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Seminars in Respiratory and Critical... Feb 2020Invasive pulmonary aspergillosis (IPA) remains difficult to diagnose and to treat. Most common risk factors are prolonged neutropenia, hematopoietic stem cell or solid... (Review)
Review
Invasive pulmonary aspergillosis (IPA) remains difficult to diagnose and to treat. Most common risk factors are prolonged neutropenia, hematopoietic stem cell or solid organ transplantation, inherited or acquired immunodeficiency, administration of steroids or other immunosuppressive agents including monoclonal antibodies and new small molecules used for cancer therapy. Critically ill patients are also at high risk of IPA. Clinical signs are unspecific. Early computed tomography (CT)-scan identifies the two main aspects, angioinvasive and airway invasive aspergillosis. Although CT-scan findings are not fully specific they usually allow early initiation of therapy before mycological confirmation of the diagnosis. Role of F-fludeoxyglucose positron emission tomography with computed tomography (F-FDG PET/CT) is discussed. Confirmation is based on microscopy and culture of respiratory samples, histopathology in case of biopsy, and importantly by detection of galactomannan using an immunoassay in serum and bronchoalveolar lavage fluid. Deoxyribonucleic acid detection by polymerase chain reaction is now standardized and increases the diagnosis yield. Two point of care tests detecting an glycoprotein using a lateral flow assay are also available. Mycological results allow classification into proven (irrespective of underlying condition), probable or possible (for cancer and severely immunosuppressed patients) or putative (for critically ill patients) IPA. New antifungal agents have been developed over the last 2 decades: new azoles (voriconazole, posaconazole, isavuconazole), lipid formulations of amphotericin B (liposomal amphotericin B, amphotericin B lipid complex), echinocandins (caspofungin, micafungin, anidulafungin). Results of main trials assessing these agents in monotherapy or in combination are presented as well as the recommendations for their use according to international guidelines. New agents are under development.
Topics: Amphotericin B; Antifungal Agents; Aspergillus; Bronchoalveolar Lavage Fluid; Galactose; Humans; Immunocompromised Host; Invasive Pulmonary Aspergillosis; Mannans; Microbial Sensitivity Tests; Positron Emission Tomography Computed Tomography; Practice Guidelines as Topic; Radiography, Thoracic; Triazoles
PubMed: 32000286
DOI: 10.1055/s-0039-3401990 -
Journal of Enzyme Inhibition and... Dec 2022With increasing number of immunocompromised patients as well as drug resistance in fungi, the risk of fatal fungal infections in humans increases as well. The action of... (Review)
Review
With increasing number of immunocompromised patients as well as drug resistance in fungi, the risk of fatal fungal infections in humans increases as well. The action of echinocandins is based on the inhibition of β-(1,3)-d-glucan synthesis that builds the fungal cell wall. Caspofungin, micafungin, anidulafungin and rezafungin are semi-synthetic cyclic lipopeptides. Their specific chemical structure possess a potential to obtain novel derivatives with better pharmacological properties resulting in more effective treatment, especially in infections caused by and species. In this review we summarise information about echinocandins with closer look on their chemical structure, mechanism of action, drug resistance and usage in clinical practice. We also introduce actual trends in modification of this antifungals as well as new methods of their administration, and additional use in viral and bacterial infections.
Topics: Antifungal Agents; Aspergillus; Candida; Cell Wall; Drug Design; Echinocandins; Glucans; Microbial Sensitivity Tests; Molecular Structure
PubMed: 35296203
DOI: 10.1080/14756366.2022.2050224 -
Expert Opinion on Drug Safety Sep 2021Invasive fungal infections continue to be important causes of morbidity and mortality in severely ill and immunocompromised patient populations. The past three decades... (Comparative Study)
Comparative Study Review
INTRODUCTION
Invasive fungal infections continue to be important causes of morbidity and mortality in severely ill and immunocompromised patient populations. The past three decades have seen a considerable expansion in antifungal drug research, resulting in the clinical development of different classes of antifungal agents with different pharmacologic properties. Among drug-specific characteristics of antifungal agents, renal disposition and nephrotoxicity are important clinical considerations as many patients requiring antifungal therapy have compromised organ functions or are receiving other potentially nephrotoxic medications.
AREAS COVERED
The present article reviews incidence, severity and mechanisms of nephrotoxicity associated with antifungal agents used for prevention and treatment of invasive fungal diseases by discussing distribution, metabolism, elimination and drug-related adverse events in the context of safety data from phase II and III clinical studies.
EXPERT OPINION
Based on the available data amphotericin B deoxycholate has the highest relative potential for nephrotoxicity, followed by the lipid formulations of amphotericin B, and, to a much lesser extent and by indirect mechanisms, the antifungal triazoles.
Topics: Animals; Antifungal Agents; Drug Development; Drug Interactions; Humans; Immunocompromised Host; Incidence; Invasive Fungal Infections; Kidney; Renal Insufficiency; Severity of Illness Index
PubMed: 33896310
DOI: 10.1080/14740338.2021.1922667 -
Virulence Dec 2022Antifungal resistance to pathogens increases morbidity and mortality of immunosuppressive patients, an emerging crisis worldwide. Understanding the prevalence and... (Review)
Review
Antifungal resistance to pathogens increases morbidity and mortality of immunosuppressive patients, an emerging crisis worldwide. Understanding the prevalence and antifungal susceptibility pattern is necessary to control and treat candidiasis. We aimed to systematically analyse the susceptibility profiles of species published in the last ten years (December 2011 to December 2021) from mainland China. The studies were collected from PubMed, Google Scholar, and Science Direct search engines. Out of 89 included studies, a total of 44,716 isolates were collected, mainly comprising (49.36%), (21.89%), (13.92%), and (11.37%). The lowest susceptibility was detected for azole group; fluconazole susceptibilities against , and were 93.25%, 91.6%, 79.4%, 77.95%, 76%, 50%, and 0% respectively. Amphotericin B and anidulafungin were the most susceptible drugs for all species. Resistance to azole was mainly linked with mutations in , and genes. Mutation in and in and causing resistance to echinocandins was stated in two studies. Gaps in the studies' characteristics were detected, such as 79.77%, 47.19 %, 26.97%, 7.86%, and 4.49% studies did not mention the mortality rates, age, gender, breakpoint reference guidelines, and fungal identification method, respectively. The current study demonstrates the overall antifungal susceptibility pattern of species, gaps in surveillance studies and risk-reduction strategies that could be supportive in candidiasis therapy and for the researchers in their future studies.
Topics: Humans; Amphotericin B; Anidulafungin; Antifungal Agents; Azoles; Candida; Candida albicans; Candida glabrata; Candida parapsilosis; Candida tropicalis; Candidiasis; Echinocandins; Fluconazole; Microbial Sensitivity Tests
PubMed: 36120738
DOI: 10.1080/21505594.2022.2123325 -
Clinical Microbiology and Infection :... Nov 2020EUCAST has revised the definition of the susceptibility category I from 'Intermediate' to 'Susceptible, Increased exposure'. This implies that I can be used where the... (Review)
Review
BACKGROUND
EUCAST has revised the definition of the susceptibility category I from 'Intermediate' to 'Susceptible, Increased exposure'. This implies that I can be used where the drug concentration at the site of infection is high, either because of dose escalation or through other means to ensure efficacy. Consequently, I is no longer used as a buffer zone to prevent technical factors from causing misclassifications and discrepancies in interpretations. Instead, an Area of Technical Uncertainty (ATU) has been introduced for MICs that cannot be categorized without additional information as a warning to the laboratory that decision on how to act has to be made. To implement these changes, the EUCAST-AFST (Subcommittee on Antifungal Susceptibility Testing) reviewed all, and revised some, clinical antifungal breakpoints.
OBJECTIVES
The aim was to present an overview of the current antifungal breakpoints and supporting evidence behind the changes.
SOURCES
This document is based on the ten recently updated EUCAST rationale documents, clinical breakpoint and breakpoint ECOFF documents.
CONTENT
The following breakpoints (in mg/L) have been revised or established for Candida species: micafungin against C. albicans (ATU = 0.03); amphotericin B (S ≤/> R = 1/1), fluconazole (S ≤/> R = 2/4), itraconazole (S ≤/> R = 0.06/0.06), posaconazole (S ≤/> R = 0.06/0.06) and voriconazole (S ≤/> R = 0.06/0.25) against C. dubliniensis; fluconazole against C. glabrata (S ≤/> R = 0.001/16); and anidulafungin (S ≤/> R = 4/4) and micafungin (S ≤/> R = 2/2) against C. parapsilosis. For Aspergillus, new or revised breakpoints include itraconazole (ATU = 2) and isavuconazole against A. flavus (S ≤/> R = 1/2, ATU = 2); amphotericin B (S ≤/> R = 1/1), isavuconazole (S ≤ /> R = 1/2, ATU = 2), itraconazole (S ≤/> R = 1/1, ATU = 2), posaconazole (ATU = 0.25) and voriconazole (S ≤/> R = 1/1, ATU = 2) against A. fumigatus; itraconazole (S ≤/> R = 1/1, ATU = 2) and voriconazole (S ≤/> R = 1/1, ATU = 2) against A. nidulans; amphotericin B against A. niger (S ≤/> R = 1/1); and itraconazole (S ≤/> R = 1/1, ATU = 2) and posaconazole (ATU = 0.25) against A. terreus.
IMPLICATIONS
EUCAST-AFST has released ten new documents summarizing existing and new breakpoints and MIC ranges for control strains. A failure to adopt the breakpoint changes may lead to misclassifications and suboptimal or inappropriate therapy of patients with fungal infections.
Topics: Amphotericin B; Antifungal Agents; Aspergillus; Candida; Fluconazole; Itraconazole; Microbial Sensitivity Tests; Practice Guidelines as Topic; Triazoles; Voriconazole
PubMed: 32562861
DOI: 10.1016/j.cmi.2020.06.007 -
Clinical Microbiology and Infection :... Nov 2020The goal of therapeutic drug monitoring (TDM) is to determine the appropriate exposure of difficult-to-manage medications to optimize the clinical outcomes in patients... (Review)
Review
BACKGROUND
The goal of therapeutic drug monitoring (TDM) is to determine the appropriate exposure of difficult-to-manage medications to optimize the clinical outcomes in patients in various clinical situations. Concerning antifungal treatment, and knowing that this procedure is expensive and time-consuming, TDM is particularly recommended for certain systemic antifungals: i.e., agents with a well-defined exposure-response relationship and unpredictable pharmacokinetic profile or narrow therapeutic index. Little evidence supports the routine use of TDM for polyenes (amphotericin B), echinocandins, fluconazole or new azoles such as isavuconazole, despite the fact that a better understanding of antifungal exposure may lead to a better response.
AIMS
The aim of this work is to review published pharmacokinetic/pharmacodynamic data on systemically administered antifungals, focusing on those for which monitoring is not routinely recommended by experts.
SOURCES
A MEDLINE search of the literature in English was performed introducing the following search terms: amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, triazoles, caspofungin, micafungin, anidulafungin, echinocandins, pharmacokinetics, pharmacodynamics, and therapeutic drug monitoring. Review articles and guidelines were also screened.
CONTENT
This review collects different pharmacokinetic/pharmacodynamic aspects of systemic antifungals and summarizes recent threshold values for clinical outcomes and adverse events. Although for polyenes, echinocandins, fluconazole and isavuconazole extensive clinical validation is still required for a clear threshold and a routine monitoring recommendation, particular points such as liposome structure or complex pathophysiological conditions affecting final exposure are discussed. For the rest, their better-defined exposure-response/toxicity relationships allow access to useful threshold values and to justify routine monitoring. Additionally, clinical data are needed to better define thresholds that can minimize the development of antifungal resistance.
IMPLICATIONS
General TDM for all systemic antifungals is not recommended; however, this approach may help to establish an adequate antifungal exposure for a favourable response, prevention of toxicity or development of resistance in special clinical circumstances.
Topics: Antifungal Agents; Drug Monitoring; Echinocandins; Fluconazole; Humans; Mycoses; Nitriles; Polyenes; Practice Guidelines as Topic; Pyridines; Triazoles
PubMed: 32535150
DOI: 10.1016/j.cmi.2020.05.037 -
Cells Nov 2023Candidiasis is a highly pervasive infection posing major health risks, especially for immunocompromised populations. Pathogenic species have evolved intrinsic and... (Review)
Review
Candidiasis is a highly pervasive infection posing major health risks, especially for immunocompromised populations. Pathogenic species have evolved intrinsic and acquired resistance to a variety of antifungal medications. The primary goal of this literature review is to summarize the molecular mechanisms associated with antifungal resistance in species. Resistance can be conferred via gain-of-function mutations in target pathway genes or their transcriptional regulators. Therefore, an overview of the known gene mutations is presented for the following antifungals: azoles (fluconazole, voriconazole, posaconazole and itraconazole), echinocandins (caspofungin, anidulafungin and micafungin), polyenes (amphotericin B and nystatin) and 5-fluorocytosine (5-FC). The following mutation hot spots were identified: (1) ergosterol biosynthesis pathway mutations (ERG11 and UPC2), resulting in azole resistance; (2) overexpression of the efflux pumps, promoting azole resistance (transcription factor genes: and ; transporter genes: CDR1, CDR2, MDR1, PDR16 and SNQ2); (3) cell wall biosynthesis mutations (FKS1, FKS2 and PDR1), conferring resistance to echinocandins; (4) mutations of nucleic acid synthesis/repair genes (FCY1, FCY2 and FUR1), resulting in 5-FC resistance; and (5) biofilm production, promoting general antifungal resistance. This review also provides a summary of standardized inhibitory breakpoints obtained from international guidelines for prominent species. Notably, , and demonstrate fluconazole resistance.
Topics: Antifungal Agents; Candida; Fluconazole; Echinocandins; Azoles
PubMed: 37998390
DOI: 10.3390/cells12222655 -
Antibiotics (Basel, Switzerland) Nov 2020Control of fungal pathogens is increasingly problematic due to the limited number of effective drugs available for antifungal therapy. Conventional antifungal drugs...
Control of fungal pathogens is increasingly problematic due to the limited number of effective drugs available for antifungal therapy. Conventional antifungal drugs could also trigger human cytotoxicity associated with the kidneys and liver, including the generation of reactive oxygen species. Moreover, increased incidences of fungal resistance to the classes of azoles, such as fluconazole, itraconazole, voriconazole, or posaconazole, or echinocandins, including caspofungin, anidulafungin, or micafungin, have been documented. Of note, certain azole fungicides such as propiconazole or tebuconazole that are applied to agricultural fields have the same mechanism of antifungal action as clinical azole drugs. Such long-term application of azole fungicides to crop fields provides environmental selection pressure for the emergence of pan-azole-resistant fungal strains such as having TR34/L98H mutations, specifically, a 34 bp insertion into the cytochrome P450 51A () gene promoter region and a leucine-to-histidine substitution at codon 98 of . Altogether, the emerging resistance of pathogens to currently available antifungal drugs and insufficiency in the discovery of new therapeutics engender the urgent need for the development of new antifungals and/or alternative therapies for effective control of fungal pathogens. We discuss the current needs for the discovery of new clinical antifungal drugs and the recent drug repurposing endeavors as alternative methods for fungal pathogen control.
PubMed: 33203147
DOI: 10.3390/antibiotics9110812 -
Antimicrobial Agents and Chemotherapy Jun 2021Concentrations of anidulafungin and micafungin were determined in eight different tissues obtained during autopsy of four deceased individuals who had been treated with...
Concentrations of anidulafungin and micafungin were determined in eight different tissues obtained during autopsy of four deceased individuals who had been treated with anidulafungin and of seven who had received micafungin. The largest amounts were recovered from liver, with anidulafungin concentrations of 11.01 to 66.50 μg/g and micafungin levels of 0.36 to 5.53 μg/g (0.65 μg/g 30 days after the last administration). The lowest anidulafungin levels were measured in skeletal muscle, and the lowest micafungin concentrations were in kidneys.
Topics: Anidulafungin; Antifungal Agents; Echinocandins; Humans; Lipopeptides; Micafungin; Tissue Distribution
PubMed: 33875434
DOI: 10.1128/AAC.00169-21