MBX-7591: a promising drug candidate against drug-resistant fungal infections.

Invasive fungal infections (IFIs) caused by pathogenic fungi pose a significant public health concern, particularly for immunocompromised individuals. Mortality rates for IFIs remain high, and currently available treatment options are limited. Existing antifungal agents often suffer from limited clinical efficacy, poor fungicidal activity within the host, potential toxicity, and increasing ineffectiveness due to emerging resistance, especially against triazole drugs, the current mainstay of antifungal treatment. A recent study has identified MBX-7591, a small molecule with promising antifungal activity against Aspergillus fumigatus and other pathogenic fungi, including strains resistant to triazoles (C. Gutierrez-Perez, C. Puerner, J. T. Jones, S. Vellanki, E. M. Vesely, et al., mBio e01166-24, 2024, https://doi.org/10.1128/mbio.01166-24). This novel compound appears to inhibit stearoyl-CoA 9-desaturase, a key enzyme involved in fungal fatty acid biosynthesis. By disrupting the conversion of saturated fatty acids to oleic acid, MBX-7591 offers a unique mechanism of action, potentially reducing the risk of resistance development. Here, we now discuss the implications of these groundbreaking findings for overcoming antifungal drug resistance.

Voriconazole successfully treats chytridiomycosis in frogs.

Chytridiomycosis is a devastating disease and is a key cause of amphibian population declines around the world. Despite active research on this amphibian disease system for over 2 decades, we still do not have treatment methods that are safe and that can be broadly used across species. Here, we show evidence that voriconazole is a successful method of treatment for 1 species of amphibian in captivity and that this treatment could offer benefits over other treatment options like heat or itraconazole, which are not able to be used for all species and life stages. We conducted 2 treatments of chytridiomycosis using voriconazole. The treatment was effective and resulted in 100% pathogen clearance, and mortality ceased. Additionally, treating frogs with voriconazole requires less handling than treatment methods like itraconazole and requires no specialized equipment, like heat treatment. We highlight that clinical treatment trials should be conducted to identify an optimum dosage and treatment time and that trials should test whether this treatment is safe and effective for tadpoles and other species.

Peritoneal dialysis-related peritonitis caused by Stephanoascus ciferrii: A Case Report.

Stephanoascus ciferrii, a conditional pathogenic fungus prevalent in nature, is more frequently encountered in patients with compromised immunity. However, the literature rarely reports infections caused by Stephanoascus ciferrii in peritoneal dialysis patients. Here, we detail the case of a 66-year-old female suffering from renal failure who experienced catheter-related infection during peritoneal dialysis. Dialysate turbidity prompted the detection of Stephanoascus ciferrii in both peritoneal dialysate and tubes through microbiological cultures. Subsequent treatment involved antifungal drugs and a transition to hemodialysis, resulting in the disappearance of peritonitis symptoms and the patient's discharge. In recent years, fungal infections, particularly dialysis-related infections, are on the rise. This marks the first reported case of catheter-related peritonitis infection caused by Stephanoascus ciferrii. Compared to bacterial infections, fungal infections pose challenges due to limited drug options, significant side effects, and prolonged treatment durations. Hence, prompt pathogen diagnosis and drug sensitivity testing are crucial for effective clinical treatment. In essence, this scientific case report underscores the uncommon occurrence of catheter-related peritonitis attributed to Stephanoascus ciferrii in a peritoneal dialysis patient with renal failure, emphasizing the distinctive management challenges and underscoring the critical significance of prompt diagnosis and suitable intervention in such instances.

Tackling multi-drug resistant fungi by efflux pump inhibitors.

The emergence of multidrug-resistant fungi is of grave concern, and its infections are responsible for significant deaths among immunocompromised patients. The treatment of fungal infections primarily relies on a clinical class of antibiotics, including azoles, polyenes, echinocandins, polyketides, and a nucleotide analogue. However, the incidence of fungal infections is increasing as the treatment for human and plant fungal infections overlaps with antifungal drugs. The need for new antifungal agents acting on different targets than known targets is undeniable. Also, the pace at which loss of fungal susceptibility to antibiotics cannot be undermined. There are several modes by which fungi can develop resistance to antibiotics, including reduced drug uptake, drug target alteration, and a reduction in the cellular concentration of the drug due to active extrusions and biofilm formation. The efflux pump's overexpression in the fungi primarily reduced the antibiotic's concentration to a sub-lethal concentration, thus responsible for developing resistant fungus strains. Several strategies are used to check antibiotic resistance in multi-drug resistant fungi, including synthesizing antibiotic analogs and giving antibiotics in combination therapies. Among them, the efflux pump protein inhibitors are considered potential adjuvants to antibiotics and can block the efflux of antibiotics by inhibiting efflux pump protein transporters. Moreover, it can sensitize the antifungal drugs to multi-drug resistant fungi with overexpressed efflux pump proteins. This review discusses the natural lead molecules, repurposable drugs, and formulation strategies to overcome the efflux pump activity in the fungi.

Siderophore-Conjugated Antifungals: A Strategy to Potentially Cure Fungal Infections.

Fungi pose a global threat to humankind due to the increasing emergence of multi-drug-resistant fungi. There is a rising incidence of invasive fungal infections. Due to the structural complexity of fungal cell membranes, only a few classes of antifungal agents are effective and have been approved by the U.S. FDA. Hence, researchers globally are focusing on developing novel strategies to cure fungal infections. One of the potential strategies is the "Trojan horse" approach, which uses the siderophore-mediated iron acquisition (SIA) system to scavenge iron to deliver potent antifungal agents for therapeutics and diagnostics. These siderophore conjugates chelate to iron and are taken up through siderophore-iron transporters, which are overexpressed exclusively on microbes such as bacteria or fungi, but not mammalian cells. Our comprehensive review delves into recent advancements in the design of siderophore-conjugated antifungal agents to gain fungal cell entry. Notably, our focus extends to unraveling the intricate relationship between the structure of natural siderophores or siderophore-like molecules and the resulting antifungal activity. By exploring these design strategies, we aim to contribute to the ongoing discourse on combating drug-resistant fungal infections and advancing the landscape of antifungal theranostics.

Nanoformulations for dismantling fungal biofilms: The latest arsenals of antifungal therapy.

Globally, fungal infections have evolved as a strenuous challenge for clinicians, particularly in patients with compromised immunity in intensive care units. Fungal co-infection in Covid-19 patients has made the situation more formidable for healthcare practitioners. Surface adhered fungal population known as biofilm often develop at the diseased site to elicit antifungal tolerance and recalcitrant traits. Thus, an innovative strategy is required to impede/eradicate developed biofilm and avoid the formation of new colonies. The development of nanocomposite-based antibiofilm solutions is the most appropriate way to withstand and dismantle biofilm structures. Nanocomposites can be utilized as a drug delivery medium and for fabrication of anti-biofilm surfaces capable to resist fungal colonization. In this context, the present review comprehensively described different forms of nanocomposites and mode of their action against fungal biofilms. Amongst various nanocomposites, efficacy of metal/organic nanoparticles and nanofibers are particularly emphasized to highlight their role in the pursuit of antibiofilm strategies. Further, the inevitable concern of nanotoxicology has also been introduced and discussed with the exigent need of addressing it while developing nano-based therapies. Further, a list of FDA-approved nano-based antifungal formulations for therapeutic usage available to date has been described. Collectively, the review highlights the potential, scope, and future of nanocomposite-based antibiofilm therapeutics to address the fungal biofilm management issue.

Antifungal resistance: why are we losing this battle?

The emergence of fungal pathogens and changes in the epidemiological landscape are prevalent issues in clinical mycology. Reports of resistance to antifungals have been reported. This review aims to evaluate molecular and nonmolecular mechanisms related to antifungal resistance. Mutations in the ERG genes and overexpression of the efflux pump (MDR1, CDR1 and CDR2 genes) were the most reported molecular mechanisms of resistance in clinical isolates, mainly related to Azoles. For echinocandins, a molecular mechanism described was mutation in the FSK genes. Furthermore, nonmolecular virulence factors contributed to therapeutic failure, such as biofilm formation and selective pressure due to previous exposure to antifungals. Thus, there are many public health challenges in treating fungal infections.

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Status and Challenge of Antifungal Stewardship at the Osaka Metropolitan University Hospital.

Antifungal stewardship (AFS), compared with antimicrobial stewardship (AS), requires more advanced knowledge, skills, and multidisciplinary collaboration in its implementation. Therefore, fewer facilities are performing AFS compared with AS. At our hospital, we started AS and AFS in 2014. Our AFS programs include the following: i) interventions for patients with yeast-positive blood cultures, ii) introduction of a conditional antifungal notification system, and iii) commencement of AS team rounds. AFS for filamentous fungi includes bronchoscopy and microbial identification, including genetic and drug susceptibility testing. These AFS activities have improved several processes and outcome measures. However, our AFS team has faced several problems owing to the impact of COVID-19. This review introduces the practice of AFS, which we initiated at our hospital in 2014, and presents the current problems.

PILOT STUDY OF INTRACOELOMIC TERBINAFINE IMPLANTS IN GREATER SIRENS (SIREN LACERTINA).

Chytridiomycosis caused by Batrachochytrium dendrobatidis (Bd) has been documented in greater sirens (Siren lacertina) in the wild and in the pet trade. This study evaluated the use of terbinafine-impregnated implants for chytridiomycosis prophylaxis in greater sirens exposed to Bd. Implants were placed intracoelomically in both control (blank implant, n = 4) and treatment (24.5 mg of terbinafine implant, n = 4) groups. Sirens were exposed to Bd zoospores via 24-h immersion bath at 1 and 2 mon postimplant placement. Blood was collected monthly for plasma terbinafine levels, and skin swabs were collected weekly for Bd quantitative PCR. Animals with terbinafine implants had detectable concentrations of plasma terbinafine ranging from 17 to 102 ng/ml. Only one terbinafine-implanted animal had a peak concentration above the published minimum inhibitory concentration for terbinafine against Bd zoospores (63 ng/ml); however, it is unknown how plasma terbinafine concentrations relate to concentrations in the skin. There was no difference between the two treatment groups in clinical signs or Bd clearance rate, and no adverse effects from implants were observed. These findings indicate using intracoelomic drug implants for drug delivery in amphibians is safe; however, terbinafine efficacy in preventing Bd chytridiomycosis in sirens remains unclear. Further investigation of the use of intracoelomic implants and identification of effective drugs and doses in other amphibian species against Bd and other infectious diseases is warranted, as this may provide a practical method for long-term drug delivery in wildlife.

The Antifungal Potential of Niclosamide and Structurally Related Salicylanilides.

Human mycoses cover a diverse field of fungal diseases from skin disorders to systemic invasive infections and pose an increasing global health problem based on ineffective treatment options, the hampered development of new efficient drugs, and the emergence of resistant fungal strains. Niclosamide is currently applied for the treatment of worm infections. Its mechanisms of action, which include the suppression of mitochondrial oxidative phosphorylation (also known as mitochondrial uncoupling), among others, has led to a repurposing of this promising anthelmintic drug for the therapy of further human diseases such as cancer, diabetes, and microbial infections. Given the urgent need to develop new drugs against fungal infections, the considerable antifungal properties of niclosamide are highlighted in this review. Its chemical and pharmacological properties relevant for drug development are also briefly mentioned, and the described mitochondria-targeting mechanisms of action add to the current arsenal of approved antifungal drugs. In addition, the activities of further salicylanilide-based niclosamide analogs against fungal pathogens, including agents applied in veterinary medicine for many years, are described and discussed for their feasibility as new antifungals for humans. Preliminary structure-activity relationships are determined and discussed. Various salicylanilide derivatives with antifungal activities showed increased oral bioavailabilities when compared with niclosamide. The simple synthesis of salicylanilide-based drugs also vouchsafes a broad and cost-effective availability for poorer patient groups. Pertinent literature is covered until 2024.

Recent Advancements in Radiopharmaceuticals for Infection Imaging.

COVID-19 pandemic has heightened the interest toward diagnosis and treatment of infectious diseases. Nuclear medicine, with its powerful scintigraphic, single photon emission computer tomography (SPECT), and positron emission tomography (PET) imaging modalities, has always played an important role in diagnosis of infections and distinguishing them from the sterile inflammation. In addition to the clinically available radiopharmaceuticals, there has been a decades-long effort to develop more specific imaging agents with some examples being radiolabeled antibiotics and antimicrobial peptides for bacterial imaging, radiolabeled antifungals for fungal infections imaging, radiolabeled pathogen-specific antibodies, and molecular engineered constructs. In this chapter, we discuss some examples of the work published in the last decade on developing nuclear imaging agents for bacterial, fungal, and viral infections to generate more interest among nuclear medicine community toward conducting clinical trials of these novel probes, as well as toward developing novel radiotracers for imaging infections.

Drug repurposing for fungal infections.

The rise of multidrug-resistant bacteria is a well-recognized threat to world health, necessitating the implementation of effective treatments. This issue has been identified as a top priority on the global agenda by the World Health Organization. Certain strains, such as Candida glabrata, Candida krusei, Candida lusitaniae, Candida auris, select cryptococcal species, and opportunistic Aspergillus or Fusarium species, have significant intrinsic resistance to numerous antifungal medicines. This inherent resistance and subsequent suboptimal clinical outcomes underscore the critical imperative for enhanced therapeutic alternatives and management protocols. The challenge of effectively treating fungal infections, compounded by the protracted timelines involved in developing novel drugs, underscores the pressing need to explore alternative therapeutic avenues. Among these, drug repurposing emerges as a particularly promising and expeditious solution, providing cost-effective solutions and safety benefits. In the fight against life-threatening resistant fungal infections, the idea of repurposing existing medications has encouraged research into both established and new compounds as a last-resort therapy. This chapter seeks to provide a comprehensive overview of contemporary antifungal drugs, as well as their key resistance mechanisms. Additionally, it seeks to provide insight into the antimicrobial properties of non-traditional drugs, thereby offering a holistic perspective on the evolving landscape of antifungal therapeutics.

Severe pneumonia with pleural effusion caused by co-infection of Paecilomyces variotii and Penicillium oxalicum in a diabetic patient.

BACKGROUND PAECILOMYCES: and Penicillium are considered as rare opportunistic pathogens in immunocompromised hosts, and pneumonia caused by Paecilomyces and Penicillium is rare. In this study, we present first case of severe pneumonia with pleural effusion caused by co-infection of Paecilomyces variotii (P. variotii) and Penicillium oxalicum (P. oxalicum) in a 66-year-old female with poorly controlled type 2 diabetes. CASE PRESENTATION: A 56-year-old woman patient presented to hospital for nausea, poor appetite, and vomiting for one day. On the second day of admission, blood culture and renal puncture fluid culture grew multidrug-resistant Escherichia coli (imipenem/cilastatin sensitive), and she received combination therapy with imipenem/cilastatin (1 g, every 8 h) and vancomycin (0.5 g, every 12 h). On the fourth day, she developed symptoms of respiratory failure. Pulmonary computed tomography (CT) showed an increase in pneumonia compared to before, with minor pleural effusion on both sides. Two fungi were isolated repeatedly from BALF culture, which were confirmed as P. variotii and P. oxalicum by Internal transcribed spacer (ITS) sequencing. Her pleural effusion was completely absorbed, pneumonia symptoms have significantly improved and discharged with receiving liposomal amphotericin B treatment for four weeks. CONCLUSIONS: It is worth noting that clinicians and laboratory personnel should not simply consider Paecilomyces and Penicillium species as contaminants, especially in immunocompromised patients. Early fungal identification and antifungal drug sensitivity are crucial for clinical drug selection and patient prognosis.

Clinical application of voriconazole in pediatric patients: a systematic review.

The purpose of this study was to review the literature on the clinical use of voriconazole (VRC) in pediatric patients. MEDLINE, Embase, PubMed, Web of Science, and Cochrane Library were searched from January 1, 2000, to August 15, 2023 for relevant clinical studies on VRC use in pediatric patients. Data were collected based on inclusion and exclusion criteria, and a systematic review was performed on recent research related to the use of VRC in pediatric patients. This systematic review included a total of 35 observational studies among which there were 16 studies investigating factors influencing VRC plasma trough concentrations (Ctrough) in pediatric patients, 14 studies exploring VRC maintenance doses required to achieve target range of Ctrough, and 11 studies focusing on population pharmacokinetic (PPK) research of VRC in pediatric patients. Our study found that the Ctrough of VRC were influenced by both genetic and non-genetic factors. The optimal dosing of VRC was correlated with age in pediatric patients, and younger children usually required higher VRC doses to achieve target Ctrough compared to older children. Establishing a PPK model for VRC can assist in achieving more precise individualized dosing in children.

Epidemiology and Management of Infections in Liver Transplant Recipients.

Background: Improvements in liver transplant (LT) outcomes are attributed to advances in surgical techniques, use of potent immunosuppressants, and rigorous pre-LT testing. Despite these improvements, post-LT infections remain the most common complication in this population. Bacteria constitute the most common infectious agents, while fungal and viral infections are also frequently encountered. Multi-drug-resistant bacterial infections develop because of polymicrobial overuse and prolonged hospital stays. Immediate post-LT infections are commonly caused by viruses. Conclusions: Appropriate vaccination, screening of both donor and recipients before LT and antiviral prophylaxis in high-risk individuals are recommended. Antimicrobial drug resistance is common in high-risk LT and associated with poor outcomes; epidemiology and management of these cases is discussed. Additionally, we also discuss the effect of coronavirus disease 2019 (COVID-19) infection and monkeypox in the LT population.

Impact of lumacaftor/ivacaftor on the bacterial and fungal respiratory pathogens in cystic fibrosis: a prospective multicenter cohort study in Sweden.

BACKGROUND: A significant decline in pulmonary exacerbation rates has been reported in CF patients homozygous for F508del treated with lumacaftor/ivacaftor. However, it is still unclear whether this reduction reflects a diminished microbiological burden. OBJECTIVES: The aim of this study was to determine the impact of lumacaftor/ivacaftor on the bacterial and fungal burden. DESIGN: The study is a prospective multicenter cohort study including 132 CF patients homozygous for F508del treated with lumacaftor/ivacaftor. METHODS: Clinical parameters as well as bacterial and fungal outcomes 1 year after initiation of lumacaftor/ivacaftor were compared to data from 2 years prior to initiation of the treatment. Changes in the slope of the outcomes before and after the onset of treatment were assessed. RESULTS: Lung function measured as ppFEV1 (p < 0.001), body mass index (BMI) in adults (p < 0.001), and BMI z-score in children (p = 0.007) were improved after initiation of lumacaftor/ivacaftor. In addition, the slope of the prevalence of Streptococcus pneumoniae (p = 0.007) and Stenotrophomonas maltophilia (p < 0.001) shifted from positive to negative, that is, became less prevalent, 1 year after treatment, while the slope for Candida albicans (p = 0.009), Penicillium spp (p = 0.026), and Scedosporium apiospermum (p < 0.001) shifted from negative to positive. CONCLUSION: The current study showed a significant improvement in clinical parameters and a reduction of some of CF respiratory microorganisms 1 year after starting with lumacaftor/ivacaftor. However, no significant changes were observed for Pseudomonas aeruginosa, Staphylococcus aureus, or Aspergillus fumigatus, key pathogens in the CF context.

The practice and evaluation of antifungal stewardship programs at a tertiary first-class hospital in China.

BACKGROUND: The sharp increase in fungal infections, insufficient diagnostic and treatment capabilities for fungal infections, poor prognosis of patients with fungal infections as well as the increasing drug resistance of fungi are serious clinical problems. It is necessary to explore the implementation and evaluation methods of antifungal stewardship (AFS) to promote the standardized use of antifungal drugs. METHODS: The AFS programme was implemented at a tertiary first-class hospital in China using a plan-do-check-act (PDCA) quality management tool. A baseline investigation was carried out to determine the utilization of antifungal drugs in pilot hospitals, analyse the existing problems and causes, and propose corresponding solutions. The AFS programme was proposed and implemented beginning in 2021, and included various aspects, such as team building, establishment of regulations, information construction, prescription review and professional training. The management effectiveness was recorded from multiple perspectives, such as the consumption of antifungal drugs, the microbial inspection rate of clinical specimens, and the proportion of rational prescriptions. The PDCA management concept was used for continuous improvement to achieve closed-loop management. RESULTS: In the first year after the implementation of the AFS programme, the consumption cost, use intensity and utilization rate of antifungal drugs decreased significantly (P < 0.01). The proportion of rational antifungal drug prescriptions markedly increased, with the proportion of prescriptions with indications increasing from 86.4% in 2019 to 97.0% in 2022, and the proportion of prescriptions with appropriate usage and dosage increased from 51.9 to 87.1%. In addition, after the implementation of the AFS programme, physicians' awareness of the need to complete microbial examinations improved, and the number of fungal cultures and serological examinations increased substantially. Statistics from drug susceptibility tests revealed a decrease in the resistance rate of Candida to fluconazole. CONCLUSION: This study indicated that the combination of AFS and the PDCA cycle could effectively reduce antifungal consumption and promote the rational use of antifungal drugs, providing a reference for other health care systems to reduce the overuse of antifungal drugs and delay the progression of fungal resistance.

Construction and Activity Evaluation of Novel Bifunctional Inhibitors and a COF Carrier Based on a Fungal Infection Microenvironment.

Faced with increasingly serious fungal infections and drug resistance issues, three different series of novel dual-target (programmed death ligand 1/14 α-demethylase) compounds were constructed through the fragment combination pathway in the study. Their chemical structures were synthesized, characterized, and evaluated. Among them, preferred compounds 10c-1, 17b-1, and 18b-2 could efficiently exert their antifungal and antidrug-resistant fungal ability through blocking ergosterol biosynthesis, inducing the upregulation of reactive oxygen species level, and triggering apoptosis. Especially, compound 18b-2 exhibited the synergistic function of fungal inhibition and immune activation. Moreover, the covalent organic framework carrier was also generated based on the acidic microenvironment of fungal infection to improve the bioavailability and targeting of preferred compounds; this finally accelerated the body's recovery rate.