Therapeutic drug monitoring of azole antifungal agents.

Deep-seated mycoses are generally opportunistic infections that are difficult to diagnose and treat. They are expected to increase with the spread of advanced medical care and aging populations, thus highlighting the need for safe, effective, and rapid drug-based treatments. Depending on a patient's age, sex, underlying diseases, and immune system status, therapeutic drug monitoring (TDM) may be important for assessing variable pharmacokinetic parameters, as well as preventing drug-drug interactions, adverse events, and breakthrough infections caused by fungal resistance. Azole antifungal agents play an important role in the prevention and treatment of deep-seated fungal infections, with each azoles having its own unique pharmacokinetic properties and specific adverse events. Therefore, it is necessary to use national and international guidelines to build evidence for the expansion of TDM indications. This review focuses on the clinical utility and future perspectives of TDM using azole antifungal agents, in the context of recent evidence in the literature.

Increasing rate of non-Candida albicans yeasts and fluconazole resistance in yeast isolates from women with recurrent vulvovaginal candidiasis in Leeds, United Kingdom.

OBJECTIVES: Azoles have been the mainstay of recurrent vulvovaginal candidiasis (RVVC) for many years. Because of a recent anecdotal increase in non-Candida albicans yeasts (NCAY) and azole-resistant C. albicans cases, their prevalence was calculated from cultures for yeasts in women with complicated/RVVC over 3 years. METHODS: Retrospective data search of vaginal cultures from adult women in Leeds, UK between April 2018 and March 2021 was conducted. Samples with clinical details of complicated/RVVC had full yeast identification and antifungal susceptibility performed. Differences in prevalence between 12-month periods were determined using χ2 tests. RESULTS: Over the 3 years, cultures were performed on 5461 vaginal samples from women with clinical information indicating they had complicated/RVVC, RVVC, with 1828 (33.5%) growing yeasts.Over 85% of yeasts each year were C. albicans, however the proportion declined yearly with an increase in NCAY species. Nakaseomyces glabrata was the most frequent NCAY species isolated, increasing from 2.8% in 2018-19 to 6.8% in 2020-21. Total NCAY species increased from 6.0% in 2018-19 to 12.6% in 2020-21. Fluconazole-sensitive dose-dependant (SDD) and resistant isolates increased from 3.5% in 2018-19 to 7.7% in 2019-20 and 9.6% in 2020-21. Most resistance was in C. albicans and the majority of cases were seen in primary care. Most fluconazole non-sensitive isolates were either SDD or resistant to itraconazole (77% and 23%, respectively) and were intermediate or resistant to voriconazole (36.4% and 60%, respectively). CONCLUSION: There was a significant increase in the prevalence of NCAY and fluconazole-resistant C. albicans in complicated/RVVC cultures over these 3 years. Successful treatment of such cases can be very challenging. The exact reasons for this increase remain unclear but it follows a policy change that encouraged a clinical diagnosis and empirical treatment of vulvovaginal candidiasis, rather than fungal culture, in primary care.

Analogs of the anti-malaria drug mefloquine have broad-spectrum antifungal activity and are efficacious in a model of disseminated Candida auris infection.

Only three classes of antifungal drugs are currently in clinical use. Here, we report that derivatives of the malarial drug mefloquine have broad-spectrum antifungal activity including difficult-to-treat molds and endemic fungi. Pharmacokinetic and efficacy studies of NSC-4377 indicate that it penetrates the central nervous system and is active against Candida auris in vivo. These data strongly support the further development of mefloquine analogs as a potentially new class of antifungal molecules.

Discovery of Arylpiperazines with Broad-Spectrum Antimicrobial Activity and Favorable Pharmacokinetic Profiles.

Microorganisms can induce diseases with significant clinical implications for human health. Multidrug-resistant microorganisms have been on the rise worldwide over the past few decades, and no new antibiotics have been introduced to the market in a considerable amount of time. Such situation highlights the urgency of discovering new antimicrobial drugs to address this pressing issue. Therefore, the objective of this study was to identify bioactive compounds against 15 species of bacteria and 5 species of fungi of clinical relevance through in vitro screening of 58 synthetic compounds from four chemical classes of our internal library of synthetic compounds. Our findings highlight arylpiperazines 18, 20, 26, 27, and 29, and the aminothiazole 50, as potent broad-spectrum antimicrobials (MICs = 12.5 - 15.6 mg.mL-1) against clinically relevant bacteria and fungi. Additionally, these compounds displayed low cytotoxicity against various host cells and a favorable in vitro pharmacokinetic profile for oral administration. Indeed, all six showed adequate lipophilicity, high gastrointestinal permeability, metabolic stability in human and mouse liver microsomes, and satisfactory aqueous solubility. Thus, they emerge as promising starting points for hit-to-lead studies towards new antibacterial and antifungal agents, especially against Staphylococcus epidermidis, Staphylococcus aureus, Lactobacillus paracasei and Candida orthopsilosis.

Extended Use of Topical Efinaconazole Remains Safe and Can Provide Continuing Benefits for Dermatophyte Toenail Onychomycosis.

INTRODUCTION: Efinaconazole 10% topical solution labeling for onychomycosis describes phase III trials of 12 months of treatment; the slow growth of onychomycotic nails suggests a longer treatment period may increase efficacy. We present here the first evaluation of extended use of efinaconazole 10% topical solution for up to 24 months. MATERIALS AND METHODS: Enrolled patients (n = 101) had one target great toenail with mild to moderate distal lateral subungual onychomycosis and applied efinaconazole 10% topical solution to all affected toenails once daily for 18 months (EFN18) or 24 months (EFN24). Efficacy and safety were evaluated at each visit by visual review and mycology sampling. RESULTS: Regarding the target toenail for patients treated for 24 months (EFN24), mycological cure (negative microscopy and culture) was 66.0% at Month 12, increasing to 71.7% at Month 24; effective cure (mycological cure and ≤10% affected nail) was 13.2% at Month 12, rising to 22.6% at Month 24. Mild to moderate application site reactions (symptoms of erythema/scaling) were the only efinaconazole-related reactions, in eight patients (7.9%). No systemic efinaconazole events or drug interactions were found. Patients aged 70 years or more had similar efficacy to younger patients at all time periods and did not show any increased treatment risks. Thinner nails exhibited better clearance versus thicker nails. A higher proportion of patients with Trichophyton mentagrophytes complex infection experienced application site reactions (35.7%), and a higher effective cure was found at Month 24 versus T. rubrum patients. CONCLUSION: There is a trend of increasing mycological cure and effective cure beyond Month 12 to Month 24, without an increased safety risk. The enrolled population in this trial was significantly older than in the phase III trials, with a greater degree of onychomycosis severity; however, increased age did not appear to reduce the chance of efficacy to Month 24 in this study. Our data suggest that lack of ability to clear nail dystrophy remains a significant problem for patients, rather than any lack of efinaconazole action over long-term treatment periods.

Optimized Antifungal Therapy for Chronic Pulmonary Aspergillosis.

Chronic pulmonary aspergillosis (CPA) represents a spectrum of lung disorders caused by local proliferation of Aspergillus hyphae in individuals with non-systemic or mildly systemic immunodepression or altered pulmonary integrity due to underlying disease. While long-term systemic antifungal treatment is still the mainstay for management, surgery is considered mainly in rarer invasive disease manifestations such as sinusitis and osteomyelitis. Optimal application of existing antifungal agents with suitable pharmacokinetic properties is important for the treatment of diseases such as CPA, which requires long-term use. Appropriate management of side effects by therapeutic drug monitoring, maintenance of adherence, and assessment of drug resistance to Aspergillus can provide safe and effective treatment in the future. Most available antifungal agents for the management of mycoses in humans have disadvantages that can limit their use in clinical practice. By contrast, second generation antifungals such as triazoles have advantages of extended antifungal spectrum and availability in both oral and intravenous formulations. Isavuconazole, a new extended spectrum triazole, has been shown to be effective against Aspergillus. The safety profile and excellent pharmacokinetic characteristics of isavuconazole make it an attractive option for treatment of invasive fungal infections including CPA. With this drug now available in Japan, new evidence is expected to expand treatment options. This review focuses on the selection of antifungal agents based on national and international guidelines and the characteristics of each agent for their appropriate use in CPA.

Candidaemia: A 9-Year Retrospective Analysis of Epidemiology and Antimicrobial Susceptibility in Tertiary Care Hospitals in Western China.

Purpose: This investigation endeavors to scrutinize the resistance profiles to antifungal agents, alongside the clinical distribution of Candida isolates that yielded positive results in blood cultures at Suining Central Hospital spanning the years 2015 to 2023. The objective is to provide crucial epidemiological insights that may aid in early clinical intervention and judicious deployment of antifungal therapies. Methods: This retrospective analysis analyses data on 182 different Candida strains with positive clinical blood cultures obtained from the Microbiology Laboratory of Suining Central Hospital over a period of nine consecutive years. The study involved identification of Candida species and assessment of resistance patterns to fungal drugs. Results: Our analysis revealed that the median age of patients diagnosed with Candidaemia from the 182 strains was 62 years, with a distribution of 63.7% females and 36.3% males. Within the cohort of 182 Candida strains, Candida albicans constituted 32.4%, while non-albicans Candida species comprised 67.6% of the cases. Specifically, Candida tropicalis represented 37.4%, Candida glabrata 12.1%, Candida parapsilosis 11.0%,Candida guilliermondii 3.8%, and both Candida krusei and Candida Dublin accounted for 1.6% each. These Candida species were predominantly identified in intensive care units (ICU), hematology, gastroenterology, neurology centers, and endocrine metabolism units. Conclusion: The findings of this investigation suggest a shift in the prevalence of non-Candida albicans species, notably C. tropicalis, as the predominant cause of Candidaemia at Suining Central Hospital, surpassing C. albicans. Although instances of antifungal resistance are infrequent, there has been a notable rise in resistance to azoles. This study provides important insights into the local epidemiology, which will be essential for informing the selection of empirical antifungal therapy and contributing to the global surveillance of antifungal resistance.

Consumption Trends of Antifungal and Antiprotozoal Agents for Human Systemic Use in Kazakhstan from 2017 to 2023.

BACKGROUND/OBJECTIVES: While multiple studies have investigated antibiotic consumption rates, there are few studies on the consumption of systemic antifungals and antiprotozoals. This study aims to fill this gap by providing a comprehensive analysis of nationwide consumption trends in Kazakhstan over a seven-year period (2017-2023). METHODS: Defined daily doses per 1000 inhabitants per day were calculated for systemic antifungals (J02 code of the Anatomical Therapeutic Chemical Classification System (ATC)) and antiprotozoals (P01 code of the ATC). Time series analyses were applied to examine historical trends, evaluate the impact of the COVID-19 pandemic, and make future projections until 2030. RESULTS: The total consumption increased over the study period, with an average annual percent change of 1.11% for antifungals and 5.48% for antiprotozoals. Fluconazole was the most consumed antifungal agent, whereas metronidazole was the most consumed antiprotozoal agent. The COVID-19 pandemic had a positive but insignificant effect on the consumption of antifungals and a negative and also insignificant effect on the consumption of antiprotozoals. Forecast modeling indicates that the future trends in antifungal and antiprotozoal consumption until 2030 will largely remain stable, with the exception of antiprotozoal consumption in the hospital sector, which is projected to decline. CONCLUSIONS: These findings offer valuable insights into the development and implementation of targeted antimicrobial stewardship programs in Kazakhstan.

Advancements in Combating Fungal Infections: A Comprehensive Review on the Development of Azole Hybrid Antifungals.

OBJECTIVE: In this review, we have summarized antifungal agents containing potent azole analogues. DATA ACQUISITION: The provided literature is related to the development and application of azole derivatives and has been accessed from electronic data bases such as Science direct, Google Scholar, and Pubmed using keywords such as "design, synthesis and evaluation", "azole hybrids", "diazole hybrids", "indazole derivatives", "imidazole derivatives", "triazole derivatives", "tetrazole derivatives" and related combinations. RESULT: From this review, it was identified that azole derivatives with promising antifungal activity play a vital role in drug discovery and development. The literature revealed that azole derivatives can effectively fight several types of microorganisms, such as Candida albicans, Aspergillus niger, and others. The rational design and structure‒activity relationship of these compounds are discussed in this paper, highlighting their potential as effective therapeutic options against various fungal pathogens. Moreover, this work addresses the challenges and future directions in the development of azole hybrids. The results of docking studies of several of the hybrids that the researchers provided are also summarized. CONCLUSION: The current work attempts to review such innovations, which may lead to the preparation of novel therapeutics. More research is required to confirm their safety and effectiveness in clinical practices.

A Real-World Data Observational Analysis of the Impact of Liposomal Amphotericin B on Renal Function Using Machine Learning in Critically Ill Patients.

BACKGROUND: Liposomal amphotericin B (L-AmB) has become the mainstay of treatment for severe invasive fungal infections. However, the potential for renal toxicity must be considered. AIMS: To evaluate the incidence of acute kidney injury (AKI) in critically ill patients receiving L-AmB for more than 48 h. METHODS: Retrospective, observational, single-center study. Clinical, demographic and laboratory variables were obtained automatically from the electronic medical record. AKI incidence was analyzed in the entire population and in patients with a "low" or "high" risk of AKI based on their creatinine levels at the outset of the study. Factors associated with the development of AKI were studied using random forest models. RESULTS: Finally, 67 patients with a median age of 61 (53-71) years, 67% male, a median SOFA of 4 (3-6.5) and a crude mortality of 34.3% were included. No variations in serum creatinine were observed during the observation period, except for a decrease in the high-risk subgroup. A total of 26.8% (total population), 25% (low risk) and 13% (high risk) of patients developed AKI. Norepinephrine, the SOFA score, furosemide (general model), potassium, C-reactive protein and procalcitonin (low-risk subgroup) were the variables identified by the random forest models as important contributing factors to the development of AKI other than L-AmB administration. CONCLUSIONS: The development of AKI is multifactorial and the administration of L-AmB appears to be safe in this group of patients.

Are Mouthwashes Really Effective against Candida spp.?

Oral candidiasis is an opportunistic infection caused by fungi of the genus Candida. Nystatin, fluconazole, and miconazole are the most widely used antifungal drugs in dentistry, but in recent years, they have been shown to be less effective due to the increase in the resistance to antifungal drugs. The growing challenge of antifungal resistance emphasizes the importance of exploring not only alternative strategies in the fight against Candida spp. infections but also supportive treatment for pharmacological treatment for oral candidiasis. This review aims to evaluate and compare the in vitro reports on antifungal efficacy against Candida spp. exhibited by mouthwashes distributed on the European market. The research question was elaborated through the PEO framework recommended by PRISMA 2020. A bibliographic search strategy was developed for the scientific online databases Pubmed and ScienceDirect. According to the eligibility criteria, 21 papers were included in this study over a 27-year period. Mouthwashes containing chlorhexidine digluconate, cetylpyridinium chloride, hexetidine, and fluorine compounds among others, and natural antimicrobials, such as menthol, thymol, eucalyptol, and Glycyrrhiza glabra extracts, have demonstrated antifungal effectiveness. Nonetheless, the methodological variance introduces ambiguity concerning the comparative efficacy of distinct molecules or mouthwash formulations and complicates the evaluation and the comparison of results between studies. Some mouthwashes commercially available in Europe have the potential to be used in anti-Candida therapy and prevention since they have shown antifungal effect.

Monoterpene antifungal activities: evaluating geraniol, citronellal, and linalool on Candida biofilm, host inflammatory responses, and structure-activity relationships.

Introduction: Despite the rising concern with fungal resistance, a myriad of molecules has yet to be explored. Geraniol, linalool, and citronellal are monoterpenes with the same molecular formula (C10H18O), however, neither the effect of these compounds on inflammatory axis induced by Candida spp. nor the antibiofilm Structure-Activity Relationship (SAR) have been well-investigated. Herein we analyzed geraniol, linalool and citronellal antifungal activity, cytotoxicity, and distinctive antibiofilm SAR, also the influence of geraniol on Candida spp induced dysregulated inflammatory axis, and in vivo toxicity. Methods: Minimal inhibitory (MIC) and fungicidal (MFC) concentrations against Candida spp were defined, followed by antibiofilm activity (CFU-colony forming unit/mL/g of dry weight). Cytotoxic activity was assessed using human monocytes (THP-1) and oral squamous cell (TR146). Geraniol was selected for further analysis based on antifungal, antibiofilm and cytotoxic results. Geraniol was tested using a dual-chamber co-culture model with TR146 cells infected with C. albicans, and THP-1 cells, used to mimic oral epithelium upon fungal infection. Expression of Candida enzymes (phospholipase-PLB and aspartyl proteases-SAP) and host inflammatory cytokines (interleukins: IL-1ß, IL-6, IL-17, IL-18, IL-10, and Tumor necrosis factor-TNF) were analyzed. Lastly, geraniol in vivo toxicity was assessed using Galleria mellonella. Results: MIC values obtained were 1.25-5 mM/mL for geraniol, 25-100 mM/mL for linalool, and 100-200 mM/mL for citronellal. Geraniol 5 and 50 mM/mL reduced yeast viability during biofilm analysis, only 500 mM/mL of linalool was effective against a 72 h biofilm and no biofilm activity was seen for citronellal. LD50 for TR146 and THP-1 were, respectively: geraniol 5.883 and 8.027 mM/mL; linalool 1.432 and 1.709 mM/mL; and citronellal 0.3006 and 0.1825 mM/mL. Geraniol was able to downregulate expression of fungal enzymes and host pro-inflammatory cytokines IL-1ß, IL-6, and IL-18. Finally, safety in vivo parameters were observed up to 20 mM/Kg. Discussion: Despite chemical similarities, geraniol presented better antifungal, antibiofilm activity, and lower cytotoxicity when compared to the other monoterpenes. It also showed low in vivo toxicity and capacity to downregulate the expression of fungal enzymes and host pro-inflammatory cytokines. Thus, it can be highlighted as a viable option for oral candidiasis treatment.

Impact of new antifungal medications on onychomycosis prescriptions and costs in Japan: A nationwide claims database study.

Onychomycosis, a fungal nail infection, is a common dermatological condition in Japan, with a prevalence of approximately 5%-10%. Despite the introduction of new antifungal medications and updated treatment guidelines published in 2019, data on real-world prescription trends and the associated medical costs are limited. This study aimed to investigate the prescription patterns and medical costs of topical and oral antifungal medications for onychomycosis in Japan from fiscal years 2014 to 2021 using the National Database of Health Insurance Claims and Specific Health Checkups of Japan Open Data. We analyzed the annual prescription volumes and medical costs of four antifungal medications: efinaconazole, luliconazole, fosravuconazole, and terbinafine. The prescription volume of efinaconazole, a topical medication launched in 2014, rapidly increased and dominated the market share. Fosravuconazole, an oral medication introduced in 2018, showed an increasing trend, coinciding with a decline in efinaconazole prescriptions. Terbinafine, a well-established oral medication, experienced a substantial decrease in prescription volume. The sex- and age-adjusted prescription volume per 100 000 population was higher among older adults, particularly for efinaconazole. The total medical costs for onychomycosis treatment more than doubled in fiscal year 2015 compared with that for 2014, mainly driven by efinaconazole prescriptions, and exceeded 30 billion Japanese yen in fiscal years 2019-2021. The costs slightly decreased in fiscal years 2020 and 2021, possibly due to the introduction of fosravuconazole. The predominance of topical prescriptions, especially in older adults, raises concerns regarding adherence to the Japanese guidelines that recommend oral antifungals as the first-line treatment for onychomycosis. The substantial increase in medical costs also highlights the economic burden of onychomycosis and the need for cost-effective treatment strategies. This study provides valuable insights into the real-world prescription trends and medical costs of onychomycosis treatment in Japan, suggesting an opportunity to assess potential gaps between guideline recommendations and clinical practice.

Recognition of Antifungal-Resistant Dermatophytosis by Infectious Diseases Specialists, United States.

Antifungal-resistant dermatophyte infections have recently emerged as a global public health concern. A survey of US infectious diseases specialists found that only 65% had heard of this issue and just 39% knew how to obtain testing to determine resistance. Increased clinician awareness and access to testing for antifungal-resistant dermatophytosis are needed.

Emerging therapeutics: The imidazo[1,2-b]pyridazine scaffold as a novel drug candidate for eumycetoma, a neglected tropical disease.

Mycetoma is a neglected invasive infection endemic in tropical and subtropical regions, presenting as a chronic subcutaneous inflammatory mass that can spread to deeper structures, leading to deformities, disabilities, and potentially mortality. The current treatment of eumycetoma, the fungal form of mycetoma, involves antifungal agents, such as itraconazole, combined with surgical intervention. However, this approach has limited success, with low cure rates and a high risk of recurrence. This study addresses to the urgent need for more effective therapeutics by designing and synthesising 47 diversely pharmacomodulated imidazo [1,2-b]pyridazine derivatives using a simple synthetic pathway with good yields and purity. Of these, 17 showed promising in vitro activity against Madurella mycetomatis, the prime causative agent of eumycetoma, with IC50 ≤ 5 µM and demonstrated significantly lower cytotoxicity compared to standard treatments in NIH-3T3 fibroblasts. Notably, compound 14d exhibited an excellent activity with an IC50 of 0.9 µM, in the same order then itraconazole (IC50 = 1.1 µM), and achieved a favourable selectivity index of 16 compared to 0.8 for itraconazole. These promising results warrant further research to evaluate the clinical potential of these novel compounds as safer, more effective treatments for eumycetoma, thus addressing a profound gap in current therapeutic strategies.

Methoxy Chalcone Derivatives: Promising Antimicrobial Agents Against Phytopathogens.

Chalcone (E)-1,3-diphenyl-prop-2-en-1-one and a series of 14 methoxylated derivatives have been synthesized via Claisen-Schmidt aldol condensation and characterized by FTIR, CG/MS/DIC, 1D (1H and 13C), 2D (COSY, HSQC, and HMBC) NMR, and EMAR techniques. All molecules were tested at 1 mM concentration for antifungal (Sclerotium sp., Macrophomina phaesolina and Colletotrichum gloeosporioides), antibacterial (Acidovorax citrulli two strains), and antiprotozoal (Phytomonas serpens) activities. Unmodified chalcone (CH0) and derivatives CH1, CH2, CH8 stood out in terms of antifungal activity. CH0 presented IC50 values of 47.3 µM (9.8 µg/mL) for the fungus C. gloeosporioides. In addition, fluorescence microscopy indicated that CH0 promoted loss of hyphal cell membrane integrity. The CH1 and CH2 derivatives promoted the inhibition of Sclerotium sp. with IC50 of 127.5 µM (32.9 µg/mL) and 110.4 µM (29.6 µg/mL), respectively. All molecules showed high activity against the phytoparasite P. serpens with IC50 values of 0.98, 2.40, 10.25, and 3.11 µM for the derivatives CH2, CH3, CH5 and CH14 respectively. The results demonstrated that derivatives methoxylated in both rings (CH2) as well as derivatives with a furan ring associated with the methoxy group in ring A, as well as unmodified chalcone can be promising agricultural fungicides for controlling the fungi studied.

Determining sensitivity and specificity of risk scores for QTc interval prolongation in hemato-oncology patients prescribed systemic antifungal therapy: a retrospective cross-sectional study.

BACKGROUND: QTc interval prolongation can result in potentially lethal arrhythmias. One risk factor is QTc-prolonging drugs, including some antifungals often used in hemato-oncology patients. Screening tools for patients at risk have not yet been investigated in this patient population. AIM: Our aim was to evaluate the sensitivity and specificity of five QTc risk scores in hemato-oncology patients receiving systemic antifungal therapy. METHOD: Data were retrieved from an internal study database including adult hemato-oncology patients prescribed systemic antifungal therapy. Data on QTc-prolonging medication, risk factors for QTc prolongation, and electrocardiograms (ECG) were collected retrospectively for a period of 12 months. The QTc risk scores according to Tisdale, Vandael, Berger, Bindraban, and Aboujaoude as well as their sensitivity and specificity were calculated. RESULTS: During the evaluated period, 77 patients were prescribed systemic antifungals resulting in 187 therapy episodes. Regarding therapy episodes, median age was 56 years (IQR 44-68), 41% (77) were female, and a median of 3 QTc-prolonging drugs were prescribed (range 0-6). ECGs were available for 45 (24%) of the therapy episodes 3-11 days after initiation of the antifungal therapy, 22 of which showed QTc prolongation. Regarding these 45 therapy episodes, sensitivity and specificity of the risk scores were calculated as follows: Tisdale 86%/22%, Vandael 91%/35%, Berger 32%/83%, Bindraban 50%/78%, Aboujaoude 14%/87%. CONCLUSION: The QTc risk scores according to Tisdale and Vandael showed sufficient sensitivity for risk stratification in the studied patient population. In contrast, risk scores according to Berger, Bindraban, and Aboujaoude cannot be considered suitable due to poor sensitivity.

Breaking the mold: Insights into the clinical management and outcomes of rhinocerebral mucormycosis in adults.

Background: Rhinocerebral mucormycosis is a rare, life-threatening fungal infection that affects the sinuses, nasal passages, and brain. Its management remains challenging owing to high mortality rates. Combination antifungal therapy is an area of ongoing research aimed at improving outcomes. We aimed to describe the clinical management and outcomes of patients with rhinocerebral mucormycosis who were treated with antifungal combination therapy. Methods: This retrospective case series included 10 patients diagnosed with rhinocerebral mucormycosis at two academic medical centers between January 2008 and July 2023 who received initial antifungal therapy with liposomal amphotericin B (L-AmB), alone or in combination, within 24 h of diagnosis. Clinical data were extracted from the medical records. Results: Most patients were males (70 %) with uncontrolled diabetes (71.4 %). L-AmB was used as the initial therapy in all patients, either as monotherapy (n = 4) or combination therapy (n = 6), followed by posaconazole maintenance. The combinations included L-AmB with posaconazole (n = 4), L-AmB with micafungin (n = 3), or both (n = 3). The overall mortality rate was 50 %. Survivors had high morbidity, with median 31-day hospitalizations and 50 % readmission rate. Conclusions: Despite aggressive management, rhinocerebral mucormycosis has high mortality and morbidity rates. While combination antifungal therapy aims to improve cure rates, our case series showed higher mortality rates than monotherapy. Additional research is warranted to optimize management approaches for this devastating infection.

Epidemiological changes of invasive fungal disease in children with cancer: Prospective study of the National Child Program of Antineoplastic Drugs network, Chile.

BACKGROUND: Invasive fungal diseases (IFD) are high morbidity and mortality infections in children with cancer suffering episodes of high-risk febrile neutropenia (HRFN). IFD epidemiology has changed in the last two decades, with an increasing incidence in recent years due to the growing number of immunocompromised children at risk for IFD. The aim of this study was to evaluate the incidence of IFD in children with cancer in the period 2016-2020 compared to 2004-2006 in six hospitals in Chile. METHODS: Prospective, multicentre study, carried out between 2016 and 2020 in six hospitals in Chile. The defined cohort corresponds to a dynamic group of HRFN episodes in patients <18 years old with cancer, who at the fourth day of evolution still presented fever and neutropenia (persistent HRFN). Each episode was followed until resolution of FN. The incidence of IFD was calculated between 2016 and 2020 and compared with data obtained in the period 2004-2006. The incidence rate was estimated. RESULTS: A total of 777 episodes of HRFN were analysed; 257 (33.1%) were considered as persistent-HRFN occurring in 174 patients. The median age was 7 years (IQR: 3-12 years) and 52.3% (N = 91) were male. Fifty-three episodes of IFD were detected: 21 proven, 14 probable and 18 possible. Possible IFD were excluded, leaving 239 episodes of persistent-HRFN with an IFD incidence of 14.6% (95% CI 10.5-19.9) and an incidence rate of 13.6 IFD cases per 1000 days of neutropenia (95% CI 9.5-20.0). Compared to 2004-2006 cohort (incidence: 8.5% (95% CI 5.2-13.5)), a significant increase in incidence of 6.1% (95% CI 0.2-12.1, p = .047) was detected in cohorts between 2016 and 2020. CONCLUSION: We observed a significant increase in IFD in 2016-2020, compared to 2004-2006 period.

Candida Tropicalis Endocarditis: A case report and literature review.

Fungi rarely cause infective endocarditis but when they do, they are often associated with poor outcomes. Candida tropicalis accounts for only 10% of Candida endocarditis cases. A case of a 30-year-old male with a history of intravenous drug abuse was reported to the emergency department in August, 2021 with right-sided leg pain and fever for 3 days. A trans-thoracic echocardiogram showed a vegetation on the aortic valve and a computed tomography angiogram showed complete nonopacification of the right-sided common iliac artery and the superficial femoral artery just distal to its branching of the right profunda femoris artery. An emergent right iliofemoral embolectomy was done. Candida tropicalis was isolated from tissue and blood cultures. The patient was successfully treated with aortic valve replacement and intravenous caspofungin. The other reported cases of Candida tropicalis were reviewed and findings were compared with those reported in patients with Candida albicans and Candida parapsilosis endocarditis.