Invasive candidiasis represents a major global health concern, with incidence and mortality rates expected to rise due to medical advancements and unavoidable risk factors. This retrospective, multicentric study was conducted in eight hospitals in a northeastern Italian region, enrolling adult patients diagnosed with candidemia from 1 January 2018 to 31 December 2022. Epidemiological trends and clinical characteristics were analyzed and compared to those from a prior regional study (2009-2011), allowing a fourteen-year comparative evaluation. A shift in species distribution was observed, with a decline in Candida albicans (from 65.7% to 57.8%) and a rise in non-albicans species, particularly the Candida parapsilosis complex (from 16.1% to 18.2%). Guideline adherence was assessed applying the EQUAL Candida score; scores ≥ than 11.5 were independently associated with improved in-hospital survival (HR 3.51, p < 0.001). Among individual score components, empiric echinocandin therapy and central venous catheter removal correlated with better outcomes. Centers with routine infectious disease (ID) consultations showed higher survival and adherence, reinforcing the value of specialist involvement. These findings support local epidemiological and management practice surveillance program adoption to address context-specific gaps, promote the adoption of best practices in Candida BSI management-as expanded ID specialist consultations and education programs-and, ultimately, reduce candidemia-related mortality rates.

Intra-abdominal candidiasis (IAC), with or without candidemia, is a common condition in patients in intensive care units (ICUs). Early diagnosis of IAC remains a challenge for clinicians despite new biomarkers. Early and appropriate antifungal treatment, which is associated with better clinical outcomes, is negatively affected by the increased isolation of non-albicans Candida strains that are resistant to the commonly used azoles and echinocandins. Based on the pharmacokinetic (PK) and pharmacodynamic (PD) properties of the different treatment options, liposomal amphotericin B, rezafungin or high doses of anidulafungin appear to be the most appropriate first-line options for complicated IAC in ICUs.

Candida species are the predominant cause of fungal infections in patients treated in hospital, contributing substantially to morbidity and mortality. Candidaemia and other forms of invasive candidiasis primarily affect patients who are immunocompromised or critically ill. In contrast, mucocutaneous forms of candidiasis, such as oral thrush and vulvovaginal candidiasis, can occur in otherwise healthy individuals. Although mucocutaneous candidiasis is generally not life-threatening, it can cause considerable discomfort, recurrent infections, and complications, particularly in patients with underlying conditions such as diabetes or in those taking immunosuppressive therapies. The rise of difficult-to-treat Candida infections is driven by new host factors and antifungal resistance. Pathogens, such as Candida auris (Candidozyma auris) and fluconazole-resistant Candida parapsilosis, pose serious global health risks. Recent taxonomic revisions have reclassified several Candida spp, potentially causing confusion in clinical practice. Current management guidelines are limited in scope, with poor coverage of emerging pathogens and new treatment options. In this Review, we provide updated recommendations for managing Candida infections, with detailed evidence summaries available in the appendix.

Serum 1,3-β-d-glucan (BDG) tests are frequently used for diagnosing invasive candidiasis. However, BDG tests remain negative in many patients with candidemia, and factors influencing the probability for positive test results are poorly understood.

To study clinical and microbiological factors predictive of a positive BDG test, as well as the association of a positive BDG test with mortality in patients with candidemia.

In a retrospective cohort of patients with candidemia, BDG was analysed by the Glucatell assay and the Wako Beta-Glucan Test. Predisposing conditions, focus of infection and other variables were retrieved from medical charts and laboratory databases. Their association with a positive BDG test, and the association between positive BDG and death was tested in univariate analysis and multivariable logistic regression.

We included 134 patients with candidemia. Positive BDG and a non-abdominal deep-seated focus of infection (e.g., hematogenously disseminated infection and deep mediastinal/pleural candidiasis) were positively correlated in univariate and multivariable analyses [Wako adjusted odds ratio 9.11 (95% CI 1.66-172, p = 0.039), Glucatell adjOR 9.14 (95% CI 1.66-172, p = 0.039)]. Having a positive BDG test increased the risk for 90 days mortality after controlling for potential confounders, mainly age, septic shock, and ICU admission [Wako adjOR 4.73 (95% CI 1.71-14.7, p = 0.0043), Glucatell adjOR 3.59 (95% CI 1.33-10.6, p = 0.015)].

In patients with candidemia, a positive BDG test is more common in the presence of a concomitant non-abdominal deep-seated infection. Patients with a positive BDG test have a higher 90-day mortality.

The increasing prevalence of candidemia and invasive candidiasis infections caused by Candida auris represents a global health risk. Such infections are difficult to treat as they are often multidrug-resistant and are linked to high rates of mortality. Rezafungin is a second-generation echinocandin with antifungal activity against a range of Candida species, including wild type, and azole- and some echinocandin-resistant isolates. Its stability and prolonged half-life permit less frequent dosing compared with other echinocandins, leading to high front-loaded exposures and potential earlier mycological clearance from infection sites. These properties make rezafungin a candidate for the treatment of candidemia and invasive candidiasis infections due to C. auris. Accordingly, this narrative review article describes available evidence for the activity and effectiveness of rezafungin against C. auris isolates and infections. To date, the activity of rezafungin against C. auris isolates and infections has been demonstrated in in vitro and in vivo non-clinical experiments, and in pharmacokinetic/pharmacodynamic target attainment estimations utilizing clinical data. With similar potency to other echinocandins, rezafungin demonstrates in vitro and in vivo activity that is comparable to or better than that seen with other echinocandins, and similar to that for rezafungin in other Candida species. Like other echinocandins, its activity is reduced in fks-mutant isolates. Although there is currently a dearth of data on the therapeutic activity of rezafungin against C. auris, it is reasonable that rezafungin may be a viable choice for treating candidemia and invasive candidiasis caused by C. auris. Further clinical investigations are necessary.

Invasive candidiasis is a life-threatening infection associated with high mortality, necessitating early and effective treatment. Micafungin, an echinocandin, is recommended as initial therapy for invasive candidiasis. However, the optimal micafungin dose relative to patients' body constitutional parameters (BCPs) remains unclear. This study aimed to evaluate the relationship between the dose of micafungin per BCPs (Dose/BCPs) and treatment outcomes.

This two-center retrospective study included patients treated with micafungin who had confirmed positive blood cultures for Candida species between January 1, 2010, and December 31, 2020. We assessed the association between Dose/BCP and treatment success, as well as time to recovery following micafungin therapy.

Eighty-three patients were included in the analysis, with a median age of 78 years. The primary isolated Candida species were Candida albicans (n = 34), Candida parapsilosis (n = 19), and Candida glabrata (n = 16). The treatment success rate was 44.6 % and was significantly associated with age ≥75 years. Although no significant differences in Dose/BCP were observed between the success and failure groups, patients with a Dose/BSA ≥100 mg/m2 experienced a significantly shorter time to recovery with micafungin therapy.

Our study identified an association between Dose/BSA and the time to recovery with micafungin therapy. While some missing data, including APACHE-II scores, limit the robustness of the findings because of the retrospective design, dose adjustment to achieve Dose/BSA ≥100 mg/m2 may be beneficial in antifungal stewardship. This adjustment could reduce treatment duration with this broad-spectrum antifungal agent.

Invasive fungal infections in the intensive care unit (ICU) are not uncommon and most cases are caused by Candida species, specifically Candida albicans. However, recently, there has been an increase in non-albicans Candida spp. (C. glabrata; C. parapsilosis) causing invasive fungal infections. This has led to an increasing awareness of this infection due to the increase in documented antifungal resistance in many of these Candida species. In addition, manifestations of invasive candidiasis are often non-specific, and the diagnosis remains extremely challenging. Unfortunately, delays in antifungal therapy continue to hamper the morbidity; length of stay; and the mortality of these infections. Although the echinocandins are the drugs of choice in these infections, antifungal resistance among the non-albicans species (C. glabrata; C. krusei; C. auris; C. parapsilosis) is being observed more frequently. This has led to an increase in morbidity and mortality, specifically in critically ill patients. Overall, the diagnosis and management of invasive candidiasis in the ICU remain challenging. It is imperative that the critical care physician keeps this infection at the forefront of their differential diagnosis in order to decrease the mortality rate of these individuals. In this review, we discuss the current epidemiologic trends, diagnosis, and management of invasive candidiasis in the intensive care unit setting.

The rising prevalence of fungal infections, especially those caused by Candida species, presents a major risk to global health. With approximately 1.5 million deaths annually, the urgency for effective treatment options has never been greater. Candida spp. are the leading cause of invasive infections, significantly impacting immunocompromised patients and those in healthcare settings. C. albicans, C. parapsilosis and the emerging species C. auris are categorized as highly dangerous species because of their pathogenic potential and increasing drug resistance. This review comparatively describes the formation of microbial biofilms of both bacterial and fungal origin, including major pathogens, thereby creating a novel focus. Biofilms can further complicate treatment, as these structures provide enhanced resistance to antifungal therapies. Traditional antifungal agents, including polyenes, azoles and echinocandins, have shown effectiveness, yet resistance development continues to rise, necessitating the exploration of novel therapeutic approaches. Antimicrobial peptides (AMPs) such as the anti-biofilm peptides Pom-1 and Cm-p5 originally isolated from snails represent promising candidates due to their unique mechanisms of action and neglectable cytotoxicity. This review article discusses the challenges posed by Candida infections, the characteristics of important species, the role of biofilms in virulence and the potential of new therapeutic options like AMPs.

Candidemia and invasive candidiasis represent critical healthcare-associated fungal infections that pose substantial challenges to medical systems worldwide. These conditions arise when fungi from the Candida genus infiltrate the bloodstream or deeper tissues, leading to a range of clinical manifestations. Among the various species, Candida albicans continues to hold its position as the most frequently encountered causative agent, largely due to its prevalence and adaptability within human hosts. However, it is far from the only significant player; other Candida species, such as Candida glabrata, Candida parapsilosis, and the particularly concerning Candida auris, contribute significantly to the disease burden and exhibit varying dominance depending on geographic regions. The clinical presentation of these infections can differ widely, spanning from subtle, almost imperceptible symptoms in some patients to severe, life-threatening fulminant sepsis in others, often accompanied by alarmingly high mortality rates that underscore the urgency of effective management strategies. Several well-established risk factors predispose individuals to developing invasive candidiasis and candidemia. Breaches in the body's natural barriers-such as the skin (cutaneous) or the gastrointestinal (GI) tract-provide entry points for these opportunistic pathogens. Additionally, deficiencies in the host's immune responses, whether due to medical treatments, underlying diseases, or genetic predispositions, heighten vulnerability to infection. Among the diverse Candida species, Candida auris has emerged as an especially troubling entity in recent years. This multidrug-resistant species is notorious for its resistance to standard antifungal therapies, which complicates treatment efforts and contributes to elevated morbidity and mortality rates. Its rapid global spread has positioned it as a formidable public health threat, prompting heightened surveillance and research into its behavior and control.

Rezafungin (Rezzayo®) is a next-generation echinocandin antifungal with improved pharmacokinetic properties over first-generation echinocandins that allows for once-weekly rather than once-daily intravenous administration. It has recently been approved for the treatment of adults with invasive candidiasis in the EU and UK, and is approved for adults who have limited or no alternative options for the treatment of candidaemia and invasive candidiasis in the USA. In the pivotal phase 3 ReSTORE trial, rezafungin was non-inferior to caspofungin (a first-line echinocandin antifungal agent) based both on global cure rates at day 14 and all-cause mortality rates at day 30 in adults with candidaemia or invasive candidiasis. Additionally, the once-weekly administration of rezafungin has the potential advantage of front-loading the dose and increasing drug exposure, with some evidence suggesting that rezafungin may achieve earlier infection clearance relative to caspofungin. Rezafungin was generally well tolerated, with the most common treatment-emergent adverse events being hypokalaemia, pyrexia, diarrhoea and anaemia. Therefore, rezafungin is a useful addition to the treatments currently available for invasive candidiasis in adults, with potential benefits associated with less frequent administration compared with first-generation echinocandins.

Currently, the molecular mechanisms of azole resistance in C. glabrata are unresolved. This study aims to detect azole resistance of C. glabrata after exposure to fluconazole (Diflucan) in vitro. After 50 days of induction, the five susceptible isolates of C. glabrata demonstrated cross-resistance to azoles (fluconazole (Diflucan), voriconazole and itraconazole). Mutations in PDR1 or ERG11 genes are key nodes in azole resistance of C. glabrata. DNA-Sequencing revealed three(3/5) fluconazole (Diflucan)-resistant isolates had undergone missense mutations (R376Q, R772K, E1083K in PDR1 and F135L in ERG11), all of which were newly discovered and previously unreported. mRNA expression of resistant genes in five resistant isolated was elevated, with CDR1 being the most prominent. Analysis using flow cytometry revealed that resistant strains showed decreased R6G uptake and increased efflux efficiency, but no obvious significance difference in biofilm production. C. glabrata acquires azole cross-resistance upon continuous exposed to fluconazole (Diflucan) and could remain resistant without antifungal agents. The development of azole resistance in C. glabrata has been linked to genes associated with efflux pump transporters and the ergosterol synthesis pathway. However, the relationship between resistance and newly discovered missense mutation sites requires further investigation.

Candidaemia in children is associated with high mortality. The epidemiology of Candida bloodstream infection is changing with rising rates of fluconazole resistance worldwide and the emergence of novel multidrug-resistant species such as Candida auris, which is associated with outbreaks. Guidelines on the management of candidaemia emphasise identification of species and determination of antifungal susceptibility to guide appropriate treatment, performing relevant investigations to rule out deep-seated infection, and removal of central venous catheters. However, it is difficult to apply guidelines in routine practice. The European Confederation of Medical Mycology candidaemia scoring tool (the EQUAL score) has facilitated adherence to guidelines by using a point-based system. We have designed a point-based paediatric EQUAL (paed-EQUAL) score tool for the management of candidaemia in neonates and children. The paed-EQUAL scoring tool can be applied to improve guideline adherence and facilitate antifungal stewardship.

Outcomes are reported for 6 adults receiving rezafungin for chronic, hard-to-treat, invasive candidiasis (including Candida parapsilosis) during an early access program. Rezafungin was well tolerated and administered via once-weekly outpatient intravenous infusion for up to 39 weeks during the program, enabling hospital discharge and replacing daily antifungal infusions.

Achieving and maintaining therapeutic drug exposures with antifungals can be challenging in special patient populations, such as those with organ dysfunction (liver or kidney) or obesity, or elderly patients, due to dose-exposure relationships and potential drug-drug interactions. Dose adjustments may be needed in these populations to maintain therapeutic efficacy and/or prevent toxicity. We reviewed specific dosing considerations for antifungals in special populations with candidaemia and/or invasive candidiasis, focusing on those relating to echinocandins (based on prescribing information), and then explored the utility of the second-generation echinocandin rezafungin in treating these populations (based on currently available data identified from a PubMed and congress abstract search). Available data showed that echinocandins may sometimes require dosing modifications for special populations with candidaemia/invasive candidiasis, primarily due to decreases in pharmacokinetic exposures. Rezafungin appears to be suitable for use in a variety of special populations without the need for dose modifications based on available data, including patients with organ dysfunction or obesity, and elderly and critically ill patients. Further research is needed in populations where rezafungin data are not available including children, people living with HIV, patients receiving extracorporeal membrane oxygenation and those with underlying neurological conditions.

Candidemia infection remains a critical challenge in intensive care units (ICUs), with high morbidity and mortality rates despite advances in therapeutic practices. This multicenter prospective surveillance study assessed the epidemiology, clinical management, and mortality predictors of candidemia in critically ill patients across two periods (2010-2012 and 2017-2018) in 11 tertiary hospitals in Brazil. Among 314 ICU patients with candidemia, the overall mortality rate was 60.2%, with no significant reduction over time (58.8% vs. 62.6%, p = 0.721). Candida albicans was the predominant pathogen (43.6%), followed by C. tropicalis (20%) and C. glabrata (13.7%). The use of echinocandins increased significantly in the second period (21.1% to 41.7%, p < 0.001); however, 70% of patients still did not receive these agents as first-line therapy. Catheter removal due to candidemia was performed in only 52.1% of cases but was associated with improved 30-day survival (p < 0.001). Multivariate analysis identified cancer, inadequate treatment, and vasoactive drug use as independent predictors of mortality. Our findings underscore persistent gaps in adherence to guidelines, particularly regarding timely echinocandin initiation and catheter removal. Strengthening therapeutic strategies focused on these key interventions is essential to improving outcomes for ICU patients with candidemia.

A post hoc analysis used pooled STRIVE/ReSTORE trial data to determine outcomes with rezafungin versus caspofungin by Candida species and antifungal susceptibility.

The efficacy and safety of once weekly rezafungin 400/200 mg versus once daily caspofungin 70/50 mg was demonstrated in the randomized, 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 MICs. Susceptibility was determined using European Committee on Antimicrobial Susceptibility Testing E.Def 7.4 broth microdilution methodology, with Tween 20-supplemented medium for rezafungin.

A total of 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 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.

Rezafungin appears to be an effective treatment for candidaemia/invasive candidiasis irrespective of baseline Candida species.

Secondary peritonitis with intra-abdominal abscesses (IAA) is difficult to treat because of the supposed low rate of penetration of antimicrobial drugs at the site of infection. However, clinical data about the actual bioavailability of antimicrobial drugs in IAA are scarce. This prospective observational study aimed at assessing the drug penetration in IAA of the antibiotics (piperacillin-tazobactam, carbapenems) and antifungals (fluconazole, echinocandins) that are usually recommended for the treatment of intra-abdominal infections. Patients with IAA who underwent a radiological or surgical drainage procedure were included. Antimicrobial drug concentrations were measured in IAA (CIAA) and in a simultaneous plasma sample (Cplasma) to assess the CIAA/Cplasma ratio. The pharmacodynamic target was defined as a CIAA equal or superior to the clinical breakpoints of susceptibility of the most relevant intra-abdominal pathogens. Clinical outcomes were assessed at hospital discharge. A total of 54 antimicrobial drug measurements were performed in 39 IAA samples originating from 36 patients. Despite important inter-individual variability, piperacillin-tazobactam exhibited the highest CIAA/Cplasma ratios (median 2). The rates of target achievement were 75%-80% for piperacillin-tazobactam and meropenem but 0% for imipenem and ertapenem. These results tended to correlate with clinical outcomes (96% success rate versus 73%, respectively, P = 0.07). Among antifungals, fluconazole exhibited higher CIAA/Cplasma ratios and rates of target achievement compared to echinocandins. However, no differences in clinical outcomes were observed. These results provide unique information about antimicrobial drug penetration in IAA in real clinical conditions and suggest that piperacillin-tazobactam and meropenem may have better efficacy compared to imipenem or ertapenem.

Multidrug resistance in the pathogenic fungus Candida glabrata is a growing global threat. Here, we study mechanisms of multidrug resistance in this pathogen. Exposure of C. glabrata cells to micafungin (an echinocandin) leads to the isolation of a mutant exhibiting resistance to echinocandin and azole antifungals. The drug-resistant phenotype is due to a non-synonymous mutation (R70H) in gene IPI1, which is involved in pre-rRNA processing. Azole resistance in the ipi1R70H mutant depends on the Pdr1 transcription factor, which regulates the expression of multidrug transporters. The C. glabrata Ipi1 protein physically interacts with the ribosome-related chaperones Ssb and Ssz1, both of which bind to Pdr1. The Ipi1-Ssb/Ssz1 complex inhibits Pdr1-mediated gene expression and multidrug resistance in C. glabrata, in contrast to Saccharomyces cerevisiae where Ssz1 acts as a positive regulator of Pdr1. Furthermore, micafungin exposure reduces metabolic activity and cell proliferation in the ipi1R70H mutant, which may contribute to micafungin tolerance.

Intra-abdominal candidiasis (IAC) is associated with significant diagnostic and therapeutic challenges in critically ill patients. Traditional fungal cultures are slow, delaying appropriate antifungal treatment. (1,3)-β-D-glucan (BDG), a component of the fungal cell wall, has emerged as a potential biomarker for IAC, but its use in ICU settings is complicated by frequent false-positives results from invasive procedures and underlying conditions. This review examines the diagnostic value of BDG when present in serum and peritoneal fluid. While serum BDG is effective for excluding invasive fungal infections like candidemia, its specificity for IAC remains low in critically ill patients. Recent studies suggest that BDG levels in peritoneal fluid may provide better diagnostic accuracy, distinguishing IAC from bacterial peritonitis with higher specificity. We discuss the advantages, limitations, and practical aspects of BDG testing, emphasizing the potential of peritoneal BDG as a complementary tool. Further research is needed to refine diagnostic thresholds, validate its clinical utility, and establish the role of peritoneal BDG in improving timely, targeted antifungal treatment for IAC.

Oral diseases such as dental caries, periodontitis, and oral cancer are prevalent and present significant challenges to global public health. Although these diseases are typically treated through procedures like dental preparation and resin filling, scaling and root planning, or surgical excision, these interventions are often not entirely effective, and postoperative drug therapy is usually required. Traditional drug treatments, however, are limited by factors such as poor drug penetration, significant side effects, and the development of drug resistance. As a result, there is a growing need for novel drug delivery systems that can enhance therapeutic efficacy, reduce side effects, and improve treatment outcomes. In recent years, drug-loaded vesicles, such as liposomes, polymersomes, and extracellular vesicles (EVs), have emerged as promising drug delivery platforms due to their high drug encapsulation efficiency, controlled release properties, and excellent biocompatibility. This review provides an in-depth examination of the characteristics, advantages, and limitations of liposomes, polymersomes, and extracellular vesicles in the context of oral disease treatment. It further explores the reasons for their advantages and limitations and discusses the specific applications, development prospects, and strategies for optimizing these vesicle-based systems for improved clinical outcomes.

Echinocandin drugs are the current first-line therapy for fungal infections caused by Candida spp. Most patients require once-daily intravenous (IV) administration in a hospital or outpatient setting for treatment, which may negatively impact their quality of life and stress healthcare resources. Similar to other echinocandins, the novel FDA-, EMA-, and Medical and Healthcare Products Regulatory Agency-approved echinocandin, rezafungin (CD101), exhibited strong antifungal activity against several fungal pathogens and a low drug-drug interaction liability, which are important for medically complex patients. A pharmacometric-based approach has been adopted throughout the development of rezafungin, which contrasts with older echinocandins where dosing regimens were largely derived empirically, and only recently based on pharmacometric guidance. This state-of-the-art approach used model-based simulations incorporating pre-clinical and clinical data as it became available to optimize the dosing regimen for rezafungin. The enhanced stability of the molecular structure and the safety profile of rezafungin allow for the administration of once-weekly IV doses, compared to the daily dosing requirement for other echinocandin drugs, with this distinctive pharmacokinetic profile of rezafungin resulting in a front-loaded dosing regimen with high exposures early in therapy for enhanced fungal killing. The long shelf-life of rezafungin makes this echinocandin more flexible in terms of storage and manufacturing. Demonstrated across clinical development, rezafungin may provide patients with next-generation first-line antifungal treatment for the treatment of candidaemia and invasive candidiasis.

In the intensive care unit (ICU), patients undergoing mechanical ventilation (MV) often exhibit Candida colonization. This study aims to systematically review and analyze the effects of Candida colonization on the outcomes of mechanically ventilated patients and its relationship with bacterial pathogens associated with ventilator-associated pneumonia (VAP).

We conducted a comprehensive search across PubMed, Embase, Web of Science (WOS), and the Cochrane Central Register of Controlled Trials (CENTRAL) without language restrictions to identify eligible studies. Inclusion criteria involved patients undergoing MV for >2 days, encompassing those with clinically suspected VAP (csVAP), and confirmed VAP patients. We assessed the impact of Candida colonization on patient prognosis, length of ICU stay, bacterial pathogens responsible for VAP, and inflammatory markers. The study protocol was registered with PROSPER (CRD42024580547).

Thirteen studies involving 3,802 patients were included in our analysis. The prevalence of Candida colonization among MV patients ranged from 10 % to 56 %. Our findings indicated that Candida airway colonization was associated with poorer patient prognosis (95 % CI 1.13-1.52, p < 0.05, I² = 39 %). Among patients who developed VAP, Candida colonization correlated with increased detection rates of Pseudomonas aeruginosa (RR = 1.37, 95 % CI 1.07-1.75, p = 0.01, I² = 3 %) and Acinetobacter baumannii (RR= 1.48, 95 % CI 1.17-1.86, p < 0.01, I² = 27 %). Additionally, an association with antibiotic resistance was observed, although the quality of evidence was low. In studies that recorded patients' inflammatory markers, no significant effect of Candida colonization on inflammatory markers (procalcitonin, interleukin-6) was observed.

Candida airway colonization is highly prevalent among mechanically ventilated patients and should be considered a marker of poor prognosis when it occurs. Antibiotics should be used more carefully when Candida colonization is detected in the respiratory tract of mechanically ventilated patients.

Rezafungin, formerly SP3025 and CD101, is a next-generation echinocandin, chemically related to anidulafungin, with differentiated pharmacokinetic characteristics, including a prolonged half-life allowing extended-interval dosing.

Herein, we discuss the role of rezafungin in the treatment of candidemia and invasive candidiasis, with a specific focus on pharmacokinetics considerations.

Rezafungin exhibits potent in vitro activity against most wild-type and azole-resistant Candida species, including Candida auris. The differentiated PK characteristics of rezafungin which enables once weekly dosing could reduce catheter overuse and provide a rapid transition to outpatient treatment for Candida infections in which azoles cannot be used, due to resistance or drug-drug interactions. Besides weekly dosing, other potential pharmacokinetic/pharmacodynamic advantages of rezafungin are its good penetration into anatomically challenging sites and a potentially reduced probability of local resistance promotion, making it an attractive option also for deep-seated infections that could warrant dedicated clinical investigation.

Candida species are the most common cause of invasive fungal disease, and children with hematologic malignancy are at increased risk. Non- albicans Candida (NAC) now account for more than half of all invasive candidiasis (IC) and carry a worse prognosis. We aimed to compare the epidemiology, risk factors, organ dissemination, biomarkers and outcomes in IC based on the species implicated and evaluate trends in antifungal resistance over time.

Patients 0-18 years of age with hematologic malignancy and IC at 2 centers were included. Fifty-three patients from 2011 to 2022 were identified. Information related to demographics, host and risk factors, Candida species and antifungal susceptibilities, treatment and outcomes was collected via retrospective chart review. Data were analyzed at the species level.

The incidence rate of IC was 29 per 1000 patients with leukemia and lymphoma. The median time to infection from diagnosis of malignancy was 38 days. Candida tropicalis (n = 17; 30%) was the most identified species followed by Candida albicans (n = 14; 25%). Patients with C. tropicalis infection were more likely to have dissemination to the eyes ( P = 0.035), spleen ( P = 0.001) and skin ( P = 0.003) than patients with C. albicans or other NAC. Of the 34 patients who underwent dilated retinal examination, 24% (n = 8) had evidence of intraocular candidiasis. Seven of the 8 patients with intraocular disease had prolonged candidemia (3 or more days; P = 0.003). The 12-week crude mortality rate was 16.9%.

NAC, specifically C. tropicalis , accounted for most of the IC in children with hematological malignancies. Screening for intraocular candidiasis continues to play an important role in patients with IC, and future studies are needed to determine if screening can be limited to patients with select risk factors.

Anidulafungin is recommended as a first-line treatment for invasive Candida infections in critically ill patients. Pharmacokinetic (PK) variability is large in critically ill patients, potentially compromising pharmacokinetic-pharmacodynamic (PKPD) target attainment under standard dosing. We aimed to assess anidulafungin exposure, PKPD target attainment, and population (pop)PK in critically ill patients.

Adult ICU patients receiving standard anidulafungin dosing [200 mg on day 1, then 100 mg daily] were included (NCT04045366). We performed rich blood sampling on an early (day 2 ± 1) and/or late (day 5 ± 1) treatment day. Using total anidulafungin plasma concentrations, we developed a popPK model (NONMEM7.5) and conducted Monte Carlo simulations (n = 1,000 per virtual patient) to evaluate the impact of patient factors on PKPD target attainment (AUC24h target 83.5 mg×h/L).

Twenty patients contributed 188 anidulafungin concentrations. PKPD target attainment was 45% and 65% on early and late sampling days, respectively. A two-compartment popPK model with first-order elimination described the data. Anidulafungin clearance increased with bodyweight and central volume of distribution increased as serum albumin decreased. Both bodyweight and serum albumin had a clinically relevant impact on PKPD target attainment at day 1 (area under the ROC curve; AUROC 0.82 and 0.62, respectively), and bodyweight on PKPD target attainment at day 14 (AUROC 0.94). Standard anidulafungin dosing regimen fails to achieve adequate target attainment throughout the treatment period.

Standard anidulafungin dosing is insufficient for achieving adequate exposure in critically ill patients. An interactive simulation tool is provided to aid dose-finding research and explore different dosing strategies and targets.

Candida auris is a pathogenic yeast of particular concern because of its ability to cause nosocomial outbreaks of invasive candidiasis (IC) and to develop resistance to all current antifungal drug classes. Most C. auris clinical isolates are resistant to fluconazole, an azole drug that is used for the treatment of IC. Azole resistance may arise from diverse mechanisms, such as mutations of the target gene (ERG11) or upregulation of efflux pumps via gain of function mutations of the transcription factors TAC1 and/or MRR1. To explore novel mechanisms of azole resistance in C. auris, we applied an in vitro evolutionary protocol to induce azole resistance in a TAC1A/TAC1B/MRR1 triple-deletion strain. Azole-resistant isolates without ERG11 mutations were further analyzed. In addition to a whole chromosome aneuploidy of chromosome 5, amino acid substitutions were recovered in the transcription factor Upc2 (N592S, L499F), the ubiquitin ligase complex consisting of Ubr2 (P708T, H1275P) and Mub1 (Y765*), and the mitochondrial protein Mrs7 (D293H). Genetic introduction of these mutations in an azole-susceptible wild-type C. auris isolate of clade IV resulted in significantly decreased azole susceptibility. Real-time reverse transcription PCR analyses were performed to assess the impact of these mutations on the expression of genes involved in azole resistance, such as ERG11, the efflux pumps CDR1 and MDR1 or the transcription factor RPN4. In conclusion, this work provides further insights in the complex and multiple pathways of azole resistance of C. auris. Further analyses would be warranted to assess their respective role in azole resistance of clinical isolates.

The incidence of invasive fungal infections is increasing in immune-competent and immune-compromised patients. An examination of the recent literature related to the treatment of fungal infections was performed to address two clinical questions. First, in patients with proven or probable invasive pulmonary aspergillosis, should combination therapy with a mold-active triazole plus echinocandin be administered vs. mold-active triazole monotherapy? Second, in critically ill patients at risk for invasive candidiasis who are non-neutropenic and are not transplant recipients, should systemic antifungal agents be administered either as prophylaxis or as empiric therapy?

A multidisciplinary panel reviewed the available data concerning the two questions. The evidence was evaluated, and recommendations were generated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.

A conditional recommendation was made for patients with proven or probable invasive pulmonary aspergillosis to receive either initial combination therapy with a mold-active triazole plus an echinocandin or initial mold-active triazole monotherapy based on low-quality evidence. Further, a conditional weak recommendation was made against routine administration of prophylactic or empiric antifungal agents targeting Candida species for critically ill patients without neutropenia or a history of transplant based on low-quality evidence.

The recommendations presented in these Guidelines are the result of an analysis of currently available evidence. Additional research and new clinical data will prompt an update in the future.

Fungal infections are increasingly prevalent; however, antifungal stewardship attracts little funding or attention. Previous studies have shown that knowledge of guidelines and scientific evidence regarding antifungals is poor, leading to prescribing based on personal experiences and the inherent biases this entails. We carried out a retrospective study of inpatient antifungal usage at two major hospitals. We assessed the longitudinal trends in antifungal usage and the effect of COVID-19 on antifungal prescription, alongside levels of empirical and diagnostically targeted antifungal usage. Our results showed that the longitudinal patterns of total systemic antifungal usage within the trusts were similar to national prescribing trends; however, the composition of antifungals varied considerably, even when looking exclusively at the more homogenous group of COVID-19 patients. We showed a high level of empirical antifungal use in COVID-19 patients, with neither trust adhering to international recommendations and instead appearing to follow prior prescribing habits. This study highlights the significant challenges to optimise antifungal use with prescribing behaviour largely dictated by habit, a lack of adherence to guidelines, and high rates of empirical non-diagnostic-based prescribing. Further research and resources are required to understand the impact of antifungal stewardship on improving antifungal prescribing behaviours in this setting and the effects on outcome.

Invasive candidiasis/candidemia (IC/C) is associated with a substantial health economic burden driven primarily by prolonged hospital stay. The once-weekly IV echinocandin, rezafungin acetate, has demonstrated non-inferiority to caspofungin in the treatment of IC/C. This paper reports a post hoc pooled exploratory analysis of length of stay (LoS) for hospital and intensive care unit (ICU) stays in two previously published clinical trials (ReSTORE [NCT03667690] and STRIVE [NCT02734862], that compared rezafungin with daily IV caspofungin (stable patients in the caspofungin group who met relevant criteria could step down to fluconazole after 3 days or more).

LoS outcomes were analysed descriptively in the pooled modified intention to treat (mITT) population (all patients who had a documented Candida infection in line with trial requirements and received at least one dose of study drug). In addition, to adjust for an imbalance between treatment groups in the proportion receiving mechanical ventilation at baseline, a generalised linear model with mechanical ventilation as a binary covariate was applied. Responses to an exploratory question in the phase 3 trial on possible earlier discharge with weekly rezafungin are also reported.

294 patients were included (rezafungin 139, caspofungin 155), of whom 126 (43%) had ICU admission. Patients treated with rezafungin had a numerically shorter LoS than with caspofungin in all analyses. Mean total LoS was 25.2 days, vs 28.3 days with caspofungin, and mean ICU LoS was 16.1 vs 21.6 days for rezafungin and caspofungin, respectively. After adjustment for mechanical ventilation status the difference in ICU LoS was 4.1 days, a relative difference of 24% (95% CI -11%, 72%). Physicians would have considered earlier discharge for 16% of patients (30/187) with weekly rezafungin, an average of 5-6 days earlier.

Rezafungin may enable shorter hospital and ICU LoS in IC/C compared with daily IV caspofungin, with accompanying savings in resource use. Further research is needed to confirm this in the real-world setting.

NCT03667690 (ReSTORE; September 12, 2018); NCT02734862 (STRIVE; April 12, 2016).

The global burden of invasive fungal disease is substantial and escalating. Combination antifungal therapy (CAF) may improve patient outcomes by reducing development of resistance, improving drug penetration and rate of fungal clearance, and allowing for lower and less toxic antifungal drug doses; yet, increased cost, antagonism, drug-drug interactions, and toxicity are concerns. Clinical practice guidelines recommend antifungal monotherapy, rather than CAF, for most invasive fungal diseases due to a lack of comparative randomized clinical trials. An examination of the existing body of CAF research should frame new hypotheses and determine priorities for future CAF clinical trials. We performed a systematic review of CAF clinical studies for invasive candidiasis, cryptococcosis, invasive aspergillosis, and mucormycosis. Additionally, we summarized findings from animal models of CAF and assessed laboratory methods available to evaluate CAF efficacy. Future CAF trials should be prioritized according to animal models showing improved survival and observational clinical data supporting efficacy and safety.

Rezafungin is an echinocandin approved in the US and EU to treat candidaemia and/or invasive candidiasis. This post-hoc, pooled analysis of the Phase 2 STRIVE and Phase 3 ReSTORE trials assessed rezafungin versus caspofungin in patients with candidaemia and/or invasive candidiasis (IC) in the intensive care unit (ICU) at randomisation.

STRIVE and ReSTORE were randomised double-blind trials in adults with systemic signs and mycological confirmation of candidaemia and/or IC in blood or a normally sterile site ≤ 96 h before randomisation. Data were pooled for patients in the ICU at randomisation who received intravenous rezafungin (400 mg loading dose then 200 mg once weekly) or caspofungin (70 mg loading dose then 50 mg once daily) for ≤ 4 weeks. Outcomes were Day 30 all-cause mortality (primary outcome), Day 5 and 14 mycological eradication, time to negative blood culture, mortality attributable to candidaemia/invasive candidiasis, safety, and pharmacokinetics.

Of 294 patients in STRIVE/ReSTORE, 113 were in the ICU at randomisation (rezafungin n = 46; caspofungin n = 67). At baseline, ~ 30% of patients in each group had impaired renal function and/or an Acute Physiologic Assessment and Chronic Health Evaluation II score ≥ 20. One patient (in the caspofungin group) was neutropenic at baseline. Day 30 all-cause mortality was 34.8% for rezafungin versus 25.4% for caspofungin. Day 5 and 14 mycological eradication was 78.3% and 71.7% for rezafungin versus 59.7% and 65.7% for caspofungin, respectively. Median time to negative blood culture was 18 (interquartile range, 12.6-43.0) versus 38 (interquartile range, 15.9-211.3) h for rezafungin versus caspofungin (stratified log-rank P = 0.001; nominal, not adjusted for multiplicity). Candidaemia/IC-attributable deaths occurred in two rezafungin patients versus one caspofungin patient. Safety profiles were similar between groups. Overall, 17.4% (rezafungin) versus 29.9% (caspofungin) of patients discontinued due to treatment-emergent adverse events. Rezafungin exposure following the initial 400-mg dose was comparable between patients in the ICU at randomisation (n = 50) and non-ICU patients (n = 117).

Rezafungin was well tolerated and efficacious in critically ill, mainly non-neutropenic patients with candidaemia and/or IC. This analysis provides additional insights into the efficacy and safety of rezafungin in the ICU population.

This study aimed to use systematic review and meta-analysis to establish the influence of antifungal therapy on pulmonary Candida colonisation of patients with mechanical ventilation (MV).

Systematic review and meta-analysis.

An extensive search was undertaken on publications from inception to 25 July 2023, through PubMed, Web of Science, Medline, Embase, China National Knowledge Infrastructure, Wanfang Data and VIP Databases.

Randomised trials, cohort studies and case-control studies comparing the efficacy of antifungal treatment in immunocompetent patients with pulmonary Candida colonisation after invasive ventilation.

Two reviewers independently extracted the data and assessed the quality of studies. Dichotomous outcomes were expressed as ORs with 95% CIs. Continuous outcomes were expressed as standardised mean differences (SMD) with 95% CIs.

The primary outcomes included intensive care unit (ICU), hospital, 28-day, and 90-day mortality. The secondary outcomes included ICU length of stay, MV duration and ventilator-associated pneumonia (VAP).

Nine high-quality studies were included. According to the data collected from these nine studies, there is no significant evidence showing a difference between the therapy group treated with antifungal drugs and the control group without antifungal drugs in clinical outcomes, including ICU mortality (OR: 1.37; 95% CI 0.84 to 2.22), hospital mortality (OR: 1.17; 95% CI 0.57 to 2.38), 28-day mortality (OR: 0.71; 95% CI 0.45 to 1.14), 90-day mortality (OR: 0.76; 95% CI 0.35 to 1.63), ICU length of stay (SMD: -0.15; 95% CI -0.88 to 0.59), MV duration (SMD: 0.11; 95% CI -0.88 to 1.10) and VAP (OR: 1.54; 95% CI 0.56 to 4.20). Subgroup analysis of different treatment types indicates that the combined effect size is stable and unaffected by different treatment types including inhalation (OR: 2.32; 95% CI 0.30 to 18.09) and intravenous (OR: 0.65; 95% CI 0.13 to 3.34).

The application of antifungal treatment did not improve clinical outcomes in patients with MV. We do not suggest initiating antifungal treatment in patients with Candida pulmonary colonisation after invasive ventilation.

International Prospective Register of Systematic Reviews, CRD42020161138.