.
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Sazali Hamzah A, Fazli Mohammat M, Wibowo A, Shaameri Z, Nur Ain Abdul Rashid F, Hidayah Pungot N. Five-Membered Nitrogen Heterocycles as New Lead Compounds in Drug Discovery. HETEROCYCLES 2022. [DOI: 10.3987/rev-22-sr(r)7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Dental and Oral Manifestations of COVID-19 Related Mucormycosis: Diagnoses, Management Strategies and Outcomes. J Fungi (Basel) 2021; 8:jof8010044. [PMID: 35049983 PMCID: PMC8781413 DOI: 10.3390/jof8010044] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 12/28/2021] [Accepted: 12/29/2021] [Indexed: 12/14/2022] Open
Abstract
It has been nearly two years since the pandemic caused by the novel coronavirus disease (COVID-19) has affected the world. Several innovations and discoveries related to COVID-19 are surfacing every day and new problems associated with the COVID-19 virus are also coming to light. A similar situation is with the emergence of deep invasive fungal infections associated with severe acute respiratory syndrome 2 (SARS-CoV-2). Recent literature reported the cases of pulmonary and rhino-cerebral fungal infections appearing in patients previously infected by COVID-19. Histopathological analysis of these cases has shown that most of such infections are diagnosed as mucormycosis or aspergillosis. Rhino-orbital-cerebral mucormycosis usually affects the maxillary sinus with involvement of maxillary teeth, orbits, and ethmoidal sinuses. Diabetes mellitus is an independent risk factor for both COVID-19 as well as mucormycosis. At this point, there is scanty data on the subject and most of the published literature comprises of either case reports or case series with no long-term data available. The aim of this review paper is to present the characteristics of COVID-19 related mucormycosis and associated clinical features, outcome, diagnostic and management strategies. A prompt diagnosis and aggressive treatment planning can surely benefit these patients.
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Hashemian SM, Farhadi T, Velayati AA. Caspofungin: a review of its characteristics, activity, and use in intensive care units. Expert Rev Anti Infect Ther 2020; 18:1213-1220. [PMID: 32662712 DOI: 10.1080/14787210.2020.1794817] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Candidemia is the fourth frequent reason of healthcare-related bloodstream infections in critically ill patients. For initial management of (suspected) invasive candidiasis in critically ill patients, usage of an echinocandin, e.g. caspofungin, has been recommended. AREAS COVERED In this study, characteristics of caspofungin and its use in intensive care unit (ICU) patients are reviewed based on an electronic search using PubMed and Google scholar. EXPERT OPINION Caspofungin is a semisynthetic derivative from pneumocandin B and the first member of the echinocandins that was approved by the U.S. Food and Drug Administration (FDA) to fight fungal infection. Caspofungin inhibits the enzyme β(1,3)-D-glucan synthase of the fungal cell wall resulted in inhibition of the synthesis of β(1,3)-D-glucan. For critically ill patients, inter- and intraindividual variations affect the caspofungin concentration. The incidence rates and densities of candidemia in surgical ICUs may be higher than medical ICUs resulting in a higher burden of candidemia in surgical ICUs. However, the mortality rate in surgical ICU patients with candidemia is higher than that medical ICU patients due to differences in their underlying conditions.
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Affiliation(s)
- Seyed MohammadReza Hashemian
- Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Sciences , Tehran, Iran.,Chronic Respiratory Diseases Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences , Tehran, Iran
| | - Tayebeh Farhadi
- Chronic Respiratory Diseases Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences , Tehran, Iran
| | - Ali Akbar Velayati
- Chronic Respiratory Diseases Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences , Tehran, Iran
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10
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Ansari S, Ahmadi B, Norouzi M, Ansari Z, Afsarian MH, Lotfali E, Rezaei-Matehkolaei A. Epidermophyton floccosum: nucleotide sequence analysis and antifungal susceptibility testing of 40 clinical isolates. J Med Microbiol 2019; 68:1655-1663. [PMID: 31573466 DOI: 10.1099/jmm.0.001074] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Purpose. Epidermophyton floccosum is an anthropophilic dermatophyte species, which is one of the common causative agents of dermatophytosis in different parts of the world. The aim of the present investigation was to evaluate the genetic diversity of E. floccosum strains isolated from different parts of Iran and to define the in vitro susceptibility profiles of seven antifungal drugs against these clinical isolates.Methodology. Forty clinical strains of E. floccosum isolated from 40 patients with dermatophytosis were subjected to DNA extraction and PCR amplification of the ITS rDNA region using universal primers ITS1 and ITS4. The in vitro activities of griseofulvin, itraconazole, voriconazole, posaconazole, caspofungin, ketoconazole and terbinafine were determined using a broth microdilution method according to the CLSI-M-38A2 protocol.Results. A mean genetic similarity of 99.5 % was found between E. floccosum strains, with intraspecies differences ranging from 0 to 3 nt. The geometric mean (GM) MICs and minimum effective concentrations (MECs) across all isolates were, in increasing order, as follows: terbinafine (GM=0.018 mg l-1), posaconazole (GM=0.022 mg l-1), itraconazole (GM=0.034 mg l-1) and voriconazole (GM=0.045 mg l-1), which had low MICs against all tested strains, whereas caspofungin (GM=0.22 mg l-1), ketoconazole (GM=0.41 mg l-1) and griseofulvin (GM=0.62 mg l-1) demonstrated higher MICs.Conclusion. Our study showed low intraspecies variation within strains of E. floccosum. Furthermore, terbinafine, posaconazole, itraconazole and voriconazole were shown to be the most potent antifungal drugs against E. floccosum strains.
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Affiliation(s)
- Saham Ansari
- Department of Medical Parasitology and Mycology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bahram Ahmadi
- Department of Medical Laboratory Sciences, School of Para-Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Maryam Norouzi
- Department of Medical Parasitology and Mycology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zohreh Ansari
- Department of Chemistry, Shiraz Branch, Islamic Azad University, Shiraz, Iran
| | - Mohammad Hosein Afsarian
- Department of Medical Mycology and Parasitology, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Ensieh Lotfali
- Department of Medical Parasitology and Mycology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Rezaei-Matehkolaei
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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11
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Efficacy and Safety of Echinocandins for the Treatment of Invasive Candidiasis in Children: A Meta-analysis. Pediatr Infect Dis J 2019; 38:42-49. [PMID: 29596219 DOI: 10.1097/inf.0000000000002032] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Echinocandins are recommended for the treatment of suspected or confirmed invasive candidiasis (IC) in adults. Less is known about the use of echinocandins for the management of IC in children. The aim of this study was to investigate the overall efficacy and safety of echinocandin class in neonatal and pediatric patients with IC. METHODS PubMed, Cochrane Central, Scopus and Clinical trial registries were searched up to July 27, 2017. Eligible studies were randomized controlled trials that evaluated the efficacy and safety of any echinocandin versus agents of other antifungal classes for the treatment of IC in pediatric patients. The primary outcome was treatment success with resolution of symptoms and signs, and absence of IC. In the meta-analysis a random effects model was used, and the odds ratio (OR) and 95% confidence intervals (CIs) were calculated. RESULTS Four randomized clinical trials (324 patients), 2 confirmed IC (micafungin vs. liposomal amphotericin B (L-AmB) and caspofungin vs. L-AmB) and 2 empirical therapy trials (caspofungin vs. deoxycholate amphotericin B and caspofungin vs. L-AmB) were included. There was no significant difference between echinocandins and comparator in terms of treatment success (OR = 1.61, 95% CI: 0.74-3.50) and incidence of treatment-related adverse events (OR = 0.70, 95% CI: 0.39-1.26). However, fewer children treated with echinocandins discontinued treatment because of adverse events than amphotericin B formulations (OR = 0.26, 95% CI: 0.08-0.82, P = 0.02). CONCLUSIONS In the treatment of IC in children, echinocandins show non-inferior efficacy compared with amphotericin B formulations with fewer discontinuations than in comparator arm.
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12
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Ottilie S, Goldgof GM, Cheung AL, Walker JL, Vigil E, Allen KE, Antonova-Koch Y, Slayman CW, Suzuki Y, Durrant JD. Two inhibitors of yeast plasma membrane ATPase 1 (ScPma1p): toward the development of novel antifungal therapies. J Cheminform 2018; 10:6. [PMID: 29464421 PMCID: PMC5820243 DOI: 10.1186/s13321-018-0261-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Accepted: 02/10/2018] [Indexed: 01/07/2023] Open
Abstract
Given that many antifungal medications are susceptible to evolved resistance, there is a need for novel drugs with unique mechanisms of action. Inhibiting the essential proton pump Pma1p, a P-type ATPase, is a potentially effective therapeutic approach that is orthogonal to existing treatments. We identify NSC11668 and hitachimycin as structurally distinct antifungals that inhibit yeast ScPma1p. These compounds provide new opportunities for drug discovery aimed at this important target.![]()
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Affiliation(s)
- Sabine Ottilie
- Division of Host Pathogen Systems and Therapeutics, Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Gregory M Goldgof
- Division of Host Pathogen Systems and Therapeutics, Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.,Department of Synthetic Biology and Bioenergy, J. Craig Venter Institute, La Jolla, CA, 92037, USA
| | - Andrea L Cheung
- Division of Host Pathogen Systems and Therapeutics, Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Jennifer L Walker
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Edgar Vigil
- Division of Host Pathogen Systems and Therapeutics, Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Kenneth E Allen
- Department of Genetics, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Yevgeniya Antonova-Koch
- Division of Host Pathogen Systems and Therapeutics, Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Carolyn W Slayman
- Department of Genetics, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Yo Suzuki
- Department of Synthetic Biology and Bioenergy, J. Craig Venter Institute, La Jolla, CA, 92037, USA
| | - Jacob D Durrant
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
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13
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Affiliation(s)
- I. W. Hamley
- Department of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, United Kingdom
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14
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Nielsen DS, Shepherd NE, Xu W, Lucke AJ, Stoermer MJ, Fairlie DP. Orally Absorbed Cyclic Peptides. Chem Rev 2017; 117:8094-8128. [PMID: 28541045 DOI: 10.1021/acs.chemrev.6b00838] [Citation(s) in RCA: 294] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Peptides and proteins are not orally bioavailable in mammals, although a few peptides are intestinally absorbed in small amounts. Polypeptides are generally too large and polar to passively diffuse through lipid membranes, while most known active transport mechanisms facilitate cell uptake of only very small peptides. Systematic evaluations of peptides with molecular weights above 500 Da are needed to identify parameters that influence oral bioavailability. Here we describe 125 cyclic peptides containing four to thirty-seven amino acids that are orally absorbed by mammals. Cyclization minimizes degradation in the gut, blood, and tissues by removing cleavable N- and C-termini and by shielding components from metabolic enzymes. Cyclization also folds peptides into bioactive conformations that determine exposure of polar atoms to solvation by water and lipids and therefore can influence oral bioavailability. Key chemical properties thought to influence oral absorption and bioavailability are analyzed, including molecular weight, octanol-water partitioning, hydrogen bond donors/acceptors, rotatable bonds, and polar surface area. The cyclic peptides violated to different degrees all of the limits traditionally considered to be important for oral bioavailability of drug-like small molecules, although fewer hydrogen bond donors and reduced flexibility generally favored oral absorption.
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Affiliation(s)
- Daniel S Nielsen
- Division of Chemistry and Structural Biology, and ‡Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, QLD 4072, Australia
| | - Nicholas E Shepherd
- Division of Chemistry and Structural Biology, and ‡Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, QLD 4072, Australia
| | - Weijun Xu
- Division of Chemistry and Structural Biology, and ‡Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, QLD 4072, Australia
| | - Andrew J Lucke
- Division of Chemistry and Structural Biology, and ‡Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, QLD 4072, Australia
| | - Martin J Stoermer
- Division of Chemistry and Structural Biology, and ‡Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, QLD 4072, Australia
| | - David P Fairlie
- Division of Chemistry and Structural Biology, and ‡Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, QLD 4072, Australia
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15
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Sang P, Shi Y, Teng P, Cao A, Xu H, Li Q, Cai J. Antimicrobial AApeptides. Curr Top Med Chem 2017; 17:1266-1279. [PMID: 27758686 DOI: 10.2174/1568026616666161018145945] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2016] [Revised: 05/10/2016] [Accepted: 05/18/2016] [Indexed: 12/26/2022]
Abstract
Antibiotic resistance is one of the biggest public concerns in the 21st century. Host-defense peptides (HDPs) can potentially mitigate the problem through bacterial membrane disruption; however, they suffer from moderate activity and low stability. We recently developed a new class of peptidomimetics termed "AApeptides". This class of peptidomimetics can mimic the mechanism of action of HDPs, and effectively arrest the growth of multidrug resistant Gram-positive and Gram-negative bacteria. As they are built on unnatural backbone, they are resistant to proteolytic degradation. In this review, we summarize the development of this class of antimicrobial peptidomimetics, and discuss the future perspective on how they can move forward on combating antibiotic resistance.
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Affiliation(s)
- Peng Sang
- Department of Chemistry, University of South Florida, Tampa, FL, 33260, United States
| | - Yan Shi
- Department of Chemistry, University of South Florida, Tampa, FL, 33260, United States
| | - Peng Teng
- Department of Chemistry, University of South Florida, Tampa, FL, 33260, United States
| | - Annie Cao
- Department of Chemistry, University of South Florida, Tampa, FL, 33260, United States
| | - Hai Xu
- College of Chemistry and Chemical Engineering, Central South University, Changsha, HN 410083, China
| | - Qi Li
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jianfeng Cai
- Department of Chemistry, University of South Florida, Tampa, United States
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16
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Girmenia C, Iori AP. An update on the safety and interactions of antifungal drugs in stem cell transplant recipients. Expert Opin Drug Saf 2016; 16:329-339. [PMID: 28004589 DOI: 10.1080/14740338.2017.1273900] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Invasive fungal diseases (IFDs) are a major cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). Improvement in the management of IFDs have been achieved with the availability of new effective and safe antifungal drugs, however, many of these newer treatments have some limitations in their variable toxicity and unique predisposition for pharmacokinetic drug-drug interactions. Areas covered: This article is an update of a previous review published in this journal evaluating the safety profile of the antifungal drugs. Interesting new features include the availability of the new drug isavuconazole and the new tablet and intravenous formulations of posaconazole. Different dosages and new ways of administration of liposomal Amphotericin B (L-AmB) and echinocandins may be considered in the HSCT practice. Expert opinion: Nephrotoxicity continues to be a clinically relevant and frequent side effect of L-AmB which may cause a reduced clearance of other renally eliminated drugs frequently used in HSCT patients. Echinocandins are favorable therapeutic options in view of their low toxicity and uncommon drug-drug interactions. Important limitations of triazoles are represented by hepatic toxicity and certain side effects particularly after prolonged treatments. The new triazole isavuconazole and the new tablet formulation of posaconazole will be probably increasingly used in the HSCT setting not only due to their efficacy but in particular for their interesting toxicity profile and pharmacokinetic characteristics. The knowledge of these pharmacological findings is crucial in the daily care of allogeneic HSCT patients.
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Affiliation(s)
- Corrado Girmenia
- a Dipartimento di Ematologia, Oncologia, Anatomia Patologica e Medicina Rigenerativa, Azienda Policlinico Umberto I , Sapienza University , Rome , Italy
| | - Anna Paola Iori
- a Dipartimento di Ematologia, Oncologia, Anatomia Patologica e Medicina Rigenerativa, Azienda Policlinico Umberto I , Sapienza University , Rome , Italy
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17
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Aminov R. History of antimicrobial drug discovery: Major classes and health impact. Biochem Pharmacol 2016; 133:4-19. [PMID: 27720719 DOI: 10.1016/j.bcp.2016.10.001] [Citation(s) in RCA: 153] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 10/04/2016] [Indexed: 12/12/2022]
Abstract
The introduction of antibiotics into clinical practice revolutionized the treatment and management of infectious diseases. Before the introduction of antibiotics, these diseases were the leading cause of morbidity and mortality in human populations. This review presents a brief history of discovery of the main antimicrobial classes (arsphenamines, β-lactams, sulphonamides, polypeptides, aminoglycosides, tetracyclines, amphenicols, lipopeptides, macrolides, oxazolidinones, glycopeptides, streptogramins, ansamycins, quinolones, and lincosamides) that have changed the landscape of contemporary medicine. Given within a historical timeline context, the review discusses how the introduction of certain antimicrobial classes affected the morbidity and mortality rates due to bacterial infectious diseases in human populations. Problems of resistance to antibiotics of different classes are also extensively discussed.
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Affiliation(s)
- Rustam Aminov
- School of Medicine and Dentistry, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom.
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18
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Mukkada S, Kirby J, Apiwattanakul N, Hayden RT, Caniza MA. Use of Fungal Diagnostics and Therapy in Pediatric Cancer Patients in Resource-Limited Settings. CURRENT CLINICAL MICROBIOLOGY REPORTS 2016; 3:120-131. [PMID: 27672551 PMCID: PMC5034939 DOI: 10.1007/s40588-016-0038-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Fungal diseases are an important cause of mortality in immunocompromised hosts, and their incidence in pediatric cancer patients in low- to middle-income countries is underestimated. In this review, we present relevant, up-to-date information about the most common opportunistic and endemic fungal diseases among children with cancer, their geographic distribution, and recommended diagnostics and treatment. Efforts to improve the care of children with cancer and fungal disease must address the urgent need for sustainable and cost-effective solutions that improve training, fungal disease testing capability, and the use of available resources. We hope that the collective information presented here will be used to advise healthcare providers, regional and country health leaders, and policymakers of the current challenges in diagnosing and treating fungal infections in children with cancer in low- to middle-income countries.
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Affiliation(s)
- Sheena Mukkada
- Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA
- Division of Infectious Diseases, Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis, TN, USA
| | - Jeannette Kirby
- Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Nopporn Apiwattanakul
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Randall T. Hayden
- Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Miguela A. Caniza
- Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA
- Department of Global Pediatric Medicine, St Jude Children’s Research Hospital, Memphis, TN, USA
- International Outreach Program, St. Jude Children's Research Hospital, Memphis, TN, USA
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19
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Ngo HX, Shrestha SK, Garneau-Tsodikova S. Identification of Ebsulfur Analogues with Broad-Spectrum Antifungal Activity. ChemMedChem 2016; 11:1507-16. [PMID: 27334363 DOI: 10.1002/cmdc.201600236] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 05/30/2016] [Indexed: 11/10/2022]
Abstract
Invasive fungal infections are on the rise due to an increased population of critically ill patients as a result of HIV infections, chemotherapies, and organ transplantations. Current antifungal drugs are helpful, but are insufficient in addressing the problem of drug-resistant fungal infections. Thus, there is a growing need for novel antimycotics that are safe and effective. The ebselen scaffold has been evaluated in clinical trials and has been shown to be safe in humans. This makes ebselen an attractive scaffold for facile translation from bench to bedside. We recently reported a library of ebselen-inspired ebsulfur analogues with antibacterial properties, but their antifungal activity has not been characterized. In this study, we repurposed ebselen, ebsulfur, and 32 additional ebsulfur analogues as antifungal agents by evaluating their antifungal activity against a panel of 13 clinically relevant fungal strains. The effect of induction of reactive oxygen species (ROS) by three of these compounds was evaluated. Their hemolytic and cytotoxicity activities were also determined using mouse erythrocytes and mammalian cells. The MIC values of these compounds were found to be in the range of 0.02-12.5 μg mL(-1) against the fungal strains tested. Notably, yeast cells treated with our compounds showed an accumulation of ROS, which may further contribute to the growth-inhibitory effect against fungi. This study provides new lead compounds for the development of antimycotic agents.
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Affiliation(s)
- Huy X Ngo
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536-0596, USA
| | - Sanjib K Shrestha
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536-0596, USA
| | - Sylvie Garneau-Tsodikova
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536-0596, USA.
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20
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Shirey K, Stover KR, Cleary J, Hoang N, Hosler J. Membrane-Anchored Cyclic Peptides as Effectors of Mitochondrial Oxidative Phosphorylation. Biochemistry 2016; 55:2100-11. [PMID: 26985698 DOI: 10.1021/acs.biochem.5b01368] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The echinocandins are membrane-anchored, cyclic lipopeptides (CLPs) with antifungal activity due to their ability to inhibit a glucan synthase located in the plasma membrane of fungi such as Candida albicans. A hydrophobic tail of an echinocandin CLP inserts into a membrane, placing a six-amino acid cyclic peptide near the membrane surface. Because processes critical for the function of the electron transfer complexes of mitochondria, such as proton uptake and release, take place near the surface of the membrane, we have tested the ability of two echinocandin CLPs, caspofungin and micafungin, to affect the activity of electron transfer complexes in isolated mammalian mitochondria. Indeed, caspofungin and micafungin both inhibit whole chain electron transfer in isolated mitochondria at low micromolar concentrations. The effects of the CLPs are fully reversible, in some cases simply via the addition of bovine serum albumin to bind the CLPs via their hydrophobic tails. Each CLP affects more than one complex, but they still exhibit specificity of action. Only caspofungin inhibits complex I, and the CLP inhibits liver but not heart complex I. Both CLPs inhibit heart and liver complex III. Caspofungin inhibits complex IV activity, while, remarkably, micafungin stimulates complex IV activity nearly 3-fold. Using a variety of assays, we have developed initial hypotheses for the mechanisms by which caspofungin and micafungin alter the activities of complexes IV and III. The dication caspofungin partially inhibits cytochrome c binding at the low-affinity binding site of complex IV, while it also appears to inhibit the release of protons from the outer surface of the complex, similar to Zn(2+). Anionic micafungin appears to stimulate complex IV activity by enhancing the transfer of protons to the O2 reduction site. For complex III, we hypothesize that each CLP binds to the cytochrome b subunit and the Fe-S subunit to inhibit the required rotational movement of the latter.
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Affiliation(s)
- Kristin Shirey
- Department of Biochemistry and ‡School of Pharmacy, University of Mississippi Medical Center , 2500 North State Street, Jackson, Mississippi 39216, United States
| | - Kayla R Stover
- Department of Biochemistry and ‡School of Pharmacy, University of Mississippi Medical Center , 2500 North State Street, Jackson, Mississippi 39216, United States
| | - John Cleary
- Department of Biochemistry and ‡School of Pharmacy, University of Mississippi Medical Center , 2500 North State Street, Jackson, Mississippi 39216, United States
| | - Ngoc Hoang
- Department of Biochemistry and ‡School of Pharmacy, University of Mississippi Medical Center , 2500 North State Street, Jackson, Mississippi 39216, United States
| | - Jonathan Hosler
- Department of Biochemistry and ‡School of Pharmacy, University of Mississippi Medical Center , 2500 North State Street, Jackson, Mississippi 39216, United States
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21
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Chew SY, Than LTL. Vulvovaginal candidosis: contemporary challenges and the future of prophylactic and therapeutic approaches. Mycoses 2016; 59:262-73. [PMID: 26765516 DOI: 10.1111/myc.12455] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Revised: 11/19/2015] [Accepted: 12/08/2015] [Indexed: 12/16/2022]
Abstract
Vulvovaginal candidosis (VVC) is a common gynaecological disorder that is delineated by the inflammation of vaginal wall and it is caused by the opportunistic fungal pathogen Candida species. In fact, three out of every four women will experience at least one occasion of VVC during some point in their lives. Although uncomplicated VVC is relatively harmless, the complicated VVC such as recurrent attack often creates restlessness and depression in the patients, thus greatly affects their quality of life. Managements of VVC are usually associated with the use of antimycotic suppositories, topical cream or oral agents. These antimycotic agents are either available over-the-counter or prescribed by the clinicians. In recent decades, the rise of clinical challenges such as the increased prevalence of resistant Candida strains, recurrent VVC infection and adverse effects of multidrug interactions have necessitated the development of novel therapeutic or prophylactic options to combat the complicated VVC in the future. In this review, we discuss the current antimycotic treatments available for Candida vaginitis and the problems that exist in these seemingly effective treatments. Besides, we attempt to contemplate some of the future and prospective strategies surrounding the development of alternative therapeutic and prophylactic options in treating and preventing complicated VVC respectively.
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Affiliation(s)
- Shu Yih Chew
- Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43300, Serdang, Selangor, Malaysia
| | - Leslie Thian Lung Than
- Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43300, Serdang, Selangor, Malaysia
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22
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Bhattacharyya S, Gupta P, Banerjee G, Jain A, Singh M. Inhibition of biofilm formation and lipase in Candida albicans by culture filtrate of Staphylococcus epidermidis in vitro. Int J Appl Basic Med Res 2014; 4:S27-30. [PMID: 25298939 PMCID: PMC4181128 DOI: 10.4103/2229-516x.140721] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2013] [Accepted: 03/28/2014] [Indexed: 11/29/2022] Open
Abstract
Background: Candida spp. are fourth most common cause of bloodstream infection in developed countries and emerging agents of fungemia in developing countries, with considerable attributable mortality. Candidemia is associated with the formation of complex, structured microbial communities called biofilms. Biofilm formation makes treatment difficult due to improper drug penetration and factors like high cost and adverse effects of antifungal drugs available. Hence, low-cost alternatives are urgently required to treat device-associated invasive candidiasis. Objectives: To study the effect of culture filtrate of Staphylococcus epidermidis on biofilm formation and lipase expression of Candida albicans in vitro. Materials and Methods: Yeast cells isolated from clinical samples were suspended to a turbidity of 106 in (a) Yeast extract-peptone-dextrose (YPD) broth and (b) culture filtrate, and 100 μl of each were dispensed in separate wells of microtiter plate. After repeated washing and reloading with respective liquid media, readings were taken spectrophotometrically. To check for lipase inhibition, yeasts were incubated overnight in YPD and filtrate and subcultured on media containing Tween-80 and CaCl2. Positive lipase activity was denoted by haziness around colonies. Results: Mean reading of C. albicans in YPD broth was 0.579 while the same when yeasts were suspended in S. epidermidis culture filtrate was 0.281 (P < 0.05 by Z-test of significance). Lipase of C. albicans was inhibited by culture filtrate. Filtrate was found to be nontoxic to human cell line. Conclusions: Culture filtrate of S. epidermidis can hence pave the way for development of new strategies to inhibit biofilm formation in device-associated candidemia.
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Affiliation(s)
| | - Prashant Gupta
- Department of Microbiology, KGMU, Lucknow, Uttar Pradesh, India
| | - Gopa Banerjee
- Department of Microbiology, KGMU, Lucknow, Uttar Pradesh, India
| | - Amita Jain
- Department of Microbiology, KGMU, Lucknow, Uttar Pradesh, India
| | - Mastan Singh
- Department of Microbiology, KGMU, Lucknow, Uttar Pradesh, India
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23
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Szychowski J, Truchon JF, Bennani YL. Natural products in medicine: transformational outcome of synthetic chemistry. J Med Chem 2014; 57:9292-308. [PMID: 25144261 DOI: 10.1021/jm500941m] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
This review brings to the forefront key synthetic modifications on natural products (NPs) that have yielded successful drugs. The emphasis is placed on the power of targeted chemical transformations in enhancing the therapeutic value of NPs through optimization of pharmacokinetics, stability, potency, and/or selectivity. Multiple classes of NPs such as macrolides, opioids, steroids, and β-lactams used to treat a variety of conditions such as cancers, infections, inflammation are exemplified. Molecular modeling or X-ray structures of NP/protein complexes supporting the observed boost in therapeutic value of the modified NPs are also discussed. Significant advancement in synthetic chemistry, in structure determination, and in the understanding of factors controlling pharmacokinetics can now better position drug discovery teams to undertake NPs as valuable leads. We hope that the beneficial NPs synthetic modifications outlined here will reignite medicinal chemists' interest in NPs and their derivatives.
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Affiliation(s)
- Janek Szychowski
- Vertex Pharmaceuticals (Canada), Inc. , 275 Armand-Frappier, Laval, Québec H7V 4A7, Canada
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24
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Mihu MR, Pattabhi R, Nosanchuk JD. The impact of antifungals on toll-like receptors. Front Microbiol 2014; 5:99. [PMID: 24672516 PMCID: PMC3954077 DOI: 10.3389/fmicb.2014.00099] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Accepted: 02/25/2014] [Indexed: 01/23/2023] Open
Abstract
Fungi are increasingly recognized as major pathogens in immunocompromised individuals. With the increase in the number of fungal infections each year and the development of resistance to current therapy, new approaches to treatment including stimulation of the immune response in addition to concurrent pharmacotherapy is ongoing. The most common invasive fungal infections are caused by Candida spp., Aspergillus spp., and Cryptococcus spp. Amphotericin B (AmB) has remained the cornerstone of therapy against many fulminant fungal infections but its use is limited by its multitude of side effects. Echinocandins are a newer class of antifungal drugs with activity against Candida spp. and Aspergillus spp. and constitutes an alternative to AmB due to superior patient tolerability and fewer side effects. Due to their oral delivery, azoles continue to be heavily used for simple and complex diseases, such as fluconazole for candidal vaginitis and voriconazole for aspergillosis. The objective of this paper is to present current knowledge regarding the multiple interactions between the broad spectrum antifungals and the innate immune response, primarily focusing on the toll-like receptors.
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Affiliation(s)
- Mircea R Mihu
- Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine-Montefiore Medical Center Bronx, NY, USA
| | - Rodney Pattabhi
- Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine-Montefiore Medical Center Bronx, NY, USA
| | - Joshua D Nosanchuk
- Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine-Montefiore Medical Center Bronx, NY, USA ; Department of Microbiology and Immunology, Albert Einstein College of Medicine-Montefiore Medical Center Bronx, NY, USA
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25
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Niu Y, Wu H, Li Y, Hu Y, Padhee S, Li Q, Cao C, Cai J. AApeptides as a new class of antimicrobial agents. Org Biomol Chem 2013; 11:4283-90. [PMID: 23722277 DOI: 10.1039/c3ob40444g] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Antibiotic resistance is an increasing public health concern around the world, and is recognized as one of the greatest threats facing humankind in the 21(st) century. Natural antimicrobial peptides (AMPs) are small cationic amphiphilic peptides found in virtually all living organisms, and play a key role in the defense against bacterial infections. Compared with conventional antibiotics, which target specific metabolic processes, AMPs are able to adopt globally amphipathic conformations, and kill bacteria through disruption of their membranes. As such, AMPs do not readily induce drug-resistance. However, AMPs are associated with intrinsic drawbacks such as low-to-moderate activity, susceptibility to enzymatic degradation, and inconvenience for optimization. Recently, we have developed a new class of peptidomimetics termed "AApeptides". Such peptide mimics are highly resistant to protease degradation and are straightforward for chemical diversification and development. Our current studies show that AApeptides with globally amphipathic structures can mimic the bactericidal mechanism of AMPs, and display potent and broad-spectrum activity against both Gram-positive and -negative multi-drug-resistant bacteria. In this review, we summarize our current findings of antimicrobial AApeptides, and discuss potential future directions on the development of more potent and specific analogues.
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Affiliation(s)
- Youhong Niu
- Department of Chemistry, University of South Florida, 4202 E. Fowler Ave, Tampa, FL 33620, USA
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26
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Zhang J, Silao FGS, Bigol UG, Bungay AAC, Nicolas MG, Heitman J, Chen YL. Calcineurin is required for pseudohyphal growth, virulence, and drug resistance in Candida lusitaniae. PLoS One 2012; 7:e44192. [PMID: 22952924 PMCID: PMC3432075 DOI: 10.1371/journal.pone.0044192] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2012] [Accepted: 07/30/2012] [Indexed: 11/19/2022] Open
Abstract
Candida lusitaniae is an emerging fungal pathogen that infects immunocompromised patients including HIV/AIDS, cancer, and neonatal pediatric patients. Though less prevalent than other Candida species, C. lusitaniae is unique in its ability to develop resistance to amphotericin B. We investigated the role of the calcium-activated protein phosphatase calcineurin in several virulence attributes of C. lusitaniae including pseudohyphal growth, serum survival, and growth at 37°C. We found that calcineurin and Crz1, a C. albicans Crz1 homolog acting as a downstream target of calcineurin, are required for C. lusitaniae pseudohyphal growth, a process for which the underlying mechanism remains largely unknown in C. lusitaniae but hyphal growth is fundamental to C. albicans virulence. We demonstrate that calcineurin is required for cell wall integrity, ER stress response, optimal growth in serum, virulence in a murine systemic infection model, and antifungal drug tolerance in C. lusitaniae. To further examine the potential of targeting the calcineurin signaling cascade for antifungal drug development, we examined the activity of a calcineurin inhibitor FK506 in combination with caspofungin against echinocandin resistant C. lusitaniae clinical isolates. Broth microdilution and drug disk diffusion assays demonstrate that FK506 has synergistic fungicidal activity with caspofungin against echinocandin resistant isolates. Our findings reveal that pseudohyphal growth is controlled by the calcineurin signaling cascade, and highlight the potential use of calcineurin inhibitors and caspofungin for emerging drug-resistant C. lusitaniae infections.
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Affiliation(s)
- Jing Zhang
- Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, United States of America
- Department of Chemistry, Duke University, Durham, North Carolina, United States of America
| | - Fitz Gerald S. Silao
- Department of Microbiology and Parasitology, University of Perpetual Help – Dr. Jose G. Tamayo Medical University, Biñan, Laguna, Philippines
| | - Ursela G. Bigol
- Environment and Biotechnology Division, Department of Science and Technology, Bicutan, Philippines
| | - Alice Alma C. Bungay
- Department of Microbiology and Parasitology, University of Perpetual Help – Dr. Jose G. Tamayo Medical University, Biñan, Laguna, Philippines
- National Institutes of Health-Philippines, University of the Philippines, Manila, Philippines
| | - Marilou G. Nicolas
- National Institutes of Health-Philippines, University of the Philippines, Manila, Philippines
| | - Joseph Heitman
- Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, United States of America
- * E-mail: (JH); (Y-LC)
| | - Ying-Lien Chen
- Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, United States of America
- * E-mail: (JH); (Y-LC)
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27
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Girmenia C, Iori AP. Safety and interactions of new antifungals in stem cell transplant recipients. Expert Opin Drug Saf 2012; 11:803-18. [DOI: 10.1517/14740338.2012.712111] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Kim N, Kim JK, Hwang D, Lim YH. The possible mechanism of rhapontigenin influencing antifungal activity on Candida albicans. Med Mycol 2012; 51:45-52. [PMID: 22662760 DOI: 10.3109/13693786.2012.689021] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Rhapontigenin, an aglycone of rhapontin, was produced by biotransformation and we investigated its antifungal activity against Candida albicans, one of the most important opportunistic fungal pathogens. Rhapontigenin is found to have, in vitro, inhibitory activity with a minimal inhibitory concentration (MIC) value against all test isolates of 128-256 μg/ml. We detected increased reactive oxygen species (ROS) levels in yeast cultures treated with rhapontigenin at the MIC. Rhapontigenin inhibited DNA, RNA, and protein synthesis, especially RNA synthesis, and induced morphological changes and apoptosis of C. albicans. The apoptotic effect of rhapontigenin on C. albicans at subinhibitory concentrations was higher in the stationary growth phase than in the exponential phase, while the opposite results were noted with amphotericin B. The mechanism of antifungal activity of rhapontigenin may be associated with the generation of ROS that might induce apoptosis and it may also involve the inhibition of ergosterol biosynthesis.
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Affiliation(s)
- Narae Kim
- Department of Biomedical Science, College of Health Science, Korea University, Seoul, Korea
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Anjos J, Fernandes C, Silva BMA, Quintas C, Abrunheiro A, Gow NAR, Gonçalves T. β(1,3)-glucan synthase complex from Alternaria infectoria, a rare dematiaceous human pathogen. Med Mycol 2012; 50:716-25. [PMID: 22548239 DOI: 10.3109/13693786.2012.675525] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
The fungal cell wall polymer β-(1,3)-D-glucan is synthesized by the enzyme β-(1,3)- D-glucan synthase that is a complex composed of at least two proteins, Rho1p and Fks1p. Here, we report the nucleotide sequence of a single FKS gene and of the regulatory unit, RHO1 from the dematiaceous pathogenic fungus Alternaria infectoria. The predicted AiFks and AiRho share, respectively, 93% and 100% identity with that of Drechslera tritici-repentis. We also report that the sensitivity to caspofungin of eight different A. infectoria clinical strains is similar, with a MIC > 32 µg/ml and a MEC of 1 µg/ml, except for one strain which had a MEC of 1.4 µg/ml. This same strain exhibited one substitution at the hot spot 2, S1405A, compatible with less susceptible phenotypes, with the other seven strains having no mutations in either hot spot 1 or 2. The relative quantification of the expression of AiFKS and of AiRHO demonstrated a decrease in response to an exposure to caspofungin at 0.5 µg/ml.
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Affiliation(s)
- Jorge Anjos
- CNC-Centre for Neurosciences and Cell Biology, University of Coimbra, Portugal
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30
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Martos AI, Martín-Mazuelos E, Romero A, Serrano C, González T, Almeida C, Puche B, Cantón E, Pemán J, Espinel-Ingroff A. Evaluation of disk diffusion method compared to broth microdilution for antifungal susceptibility testing of 3 echinocandins against Aspergillus spp. Diagn Microbiol Infect Dis 2012; 73:53-6. [DOI: 10.1016/j.diagmicrobio.2012.01.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2011] [Revised: 01/15/2012] [Accepted: 01/17/2012] [Indexed: 11/27/2022]
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Niu Y, Padhee S, Wu H, Bai G, Qiao Q, Hu Y, Harrington L, Burda WN, Shaw LN, Cao C, Cai J. Lipo-γ-AApeptides as a new class of potent and broad-spectrum antimicrobial agents. J Med Chem 2012; 55:4003-9. [PMID: 22475244 DOI: 10.1021/jm300274p] [Citation(s) in RCA: 98] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
There is increasing demand to develop antimicrobial peptides (AMPs) as next generation antibiotic agents, as they have the potential to circumvent emerging drug resistance against conventional antibiotic treatments. Non-natural antimicrobial peptidomimetics are an ideal example of this, as they have significant potency and in vivo stability. Here we report for the first time the design of lipidated γ-AApeptides as antimicrobial agents. These lipo-γ-AApeptides show potent broad-spectrum activities against fungi and a series of Gram-positive and Gram-negative bacteria, including clinically relevant pathogens that are resistant to most antibiotics. We have analyzed their structure-function relationship and antimicrobial mechanisms using membrane depolarization and fluorescent microscopy assays. Introduction of unsaturated lipid chain significantly decreases hemolytic activity and thereby increases the selectivity. Furthermore, a representative lipo-γ-AApeptide did not induce drug resistance in S. aureus, even after 17 rounds of passaging. These results suggest that the lipo-γ-AApeptides have bactericidal mechanisms analogous to those of AMPs and have strong potential as a new class of novel antibiotic therapeutics.
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Affiliation(s)
- Youhong Niu
- Department of Chemistry, CHE 205, University of South Florida, 4202 E. Fowler Avenue, Tampa, Florida 33620, USA
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Fungal infections: their diagnosis and treatment in transplant recipients. Int J Hepatol 2012; 2012:106923. [PMID: 22966464 PMCID: PMC3433127 DOI: 10.1155/2012/106923] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2012] [Accepted: 04/23/2012] [Indexed: 11/18/2022] Open
Abstract
Systemic fungal infections typically occur in individuals who are seriously ill with recognized risk factors such as those frequently found in transplant recipients. Unfortunately, they are often diagnosed late, when the efficacy of the available treatments is low, often less than 50%, and the cost in terms of lives lost, hospital length of stay, and total hospital costs is substantially increased. The application of antifungal therapies associated with reported efficacy rates greater than 50% are those used prophylactically. When used prophylactically, these infections are reduced in greater than 95% of the expected cases. The choice of a prophylactic agent should be based upon its ease of administration, lack of adverse effects, reduced likelihood of potential drug interactions, and its efficacy in patients with established risk factors and comorbid disease processes that include renal, hepatic, and chronic pulmonary disease. The indications for the use of currently available antifungal agents, their adverse effects, drug interactions, ease of dosing, and applicability in patients with preexisting disease states, and especially in liver transplant recipients, are presented in this paper.
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Abstract
It has been nearly a decade since caspofungin was approved for clinical use as the first echinocandin class antifungal agent, followed by micafungin and anidulafungin. The echinocandin drugs target the fungal cell wall by inhibiting the synthesis of β-1,3-D-glucan, a critical cell wall component of many pathogenic fungi. They are fungicidal for Candida spp. and fungistatic for moulds, such as Aspergillus fumigatus, where they induce abnormal morphology and growth properties. The echinocandins have a limited antifungal spectrum but are highly active against most Candida spp., including azole-resistant strains and biofilms. As they target glucan synthase, an enzyme absent in mammalian cells, the echinocandins have a favorable safety profile. They show potent MIC and epidemiological cutoff values against susceptible Candida and Aspergillus isolates, and the frequency of resistance is low. When clinical breakthrough occurs, it is associated with high MIC values and mutations in Fks subunits of glucan synthase, which can reduce the sensitivity of the enzyme to the drug by several thousand-fold. Such strains were not adequately captured by an early clinical breakpoint for susceptibility prompting a revised lower value, which addresses the FKS resistance mechanism and new pharmacokinetic/pharmacodynamic studies. Elevated MIC values unlinked to therapeutic failure can occur and result from adaptive cell behavior, which is FKS-independent and involves the molecular chaperone Hsp90 and the calcineurin pathway. Mutations in FKS1 and/or FKS2 alter the kinetic properties of glucan synthase, which reduces the relative fitness of mutant strains causing them to be less pathogenic. The echinocandin drugs also modify the cell wall architecture exposing buried glucans, which in turn induce a variety of important host immune responses. Finally, the future for glucan synthase inhibitors looks bright with the development of new orally active compounds.
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Affiliation(s)
- David S Perlin
- Public Health Research Institute, New Jersey Medical School-UMDNJ, Newark, NJ 07103, USA.
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Pharmacology and metabolism of anidulafungin, caspofungin and micafungin in the treatment of invasive candidosis: review of the literature. Eur J Med Res 2011; 16:159-66. [PMID: 21486730 PMCID: PMC3352072 DOI: 10.1186/2047-783x-16-4-159] [Citation(s) in RCA: 109] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Echinocandins represent the newest class of antifungal agents. Currently, three echinocandins, anidulafungin, caspofungin and micafungin are licensed for clinical use in various indications. They act as inhibitors of β-(1,3)-glucan synthesis in the fungal cell wall and have a favorable pharmacological profile. They have a broad spectrum of activity against all Candida species. Higher MIC's have been observed against C. parapsilosis and C. guilliermondii. Data from clinical trials for invasive Candida infections/candidaemia suggest that the clinical outcome of patients treated with either drug may be very similar. A comparison has been done between caspofungin and micafungin but for anidulafungin a comparative trial with another echinocandin is still lacking. All three drugs are highly effective if not superior to treatment with either fluconazole or Amphotericin B, particularly in well-defined clinical settings such as invasive Candida infections, Candida oesophagitis and candidaemia. Differences between the three echinocandins with regard to the route of metabolism, requirement for a loading dose, dose adjustment in patients with moderate to severe hepatic disease and different dosing schedules for different types of Candida infections have to be considered. Relevant drug-drug interactions of Caspofungin and Micafungin are minimal. Anidulafungin has no significant drug interactions at all. However, echinocandins are available only for intravenous use. All three agents have an excellent safety profile.
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Grover ND. Echinocandins: A ray of hope in antifungal drug therapy. Indian J Pharmacol 2011; 42:9-11. [PMID: 20606829 PMCID: PMC2885632 DOI: 10.4103/0253-7613.62396] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2008] [Revised: 02/06/2009] [Accepted: 03/12/2010] [Indexed: 11/05/2022] Open
Abstract
Invasive fungal infections are on the rise. Amphotericin B and azole antifungals have been the mainstay of antifungal therapy so far. The high incidence of infusion related toxicity and nephrotoxicity with amphotericin B and the emergence of fluconazole resistant strains of Candida glabrata egged on the search for alternatives. Echinocandins are a new class of antifungal drugs that act by inhibition of β (1, 3)-D- glucan synthase, a key enzyme necessary for integrity of the fungal cell wall. Caspofungin was the first drug in this class to be approved. It is indicated for esophageal candidiasis, candidemia, invasive candidiasis, empirical therapy in febrile neutropenia and invasive aspergillosis. Response rates are comparable to those of amphotericin B and fluconazole. Micafungin is presently approved for esophageal candidiasis, for prophylaxis of candida infections in patients undergoing hematopoietic stem cell transplant (HSCT) and in disseminated candidiasis and candidemia. The currently approved indications for anidulafungin are esophageal candidiasis, candidemia and invasive candidiasis. The incidence of infusion related adverse effects and nephrotoxicity is much lower than with amphotericin B. The main adverse effect is hepatotoxicity and derangement of serum transaminases. Liver function may need to be monitored. They are, however, safer in renal impairment. Even though a better pharmacoeconomical choice than amphotericin B, the higher cost of these drugs in comparison to azole antifungals is likely to limit their use to azole resistant cases of candidial infections and as salvage therapy in invasive aspergillosis rather than as first line drugs.
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Affiliation(s)
- Neeta D Grover
- Department of Pharmacology, Bharati Vidyapeth University Medical College and Hospital, Sangli, Maharashtra, India
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37
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Holt SL, Drew RH. Echinocandins: Addressing outstanding questions surrounding treatment of invasive fungal infections. Am J Health Syst Pharm 2011; 68:1207-20. [DOI: 10.2146/ajhp100456] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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Churches QI, White JM, Hutton CA. Synthesis of β,γ-dihydroxyhomotyrosines by a tandem Petasis-asymmetric dihydroxylation approach. Org Lett 2011; 13:2900-3. [PMID: 21561144 DOI: 10.1021/ol200917s] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Petasis reactions of substituted styrenylboronic acids and glyoxylic acid, employing tert-butylsulfinamide as the 'amine' component, proceed with high stereoselectivity to produce β,γ-dehydrohomoarylalanine derivatives. Subsequent asymmetric dihydroxylation under neutral conditions gives the corresponding protected β,γ-dihydroxyhomoarylalanines with up to 15:1 dr. The method has been exploited in the efficient, stereoselective synthesis of protected β,γ-dihydroxyhomotyrosine, a component of the antifungal cyclic peptide echinocandin B.
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Affiliation(s)
- Quentin I Churches
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3010, Australia
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39
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Bogard KN, Peterson NT, Plumb TJ, Erwin MW, Fuller PD, Olsen KM. Antibiotic dosing during sustained low-efficiency dialysis: Special considerations in adult critically ill patients*. Crit Care Med 2011; 39:560-70. [DOI: 10.1097/ccm.0b013e318206c3b2] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Ishibashi KI, Kurone Y, Motoi M, Miura NN, Adachi Y, Shirasu Y, Ohno N. The influence of β-glucan on the growth and cell wall architecture of Aspergillus spp. Microbiol Immunol 2011; 54:666-72. [PMID: 21044140 DOI: 10.1111/j.1348-0421.2010.00264.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
β-1,3-glucan is a major component of fungal cell walls with various biological activities, including effects on the production of inflammatory mediators in vivo and in vitro. However, few reports have examined its influence on the fungal cell itself. In this study, the influences of β-1,3-glucan on the growth and cell wall structure of fungi was examined. Aspergillus fumigatus was cultured with a synthetic medium, C-limiting medium, in the presence or absence of β-1,3-glucan. Hyphal growth was promoted in liquid and solid-cultures by adding β-1,3-glucan. Glucose and dextran did not induce growth. The influence on cell wall structure of the β-glucan-added cultures was examined by enzymolysis and NMR spectroscopy and the amount of β-1,3-glucan found to be changed. β-1,3-glucan has been widely detected in the environment. In this study, it was demonstrated that β-1,3-glucan causes promotion of the growth, and a change in the cell wall architecture, of Aspergillus. Unregulated distribution of β-1,3-glucan would be strongly related to the incidence of infectious diseases and allergy caused by Aspergillus spp.
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Affiliation(s)
- Ken-ichi Ishibashi
- Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
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Martos AI, Romero A, González MT, González A, Serrano C, Castro C, Pemán J, Cantón E, Martín-Mazuelos E. Evaluation of the Etest method for susceptibility testing of Aspergillus spp. and Fusarium spp. to three echinocandins. Med Mycol 2010; 48:858-61. [PMID: 20144131 DOI: 10.3109/13693781003586943] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
We performed Etest and broth microdilution (BMD) susceptibility testing of caspofungin, micafungin and anidulafungin against 67 clinical isolates of Aspergillus spp. and 10 Fusarium spp. Minimal effective concentrations (MECs) by BMD were read after 24 h of incubation at 35 degrees C and Etest MICs were read at 24 and 48 h. MECs < or =0.25 mg/l were obtained with caspofungin for all Aspergillus spp. tested but Etest MICs were < or =1 mg/l at 24 h. The agreement between caspofungin Etest and broth microdilution was good for all Aspergillus species tested (range 82.4-100%) except for A. niger and A. glaucus at 24 h of incubation. Micafungin and anidulafungin MEC and MIC results were lower than those of caspofungin (< or =0.015 mg/l) at 24 and 48 h for all Aspergillus tested. The agreement between the methods was excellent (100%) for micafungin and anidulafungin for all Aspergillus species tested. The three echinocandins were inactive against all isolates of Fusarium spp. showing MECs and MICs >8 mg/l. The Etest method could be a suitable procedure to test the susceptibility of most Aspergillus species to caspofungin, micafungin and anidulafungin; the best agreement was at 24 h.
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Affiliation(s)
- A I Martos
- Microbiology Service, University Hospital of Valme, Seville-Cádiz Road, Seville, Spain.
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Bartell A, Phatak A, Horn K, Postelnick M. Drug Interactions Involving Antifungal Drugs: Time Course and Clinical Significance. CURRENT FUNGAL INFECTION REPORTS 2010. [DOI: 10.1007/s12281-010-0014-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Pound MW, Townsend ML, Drew RH. Echinocandin pharmacodynamics: review and clinical implications. J Antimicrob Chemother 2010; 65:1108-18. [PMID: 20335190 DOI: 10.1093/jac/dkq081] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Echinocandins have made a significant impact in the treatment of select invasive fungal infections, most notably invasive candidiasis and aspergillosis. However, treatment outcomes for such infections are still less than optimal, prompting an examination of dosing and administration techniques in an attempt to exploit known pharmacodynamic properties and improve outcomes. Echinocandins generally exhibit concentration-dependent, fungicidal activity against Candida spp. and fungistatic activity against Aspergillus spp. However, increasing drug concentrations of echinocandins above the organism's MIC may result in a paradoxical increase in fungal growth as demonstrated in some in vitro and in vivo models (known most commonly as the 'Eagle effect'). Therefore, the potential impact of dose escalations on improving the clinical efficacy of echinocandins based on in vitro and animal models are uncertain and are still being evaluated. In addition, such strategies have to consider the potential for increased treatment-related toxicities and costs. To date, published clinical studies (both superiority and non-inferiority) demonstrating the potential for dose-related improvements in treatment outcomes have been limited to mucocutaneous and oesophageal candidiasis. Further research is needed to determine if a role exists for optimizing echinocandin pharmacodynamics in various clinical settings.
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Affiliation(s)
- Melanie W Pound
- Campbell University School of Pharmacy, Buies Creek, NC, USA.
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Abstract
PURPOSE OF REVIEW Antifungal drug resistance is a confounding factor that negatively impacts clinical outcome for patients with serious mycoses. Early detection of fungi in blood or other specimens with a rapid assessment of drug susceptibility could improve the survival of patients with invasive disease by accelerating the initiation of appropriate antifungal treatment. Recent years have seen the growth of molecular technology that is ideally suited for fungal identification and assessment of drug resistance mechanisms. RECENT FINDINGS Elucidation of the genetic mechanisms responsible for triazole and echinocandin resistance in prominent Candida spp. and Aspergillus spp. provides an opportunity to develop molecular diagnostic platforms suitable for rapid detection of primary and secondary drug resistance. Several highly dynamic and robust amplification/detection methodologies are now available that can provide simultaneous species identification and high fidelity discrimination of resistance alleles. SUMMARY Molecular diagnostic platforms are ideal for rapid detection of fungal pathogens and they provide an opportunity to develop in parallel molecular assays that can evaluate antifungal drug resistance.
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Excess mortality, length of stay and cost attributable to candidaemia. J Infect 2009; 59:360-5. [PMID: 19744519 DOI: 10.1016/j.jinf.2009.08.020] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2008] [Revised: 05/11/2009] [Accepted: 08/08/2009] [Indexed: 02/06/2023]
Abstract
BACKGROUND There were 1967 reports of Candida species isolated from blood specimens in 2007 in the UK (excluding Scotland). Such infections are particularly common in the intensive care unit (ICU). The impact of candidaemia on mortality, length of stay (LOS) and cost in a UK hospital was examined. METHODS A retrospective analysis of candidaemia episodes and appropriate matched controls was undertaken based on data from the ICU, high dependency units and hospital wards at Wythenshawe Hospital in Manchester. The study covered the period November 2003-February 2007. RESULTS In total, 48 case-patients of candidaemia and 81 control-patients were identified. The attributable mortality due to candidaemia varied from 21.5% to 34.7%. Candidaemia patients spend on average 5.6 days more in the ICU than matched patients and generate mean additional costs of at least 8252 UK pounds per patient, 16,595 pounds in adults only. CONCLUSION Candidaemia remains a severe disease associated with high attributable mortality in the UK. In addition, candidaemia leads to additional ICU length of stay and costs. The implication is an attributable cost of at least 16.2 million UK pounds with 683 deaths attributable to candidaemia per year in the UK.
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Abstract
Candida spp. are currently the fourth most common cause of bloodstream infections in US hospitals, and the third most common cause of bloodstream infections in the intensive care unit. Over the last 2 decades there has been a shift towards a greater involvement of non-Candida albicans spp. as the cause of candidemia. Several of these non-albicans spp. (e.g., C. glabrata and C. krusei ) exhibit resistance to traditional triazole antifungals like fluconazole, and cross-resistance with newer triazoles, focusing attention on the first-line use of antifungals such as the echinocandins, which possess improved activity against fluconazole-resistant strains. Recent treatment guidelines from the Infectious Diseases Society of America (IDSA) recommend an echinocandin as primary therapy for nonneutropenic or neutropenic patients with moderately severe to severe candidiasis and for patients at risk for infection with a triazole-resistant strain. However, further improvement in candidemia-associated mortality will only be attainable with the development and validation of new diagnostic tools that will allow earlier detection, discrimination, and treatment of invasive candidiasis. Clinicians should remain vigilant to wider emergence of Candida spp. with echinocandin resistance.
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Affiliation(s)
- Russell E Lewis
- Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, Houston, TX, USA.
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48
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Abstract
Antimicrobial drugs are useful for the empiric and definitive treatment of infections in surgical patients. They are also important agents for perioperative antimicrobial prophylaxis. The proper selection and use of these drugs is a critical skill for surgeons. Although these agents have many beneficial effects, they also possess occasional adverse effects and should not be used indiscriminately.
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Affiliation(s)
- Nilam P Patel
- Critical Care, Department of Pharmacy, Cleveland, OH 44109-1998, USA
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de la Torre P, Meyer DK, Reboli AC. Anidulafungin: a novel echinocandin for candida infections. Future Microbiol 2009; 3:593-601. [PMID: 19072176 DOI: 10.2217/17460913.3.6.593] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
A third echinocandin, anidulafungin, has recently been approved for Candida infections in the non-neutropenic patient. In the EU it is indicated for invasive candidiasis; in 2006 it was approved in the USA for candida esophagitis, candidemia, and two types of invasive infections, peritonitis and intra-abdominal abscesses. It is fungicidal against Candida species and fungistatic against Aspergillus species. In addition to its favorable tolerability in studies to date, it does not need adjustment for renal or hepatic insufficiency and has no known drug interactions. A steady state concentration can be achieved on day 2 following a loading dose of twice the maintenance concentration on day 1, and the drug is administered intravenously once daily. Cross resistance with other classes of antifungals is not a concern as it possesses a unique mechanism of action.
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Affiliation(s)
- Pola de la Torre
- Division of Infectious Diseases, Cooper University Hospital, University of Medicine & Dentistry of New Jersey, Robert Wood Johnson Medical School, NJ, USA.
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Chandwani S, Wentworth C, Burke TA, Patterson TF. Utilization and dosage pattern of echinocandins for treatment of fungal infections in US hospital practice. Curr Med Res Opin 2009; 25:385-93. [PMID: 19192983 DOI: 10.1185/03007990802619599] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
OBJECTIVE With the availability of multiple echinocandins in the US, recommended dosages and dosing schedules vary by agent but actual utilization practices are unknown. The purpose of this study was to describe the utilization and dosage pattern of intravenous echinocandins for treatment of fungal infections in US hospitals. METHODS The Premier Perspective Database was used to describe echinocandin use in 332 US hospitals. Adult patients hospitalized from January, 2006 through June, 2007 with at least one billing record for anidulafungin (Eraxis ** ), caspofungin (Cancidas dagger ), or micafungin (Mycamine double dagger ) were included. Hospitalizations with > 1 echinocandin or >or= 1 dosage with an FDA approved indication for fungal prophylaxis were excluded. Mixed multivariable models were developed to identify factors associated with mean daily dose. ** Eraxis, a registered trade name owned by Pfizer, Inc., New York, NY, USA dagger Cancidas, a registered trade name owned by Merck & Co., Inc., Whitehouse Station, NJ, USA double dagger Mycamine, a registered trade name owned by Astellas Pharma US, Inc., Deerfield, IL, USA. RESULTS The number of unique patient hospitalizations was 708 for anidulafungin, 15 739 for caspofungin, and 1199 for micafungin. A single echinocandin was utilized at 88.6% of hospitals. Micafungin patients had the highest prevalence of cancer, bone marrow transplant, solid organ transplant, HIV/AIDS, fungal infection, and neutropenia. Mean day 1 dose of echinocandin therapy was 171.2 +/- 85.4 mg, 79.7 +/- 25.6 mg, and 154.3 +/- 67.3 mg; and mean day 2 onwards dose was 98.7 +/- 39.4 mg, 53.1 +/- 12.5 mg, 122.6 +/- 39.4 mg for anidulafungin, caspofungin and micafungin, respectively. Commonly used loading doses were 200 mg (55.6%) for anidulafungin, 70 mg (57.2%) for caspofungin, and 200 mg (21.2%) for micafungin. The first-day dose of echinocandin therapy (vs. subsequent days) was most strongly associated with mean daily dose. CONCLUSIONS In hospital practice, the mean dosages were consistent with the recommended loading and maintenance dosages for caspofungin and anidulafungin. Patients frequently received a loading dose of > 150 mg on day 1 of micafungin which was inconsistent with recommended dosing schedules. Micafungin maintenance dosages > 100 mg were also commonly used. Lack of information on reason for initiating echinocandin therapy was an important study limitation.
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