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BACKGROUND: Rezafungin, a novel, once-weekly echinocandin for the treatment of candidemia and/or invasive candidiasis (IC) was noninferior to caspofungin for day 30 all-cause mortality (ACM) and day 14 global cure in the phase 3 ReSTORE trial (NCT03667690). We conducted preplanned subgroup analyses for patients with a positive culture close to randomization in ReSTORE. METHODS: ReSTORE was a multicenter, double-blind, double-dummy, randomized trial in patients aged ≥18 years with candidemia and/or IC treated with once-weekly intravenous rezafungin (400 mg/200 mg) or once-daily intravenous caspofungin (70 mg/50 mg). This analysis comprised patients with a positive blood culture drawn between 12 hours before and 72 hours after randomization or a positive culture from another normally sterile site sampled between 48 hours before and 72 hours after randomization. Efficacy endpoints included day 30 ACM, day 14 global cure rate, and day 5 and 14 mycological response. Adverse events were evaluated. RESULTS: This analysis included 38 patients randomized to rezafungin and 46 to caspofungin. In the rezafungin and caspofungin groups, respectively, day 30 ACM was 26.3% and 21.7% (between-group difference [95% confidence interval], 4.6% [-13.7%, 23.5%]), day 14 global response was 55.3% and 50.0% (between-group difference, 5.3% [-16.1%, 26.0%]), and day 5 mycological eradication was 71.1% and 50.0% (between-group difference, 21.1% [-0.2%, 40.2%]). Safety was comparable between treatments. CONCLUSIONS: These findings support the efficacy and safety of rezafungin compared with caspofungin for the treatment of candidemia and/or IC in patients with a positive culture close to randomization, with potential early treatment benefits for rezafungin.

Rezafungin is a long-acting, intravenously administered echinocandin for the treatment of candidemia and invasive candidiasis (IC). Non-inferiority of rezafungin vs caspofungin for the treatment of adults with candidemia and/or IC was demonstrated in the Phase 3 ReSTORE study based on the primary endpoints of day 14 global cure and 30-day all-cause mortality. Here, an analysis of ReSTORE data evaluating efficacy outcomes by baseline Candida species is described. Susceptibility testing was performed for Candida species using the Clinical and Laboratory Standards Institute reference broth microdilution method. There were 93 patients in the modified intent-to-treat population who received rezafungin; 94 received caspofungin. Baseline Candida species distribution was similar in the two treatment groups; C. albicans (occurring in 41.9% and 42.6% of patients in the rezafungin and caspofungin groups, respectively), C. glabrata (25.8% and 26.6%), and C. tropicalis (21.5% and 18.1%) were the most common pathogens. Rates of global cure and mycological eradication at day 14 and day 30 all-cause mortality by Candida species were comparable in the rezafungin and caspofungin treatment groups and did not appear to be impacted by minimal inhibitory concentration (MIC) values for either rezafungin or caspofungin. Two patients had baseline isolates with non-susceptible MIC values (both in the rezafungin group: one non-susceptible to rezafungin and one to caspofungin, classified as intermediate); both were candidemia-only patients in whom rezafungin treatment was successful based on the day 30 all-cause mortality endpoint. This analysis of ReSTORE demonstrated the efficacy of rezafungin for candidemia and IC in patients infected with a variety of Candida species.

Candida parapsilosis is a common cause of non-albicans Candida species causing candidemia, particularly invasive candidiasis. This study aimed to characterize candidemia due to the C. parapsilosis complex with serial episodes, including clinical and mycological features. Methods: Blood isolates of the C. parapsilosis complex were collected from February 2019 to January 2023 at a tertiary Korean hospital. Species identification was performed using Vitek 2 or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and antifungal susceptibility testing was performed using the Sensititre YeastOne® system. Clinical information was collected, and characteristics were analyzed according to single or serial isolates. Results: A total of 586 blood isolates of the C. parapsilosis complex were recovered from 68 candidemia patients during the study period. Of them, only the first isolate per patient was investigated. The only two isolates were resistant to fluconazole and no isolate was resistant to echinocandins, amphotericin B, or 5-FC. A single episode of candidemia occurred in 35 patients, while serial episodes occurred in 33 patients. Underlying liver diseases, use of vasopressors, ICU admission, severe sepsis, and CVC use were more frequent in patients with serial episodes. There was no significant difference in the median MIC values of antifungal agents or the use of azoles or amphotericin B between single and serial episodes. However, patients with serial episodes more frequently received echinocandin therapy. Overall, there was no significant difference in the 30-day mortality rate between patients with single and serial episodes. Conclusion: Our data indicate that several factors related to the underlying conditions of the patients are associated with C. parapsilosis candidemia with serial episodes, rather than the characteristics of Candida itself. [ABSTRACT FROM AUTHOR]

Introduction: Drug resistance to echinocandins, first-line drugs used to treat Candida auris infection, is rapidly emerging. However, the accumulation of mutations in genes other than FKS1 (before an isolate develops to resistance via FKS1 mutations), remains poorly understood. Methods: Four clinical cases and 29 isolates associated with the incremental process of echinocandin resistance were collected and analyzed using antifungal drug susceptibility testing and genome sequencing to assess the evolution of echinocandin resistance. Findings: Six echinocandin minimum inhibitory concentration (MIC)-elevated C. auris strains and seven resistant strains were isolated from the urinary system of patients receiving echinocandin treatment. Meanwhile, phylogenetic analyses illustrated that the echinocandin-resistant strains were closely related to other strains in the same patient. Genomic data revealed that the echinocandin-resistant strains had FKS1 mutations. Furthermore, three categories (ECN-S/E/R) of non-synonymous mutant SNP genes (such as RBR3, IFF6, MKC1, MPH1, RAD2, and MYO1) in C. auris appeared to be associated with the three-stage-evolutionary model of echinocandin resistance in C. glabrata: cell wall stress, drug adaptation, and genetic escape (FKS mutation). Interpretation: Echinocandin-resistant C. auris undergoes spatial and temporal phase changes closely related to echinocandin exposure, particularly in the urinary system. These findings suggest that FKS1 mutations mediate an evolutionary accumulation of echinocandin resistance followed by modulation of chromosome remodelling and DNA repair processes that ultimately lead to FKS1 hot spot mutations and the development of drug resistance. This study provides an in-depth exploration of the molecular pathways involved in the evolution of Candida auris echinocandin resistance.

Objectives: To evaluate the clinical outcomes of anidulafungin for candidemia treatment in critically ill patients with obesity. Methods: A multicenter, retrospective cohort study was conducted in Saudi Arabia for critically ill adults with candidemia who received anidulafungin. Patients with obesity have a body mass index ≥30 kg/m2. The primary outcome was the clinical cure rate. Results: A total of 146 patients were included, 64 of whom were obese. There were no statistically significant differences in the clinical cure rate (P = 0.63), microbiological cure rate (P = 0.27), or the median time for a clinical cure (P = 0.13) for patients with obesity compared to non-obese patients. The median time for a microbiological cure was longer in non-obese patients than in patients with obesity (P = 0.04). The median hospital length of stay and the median mechanical ventilation durations were numerically longer in patients with obesity. Conclusions: Clinical and microbiological cure rates and time for clinical cure were statistically similar for both groups. Considering the study's limitations (especially with a small sample size), it is uncertain if patients with obesity have similar effectiveness to non-obese patients. Future studies with larger sample sizes are warranted to evaluate if obesity negatively impacts anidulafungin's clinical outcomes for candidemia.

ABSTRACT The minimum inhibitory concentration (MIC) of echinocandins against Aspergillus spp. does not represent the actual inhibition threshold of echinocandins. Therefore, the recommended method to evaluate their activity is determining the minimum effective concentration (MEC) in broth microdilution, a method that is less common in clinical settings. This study aimed to assess a user-friendly commercial method, Sensititre YeastOne (SYO), to determine the effectiveness of echinocandins (caspofungin, anidulafungin and micafungin) against Aspergillus spp. Echinocandins MEC was determined against 23 isolates of Aspergillus spp. using SYO and the reference Clinical and Laboratory Standards Institute (CLSI) method. MECs were read with an inverted microscope and a reading mirror. Essential agreement (EA) between the tested methods was defined as a ±twofold dilution difference. There was a high EA (91%–100%) between the reference method and SYO in determining echinocandins MEC against Aspergillus isolates using inverted microscopy. A high EA was also observed between SYO MEC determined by inverted microscopy and a reading mirror, but different incubation times were required. SYO is a reliable, simple method for determining the MEC of echinocandins against Aspergillus isolates, preferably with an inverted microscope, and can be easily used in clinical laboratories when echinocandin susceptibility testing is required.IMPORTANCEUsing a commercial method such as Sensititre YeastOne (SYO) to determine the minimum effective concentration (MEC) of echinocandins against Aspergillus spp. has been shown to be a reliable alternative to the Clinical and Laboratory Standards Institute (CLSI) reference method. This makes it more suitable for high-volume clinical laboratories. SYO provides accurate results comparable to the standard method and could potentially improve patient care by guiding more optimal antifungal treatment choices for patients with Aspergillus infections.

ABSTRACT: Objectives: This study aimed to identify the resistance mechanisms to micafungin and fluconazole in a clinical isolate of Candida glabrata. Methods: The isolate was whole-genome sequenced to identify amino acid changes in key proteins involved in antifungal resistance, and the isolate was further characterised by pathogenicity-related phenotypic assays that supported the sequencing results. Results: Amino acid substitutions were detected in 8 of 17 protein candidates. Many of these substitutions were novel, including in CHS3, CHS3B, and KRE5, which are involved in the development of micafungin resistance. Regarding fluconazole resistance, overexpression of efflux pumps was observed. Our isolate did not exhibit an increased virulence potential compared with the control strain; however, a significant increase in chitin content and potential to resist the cell surface disruptant sodium dodecyl sulphate was observed. Conclusions: This clinical Candida glabrata isolate experienced a change in cell wall architecture, which correlates with the development of micafungin resistance.

Background: Although neurotoxicity is a major adverse event associated with busulfan, little information is available regarding the association between drug interactions and neurological symptoms during busulfan‐based regimens. This study evaluated the association between prophylactic echinocandins and neurological complications in patients receiving busulfan‐containing conditioning regimens for stem cell transplantation. Methods: We retrospectively included consecutive patients who administered intravenous busulfan as a conditioning regimen at our facility between 2007 and 2022. Prophylactic echinocandin use was defined as the use of an echinocandin antifungal drug to prevent invasive fungal disease in SCT recipients. The primary outcome was the incidence of neurological complications within 7 days of busulfan initiation and was compared between the echinocandin group (patients received prophylactic echinocandin) and nonechinocandin group (patients received prophylactic antifungal drugs other than echinocandin and those without antifungal prophylaxis). Results: Among the 59 patients included in this study, the incidence of neurological complications in the echinocandin (n = 26) and nonechinocandin groups (n = 33) was 30.8% and 63.6%, respectively. We observed a negative association between prophylactic echinocandin use and the development of neurological complications after adjusting for the propensity score for receiving prophylactic echinocandins (adjusted odds ratio 0.294, 95% confidence interval 0.090 to 0.959). We observed a lower incidence of neurological complications in the echinocandin group than in the nonechinocandin group. Conclusion: Our results suggested that the choice of antifungal prophylaxis is associated with busulfan neurotoxicity. [ABSTRACT FROM AUTHOR]

Despite advancements, invasive fungal infections (IFI) still carry high mortality rates, often exceeding 30%. The challenges in diagnosis, coupled with limited effective antifungal options, make managing IFIs complex. Antifungal drugs are essential for IFI management, but their efficacy can be diminished by drug–drug interactions and pharmacokinetic variability. Therapeutic Drug Monitoring (TDM), especially in the context of triazole use, has emerged as a valuable strategy to optimize antifungal therapy. This review provides current evidence regarding the potential benefits of TDM in IFI management. It discusses how TDM can enhance treatment response, safety, and address altered pharmacokinetics in specific patient populations. TDM plays a crucial role in achieving optimal therapeutic outcomes in IFI management, particularly for certain antifungal agents. Preclinical studies consistently show a link between therapeutic drug levels and antifungal efficacy. However, clinical research in mycology faces challenges due to patient heterogeneity and the diversity of fungal infections. TDM's potential advantages in guiding Echinocandin therapy for critically ill patients warrant further investigation. Additionally, for drugs like Posaconazole, assessing whether serum levels or alternative markers like saliva offer the best measure of efficacy is an intriguing question. [ABSTRACT FROM AUTHOR]

Background Scant real-world outcomes data are available among hospitalized patients with candidemia (C) or invasive candidiasis without candidemia (IC) who were treated with an echinocandin and few have assessed if there is an opportunity to accelerate the transition of their care to the outpatient setting. This study described the outcomes associated with echinocandin therapy for C/IC and determined the proportion of patients on an echinocandin at hospital discharge (HD) who were potentially eligible for an earlier HD. Methods A retrospective, multicenter observational study was performed using the PINC AI Healthcare Database (January 2016–April 2019) of hospitalized adult patients with C/IC who received ≥3 days of an echinocandin. Outcomes included post–index culture hospital costs and discharge location. Patients were considered potentially dischargeable earlier than actual HD day if they met the following 3 criteria prior to their actual HD day: resided on a non–intensive care unit hospital ward until HD, received any oral medications, and had no diagnostic/therapeutic interventions. Results A total of 1865 patients met study criteria. Mean (standard deviation) post–index culture hospital costs for patients with C and IC were 50 196 (64 630) US dollars and 61 551 (73 080) US dollars, respectively. Of the 1008 patients on an echinocandin near HD and discharged alive, 432 (42.9%) were potentially dischargeable prior to their actual hospital day. Most patients (35.8%) were discharged to a long-term care facility. Conclusions The findings suggest that a high proportion of hospitalized C/IC patients receiving an echinocandin near the time of HD were potentially dischargeable earlier. Like all studies of this nature, the findings need to be prospectively validated. [ABSTRACT FROM AUTHOR]

ABSTRACTRecent epidemiological studies documented an alarming increase in the prevalence of echinocandin-resistant (ECR) Candida glabrata blood isolates. ECR isolates are known to arise from a minor subpopulation of a clonal population, termed echinocandin persisters. Although it is believed that isolates with a higher echinocandin persistence (ECP) are more likely to develop ECR, the implication of ECP needs to be better understood. Moreover, replacing laborious and time-consuming traditional approaches to determine ECP levels with rapid, convenient, and reliable tools is imperative to advance our understanding of this emerging concept in clinical practice. Herein, using extensive ex vivo and in vivo systemic infection models, we showed that high ECP isolates are less effectively cleared by micafungin treatment and exclusively give rise to ECR colonies. Additionally, we developed a flow cytometry-based tool that takes advantage of a SYTOX-based assay for the stratification of ECP levels. Once challenged with various collections of echinocandin-susceptible blood isolates, our assay reliably differentiated ECP levels in vitro and predicted ECP levels in real time under ex vivo and in vivo conditions when compared to traditional methods relying on colony-forming unit counting. Given the high and low ECP predictive values of 92.3% and 82.3%, respectively, our assay showed a high agreement with traditional approach. Collectively, our study supports the concept of ECP level determination in clinical settings and provides a robust tool scalable for high-throughput settings. Application of this tool facilitates the interrogation of mutant and drug libraries to further our understanding of persister biology and designing anti-persister therapeutics.IMPORTANCECandida glabrata is a prevalent fungal pathogen able to replicate inside macrophages and rapidly develop resistance against frontline antifungal echinocandins. Multiple studies have shown that echinocandin resistance is fueled by the survival of a small subpopulation of susceptible cells surviving lethal concentrations of echinocandins. Importantly, bacterial pathogens that exhibit high antibiotic persistence also impose a high burden and generate more antibiotic-resistant colonies. Nonetheless, the implications of echinocandin persistence (ECP) among the clinical isolates of C. glabrata have not been defined. Additionally, ECP level determination relies on a laborious and time-consuming method, which is prone to high variation. By exploiting in vivo systemic infection and ex vivo models, we showed that C. glabrata isolates with a higher ECP are associated with a higher burden and more likely develop echinocandin resistance upon micafungin treatment. Additionally, we developed an assay that reliably determines ECP levels in real time. Therefore, our study identified C. glabrata isolates displaying high ECP levels as important entities and provided a reliable and convenient tool for measuring echinocandin persistence, which is extendable to other fungal and bacterial pathogens.

Candida parapsilosis is a common cause of non-albicans Candida species causing candidemia, particularly invasive candidiasis. This study aimed to characterize candidemia due to the C. parapsilosis complex with serial episodes, including clinical and mycological features. Methods: Blood isolates of the C. parapsilosis complex were collected from February 2019 to January 2023 at a tertiary Korean hospital. Species identification was performed using Vitek 2 or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and antifungal susceptibility testing was performed using the Sensititre YeastOne® system. Clinical information was collected, and characteristics were analyzed according to single or serial isolates. Results: A total of 586 blood isolates of the C. parapsilosis complex were recovered from 68 candidemia patients during the study period. Of them, only the first isolate per patient was investigated. The only two isolates were resistant to fluconazole and no isolate was resistant to echinocandins, amphotericin B, or 5-FC. A single episode of candidemia occurred in 35 patients, while serial episodes occurred in 33 patients. Underlying liver diseases, use of vasopressors, ICU admission, severe sepsis, and CVC use were more frequent in patients with serial episodes. There was no significant difference in the median MIC values of antifungal agents or the use of azoles or amphotericin B between single and serial episodes. However, patients with serial episodes more frequently received echinocandin therapy. Overall, there was no significant difference in the 30-day mortality rate between patients with single and serial episodes. Conclusion: Our data indicate that several factors related to the underlying conditions of the patients are associated with C. parapsilosis candidemia with serial episodes, rather than the characteristics of Candida itself.

ABSTRACTAspergillus fumigatus is a major invasive mold pathogen and the most frequent etiologic agent of invasive aspergillosis. The currently available treatments for invasive aspergillosis are limited in both number and efficacy. Our recent work has uncovered that the β-glucan synthase inhibitors, the echinocandins, are fungicidal against strains of A. fumigatus with defects in septation initiation network (SIN) kinase activity. These drugs are known to be fungistatic against strains with normal septation. Surprisingly, SIN kinase mutant strains also failed to invade lung tissue and were significantly less virulent in immunosuppressed mouse models. Inhibiting septation in filamentous fungi is therefore an exciting therapeutic prospect to both reduce virulence and improve current antifungal therapy. However, the SIN remains understudied in pathogenic fungi. To address this knowledge gap, we characterized the putative regulatory components of the A. fumigatus SIN. These included the GTPase, SpgA, it’s two-component GTPase-activating protein, ByrA/BubA, and the kinase activators, SepM and MobA. Deletion of spgA, byrA, or bubA resulted in no overt septation or echinocandin susceptibility phenotypes. In contrast, our data show that deletion of sepM or mobA largely phenocopies disruption of their SIN kinase binding partners, sepL and sidB, respectively. Reduced septum formation, echinocandin hypersusceptibility, and reduced virulence were generated by loss of either gene. These findings provide strong supporting evidence that septa are essential not only for withstanding the cell wall disrupting effects of echinocandins but are also critical for the establishment of invasive disease. Therefore, pharmacological SIN inhibition may be an exciting strategy for future antifungal drug development.IMPORTANCESepta are important structural determinants of echinocandin susceptibility and tissue invasive growth for the ubiquitous fungal pathogen Aspergillus fumigatus. Components of the septation machinery therefore represent promising novel antifungal targets to improve echinocandin activity and reduce virulence. However, little is known about septation regulation in A. fumigatus. Here, we characterize the predicted regulatory components of the A. fumigatus septation initiation network. We show that the kinase activators SepM and MobA are vital for proper septation and echinocandin resistance, with MobA playing an essential role. Null mutants of mobA displayed significantly reduced virulence in a mouse model, underscoring the importance of this pathway for A. fumigatus pathogenesis.

Candida auris is an emerging, multidrug‐resistant yeast, causing outbreaks in healthcare facilities. Echinocandins are the antifungal drugs of choice to treat candidiasis, as they cause few side effects and resistance is rarely found. Previously, immunocompromised patients from Kuwait with C. auris colonisation or infection were treated with echinocandins, and within days to months, resistance was reported in urine isolates. To determine whether the development of echinocandin resistance was due to independent introductions of resistant strains or resulted from intra‐patient resistance development, whole genome sequencing (WGS) single‐nucleotide polymorphism (SNP) analysis was performed on susceptible (n = 26) and echinocandin‐resistant (n = 6) isolates from seven patients. WGS SNP analysis identified three distinct clusters differing 17–127 SNPs from two patients, and the remaining isolates from five patients, respectively. Sequential isolates within patients had a maximum of 11 SNP differences over a time period of 1–10 months. The majority of isolates with reduced susceptibility displayed unique FKS1 substitutions including a novel FKS1M690V substitution, and nearly all were genetically related, ranging from only three to six SNP differences compared to susceptible isolates from the same patient. Resistant isolates from three patients shared the common FKS1S639F substitution; however, WGS analysis did not suggest a common source. These findings strongly indicate that echinocandin resistance is induced during antifungal treatment. Future studies should determine whether such echinocandin‐resistant strains are capable of long‐term colonisation, cause subsequent breakthrough candidiasis, have a propensity to cross‐infect other patients, or remain viable for longer time periods in the hospital environment. [ABSTRACT FROM AUTHOR]

BackgroundCandida empyema thoracis (pleural empyema) is an uncommon manifestation of invasive candidiasis, for which optimal treatment is unknown.MethodsThis is a retrospective study of patients with Candida empyema at 2 academic medical centers from September 2006 through December 2015.ResultsWe identified 81 patients with Candida empyema (median age, 62 years; 68% men). Sixty-five percent of patients underwent surgery or an invasive intervention of the thorax or abdomen within the preceding 90 days. Candida empyema originated from intrathoracic (51%) or intra-abdominal sources (20%), spontaneous esophageal rupture (12%), pleural space manipulation (9%), and pneumonia (6%). Eighty-four percent and 41% of patients were intensive care unit residents and in septic shock, respectively, within 3 days of diagnosis. Causative species were Candida albicans (65%), Candida glabrata (26%), Candida parapsilosis (11%), Candida tropicalis (4%), Candida krusei (2%), and Candida dubliniensis (1%). Bacteria were recovered from empyemas in 51% of patients. Concurrent candidemia was diagnosed in only 2% of patients. Management included pleural drainage and antifungal treatment in 98% and 85% of patients, respectively. Mortality at 100 days was 27%, and it was highest for cases stemming from esophageal rupture (67%). Spontaneous esophageal rupture and echinocandin rather than fluconazole treatment were independent risk factors for death at 100 days (P = .003 and .04, respectively); receipt of antifungal therapy was an independent predictor of survival (P = .046).ConclusionsCandida empyema mortality rates were lower than reported previously. Optimal management included pleural drainage and fluconazole treatment. Superiority of fluconazole over echinocandins against Candida empyema needs to be confirmed in future studies.

Candida auris is a multidrug-resistant fungal pathogen that presents a serious threat to global human health. Since the first reported case in 2009 in Japan, C. auris infections have been reported in more than 40 countries, with mortality rates between 30% and 60%. In addition, C. auris has the potential to cause outbreaks in health care settings, especially in nursing homes for elderly patients, owing to its efficient transmission via skin-to-skin contact. Most importantly, C. auris is the first fungal pathogen to show pronounced and sometimes untreatable clinical drug resistance to all known antifungal classes, including azoles, amphotericin B, and echinocandins. In this review, we explore the causes of the rapid spread of C. auris. We also highlight its genome organization and drug resistance mechanisms and propose future research directions that should be undertaken to curb the spread of this multidrug-resistant pathogen. [ABSTRACT FROM AUTHOR]

Invasive Candida Infections (ICIs) have undergone a series of significant epidemiological, pathophysiological, and clinical changes during the last decades, with a shift toward non-albicans species, an increase in the rate of exogenous infections and clinical manifestations ranging from candidemia to an array of highly invasive and life-threatening clinical syndromes. The long-acting echinocandin rezafungin exhibits potent in-vitro activity against most wild-type and azole-resistant Candida spp. including C.auris. The following topics regarding candidemia only and ICIs were reviewed and addressed: i) pathogenesis; ii) epidemiology and temporal evolution of Candida species; iii) clinical approach; iv) potential role of the novel long-acting rezafungin in the treatment of ICIs. Authors' expert opinion focused on considering the potential role of rezafungin in the evolving context of ICIs. Rezafungin, which combines a potent in-vitro activity against Candida species, including azole-resistant strains and C.auris, with a low likelihood of drug–drug interactions and a good safety profile, may revolutionize the treatment of candidemia/ICI. Indeed, it may shorten the length of hospital stays when clinical conditions allow and extend outpatient access to treatment of invasive candidiasis, especially when prolonged treatment duration is expected. [ABSTRACT FROM AUTHOR]

With the increasing proportion of Candida glabrata in patients with candidiasis, C. glabrata has become one of the most common pathogenic Candida in clinical practice. There are limited types of antifungal drugs, and the consequent problem of drug resistance is severely increasing, which brings difficulties to clinical treatment. The resistance mechanisms of C. glabrata to azoles, echinocandins and polyenes were reviewed in this paper. [ABSTRACT FROM AUTHOR]

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 Background Invasive candidiasis and/or candidemia (IC/C) is a common fungal infection leading to significant health and economic losses worldwide. Caspofungin was shown to be more effective than fluconazole in treating inpatients with IC/C. However, cost-effectiveness of caspofungin for treating IC/C in Ethiopia remains unknown. We aimed to assess the cost-utility of caspofungin compared to fluconazole-initiated therapies as primary treatment of IC/C in Ethiopia. Methods A Markov cohort model was developed to compare the cost-utility of caspofungin versus fluconazole antifungal agents as first-line treatment for adult inpatients with IC/C from the Ethiopian health system perspective. Treatment outcome was categorized as either a clinical success or failure, with clinical failure being switched to a different antifungal medication. Liposomal amphotericin B (L-AmB) was used as a rescue agent for patients who had failed caspofungin treatment, while caspofungin or L-AmB were used for patients who had failed fluconazole treatment. Primary outcomes were expected quality-adjusted life years (QALYs), costs (US$2021), and the incremental cost-utility ratio (ICUR). These QALYs and costs were discounted at 3% annually. Cost data was obtained from Addis Ababa hospitals while locally unavailable data were derived from the literature. Cost-effectiveness was assessed against the recommended threshold of 50% of Ethiopia’s gross domestic product/capita (i.e.,US$476). Deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of the findings. Results In the base-case analysis, treatment of IC/C with caspofungin as first-line treatment resulted in better health outcomes (12.86 QALYs) but higher costs (US$7,714) compared to fluconazole-initiated treatment followed by caspofungin (12.30 QALYs; US$3,217) or L-AmB (10.92 QALYs; US$2,781) as second-line treatment. Caspofungin as primary treatment for IC/C was not cost-effective when compared to fluconazole-initiated therapies. Fluconazole-initiated treatment followed by caspofungin was cost-effective for the treatment of IC/C compared to fluconazole with L-AmB as second-line treatment, at US$316/QALY gained. Our findings were sensitive to medication costs, drug effectiveness, infection recurrence, and infection-related mortality rates. At a cost-effectiveness threshold of US$476/QALY, treating IC/C patient with fluconazole-initiated treatment followed by caspofungin was more likely to be cost-effective in 67.2% of simulations. Conclusion Our study showed that the use of caspofungin as primary treatment for IC/C in Ethiopia was not cost-effective when compared with fluconazole-initiated treatment alternatives. The findings supported the use of fluconazole-initiated therapy with caspofungin as a second-line treatment for patients with IC/C in Ethiopia.

Breakthrough candidemia (BrC) is a significant problem in immunocompromised patients, particularly those with hematological disorders. To assess the characteristics of BrC in patients with hematologic disease treated with novel antifungal agents, we collected clinical and microbiological information on said patients from 2009 to 2020 in our institution. Forty cases were identified, of which 29 (72.5%) received hematopoietic stem cell transplant (HSCT)-related therapy. At BrC onset, the most administered class of antifungal agents were echinocandins, administered to 70% of patients. Candida guilliermondii complex was the most frequently isolated species (32.5%), followed by C. parapsilosis (30%). These two isolates were echinocandin-susceptible in vitro but had naturally occurring FKS gene polymorphisms that reduced echinocandin susceptibility. Frequent isolation of these echinocandin-reduced-susceptible strains in BrC may be associated with the widespread use of echinocandins. In this study, the 30-day crude mortality rate in the group receiving HSCT-related therapy was significantly higher than in the group not receiving it (55.2% versus 18.2%, P  = .0297). Most patients affected by C. guilliermondii complex BrC (92.3%) received HSCT-related therapy and had a 30-day mortality rate of 53.8%; despite treatment administration, 3 of 13 patients had persistent candidemia. Based on our results, C. guilliermondii complex BrC is a potentially fatal condition in patients receiving HSCT-related therapy with echinocandin administration. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the effectiveness of fluconazole and echinocandins in the treatment of candidemia caused by both fluconazole- and echinocandin-susceptible common Candida species. A retrospective study which enrolled adult candidemia patients ≥19 years diagnosed at a tertiary care hospital in the Republic of Korea from 2013 to 2018 was conducted. Common Candida species were defined as C. albicans, C. tropicalis, and C. parapsilosis. Cases of candidemia were excluded based on the following exclusion criteria: (1) candidemia showed resistance to either fluconazole or echinocandins, or (2) candidemia was caused by other Candida species than common Candida species. In order to compare the mortality rates between patients who receive fluconazole or echinocandins, the propensity scores on variables of baseline characteristics using the multivariate logistic regression analysis were employed to balance the antifungal treatment groups, and a Kaplan–Meier survival analysis was performed. Fluconazole and echinocandins were used in 40 patients and in 87 patients, respectively. The propensity score matching included 40 patients in each treatment group. After matching, the rates of 60-day mortality after candidemia were 30% in the fluconazole group and 42.5% in the echinocandins group, and a Kaplan–Meier survival analysis showed no significant difference between antifungal treatment groups, p = 0.187. A multivariable analysis demonstrated that septic shock was significantly associated with the 60-day mortality, whereas fluconazole antifungal treatment was not associated with an excess 60-day mortality. In conclusion, our study results suggest that fluconazole use in the treatment of candidemia caused by susceptible common Candida species may be not associated with increased 60-day mortality compared to echinocandins. [ABSTRACT FROM AUTHOR]

Outbreaks of invasive infections, with high mortality rates, caused by multidrug-resistant Candida auris have been reported worldwide. Although hotspot mutations in FKS1 are an established cause of echinocandin resistance, the actual contribution of these mutations to echinocandin resistance remains unknown. Here, we sequenced the FKS1 gene of a caspofungin-resistant clinical isolate (clade I) and identified a novel resistance mutation (G4061A inducing R1354H). We applied the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system to generate a recovered strain (H1354R) in which only this single nucleotide mutation was reverted to its wild-type sequence. We also generated mutant strains with only the R1354H mutation introduced into C. auris wild-type strains (clade I and II) and analyzed their antifungal susceptibility. Compared to their parental strains, the R1354H mutants exhibited a 4- to 16-fold increase in caspofungin minimum inhibitory concentration (MIC) while the H1354R reverted strain exhibited a 4-fold decrease in caspofungin MIC. In a mouse model of disseminated candidiasis, the in vivo therapeutic effect of caspofungin was more closely related to the FKS1 R1354H mutation and the virulence of the strain than its in vitro MIC. The CRISPR-Cas9 system could thus aid in elucidating the mechanism underlying drug resistance in C. auris. [ABSTRACT FROM AUTHOR]

Until recently, little was known about the susceptibility pattern of Cyberlindnera fabianii (Cy. fabianii) planktonic cells and biofilms regarding the most frequently administered systemic antifungals, despite the high mortality rate and its potential role in catheter-related infections. In the current study, the activity of fluconazole, amphotericin B and echinocandins (anidulafungin, caspofungin and micafungin) was determined against planktonic and sessile cells of Cy. fabianii clinical isolates (n = 8). Planktonic minimum inhibitory concentrations (MICs) ranged from 1 to 2, from 0.25 to 1, from 0.015 to 0.06, from 0.03 to 0.12 and from 0.25 to 0.5 mg/l for fluconazole, amphotericin B, anidulafungin, caspofungin and micafungin, respectively. One-day-old biofilms were highly resistant to fluconazole (MIC ranged from 512 to > 512) compared to planktonic counterparts, but not to amphotericin B (MIC ranged from 0.25 to 2 mg/l) and echinocandins (MIC ranged from 0.06 to 2 mg/l). Based on the calculated planktonic killing rates, the highest activity was observed in the case of anidulafungin (k values ranged from 0.37 to 2.09), while micafungin, caspofungin, amphotericin B and fluconazole exerted 0.46–1.47, 0.14–0.86, −0.03 to 2.08 and −0.15 to 0.09 killing rate value ranges, respectively. The obtained in vitro planktonic and sessile susceptibility patterns suggest that echinocandins and amphotericin B may be the most reliable treatment option for the treatment of Cy. fabianii infections. [ABSTRACT FROM AUTHOR]

Caspofungin is a drug that is used for fungal infections that are difficult to treat, including invasive aspergillosis and candidemia, as well as other forms of invasive candidiasis. The aim of this study was to incorporate Azone in a caspofungin gel (CPF-AZ-gel) and compare it with a promoter-free caspofungin gel (CPF-gel). An in vitro release study using a polytetrafluoroethylene membrane and ex vivo permeation into human skin was adopted. The tolerability properties were confirmed by histological analysis, and an evaluation of the biomechanical properties of the skin was undertaken. Antimicrobial efficacy was determined against Candida albicans, Candida glabrata, Candida parapsilosis, and Candida tropicalis. CPF-AZ-gel and CPF-gel, which had a homogeneous appearance, pseudoplastic behavior, and high spreadability, were obtained. The biopharmaceutical studies confirmed that caspofungin was released following a one-phase exponential association model and the CPF-AZ gel showed a higher release. The CPF-AZ gel showed higher retention of caspofungin in the skin while limiting the diffusion of the drug to the receptor fluid. Both formulations were well-tolerated in the histological sections, as well as after their topical application in the skin. These formulations inhibited the growth of C. glabrata, C. parapsilosis, and C. tropicalis, while C. albicans showed resistance. In summary, dermal treatment with caspofungin could be used as a promising therapy for cutaneous candidiasis in patients that are refractory or intolerant to conventional antifungal agents. [ABSTRACT FROM AUTHOR]

Echinocandin antifungal drugs, including micafungin, anidulafungin, and caspofungin, have been recently reported to exhibit antiviral effects against various viruses such as flavivirus, alphavirus, and coronavirus. In this study, we focused on micafungin and its derivatives and analyzed their antiviral activities against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The micafungin derivatives Mi-2 and Mi-5 showed higher antiviral activity than micafungin, with 50% maximal inhibitory concentration (IC50) of 5.25 and 6.51 µM, respectively (3.8 to 4.7-fold stronger than micafungin) and 50% cytotoxic concentration (CC50) of >64 µM in VeroE6/TMPRSS2 cells. This high anti-SARS-CoV-2 activity was also conserved in human lung epithelial cell-derived Calu-3 cells. Micafungin, Mi-2, and Mi-5 were suggested to inhibit the intracellular virus replication process; additionally, these compounds were active against SARS-CoV-2 variants, including Delta (AY.122, hCoV-19/Japan/TY11-927/2021), Omicron (BA.1.18, hCoV-19/Japan/TY38-873/2021), a variant resistant to remdesivir (R10/E796G C799F), and a variant resistant to casirivimab/imdevimab antibody cocktail (E406W); thus, our results provide basic evidence for the potential use of micafungin derivatives for developing antiviral agents. [ABSTRACT FROM AUTHOR]

During the past decade, Candida auris emerged across the world, causing nosocomial outbreaks in both pediatric and adult populations, particularly in intensive care settings. We reviewed the epidemiological trends and the clinical and microbiological characteristics of C. auris infection, focusing on the pediatric population. The review is based on 22 studies, which included about 250 pediatric patients with C. auris infection, across multiple countries; neonates and premature babies were the predominant pediatric patient group affected. The most common type of infection reported was bloodstream infection, which was associated with exceptionally high mortality rates. Antifungal treatment varied widely between the patients; this signifies a serious knowledge gap that should be addressed in future research. Advances in molecular diagnostic methods for rapid and accurate identification and for detection of resistance may prove especially valuable in future outbreak situations, as well as the development of investigational antifungals. However, the new reality of a highly resistant and difficult-to-treat pathogen calls for preparedness of all aspects of patient care. This spans from laboratory readiness, to raising awareness among epidemiologists and clinicians for global collaborative efforts to improve patient care and limit the spread of C. auris. [ABSTRACT FROM AUTHOR]

Background This study was performed to compare clinical characteristics and outcomes between patients with bloodstream infections (BSIs) caused by Candida auris and those with BSIs caused by other Candida spp. Methods A multicenter retrospective case-control study was performed at 3 hospitals in Brooklyn, New York, between 2016 and 2020. The analysis included patients ≥18 years of age who had a positive blood culture for any Candida spp. and were treated empirically with an echinocandin. The primary outcome was the 30-day mortality rate. Secondary outcomes were 14-day clinical failure, 90-day mortality rate, 60-day microbiologic recurrence, and in-hospital mortality rate. Results A total of 196 patients were included in the final analysis, including 83 patients with candidemia caused by C. auris. After inverse propensity adjustment, C. auris BSI was not associated with increased 30-day (adjusted odds ratio, 1.014 [95% confidence interval,.563–1.828]); P =.96) or 90-day (0.863 [.478–1.558]; P =.62) mortality rates. A higher risk for microbiologic recurrence within 60 days of completion of antifungal therapy was observed in patients with C. auris candidemia (adjusted odds ratio, 4.461 [95% confidence interval, 1.033–19.263]; P =.045). Conclusions C. auris BSIs are not associated with a higher mortality risk than BSIs caused by other Candida spp. The rate of microbiologic recurrence was higher in the C. auris group. [ABSTRACT FROM AUTHOR]

Delays in the treatment of proven invasive fungal disease have been shown to be harmful. However, empiric treatment for all patients at risk of infection has not demonstrated benefit. This study evaluates the effects of a micafungin stewardship initiative on the duration of therapy and clinical outcomes at the University of Mississippi Medical Center in Jackson, Mississippi. This single-center quasi-experiment evaluated patients who received micafungin. Adult inpatients who received at least one treatment dose of micafungin in the pre-intervention (1 October 2020 to 30 September 2021) or post-intervention (1 October 2021 to 30 April 2022) groups were included. Patients were placed on micafungin for prophylaxis and those who required definitive micafungin therapy were excluded. An algorithm was used to provide real-time recommendations in order to assess change in the treatment days of micafungin therapy. A total of 282 patients were included (141 pre-group versus 141 post-group). Over 80% of the patients included in the study were in an intensive care unit, and other baseline characteristics were similar. The median number of treatment days with micafungin was 4 [IQR 3-6] in the pre-group and 3 [IQR 2-6] in the post-group (p = 0.005). Other endpoints, such as time to discontinuation or de-escalation, hospital mortality, and hospital length of stay, were not significantly different between the groups. An antifungal stewardship initiative can be an effective way to decrease unnecessary empiric antifungal therapy for patients who are at risk of invasive fugal disease. [ABSTRACT FROM AUTHOR]

Background and Purpose: Vulvovaginal candidiasis (VVC) is considered the most common mucosal infection caused by Candida species. Azoles were considered the firstline treatment for VVC or recurrent vulvovaginal candidiasis (RVVC) in both healthy and immunocompromised populations. Recently, azole-resistant isolates, especially among non-albicans Candida samples have been encountered. This study aimed to evaluate the antifungal susceptibility profile of Candida spp. isolated from VVC or RVVC patients and assess the molecular resistance mechanism of Candida spp. to azole and echinocandin.Materials and Methods: Point mutation analysis was performed on the ERG11 and FKS candidate genes of azole- and caspofungin-resistant Candida albicans and Candida glabrata isolates. Real-time polymerase chain reaction was performed to gain insight into the differential expression of ERG11 mRNA.Results: Variations in the amino acid D116E were observed in fluconazole- and itraconazole-resistant C. albicans strains, and changes in amino acid E517Q were observed only in fluconazole-resistant C. albicans strains. No polymorphisms were observed in the complete sequence alignment of the ERG11 gene in one azole-resistant C. glabrata isolate. The mutation triggered the changes in the amino acid serine in the reference gene FKS1 by the leucine at position 642 (S642L) of the isolates.Conclusion: In patients with persistent or recurrent infection, the choice of an antifungal agent is often challenging and requires monitoring of the antifungal susceptibility of the colonizing strain. C. albicans and C. glabrata isolates can be resistant to azole and caspofungin antifungal agents without mutations in the ERG 11 and HS1 regions of the FKS1 gene.

ABSTRACT: Objectives: In this study, we examined the toxicities, including poisoning and overdoses, with polyene, azole, flucytosine and echinocandin antifungals reported to the Swiss National Poison Centre. Methods: An observational cross-sectional study on antifungals was performed based on reports between 1995 and 2016 to Tox Info Suisse. Patient demographic and clinical characteristics were summarised among all reported calls, stratified by age group. In secondary analyses, we evaluated cases with clinical follow-up information. Results: In total, 149 cases were reported to the National Poison Centre during the study period, of which 49 (32.9%) were male and 91 (61.1%) were female, and 95 (63.8%) were adults and 54 (36.2%) were children (age ≤16 years). The most frequently reported drug class was azoles (136; 91.3%). In 31 cases (20.8%) reported by treating physicians, further clinical follow-up information was available. Nearly one-half of these patients were asymptomatic (15/31; 48.4%). In 11 patients (35.5%) among those with symptoms, the symptoms of toxicity were categorised with a strong causality to the respective antifungal. Clinical findings caused by triazoles were effects in the gastrointestinal tract, hallucinations and predelirium state. Clinical findings caused by polyenes were mostly minor symptoms with infusion-related effects or hypokalaemia. The severity was categorised as minor in 6 (54.5%) of 11 cases and as moderate in 5 cases (45.5%). Conclusion: Despite high administered doses, no severe or fatal cases occurred within the study period. Although various toxicities can occur with antifungal administration and overdoses, they showed a favourable safety profile.

• The cure rate similar in obese and non-obese critically ill patients on standard anidulafungin. • There is a longer time to microbiological cure in non-obese patients vs patients with obesity on standard anidulafungin. • Obese and non-obese patients had comparable clinical outcomes on anidulafungin for candidemia. To evaluate the clinical outcomes of anidulafungin for candidemia treatment in critically ill patients with obesity. A multicenter, retrospective cohort study was conducted in Saudi Arabia for critically ill adults with candidemia who received anidulafungin. Patients with obesity have a body mass index ≥30 kg/m2. The primary outcome was the clinical cure rate. A total of 146 patients were included, 64 of whom were obese. There were no statistically significant differences in the clinical cure rate (P = 0.63), microbiological cure rate (P = 0.27), or the median time for a clinical cure (P = 0.13) for patients with obesity compared to non-obese patients. The median time for a microbiological cure was longer in non-obese patients than in patients with obesity (P = 0.04). The median hospital length of stay and the median mechanical ventilation durations were numerically longer in patients with obesity. Clinical and microbiological cure rates and time for clinical cure were statistically similar for both groups. Considering the study's limitations (especially with a small sample size), it is uncertain if patients with obesity have similar effectiveness to non-obese patients. Future studies with larger sample sizes are warranted to evaluate if obesity negatively impacts anidulafungin's clinical outcomes for candidemia. [ABSTRACT FROM AUTHOR]

Rezafungin, a new echinocandin with an extended half‐life, exhibits potent activity against Candida spp. Aside from the MIC, specific interactions between antifungal and isolate, including the duration of anti‐infective activity, may impact dose interval choices and infection outcome. We evaluated rezafungin and micafungin post‐antifungal effect (PAFE) against C. albicans, C. parapsilosis and C. glabrata. Six Candida spp. isolates were tested, including two of each species, C. albicans, C. parapsilosis and C. glabrata. Antifungal susceptibility testing was performed using the CLSI reference broth microdilution method. Antifungal concentrations of 1x, 4x and 16x the baseline MIC were used for PAFE determinations. Colony counts were performed at T0 (pre‐exposure), after the 1‐h drug exposure, after the cell wash (T1), and at T2, T4, T8, T12, T24 and T48 h. Rezafungin PAFE results were equivalent to micafungin PAFE values for one C. albicans (>14.9 h) and both C. glabrata (>40 h) isolates for all concentrations tested. The rezafungin and micafungin PAFEs could not be determined against one C. albicans isolate. Prolonged PAFE results were also noted for rezafungin (range, 18.4 to >40 h) against both C. parapsilosis isolates at all concentrations, while no micafungin PAFE or a short PAFE (range, 1.8 to 7.4 h) was observed against these organisms, except at 16x bMIC. Rezafungin showed sustained growth inhibition following drug removal and displayed equivalent or longer PAFE values than micafungin against all tested Candida spp. [ABSTRACT FROM AUTHOR]

Micafungin, a semisynthetic derivative of the cyclic hexapeptide FR901379 produced by Coleophoma empetri fermentation, is the only O- sulfonated echinocandin-type antifungal drug. However, the detailed formation mechanism of O -sulfonate group, whether before or after the assembly of hexapeptide, remains elusive. Here, we confirmed that O -sulfonylation occurs after hexapeptide assembly as a kind of postmodification in the biosynthesis of FR901379. The released cyclic hexapeptide was hydroxylated by cytochrome P450 McfP and successively sulfonated by sulfotransferase McfS. And other three echinocandin sulfotransferases were identified through genome mining by using McfS as a sequence probe. Moreover, pneumocandin B 0 , the precursor of caspofungin, could be O -sulfonated by heterologously introducing the McfP-McfS into the pneumocandin B 0- producing species Glarea lozoyensis. The water-solubility of sulfonated pneumocandin B 0 is 4000 times higher than that of pneumocandin B 0. The revealed O -sulfonation mechanism will provide new insights into the design and production of novel sulfonated echinocandins by metabolic engineering. [Display omitted] • The O-sulfonate group of FR901379 was introduced by cytochrome P450 McfP and sulfotransferase McfS after peptide assembly. • The post-modification stage of released cyclized hexapeptide was elucidated by gene deletion in vivo and enzymatic analysis in vitro. • Three echinocandin sulfotransferases were identified through genome mining by using McfS as sequence probe. • The cell factory producing sulfonated pneumocandin B 0 was constructed by heterologously refactoring sulfonylation module. [ABSTRACT FROM AUTHOR]

Background: The severe fever with thrombocytopenia syndrome disease (SFTS), caused by the novel tick-borne SFTS virus (SFTSV), was listed among the top 10 priority infectious disease by World Health Organization due to the high fatality rate of 5-30% and the lack of effective antiviral drugs and vaccines and therefore raised the urgent need to develop effective anti-SFTSV drugs to improve disease treatment.Methods: The antiviral drugs to inhibit SFTSV infection were identified by screening the library containing 1340 FDA-approved drugs using the SFTSV infection assays in vitro. The inhibitory effect on virus entry and the process of clathrin-mediated endocytosis under different drug doses was evaluated based on infection assays by qRT-PCR to determine intracellular viral copies, by Western blot to characterize viral protein expression in cells, and by immunofluorescence assays (IFAs) to determine virus infection efficiencies. The therapeutic effect was investigated in type I interferon receptor defective A129 mice in vivo with SFTSV infection, from which lesions and infection in tissues caused by SFTSV infection were assessed by H&E staining and immunohistochemical analysis.Results: Six drugs were identified as exerting inhibitory effects against SFTSV infection, of which anidulafungin, an antifungal drug of the echinocandin family, has a strong inhibitory effect on SFTSV entry. It suppresses SFTSV internalization by impairing the late endosome maturation and decreasing virus fusion with the membrane. SFTSV-infected A129 mice had relieving symptoms, reduced tissue lesions, and improved disease outcomes following anidulafungin treatment. Moreover, anidulafungin exerts an antiviral effect in inhibiting the entry of other viruses including SARS-CoV-2, SFTSV-related Guertu virus and Heartland virus, Crimean-Congo hemorrhagic fever virus, Zika virus, and Herpes simplex virus 1.Conclusions: The results demonstrated that the antifungal drug, anidulafungin, could effectively inhibit virus infection by interfering with virus entry, suggesting it may be utilized for the clinical treatment of infectious viral diseases, in addition to its FDA-approved use as an antifungal. The findings also suggested to further evaluate the anti-viral effects of echinocandins and their clinical importance for patients with infection of viruses, which may promote therapeutic strategies as well as treatments and improve outcomes pertaining to various viral and fungal diseases. [ABSTRACT FROM AUTHOR]

Patients with invasive candidiasis (IC) have complex medical and infectious disease problems that often require continued care after discharge. This study aimed to assess echinocandin use at hospital discharge and develop a transition of care (TOC) model to facilitate discharge for patients with IC. This was a mixed method study design that used epidemiologic assessment to better understand echinocandin use at hospital discharge TOC. Using grounded theory methodology focused on patients given echinocandins during their last day of hospitalization, a TOC model for patients with IC, the invasive candidiasis [I Can] discharge model was developed to better understand discharge barriers. A total of 33% (1405/4211) echinocandin courses were continued until the last day of hospitalization. Of 536 patients chosen for in-depth review, 220 (41%) were discharged home, 109 (20%) were transferred, and 207 (39%) died prior to discharge. Almost half (46%, 151/329) of patients discharged alive received outpatient echinocandin therapy. Independent predictors for outpatient echinocandin use were osteomyelitis (OR, 4.1; 95% CI, 1.1–15.7; p = 0.04), other deep-seated infection (OR, 4.4; 95% CI, 1.7–12.0; p = 0.003), and non-home discharge location (OR, 3.9, 95% CI, 2.0–7.7; p < 0.001). The I Can discharge model was developed encompassing four distinct themes which was used to identify potential barriers to discharge. Significant echinocadin use occurs at hospital discharge TOC. The I Can discharge model may help clinical, policy, and research decision-making processes to facilitate smoother and earlier hospital discharges. [ABSTRACT FROM AUTHOR]

Introduction: Drug resistance to echinocandins, first-line drugs used to treat Candida auris infection, is rapidly emerging. However, the accumulation of mutations in genes other than FKS 1 (before an isolate develops to resistance via FKS 1 mutations), remains poorly understood. Methods: Four clinical cases and 29 isolates associated with the incremental process of echinocandin resistance were collected and analyzed using antifungal drug susceptibility testing and genome sequencing to assess the evolution of echinocandin resistance., Findings: Six echinocandin minimum inhibitory concentration (MIC)-elevated C. auris strains and seven resistant strains were isolated from the urinary system of patients receiving echinocandin treatment. Meanwhile, phylogenetic analyses illustrated that the echinocandin-resistant strains were closely related to other strains in the same patient. Genomic data revealed that the echinocandin-resistant strains had FKS 1 mutations. Furthermore, three categories (ECN-S/E/R) of non-synonymous mutant SNP genes (such as RBR 3, IFF 6, MKC 1, MPH 1, RAD 2, and MYO 1) in C. auris appeared to be associated with the three-stage-evolutionary model of echinocandin resistance in C. glabrata : cell wall stress, drug adaptation, and genetic escape ( FKS mutation)., Interpretation: Echinocandin-resistant C. auris undergoes spatial and temporal phase changes closely related to echinocandin exposure, particularly in the urinary system. These findings suggest that FKS1 mutations mediate an evolutionary accumulation of echinocandin resistance followed by modulation of chromosome remodelling and DNA repair processes that ultimately lead to FKS 1 hot spot mutations and the development of drug resistance. This study provides an in-depth exploration of the molecular pathways involved in the evolution of Candida auris echinocandin resistance.

Objectives: A post hoc analysis used pooled STRIVE/ReSTORE trial data to determine outcomes with rezafungin versus caspofungin by Candida species and antifungal susceptibility., Methods: The efficacy and safety of once-weekly rezafungin 400/200 mg versus once-daily caspofungin 70/50 mg was demonstrated in the randomised, double-blind Phase 2 STRIVE (NCT02734862) and Phase 3 ReSTORE (NCT03667690) trials involving adults with candidaemia and/or invasive candidiasis. In this analysis, data were pooled for patients with a documented Candida infection within 96 hours of randomization who also received ≥1 dose of study drug. Treatment outcomes were evaluated by Candida species and baseline minimum inhibitory concentrations (MICs). Susceptibility was determined using EUCAST E.Def 7.4 broth microdilution methodology, with Tween 20-supplemented medium for rezafungin., Results: 294 patients were included (rezafungin: N=139, caspofungin: N=155). Susceptibility testing at baseline identified three rezafungin non-susceptible isolates. Day 14 global cure rates were numerically similar between groups for C. albicans (rezafungin: 61.0% [36/59], caspofungin: 65.2% [45/69]) and C. tropicalis (rezafungin: 70.4% [19/27], caspofungin: 63.6% [14/22]), but higher with rezafungin than caspofungin for C. glabrata (rezafungin: 71.1% [27/38%], caspofungin: 60.0% [21/35]) and C. parapsilosis (rezafungin: 78.6% [11/44], caspofungin: 55.6% [15/27]). Day 30 all-cause mortality (ACM) rates were numerically similar between groups for C. albicans (rezafungin: 22.0% [13/59], caspofungin: 18.8% [13/69]) and C. glabrata (rezafungin: 15.8% [6/38], caspofungin: 11.4% [4/35]), but higher with caspofungin than rezafungin for C. tropicalis (rezafungin: 18.5% [5/27], caspofungin: 31.8% [2/22]) and C. parapsilosis (rezafungin: 7.1% [1/14], caspofungin: 29.6% [8/27]). Day 5/14 mycological eradication rates were numerically similar between treatments for C. albicans and C. parapsilosis, but higher with rezafungin for C. glabrata and C. tropicalis. Outcomes by Candida species were not associated with treatment-specific MICs., Conclusions: Rezafungin appears to be an effective treatment for candidaemia/invasive candidiasis irrespective of baseline Candida species., Competing Interests: Conflict of interest MCA has, over the past 5 years, received research grants/contract work (paid to the Statens Serum Institut) from Cidara Therapeutics (including for generating MICs for this study), F2G/Shionogi, Gilead and Scynexis, and speaker honoraria (personal fees) from Chiesi, F2G and Gilead. She is the current chairperson of the EUCAST-AFST. MB reports honoraria from, and data safety monitoring board/advisory board membership for, Angelini, Astellas, Bayer, bioMérieux, Cidara Therapeutics, Gilead, Menarini, MSD, Nabriva and Shionogi, outside of the submitted work. CGC was an employee of JMI Laboratories at the time testing was conducted, and is currently an employee of bioMérieux (St Louis, MO, USA). MC was an employee of JMI Laboratories at the time of the study. In 2022, JMI Laboratories was contracted to provide services for AbbVie, AimMax Therapeutics, Amicrobe, Appili Therapeutics, Armata Pharmaceuticals, Astellas Pharma, Basilea Pharmaceutica, Becton, bioMérieux, Biosergen, Bugworks, Cerba Research, Cidara Therapeutics, Cipla USA, ContraFect Corporation, CorMedix, Crestone, Curza Global, Diamond V, Dickinson and Company, Discuva Entasis Therapeutics, Enveda Biosciences, Evopoint Biosciences, Fedora Pharmaceuticals, Fox Chase Chemical Diversity Center, Genentech, Gilead Sciences, GSK Institute for Clinical Pharmacodynamics, Iterum Therapeutics, Janssen Biopharma, Johnson & Johnson, Kaleido Biosciences, LifeMine Therapeutics, Medpace, Lysovant Sciences, Meiji Seika Pharma, Melinta Therapeutics, Menarini Group, Merck & Co., MicuRx Pharmaceutical, Mundipharma International Mutabilis, Nabriva Therapeutics, National Cancer Institute, National Institutes of Health, Ohio State University, Omnix Medical Paratek Pharmaceuticals, Pfizer, PolyPid, PPD, Prokaryotics, Pulmocide, Qpex Biopharma, Revagenix, Roche Holding, Roivant Sciences, Scynexis, SeLux Diagnostics, Shionogi & Co., Sinovent Pharmaceuticals, Spero Therapeutics, Sumitovant Biopharma, TenNor Therapeutics, ThermoFisher Scientific, U.S. Food and Drug Administration, VenatoRx Pharmaceuticals, Washington University, Watershed Medical, Wockhardt and Zoetis. OAC reports grants or contracts from Cidara Therapeutics, F2G, Gilead, MSD, Mundipharma, Pfizer and Scynexis; consulting fees from Basilea, Cidara Therapeutics, Gilead, GSK, Janssen, Matinas, Mundipharma, Pfizer, Scynexis and Shionogi; speaker honoraria from Al-Jazeera Pharmaceuticals/Hikma, Gilead, Grupo Biotoscana/United Medical/Knight, GSK, MSD, Mundipharma, Pfizer, Sandoz and Shionogi; and participation on a data review committee or data and safety monitoring board for Cidara Therapeutics, Janssen and Pulmocide. PMH reports grants or contracts, and consulting fees, from Baxter, Cytosorbents and Pfizer; honoraria from Baxter and Cytosorbents; and support for attending meetings from Mundipharma and Pfizer, outside of the submitted work. JBL is an employee of, and shareholder in, Cidara Therapeutics. NM is an employee of Mundipharma. SN reports lectures and advisory boards for bioMérieux, Fisher, Medtronic, MSD, Mundipharma, Paykel and Pfizer. AR has received consulting fees and honoraria from Gilead, Meiji and, Tillots; and support for attending meetings from Angelini, Gilead, Meiji, Menarini and Mundipharma. ER has received research grants from AbbVie, Cidara Therapeutics, Merck, Pfizer and Shionogi to his institution, and is a scientific advisor and member of the speaker bureau for Gilead, Merck, Mundipharma, Pfizer and Shionogi. TS is an employee of, and shareholder in, Cidara Therapeutics. AS reports a grant from Gilead and, outside of the submitted work, a grant from Pfizer; consulting fees and honoraria from Angelini, Gilead, Menarini, MSD, Pfizer and Shionogi; and support for attending meetings from Pfizer., (Copyright © 2024. Published by Elsevier Ltd.)

The IA-DUET study aimed to compare azole-echinocandin combination with azole monotherapy for invasive aspergillosis. Recruitment was hindered by patient ineligibility, competing studies, and guidelines favoring combination therapy when azole resistance was unknown. The low IA-attributable mortality suggests future trials may benefit from cluster randomization or composite endpoints to enhance efficiency., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The minimum inhibitory concentration (MIC) of echinocandins against Aspergillus spp. does not represent the actual inhibition threshold of echinocandins. Therefore, the recommended method to evaluate their activity is determining the minimum effective concentration (MEC) in broth microdilution, a method that is less common in clinical settings. This study aimed to assess a user-friendly commercial method, Sensititre YeastOne (SYO), to determine the effectiveness of echinocandins (caspofungin, anidulafungin and micafungin) against Aspergillus spp. Echinocandins MEC was determined against 23 isolates of Aspergillus spp. using SYO and the reference Clinical and Laboratory Standards Institute (CLSI) method. MECs were read with an inverted microscope and a reading mirror. Essential agreement (EA) between the tested methods was defined as a ±twofold dilution difference. There was a high EA (91%-100%) between the reference method and SYO in determining echinocandins MEC against Aspergillus isolates using inverted microscopy. A high EA was also observed between SYO MEC determined by inverted microscopy and a reading mirror, but different incubation times were required. SYO is a reliable, simple method for determining the MEC of echinocandins against Aspergillus isolates, preferably with an inverted microscope, and can be easily used in clinical laboratories when echinocandin susceptibility testing is required.IMPORTANCEUsing a commercial method such as Sensititre YeastOne (SYO) to determine the minimum effective concentration (MEC) of echinocandins against Aspergillus spp. has been shown to be a reliable alternative to the Clinical and Laboratory Standards Institute (CLSI) reference method. This makes it more suitable for high-volume clinical laboratories. SYO provides accurate results comparable to the standard method and could potentially improve patient care by guiding more optimal antifungal treatment choices for patients with Aspergillus infections., Competing Interests: The authors declare no conflict of interest.

Abstract Background Periprosthetic fungal infections are considered rare and opportunistic infections. Treatment is difficult, and established standards do not yet exist. The choice of the appropriate antifungal drug might affect the patient outcome. Cases All the three cases presented showed polybacterial recurrent infection of the revision hip arthroplasty. All patients were of younger age, had multiple revisions of the endoprosthesis, each had a large partial femoral replacement greater than 40% of the femoral length, gentamycin-loaded cement, and a long anchoring distance of the used intramedullary stem. Due to the severe life-threatening infection with deep osteomyelitis, an amputation had to be performed. However, despite surgical intervention, the fungal dominated infection persisted. Finally, only the use of caspofungin allowed permanent infection control. Conclusion The polybacterial infection is driven by the symbiosis between fungi and bacteria. Therefore, eradication of the fungus is required to achieve elimination of the bacteria. Antimycotics of the echinocandin-class, such as caspofungin, may be considered as initial treatment.

ABSTRACT The proposed life cycle of fungi in the genus Pneumocystis has typically included both an asexual cycle via binary fission and a sexual cycle. Until recently, the strategy used for sexual replication was largely unknown, but genomic and functional assays now support a mode known as primary homothallism (self-fertilization). The question of whether an asexual cycle contributes to the growth of these fungi remains. Treatment of Pneumocystis pneumonia in immunosuppressed rodent models with the class of drugs known as echinocandins is challenging the historical concept of asexual replication. The echinocandins target 1,3-β-D-glucan (BG) synthesis resulting in death for most fungi. Because Pneumocystis species have both non-BG expressing life cycle stages (trophic forms) and BG-expressing asci, treatment with anidulafungin and caspofungin resulted in elimination of asci, with large numbers of non-BG expressing organisms remaining in the lungs. Transcriptional analyses of anidulafungin treated Pneumocystis murina-infected lungs indicated that these agents were blocking the sexual cycle. In the present study, we explored whether there was an asexual or alternative method of replication that could rescue P. murina survival and growth in the context of anidulafungin treatment. The effects of anidulafungin treatment on early events in the sexual cycle were investigated by RT-qPCR targeting specific mating genes, including mam2, map3, matMi, matPi, and matMc. Results from the in vivo and gene expression studies clearly indicated there was no rescue by an asexual cycle, supporting these fungi’s reliance on the sexual cycle for survival and growth. Dysregulation of mating-associated genes showed that anidulafungin induced effects early in the mating process. IMPORTANCE The concept of a sexually obligate fungus is unique among human fungal pathogens. This reliance can be exploited for drug development and here we show a proof of principle for this unusual target. Most human fungal pathogens eschew the mammalian environment with its battery of immune responses. Pneumocystis appear to have evolved to survive in such an environment, perhaps by using sexual replication to help in DNA repair and to introduce genetic variation in its major surface antigen family because the lung is the primary environment of these pathogens. The concept of primary homothallism fits well into its chosen ecosystem, with ready mating partners expressing both mating type receptors, and a sexual cycle that can introduce beneficial genetic variation without the need for outbreeding.

ABSTRACT Aspergillus fumigatus is a deadly opportunistic fungal pathogen responsible for ~100,000 annual deaths. Azoles are the first line antifungal agent used against A. fumigatus, but azole resistance has rapidly evolved making treatment challenging. Caspofungin is an important second-line therapy against invasive pulmonary aspergillosis, a severe A. fumigatus infection. Caspofungin functions by inhibiting β-1,3-glucan synthesis, a primary and essential component of the fungal cell wall. A phenomenon termed the caspofungin paradoxical effect (CPE) has been observed in several fungal species where at higher concentrations of caspofungin, chitin replaces β-1,3-glucan, morphology returns to normal, and growth rate increases. CPE appears to occur in vivo, and it is therefore clinically important to better understand the genetic contributors to CPE. We applied genomewide association (GWA) analysis and molecular genetics to identify and validate candidate genes involved in CPE. We quantified CPE across 67 clinical isolates and conducted three independent GWA analyses to identify genetic variants associated with CPE. We identified 48 single nucleotide polymorphisms (SNPs) associated with CPE. We used a CRISPR/Cas9 approach to generate gene deletion mutants for seven genes harboring candidate SNPs. Two null mutants, ΔAfu3g13230 and ΔAfu4g07080 (dscP), resulted in reduced basal growth rate and a loss of CPE. We further characterized the dscP phosphatase-null mutant and observed a significant reduction in conidia production and extremely high sensitivity to caspofungin at both low and high concentrations. Collectively, our work reveals the contribution of Afu3g13230 and dscP in CPE and sheds new light on the complex genetic interactions governing this phenotype. IMPORTANCE This is one of the first studies to apply genomewide association (GWA) analysis to identify genes involved in an Aspergillus fumigatus phenotype. A. fumigatus is an opportunistic fungal pathogen that causes hundreds of thousands of infections and ~100,000 deaths each year, and antifungal resistance has rapidly evolved in this species. A phenomenon called the caspofungin paradoxical effect (CPE) occurs in some isolates, where high concentrations of the drug lead to increased growth rate. There is clinical relevance in understanding the genetic basis of this phenotype, since caspofungin concentrations could lead to unintended adverse clinical outcomes in certain cases. Using GWA analysis, we identified several interesting candidate polymorphisms and genes and then generated gene deletion mutants to determine whether these genes were important for CPE. Two of these mutant strains (ΔAfu3g13230 and ΔAfu4g07080/ΔdscP) displayed a loss of the CPE. This study sheds light on the genes involved in clinically important phenotype CPE.

Background This study quantifies the mortality attributable to Candida bloodstream infections (BSI) in the modern era of echinocandins. Methods We conducted a retrospective cohort study of adult patients admitted to Barnes Jewish Hospital, a 1368-bed tertiary care academic hospital, in Saint Louis, Missouri, from 1 February 2012 to 30 April 2019. We identified 626 adult patients with Candida BSI that were frequency-matched with 6269 control patients that had similar Candida BSI risk-factors. The 90-day all-cause mortality attributable to Candida BSI was calculated using three methods—propensity score matching, matching by inverse weighting of propensity score, and stratified analysis by quintile. Results The 90-day crude mortality was 42.4% (269 patients) for Candida BSI cases and 17.1% (1083 patients) for frequency-matched controls. Following propensity score-matching, the attributable risk difference for 90-day mortality was 28.4% with hazard ratio (HR) of 2.12 (95% confidence interval [CI], 1.98–2.25, P  < .001). In the stratified analysis, the risk for mortality at 90 days was highest in patients in the lowest risk quintile to develop Candida BSI (hazard ratio [HR] 3.13 (95% CI, 2.33–4.19). Patients in this lowest risk quintile accounted for 81(61%) of the 130 untreated patients with Candida BSI. Sixty-nine percent of untreated patients (57/83) died versus 35% of (49/127) of treated patients (P  < .001). Conclusions Patients with Candida BSI continue to experience high mortality. Mortality attributable to Candida BSI was more pronounced in patients at lowest risk to develop Candida BSI. A higher proportion of these low-risk patients went untreated, experienced higher mortality, and should be the target of aggressive interventions to ensure timely, effective treatment. [ABSTRACT FROM AUTHOR]