Therapeutic innovation for multi-resistant candidemics: synergy of isavuconazole and caspofungin association

Fungal infections occurring in immunocompromised patients after immuno-chemotherapy treatment, are often difficult to eradicate and capable of even being fatal. Systemic mycoses affecting severely immunocompromised patients often manifest acutely with rapidly progressive pneumonia, fungemia, or manifestations of extrapulmonary dissemination. Opportunistic fungal infections (mycoses) include several pathogens elements, as Candidiasis, Aspergillosis, Mucormycosis (zygomycosis) and Fusariosis. Prompt diagnosis and effective therapy are needed to improve the associated morbidity and mortality, especially in cases with non-canonical fungal localizations and not responsive to the available antifungal drugs.

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Antifungal Resistance, Metabolic Routes as Drug Targets, and New Antifungal Agents: An Overview about Endemic Dimorphic Fungi

Mediators of Inflammation ◽

10.1155/2017/9870679 ◽

2017 ◽

Vol 2017 ◽

pp. 1-16 ◽

Cited By ~ 22

Author(s):

Juliana Alves Parente-Rocha ◽

Alexandre Melo Bailão ◽

André Correa Amaral ◽

Carlos Pelleschi Taborda ◽

Juliano Domiraci Paccez ◽

...

Keyword(s):

Drug Targets ◽

Antifungal Agents ◽

Fungal Infections ◽

Public Health Problem ◽

Antifungal Drugs ◽

Fungal Resistance ◽

Immunocompromised Patients ◽

Dimorphic Fungi ◽

Novel Drug ◽

Novel Drug Targets

Diseases caused by fungi can occur in healthy people, but immunocompromised patients are the major risk group for invasive fungal infections. Cases of fungal resistance and the difficulty of treatment make fungal infections a public health problem. This review explores mechanisms used by fungi to promote fungal resistance, such as the mutation or overexpression of drug targets, efflux and degradation systems, and pleiotropic drug responses. Alternative novel drug targets have been investigated; these include metabolic routes used by fungi during infection, such as trehalose and amino acid metabolism and mitochondrial proteins. An overview of new antifungal agents, including nanostructured antifungals, as well as of repositioning approaches is discussed. Studies focusing on the development of vaccines against antifungal diseases have increased in recent years, as these strategies can be applied in combination with antifungal therapy to prevent posttreatment sequelae. Studies focused on the development of a pan-fungal vaccine and antifungal drugs can improve the treatment of immunocompromised patients and reduce treatment costs.

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A treated case of rhinocerebral zygomycosis with aspergillosis: a case report from India

Access Microbiology ◽

10.1099/acmi.0.000139 ◽

2020 ◽

Vol 2 (8) ◽

Author(s):

Shalini Malhothra ◽

Sabyasachi Mandal ◽

Rajkumari Meena ◽

Priti Patel ◽

Nirmaljit Kaur Bhatia ◽

...

Keyword(s):

Amphotericin B ◽

Fungal Infections ◽

Clinical Sample ◽

Rapid Diagnosis ◽

Arterial System ◽

Immunocompromised Patients ◽

Direct Examination ◽

Intravenous Amphotericin ◽

Endoscopic Debridement ◽

Prompt Diagnosis

Zygomycosis and aspergillosis are two serious fungal infections that are commonly seen in immunocompromised patients. Since both of these infections involve fungi that invade vessels of the arterial system, an early and rapid diagnosis by direct examination of KOH mounts of the relevant clinical sample can clinch the diagnosis. Here, we present a case of a 60-year-old diabetic patient who presented with swelling and pain over the nose and left eye for 7 days with loss of vision in the left eye. After investigation, the patient was diagnosed as having rhinocerebral mucormycosis and aspergillosis, and was initially treated with amphotericin B (1 mg kg−1 day−1 intravenously), followed by endoscopic debridement under general anaesthesia. The patient gradually improved after surgery, and treatment with intravenous amphotericin B was continued along with the addition of 200 mg oral voriconazole twice daily (for the aspergillosis). With prompt diagnosis and treatment, the patient survived these fatal fungal co-infections and finally was discharged.

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Identification of Promising Antifungal Drugs against Scedosporium and Lomentospora Species after Screening of Pathogen Box Library

Journal of Fungi ◽

10.3390/jof7100803 ◽

2021 ◽

Vol 7 (10) ◽

pp. 803

Author(s):

Rodrigo Rollin-Pinheiro ◽

Luana Pereira Borba-Santos ◽

Mariana Ingrid Dutra da Silva Xisto ◽

Yuri de Castro-Almeida ◽

Victor Pereira Rochetti ◽

...

Keyword(s):

Fungal Infections ◽

Antifungal Susceptibility ◽

Antifungal Drugs ◽

Positive Interactions ◽

Immunocompromised Patients ◽

Planktonic Cells ◽

Morphological Alterations ◽

Susceptibility Tests ◽

Therapeutic Alternatives ◽

Scanning Electron

Fungal infections have been increasing during the last decades. Scedosporium and Lomentospora species are filamentous fungi most associated to those infections, especially in immunocompromised patients. Considering the limited options of treatment and the emergence of resistant isolates, an increasing concern motivates the development of new therapeutic alternatives. In this context, the present study screened the Pathogen Box library to identify compounds with antifungal activity against Scedosporium and Lomentospora. Using antifungal susceptibility tests, biofilm analysis, scanning electron microscopy (SEM), and synergism assay, auranofin and iodoquinol were found to present promising repurposing applications. Both compounds were active against different Scedosporium and Lomentospora, including planktonic cells and biofilm. SEM revealed morphological alterations and synergism analysis showed that both drugs present positive interactions with voriconazole, fluconazole, and caspofungin. These data suggest that auranofin and iodoquinol are promising compounds to be studied as repurposing approaches against scedosporiosis and lomentosporiosis.

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Refractory hypercalcaemia associated with disseminated Cryptococcus neoformans infection

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-20-0186 ◽

2021 ◽

Vol 2021 ◽

Author(s):

Jasmine Jiang Zhu ◽

William J Naughton ◽

Kim Hay Be ◽

Nicholas Ensor ◽

Ada S Cheung

Keyword(s):

Fungal Infection ◽

Cryptococcus Neoformans ◽

Fungal Infections ◽

Effective Therapy ◽

Differential Diagnoses ◽

High Dose ◽

List Type ◽

Immunocompromised Patients ◽

Severe Hypercalcaemia

Summary Hypercalcaemia is a very common endocrine condition, yet severe hypercalcaemia as a result of fungal infection is rarely described. There are have only been two reported cases in the literature of hypercalcaemia associated with Cryptococcus infection. Although the mechanism of hypercalcaemia in these infections is not clear, it has been suggested that it could be driven by the extra-renal production of 1-alpha-hydroxylase by macrophages in granulomas. We describe the case of a 55-year-old woman with a 1,25-OH D-mediated refractory hypercalcaemia in the context of a Cryptococcus neoformans infection. She required treatment with antifungals, pamidronate, calcitonin, denosumab and high-dose glucocorticoids. A disseminated fungal infection should be suspected in immunosuppressed individuals presenting with hypercalcaemia. Learning point In immunocompromised patients with unexplained hypercalcaemia, fungal infections should be considered as the differential diagnoses; Glucocorticoids may be considered to treat 1,25-OH D-driven hypercalcaemia; however, the benefits of lowering the calcium need to be balanced against the risk of exacerbating an underlying infection; Fluconazole might be an effective therapy for both treatment of the hypercalcaemia by lowering 1,25-OH D levels as well as of the fungal infection.

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Alexidine dihydrochloride has broad spectrum a ctivities against diverse fungal pathogens

10.1101/429944 ◽

2018 ◽

Author(s):

Zeinab Mamouei ◽

Abdullah Alqarihi ◽

Shakti Singh ◽

Shuying Xu ◽

Michael K. Mansour ◽

...

Keyword(s):

Mammalian Cell ◽

Fungal Pathogens ◽

Fungal Infections ◽

Antifungal Drugs ◽

Immunocompromised Patients ◽

Drug Resistant ◽

Cell Toxicity ◽

Diverse Range ◽

Mammalian Cell Toxicity

AbstractInvasive fungal infections due to Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans, constitute a substantial threat to hospitalized, immunocompromised patients. Further, the presence of drug-recalcitrant biofilms on medical devices, and emergence of drug-resistant fungi such as Candida auris, introduce treatment challenges with current antifungal drugs. Worse, currently there is no approved drug capable of obviating preformed biofilms which increases the chance of infection relapses. Here, we screened a small molecule Prestwick Chemical Library, consisting of 1200 FDA approved off-patent drugs, against C. albicans, C. auris and A. fumigatus, to identify those that inhibit growth of all three pathogens. Inhibitors were further prioritized for their potency against other fungal pathogens, and their ability to kill preformed biofilms. Our studies identified the bis-biguanide Alexidine dihydrochloride (AXD), as a drug with the highest antifungal and anti-biofilm activity against a diverse range of fungal pathogens. Finally, AXD significantly potentiated the efficacy of fluconazole against biofilms, displayed low mammalian cell toxicity, and eradicated biofilms growing in mice central venous catheters in vivo, highlighting its potential as a pan-antifungal drug.ImportanceThe prevalence of fungal infections has seen a rise in the past decades due to advances in modern medicine leading to an expanding population of device-associated and immunocompromised patients. Furthermore, the spectrum of pathogenic fungi has changed, with the emergence of multi-drug resistant strains such as C. auris. High mortality related to fungal infections point to major limitations of current antifungal therapy, and an unmet need for new antifungal drugs. We screened a library of repurposed FDA approved inhibitors to identify compounds with activities against a diverse range of fungi, in varied phases of growth. The assays identified Alexidine dihydrochloride (AXD) to have pronounced antifungal activity including against preformed biofilms, at concentrations lower than mammalian cell toxicity. AXD potentiated the activity of fluconazole and amphotericin B against Candida biofilms in vitro, and prevented biofilm growth in vivo. Thus AXD has the potential to be developed as a pan-antifungal, anti-biofilm drug.

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Alexidine Dihydrochloride Has Broad-Spectrum Activities against Diverse Fungal Pathogens

mSphere ◽

10.1128/msphere.00539-18 ◽

2018 ◽

Vol 3 (5) ◽

Cited By ~ 8

Author(s):

Zeinab Mamouei ◽

Abdullah Alqarihi ◽

Shakti Singh ◽

Shuying Xu ◽

Michael K. Mansour ◽

...

Keyword(s):

Mammalian Cell ◽

Fungal Pathogens ◽

Fungal Infections ◽

Antifungal Drugs ◽

Immunocompromised Patients ◽

Cell Toxicity ◽

Diverse Range ◽

Content Type ◽

Mammalian Cell Toxicity

ABSTRACT Invasive fungal infections due to Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans constitute a substantial threat to hospitalized immunocompromised patients. Further, the presence of drug-recalcitrant biofilms on medical devices and emergence of drug-resistant fungi, such as Candida auris, introduce treatment challenges with current antifungal drugs. Worse, currently there is no approved drug capable of obviating preformed biofilms, which increase the chance of infection relapses. Here, we screened a small-molecule New Prestwick Chemical Library, consisting of 1,200 FDA-approved off-patent drugs against C. albicans, C. auris, and A. fumigatus, to identify those that inhibit growth of all three pathogens. Inhibitors were further prioritized for their potency against other fungal pathogens and their ability to kill preformed biofilms. Our studies identified the bis-biguanide alexidine dihydrochloride (AXD) as a drug with the highest antifungal and antibiofilm activity against a diverse range of fungal pathogens. Finally, AXD significantly potentiated the efficacy of fluconazole against biofilms, displayed low mammalian cell toxicity, and eradicated biofilms growing in mouse central venous catheters in vivo, highlighting its potential as a pan-antifungal drug. IMPORTANCE The prevalence of fungal infections has seen a rise in the past decades due to advances in modern medicine leading to an expanding population of device-associated and immunocompromised patients. Furthermore, the spectrum of pathogenic fungi has changed, with the emergence of multidrug-resistant strains such as C. auris. High mortality related to fungal infections points to major limitations of current antifungal therapy and an unmet need for new antifungal drugs. We screened a library of repurposed FDA-approved inhibitors to identify compounds with activities against a diverse range of fungi in varied phases of growth. The assays identified alexidine dihydrochloride (AXD) to have pronounced antifungal activity, including against preformed biofilms, at concentrations lower than mammalian cell toxicity. AXD potentiated the activity of fluconazole and amphotericin B against Candida biofilms in vitro and prevented biofilm growth in vivo. Thus, AXD has the potential to be developed as a pan-antifungal, antibiofilm drug.

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Evaluation of Human Body Fluids for the Diagnosis of Fungal Infections

BioMed Research International ◽

10.1155/2013/698325 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

Parisa Badiee

Keyword(s):

Human Body ◽

Fungal Infections ◽

Body Fluids ◽

Invasive Fungal Infections ◽

Morbidity And Mortality ◽

Immunocompromised Patients ◽

Biopsy Material ◽

Etiologic Agents ◽

Sterile Body Fluids

Invasive fungal infections are a major cause of morbidity and mortality in immunocompromised patients. Because the etiologic agents of these infections are abundant in nature, their isolation from biopsy material or sterile body fluids is needed to document infection. This review evaluates and discusses different human body fluids used to diagnose fungal infections.

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Antifungal agents

10.1093/med/9780198755388.003.0046 ◽

2017 ◽

Author(s):

Donna M. MacCallum

Keyword(s):

Antifungal Agent ◽

Antifungal Agents ◽

Drug Class ◽

Fungal Infections ◽

Fungal Species ◽

Invasive Fungal Infections ◽

Antifungal Drugs ◽

Morbidity And Mortality ◽

Significant Morbidity ◽

Drug Formulations

Although invasive fungal infections lead to significant morbidity and mortality, there remain limited numbers of antifungal drugs available to treat these infections. This chapter describes and discusses the therapeutic antifungal agent classes currently available clinically to treat invasive fungal infections. These include the polyenes, azoles, echinocandins, and flucytosine (5-fluorocytosine). For each drug class, those currently used clinically are listed and their modes of action described. The effectiveness of drugs against different fungal species is explored and any drawbacks to the use of each drug are discussed. Drug formulations and indications for the use of each antifungal agent are also detailed.

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Hodgkin Disease and Pregnancy - A Case Report

Macedonian Medical Review ◽

10.2478/mmr-2014-0021 ◽

2014 ◽

Vol 68 (2) ◽

pp. 104-106

Author(s):

Aleksandra Pivkova Veljanovska ◽

Sonja Genadieva Stavrik ◽

Zlate Stojanoski ◽

Lazar Cadievski ◽

Adela Stefanija ◽

...

Keyword(s):

Case Report ◽

Pregnant Women ◽

Hodgkin Disease ◽

Morbidity And Mortality ◽

Chemotherapy Treatment ◽

Related Factors ◽

Hematological Disorder

Abstract The article presents a case with diagnosed Hodgkin disease (HD) during pregnancy. The aim of this case study was to present diagnostic possibilities in determining HD stage during pregnancy and therapeutic dilemmas. The incidence of HD during pregnancy is 3.2% of all cases with this malignant hematological disorder. The treatment of this disease during pregnancy depends on disease-related factors, pregnancy-related factors, as well as possible implications for fetal morbidity and mortality. The need of analysis of the nature of the disease during pregnancy indicates examination of a larger series of pregnant women with HD and the drawn conclusions affect the decision whether chemotherapy treatment should start immediately or it should be postponed for after delivery.

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Potential of Nanoparticles in Combating Candida Infections

Letters in Drug Design & Discovery ◽

10.2174/1570180815666181015145224 ◽

2019 ◽

Vol 16 (5) ◽

pp. 478-491 ◽

Cited By ~ 5

Author(s):

Faizan Abul Qais ◽

Mohd Sajjad Ahmad Khan ◽

Iqbal Ahmad ◽

Abdullah Safar Althubiani

Keyword(s):

Targeted Delivery ◽

Recent Progress ◽

Antifungal Agents ◽

Fungal Infections ◽

Fold Increase ◽

Antifungal Drugs ◽

Low Toxicity ◽

Candida Infections ◽

Made In

Aims: The aim of this review is to survey the recent progress made in developing the nanoparticles as antifungal agents especially the nano-based formulations being exploited for the management of Candida infections. Discussion: In the last few decades, there has been many-fold increase in fungal infections including candidiasis due to the increased number of immunocompromised patients worldwide. The efficacy of available antifungal drugs is limited due to its associated toxicity and drug resistance in clinical strains. The recent advancements in nanobiotechnology have opened a new hope for the development of novel formulations with enhanced therapeutic efficacy, improved drug delivery and low toxicity. Conclusion: Metal nanoparticles have shown to possess promising in vitro antifungal activities and could be effectively used for enhanced and targeted delivery of conventionally used drugs. The synergistic interaction between nanoparticles and various antifungal agents have also been reported with enhanced antifungal activity.

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