Opportunistic Fungal Infections Research Articles

Clinicopathologic Spectrum and Outcomes of Infections Diagnosed on Graft Biopsies and Nephrectomy in Live Renal Allograft Recipients: An Institutional Experience.

Modern immunosuppressive regimens have reduced rejection episodes in renal allograft recipients but have increased the risk of opportunistic infections. Infections are considered to be the second leading cause of death after cardiovascular complications in renal allograft recipients. Data on opportunistic infections affecting the allograft itself are scarce. The present study describes the spectrum of renal opportunistic infections and their outcomes diagnosed on renal allograft biopsies and nephrectomy specimens. Our retrospective observational study was conducted from December 2011 to December 2021. We analyzed infectious episodes diagnosed on renal allograft biopsies or graft nephrectomy specimens. We obtained clinical, epidemiological, and laboratory details for analyses from hospital records. BK virus nephropathy was the most common opportunistic infection affecting the allograft, accounting for 47% of cases, followed by bacterial graft pyelonephritis (25%). Mucormycosis was the most common fungal infection. The diagnosis of infection from day of transplant ranged from 14 days to 39 months. Follow-up periods ranged from 1 to 10 years. Mortality was highest among patients with opportunistic fungal infection (62%), followed by viral infections, and graft failure rate was highest in patients with graft pyelonephritis (50%). Among patients with BK polyomavirus nephropathy, 45% had stable graft function compared with just 33% of patients with bacterial graft pyelonephritis. BK polyoma virus infection was the most common infection affecting the renal allograft in our study. Although fungal infections caused the highest mortality among our patients, bacterial graft pyelonephritis was responsible for maximum graft failure. Correctly identifying infections on histology is important so that graft and patient life can be prolonged.

Hematological Indices in COVID-19 Patients with Rhinosinusitis Mucormycosis.

Rhinosinusitis mucormycosis (RM) is an invasive opportunistic fungal infection, especially among COVID-19 patients. The current study aimed to assess the peripheral blood hematological disorders of COVID-19 patients-associated RM. During ten month, in two COVID-19 centers in Mashhad, Iran, from June 2021 to March 2022, eighty-three patients suspected of COVID-19 with rhinosinusitis or rhino-orbital mucormycosis participated in this study. The hematological indices of these patients were measured by independent sample T-test or Mann-Whitney test for quantitative data, and the qualitative variables were analyzed using Chi-square or Fisher's exact test in SPSS version 20 at a significance level of 0.05. Of the COVID-19 patients, 40 (48.2%) were affected by RM, and leukocytosis due to neutrophilia was observed in 30% of them. Leukocyte counts were normal in 10 (25%) patients, but 1 (2.5%) and 3 (7.5%) had leukopenia and lymphopenia, respectively. Leukocytosis plus lymphopenia was observed in 7 (17.5%) patients. Also, the synchronicity of leukopenia and lymphopenia was seen in 5 (12.5%) patients. Leukopenia, lymphopenia, and neutropenia have occurred concurrently in 2 (5%) patients. The complete blood count (CBC) showed that RBCs, hemoglobin (Hb), hematocrit (HCT), MCH, MCHC, platelet (PLT), and lymphocytes decreased while neutrophils increased. Among the hematological parameters, leukocytosis due to neutrophilia and reduction in Hb, HCT, and PLT are more dominant factors in COVID-19 patients-associated RM.

The Effect of the COVID-19 Epidemic on the Prevalence of Opportunistic Fungal Infections and the Consumption of Antifungal Drugs in Patients Hospitalized in Abadan Hospitals

The Effect of the COVID-19 Epidemic on the Prevalence of Opportunistic Fungal Infections and the Consumption of Antifungal Drugs in Patients Hospitalized in Abadan Hospitals

Glucocorticoids as a risk factor for infection and adverse outcomes in non-HIV and non-transplant patients with cryptococcal meningitis.

Cryptococcal meningitis (CM), an opportunistic fungal infection affecting immunocompromised hosts, leads to high mortality. The role of previous exposure to glucocorticoids as a risk factor and as an outcome modulator has been observed, but systematic studies are lacking. The primary aim of this study is to evaluate the impact of glucocorticoid use on the clinical outcomes, specifically mortality, of non-HIV and non-transplant (NHNT) patients diagnosed with CM. We queried a global research network to identify adult NHNT patients with CM based on ICD codes or recorded specific Cryptococcus CSF lab results with or without glucocorticoid exposure the year before diagnosis. We performed a propensity score-matched analysis to reduce the risk of confounding and analysed outcomes by glucocorticoid exposure. We used a Cox proportional hazards model for survival analysis. We identified 764 patients with a history of glucocorticoid exposure and 1267 patients without who developed CM within 1 year. After propensity score matching of covariates, we obtained 627 patients in each cohort. The mortality risk in 1 year was greater in patients exposed to prior glucocorticoids(OR: 1.3, CI: 1.2-2.0, p = 0.002). We found an excess of 45 deaths among CM patients with previous glucocorticoid use (7.4% increased absolute risk of dying within 1 year of diagnosis) compared to CM controls without glucocorticoid exposure. Hospitalisation, intensive care unit admission, emergency department visits, stroke and cognitive dysfunction also showed significant, unfavourable outcomes in patients with glucocorticoid-exposed CM compared to glucocorticoid-unexposed CM patients. Previous glucocorticoid administration in NHNT patients seems to associate with 1-year mortality after CM adjusted for possible confounders related to demographics, comorbidities and additional immunosuppressive medications. Serial CrAg screening might be appropriate for higher-risk patients on glucocorticoids after further cost-benefit analyses.

Gastrointestinal bleeding in a kidney transplant recipient.

Opportunistic infections are common in transplant recipients, but gastrointestinal bleed is rarely reported to be due to opportunistic fungal infections, and hence could present as a diagnostic challenge. We report a case of disseminated histoplasmosis in a kidney transplant recipient whose initial presentation was acute lower gastrointestinal bleeding with no other symptoms. The colonoscopy showed scattered punchout circular colonic ulcers with biopsy revealing budding yeasts consistent with a diagnosis of histoplasmosis. The patient was successfully treated with a prolonged course of intravenous amphotericin B followed by oral itraconazole.

Dynamics of host immune responses and a potential function of Trem2hi interstitial macrophages in Pneumocystis pneumonia.

Pneumocystis pneumonia (PCP) is a life-threatening opportunistic fungal infection with a high mortality rate in immunocompromised patients, ranging from 20 to 80%. However, current understanding of the variation in host immune response against Pneumocystis across different timepoints is limited. In this study, we conducted a time-resolved single-cell RNA sequencing analysis of CD45+ cells sorted from lung tissues of mice infected with Pneumocystis. The dynamically changes of the number, transcriptome and interaction of multiply immune cell subsets in the process of Pneumocystis pneumonia were identified according to bioinformatic analysis. Then, the accumulation of Trem2hi interstitial macrophages after Pneumocystis infection was verified by flow cytometry and immunofluorescence. We also investigate the role of Trem2 in resolving the Pneumocystis infection by depletion of Trem2 in mouse models. Our results characterized the CD45+ cell composition of lung in mice infected with Pneumocystis from 0 to 5 weeks, which revealed a dramatic reconstitution of myeloid compartments and an emergence of PCP-associated macrophage (PAM) following Pneumocystis infection. PAM was marked by the high expression of Trem2. We also predicted that PAMs were differentiated from Ly6C+ monocytes and interacted with effector CD4+ T cell subsets via multiple ligand and receptor pairs. Furthermore, we determine the surface markers of PAMs and validated the presence and expansion of Trem2hi interstitial macrophages in PCP by flow cytometry. PAMs secreted abundant pro-inflammation cytokines, including IL-6, TNF-α, GM-CSF, and IP-10. Moreover, PAMs inhibited the proliferation of T cells, and depletion of Trem2 in mouse lead to reduced fungal burden and decreased lung injury in PCP. Our study delineated the dynamic transcriptional changes in immune cells and suggests a role for PAMs in PCP, providing a framework for further investigation into PCP's cellular and molecular basis, which could provide a resource for further discovery of novel therapeutic targets.

A clinical update on fungal disease of human skin

AbstractFungi cause cutaneous pathology in humans in three broad categories: superficial mycoses, subcutaneous mycoses, and systemic or opportunistic mycoses. In this chapter, we will discuss recent updates in treatment for dermatological diagnoses in each of these categories. We will also discuss dermatologically relevant emerging fungal pathogens.

Retrieved from the jaws of death – A successfully managed case of rhino- cerebral mucormycosis despite healthcare constraints due to economic turmoil

Rhino- orbital-cerebral mucormycosis is a rapidly progressive life-threatening fungal infection which primarily affects the nose, paranasal sinuses and orbit. It is an opportunistic fungal infection caused by fungi of order Mucorales. They are a group of ubiquitous fungi which grow on decaying vegetation and a wide variety of organic compounds, and they pose a huge threat to life by direct invasion of the vital structures in the body. Early identification and treatment of this disease is therefore of paramount importance for a better outcome. We report a case of a 65-year-old man with a background history of poorly controlled type 2 diabetes mellitus, hypertension and chronic kidney disease, who presented with a diffuse headache of 5 days along with left sided facial oedema, redness of left eye and visual disturbance. Imaging studies revealed sinusitis involving multiple sinuses and the nasal mucosal biopsy showed fungal hyphae. Considering the clinical presentation and the overall findings from the investigations a diagnosis of rhino-cerebral mucormycosis was made. Medical management was done with administration of intravenous Amphotericin B and IV itraconazole along with other supportive medication. Patient had a successful recovery after a lengthy hospital stay which included surgical debridement of affected tissues and the medical treatment even with challenges faced due to unavailability of drugs due to economic constraints on health.

Pneumocystis jirovecii Pneumonia in HIV-Negative, Non-transplant Patients: Epidemiology, Clinical Manifestations, Diagnosis, Treatment, and Prevention.

Pneumocystis jirovecii pneumonia (PJP) is an opportunistic fungal infection that is increasingly seen in HIV-negative patients with immune compromise due to other etiologies. We lack comprehensive clinical recommendations for this population. In non-HIV cases, PJP has a mortality rate of up to 50%, which is unacceptable despite the presence of safe and effective prophylaxis and therapy. Steroid use is one of the most common risk factors for disease development. New data suggests that lower doses of the preferred treatment regimen, TMP-SMX, may be equally effective for treatment while limiting side effects. While commonly used, the benefit of corticosteroids for the treatment of PJP has recently been called into question, with a recent multicenter cohort demonstrating no benefit among solid organ transplant recipients. A high suspicion of PJP in individuals with pneumonia during immunosuppressant use is crucial. Therapeutic options are evolving to decrease potential side effects while maintaining efficacy in this highly morbid disease.

Candidiasis in breast cancer: Tumor progression or not?

Candida albicans is an "opportunistic fungal agent" in cancer patients that can become colonized in both mucosal and deep tissues and cause severe infections. Most evidence has shown that C. albicans can enhance the progress of different cancers by several mechanisms such as generating virulence factors, participation in endogenous production of pro-inflammatory mediators, and stimulating a wide range of immune cells in the host. The main idea of this review is to describe a range of Candida-used mechanisms that are important in candidiasis-associated malignant processes and cancer development, particularly breast cancer. This review intends to provide a detailed discussion on different regulatory mechanisms of C. albicans that undoubtedly help to open new therapeutic horizons of cancer therapy in patients with fungal infection. The current therapeutic approach is not fully effective in immunocompromised and cancer patients, and further studies are required to find new products with effective antifungal properties and minimal side effects to increase the susceptibility of opportunistic fungal infections to conventional antifungal agents. So, in this situation, a special therapy should be considered to control the infection and simultaneously have the most therapeutic index on tumor patients.

Genome-based solutions for managing mucormycosis.

An uncommon opportunistic fungal infection known as mucormycosis is caused by a class of molds called mucoromycetes. Currently, antifungal therapy and surgical debridement are the primary treatment options for mucormycosis. Despite the importance of comprehensive knowledge on mucormycosis, there is a lack of well-annotated databases that provide all relevant information. In this study, we have gathered and organized all available information related to mucormycosis that include disease's genome, proteins, diagnostic methods. Furthermore, using the AlphaFold2.0 prediction tool, we have predicted the tertiary structures of potential drug targets. We have categorized the information into three major sections: "genomics/proteomics," "immunotherapy," and "drugs." The genomics/proteomics module contains information on different strains responsible for mucormycosis. The immunotherapy module includes putative sequence-based therapeutics predicted using established tools. Drugs module provides information on available drugs for treating the disease. Additionally, the drugs module also offers prerequisite information for designing computationally aided drugs, such as putative targets and predicted structures. In order to provide comprehensive information over internet, we developed a web-based platform MucormyDB (https://webs.iiitd.edu.in/raghava/mucormydb/).

Identification and Speciation of Various Fungal Co-infections in COVID-19 Patients by Different Laboratory Diagnostic Methods: A Retrospective Observational Study

Introduction: Respiratory illness caused by a novel coronavirus was first noted in December 2019 in Wuhan, Hubei Province, China. Later, the novel coronavirus was referred to as Severe and critical Acute Respiratory Syndrome Coronavirus-2 (SARS- CoV-2) by the International Committee on Taxonomy of Viruses (ICTV). However, the types of co-infected pathogens and the proportion of co-infection in SARS-CoV-2-positive patients were unclear. Co-infection with certain pathogens may also hinder accurate disease diagnosis. Aim: To determine the most suitable sample type for a better culture outcome and to identify the various opportunistic fungal infections related to Coronavirus Disease 2019 (COVID-19) patients. Materials and Methods: This retrospective observational study was conducted between November 2021 to January 2022 at Department of Microbiology, Government Medical College, Surat, Gujarat, India. The data collection was done in the month of November 2021 followed by data analysis in December 2021 to January 2022. A total of 252 suspected cases of fungal co-infection were sampled (including swabs, tissues, skin scrapings, Cerebrospinal fluid (CSF), sputum, pus, and drain) from different wards for fungal wet mount Potassium Hydroxide (KOH) and culture. The data was entered into Microsoft Excel (Windows 10), and analysis was performed using Microsoft Excel, including frequency distribution and percentage. Results: A total of 252 samples were received. Demographic details showed that individuals aged 41-50 years were more commonly affected, and males were affected more than females. Among the sample types, tissue samples showed the highest positivity 43 (17%), followed by scraping materials 14 (6%). Out of the total 252 cultures performed, 70 were positive. In terms of fungal speciation, Mucor species accounted for 24 (34.28%) isolates, while Aspergillus flavus accounted for 26 (37.14%), followed by other isolated fungal species. Conclusion: Fungal co-infection is observed in COVID-19 positive patients, which not only contributes to morbidity but also increases mortality. Tissue samples demonstrated the highest culture positivity. The culture results showed a higher frequency of Mucor species isolates and Aspergillus flavus compared to other isolates.

Antifungal Properties of Grape Seed Extract on Various Species of Candida Organisms: An In vitro Study

Purpose: Oral candidiasis is one of the most common fungal opportunistic infections in the mouth caused by a fungus called Candida, and it presents as commensals in all humans. Over the last few decades, the increasing incidence of Candida infections parallels the growing numbers of immunocompromised patients. This trend is aggravated by the fact that there is a reckless use of antifungals. To combat this trend, the use of natural antifungals which have fewer side effects is recommended. Black grape seed extract (GSE) has shown a promise in this regard. Materials and Methods: Candida species such as Candida krusei, Candida glabrata, Candida tropicalis, and Candida albicans were used in the study. Fungal strains were passaged in the agar Sabouraud dextrose environment from 24 h to have live and fresh strains for the test. Black GSE was obtained. Minimum inhibitory concentration (MIC), of GSE, amphotericin B and fluconazole drugs on the included fungi was examined using disc diffusion method. Then, the plates were incubated for 24 h at 37°C. Finally, growth inhibitory zone was examined. Results: The analysis of the results revealed that the growth of C. albicans and C. krusei had been stopped at the concentration of 6.25 μg/mL, but the growth of C. glabrata and C. tropicalis was inhibited at a concentration of 12.25 μg/mL and 0.8 μg/mL respectively. Conclusion: The results obtained from the present study showed that both disc diffusion method and the maximum inhibitory concentration of MIC (Macro dilution) confirms the antimicrobial susceptibility of four species of candida to GSE. We conclude the possibility of GSE as an effective alternative measure for commercial antifungal agents, especially among immunocompromised patients, However, more laboratory and clinical studies need to be conducted to validate our findings.

Inhibitory effects of trans-cinnamaldehyde on candida spp. Biofilm and planktonic form compared to nystatin: A comparative analysis

Trans-Cinnamaldehyde, an α, β-unsaturated aromatic aldehyde, was a derivative of Cinnamonnum obtusifolium - Lauraceae; its bioavailability allows it to be used in the treatment of fungal infections as Candida species causing opportunistic fungal infections are common today. Antibiotic resistance in fungi is often due to their ability to form biofilm. Therefore, new substances with antibiofilm were being investigated as alternative treatment. Representatives of Candida spp. were used to determine the MIC, MBIC50, MBIC80, MBIC100, and MFC of trans-Cinnamaldehyde compared to Nystatin which is used for treatment of Candida infections in Vietnam. The most important antibiofilm effect of trans-Cinnamaldehyde was demonstrated by the CLSI M27-A2 method. Trans-Cinnamaldehyde was given MBIC100 higher than PMIC from 10 to 20 times, while Nystatin was given MBIC100 higher than PMIC from 5 to 20 times. In addition, PMFC of trans-Cinnamaldehyde was equivalent (Candida albicans and Candida tropicalis) or only twice (Candida glabrata) PMIC. The jump in Candida biofilm inhibitory activity was short, from MBIC50 to MBIC100 (no intermediate value, MBIC80). Trans-Cinnamaldehyde extract, compared to Nystatin, had a generally similar effect in preventing the growth and loss of Candida spp. both in biofilm and planktonic form and was somewhat more effective against Candida spp. in biofilm form.

Tacrolimus Interaction with Azole Antifungals in Kidney Transplant Recipients: Is Fluconazole or Clotrimazole a Worse Offender?

The utilization of rabbit ant thymocyte globulin induction with tacrolimus-based maintenance immunosuppression may increase the risk for opportunistic fungal infections, particularly oral-esophageal candidiasis. Both are commonly prescribed for deceased donor kidney transplant recipients Tacrolimus (TAC), a calcineurin inhibitor, is metabolized hepatically by cytochrome P450 3A4/5 enzymes. Due to this, a drug interaction can occur with TAC and either fluconazole (FCZ) or clotrimazole (CTMZ). Both are commonly used for antifungal prophylaxis. While both FCZ and CTMZ inhibit CYP3A4/5, systemic absorption of CTMZ is minimal, theoretically limiting the interaction with TAC and reducing the need for dose readjustments. Medical records for adult patients receiving a renal transplant between March 2009 and September 2011 were retrospectively reviewed for TAC dose adjustments following discontinuation of the antifungal agent required to maintain therapeutic TAC blood levels. The change in TAC dose: trough ratio 4-8 weeks after azole discontinuation was greater in patients receiving FCZ compared to CTMZ (FCZ +92.9% vs CTMZ +43.4%, p=0.004). In addition, the proportion of patients requiring ≥30% TAC dose increase was 70% with FCZ versus 45% with CTMZ (p=0.006). The choice of antifungal also did not affect the number of sub-therapeutic TAC levels, the number of patients with sub-therapeutic levels pre- or post-discontinuation, or incidence of biopsy-proven allograft rejection.

Mucormycosis in COVID-19 Pandemic

Background Coronavirus disease-2019 (COVID-19) has been associated with a wide range of opportunistic fungal infections. Many countries have seen an unprecedented rise in cases of COVID-19-associated mucormycosis (CAM). The purpose of this study is to identify the correlation between the COVID-19 epidemic and mucormycosis. Our study also provides details on factors causing CAM. Methods A retrospective study from November 2020 to February 2022 includes four cases of COVID-19-associated rhino-orbital mucormycosis treated at Habib Thameur Hospital’s ENT Department. Results The mean age of patients was 67.5-years, 75% were males, and the most frequent underlying conditions were diabetes mellitus (100%). The median time interval between the diagnosis of COVID-19 and the first evidence of mucormycosis infection was 15-days; two patients required hospitalization in a COVID unit, and two patients received oxygen therapy at home. All patients received corticosteroid therapy at a dose of 1 mg/kg/d for an average of 10-days. Treatment using antifungals and surgery was described in all the patients. Amphotericin B deoxycholate was used in 75% and lipid formulation in 25%. Two patients presented renal insufficiency due to amphotericin B; the doses were adapted with good evolution. In that report, the case fatality rate was 75%. Conclusion Mucormycosis is a fatal fungal infection that usually affects patients with altered immunity. Several cases of mucormycosis in people with COVID-19 have been increasingly reported worldwide. Diabetes mellitus (DM), steroid overdose, immunosuppression, and high iron levels, combined with other factors such as prolonged hospitalization, unhygienic conditions, and the use of ventilators, combine to create an ideal environment for contracting mucormycosis. Lastly, there is a need to create awareness about fungal diseases among clinicians in order to help identify early symptoms and restrict the spread of lethal fungal diseases. A collaborative team of otolaryngologists, ophthalmologists, anesthesiologists, and resuscitators will be required in hospitals to accelerate optimal management.

Frequency of cryptococcal antigenemia in hiv treatment naïve patients with CD4 count below 200/ml

Background: Cryptococcosis is a dangerous opportunistic fungal infection that poses a significant threat to individuals with advanced HIV/AIDS and compromised cellular immunity. The objective was to determine the frequency of asymptomatic cryptococcal antigenemia in treatment naïve HIV patients. Material and Methods: This cross-sectional study was conducted at The Indus Hospital and Health Network, Karachi from July to December 2022. We included all consecutive HIV patients of age > 18 years, either gender, who were treatment naïve, with CD4 counts ≤200/μL, and did not have any symptoms of cryptococcal infection. Cryptococcal antigen (CrAg) was tested in blood based on the Direct Agglutination test. Results: A total of 100 HIV patients were enrolled. The mean age was 35.12 ± 10.93 years. The majority (78%) of the subjects were males, and 2/3rd were sexually active; exposure to birds was identified in 31% of patients. Most of the patients enrolled belonged to WHO HIV stage 1 (61%), followed by stage 4 (30%). The median CD4 count was 103.5 (IQR: 56.5 – 126.5) /μL. 48 patients had CD4 count between 101 to 200/μL, while 51 patients had CD4 count ≤100/μL. Only 2 patients were found to have CrAg positive making an overall prevalence of 2%. Both patients had a CD4 count ≤ 100/μL (n = 2/51, 3.9%). 30% of patients had other opportunistic co-infections (n = 30). Conclusion: The prevalence of asymptomatic cryptococcosis in the treatment naïve HIV is low in the Pakistani population. A routine CrAg screening can be individualized and avoided in selected patients with CD4 count >100/μL in a resource-limited country like Pakistan. Keywords: AIDS, HIV stages, Asymptomatic, Opportunistic infection.

Mucormycosis of the Mandible and Tongue: A Systematic Scoping Review

Mucormycosis is a rare human infection associated with Mucorales, a group of filamentous moulds found in different environmental niches. Its oral manifestations may occur in the mandible and tongue despite being rare. We aimed to systematically review the data on clinical manifestations, risk factors, diagnostic approaches, treatment options, and outcomes of mandibular and tongue mucormycosis. An electronic search of articles published between January 1975 and November 2022 in PubMed, Web of Science, and EMBASE databases was performed. A total of 22 articles met the inclusion criteria and reported 27 cases of oral mucormycosis in total. Fourteen patients had mandibular mucormycosis signs unrelated to COVID-19 infection, 6 had SARS-CoV-2-related mandibular mucormycosis, and 6 had manifestations in the tongue. All published case reports during the COVID-19 pandemic were from India. Patient ages ranged from 4 months old to 82 years, and most patients had important comorbidities, such as blood dyscrasias related to immune deficiency and uncontrolled type 2 diabetes mellitus. The signs and symptoms of mandibular and tongue mucormycosis varied from dental pain, loose teeth, and nonhealing sockets to dysphagia and paraesthesia of the lip. Some patients also reported trismus, draining sinus tract, and facial pain. The diagnosis of oral mucormycosis was based on a combination of clinical, radiographic, and histopathologic findings by demonstrating fungal hyphae in tissue specimens. In most cases, mucormycosis was managed with systemic amphotericin B, strict glycaemic control, and aggressive surgical debridement of infected tissue, minimising the progression of the fungal infection and thus improving the survival rate. In some cases, combined antifungal therapy, antibiotic therapy, and chlorhexidine mouthwashes were used successfully. Recognition of the signs and symptoms by oral care providers is pertinent for the early diagnosis and treatment of tongue and mandibular mucormycosis, and providers should be aware of the possibility of this opportunistic fungal infection in patients with COVID-19. A multidisciplinary approach is recommended for the management of this lethal infection.

Discovery of Lead 2-Thiazolylhydrazones with Broad-Spectrum and Potent Antifungal Activity.

Opportunistic fungal infections represent a global health problem, mainly for immunocompromised individuals. New therapeutical options are needed since several fungal strains show resistance to clinically available antifungal agents. 2-Thiazolylhydrazones are well-known as potent compounds against Candida and Cryptococcus species. A scaffold-focused drug design using machine-learning models was established to optimize the 2-thiazolylhydrazone skeleton and obtain novel compounds with higher potency, better solubility in water, and enhanced absorption. Twenty-nine novel compounds were obtained and most showed low micromolar MIC values against different species of Candida and Cryptococcus spp., including Candida auris, an emerging multidrug-resistant yeast. Among the synthesized compounds, 2-thiazolylhydrazone 28 (MIC value ranging from 0.8 to 52.17 μM) was selected for further studies: cytotoxicity evaluation, permeability study in Caco-2 cell model, and in vivo efficacy against Cryptococcus neoformans in an invertebrate infection model. All results obtained indicate the great potential of 28 as a novel antifungal agent.

Current Leads and Marketed Formulations for an Effective Treatment of Fungal Infections.

Severe antifungal infections, especially opportunistic fungal infections, are increasing tremendously in immunocompromised patients. This is basically because more patients enduring neoplastic diseases lead to the wide use of chemotherapy, thus causing immunosuppression. Patients with HIV infection, burns, pancreatitis and neutropenia are also amenable to fungal infections. Out of a plethora of antifungal drugs applied, Amphotericin B, being a broad-spectrum antimicrobial drug, has been the gold standard treatment for a diverse variety of fungal infections since the 1950s and visceral leishmaniasis since the 1960s. However, Amphotericin B has major constraints of poor bioavailability and kidney toxicity, due to which newer antifungal compounds are being used. This article discusses fungal and parasitic diseases and formulations for treating these ailments.