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Prior to the SARS-CoV-2 pandemic, antibiotic resistance was listed as the major global health care priority. Some analyses, including the O'Neill report, have predicted that deaths due to drug-resistant bacterial infections may eclipse the total number of cancer deaths by 2050. Although fungal infections remain in the shadow of public awareness, total attributable annual deaths are similar to, or exceeds, global mortalities due to malaria, tuberculosis or HIV. The impact of fungal infections has been exacerbated by the steady rise of antifungal drug resistant strains and species which reflects the widespread use of antifungals for prophylaxis and therapy, and in the case of azole resistance in Aspergillus, has been linked to the widespread agricultural use of antifungals. This review, based on a workshop hosted by the Medical Research Council and the University of Exeter, illuminates the problem of antifungal resistance and suggests how this growing threat might be mitigated., (© 2022. The Author(s).)

All serious fungal infections need appropriate antifungal therapy for successful patient outcome. Only a few classes of antifungal drugs are available, so the emergence of resistance to single drug classes and now multidrug resistance greatly hampers patient management. Azole resistance among Candida and Aspergillus species is one of the greatest challenges to clinical success, followed by echinocandin and multidrug resistance among some Candida species, especially Candida glabrata. The spread of agriculturally derived azole-resistant Aspergillus fumigatus and emerging threats such as multidrug resistant Candida auris are also alarming. The molecular mechanisms that cause drug resistance are naturally occurring in less susceptible species and are acquired in strains of susceptible organisms. Drug resistance mechanisms include altered drug-target interactions, reduced cellular drug concentrations mediated by drug efflux transporters, and permeability barriers associated with biofilms. Although C auris is inherently multidrug resistant, other strains typically develop resistance through stepwise selection of multiple drug-resistance mechanisms. Cellular stress induced by drug treatment promotes adaptation, which contributes to breakthrough resistance. Drug exposure also drives the emergence of resistance. An effective antifungal stewardship programme is essential to control drug resistance, and should incorporate rapid fungal diagnostics, therapeutic drug monitoring, and clinical intervention teams. The development of better diagnostic tools and strategies that allow targeted use of antifungals is essential to preserve drug effectiveness., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Antimicrobial resistance, a major public health concern, largely arises from excess use of antibiotic and antifungal drugs. Lack of routine diagnostic testing for fungal diseases exacerbates the problem of antimicrobial drug empiricism, both antibiotic and antifungal. In support of this contention, we cite 4 common clinical situations that illustrate this problem: 1) inaccurate diagnosis of fungal sepsis in hospitals and intensive care units, resulting in inappropriate use of broad-spectrum antibacterial drugs in patients with invasive candidiasis; 2) failure to diagnose chronic pulmonary aspergillosis in patients with smear-negative pulmonary tuberculosis; 3) misdiagnosis of fungal asthma, resulting in unnecessary treatment with antibacterial drugs instead of antifungal drugs and missed diagnoses of life-threatening invasive aspergillosis in patients with chronic obstructive pulmonary disease; and 4) overtreatment and undertreatment of Pneumocystis pneumonia in HIV-positive patients. All communities should have access to nonculture fungal diagnostics, which can substantially benefit clinical outcome, antimicrobial stewardship, and control of antimicrobial resistance.

Background: This work was intended as a proof-of-principle study to help establish carbohydrate-derived fulvic acid (CHD-FA) as a safe and effective agent that can be deployed to prevent the onset of drug-resistant bacterial and fungal infections in military and civilian personnel experiencing traumatic wound., Methods: Minimum inhibitory concentrations for CHD-FA were established on a total of 500 clinical isolates representing wound-associated drug-sensitive and drug-resistant bacterial and fungal pathogens. The efficacy of early use of CHD-FA to enhance healing of wounds infected with methicillin-resistant Staphylococcus aureus or Pseudomonas aeruginosa was evaluated in an in vivo rat model., Results: CHD-FA showed strong activity against a variety of bacterial and fungal pathogens with minimum inhibitory concentration values equal or less than 0.5%. Compared with infected but untreated wounds, improved wound healing upon CHD-FA treatment was observed in both infection models, demonstrated by wound surface area measurement, histopathologic examination, and expression profiling of wound healing genes. Up-regulation of proinflammatory cytokine interleukin 6 (IL-6) at Day 3 after infection was significantly dampened at Days 6 and 10 in the CHD-FA-treated wounds in both infection models, displaying an improved and accelerated wound healing., Conclusion: CHD-FA is a promising topical remedy for drug-resistant wound infections. It accelerated the healing process of wounds infected with methicillin-resistant S. aureus and multidrug-resistant P. aeruginosa in rats, which is linked to both its antimicrobial and anti-inflammatory properties.

Antifungal therapy is a central component of patient management for acute and chronic mycoses. Yet, treatment choices are restricted because of the sparse number of antifungal drug classes. Clinical management of fungal diseases is further compromised by the emergence of antifungal drug resistance, which eliminates available drug classes as treatment options. Once considered a rare occurrence, antifungal drug resistance is on the rise in many high-risk medical centers. Most concerning is the evolution of multidrug- resistant organisms refractory to several different classes of antifungal agents, especially among common Candida species. The mechanisms responsible are mostly shared by both resistant strains displaying inherently reduced susceptibility and those acquiring resistance during therapy. The molecular mechanisms include altered drug affinity and target abundance, reduced intracellular drug levels caused by efflux pumps, and formation of biofilms. New insights into genetic factors regulating these mechanisms, as well as cellular factors important for stress adaptation, provide a foundation to better understand the emergence of antifungal drug resistance., (Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.)

High concentrations of methylprednisolone (0.32 mg/mL) accelerated growth and attenuated spontaneous apoptosis of Exserohilum rostratum in vitro. Injection of E. rostratum conidia preexposed to 0.32 mg/mL of methylprednisolone for 7 days in immunocompetent flies led to increased mortality and a higher fungal burden. Exposure to methylprednisolone could enhance the virulence of E. rostratum., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Exserohilum species are soilborne fungi that have been uncommon causes of human disease. The ongoing outbreak in the United States warrants improved understanding of this pathogen. We systematically reviewed all cases of Exserohilum spp. infections published before the outbreak in 2012 in order to provide a better understanding of the organism and its wider spectrum of human disease. Cases of Exserohilum infections were retrieved by searching PubMed. Demographic data, underlying conditions, microbiology, clinical manifestations, therapy, and outcome were recorded and analyzed. Forty-eight evaluable cases were identified from 1975 to 2012. The number of reported cases increased more than twofold during the study period (P < 0.01). Most cases occurred in the southern United States, India, and Israel. Median age of patients was 25 years, with a male predominance. Most infections were due to E. rostratum (60.4%), followed by E. longirostratum (6.3%) and E. mcginnisii (2%), while 31.3% were unidentified species. The most frequent underlying conditions were immunosuppression (27.2%), trauma (16.6%), and atopy (12.5%). Exserohilum disease manifested as systemic (73%), cutaneous (25%), corneal (16.7%), and subcutaneous (10.4%) infection. Antifungal therapy consisted mainly of amphotericin B (44%) alone or combined with a triazole. Surgery was used in 48% of cases and was combined with antifungal therapy in 31%. The all-cause mortality was 23%, which was higher in patients with preexisting immunosuppression (56.2%; odds ratio 15.4; 95% confidence interval, 2.7-88.6). This review of the pre-outbreak reported cases highlights several aspects of epidemiology, clinical presentation, risk factors, and management of this unusual pathogen.

The diagnosis of invasive fungal infections from radiographic imaging is non-specific and problematic. As a first step toward increasing specificity, we describe the development of a broad-spectrum fungal-specific targeting molecule, which when modified with a fluorescent label fully retains its targeting properties, and provides a basis for future imaging applications.

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.

Bloodstream infections (BSIs) are a significant cause of morbidity and mortality. Successful patient outcomes are diminished by a failure to rapidly diagnose these infections and initiate appropriate therapy. A rapid and reliable diagnostic platform of high sensitivity is needed for the management of patients with BSIs. The combination of an RNA-dependent nucleic acid sequence-based amplification and molecular beacon (NASBA-MB) detection system in multiplex format was developed to rapidly detect medically important BSI organisms. Probes and primers representing pan-gram-negative, pan-gram-positive, pan-fungal, pan-Candida, and pan-Aspergillus organisms were established utilizing 16S and 28S rRNA targets for bacteria and fungi, respectively. Two multiplex panels were developed to rapidly discriminate bacterial or fungal infections at the subkingdom/genus level with a sensitivity of 1 to 50 genomes. A clinical study was performed to evaluate the accuracy of this platform by evaluating 570 clinical samples from a tertiary-care hospital group using blood bottle samples. The sensitivity, specificity, and Youden's index values for pan-gram-positive detection and pan-gram-negative detection were 99.7%, 100%, 0.997 and 98.6%, 95.9%, 0.945, respectively. The positive predictive values (PPV) and the negative predictive values (NPV) for these two probes were 100, 90.7, and 99.4, 99.4, respectively. Pan-fungal and pan-Candida probes showed 100% sensitivity, specificity, PPV, and NPV, and the pan-Aspergillus probe showed 100% NPV. Robust signals were observed for all probes in the multiplex panels, with signal detection in <15 min. The multiplex real-time NASBA-MB assay provides a valuable platform for the rapid and specific diagnosis of bloodstream pathogens, and reliable pathogen identification and characterization can be obtained in under 3 h.

BackgroundThe antifungal posaconazole concentrates within host cells and protects against Aspergillus fumigatus. The specific subcellular location of posaconazole and the mechanism by which cell-associated posaconazole inhibits fungal growth remain uncharacterized.MethodsPosaconazole was conjugated with the fluorophore boron-dipyrromethene (BDP-PCZ). A549 pulmonary epithelial cells and A. fumigatus were exposed to BDP-PCZ individually and in coculture. BDP-PCZ subcellular localization and trafficking were observed using confocal microscopy and flow cytometry.ResultsBDP-PCZ concentrated within A549 cell membranes, and in particular within the endoplasmic reticulum. Epithelial cell-associated BDP-PCZ rapidly transferred to and concentrated within A. fumigatus cell membranes on contact. BDP-PCZ transfer to conidia did not require phagocytosis and was markedly enhanced by the conidial hydrophobin RodA. Within AF, BDP-PCZ also concentrated in membranes including the endoplasmic reticulum and colocalized with the azole target enzyme CYP51a. Concentration of BDP-PCZ within host and fungal cell membranes persisted for >48 hours and could be competitively inhibited by posaconazole but not voriconazole.ConclusionsPosaconazole concentrates within host cell membranes and rapidly transfers to A. fumigatus, where it accumulates to high concentrations and persists at the site of its target enzyme. These intracellular and intercellular pharmacokinetic properties probably contribute to the efficacy of PCZ.

Fungal infections are on the rise, and emergence of drug-resistant Candida strains refractory to treatment is particularly alarming. Resistance to azole class antifungals, which have been extensively used worldwide for several decades, is so high in several prevalent fungal pathogens, that another drug class, the echinocandins, is now recommended as a first line antifungal treatment. However, resistance to echinocandins is also prominent, particularly in certain species, such as Candida glabrata. The echinocandins target 1,3-β-glucan synthase (GS), the enzyme responsible for producing 1,3-β-glucans, a major component of the fungal cell wall. Although echinocandins are considered fungicidal, C. glabrata exhibits echinocandin tolerance both in vitro and in vivo , where a subset of the cells survives and facilitates the emergence of echinocandin-resistant mutants, which are responsible for clinical failure. Despite this critical role of echinocandin tolerance, its mechanisms are still not well understood. Additionally, most studies of tolerance are conducted in vitro and are thus not able to recapitulate the fungal-host interaction. In this study, we focused on the role of cell wall integrity factors in echinocandin tolerance in C. glabrata. We identified three genes involved in the maintenance of cell wall integrity – YPS1 , YPK2 , and SLT2 – that promote echinocandin tolerance both in vitro and in a mouse model of gastrointestinal (GI) colonization. In particular, we show that mice colonized with strains carrying deletions of these genes were more effectively sterilized by daily caspofungin treatment relative to mice colonized with the wild-type parental strain. Furthermore, consistent with a role of tolerant cells serving as a reservoir for generating resistant mutations, a reduction in tolerance was associated with a reduction in the emergence of resistant strains. Finally, reduced susceptibility in these strains was due both to the well described FKS -dependent mechanisms and as yet unknown, FKS -independent mechanisms. Together, these results shed light on the importance of cell wall integrity maintenance in echinocandin tolerance and emergence of resistance and lay the foundation for future studies of the factors described herein. [ABSTRACT FROM AUTHOR]

Recurrent vulvovaginal candidiasis (RVVC) is one of the most prevalent fungal infections in humans, especially in developing countries; however, it is underestimated and regarded as an easy-to-treat condition. RVVC may be caused by dysbiosis of the microbiome and other host-, pathogen-, and antifungal drug-related factors. Although multiple studies on host-related factors affecting the outcome have been conducted, such studies on Candida -derived factors and their association with RVVC are lacking. Thus, fluconazole-tolerant (FLZT) isolates may cause fluconazole therapeutic failure (FTF), but this concept has not been assessed in the context of Candida -associated vaginitis. Iran is among the countries with the highest burden of RVVC; however, comprehensive studies detailing the clinical and microbiological features of this complication are scarce. Therefore, we conducted a 1-year prospective study with the aim to determine the RVVC burden among women referred to a gynecology hospital in Tehran, the association of the previous exposure to clotrimazole and fluconazole with the emergence of FLZT and fluconazole-resistant (FLZR) Candida isolates, and the relevance of these phenotypes to FTF. The results indicated that about 53% of the patients (43/81) experienced RVVC. Candida albicans and C. glabrata constituted approximately 90% of the yeast isolates (72 patients). Except for one FLZT C. tropicalis isolate, FLZR and FLZT phenotypes were detected exclusively in patients with RVVC; among them, 27.9% (12/43) harbored FLZR strains. C. albicans constituted 81.2% of FLZR (13/16) and 100% of the FLZT (13/13) isolates, respectively, and both phenotypes were likely responsible for FTF, which was also observed among patients with RVVC infected with fluconazole-susceptible isolates. Thus, FTF could be due to host-, drug-, and pathogen-related characteristics. Our study indicates that FLZT and FLZR isolates may arise following the exposure to over-the-counter (OTC) topical azole (clotrimazole) and that both phenotypes can cause FTF. Therefore, the widespread use of OTC azoles can influence fluconazole therapeutic success, highlighting the necessity of controlling the use of weak topical antifungals among Iranian women. [ABSTRACT FROM AUTHOR]

Rezafungin is a novel echinocandin drug being developed as a first-line option for treatment and prevention of invasive fungal infections. As a result of a structural modification in its parent molecule anidulafungin, rezafungin has acquired unique chemical stability conferring prolonged pharmacokinetics, as well as an administration advantage in the clinical setting compared to other drugs in the same class. Rezafungin displays potent in vitro activity against a wide spectrum of fungal pathogens, which is reflected in robust in vivo efficacy and/or pharmacodynamic studies using various animal models as well as in promising clinical trials data. This review describes in vivo characterization of rezafungin using animal models, current status of clinical development and key findings from these studies. [ABSTRACT FROM AUTHOR]

The recent global pandemic of COVID-19 has predisposed a relatively high number of patients to acute respiratory distress syndrome (ARDS), which carries a risk of developing super-infections. Candida species are major constituents of the human mycobiome and the main cause of invasive fungal infections, with a high mortality rate. Invasive yeast infections (IYIs) are increasingly recognized as s complication of severe COVID-19. Despite the marked immune dysregulation in COVID-19, no prominent defects have been reported in immune cells that are critically required for immunity to Candida. This suggests that relevant clinical factors, including prolonged ICU stays, central venous catheters, and broad-spectrum antibiotic use, may be key factors causing COVID-19 patients to develop IYIs. Although data on the comparative performance of diagnostic tools are often lacking in COVID-19 patients, a combination of serological and molecular techniques may present a promising option for the identification of IYIs. Clinical awareness and screening are needed, as IYIs are difficult to diagnose, particularly in the setting of severe COVID-19. Echinocandins and azoles are the primary antifungal used to treat IYIs, yet the therapeutic failures exerted by multidrug-resistant Candida spp. such as C. auris and C. glabrata call for the development of new antifungal drugs with novel mechanisms of action. [ABSTRACT FROM AUTHOR]

Human fungal pathogens are attributable to a significant economic burden and mortality worldwide. Antifungal treatments, although limited in number, play a pivotal role in decreasing mortality and morbidities posed by invasive fungal infections (IFIs). However, the recent emergence of multidrug-resistant Candida auris and Candida glabrata and acquiring invasive infections due to azole-resistant C. parapsilosis, C. tropicalis, and Aspergillus spp. in azole-naïve patients pose a serious health threat considering the limited number of systemic antifungals available to treat IFIs. Although advancing for major fungal pathogens, the understanding of fungal attributes contributing to antifungal resistance is just emerging for several clinically important MDR fungal pathogens. Further complicating the matter are the distinct differences in antifungal resistance mechanisms among various fungal species in which one or more mechanisms may contribute to the resistance phenotype. In this review, we attempt to summarize the burden of antifungal resistance for selected non-albicans Candida and clinically important Aspergillus species together with their phylogenetic placement on the tree of life. Moreover, we highlight the different molecular mechanisms between antifungal tolerance and resistance, and comprehensively discuss the molecular mechanisms of antifungal resistance in a species level. [ABSTRACT FROM AUTHOR]

Background Isavuconazole (ISA) is an attractive candidate for primary mold-active prophylaxis in high-risk patients with hematologic malignancies or hematopoietic cell transplant (HCT) recipients. However, data supporting the use of ISA for primary prophylaxis in these patients are lacking. Methods We conducted a retrospective review of breakthrough invasive fungal infections (bIFIs) among adult hematologic malignancy patients and HCT recipients who received ≥7 days of ISA primary prophylaxis between 1 September 2016 and 30 September 2018. The incidence of bIFIs in patients receiving ISA was compared to those receiving posaconazole (POS) and voriconazole (VOR) during the same time period. Results One hundred forty-five patients received 197 courses of ISA prophylaxis. Twelve bIFIs (Aspergillus fumigatus [5], Aspergillus species [2], Mucorales [2], Fusarium species [2], and Candida glabrata [1]) occurred, representing 8.3% of patients and 6.1% of courses, after a median duration of 14 days of ISA prophylaxis. All bIFIs occurred during periods of neutropenia. Seven patients (58.3%) died within 42 days of onset of bIFI. In addition, bIFIs complicated 10.2% of ISA, 4.1% of POS, and 1.1% of VOR courses among patients with de novo or relapsed/refractory acute myeloid leukemia during the study period, with invasive pulmonary aspergillosis (IPA) complicating 6.8% of ISA, 1.3% of POS, and zero VOR courses. Conclusions Although ISA has been approved for treatment of invasive Aspergillus and mucormycosis, we observed an increased rate of bIFI, notably IPA, using ISA for primary prophylaxis. These results support the need for further study to determine the role of ISA as primary prophylaxis. [ABSTRACT FROM AUTHOR]

CD101 is a novel echinocandin drug being developed to treat severe fungal infections including invasive candidiasis. We have performed a series of studies to evaluate the antifungal properties of CD101 against both echinocandin-susceptible and -resistant Candida strains. Antifungal susceptibility testing performed on a collection of 95 Candida strains including 30 caspofungin-resistant isolates containing fks mutations demonstrated comparable antifungal potency of CD101 relative to micafungin (MCF) across different Candida species. Comparable kinetic inhibition of glucan synthase activity was also observed for CD101 and MCF on both wild-type (WT) and resistant fks mutant Candida strains. Similarly, both drugs yielded nearly identical values for a mutant prevention concentration. In a murine model of invasive candidiasis, CD101 displayed better or at least comparable efficacy relative to MCF in treating WT or fks mutant Candida albicans. An exceptional long-lived pharmacokinetic profile was observed in mice following a single dose of CD101. Collectively, CD101 has great potential not only in treating invasive Candida infections but also in preventing emergence of resistance to currently approved echinocandin drugs. [ABSTRACT FROM AUTHOR]

Invasive fungal infections are an important infection concern for patients with underlying immunosuppression. Antifungal therapy is a critical component of patient care, but therapeutic choices are limited due to few drug classes. Antifungal resistance, especially among Candida species, aggravates the problem. The echinocandin drugs (micafungin, anidulafungin, and caspofungin) are the preferred choice to treat a range of candidiasis. They target the fungal-specific enzyme glucan synthase, which is responsible for the biosynthesis of a major cell wall polymer. Therapeutic failure involves acquisition of resistance, although it is a rare event among most Candida species. However, in some settings, higher-level resistance has been reported among Candida glabrata, which is also frequently resistant to azole drugs, resulting in difficult-to-treat multidrug-resistant strains. The mechanism of echinocandin resistance involves amino acid changes in “hot spot” regions of FKS-encoded subunits of glucan synthase, which decreases the sensitivity of enzyme to drug, resulting in higher minimum inhibitory concentration values. The cellular processes promoting the formation of resistant FKS strains involve complex stress response pathways that yield a variety of adaptive compensatory genetic responses. Standardized broth microdilution techniques can be used to distinguish FKS mutant strains from wild type, but testing C. glabrata with caspofungin should be approached cautiously. Finally, clinical factors that promote echinocandin resistance include prophylaxis, host reservoirs including biofilms in the gastrointestinal tract, and intra-abdominal infections. An understanding of clinical and molecular factors that promote echinocandin resistance is critical to develop better diagnostic tools and therapeutic strategies to overcome resistance. [ABSTRACT FROM AUTHOR]

The article offers information on the stress response and emergence of multidrug resistance in fungal infections. Topics discussed include treatment of Candida infections with azole antifungal agents, role of cellular stress responses in genetic instability and drug tolerance, and promotion of genomic rearrangements and mutagenic lesions.

Ergosterol is an important constituent of fungal membranes. Azoles inhibit ergosterol biosynthesis, although the cellular basis for their antifungal activity is not understood. We used multiple approaches to demonstrate a critical requirement for ergosterol in vacuolar H+-ATPase function, which is known to be essential for fungal virulence. Ergosterol biosynthesis mutants of S. cerevisiae failed to acidify the vacuole and exhibited multiple vma2 phenotypes. Extraction of ergosterol from vacuolar membranes also inactivated V-ATPase without disrupting membrane association of its subdomains. In both S. cerevisiae and the fungal pathogen C. albicans, fluconazole impaired vacuolar acidification, whereas concomitant ergosterol feeding restored V-ATPase function and cell growth. Furthermore, fluconazole exacerbated cytosolic Ca2+ and H+ surges triggered by the antimicrobial agent amiodarone, and impaired Ca2+ sequestration in purified vacuolar vesicles. These findings provide a mechanistic basis for the synergy between azoles and amiodarone observed in vitro. Moreover, we show the clinical potential of this synergy in treatment of systemic fungal infections using a murine model of Candidiasis. In summary, we demonstrate a new regulatory component in fungal V-ATPase function, a novel role for ergosterol in vacuolar ion homeostasis, a plausible cellular mechanism for azole toxicity in fungi, and preliminary in vivo evidence for synergism between two antifungal agents. New insights into the cellular basis of azole toxicity in fungi may broaden therapeutic regimens for patient populations afflicted with systemic fungal infections. [ABSTRACT FROM AUTHOR]

Abstract: Invasive fungal infections cause morbidity and mortality in severely ill patients, and limited drug classes restrict treatment choices. The echinocandin drugs are the first new class of antifungal compounds that target the fungal cell wall by blocking β-1,3-d-glucan synthase. Elevated MIC values with occasional treatment failure have been reported for strains of Candida. Yet, an uncertain correlation exists between clinical failure and elevated MIC values for the echinocandin drugs. Fungi display several adaptive physiological mechanisms that result in elevated MIC values. However, resistance to echinocandin drugs among clinical isolates is associated with amino acid substitutions in two “hot-spot” regions of Fks1, the major subunit of glucan synthase. The mutations, yielding highly elevated MIC values, are genetically dominant and confer cross-resistance to all echinocandin drugs. Prominent Fks1 mutations decrease the sensitivity of glucan synthase for drug by 1000-fold or more, and strains harboring such mutations may require a concomitant increase in drug to reduce fungal organ burdens in animal infection models. The Fks1-mediated resistance mechanism is conserved in a wide variety of Candida spp. and can account for intrinsic reduced susceptibility of certain species. Fks1 mutations confer resistance in both yeasts and moulds suggesting that this mechanism is pervasive in the fungal kingdom. [Copyright &y& Elsevier]

The high clinical mortality and economic burden posed by invasive fungal infections (IFIs), along with significant agricultural crop loss caused by various fungal species, has resulted in the widespread use of antifungal agents. Selective drug pressure, fungal attributes, and host- and drug-related factors have counteracted the efficacy of the limited systemic antifungal drugs and changed the epidemiological landscape of IFIs. Species belonging to Candida, Aspergillus, Cryptococcus, and Pneumocystis are among the fungal pathogens showing notable rates of antifungal resistance. Drug-resistant fungi from the environment are increasingly identified in clinical settings. Furthermore, we have a limited understanding of drug class-specific resistance mechanisms in emerging Candida species. The establishment of antifungal stewardship programs in both clinical and agricultural fields and the inclusion of species identification, antifungal susceptibility testing, and therapeutic drug monitoring practices in the clinic can minimize the emergence of drug-resistant fungi. New antifungal drugs featuring promising therapeutic profiles have great promise to treat drug-resistant fungi in the clinical setting. Mitigating antifungal tolerance, a prelude to the emergence of resistance, also requires the development of effective and fungal-specific adjuvants to be used in combination with systemic antifungals. [ABSTRACT FROM AUTHOR]

Abstract: Azole resistance in Aspergillus spp. is unusual. We report a patient who received long-term treatment with itraconazole and voriconazole for bilateral chronic cavitary aspergillosis with aspergillomas whose isolates of Aspergillus fumigatus developed simultaneous resistance to itraconazole and voriconazole. A novel mutation (G138C) in the target gene (cyp51A) encoding 14α-demethylase was detected. The patient had some response to intravenous caspofungin, which he received six times weekly, without the development of resistance over 9 months. [Copyright &y& Elsevier]