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Pharmacodynamics of Antifungal Drugs
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Pharmacodynamics of Antifungal Drugs

A special issue of Journal of Fungi (ISSN 2309-608X). This special issue belongs to the section "Fungal Pathogenesis and Disease Control".

Deadline for manuscript submissions: closed (15 April 2023) | Viewed by 19455

Special Issue Editors

Dr. Charalampos T. Antachopoulos

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Guest Editor
3rd Department of Pediatrics, Medical Faculty, Aristotle University School of Health Sciences, Hippokration Hospital, Thessaloniki, Greece
Interests: pharmacology of antifungal drugs and newer antimicrobial agents in pediatric patients; invasive fungal infections; nosocomial infections caused by multidrug-resistant gram-negative bacteria
Special Issues, Collections and Topics in MDPI journals
Dr. Joseph Meletiadis

E-Mail Website
Guest Editor
Clinical Microbiology Laboratory, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
Interests: in vitro antifungal susceptibility testing; preclinical models of fungal infections; pharmacokinetics and pharmacodynamics of antifungal drugs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The successful treatment of invasive fungal infections is challenging, as they often occur in patients with severely impaired immune responses. The appropriate choice and use of antifungal agents are among the cornerstones of appropriate management. A comprehensive knowledge and understanding of the pharmacodynamics of antifungal drugs elucidates dose–response relationships and is expected to lead to optimized dosage regimens in various circumstances. In this Special Issue, therefore, we invite colleagues to submit original research or review articles in the field of antifungal drug pharmacodynamics. More specific topics that could be covered include drug actions, pharmacodynamic measures of antifungal drug action (inhibitory and fungicidal concentrations, killing rates, postantifungal effects), pharmacodynamic drug–drug interactions, pharmacokinetic/pharmacodynamic characteristics of antifungal drugs (preclinical and clinical), pharmacodynamic modelling, development of appropriate models for in vitro or in vivo pharmacodynamic studies, evaluation of the impact of pharmacodynamic-based dosing approaches on patient outcome, identified knowledge gaps or advances pertaining to the pharmacodynamics of already licensed antifungal agents, as well as the pharmacodynamic properties of antifungals in clinical development. Besides these specific topics, any other papers highlighting important developments or novel perspectives in this field will be welcome.  

Dr. Charalampos T. Antachopoulos
Dr. Joseph Meletiadis
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Fungi is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • invasive fungal infections
  • antifungal agents
  • pharmacodynamics
  • dose-response relationship
  • in vivo/in vitro models

Published Papers (6 papers)

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Research

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11 pages, 799 KiB  
Article
Multicenter Collaborative Study of the Interaction of Antifungal Combinations against Candida Spp. by Loewe Additivity and Bliss Independence-Based Response Surface Analysis
by Joseph Meletiadis, David R. Andes, Shawn R. Lockhart, Mahmoud A. Ghannoum, Cindy C. Knapp, Luis Ostrosky-Zeichner, Michael A. Pfaller, Vishnu Chaturvedi and Thomas J. Walsh
J. Fungi 2022, 8(9), 967; https://doi.org/10.3390/jof8090967 - 16 Sep 2022
Cited by 3 | Viewed by 2139
Abstract
Combination antifungal therapy is widely used but not well understood. We analyzed the spectrophotometric readings from a multicenter study conducted by the New York State Department of Health to further characterize the in vitro interactions of the major classes of antifungal agents against [...] Read more.
Combination antifungal therapy is widely used but not well understood. We analyzed the spectrophotometric readings from a multicenter study conducted by the New York State Department of Health to further characterize the in vitro interactions of the major classes of antifungal agents against Candida spp. Loewe additivity-based fractional inhibitory concentration index (FICi) analysis and Bliss independence-based response surface (BIRS) analysis were used to analyze two-drug inter- and intraclass combinations of triazoles (AZO) (voriconazole, posaconazole), echinocandins (ECH) (caspofungin, micafungin, anidulafungin), and a polyene (amphotericin B) against Candida albicans, C. parapsilosis, and C. glabrata. Although mean FIC indices did not differ statistically significantly from the additivity range of 0.5–4, indicating no significant pharmacodynamic interactions for all of the strain–combinations tested, BIRS analysis showed that significant pharmacodynamic interactions with the sum of percentages of interactions determined with this analysis were strongly associated with the FIC indices (Χ2 646, p < 0.0001). Using a narrower additivity range of 1–2 FIC index analysis, statistically significant pharmacodynamic interactions were also found with FICi and were in agreement with those found with BIRS analysis. All ECH+AB combinations were found to be synergistic against all Candida strains except C. glabrata. For the AZO+AB combinations, synergy was found mostly with the POS+AB combination. All AZO+ECH combinations except POS+CAS were synergistic against all Candida strains although with variable magnitude; significant antagonism was found for the POS+MIF combination against C. albicans. The AZO+AZO combination was additive for all strains except for a C. parapsilosis strain for which antagonism was also observed. The ECH+ECH combinations were synergistic for all Candida strains except C. glabrata for which they were additive; no antagonism was found. Full article
(This article belongs to the Special Issue Pharmacodynamics of Antifungal Drugs)
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10 pages, 2699 KiB  
Article
In Vitro Activity of Novel Lipopeptides against Triazole-Resistant Aspergillus fumigatus
by Simona Fioriti, Oscar Cirioni, Oriana Simonetti, Lucia Franca, Bianca Candelaresi, Francesco Pallotta, Damian Neubauer, Elzbieta Kamysz, Wojciech Kamysz, Benedetta Canovari, Lucia Brescini, Gianluca Morroni and Francesco Barchiesi
J. Fungi 2022, 8(8), 872; https://doi.org/10.3390/jof8080872 - 18 Aug 2022
Cited by 3 | Viewed by 2327
Abstract
Aspergillosis, which is mainly sustained by Aspergillus fumigatus, includes a broad spectrum of diseases. They are usually severe in patients with co-morbidities. The first-line therapy includes triazoles, for which an increasing incidence of drug resistance has been lately described. As a consequence [...] Read more.
Aspergillosis, which is mainly sustained by Aspergillus fumigatus, includes a broad spectrum of diseases. They are usually severe in patients with co-morbidities. The first-line therapy includes triazoles, for which an increasing incidence of drug resistance has been lately described. As a consequence of this, the need for new and alternative antifungal molecules is absolutely necessary. As peptides represent promising antimicrobial molecules, two lipopeptides (C14-NleRR-NH2, C14-WRR-NH2) were tested to assess the antifungal activity against azole-resistant A. fumigatus. Antifungal activity was evaluated by determination of minimum inhibitory concentrations (MICs), time–kill curves, XTT assay, optical microscopy, and checkerboard combination with isavuconazole. Both lipopeptides showed antifungal activity, with MICs ranging from 8 mg/L to 16 mg/L, and a dose-dependent effect was confirmed by both time–kill curves and XTT assays. Microscopy showed that hyphae growth was hampered at concentrations equal to or higher than MICs. The rising antifungal resistance highlights the usefulness of novel compounds to treat severe fungal infections. Although further studies assessing the activity of lipopeptides are necessary, these molecules could be effective antifungal alternatives that overcome the current resistances. Full article
(This article belongs to the Special Issue Pharmacodynamics of Antifungal Drugs)
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16 pages, 3237 KiB  
Article
In Vitro Activity of Amphotericin B in Combination with Colistin against Fungi Responsible for Invasive Infections
by Patrick Schwarz, Ilya Nikolskiy, Anne-Laure Bidaud, Frank Sommer, Gert Bange and Eric Dannaoui
J. Fungi 2022, 8(2), 115; https://doi.org/10.3390/jof8020115 - 26 Jan 2022
Cited by 9 | Viewed by 2729
Abstract
The in vitro interaction of amphotericin B in combination with colistin was evaluated against a total of 86 strains comprising of 47 Candida species (10 Candida albicans, 15 Candida auris, five Candida glabrata, three Candida kefyr, five Candida krusei [...] Read more.
The in vitro interaction of amphotericin B in combination with colistin was evaluated against a total of 86 strains comprising of 47 Candida species (10 Candida albicans, 15 Candida auris, five Candida glabrata, three Candida kefyr, five Candida krusei, four Candida parapsilosis and five Candida tropicalis), 29 Aspergillus species (five Aspergillus flavus, 10 Aspergillus fumigatus, four Aspergillus nidulans, five Aspergillus niger, and five Aspergillus terreus), and 10 Rhizopus species (seven Rhizopus arrhizus, one Rhizopus delemar and two Rhizopus microsporus) strains. For the determination of the interaction, a microdilution checkerboard technique based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) reference method for antifungal susceptibility testing was used. Results of the checkerboard technique were evaluated by the fractional inhibitory concentration index (FICI) based on the Loewe additivity model for all isolates. Different inhibition endpoints were used to capture both the interaction at MIC and sub-MIC levels. Additionally, checkerboard technique results for Candida species were evaluated by response surface analysis based on the Bliss independence model. Against common Candida species, the combination was synergistic for 75% of the strains by FICI and for 66% of the strains by response surface analysis. For C. tropicalis, the interaction was antagonistic for three isolates by FICI, but antagonism was not confirmed by response surface analysis. Interestingly, synergistic and antagonistic FICIs were simultaneously present on checkboard microplates of all three strains. Against C. auris the combination was synergistic for 73% of the strains by response surface analysis and for 33% of the strains by FICI. This discrepancy could be related to the insensitivity of the FICI to detect weak interactions. Interaction for all other strains was indifferent. For Aspergillus and Rhizopus species combination exhibited only indifferent interactions against all tested strains. Full article
(This article belongs to the Special Issue Pharmacodynamics of Antifungal Drugs)
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Review

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20 pages, 917 KiB  
Review
Pharmacodynamics, Mechanisms of Action and Resistance, and Spectrum of Activity of New Antifungal Agents
by Nathan P. Wiederhold
J. Fungi 2022, 8(8), 857; https://doi.org/10.3390/jof8080857 - 16 Aug 2022
Cited by 25 | Viewed by 5669
Abstract
Several new antifungals are currently in late-stage development, including those with novel pharmacodynamics/mechanisms of action that represent new antifungal classes (manogepix, olorofim, ATI-2307, GR-2397). Others include new agents within established classes or with mechanisms of action similar to clinically available antifungals (ibrexafungerp, rezafungin, [...] Read more.
Several new antifungals are currently in late-stage development, including those with novel pharmacodynamics/mechanisms of action that represent new antifungal classes (manogepix, olorofim, ATI-2307, GR-2397). Others include new agents within established classes or with mechanisms of action similar to clinically available antifungals (ibrexafungerp, rezafungin, oteseconazole, opelconazole, MAT2203) that have been modified in order to improve certain characteristics, including enhanced pharmacokinetics and greater specificity for fungal targets. Many of the antifungals under development also have activity against Candida and Aspergillus strains that have reduced susceptibility or acquired resistance to azoles and echinocandins, whereas others demonstrate activity against species that are intrinsically resistant to most clinically available antifungals. The tolerability and drug–drug interaction profiles of these new agents also appear to be promising, although the number of human subjects that have been exposed to many of these agents remains relatively small. Overall, these agents have the potential for expanding our antifungal armamentarium and improving clinical outcomes in patients with invasive mycoses. Full article
(This article belongs to the Special Issue Pharmacodynamics of Antifungal Drugs)
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26 pages, 1176 KiB  
Review
Postantifungal Effect of Antifungal Drugs against Candida: What Do We Know and How Can We Apply This Knowledge in the Clinical Setting?
by Nerea Jauregizar, Guillermo Quindós, Sandra Gil-Alonso, Elena Suárez, Elena Sevillano and Elena Eraso
J. Fungi 2022, 8(7), 727; https://doi.org/10.3390/jof8070727 - 12 Jul 2022
Cited by 2 | Viewed by 2780
Abstract
The study of the pharmacological properties of an antifungal agent integrates the drug pharmacokinetics, the fungal growth inhibition, the fungicidal effect and the postantifungal activity, laying the basis to guide optimal dosing regimen selection. The current manuscript reviews concepts regarding the postantifungal effect [...] Read more.
The study of the pharmacological properties of an antifungal agent integrates the drug pharmacokinetics, the fungal growth inhibition, the fungicidal effect and the postantifungal activity, laying the basis to guide optimal dosing regimen selection. The current manuscript reviews concepts regarding the postantifungal effect (PAFE) of the main classes of drugs used to treat Candida infections or candidiasis. The existence of PAFE and its magnitude are highly dependent on both the fungal species and the class of the antifungal agent. Therefore, the aim of this article was to compile the information described in the literature concerning the PAFE of polyenes, azoles and echinocandins against the Candida species of medical interest. In addition, the mechanisms involved in these phenomena, methods of study, and finally, the clinical applicability of these studies relating to the design of dosing regimens were reviewed and discussed. Additionally, different factors that could determine the variability in the PAFE were described. Most PAFE studies were conducted in vitro, and a scarcity of PAFE studies in animal models was observed. It can be stated that the echinocandins cause the most prolonged PAFE, followed by polyenes and azoles. In the case of the triazoles, it is worth noting the inconsistency found between in vitro and in vivo studies. Full article
(This article belongs to the Special Issue Pharmacodynamics of Antifungal Drugs)
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Other

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18 pages, 2201 KiB  
Systematic Review
Antifungal Combinations against Candida Species: From Bench to Bedside
by Simona Fioriti, Lucia Brescini, Francesco Pallotta, Benedetta Canovari, Gianluca Morroni and Francesco Barchiesi
J. Fungi 2022, 8(10), 1077; https://doi.org/10.3390/jof8101077 - 13 Oct 2022
Cited by 19 | Viewed by 2861
Abstract
Candida spp. is the major causative agent of fungal infections in hospitalized patients and the fourth most common cause of nosocomial bloodstream infection (BSI). The availability of standardized methods for testing the in vitro activity of antifungals along with the expanding of antifungal [...] Read more.
Candida spp. is the major causative agent of fungal infections in hospitalized patients and the fourth most common cause of nosocomial bloodstream infection (BSI). The availability of standardized methods for testing the in vitro activity of antifungals along with the expanding of antifungal armamentarium, the rising of drug-resistance and the persistence of a high mortality rate in systemic candidiasis have led to an increased interest in combination therapy. Therefore, we aimed to review the scientific literature concerning the antifungal combinations against Candida. A literature search performed in PubMed yielded 92 studies published from 2000 to 2021: 29 articles referring to in vitro studies, six articles referring to either in vitro and in vivo (i.e., animal models) studies and 57 clinical articles. Pre-clinical studies involved 735 isolates of Candida species and 12 unique types of antifungal combination approaches including azoles plus echinocandins (19%), polyenes plus echinocandins (16%), polyenes plus azoles (13%), polyenes plus 5-flucytosine ([5-FC], 13%), azoles plus 5-FC (11%) and other types of combinations (28%). Results varied greatly, often being species-, drug- and methodology-dependent. Some combinatorial regimens exerted a synergistic effect against difficult-to-treat Candida species (i.e., azoles plus echinocandins; polyenes plus 5-FC) or they were more effective than monotherapy in prevent or reducing biofilm formation and in speeding the clearance of infected tissues (i.e., polyenes plus echinocandins). In 283 patients with documented Candida infections (>90% systemic candidiasis/BSI), an antifungal combination approach could be evaluated. Combinations included: azoles plus echinocandins (36%), 5-FC-combination therapies (24%), polyenes plus azoles (18%), polyenes plus echinocandins (16%) and other types of combination therapy (6%). Case reports describing combination therapies yielded favorable response in most cases, including difficult-to-treat fungal infections (i.e., endocarditis, osteoarticular infections, CNS infections) or difficult-to-treat fungal pathogens. The only randomized trial comparing amphotericin-B deoxycholate (AMB) plus FLU vs. AMB alone for treatment of BSI in nonneutropenic patients showed that the combination trended toward improved success and more-rapid clearance from the bloodstream. In summary, antifungal combinations against Candida have produced great interest in the past two decades. To establish whether this approach can become a reliable treatment option, additional in vitro and clinical data are warranted. Full article
(This article belongs to the Special Issue Pharmacodynamics of Antifungal Drugs)
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