Invasive fungal infections (IFIs) represent a major complication after intestine transplantation, with reported incidence rates between 40% and 49%. These infections are associated with high morbidity and allograft loss. This study evaluates the impact of post-transplant IFIs on graft outcomes in intestine transplant recipients. We conducted a retrospective cohort study of 152 patients who underwent intestine transplantation from 2008 to 2022. The primary outcome was IFI, defined as proven or probable by EORTC/MSGERC criteria. The secondary outcome was a composite of allograft failure or death. Analyses were conducted using multivariable Cox proportional hazards models, with non-baseline variables incorporated as time-dependent exposures. Among 152 intestine transplant recipients, 56 (36.8%) developed post-transplant IFI. Median time to IFI was 83.5 days (IQR 19.5-444.2), with Candida infections occurring early and non-Candida infections occurring later. Candida species accounted for 73% of IFIs, most commonly C. glabrata, C. albicans, and C. parapsilosis, with 29.3% showing fluconazole resistance. Most infections were intra-abdominal and bloodstream. Redo transplantation (HR 2.44, 95% CI 1.20-4.95; p = 0.014), anastomotic leak (HR 2.23, 95% CI 1.02-4.90; p = 0.045), and augmented immunosuppression (HR 4.73, 95% CI 1.94-11.53; p < 0.001) were independent predictors of Candida IFI. IFI was associated with a markedly increased risk of allograft loss or death (HR 3.67, 95% CI 2.30-5.83; p < 0.001). Post-transplant IFIs are common and associated with allograft loss or mortality in intestine transplant recipients. Early recognition and aggressive management of IFIs remain critical to improving transplant outcomes.

Taste dysfunction is a common symptom of oral candidiasis; however, its underlying mechanisms remain unclear. This study aimed to determine whether Candida albicans carriage, particularly its hyphal phenotype, is associated with impaired taste sensitivity. Fifty-seven participants were divided into three groups: noncarriers (n = 20), carriers without hyphae (n = 20), and carriers with hyphae (n = 17). Tongue biofilm samples were collected for Candida culture and smear tests. Salivary flow rates were measured, and taste sensitivity was assessed using standardised taste strips. Carriers underwent topical fluconazole treatment, and post-treatment taste sensitivity was re-evaluated. Carriers exhibited reduced sensitivity to sweet and bitter tastes, with an additional decline in umami sensitivity among those with hyphae. In addition, both unstimulated and stimulated salivary flow rates were significantly lower in Candida carriers than in noncarriers. Topical fluconazole treatment resulted in a marked reduction in hyphae and significant improvement in taste sensitivity. This study revealed differences in salivary flow and taste sensitivity between noncarriers and Candida albicans carriers. The presence of hyphal forms was strongly associated with greater impairment in taste function. Improvement following antifungal therapy suggests that hyphal invasion may play a key role in the pathogenesis of taste dysfunction in oral candidiasis.

ABSTRACTBackgroundInvasive candidiasis (IC), life‐threatening fungal infections with high economic burden, are often treated first‐line with daily intravenous echinocandins. A new once weekly echinocandin, rezafungin, demonstrated statistically non‐inferior efficacy and numerically shorter intensive care unit (ICU) stay compared to caspofungin in clinical trials, offering potential for earlier discharge.ObjectiveTo assess the cost‐effectiveness of rezafungin versus daily echinocandins for the treatment of IC from a UK healthcare perspective.MethodsAn economic model was developed including a short‐term decision tree (treatment duration ≤ 30 days) and a long‐term Markov model (for lifetime outcomes). Considering the impact IC has on a patient's life expectancy and quality of life, a cost‐utility analysis was performed. A cost‐minimisation analysis assuming similar efficacy among echinocandins was included as scenario analysis. Treatment response was assessed at days 5/14 with nonresponders switching to second‐line treatment. Patients with negative repeat blood cultures could step down to oral fluconazole. Rezafungin's weekly administration was estimated to lead to early discharge for 16% of patients. Risk of death was included. Efficacy and resource use estimates were from pooled trial data. Unit costs, utilities, long‐term mortality were from published literature and UK databases.ResultsRezafungin was estimated to be cost‐saving compared to daily echinocandins (discounted incremental costs: −£6028 to −£6727 vs. daily echinocandins). Quality‐adjusted life‐years (QALYs) were similar (incremental QALY: 0.03 vs. daily echinocandins), resulting in rezafungin being cost‐effective. Results were most sensitive to varying mortality and ICU length of stay.ConclusionOnce weekly rezafungin is a cost‐saving and cost‐effective treatment option in IC from the UK healthcare perspective.

Voriconazole (VRC), a triazole antifungal agent, is recommended as primary treatment for invasive aspergillosis. Due to its unpredictable dose-exposure relationship, therapeutic drug monitoring (TDM) is recommended. Despite TDM, the probability of achieving therapeutic targets is only approximately 50%. This highlights the need for new dosing strategies. Calculating the metabolic ratio (MR) of NOX, the principal N-oxide metabolite of voriconazole primarily formed by the genetically polymorphic CYP2C19 enzyme, to VRC concentrations could serve as a surrogate for phenotype information. This is particularly relevant since the CYP2C19 genotype is often unavailable in acute clinical settings. Moreover, genotype may be less informative during inflammation due to a phenomenon known as 'phenoconversion', where inflammation masks genotype effects through downregulation of CYP450 enzymes. However, before integrating NOX in population PK models and/or as an adjunct in voriconazole TDM flowcharts, it is important to understand the factors impacting NOX exposure, and hence the MR. The objective of this narrative review is therefore to summarise recent literature on patient- and drug-related covariates impacting NOX exposure. A comprehensive search was conducted in PubMed and Embase for articles published from 2003 to 2025 focusing on factors impacting NOX or the MR. Twenty-one articles were included, predominantly involving adult patients from an Asian or white ethnicity. Studies were mainly set up as pharmacokinetic (PK) studies, in which associations between NOX or MR were assessed in uni- or multivariate analyses. Key covariates identified were as follows: (1) voriconazole dose (6/11 studies)-higher doses increasing NOX, although this relationship was complicated by saturated metabolism; (2) C-reactive protein (CRP) (8/9)-higher inflammation levels correlated with reduced metabolic capacity due to CYP450 enzyme downregulation; (3) age (7/12)-children exhibited higher MR, probably driven by higher clearance due to increased CYP2C19 and FMO3 expression, while older adults (> 60 years) showed decreased MR due to a decline in CYP2C19 activity; (4) CYP2C19 genotype (10/13)-poor metabolizers had lower MR and lower NOX, supporting the utility of genotyping, if available with acceptable turnaround time. A CRP threshold of 100 mg/L has been found in some studies and may serve as a crucial indicator for clinicians in optimising dosage adjustments. Although hepatic impairment is recognised as a significant covariate for voriconazole, its influence on NOX or the MR was found limited in this review. This is likely due to the exclusion of patients with hepatic impairment from most studies, which resulted in lower interindividual variation in liver function test results. While renal function does not affect voriconazole exposure, it may impact NOX or MR, as some studies suggest a higher renal clearance of NOX compared to voriconazole. However, only one of the included studies suggested that impaired renal function resulted in a higher MR, indicating NOX accumulation. Further research is however needed. VRC dose, CRP, age and CYP2C19 genotype are the primary covariates affecting NOX or MR, and renal and liver function should also be considered in future population pharmacokinetic models and TDM protocols.

ABSTRACTBackgroundTyping Aspergillus species is crucial for understanding the sources of infection in hospital environments.ObjectivesThis study analysed clinical and air samples as well as their relationship with the clinical forms of aspergillosis. Additionally, we examined the usefulness of the Short Tandem Repeats (STR) technique with two highly discriminatory markers for analysing the Aspergillus fumigatus (A. fumigatus) profile.Patients/MethodsSeventy‐five air samples (September 2013–July 2014) and 116 clinical samples (2009–2014) were collected in a university hospital. Seventy‐two samples were typed by STR with two markers, MC3 and MC5.ResultsOf the 75 air samples collected, 10 were positive in the Bone Marrow Transplant unit, a ventilated unit with HEPA filters as were 18 in the Haematology ward, a naturally ventilated unit. Of the 116 clinical samples of Aspergillus spp., 95 were identified as A. fumigatus. High diversity was found, with 42 genotypes in 67 clinical samples and four in five environmental samples. Most isolates were collected during the demolition and renovation of the Emergency unit in the Hospital from 2013 to 2014. Genotype 1 was found in several units during different years. Despite the heterogeneity, identical genotypes were observed three times at short intervals in the same or different wards. Some of these identical genotypes were confirmed as possible clones by genome sequencing while others' genotyping matches failed to be confirmed.ConclusionDespite the diversity of clinical and environmental samples, useful correlations can be established in invasive aspergillosis surveillance programs by using this simple STR method as a preliminary step.

Atopic dermatitis (AD) is a common chronic skin disorder characterised by a highly inflamed local environment and elevated epidermal proteolytic activity. Changes in the skin mycobiome have been observed in this disease, specifically Candida albicans colonization positively correlating with AD severity, yet the mechanisms by which this fungus contributes to disease features remain elusive. This study aimed to elucidate how C. albicans can influence AD pathogenesis through its influence on keratinocyte (KC) proteolytic activity, inflammatory cytokine secretion and epidermal barrier integrity, as well as define the signaling pathways mediating these effects. Immortalized human KC were co-cultured with C. albicans and changes in KC protease expression and activity, along with the secretion of the pro-inflammatory cytokine IL-1β were assessed. Additionally, the impact of IL-1β on KC barrier formation was determined using transepithelial electrical resistance. To identify signalling pathways mediating Candida-induced phenotypes, CRISPR/Cas9 was used to establish cell lines deficient in myeloid differentiation primary response protein 88 (MyD88) or matrix metalloprotease-9 (MMP-9). C. albicans induced proteolytic activity from KC through fungal secreted aspartyl proteases (Sap4-6) and promoted IL-1β secretion via MyD88 signalling. This response increased expression and activation of host MMP-9 and led to impaired barrier function. Genetic deletion of either MYD88 or MMP9 restored barrier function in IL-1β treated cells, suggesting MMP-9 serves as a downstream effector of IL-1β/MyD88 signalling. These findings establish a mechanistic link between skin resident fungi and epidermal barrier dysfunction. We demonstrate a pathway linking fungal colonization to innate immune responses by skin cells, providing insight into how the commensal fungus C. albicans may contribute to AD pathogenesis.

ABSTRACTBackgroundThe global double‐blind, randomised, Phase 3 ReSTORE trial (NCT03667690) demonstrated noninferiority of rezafungin versus caspofungin for all‐cause mortality at Day 30 and global cure at Day 14 in patients with candidemia and/or invasive candidiasis.ObjectivesWe report outcomes for patients from China (ReSTORE China), comprising participants enrolled in the original ReSTORE trial (n = 11) and from an extended, China‐only phase (n = 47) implemented to fulfill Chinese regulatory requirements.MethodsPatients with candidemia/invasive candidiasis were randomised 1:1 to intravenous rezafungin (400 mg loading, then 200 mg once weekly) or caspofungin (70 mg loading, then 50 mg once daily) for ≤ 4 weeks. Primary endpoints were all‐cause mortality at Day 30 and global cure at Day 14 in the modified intent‐to‐treat population. Between October 2018 and March 2024, 58 patients were randomised and received study treatment (rezafungin n = 28 [modified intent‐to‐treat n = 27], caspofungin n = 30 [modified intent‐to‐treat n = 28]).ResultsAll‐cause mortality at Day 30 was 33.3% (9/27) for rezafungin versus 35.7% (10/28) for caspofungin (difference −2.4% [95% confidence interval −27.0–22.6]). Global cure at Day 14 was 48.1% (13/27) versus 46.4% (13/28), respectively (weighted difference 0.3% [95% confidence interval −25.4–26.3]). Day 5 and 14 mycological eradication rates were 70.4% and 63.0% for rezafungin versus 71.4% and 67.9% for caspofungin, respectively. Safety and tolerability profiles were similar between groups.ConclusionsRezafungin demonstrated similar efficacy and safety to caspofungin in the ReSTORE China cohort. These findings support the primary ReSTORE analysis and suggest that rezafungin could provide a new treatment option for candidemia/invasive candidiasis in China.Trial RegistrationClinicalTrials.gov identifier: NCT03667690

ABSTRACTBackgroundNitroxoline is an old antibiotic currently approved for the treatment of uncomplicated urinary tract infections. Its mode of action is based on the chelation of bivalent cations, such as zinc.ObjectivesAs zinc plays a central role in the metabolism of Aspergillus spp., we performed antifungal susceptibility testing against Nitroxoline using broth microdilution.MethodsOverall, 13 Aspergillus isolates were tested according to the EUCAST guidance document (Guinea et al. EUCAST, def. doc. 9.4, 2022) including two genetically proven Azole‐resistant strains.ResultsThe overall Minimal Inhibitory Concentration (MIC)50/90 was 0.5 mg/L.ConclusionsThese results correspond to excellent in vitro activity against Aspergillus spp.