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Fungal infections are a significant source of morbidity in the lung transplant population via direct allograft damage and predisposing patients to the development of chronic lung allograft dysfunction. Prompt diagnosis and treatment are imperative to limit allograft damage. This review article discusses incidence, risk factors, and symptoms with a specific focus on diagnostic and treatment strategies in the lung transplant population for fungal infections caused by Aspergillus, Candida, Coccidioides, Histoplasma, Blastomyces, Scedosporium/Lomentospora, Fusarium, and Pneumocystis jirovecii. Evidence for the use of newer triazole and inhaled antifungals to treat isolated pulmonary fungal infections in lung transplant recipients is also discussed. [ABSTRACT FROM AUTHOR]

Isavuconazole (ISA) is a triazole antifungal agent recommended for treatment of invasive aspergillosis or mucormycosis. The objective of this study was to evaluate ISA levels in a real world setting in a mixed patient cohort including patients with non-malignant diseases and extracorporeal treatments, and to correlate findings with efficacy and safety outcomes. We investigated 33 ISA treatment courses in 32 adult patients with hematological and other underlying diseases and assessed the clinical response, side effects and ISA trough plasma concentrations. ISA treatment led to complete and partial response in 87% of patients and was well tolerated. The median ISA plasma concentration was 3.05 µg/mL (range 1.38-9.1, IQR 1.93-4.35) in patients without renal replacement therapy (RRT) or extracorporeal membrane oxygenation (ECMO) and significantly lower in patients with RRT including cases with additional ECMO or Cytosorb® adsorber therapy (0.88 µg/mL, range 0.57-2.44, IQR 0.71-1.21). After exclusion of values obtained from four patients with ECMO or Cytosorb® adsorber the median concentration was 0.91 µg/mL (range 0.75-2.44, IQR 0.90-1.36) in the RRT group. In addition to previous recommendations we propose to monitor ISA trough plasma concentrations in certain circumstances including RRT, other extracorporeal treatments and obesity.

Case reports have identified invasive fungal diseases in persons who use cannabis, and fungal contamination of cannabis has been described. In a large health insurance claims database, persons who used cannabis were 3.5 (95% CI 2.6-4.8) times more likely than persons who did not use cannabis to have a fungal infection in 2016.

Monocytes and their derivatives, including macrophages and dendritic cells, play diverse roles in the response to fungal pathogens. Sensing of fungi by monocytes triggers signaling pathways that mediate direct effects like phagocytosis and cytokine production. Monocytes can also present fungal antigens to elicit adaptive immune responses. These monocyte-mediated pathways may be either beneficial or harmful to the host. In some instances, fungi have developed mechanisms to evade the consequences of monocyte activation and subvert these cells to promote disease. Thus, monocytes are critically involved in mediating the outcomes of these often highly fatal infections. This review will highlight the roles of monocytes in the immune response to some of the major fungi that cause invasive human disease, including Aspergillus, Cryptococcus, Candida, Histoplasma, Blastomyces, and Coccidioides, and discuss potential strategies to manipulate monocyte responses in order to enhance anti-fungal immunity in susceptible hosts.

Introduction: Fungal infections of the central nervous system present a variety of clinical syndromes, such as meningitis, encephalitis, raised intracranial pressure with a nonspecific presentation, and, in the last two decades, have increased the incidence of these fungal infections. Fungal meningoencephalitis is frequently associated with Cryptococcus, but this report stands out for presenting one species of Penicillium genus. Objectives: Here, we present the first case of meningoencephalitis associated with brain injury caused by Penicillium chrysogenum, in a patient who is immunocompetent and was admitted to Hospital Naval Marcílio Dias, Rio de Janeiro, Brazil. Methods: To identify the fungal species, we performed phenotypic and genotypic methodologies, from the culture to the sequencing of internal transcribed spacer region, and β-tubulin gene, a rare fungus in cerebrospinal fluid cultures, belonging to the genus Penicillium, was identified. Conclusion: We highlight the importance of the first report of meningoencephalitis caused by P. chrysogenum in a patient who is immunocompetent, registered in Brazil. We also emphasize the need for further studies to determine an effective treatment with the least possible side effects for patients infected by fungi that are rarely related to the most severe forms of invasive infections.

BACKGROUNDInnate immune activation impacts lung transplant outcomes. Dectin-1 is an innate receptor important for pathogen recognition. We hypothesized that genotypes reducing dectin-1 activity would be associated with infection, graft dysfunction, and death in lung transplant recipients.METHODSWe assessed the rs16910526 CLEC7A gene polymorphism Y238X, which results in dectin-1 truncation, in 321 lung allograft recipients at a single institution and in 1,129 lung allograft recipients in the multicenter Lung Transplant Outcomes Group (LTOG) cohort. Differences in dectin-1 mRNA, cytokines, protein levels, immunophenotypes, and clinical factors were assessed.RESULTSY238X carriers had decreased dectin-1 mRNA expression (P = 0.0001), decreased soluble dectin-1 protein concentrations in bronchoalveolar lavage (P = 0.008) and plasma (P = 0.04), and decreased monocyte surface dectin-1 (P = 0.01) compared with wild-type subjects. Y238X carriers had an increased risk of fungal pathogens (HR 1.17, CI 1.0-1.4), an increased risk of graft dysfunction or death (HR 1.6, CI 1.0-2.6), as well increased mortality in the UCSF cohort (HR 1.8, CI 1.1-3.8) and in the LTOG cohort (HR 1.3, CI 1.1-1.6), compared with wild-type CLEC7A subjects.CONCLUSIONIncreased rates of graft dysfunction and death associated with this dectin-1 polymorphism may be amplified by immunosuppression that drives higher fungal burden from compromised pathogen recognition.FUNDINGThe UCSF Nina Ireland Program for Lung Health Innovative Grant program, the Clinical Sciences Research & Development Service of the VA Office of Research and Development, and the Joel D. Cooper Career Development Award from the International Society for Heart and Lung Transplantation.

Introduction: Information on epidemiologic trends of dermatophytosis and its causative agents is essential for the healthcare system to improve its knowledge of associated complications. The main purpose of this study was to determine the distribution of fungal strains and the infection sites of patients with dermatophytosis. Materials and Methods: In this cross-sectional study, the demographical data and clinical characteristics of 641 patients with a positive fungal culture who were referred to Razi pathobiological laboratory, Rasht, Iran, between 2016-2021 were collected. All data were analyzed using SPSS software version 21 by a significant level of < 0.05. Results: Out of 641 patients, 70% were female and the mean age of patients was 43.98 ± 16.99 years. Laboratory analysis demonstrated that Candida Albicans (44/9%), Aspergillus (31/8%), and Dermatophytes (18%) were the most common causes of superficial cutaneous fungal infections. Among the dermatophytes, the most common pathogens were Trichophyton mentagrophytes (53%) and Trichophyton Rubrum (20.8%), also, the most common site of infection was nail (64.4%). Conclusion: Considering the high prevalence of Candida Albicans and Aspergillus, especially in females, it is important to determine preventive protocols for fungal infections and better clinical management of the patients involved.

Coronavirus disease 2019 (COVID-19) infections can be related to vast spectrum of co-existent bacterial and fungal infections. A 49-year-old diabetic male was admitted with a history of fever, cough and breathlessness since 5 days. He developed persistent headache with right sided purulent nasal discharge. Relevant histo-pathological, biochemical, microbiological and imaging studies were performed which proved it to be a dual infection of Aspergillosis and Mucormycosis. We present one such case in a COVID-19 patient to highlight its unusual clinical features along with the diagnostic and therapeutic challenges.

Fluconazole (FLZ) is the most widely used antifungal agent for treating cutaneous candidiasis. Although oral FLZ has been proved to be effective, the incidence of side effects necessitates the development of an effective formulation that could surpass the pitfalls associated with systemic availability. Accordingly, this research aimed at developing a self-assembled mixed micelles topical delivery system to enhance the topical delivery of the drug. Self-assembled mixed micelles were developed using D-α-tocopheryl polyethylene glycol 1000 succinate and phospholipids and optimized using Box-Behnken design. The optimized formulation with minimized size was then tested in vivo for the antifungal activity against C. albicans in immunocompromised mice. Treatment with the optimized formulation led to decreased peripheral erythema as well as lesions due to fungal infection in comparison to raw FLZ loaded gel. Therefore, the developed formulation was found to be a promising vehicle for the treatment of cutaneous candidiasis.

Antifungal drugs prevent topical or invasive fungal infections (mycoses) either by stopping growth of fungi (termed fungistatic) or by killing the fungal cells (termed fungicidal). Antibiotics also prevent bacterial infections through either bacteriostatic or bactericidal mechanisms. These microorganisms successfully develop resistance against conventional drugs that are designed to kill or stop them from multiplying. When a fungus no longer responds to antifungal drug treatments and continues to grow, this is known as antifungal drug resistance. Bacteria have an amazing capacity to become resistant to antibiotic action as well, and the effectiveness of the scarce antifungal arsenal is jeopardised by this antibiotic resistance, which poses a severe threat to public health.

Background: The primary burden among severely ill COVID-19 cases allocated to ICUs is secondary bacterial and fungal infections. Antimicrobial resistance is aggravated more likely by empiric overusing of antimicrobials. This study aimed to assess the microbiological profile of fungal and bacterial superinfections in laboratory confirmed COVID-19 cases and their antimicrobial susceptibility pattern. Methods: Various clinical samples were obtained from 117 critically ill COVID-19 patients in the clinical suspicion of secondary infections for assessing the pathogens accountable for the superinfections and their antimicrobial susceptibility pattern according to standard microbiological procedures. Results: Among 117 COVID-19 patients allocated to ICU, 68 (58%) had secondary infections. The most prevalent infection was of the lower respiratory tract. Most infections were bacterial 85.8%. Gram-negative isolates were the most predominant strains, accounting for 71.7%. among them, Klebsiella pneumoniae 43.4 % and Acinetobacter baumannii 20.7% were the most predominant. Majority of the bacterial strains were multidrug-resistant, all gram-negative strains showed one hundred percent resistance rate to cephalosporins, amoxicillin, and amoxicillin-clavulanic. The lowest resistance was observed for tigecycline. All gram-positive strains were susceptible to linezolid and vancomycin. Additionally, all candida isolates were susceptible to the tested antifungals. Conclusions: In hospitalized severely ill COVID-19 patients, secondary infections are most frequently caused by Gram-negative pathogens exhibiting high rate of antibiotic resistance and are associated with poor outcomes. Strict adherence to infection control measures as well as regular microbiological surveillance are required.

Ana Filipa Moleiro,1,2 Ana Maria Cunha,1 Rodrigo Vilares-Morgado,1,2 António José Cruz,3 Ana Isabel Almeida,4 Fernanda Peixoto,1 Fernando Falcão-Reis,1,2 Jorge Meira,1 Vítor Leal1 1Department of Ophthalmology, Centro Hospitalar e Universitário de São João, Porto, Portugal; 2Department of Surgery and Physiology, Faculty of Medicine of University of Porto, Porto, Portugal; 3Department of Infectious Diseases, Centro Hospitalar e Universitário de São João, Porto, Portugal; 4Department of Neuroradiology, Centro Hospitalar e Universitário de São João, Porto, PortugalCorrespondence: Ana Filipa Moleiro, Department of Ophthalmology, Centro Hospitalar e Universitário de São João, Alameda Prof. Hernâni Monteiro, Porto, 4200-319, Portugal, Tel +351 915689259, Email anafomoleiro@gmail.comAbstract: The pandemic caused by SARS-CoV-2 remains a health care concern, despite vaccination programs. Mucormycosis, especially rhino-orbital-mucormycosis, has been described as a severe complication of COVID-19. Although it has been described mostly in India and other developing countries, few cases in the western world have also been described. We present a case of rhino-orbito-mucormycosis after recovery from severe COVID-19 in Portugal. A 75-year-old diabetic and obese man presented with right proptosis associated with right eye pain and low vision one month after recovery from severe COVID-19. Considering the most probable etiology for this clinical picture, anti-fungal therapy with liposomal amphotericin B was promptly initiated, followed by endoscopic sinus debridement. However, due to persistent and progressive infection, and after a multidisciplinary revision of the case, orbital exenteration was performed. One year after surgery, the patient is stable, without clinical or imagological signs of relapse of the disease. Although the evolution of the pandemic, along with vaccination programs, led to a lower incidence of severe COVID-19 disease, there are still patients presenting with severe COVID-19, requiring intensive care and at risk for serious complications. This case illustrates the importance of being aware of the development of post-COVID-19 mucormycosis and the need for close surveillance of patients recovering from severe COVID-19. COVID-19 prompt diagnosis and multidisciplinary approach are essential for a timely intervention achieving better survival while minimizing morbidity.Keywords: Mucorales, SARS-CoV-2, orbit, fungal infections, exenteration

With the widespread use of immunosuppressive agents and the increase in patients with severe infections, the incidence of fungal infections worldwide has increased year by year. The fungal pathogens Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus cause a total of more than 1 million deaths each year. Long-term use of antifungal drugs can easily lead to fungal resistance, and the prevalence of drug-resistant fungi is a major global health challenge. In order to effectively control global fungal infections, there is an urgent need for new drugs that can exert effective antifungal activity and overcome drug resistance. We must promote the discovery of new antifungal targets and drugs, and find effective ways to control drug-resistant fungi through different ways, so as to reduce the threat of drug-resistant fungi to human life, health and safety. In the past few years, certain progress has been made in the research and development of antifungal drugs. In addition to summarizing some of the antifungal drugs currently approved by the FDA, this review also focuses on potential antifungal drugs, the repositioned drugs, and drugs that can treat drug-resistant bacteria and fungal infections, and provide new ideas for the development of antifungal drugs in the future.

Candida auris is a multidrug resistant (MDR) fungal pathogen with a crude mortality rate of 30-60%. First identified in 2009, C. auris has been rapidly rising to become a global risk in clinical settings and was declared an urgent health threat by the Centers for Disease Control and Prevention (CDC). A concerted global action is thus needed to successfully tackle the challenges created by this emerging fungal pathogen. In this brief article, we underline the importance of unique virulence traits, including its easy transformation, its persistence outside the host and its resilience against multiple cellular stresses, as well as of environmental factors that have mainly contributed to the rise of this superbug.

Introduction: Isavuconazole is an emerging therapeutic option for invasive infections caused by molds, especially aspergillosis and mucormycosis. Isavuconazole has predictable pharmacokinetics and good bioavailability. These attributes have led to some doubts regarding the need for therapeutic drug monitoring (TDM). There are no data from India regarding TDM for isavuconazole. Methods: A retrospective analysis of 50 patients who received oral isavuconazole for therapeutic purposes. Plasma isavuconazole levels were measured using a reversed phase high-performance liquid chromatography (HPLC) and UV detector with acetonitrile (ACN) as protein precipitating solvent. Results: Of the 50 cases, 5 (10.0%) patients had subtherapeutic levels, while 45 (90.0%) had therapeutic levels. Higher body weight and solid organ transplantation (SOT) were significantly associated with subtherapeutic levels of isavuconazole (p-value < 0.05 for all). Receipt of a SOT was the only independent and statistically significant factor which was associated with subtherapeutic levels of isavuconazole (p-value < 0.05). Conclusion: Our study reemphasizes the need of TDM for isavuconazole and adds to the growing evidence for the need to obtain drug levels. Factors associated with subtherapeutic levels of isavuconazole need to be assessed in larger studies to help identify those patients who are at risk of having subtherapeutic drug levels. [ABSTRACT FROM AUTHOR]

Objectives: Maximum a posteriori Bayesian estimation (MAP-BE) based on a limited sampling strategy and a population pharmacokinetic (POPPK) model is used to estimate individual pharmacokinetic parameters. Recently, we proposed a methodology that combined population pharmacokinetic and machine learning (ML) to decrease the bias and imprecision in individual iohexol clearance prediction. The aim of this study was to confirm the previous results by developing a hybrid algorithm combining POPPK, MAP-BE and ML that accurately predicts isavuconazole clearance. Methods: A total of 1727 isavuconazole rich PK profiles were simulated using a POPPK model from the literature, and MAP-BE was used to estimate the clearance based on: (i) the full PK profiles (refCL); and (ii) C24h only (C24h-CL). Xgboost was trained to correct the error between refCL and C24h-CL in the training dataset (75%). C24h-CL as well as ML-corrected C24h-CL were evaluated in a testing dataset (25%) and then in a set of PK profiles simulated using another published POPPK model. Results: A strong decrease in mean predictive error (MPE%), imprecision (RMSE%) and the number of profiles outside ± 20% MPE% (n-out20%) was observed with the hybrid algorithm (decreased in MPE% by 95.8% and 85.6%; RMSE% by 69.5% and 69.0%; n-out20% by 97.4% and 100% in the training and testing sets, respectively. In the external validation set, the hybrid algorithm decreased MPE% by 96%, RMSE% by 68% and n-out20% by 100%. Conclusion: The hybrid model proposed significantly improved isavuconazole AUC estimation over MAP-BE based on the sole C24h and may improve dose adjustment. [ABSTRACT FROM AUTHOR]

Corona Virus Disease of 2019 (COVID-19) pandemic has renewed interest in monoclonal antibodies for treating infectious diseases. During last two decades experimental data has been accumulated showing the potential of radioimmunotherapy (RIT) of infectious diseases. In addition, COVID-19 pandemic has created a novel landscape for opportunistic fungal infections in post-COVID-19 patients resulting from severe immune suppression. We analyze recent results on targeting "pan-antigens" shared by fungal pathogens in mouse models and in healthy dogs; on developing RIT of prosthetic joint infections (PJI); examine RIT as potential human immunodeficiency virus (HIV) cure strategy and analyze its mechanisms and safety. Literature review was performed using PubMed and Google Scholar and includes relevant articles from 2000 to 2022. Some of the RIT of infection applications can, hopefully, be moved into the clinic earlier than others after preclinical development: (1) RIT of opportunistic fungal infections might contribute to saving lives as current antifungal drugs do not work in severely immunocompromised patients; (2) RIT of patients with PJI. Success of RIT in these patients will allow to expand the application of RIT to other similarly vulnerable patients' populations such as cancer patients with weakened immune system and organ transplant recipients. [ABSTRACT FROM AUTHOR]

Fungal infections, named mycosis, can cause severe invasive and systemic diseases that can even lead to death. In recent years, epidemiological data have recorded an increase in cases of severe fungal infections, caused mainly by a growing number of immunocompromised patients and the emergence of fungal pathogenic forms that are increasingly resistant to antimycotic drug treatments. Consequently, an increase in the incidence of mortality due to fungal infections has also been observed. Among the most drug-resistant fungal forms are those belonging to the Candida and Aspergillus spp. Some pathogens are widespread globally, while others are endemic in some areas only. In addition, some others may represent a health threat for some specific subpopulations and not for the general public. In contrast to the extensive therapeutic armamentarium available for the antimicrobial chemotherapeutic treatment of bacteria, for fungal infections there are only a few classes of antimycotic drugs on the market, such as polyenes, azoles, echinocandins, and a few molecules are under trial. In this review, we focused on the systemic mycosis, highlighted the antifungal drug compounds available in the pipeline, and analyzed the main molecular mechanisms for the development of antifungal resistance to give a comprehensive overview and increase awareness on this growing health threat. [ABSTRACT FROM AUTHOR]

Background: Emerging fungal pathogens pose important threats to global public health. The World Health Organization has responded to the rising threat of traditionally neglected fungal infections by developing a Fungal Priority Pathogens List (FPPL). Taking the highest-ranked fungal pathogen in the FPPL, Cryptococcus neoformans, as a paradigm, we review progress made over the past two decades on its global burden, its clinical manifestation and management of cryptococcal infection, and its antifungal resistance. The purpose of this review is to drive research efforts to improve future diagnoses, therapies, and interventions associated with fungal infections. Methods: We first reviewed trends in the global burden of HIV-associated cryptococcal infection, mainly based on a series of systematic studies. We next conducted scoping reviews in accordance with the guidelines described in the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews using PubMed and ScienceDirect with the keyword Cryptococcus neoformans to identify case reports of cryptococcal infections published since 2000. We then reviewed recent updates on the diagnosis and antifungal treatment of cryptococcal infections. Finally, we summarized knowledge regarding the resistance and tolerance of C. neoformans to approved antifungal drugs. Results: There has been a general reduction in the estimated global burden of HIV-associated cryptococcal meningitis since 2009, probably due to improvements in highly active antiretroviral therapies. However, cryptococcal meningitis still accounts for 19% of AIDS-related deaths annually. The incidences of CM in Europe and North America and the Latin America region have increased by approximately two-fold since 2009, while other regions showed either reduced or stable numbers of cases. Unfortunately, diagnostic and treatment options for cryptococcal infections are limited, and emerging antifungal resistance exacerbates the public health burden. Conclusion: The rising threat of C. neoformans is compounded by accumulating evidence for its ability to infect immunocompetent individuals and the emergence of antifungal-resistant variants. Emphasis should be placed on further understanding the mechanisms of pathogenicity and of antifungal resistance and tolerance. The development of novel management strategies through the identification of new drug targets and the discovery and optimization of new and existing diagnostics and therapeutics are key to reducing the health burden. [ABSTRACT FROM AUTHOR]

Background: Neonates may require higher doses of micafungin than adults to reach the therapeutic effect for increased plasma clearance. Only poor and inconclusive data are available still now to support this hypothesis, especially with regard to central nervous system micafungin concentrations. To assess the pharmacokinetics of increased doses (8 to 15 mg/kg/day) of micafungin in preterm and term neonates with invasive candidiasis and to complete previously presented results, we analyzed the pharmacokinetic data on a total of 53 newborns treated with micafungin, whereby 3 of them had Candida meningitis and hydrocephalus. Methods: Fifty-three neonates with systemic candidiasis, three of them with meningitis, were treated for at least 14 days with intravenous micafungin (Mycamine®) at a dosage ranging from 8 to 15 mg/kg/day. Plasma and cerebrospinal fluid (CSF) concentrations of micafungin were measured before the drug administration and at 1, 2, and 8 h after the end of the infusion using high-performance liquid chromatography (HPLC). Systemic exposure was assessed according to AUC0–24, plasma clearance (CL), and half-life measured in 52/53 patients, divided by chronological age. Results and conclusions: The mean micafungin clearance is higher in neonates than in older infants (0.036 L/h/kg before 28 days of life versus 0.028 L/h/kg after 120 days). The drug half-life is shorter in neonates than in older patients (13.5 h before 28 days of life versus 14.4 h after 120 days). With doses ranging between 8 and 15 mg/kg/day, micafungin crosses the blood–brain barrier reaching therapeutic levels in CSF. [ABSTRACT FROM AUTHOR]

The finding that some mAbs are antifungal suggests that antibody immunity may play a key role in the defense of the host against mycotic infections. The discovery of antibodies that guard against fungi is a significant advancement because it gives rise to the possibility of developing vaccinations that trigger protective antibody immunity. These vaccines might work by inducing antibody opsonins that improve the function of non-specific (such as neutrophils, macrophages, and NK cells) and specific (such as lymphocyte) cell-mediated immunity and stop or aid in eradicating fungus infections. The ability of antibodies to defend against fungi has been demonstrated by using monoclonal antibody technology to reconsider the function of antibody immunity. The next step is to develop vaccines that induce protective antibody immunity and to comprehend the mechanisms through which antibodies mediate protective effects against fungus. [ABSTRACT FROM AUTHOR]

Purpose of Review: There is a dearth of robust, peer-reviewed literature detailing the epidemiology, natural history, and sequelae associated with fungal infections of urologic implants, prostheses, and permanent devices. We curated and analyzed the available literature on this topic in concordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses system (PRISMA) criteria. The purpose of this systematic review is to consolidate the available research and highlight areas that require greater exploration. Recent Findings: As hypothesized, the literature investigating fungal infections of urologic implants and prostheses is scant. There were, however, several studies detailing the mycobiome, clinical outcomes, and risk factors associated with fungal infections of indwelling urinary catheters. Of the 20 studies that met inclusion criteria, only 4 focused on prosthetic devices, 3 for inflatable penile prosthetics and 1 for the adjustable transobturator male system. There were 15 studies pertaining to chronic indwelling urinary catheters and 1 study about chronic nephrostomy tubes. Furthermore, there were no studies investigating fungal infections of common urologic implants such as slings, sacral neuromodulators, or artificial urinary sphincters. Summary: This detailed systematic review found that the vast majority of studies focus on fungal infections associated with indwelling urinary catheters. There are virtually no retrospective or prospective studies investigating fungal infections of the various urologic implants and prostheses routinely used. Moreover, nearly half the studies included in this review were published over 20 years ago. There is a pressing need for more foundational literature on this topic that may ultimately yield sound prophylactic and management strategies. [ABSTRACT FROM AUTHOR]

Fungal infections are becoming one of the main causes of morbidity and mortality in people with weakened immune systems. Mycoses are becoming more common, despite greater knowledge and better treatment methods, due to the regular emergence of resistance to the antifungal medications used in clinical settings. Antifungal therapy is the mainstay of patient management for acute and chronic mycoses. However, the limited availability of antifungal drug classes limits the range of available treatments. Additionally, several drawbacks to treating mycoses include unfavourable side effects, a limited activity spectrum, a paucity of targets, and fungal resistance, all of which continue to be significant issues in developing antifungal drugs. The emergence of antifungal drug resistance has eliminated accessible drug classes as treatment choices, which significantly compromises the clinical management of fungal illnesses. In some situations, the emergence of strains resistant to many antifungal medications is a major concern. Although new medications have been developed to address this issue, antifungal drug resistance has grown more pronounced, particularly in patients who need long-term care or are undergoing antifungal prophylaxis. Moreover, the mechanisms that cause resistance must be well understood, including modifications in drug target affinities and abundances, along with biofilms and efflux pumps that diminish intracellular drug levels, to find novel antifungal drugs and drug targets. In this review, different classes of antifungal agents, and their resistance mechanisms, have been discussed. The latter part of the review focuses on the strategies by which we can overcome this serious issue of antifungal resistance in humans. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) infection is currently a great cause of concern for the healthcare sector around the globe. SARS-CoV-2 is an RNA virus that causes a serious infection that is associated with numerous adverse effects and multiple complications associated with different organs and systems during its pathogenic cycle in humans. Individuals affected by COVID-19, especially elderly populations and immunocompromised people, are greatly vulnerable to opportunistic fungal pathogens. Aspergillosis, invasive candidiasis, and mucormycosis are widespread fungal coinfections in COVID-19 patients. Other fungal infections that are rare but are exhibiting increased incidence in the current scenario include infections caused by Pneumocystis jirovecii, Histoplasma sp., Cryptococcus sp., etc. By producing virulent spores, these pathogens increase the severity of the disease and increase the morbidity and fatality rates in COVID-19 patients globally. These infections generally occur in patients recovering from COVID-19 infection, resulting in rehospitalization. Older and immunocompromised individuals are at higher risk of developing opportunistic fungal infections. This review focuses on understanding the opportunistic fungal infections prevalent in COVID-19 patients, especially elderly people. We have also highlighted the important preventive methods, diagnostic approaches, and prophylactic measures for fungal infections. [ABSTRACT FROM AUTHOR]

Luliconazole is a broad-spectrum topical antifungal agent that acts by altering the synthesis of fungi cell membranes. Literature suggests that the recurrence of fungal infection can be avoided by altering the pH of the site of infection. Studies have also suggested that fungi thrive by altering skin pH to be slightly acidic, i.e., pH 3–5. The current study is aimed to design, develop, characterize, and evaluate an alkaline pH-based antifungal spray solution for antifungal effects. Luliconazole was used as an antifungal agent and an alkaline spray was formulated for topical application by using Eudragit RS 100, propylene glycol (PG), water, sodium bicarbonate, and ethanol via solubilization method. Herein, sodium bicarbonate was used as an alkalizing agent. Based on DSC, FTIR, PXRD, scanning electron microscopy (SEM), and rheological analysis outcomes, the drug (luliconazole) and polymer were found to be compatible. F-14 formulation containing 22% Eudragit RS 100 (ERS), 1.5% PG, and 0.25% sodium bicarbonate was optimized by adopting the quality by design approach by using design of experiment software. The viscosity, pH, drying time, volume of solution post spraying, and spray angle were, 14.99 ± 0.21 cp, 8 pH, 60 s, 0.25 mL ± 0.05 mL, and 80 ± 2, respectively. In vitro drug diffusion studies and in vitro antifungal trials against Candida albicans revealed 98.0 ± 0.2% drug diffusion with a zone of inhibition of 9 ± 0.12 mm. The findings of the optimized luliconazole topical film-forming solution were satisfactory, it was compatible with human skin, and depicted sustained drug release that suggests promising applicability in facilitated topical antifungal treatments. [ABSTRACT FROM AUTHOR]

Introduction: We aimed to investigate the risk factors for secondary lower respiratory tract fungal infection during acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Methodology: A total of 466 AECOPD patients diagnosed from March 2019 to November 2020 were divided into infection (n = 48) and noninfection (n = 418) groups. The risk factors for lower respiratory tract fungal infection were screened by logistic regression analysis, and a nomogram prediction model was established. The discriminability was validated by area under the receiver operating characteristic curve (AUC) and C-index, calibration was validated by GiViTI calibration belt and Hosmer-Lemeshow test, and clinical validity was assessed by decision curve analysis (DCA) curve. Results: Thirty fungi strains were detected, including 18 strains of Candida albicans. Pulmonary heart disease, hypoalbuminemia, use of antibiotics within 3 months before admission, use time of antibiotics ≥ 14 d, invasive operation, blood glucose ≥ 11.10 mmol/L at admission, and procalcitonin (PCT) ≥ 0.5 ng/mL when diagnosed as fungal infection independent risk factors (p < 0.05). AUC was 0.891, indicating high discriminability of the model. The threshold probability in the DCA curve was set to 31.3%, suggesting that the model had clinical validity. Conclusions: We identified the independent risk factors for lower respiratory tract fungal infection in AECOPD patients. The established model has high discriminability and calibration. Immediate intervention is beneficial when the predicted risk exceeds 31.3%. [ABSTRACT FROM AUTHOR]

Fungal infections are a serious global concern because of their ability to spread and colonize host tissues in immunocompromised individuals. Such infections have been frequently reported worldwide and are currently gaining clinical research relevance owing to their resistant character, representing a bottleneck in treating affected people. Resistant fungi are an emergent public health threat. The upsurge of such pathogens has led to new research toward unraveling the destructive potential evoked by these species. Some fungi—grouped into Candida, Aspergillus, and Cryptococcus—are causative agents of severe and systemic infections. They are associated with high mortality rates and have recently been described as sources of coinfection in COVID-hospitalized patients. Despite the efforts to elucidate the challenges of colonization, dissemination, and infection severity, the immunopathogenesis of fungal diseases remains a pivotal characteristic in fungal burden elimination. The struggle between the host immune system and the physiological strategies of the fungi to maintain cellular viability is complex. In this brief review, we highlight the relevance of drug resistance phenotypes in fungi of clinical significance, taking into consideration their physiopathology and how the scientific community could orchestrate their efforts to avoid fungal infection dissemination and deaths. [ABSTRACT FROM AUTHOR]

Key Clinical Message Early identification and management of chronic invasive fungal rhinosinusitis (CIFRS) is key to optimizing outcomes. A missed diagnosis can result in permanent vision loss, chronic facial pain, or death. We present a case of CIFRS and literature review. Abstract This case report presents a 56‐year‐old female with CIFRS involving orbital and facial complications. The patient experienced delayed diagnosis despite multiple ED visits for sinusitis with progressive facial pain and ocular deficits not alleviated with antibiotics, emphasizing the importance of early identification and maintaining high clinical suspicion for CIFRS. Prompt recognition, initiation of antifungal therapy, and aggressive surgical debridement were crucial for preventing disease progression and improving the patient's quality of life.

Background: Human exposure to fungal elements is inevitable. Normal inhalation routinely deposits fungal spores within the nose and paranasal sinuses. Incidence of fungal infections are increasing, because of the greater use of immunosuppressive, increasing incidence of transplantation, chemotherapy, HIV infection, and diabetes mellitus. The aim of this research was to study the effects of nasal irrigation with normal saline on eliminating nasal fungal flora. Methods: We studied the clinical efficacy of nasal saline irrigation on the healthy individuals in a pilot study. Nasal swabs were used to get the nasal samples from 140 cases, 90 women and 50 men, currently living in Tehran. Those cases with positive fungal cultures, underwent nasal saline irrigation. They were reevaluated with nasal sampling and culture after a week. Results: Positive fungal culture was detected in 22 cases (15.7%): saprophyte fungi were the most common (45.4%). After nasal saline irrigation, negative fungal cultures were found in 54.5% of cases (P value=0.0009). Conclusions: This study demonstrated that nasal irrigation with nasal saline appears to be both safe and effective on the eradication of nasal fungal flora. So, it seems to be useful in prevention and management of all types of fungal rhinosinusitis.

This work aimed to prepare ketoconazole-loaded ethosomes and binary ethosomes to improve its skin delivery and antifungal efficacy. A 32 factorial design was used to optimize the ethosomes and formulate ketoconazole-loaded binary ethosomes. Ethosomes and binary ethosomes were evaluated for particle size, polydispersity index, zeta potential, percent drug entrapment efficiency, drug release, skin permeation and deposition and antifungal efficacy. The ethosomes particle size ranged from 78.99±16.72 to 321.53±10.41 nm and decreased by increasing phospholipid and ethanol concentrations. The polydispersity index values were in the range of 0.17±0.01 to 0.49 ± 0.04. The percent drug entrapment efficiency ranged from 36.09±2.66 to 95.89±0.19 and increased by increasing phospholipid concentration while ethanol concentration had the opposite effect. The binary ethosomes had smaller size but similar drug entrapment efficiency and zeta potential compared with the ethosomes. They had significantly higher percent drug release (∼96%) and permeation (∼95%) through rat skin compared with the ethosomes (93% and 90%, respectively). Binary ethosomes and ethosomes had, respectively 1.9 and 1.8-fold higher drug skin permeation and 5.3- and 5.6-fold higher drug deposition in the epidermis/dermis compared with the drug suspension. The antifungal efficacy of the drug-loaded ethosomes and binary ethosomes were similar to the drug hydroalcoholic solution. Collectively, these results confirm the potential of these nanocarriers to enhance drug efficacy given their small size, sustained drug release and enhanced skin permeability.

Pulmonary aspergillosis mainly affects elderly patients, patients with pulmonary complications, patients with hematological malignancies, organ transplant recipients, or critically ill patients. Co-morbidities may result in a high rate of polypharmacy and a high risk of potential drug–drug interaction (pDDI)-related antifungal azoles, which are perpetrators of several pharmacokinetic- and pharmacodynamic-driven pDDIs. Here, we report the results of the first 2-year study of an outpatient clinic focusing on the management of therapies in patients with pulmonary aspergillosis. All patients who underwent an outpatient visit from May 2021 to May 2023 were included in this retrospective analysis. A total of 34 patients who were given an azole as an antifungal treatment (53% voriconazole, 41% isavuconazole, and 6% itraconazole) were included. Overall, 172 pDDIs were identified and classified as red- (8%), orange- (74%), or yellow-flag (18%) combinations. We suggested handling polypharmacy in those patients using specific diagnostic and pharmacologic interventions. As expected, red-flag pDDIs involved mainly voriconazole as a perpetrator (71%). However, nearly 30% of red-flag pDDIs were not related to antifungal therapy. These findings highlight the importance of conducting an overall assessment of the pharmacologic burden and the key role played by a multidisciplinary team for the optimization of therapies in patients with pulmonary aspergillosis.

The increasing cases of drug resistance and high toxicity associated with the currently used antifungal agents are a worldwide public health concern. There is an urgent need to develop new antifungal drugs with unique target mechanisms. Plant-based compounds, such as carvacrol, eugenol, coumarin, cinnamaldehyde, curcumin, thymol, etc., have been explored for the development of promising antifungal agents due to their diverse biological activities, lack of toxicity, and availability. However, researchers around the world are unable to fully utilize the potential of natural products due to limitations, such as their poor bioavailability and aqueous solubility. The development of hybrid molecules containing natural products is a promising synthetic approach to overcome these limitations and control microbes’ capability to develop resistance. Based on the potential advantages of hybrid compounds containing natural products to improve antifungal activity, there have been different reported synthesized hybrid compounds. This paper reviews different literature to report the potential antifungal activities of hybrid compounds containing natural products.

Objective: The incidence of invasive fungal infections (IFIs) has increased due to intensive chemotherapy in childhood leukemia. The aim of this study was to evaluate the incidence, risk factors, causative pathogens, and impact on survival of IFIs among pediatric leukemia patients. Materials and Methods: The hospital records of 307 children with acute lymphoblastic leukemia (ALL, n=238), acute myeloid leukemia (AML, n=51), and relapsed leukemia (n=18) between January 2010 and December 2015 were retrospectively evaluated. Results: A total of 1213 febrile neutropenia episodes were recorded and 127 (10.4%) of them were related to an IFI. Of 307 children, 121 (39.4%) developed IFIs. The mean age was significantly older in the IFI group compared to children without IFIs (p

HIV and AIDS patients are susceptible to opportunistic infections. Oral candidiasis or thrush is the primary manifestation of fungal infection in these patients. The primary objective of this literature review was to summarize established and novel treatment options for oropharyngeal fungal infections in HIV/AIDS patients. Azoles and polyenes are the two primary antifungal drug classes employed for the treatment of oral candidiasis. A literature review was conducted on Medline and Google Scholar in October of 2021 using the keywords “Oral”, “Fungal”, “HIV”, and “Treatment”. Included studies were clinical trials, meta-analyses, and randomized controlled trials. Nineteen studies regarding azoles, polyenes, and novel treatments for oropharyngeal fungal infections in HIV/AIDS patients were examined in this review. The primary concern demonstrated from these studies is increased reports of resistance to antifungals, especially development of fluconazole resistance. Additionally, studies demonstrated that fluconazole had different relapse durations comparative to other medications, and that posaconazole could possibly act as an alternate form of treatment. Nystatin was indicated as a first-line therapy for thrush in multiple studies but could be upstaged by miconazole nitrate in resource-poor settings. Amphotericin B was an effective treatment option and was shown to be resilient in terms of fungal resistance, however potent adverse side effects were reported. Alternative treatments, such as immunoglobulin antibodies and lemon grass, revealed promising antifungal effects for immunocompromised individuals. Taken together, this review provides a thorough summary of treatment options of oropharyngeal fungal infections in HIV/AIDS patients.

Internalized HIV stigma can affect health outcomes, but the mechanism underlying this relationship is poorly understood. We investigated the potential pathways for the association between internalized stigma and opportunistic infections (OIs) among women living with HIV in rural India. We conducted a cross-sectional study involving in-person interviews with 600 participants. We modeled two outcome variables, total number of OIs and fungal dermatoses, which was the most frequently reported OI. Causal mediation analysis was performed to estimate the total effect, direct effect, and indirect effect through mediators while controlling for confounders. Food insecurity was a strong mediator of the association between internalized stigma and the number of OIs (70% of the total effect) and fungal dermatoses (83% of the total effect), while the indirect effect of stigma through adherence was minimal for both outcomes. Household food insecurity may be an important mediator of the impact of HIV-related stigma on opportunistic infections.

Clinically, fungi infections of the respiratory system are uncommon. The pathogen culture and the clinical characteristics are frequently used in the clinical diagnosis of fungi. Two different patterns of invasive pulmonary candidiasis have been described: primary candida bronchopneumonia and secondary pulmonary disease arising from haematogenous dissemination or rarely primary bronchopneumonia. Primary candida bronchopneumonia is limited largely to immunocompromised patients and is thought to occur by aspiration of candida into the upper respiratory tract. This is a case of a 55-year-old male who presented with the chief complaint of dyspnoea on exertion, intermittent fever, and cough associated with expectoration of 1-month duration. The fever was moderate grade and intermittent without chills, rigours, or night sweats. Respiratory system examination revealed bilateral scattered course crackles in both lung fields. Chest X-ray revealed heterogeneous opacities in bilateral upper lobes and hyperinflation of the lung. Biopsy specimens from para hilar (centrilobular nodules) were obtained and stained with haematoxylin/eosin, periodic acid Schiff, and Gram stain. Clusters of pseudohyphae and budding yeasts were detected in the nodules, indicating candida infection. Sputum microscopy confirmed pulmonary candidiasis. The patient’s bronchoscopy was done and bronchoalveolar lavage was sent for investigations and the growth of candidiasis came positive.

Cryptococcosis usually presents in immunocompromised patients, especially HIV infection, Immunocompetent patients may occasionally present with cerebral cryptococomas, which may be difficult to distinguish from other lesions like primary tumors or metastasis. We present one case that represents this diagnosis challenge. The first orientation for the correct diagnosis was found in the lumbar puncture with inflammatory CSF, presence of yeasts and a positive culture for Crypptococcus gatti. Subsequently, a brain biopsy confirmed the nature of the lesion.Cryptococcosis should be considered in differential diagnosis of tumors in the central nervous system in immunocompetent patients. and opportune assessment impact in the early treatment and can modify the outcomes of these patients.