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Clinical Microbiology and Infection :... Jul 2019Recently there has been an increase in Candida infections worldwide. A handful of species in the genus Candida are opportunistic pathogens and have been known to cause... (Review)
Review
BACKGROUND
Recently there has been an increase in Candida infections worldwide. A handful of species in the genus Candida are opportunistic pathogens and have been known to cause infections in immunocompromised or otherwise impaired hosts. These infections can be superficial, affecting the skin or mucous membrane, or invasive, which can be life-threatening. Azoles and echinocandins are antifungal drugs used globally to treat Candida infections. However, resistance to these antifungal drugs has increased in many of the Candida species, and the effects this has in the clinical setting can be seen.
OBJECTIVES
Here, we discuss the mechanisms that Candida albicans, Candida dubliniensis, Candida glabrata, Candida parapsilosis, Candida tropicalis and Candida auris are implementing to increase resistance to azoles and echinocandins, and how they are affecting clinical, or hospital, settings worldwide.
SOURCES
Different studies and papers describing the mechanisms of antifungal drugs and Candida species evolution to becoming resistant to these drugs were looked at for this review.
CONTENT
We discuss the mechanisms that azoles and echinocandins use against Candida species to treat infections, as well as the evolution of these fungi to become resistant to these drugs, and the effect this has in the clinical settings around the globe.
IMPLICATIONS
Increased resistance to azoles and echinocandins by Candida species is an increasingly serious problem in clinical settings worldwide. Understanding the mechanisms used against antifungal drugs is imperative for patient treatment.
Topics: Antifungal Agents; Azoles; Candida; Candida albicans; Candida glabrata; Drug Resistance, Multiple, Fungal; Echinocandins; Humans; Microbial Sensitivity Tests
PubMed: 30965100
DOI: 10.1016/j.cmi.2019.03.028 -
Revista Espanola de Quimioterapia :... Jun 2023The administration of antifungals for therapeutic and, especially, prophylactic purposes is virtually a constant in patients requiring hematology-oncology treatment. Any... (Review)
Review
The administration of antifungals for therapeutic and, especially, prophylactic purposes is virtually a constant in patients requiring hematology-oncology treatment. Any attempt to prevent or treat Aspergillus or Mucor infections requires the administration of some drugs in the azole group, which include voriconazole, posaconazole and isavuconazole, noted for their activity against these pathogens. One very relevant aspect is the potential risk of interaction when associated with one of the antineoplastic drugs used to treat hematologic tumors, with serious complications. In this regard, acalabrutinib, bortezomib, bosutinib, carfilzomib, cyclophosphamide, cyclosporine A, dasatinib, duvelisib, gilteritinib, glasdegib, ibrutinib, imatinib, nilotinib, ponatinib, prednisone, ruxolitinib, tacrolimus, all-transretinoic acid, arsenic trioxide, venetoclax, or any of the vinca alkaloids, are very clear examples of risk, in some cases because their clearance is reduced and in others because of increased risk of QTc prolongation, which is particularly evident when the drug of choice is voriconazole or posaconazole.
Topics: Humans; Antifungal Agents; Voriconazole; Azoles; Antineoplastic Agents; Hematologic Neoplasms
PubMed: 37017117
DOI: 10.37201/req/013.2023 -
Mycopathologia Oct 2023Despite improvements in treatment and diagnostics over the last two decades, invasive aspergillosis (IA) remains a devastating fungal disease. The number of... (Review)
Review
Despite improvements in treatment and diagnostics over the last two decades, invasive aspergillosis (IA) remains a devastating fungal disease. The number of immunocompromised patients and hence vulnerable hosts increases, which is paralleled by the emergence of a rise in IA cases. Increased frequencies of azole-resistant strains are reported from six continents, presenting a new challenge for the therapeutic management. Treatment options for IA currently consist of three classes of antifungals (azoles, polyenes, echinocandins) with distinctive advantages and shortcomings. Especially in settings of difficult to treat IA, comprising drug tolerance/resistance, limiting drug-drug interactions, and/or severe underlying organ dysfunction, novel approaches are urgently needed. Promising new drugs for the treatment of IA are in late-stage clinical development, including olorofim (a dihydroorotate dehydrogenase inhibitor), fosmanogepix (a Gwt1 enzyme inhibitor), ibrexafungerp (a triterpenoid), opelconazole (an azole optimized for inhalation) and rezafungin (an echinocandin with long half-life time). Further, new insights in the pathophysiology of IA yielding immunotherapy as a potential add-on therapy. Current investigations show encouraging results, so far mostly in preclinical settings. In this review we discuss current treatment strategies, give an outlook on possible new pharmaceutical therapeutic options, and, lastly, provide an overview of the ongoing research in immunotherapy for IA.
Topics: Humans; Aspergillosis; Antifungal Agents; Mycoses; Invasive Fungal Infections; Azoles; Drug Resistance, Fungal
PubMed: 37100963
DOI: 10.1007/s11046-023-00727-z -
The Lancet. Microbe Jun 2023Candida parapsilosis is one of the most commen causes of life-threatening candidaemia, particularly in premature neonates, individuals with cancer of the haematopoietic... (Review)
Review
Candida parapsilosis is one of the most commen causes of life-threatening candidaemia, particularly in premature neonates, individuals with cancer of the haematopoietic system, and recipients of organ transplants. Historically, drug-susceptible strains have been linked to clonal outbreaks. However, worldwide studies started since 2018 have reported severe outbreaks among adults caused by fluconazole-resistant strains. Outbreaks caused by fluconazole-resistant strains are associated with high mortality rates and can persist despite strict infection control strategies. The emergence of resistance threatens the efficacy of azoles, which is the most widely used class of antifungals and the only available oral treatment option for candidaemia. The fact that most patients infected with fluconazole-resistant strains are azole-naive underscores the high potential adaptability of fluconazole-resistant strains to diverse hosts, environmental niches, and reservoirs. Another concern is the multidrug-resistant and echinocandin-tolerant C parapsilosis isolates, which emerged in 2020. Raising awareness, establishing effective clinical interventions, and understanding the biology and pathogenesis of fluconazole-resistant C parapsilosis are urgently needed to improve treatment strategies and outcomes.
Topics: Adult; Infant, Newborn; Humans; Fluconazole; Candida parapsilosis; Microbial Sensitivity Tests; Antifungal Agents; Candidemia; Azoles
PubMed: 37121240
DOI: 10.1016/S2666-5247(23)00067-8 -
Frontiers in Cellular and Infection... 2022Recurrent vulvovaginal candidosis (RVVC) is a chronic, difficult to treat vaginal infection, caused by species, which affects women of all ages and ethnic and social... (Review)
Review
Recurrent vulvovaginal candidosis (RVVC) is a chronic, difficult to treat vaginal infection, caused by species, which affects women of all ages and ethnic and social background. A long-term prophylactic maintenance regimen with antifungals is often necessary. In most clinical practice guidelines, oral fluconazole is recommended as the first-line treatment. Although clinical resistance to antifungal agents remains rare, overexposure to azoles may increase the development of fluconazole-resistant . strains. In addition, are frequently dose-dependent susceptible or resistant to fluconazole and other azoles, and their prevalence is rising. Available therapeutic options to treat such fluconazole-resistant and low susceptibility non- strains are limited. Ten experts from different European countries discussed problematic issues of current RVVC diagnosis and treatment in two audiotaped online sessions and two electronic follow-up rounds. A total of 340 statements were transcribed, summarized, and compared with published evidence. The profile of patients with RVVC, their care pathways, current therapeutic needs, and potential value of novel drugs were addressed. Correct diagnosis, right treatment choice, and patient education to obtain adherence to therapy regimens are crucial for successful RVVC treatment. As therapeutic options are limited, innovative strategies are required. Well- tolerated and effective new drugs with an optimized mechanism of action are desirable and are discussed. Research into the impact of RVVC and treatments on health-related quality of life and sex life is also needed.
Topics: Antifungal Agents; Azoles; Candida; Candida albicans; Candidiasis, Vulvovaginal; Female; Fluconazole; Humans; Microbial Sensitivity Tests; Quality of Life
PubMed: 36159646
DOI: 10.3389/fcimb.2022.934353 -
PLoS Pathogens Aug 2023Fungal infections are rising, with over 1.5 billion cases and more than 1 million deaths recorded each year. Among these, Candida infections are frequent in at-risk...
Fungal infections are rising, with over 1.5 billion cases and more than 1 million deaths recorded each year. Among these, Candida infections are frequent in at-risk populations and the rapid development of drug resistance and tolerance contributes to their clinical persistence. Few antifungal drugs are available, and their efficacy is declining due to the environmental overuse and the expansion of multidrug-resistant species. One way to prolong their utility is by applying them in combination therapy. Here, we highlight recently described azole potentiators belonging to different categories: natural, repurposed, or novel compounds. We showcase examples of molecules and discuss their identified or proposed mode of action. We also emphasise the challenges in azole potentiator development, compounded by the lack of animal testing, the overreliance on Candida albicans and Candida auris, as well as the limited understanding of compound efficacy.
Topics: Animals; Candida; Candida albicans; Candidiasis; Antifungal Agents; Azoles
PubMed: 37651385
DOI: 10.1371/journal.ppat.1011583 -
Cancer Jul 2021Venetoclax (VEN) combined with the hypomethylating agent (HMA) azacitidine improves survival in patients aged ≥75 years with newly diagnosed acute myeloid leukemia...
BACKGROUND
Venetoclax (VEN) combined with the hypomethylating agent (HMA) azacitidine improves survival in patients aged ≥75 years with newly diagnosed acute myeloid leukemia (AML). VEN and HMA treatment can result in prolonged and often profound neutropenia, and this warrants antifungal prophylaxis. Azole antifungals inhibit cytochrome P450 3A4, the primary enzyme responsible for VEN metabolism; this results in VEN dose reductions for each concomitant antifungal. Limited clinical data exist on outcomes for patients treated with VEN, an HMA, and various azoles.
METHODS
The time to neutrophil recovery (absolute neutrophil count [ANC] > 1000 cells/mm ) and platelet (PLT) recovery (PLT count > 100,000 cells/mm ) in 64 patients with newly diagnosed AML who achieved a response after course 1 of VEN plus an HMA were evaluated. HMA therapy included azacitidine (75 mg/m intravenously/subcutaneously for 7 days) or decitabine (20 mg/m intravenously for 5 or 10 days).
RESULTS
Forty-seven patients (73%) received an azole: posaconazole (n = 17; 27%), voriconazole (n = 9; 14%), isavuconazole (n = 20; 31%), or fluconazole (n = 1; 2%). The median time to ANC recovery were similar for patients who did receive an azole (37 days; 95% confidence interval [CI], 34-38 days) and patients who did not receive an azole (39 days; 95% CI, 30 days to not estimable; P = .8). The median time to PLT recovery was significantly longer for patients receiving azoles (28 vs 22 days; P = .01). The median times to ANC recovery (35 vs 38 days) and PLT recovery (26 vs 32 days) were similar with posaconazole and voriconazole.
CONCLUSIONS
VEN plus an HMA resulted in neutropenia and thrombocytopenia, with the latter prolonged in patients receiving concomitant azoles. Concomitant posaconazole or voriconazole and VEN (100 mg) resulted in similar ANC and PLT recovery times, suggesting the safety of these dosage combinations during course 1.
Topics: Aged; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Azoles; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Myeloid, Acute; Sulfonamides; Thrombocytopenia
PubMed: 33793970
DOI: 10.1002/cncr.33508 -
MBio Aug 2023Each year, fungi cause more than 1.5 billion infections worldwide and have a devastating impact on human health, particularly in immunocompromised individuals or...
Each year, fungi cause more than 1.5 billion infections worldwide and have a devastating impact on human health, particularly in immunocompromised individuals or patients in intensive care units. The limited antifungal arsenal and emerging multidrug-resistant species necessitate the development of new therapies. One strategy for combating drug-resistant pathogens is the administration of molecules that restore fungal susceptibility to approved drugs. Accordingly, we carried out a screen to identify small molecules that could restore the susceptibility of pathogenic species to azole antifungals. This screening effort led to the discovery of novel 1,4-benzodiazepines that restore fluconazole susceptibility in resistant isolates of , as evidenced by 100-1,000-fold potentiation of fluconazole activity. This potentiation effect was also observed in azole-tolerant strains of and in other pathogenic species. The 1,4-benzodiazepines selectively potentiated different azoles, but not other approved antifungals. A remarkable feature of the potentiation was that the combination of the compounds with fluconazole was fungicidal, whereas fluconazole alone is fungistatic. Interestingly, the potentiators were not toxic to in the absence of fluconazole, but inhibited virulence-associated filamentation of the fungus. We found that the combination of the potentiators and fluconazole significantly enhanced host survival in a model of systemic fungal infection. Taken together, these observations validate a strategy wherein small molecules can restore the activity of highly used anti-infectives that have lost potency. IMPORTANCE In the last decade, we have been witnessing a higher incidence of fungal infections, due to an expansion of the fungal species capable of causing disease (e.g., ), as well as increased antifungal drug resistance. Among human fungal pathogens, species are a leading cause of invasive infections and are associated with high mortality rates. Infections by these pathogens are commonly treated with azole antifungals, yet the expansion of drug-resistant isolates has reduced their clinical utility. In this work, we describe the discovery and characterization of small molecules that potentiate fluconazole and restore the susceptibility of azole-resistant and azole-tolerant isolates. Interestingly, the potentiating 1,4-benzodiazepines were not toxic to fungal cells but inhibited their virulence-associated filamentous growth. Furthermore, combinations of the potentiators and fluconazole decreased fungal burdens and enhanced host survival in a model of systemic fungal infections. Accordingly, we propose the use of novel antifungal potentiators as a powerful strategy for addressing the growing resistance of fungi to clinically approved drugs.
Topics: Humans; Antifungal Agents; Candida; Fluconazole; Azoles; Pharmaceutical Preparations; Microbial Sensitivity Tests; Candida albicans; Mycoses; Drug Resistance, Fungal; Benzodiazepines
PubMed: 37326546
DOI: 10.1128/mbio.00479-23 -
Molecular Microbiology Dec 2020In recent years, the role of sphingolipids in pathogenic fungi, in terms of pathogenicity and resistance to azole drugs, has been a rapidly growing field. This review... (Review)
Review
In recent years, the role of sphingolipids in pathogenic fungi, in terms of pathogenicity and resistance to azole drugs, has been a rapidly growing field. This review describes evidence about the roles of sphingolipids in azole resistance and fungal virulence. Sphingolipids can serve as signaling molecules that contribute to azole resistance through modulation of the expression of drug efflux pumps. They also contribute to azole resistance by participating in various microbial pathways such as the unfolded protein response (UPR), pH-responsive Rim pathway, and pleiotropic drug resistance (PDR) pathway. In addition, sphingolipid signaling and eisosomes also coordinately regulate sphingolipid biosynthesis in response to azole-induced membrane stress. Sphingolipids are important for fungal virulence, playing roles during growth in hosts under stressful conditions, maintenance of cell wall integrity, biofilm formation, and production of various virulence factors. Finally, we discuss the possibility of exploiting fungal sphingolipids for the development of new therapeutic strategies to treat infections caused by pathogenic fungi.
Topics: Animals; Antifungal Agents; Azoles; Biofilms; Cell Wall; Drug Resistance, Fungal; Fungi; Gene Expression Regulation, Fungal; Signal Transduction; Sphingolipids; Unfolded Protein Response; Virulence
PubMed: 32767804
DOI: 10.1111/mmi.14586 -
Journal of Ocular Pharmacology and... 2019Polyenes and azoles constitute 2 major drug classes in the antifungal armamentarium used to treat fungal infections of the eye such as fungal keratitis, endophthalmitis,... (Review)
Review
Polyenes and azoles constitute 2 major drug classes in the antifungal armamentarium used to treat fungal infections of the eye such as fungal keratitis, endophthalmitis, conjunctivitis, and blepharitis. These classes of drugs have come to occupy an important niche in ophthalmic antifungal therapy due to their broad spectrum of activity against a variety of filamentous and yeast-like fungi. Natamycin suspension (Natacyn), a polyene antifungal drug, is currently the only US FDA-approved formulation for treating ophthalmic fungal infections, whereas the other polyene and azole antifungals such as amphotericin B, fluconazole, itraconazole, ketoconazole, miconazole, voriconazole, and posaconazole are routinely used off-label in the clinical setting. Despite potent antifungal activity, the clinical utility of these agents in ophthalmic infections has been challenged by their physicochemical properties, the unique ocular anatomy and physiology, selective antifungal activity, ocular and systemic toxicity, emergence of resistance and cross-resistance, and absence of reliable techniques for developing a robust in vitro-in vivo correlation. This review discusses the aforementioned challenges and the common approaches undertaken to circumnavigate the difficulties associated with the polyene- and azole-based pharmacotherapy of ophthalmic fungal infections.
Topics: Animals; Antifungal Agents; Azoles; Eye Infections, Fungal; Humans; Microbial Sensitivity Tests; Ophthalmic Solutions; Polyenes
PubMed: 30481082
DOI: 10.1089/jop.2018.0089