Background:A recent proposal introduced criteria to distinguish uncomplicated from complicated candidemia and identify patients who might be candidates for a shortened (7-day) course of antifungal therapy. We evaluated the feasibility and potential impact of this strategy in a real-world cohort. Methods:This retrospective study included patients with candidemia at Lausanne University Hospital (2015-2024). We estimated the sample size required for a randomized non-inferiority trial comparing 7 vs 14 days of therapy for episodes with uncomplicated candidemia and the reduction in antifungal treatment days under a hypothetical 7-day treatment strategy. Results:Among 314 episodes of candidemia, 103 (33%) were classified as uncomplicated. Of the 264 (84%) episodes surviving beyond the first 5 days without limitation of care, 30-day mortality was lower in uncomplicated than complicated candidemia (7% vs 20%; P = .006). Based on a hypothetical randomized non-inferiority trial comparing 7 vs 14 days of antifungal therapy, assuming an expected event rate of 25% and a non-inferiority margin of 7.5%, 1103 patients would be required. Overall, the 314 episodes received 6377 days of antifungal therapy (median, 14 days; interquartile range 13-18). A shortened 7-day treatment strategy for uncomplicated candidemia would have reduced antifungal exposure by 799 treatment days, corresponding to a 13% reduction. Conclusions:Uncomplicated candidemia accounted for only one-third of episodes, and abbreviated therapy would yield a modest reduction in antifungal exposure. The large sample size required and limited stewardship benefit suggest that a randomized trial would be challenging to conduct.

Abstract Tintelnotia destructans is a recently described fungus within the family Phaeosphaeriaceae, previously reported only in superficial human infections such as keratitis, onychomycosis, and non-invasive sinus fungus ball. We describe the first case of invasive rhinosinusal infection due to this pathogen in a child with severe aplastic anemia. Diagnosis was established by histopathology showing submucosal fungal invasion and broad-range fungal PCR targeting 18S rRNA identifying T. destructans. Combined endoscopic surgical debridement, antifungal therapy (liposomal amphotericin B and isavuconazole) and immune reconstitution after emergency haplo-identical hematopoietic stem cell transplant ultimately led to complete recovery without recurrence 18 months after treatment, despite continued therapeutic immunosuppression for GvHD. This case expands the known pathogenic spectrum of T. destructans, demonstrating its potential to cause invasive disease in severely immunocompromised hosts. Advances in molecular diagnostic tools may expand the spectrum of fungi causing invasive fungal infections by identification of novel pathogenic species.

ABSTRACT Invasive fungal diseases are difficult to diagnose because of the limited sensitivity of culture. Panfungal PCR amplicon sequencing assays (targeting ribosomal RNA, such as 18S, 28S, ITS) are recommended for fungal identification in histopathology samples showing fungal elements. However, data describing its overall performance and consistency are lacking. This systematic literature review and meta-analysis assessed the performance of panfungal PCR on formalin-fixed paraffin-embedded (FFPE) and non-fixed (fresh or frozen) tissue samples. A systematic literature search was performed to include studies reporting the use of panfungal PCR for fungal identification in FFPE or non-fixed tissue samples. PCR sensitivity and specificity were assessed using the reference standard of histopathology showing fungal elements. Quality assessment was performed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Pooled estimates were obtained using random-effects meta-analysis. Twenty-eight studies were included. In FFPE samples (18 studies, 852 samples), sensitivity and specificity were 75.4% (95% confidence interval [CI], 59.2–86.6) and 93.5% (70.2–98.9), respectively. Sensitivity in non-fixed samples (13 studies, 207 samples) was 86.5% (74.7–93.3), while specificity could not be assessed (insufficient data). Comparative analyses showed a significantly higher sensitivity of panfungal PCR over culture (88.2%; 76–94.7 vs 52.2%; 39–65, P = 0.001). Sub-analyses could not demonstrate the superiority of one PCR target over another due to limited data. Panfungal PCR exhibited adequate sensitivity and good specificity in FFPE samples. Sensitivity was even higher in non-fixed samples and largely superior to culture. Nevertheless, large interstudy variability was observed, warranting interlaboratory studies to define the optimal PCR target and standardized protocols. IMPORTANCE Invasive fungal diseases are difficult to diagnose because of the low sensitivity of culture. Panfungal PCRs are widely used for fungal identification in tissue specimens but suffer from heterogeneous procedures and performance. This meta-analysis shows an acceptable sensitivity (75.4% and 86.5% in fixed and non-fixed samples, respectively) and good specificity (93.5%) of panfungal PCR, supporting its use, not only on histopathology-positive fixed samples but also in non-fixed samples concomitantly with other diagnostic tools (cultures and fungal-specific PCRs if available). These results provide a strong basis for further standardization of panfungal PCR techniques via interlaboratory assays to assess reproducibility and optimize analytical protocols. CLINICAL TRIALS This study is registered with PROSPERO as CRD42023461148 .

ABSTRACT Invasive fungal infections (IFIs) are associated with high mortality rates and pose important therapeutic challenges because of the limited number of antifungal drug classes, their toxicity, and the emergence of resistance. Novel first-in-class antifungal agents have been recently approved (ibrexafungerp) or are currently being tested in clinical trials and are available via expanded access programs (olorofim, fosmanogepix). Among them, fosmanogepix (a prodrug of manogepix) represents a promising future therapeutic option for many IFIs because of its broad-spectrum antifungal activity and its favorable pharmacologic properties, such as oral bioavailability, extended tissue distribution (including the central nervous system), a good safety profile, and the absence of relevant drug-drug interactions. Fosmanogepix may become an interesting alternative option for the treatment of invasive candidiasis due to multidrug-resistant isolates (e.g., Candidozyma auris ) or invasive aspergillosis due to azole-resistant Aspergillus spp. It also demonstrated very encouraging results for the treatment of invasive fusariosis and other refractory mold infections (e.g., scedosporiosis, lomentosporiosis). Novel gepix compounds have been developed and could make their niche in the future (e.g., APX2039, prodrug: APX2096, for cryptococcal meningitis, and APX2020, prodrug: APX2097, for coccidioidomycosis). This review discusses the future place of fosmanogepix in the antifungal armamentarium against IFIs.

Candidozyma auris, formerly Candida auris, is an emerging yeast that is now recognized as a major healthcare-associated pathogen worldwide. Its near-simultaneous emergence across multiple continents over the past decade, its high capacity to colonize skin, its prolonged environmental persistence, and its multidrug resistance to antifungal agents underscore its clinical and epidemiological significance. In Switzerland, the first case was documented in 2017. Since then, imported cases have been reported sporadically each year, almost exclusively among patients who were previously hospitalized in regions with high endemicity. This article presents the current epidemiological data and key issues related to infection prevention and control, and highlights the importance of implementing national recommendations.

The evidence supporting the impact of global warming on the epidemiology of infectious diseases, including fungal infections, is increasing. Fungi have a remarkable ability to adapt to heat and pollution, and to disseminate via air, water ecosystems, or wildfire smoke. Their genetic plasticity can lead to thermotolerance, the ability to find new ecological niches, and fitness gains. Natural reservoirs of the fungal biomass, which are heavily affected by global warming, may serve as the environments from where new fungal diseases originate, as illustrated by the recent emergence of Candidozyma auris and Rhodosporidiobolus fluvialis. Moreover, global warming also affects human skin/mucosal integrity and local or systemic immune responses, which could increase host susceptibility to fungal infections. This review examines the impact of global warming on the complex fungi-host interactions, which can lead to new challenges in mycology, and discusses possible mitigation strategies.

Objectives Isavuconazole (ISA) is a triazole drug approved for the treatment of invasive aspergillosis and mucormycosis. Due to the relatively low interindividual variability of ISA pharmacokinetics and the lack of defined cutoffs for efficacy and toxicity, therapeutic drug monitoring (TDM) is rarely performed. This study aimed to characterize ISA pharmacokinetics and pharmacodynamics in real-life clinical settings and assess the potential role of TDM.Methods We developed and validated a classical population pharmacokinetic (popPK) model using ISA concentrations obtained from patients undergoing TDM at three Swiss university hospitals. Additionally, we performed exploratory pharmacokinetic-pharmacodynamic analyses to investigate associations between ISA trough concentration or AUC, treatment outcomes, and hepatotoxicity using logistic regression models. Model-based simulations allowed assessing the role of TDM in clinical patient management.Results A one-compartment model with interindividual variability in clearance best described our data. Among the covariates tested, only body mass index was found to influence the ISA volume of distribution to a clinically significant extent. Exposure-response analyses suggested a trend toward an association with treatment success, but not with toxicity. Model-based simulations show that TDM could increase the proportion of patients within the currently suggested ISA target ranges.Conclusion Our results indicate that ISA exposure shows substantial variability and tends to correlate with outcome. This suggests a beneficial role for TDM in optimizing target achievement.

The yeast pathogen Candidozyma (Candida) auris can form biofilms, which contribute to its virulence and nosocomial transmission. In this study, we identified the transcription factor Wor2 as a negative regulator of biofilm formation in C. auris. Wor2 hyperactivation in a strain of clade IV via the use of a protein tagging strategy resulted in downregulation of two important adhesins, SCF1 and ALS4112, and decreased biofilm-forming capacity. We showed that the impact on biofilm was predominantly mediated via decreased SCF1 expression in this strain. However, results of adhesion assays on inert surfaces and human keratinocytes found relatively modest roles of Wor2 and Scf1 in this process, suggesting that their effect on biofilm formation is complex and not limited to the adhesion step. Finally, analyses of other strains from different clades identified three distinct WOR2 genotypes, with variable WOR2 expression levels and distinct impacts of WOR2 deletion on biofilm formation. Notably, Wor2 negatively regulated biofilm in strains of clades I, III, and IV with distinct profiles of SCF1/ALS4112 expression, while it had no impact on biofilm in a clade II strain. Taken together, this study showed that Wor2 exhibited some distinct genotypic evolution in C. auris resulting in clade- or strain-specific regulatory roles and pathways in biofilm formation.IMPORTANCECandidozyma (Candida) auris is a pathogenic yeast exhibiting a particular capacity for interhuman transmission via medical instruments, which was the cause of nosocomial outbreaks of candidemia. Adhesion to inert surfaces and subsequent biofilm formation is therefore important for C. auris propagation. This work highlights the role of the transcription factor Wor2 as a negative regulator of biofilm formation in C. auris. In a strain of clade IV, Wor2 was shown to downregulate two important adhesins (SCF1 and ALS4112). Interestingly, Wor2 exhibited different genotypes across C. auris clades and strains, which were associated with distinct differential expression of WOR2, ALS4112, and SCF1, and possibly distinct roles in biofilm formation.

Soft tissue mucormycosis is a rare fungal infection that can develop on contaminated wounds. We report a case of Mucor circinelloides ankle infection in an immunocompetent man following a high-energy motorcycle accident, which has successfully been treated by surgery (multiple debridements, arthrodesis, soft tissue defect reconstruction with flap and skin graft), systemic antifungal therapy (initial liposomal amphotericin B followed by isavuconazole) and hyperbaric oxygen. This case highlights the therapeutic challenges and need for a multidisciplinary approach of such infection.

Candidozyma auris (formerly Candida auris) is a pathogenic yeast of concern because of its ability to develop antifungal resistance and to cause nosocomial outbreaks of invasive candidiasis. Resistance to azoles (mainly fluconazole) is a hallmark of most C. auris clinical isolates and the efflux pump Cdr1 plays a key role in this process. The transcription factor Tac1b is known to regulate CDR1. TAC1b is located on chromosome 5 in tandem with TAC1a, whose function is not yet elucidated. This study aimed at investigating the respective roles of Tac1a and Tac1b in azole resistance. Hyperactivation of Tac1a using a tagging strategy resulted in markedly decreased fluconazole susceptibility similar to Tac1b hyperactivation. Tac1a and Tac1b shared a large common set of downstream targets, including CDR1, and use the same DNA-binding motif in their target gene promoters according to ChEC-seq analysis. Other common targets included the efflux pump Cdr4_1, with no role in azole resistance, and the transcription factors Zcf13 and Mrr1b, which demonstrated minor impact on azole susceptibility independently from Cdr1. Our results suggest that Tac1a could bind to the TAC1b promoter (and not inversely) and is therefore located upstream of Tac1b in this regulatory pathway. While gain-of-function mutations of azole resistance have been characterized in Tac1b, our attempts to induce such mutations in Tac1a were unsuccessful. We concluded that Tac1a and Tac1b have redundant functions but with distinct roles in the evolutionary process of azole resistance with Tac1a being the ancestral conserved gene and Tac1b having evolved to trigger azole resistance.

In recent years, we have observed a geographic expansion of tularemia cases recorded in Europe. In Switzerland, the incidence of reported cases almost tripled between 2014 and 2023. The infection is transmitted via a cutaneous, oral, or respiratory route from an animal reservoir, and arthropod vectors are one route of contamination. In Europe, the ulcero-glandular form is the most common. Complications may arise if treatment is inadequate or delayed. Treatment is based on targeted antibiotic therapy. A number of simple preventive measures can be taken to limit transmission. This article provides an overview of current knowledge about tularemia, with practical recommendations for management illustrated by a real-life clinical situation.

Background. The use of extracorporeal membrane oxygenation (ECMO) after transplantation seems to be associated with an increased risk for infectious complications. We assessed the impact of ECMO use on the incidence of infectious diseases in a nationwide cohort of heart transplant recipients. Methods. Patients undergoing heart transplantation between 2008 and 2017 and enrolled in the Swiss Transplant Cohort Study were included. We calculated incidence rates of infection at 1-y posttransplant and used Cox regression to identify infection-associated risk factors according to the pathogen group. Results. We included 306 heart transplant recipients of whom 42 patients (13.7%) received ECMO in the posttransplant period. Incidence rates at 1 y for overall infection were 259 per 100 patient-years in the ECMO group (176 for bacterial, 52 for viral and 36 for fungal infections) and 126 per 100 patient-years in the non-ECMO group (68 for bacterial, 45 for viral and 14 for fungal infections). In the ECMO group, gram-negative bacterial infections predominated over gram-positive pathogens. Use of ECMO was associated with an increased risk of overall infections (hazard ratio 1.81 [95% CI. 1.02-3.19], P = 0.04) and fungal infections (hazard ratio 3.44 [95% CI, 1.33-8.89], P = 0.01). Conclusions. In this nationwide cohort of heart transplant recipients, the use of ECMO was associated with an increased risk for overall and fungal infections. More studies are needed to evaluate whether ECMO is independently associated with infection or a surrogate for a more critical patient condition.

Candida auris is a pathogenic yeast that can develop resistance to multiple antifungals, particularly to azoles (e.g. fluconazole). Milbemycin oxime potentiates the effect of fluconazole against Candida spp. by inhibiting ABC transporters, such as Cdr1, which is involved in azole drug efflux. This study aimed to assess the interaction of milbemycin oxime and fluconazole against clinical (n = 4) and laboratory-generated (n = 4) C. auris isolates with different mechanisms of azole resistance. Interactions of milbemycin oxime and fluconazole were assessed by chequerboard assays and defined as synergistic, indifferent or antagonistic according to the FIC index (FICI) values. The fluorescent substrate rhodamine 6 g (R6G) was used to measure ABC transporter activity in the absence or presence of milbemycin oxime. A synergistic interaction between milbemycin oxime and fluconazole was observed against most isolates, including those harbouring Cdr1-independent mechanisms of azole resistance (e.g. ERG11 mutations). The highest synergism was observed in a laboratory-generated strain overexpressing CDR1, while the interaction was indifferent in a strain lacking CDR1. R6G experiments confirmed the inhibitory effect of milbemycin oxime on ABC transporters. Milbemycin oxime could represent an interesting adjunctive therapy against azole-resistant C. auris, particularly those with CDR1 overexpression.

BACKGROUND:Posaconazole (POS) prophylaxis is recommended for the prevention of invasive mould infections among patients with haematologic cancer and prolonged neutropenia or following allogeneic haematopoietic cell transplantation. Albeit rare, breakthrough invasive mould infections (bIMI) are associated with high mortality rates. OBJECTIVES:To assess the epidemiology, causes and outcomes of bIMI under POS prophylaxis. PATIENTS/METHODS:Haematologic cancer patients with a diagnosis of proven/probable bIMI while receiving POS prophylaxis for ≥ 7 days were retrospectively included in five hospitals (Switzerland and Germany). For each bIMI case, one to two non-bIMI controls receiving POS prophylaxis for the same haematologic condition were included. RESULTS:A total of 29 bIMI episodes and 46 controls were included. Baseline characteristics and median POS trough concentrations did not significantly differ between the two groups. Invasive aspergillosis was the most frequent bIMI (52%), followed by invasive mucormycosis (31%). POS non-susceptible pathogens were the causes of bIMI in 14% of cases. While insufficient POS exposure was observed in 39% of bIMI cases, this proportion was similar in the control group. Most bIMI were treated with liposomal amphotericin B first-line therapy and received multiple antifungal therapies. Overall mortality was significantly higher among bIMI compared to controls (52% vs. 20%, p = 0.005). Surgery was the only parameter significantly associated with survival. CONCLUSIONS:This case-control study shows that bIMI is associated with a significant impact on mortality. Most bIMI were attributed to presumably POS-susceptible pathogens without a clear association with POS underexposure. The causes of bIMI remain unclear and may be the conjunction of multiple parameters.

Invasive fungal diseases are associated with significant morbidity and mortality, especially among immunocompromised patients, and often prompt for rapid and aggressive treatment aiming cure. Due to the expanding magnitude of patients burdened by chronic immunosuppression and affected by fungal diseases, the diversity of clinical settings has risen. This often results in prolonged therapy (induction, consolidation and maintenance) associated with potentially severe side effects, and clinicians face the challenging decisions of when and how to stop anti-fungal therapy. Adequate duration of therapy is poorly defined, hampered by the lack of dedicated trials to the question, the heterogeneity of cases (type of fungal pathogen, localization of infection, underlying host conditions) and various confounding factors that may influence the clinical response (e.g. persistence vs recovery of immunosuppression, impact of surgery). In this review, we aim to evaluate the existing data underlying the guidelines and recommendations of treatment duration for the most frequent invasive fungal diseases (cryptococcal meningitis, Pneumocystis pneumonia, invasive aspergillosis, invasive candidiasis and mucormycosis), as well as specific localizations of deep-seated diseases (osteo-articular or central nervous system diseases and endocarditis) and emerging considerations and strategies.

Contemporary data on the epidemiology and outcomes of invasive candidiasis (IC) in solid organ transplant recipients (SOTr) are limited. This retrospective multicenter cohort study, nested within the Swiss Transplant Cohort Study, describes the epidemiology and outcomes of IC in SOTr from 2008 to 2020. Among 4755 patients identified, 205 (4.3%) had 262 episodes of IC. One-year cumulative incidence of IC was 2.8% (95% confidence interval [CI], 2.4, 3.3) and decreased during the study period (P = .046). Candidemia was less frequently encountered (0.67%, 95% CI, 0.47, 0.94) than intra-abdominal (1.4%, 95% CI, 1.1, 1.7) and other infection sites (0.93%, 95% CI, 0.68, 1.2). Most infections occurred in the first year posttransplant (65.3%, 171/262), with Candida albicans being the most common species (69.6%, 181/262), followed by C. glabrata (27.4%, 32/117). All-cause 12-week mortality was 23.5%, highest in liver (34.5%) and heart (30%) transplant recipients. Candidemia was associated with a high 12-week mortality (51.1%), significantly impacting 1-year posttransplant mortality, especially if it occurred in the first 3 months (hazard ratio, 26; 95% CI, 14.2, 47.4). In conclusion, we report high rates of IC, predominantly intra-abdominal, with decreasing incidence during the study period. Mortality remains high, especially for liver and heart transplant recipients and in patients with candidemia. Those observations can inform future prophylactic and other strategies in the care of SOTr.

Invasive candidiasis affects 1.6 million people annually, with high mortality among immunocompromised and hospitalized patients. Echinocandins are frontline antifungals, but rising resistance limits their efficacy. Here, we show that Candida albicans and multidrug-resistant Candida auris share a conserved cell wall architecture yet differ markedly in their adaptive responses to echinocandins. Solid-state NMR reveals that both species possess a rigid inner layer of tightly associated chitin microfibrils and β-1,3-glucans, supported by a flexible matrix of β-1,6-glucans and additional β-1,3-glucans. Outer mannan fibrils rely on α-1,2-linked sidechains to maintain contact with the inner wall. In both species, caspofungin rigidifies β-1,6-glucans and mannan sidechains and reduces water permeability during β-1,3-glucan depletion; however, C. albicans undergoes wall thickening and alterations in chitin and glucan dynamics, whereas C. auris maintains integrity through β-1,6-glucan upregulation. Deletion of KRE6a, which encodes β-1,6-glucan synthase, reduces echinocandin susceptibility in C. auris, further highlighting β-1,6-glucan's critical role in adaptive remodeling.