Precision Therapy for Invasive Fungal Diseases

Invasive fungal infections (IFI) are a common infection-related cause of death in immunocompromised patients. Approximately 10 million people are at risk of developing invasive aspergillosis annually. Detailed study of the pharmacokinetics (PK) and pharmacodynamics (PD) of antifungal drugs has resulted in a better understanding of optimal regimens for populations, drug exposure targets for therapeutic drug monitoring, and establishing in vitro susceptibility breakpoints. Importantly, however, each is an example of a “one size fits all strategy”, where complex systems are reduced to a singularity that ensures antifungal therapy is administered safely and effectively at the level of a population. Clearly, such a notion serves most patients adequately but is completely counter to the covenant at the centre of the clinician–patient relationship, where each patient should know whether they are well-positioned to maximally benefit from an antifungal drug. This review discusses the current therapy of fungal infections and areas of future research to maximise the effectiveness of antifungal therapy at an individual level.

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Molecular typing and in vitro antifungal susceptibility of Cryptococcus spp from patients in Midwest Brazil

The Journal of Infection in Developing Countries ◽

10.3855/jidc.4446 ◽

2014 ◽

Vol 8 (08) ◽

pp. 1037-1043 ◽

Cited By ~ 13

Author(s):

Olivia Cometti Favalessa ◽

Daphine Ariadne Jesus De Paula ◽

Valeria Dutra ◽

Luciano Nakazato ◽

Tomoko Tadano ◽

...

Keyword(s):

Amphotericin B ◽

Fungal Infections ◽

Antifungal Susceptibility ◽

Cryptococcus Gattii ◽

Antifungal Drugs ◽

Northeastern Brazil ◽

In Vitro Susceptibility ◽

Mato Grosso ◽

Hiv Negative

Introduction: Cryptococcosis is a systemic fungal infection that affects humans and animals, mainly due to Cryptococcus neoformans and Cryptococcus gattii. Following the epidemic of acquired immunodeficiency syndrome (AIDS), fungal infections by C. neoformans have become more common among immunocompromised patients. Cryptococcus gattii has primarily been isolated as a primary pathogen in healthy hosts and occurs endemically in northern and northeastern Brazil. We to perform genotypic characterization and determine the in vitro susceptibility profile to antifungal drugs of the Cryptococcus species complex isolated from HIV-positive and HIV-negative patients attended at university hospitals in Cuiabá, MT, in the Midwestern region of Brazil. Methodology: Micromorphological features, chemotyping with canavanine-glycine-bromothymol blue (CGB) agar and genotyping by URA5-RFLP were used to identify the species. The antifungal drugs tested were amphotericin B, fluconazole, flucytosine, itraconazole and voriconazole. Minimum inhibitory concentrations (MICs) were determined according to the CLSI methodology M27-A3. Results: Analysis of samples yelded C. neoformans AFLP1/VNI (17/27, 63.0%) and C. gattii AFLP6/VGII (10/27, 37.0%). The MICs ranges for the antifungal drugs were: amphotericin B (0.5-1 mg/L), fluconazole (1-16 mg/L), flucytosine (1-16 mg/L), itraconazole (0.25-0.12 mg/L) and voriconazole (0.06-0.5 mg/L). Isolates of C. neoformans AFLP1/VNI were predominant in patients with HIV/AIDS, and C. gattii VGII in HIV-negative patients. The genotypes identified were susceptible to the antifungal drugs tested. Conclusion: It is worth emphasizing that AFLP6/VGII is a predominant genotype affecting HIV-negative individuals in Cuiabá. These findings serve as a guide concerning the molecular epidemiology of C. neoformans and C. gattii in the State of Mato Grosso.

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Potential of Nanoparticles in Combating Candida Infections

Letters in Drug Design & Discovery ◽

10.2174/1570180815666181015145224 ◽

2019 ◽

Vol 16 (5) ◽

pp. 478-491 ◽

Cited By ~ 5

Author(s):

Faizan Abul Qais ◽

Mohd Sajjad Ahmad Khan ◽

Iqbal Ahmad ◽

Abdullah Safar Althubiani

Keyword(s):

Targeted Delivery ◽

Recent Progress ◽

Antifungal Agents ◽

Fungal Infections ◽

Fold Increase ◽

Antifungal Drugs ◽

Low Toxicity ◽

Candida Infections ◽

Made In

Aims: The aim of this review is to survey the recent progress made in developing the nanoparticles as antifungal agents especially the nano-based formulations being exploited for the management of Candida infections. Discussion: In the last few decades, there has been many-fold increase in fungal infections including candidiasis due to the increased number of immunocompromised patients worldwide. The efficacy of available antifungal drugs is limited due to its associated toxicity and drug resistance in clinical strains. The recent advancements in nanobiotechnology have opened a new hope for the development of novel formulations with enhanced therapeutic efficacy, improved drug delivery and low toxicity. Conclusion: Metal nanoparticles have shown to possess promising in vitro antifungal activities and could be effectively used for enhanced and targeted delivery of conventionally used drugs. The synergistic interaction between nanoparticles and various antifungal agents have also been reported with enhanced antifungal activity.

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A Novel, Rapid, and Low-Volume Assay for Therapeutic Drug Monitoring of Posaconazole and Other Long-Chain Azole-Class Antifungal Drugs

mSphere ◽

10.1128/msphere.00623-18 ◽

2018 ◽

Vol 3 (6) ◽

Cited By ~ 2

Author(s):

Gregory R. Wiedman ◽

Yanan Zhao ◽

David S. Perlin

Keyword(s):

Liquid Chromatography ◽

Therapeutic Drug Monitoring ◽

Human Serum ◽

Drug Monitoring ◽

Fungal Infections ◽

Antifungal Drugs ◽

Therapeutic Drug ◽

Serum Samples ◽

Human Serum Samples ◽

Long Chain

ABSTRACT Clinicians need a better way to accurately monitor the concentration of antimicrobials in patient samples. In this report, we describe a novel, low-sample-volume method to monitor the azole-class antifungal drug posaconazole, as well as certain other long-chain azole-class antifungal drugs in human serum samples. Posaconazole represents an important target for therapeutic drug monitoring (TDM) due to its widespread use in treating invasive fungal infections and well-recognized variability of pharmacokinetics. The current “gold standard” requires trough and peak monitoring through high-pressure liquid chromatography (HPLC) or liquid chromatography-tandem mass spectroscopy (LC-MS/MS). Other methods include bioassays that use highly susceptible strains of fungi in culture plates or 96-well formats to monitor concentrations. Currently, no method exists that is both highly accurate in detecting free drug concentrations and is also rapid. Herein, we describe a new method using reduced graphene oxide (rGO) and a fluorescently labeled aptamer, which can accurately assess clinically relevant concentrations of posaconazole and other long-chain azole-class drugs in little more than 1 h in a total volume of 100 µl. IMPORTANCE This work describes an effective assay for TDM of long-chain azole-class antifungal drugs that can be used in diluted human serum samples. This assay will provide a quick, cost-effective method for monitoring concentrations of drugs such as posaconazole that exhibit well-documented pharmacokinetic variability. Our rGO-aptamer assay has the potential to improve health care for those struggling to treat fungal infections in rural or resource-limited setting.

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Implementation of Pharmacist-driven Antifungal Stewardship Program in A Tertiary Care Hospital

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00629-21 ◽

2021 ◽

Author(s):

Emre Kara ◽

Gokhan Metan ◽

Aygin Bayraktar-Ekincioglu ◽

Dolunay Gulmez ◽

Sevtap Arikan-Akdagli ◽

...

Keyword(s):

Antifungal Therapy ◽

Clinical Pharmacist ◽

Fungal Infections ◽

Tertiary Care ◽

Antifungal Drugs ◽

Care Hospital ◽

Antifungal Stewardship ◽

Inappropriate Use ◽

Stewardship Program ◽

Antifungal Use

Objectives: Antifungal stewardship (AFS) is recommended to reduce the inappropriate use of antifungal drugs. In this study, the role of AFS in providing appropriate antifungal therapy was evaluated. Methods: This study included three periods as observation, feedback/education, and daily AFS activities. In observation period, the use of systemic antifungals was evaluated for a baseline measurement of appropriateness. In second period, monthly meetings were organized to provide feedback and education to physicians regarding antifungal therapy and the rate of adherence to the clinical guidelines. In final period, a clinical pharmacist participated in daily ward rounds to evaluate appropriateness of the antifungal therapy. A scoring system for appropriateness was used for comparison between the three periods. Results: Four hundred and eighteen episodes of antifungal therapy were evaluated. Baseline demographics of patients were similar in all three periods for age, gender, and the number of comorbidities. The indications for antifungal use were for prophylaxis in 22.7%, Candida infections in 58.6%, and invasive mould infections in 18.7%. During the third period, 157 (78.9%) recommendations were made and 151 (96.2%) were accepted. The overall appropriateness of antifungal use increased significantly for prophylaxis (30.8%, 17.9%, 46.3%, p=0.046) and treatment of fungal diseases (27.8%, 32.4%, 71.9%, p<0.001) between the first, second and third periods, respectively. A 30-day mortality was not significantly changed between the three periods (19%, 15.6% and 27.5%; p=0.050). Conclusions: Appropriateness in antifungal therapy can be augmented by the integration of an AFS program. A team-based evaluation of fungal infections and assessment of patients by a clinical pharmacist with a therapeutic perspective may help to increase the quality of antifungal therapy.

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Comparison of NCCLS and 3-(4,5-Dimethyl-2-Thiazyl)-2,5-Diphenyl-2H-Tetrazolium Bromide (MTT) Methods of In Vitro Susceptibility Testing of Filamentous Fungi and Development of a New Simplified Method

Journal of Clinical Microbiology ◽

10.1128/jcm.38.8.2949-2954.2000 ◽

2000 ◽

Vol 38 (8) ◽

pp. 2949-2954 ◽

Cited By ~ 147

Author(s):

Joseph Meletiadis ◽

Jacques F. G. M. Meis ◽

Johan W. Mouton ◽

J. Peter Donnelly ◽

Paul E. Verweij

Keyword(s):

Filamentous Fungi ◽

Clinical Laboratory ◽

Colorimetric Method ◽

Antifungal Drugs ◽

National Committee ◽

In Vitro Susceptibility ◽

Initial Inoculum ◽

Tetrazolium Bromide ◽

Mtt Method

The susceptibility of 30 clinical isolates belonging to six different species of filamentous fungi (Aspergillus fumigatus, Aspergillus flavus, Scedosporium prolificans, Scedosporium apiospermum, Fusarium solani, and Fusarium oxysporum) was tested against six antifungal drugs (miconazole, voriconazole, itraconazole, UR9825, terbinafine, and amphotericin B) with the microdilution method recommended by the National Committee for Clinical Laboratory Standards (NCCLS) (M38-P). The MICs were compared with the MICs obtained by a colorimetric method measuring the reduction of the dye 3-(4,5-dimethyl-2-thiazyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) to formazan by viable fungi. The levels of agreement between the two methods were 96 and 92% for MIC-0 (clear wells) and MIC-1 (75% growth reduction), respectively. The levels of agreement were always higher for Aspergillus spp. (97% ± 2.5%), followed byScedosporium spp. (87% ± 10.3%) and Fusariumspp. (78% ± 7.8%). The NCCLS method was more reproducible than the MTT method: 98 versus 95% for MIC-0 and 97 versus 90% for MIC-1. However, the percentage of hyphal growth as determined visually by the NCCLS method showed several discrepancies when they were compared with the percentages of MTT reduction. A new simplified assay that incorporates the dye MTT with the initial inoculum and in which the fungi are incubated with the dye for 48 h or more was developed, showing comparable levels of agreement and reproducibility with the other two methods. Furthermore, the new assay was easier to perform and more sensitive than the MTT method.

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Acylhydrazones as Antifungal Agents Targeting the Synthesis of Fungal Sphingolipids

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00156-18 ◽

2018 ◽

Vol 62 (5) ◽

Cited By ~ 32

Author(s):

Cristina Lazzarini ◽

Krupanandan Haranahalli ◽

Robert Rieger ◽

Hari Krishna Ananthula ◽

Pankaj B. Desai ◽

...

Keyword(s):

Mammalian Cells ◽

Antifungal Agents ◽

Fungal Infections ◽

Antifungal Drugs ◽

Fungal Resistance ◽

Content Type ◽

Highly Active ◽

Pharmacokinetic Properties ◽

Pass Through

ABSTRACTThe incidence of invasive fungal infections has risen dramatically in recent decades. Current antifungal drugs are either toxic, likely to interact with other drugs, have a narrow spectrum of activity, or induce fungal resistance. Hence, there is a great need for new antifungals, possibly with novel mechanisms of action. Previously our group reported an acylhydrazone called BHBM that targeted the sphingolipid pathway and showed strong antifungal activity against several fungi. In this study, we screened 19 derivatives of BHBM. Three out of 19 derivatives were highly active againstCryptococcus neoformansin vitroand had low toxicity in mammalian cells. In particular, one of them, called D13, had a high selectivity index and showed better activity in an animal model of cryptococcosis, candidiasis, and pulmonary aspergillosis. D13 also displayed suitable pharmacokinetic properties and was able to pass through the blood-brain barrier. These results suggest that acylhydrazones are promising molecules for the research and development of new antifungal agents.

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In vitro susceptibility of 188 clinical and environmental isolates of Aspergillus flavus for the new triazole isavuconazole and seven other antifungal drugs

Mycoses ◽

10.1111/j.1439-0507.2010.01996.x ◽

2011 ◽

Vol 54 (5) ◽

pp. e583-e589 ◽

Cited By ~ 37

Author(s):

M. R. Shivaprakash ◽

Erik Geertsen ◽

Arunaloke Chakrabarti ◽

Johan W. Mouton ◽

Jacques F. Meis

Keyword(s):

Aspergillus Flavus ◽

Antifungal Drugs ◽

Environmental Isolates ◽

In Vitro Susceptibility

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Current and Emerging Azole Antifungal Agents

Clinical Microbiology Reviews ◽

10.1128/cmr.12.1.40 ◽

1999 ◽

Vol 12 (1) ◽

pp. 40-79 ◽

Cited By ~ 676

Author(s):

Daniel J. Sheehan ◽

Christopher A. Hitchcock ◽

Carol M. Sibley

Keyword(s):

Fungal Pathogens ◽

Antifungal Agents ◽

Susceptibility Testing ◽

Fungal Infections ◽

Mechanisms Of Action ◽

Current Status ◽

In Vitro Susceptibility ◽

Clinical Resistance ◽

In Vitro Susceptibility Testing

SUMMARY Major developments in research into the azole class of antifungal agents during the 1990s have provided expanded options for the treatment of many opportunistic and endemic fungal infections. Fluconazole and itraconazole have proved to be safer than both amphotericin B and ketoconazole. Despite these advances, serious fungal infections remain difficult to treat, and resistance to the available drugs is emerging. This review describes present and future uses of the currently available azole antifungal agents in the treatment of systemic and superficial fungal infections and provides a brief overview of the current status of in vitro susceptibility testing and the growing problem of clinical resistance to the azoles. Use of the currently available azoles in combination with other antifungal agents with different mechanisms of action is likely to provide enhanced efficacy. Detailed information on some of the second-generation triazoles being developed to provide extended coverage of opportunistic, endemic, and emerging fungal pathogens, as well as those in which resistance to older agents is becoming problematic, is provided.

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