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Applied Biochemistry and Biotechnology Sep 2022Fungi are a small but important part of the human microbiota and several fungi are familiar to the immune system, yet certain can cause infections in immunocompromised... (Review)
Review
Fungi are a small but important part of the human microbiota and several fungi are familiar to the immune system, yet certain can cause infections in immunocompromised hosts and referred as opportunistic pathogens. The fungal coinfections in COVID-19 hosts with predisposing conditions and immunosuppressive medications are posing higher severity and death. The immunological counteraction (innate/adaptive immunity) is triggered when the PRRs on the host cells recognize the fungal PAMPs. However, in simultaneous infections (COVID-19 and fungal coinfection), the synergism of TLR and NLR may hyperactivate the immune cells which dramatically increase the cytokine level and generate cytokine storm. Fungal colonization in the human gut assists the development of microbiome assembly, ecology, and shaping immune response. However, SARS-CoV-2 infection represented unstable mycobiomes and long-term dysbiosis in a large proportion in COVID-19 patients. Normally, amphotericin B is considered as first-line treatment for invasive fungal infection. So, amphotericin B therapy is recommended in COVID-19 hosts with serious fungal infections. Still, the long-term corticosteroid supplementation prescribed in case of severe pneumonia and lower oxygen levels may result in systemic fungal infection in COVID-19 patients, eventually limiting the lifesaving benefits of available medications. Also, due to the evolution of fungal resistance to available antibiotics, the current treatments are becoming ineffective. Therefore, this review summarizes the concerns, needed to deal with the impending crises.
Topics: Amphotericin B; COVID-19; Humans; Immunity; Mycoses; Pandemics; SARS-CoV-2
PubMed: 35648275
DOI: 10.1007/s12010-022-03979-5 -
European Journal of Pharmaceutics and... Feb 2023The incidence and prevalence of invasive fungal infections have increased significantly over the last few years, leading to a global health problem due to the lack of...
The incidence and prevalence of invasive fungal infections have increased significantly over the last few years, leading to a global health problem due to the lack of effective treatments. Amphotericin B (AmB) and itraconazole (ITR) are two antifungal drugs with different mechanisms of action. In this work, AmB and ITR have been formulated within granules to elicit an enhanced pharmacological effect, while enhancing the oral bioavailability of AmB. A Quality by Design (QbD) approach was utilised to prepare fixed-dose combination (FDC) granules consisting of a core containing AmB with functional excipients, such as inulin, microcrystalline cellulose (MCC), chitosan, sodium deoxycholate (NaDC) and Soluplus® and polyvinyl pyrrolidone (PVP), coated with a polymeric layer containing ITR with Soluplus® or a combination of Poloxamer 188 and hydroxypropyl methyl cellulose-acetyl succinate (HPMCAS). A Taguchi design of experiments (DoE) with 7 factors and 2 levels was carried out to understand the key factors impacting on the physicochemical properties of the formulation followed by a Box-Behnken design with 3 factors in 3 levels chosen to optimise the formulation parameters. The core of the FDC granules was obtained by wet granulation and later coated using a fluidized bed. In vitro antifungal efficacy was demonstrated by measuring the inhibition halo against different species of Candida spp., including C. albicans (24.19-30.48 mm), C. parapsilosis (26.38-27.84 mm) and C. krusei (11.48-17.92 mm). AmB release was prolonged from 3 to 24 h when the AmB granules were coated. In vivo in CD-1 male mice studies showed that these granules were more selective towards liver, spleen and lung compared to kidney (up to 5-fold more selective in liver, with an accumulation of 8.07 µg AmB/g liver after twice-daily 5 days administration of granules coated with soluplus-ITR), resulting in an excellent oral administration option in the treatment of invasive mycosis. Nevertheless, some biochemical alterations were found, including a decrease in blood urea nitrogen (∼17 g/dl) and alanine aminotransferase (<30 U/l) and an increase in the levels of bilirubin (∼0.2 mg/dl) and alkaline phosphatase (<80 U/l), which could be indicative of a liver failure. Once-daily regimen for 10 days can be a promising therapy.
Topics: Male; Mice; Animals; Amphotericin B; Antifungal Agents; Itraconazole; Mycoses; Candida albicans
PubMed: 36623752
DOI: 10.1016/j.ejpb.2023.01.003 -
Cell and Tissue Banking Dec 2022To determine the effectiveness of two methods to improve the microbial safety of human corneas preserved in organ culture. We compared the number of positive...
To determine the effectiveness of two methods to improve the microbial safety of human corneas preserved in organ culture. We compared the number of positive preservation solutions of corneas in organ culture in which the initial short-term hypothermic corneal maintenance solution was supplemented with amphotericin B 2.5 µg/mL and the historical data of microbial test results (2015-2019). In addition, we appraised the efficacy of Gram stain to detect bacterial or fungal contamination in the organ culture solutions of corneas from at-risk donors compared to the culture tests of corneas from not-at-risk donors. Statistical analysis was performed using STATA and statistical significance set at p < 0.05. The number of positive culture tests after preservation was 15 (0.5%) in 2020 compared to a mean of 37 (1.2%) in the period 2015-2019 (p < 0.01), with 10 (1.0%) positive samples in the cohort of 998 corneas from at-risk donors and 5 (0.2%) in the 2046 corneas from not-at-risk donors (p < 0.01). All corneas from at-risk donors tested positive at Gram stain and the results were available 1-3 days before those of the conventional culture tests. Amphotericin B supplementation in the short-term maintenance solution markedly reduced the number of positive microbial tests after organ culture and the early detection of contaminants, including slow-growing microorganisms, by Gram stain before the standard culture results. This meant fewer corneas being discarded and a greater likelihood of preventing post-graft infections.
Topics: Humans; Amphotericin B; Cornea; Tissue Donors; Organ Culture Techniques; Bacteria; Organ Preservation; Corneal Transplantation; Eye Banks
PubMed: 34791554
DOI: 10.1007/s10561-021-09981-1 -
PLoS Neglected Tropical Diseases Mar 2021There is a continued need to develop effective and safe treatments for visceral leishmaniasis (VL). Preclinical studies on pharmacokinetics and pharmacodynamics of...
BACKGROUND
There is a continued need to develop effective and safe treatments for visceral leishmaniasis (VL). Preclinical studies on pharmacokinetics and pharmacodynamics of anti-infective agents, such as anti-bacterials and anti-fungals, have provided valuable information in the development and dosing of these agents. The aim of this study was to characterise the pharmacokinetic and pharmacodynamic properties of the anti-leishmanial drugs AmBisome and miltefosine in a preclinical disease model of VL.
METHODOLOGY / PRINCIPAL FINDINGS
BALB/c mice were infected with L. donovani (MHOM/ET/67/HU3) amastigotes. Groups of mice were treated with miltefosine (orally, multi-dose regimen) or AmBisome (intravenously, single dose regimen) or left untreated as control groups. At set time points groups of mice were killed and plasma, livers and spleens harvested. For pharmacodynamics the hepatic parasite burden was determined microscopically from tissue impression smears. For pharmacokinetics drug concentrations were measured in plasma and whole tissue homogenates by LC-MS. Unbound drug concentrations were determined by rapid equilibrium dialysis. Doses exerting maximum anti-leishmanial effects were 40 mg/kg for AmBisome and 150 mg/kg (cumulatively) for miltefosine. AmBisome displayed a wider therapeutic range than miltefosine. Dose fractionation at a total dose of 2.5 mg/kg pointed towards concentration-dependent anti-leishmanial activity of AmBisome, favouring the administration of large doses infrequently. Protein binding was >99% for miltefosine and amphotericin B in plasma and tissue homogenates.
CONCLUSION / SIGNIFICANCE
Using a PK/PD approach we propose optimal dosing strategies for AmBisome. Additionally, we describe pharmacokinetic and pharmacodynamic properties of miltefosine and compare our findings in a preclinical disease model to available knowledge from studies in humans. This approach also presents a strategy for improved use of animal models in the drug development process for VL.
Topics: Amphotericin B; Animals; Antiprotozoal Agents; Drug Therapy, Combination; Homeodomain Proteins; Humans; Leishmaniasis, Visceral; Liver; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Parasite Load; Phosphorylcholine; Protein Binding
PubMed: 33651812
DOI: 10.1371/journal.pntd.0009013 -
BMC Infectious Diseases Aug 2023Candida auris is an emerging yeast pathogen that can cause invasive infections, particularly candidemia, in healthcare settings. Candida auris is characterized by...
BACKGROUND
Candida auris is an emerging yeast pathogen that can cause invasive infections, particularly candidemia, in healthcare settings. Candida auris is characterized by resistance to multiple classes of antifungal drugs and high mortality.
OBJECTIVE
To describe the risk factors, clinical characteristics, antifungal susceptibility pattern and outcomes of Candida auris blood stream infection.
METHODS
We conducted a retrospective review of electronic medical records of C. auris fungemia cases in the facilities under Hamad Medical corporation, Qatar from 1/11/2018 to 31/7/2021. Demographic data, risk factors, antibiogram and 30-day outcome are described.
RESULTS
We identified 36 patients with C. auris fungemia. Most of the patients were in intensive care unit following severe COVID-19 pneumonia and had received steroids and broad-spectrum antibiotics. Most cases were central line related. Over 90% of isolates were non-susceptible to fluconazole, while amphotericin B resistance reached 85%. Factors associated with high mortality included initial SOFA score of 9 or above and absence of source control.
CONCLUSION
Our study reveals a concerning 41.6% mortality rate within 30 days of C. auris candidemia. Furthermore, the prevalence of amphotericin B resistance in Qatar exceeds what has been reported in the literature necessitating further exploration. Echinocandins retains nearly 100% susceptibility and should be prioritized as the treatment of choice. These findings emphasize the need for vigilant monitoring and appropriate management strategies to combat C. auris infections and improve patient outcomes.
Topics: Humans; Amphotericin B; Antifungal Agents; Candida auris; Candidemia; COVID-19; Microbial Sensitivity Tests; Qatar
PubMed: 37544995
DOI: 10.1186/s12879-023-08477-5 -
Drug Delivery Dec 2021Cryptococcal meningitis is a fungal infectious disease with a poor prognosis and high mortality. Amphotericin B (AMB) is the first choice for the treatment of... (Comparative Study)
Comparative Study
Cryptococcal meningitis is a fungal infectious disease with a poor prognosis and high mortality. Amphotericin B (AMB) is the first choice for the treatment of cryptococcal meninges. The blood-brain barrier (BBB) is the major barrier for the effective delivery of drugs to the brain. In this study, AMB was incorporated in a thermosensitive gel for intrathecal injection. We first synthesized AMB-loaded thermogel, investigated its in vitro cumulative release, and in vivo neurotoxicity, and therapeutic effect. The thermosensitive gel was comprised of 25 wt% poly (lactic acid-co-glycolic acid)-poly (ethylene glycol)-poly (lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock polymer aqueous solution. The AMB loaded in the thermosensitive gel (AMB in gel) had low viscosity at low temperature and resulted in the formation of a non-flowing gel at 37 °C (physiological temperature). AMB loading in gel sustained its release for 36 days and the cumulative release rate was satisfactory. Compared with the AMB solution, intrathecal administration of AMB in gel could reduce the neurovirulence of AMB and get a better treatment effect. The findings of the current study show that the injectable PLGA-PEG-PLGA thermogel is a biocompatible carrier for the delivery of drugs into the intrathecal.
Topics: Amphotericin B; Animals; Antifungal Agents; Delayed-Action Preparations; Drug Carriers; Drug Delivery Systems; Drug Liberation; Hydrogels; Injections, Spinal; Male; Neurotoxicity Syndromes; Polyethylene Glycols; Polyglactin 910; Rats; Rats, Sprague-Dawley; Temperature; Viscosity
PubMed: 33657949
DOI: 10.1080/10717544.2021.1892242 -
Frontiers in Cellular and Infection... 2022Visceral leishmaniasis (VL) and post kala-azar dermal leishmaniasis (PKDL) affect most of the poor populations worldwide. The current treatment modalities include...
Visceral leishmaniasis (VL) and post kala-azar dermal leishmaniasis (PKDL) affect most of the poor populations worldwide. The current treatment modalities include liposomal formulation or deoxycholate salt of amphotericin B, which has been associated with various complications and severe side effects. Encouraged from the recent marked antimalarial effects from plant-derived glycosides, in this study, we have exploited a green chemistry-based approach to chemically synthesize a library of diverse glycoside derivatives (Gly1-12) and evaluated their inhibitory efficacy against the AG83 strain of . Among the synthesized glycosides, the inhibitory activity of Glycoside-2 (Gly2) (1.13 µM IC50 value) on promastigote demonstrated maximum cytotoxicity with ~94% promastigote death as compared to amphotericin B that was taken as a positive control. The antiproliferative effect of Gly2 on promastigote encouraged us to analyze the structure-activity relationship of Gly2 with Gp63, a zinc metalloprotease that majorly localizes at the surface of the promastigote and has a role in its development and multiplication. The result demonstrated the exceptional binding affinity of Gly2 toward the catalytic domain of Gp63. These data were thereafter validated through cellular thermal shift assay in a physiologically relevant cellular environment. Mechanistically, reduced multiplication of promastigotes on treatment with Gly2 induces the destabilization of redox homeostasis in promastigotes by enhancing reactive oxygen species (ROS), coupled with depolarization of the mitochondrial membrane. Additionally, Gly2 displayed strong lethal effects on infectivity and multiplication of amastigote inside the macrophage in the amastigote-macrophage infection model as compared to amphotericin B treatment. Gp63 is also known to bestow protection against complement-mediated lysis of parasites. Interestingly, Gly2 treatment enhances the complement-mediated lysis of promastigotes in serum physiological conditions. In addition, Gly2 was found to be equally effective against the clinical promastigote forms of PKDL strain (IC50 value of 1.97 µM); hence, it could target both VL and PKDL simultaneously. Taken together, this study reports the serendipitous discovery of Gly2 with potent antileishmanial activity and proves to be a novel chemotherapeutic prototype against VL and PKDL.
Topics: Amphotericin B; Antiprotozoal Agents; Glycosides; Humans; Leishmania donovani; Leishmaniasis, Visceral; Metalloproteases
PubMed: 35601095
DOI: 10.3389/fcimb.2022.803048 -
Indian Journal of Dermatology,... 2022Background Although topical amphotericin B cream is effective for the treatment of nondermatophyte mold onychomycosis in vitro, studies of its effectiveness and safety... (Randomized Controlled Trial)
Randomized Controlled Trial
Effectiveness and safety of topical amphotericin B in 30% dimethyl sulfoxide cream versus 30% dimethyl sulfoxide cream for nondermatophyte onychomycosis treatment: A pilot study.
Background Although topical amphotericin B cream is effective for the treatment of nondermatophyte mold onychomycosis in vitro, studies of its effectiveness and safety in vivo are limited. Objectives We studied the effectiveness and safety of topical 0.3% amphotericin B in 30% dimethyl sulfoxide cream (amphotericin B cream) in nondermatophyte mold onychomycosis using the vehicle cream 30% dimethyl sulfoxide cream as control. Methods This randomized controlled study was conducted between January 2019 and November 2020. Patients diagnosed with nondermatophyte mold onychomycosis were randomly divided into two groups of ten patients each: one treated with amphotericin B cream and the other with the vehicle cream. Clinical and mycological cure as well as safety were evaluated. Results Ten patients each treated with amphotericin B cream and the vehicle cream were included in the study, but only nine patients in the vehicle cream group were available for follow up. All the 19 evaluable patients had distal lateral subungual onychomycosis and the great toenails were affected in 18 (94.7%) of these. Mycological cure was achieved in 8 (80%) patients treated with amphotericin B cream and in 4 (44.4%) patients using the control (vehicle) cream. Clinical cure was achieved in 7 (70%) patients treated with amphotericin B cream, but only in 2 (22.2%) patients on the control cream. No adverse events were observed. Limitations The small sample size and the fact that PCR fungal identification that provides accurate identification of fungal species was not performed are limitations of our study. Conclusion Topical amphotericin B cream was both very effective and safe in the treatment nondermatophyte mold onychomycosis. The control (vehicle) cream containing 30% dimethyl sulfoxide also demonstrated some antifungal activity.
Topics: Administration, Topical; Amphotericin B; Antifungal Agents; Dimethyl Sulfoxide; Foot Dermatoses; Humans; Onychomycosis; Pilot Projects; Treatment Outcome
PubMed: 34877858
DOI: 10.25259/IJDVL_359_2021 -
Clinical Microbiology and Infection :... Aug 2023During the COVID-19 pandemic in Qatar, many patients who were severely ill were colonized and infected by Candida auris, an invasive multidrug-resistant yeast pathogen...
Molecular characterization of Candida auris outbreak isolates in Qatar from patients with COVID-19 reveals the emergence of isolates resistant to three classes of antifungal drugs.
OBJECTIVES
During the COVID-19 pandemic in Qatar, many patients who were severely ill were colonized and infected by Candida auris, an invasive multidrug-resistant yeast pathogen that spreads through nosocomial transmission within healthcare facilities. Here, we investigated the molecular epidemiology of these C. auris isolates and the mechanisms associated with antifungal drug resistance.
METHODS
Whole genomes of 76 clinical C. auris isolates, including 65 from patients with COVID-19 collected from March 2020 to June 2021, from nine major hospitals were sequenced on Illumina NextSeq. Single nucleotide polymorphisms were used to determine their epidemiological patterns and mechanisms for antifungal resistance. The data were compared with those published prior to the COVID-19 pandemic from 2018 to 2020 in Qatar.
RESULTS
Genomic analysis revealed low genetic variability among the isolates from patients with and without COVID-19, confirming a clonal outbreak and ongoing dissemination of C. auris among various healthcare facilities. Based on antifungal susceptibility profiles, more than 70% (22/28) of isolates were resistant to both fluconazole and amphotericin B. Variant analysis revealed the presence of multi-antifungal resistant isolates with prominent amino acid substitutions: Y132F in ERG11 and V704L in CDR1 linked to reduced azole susceptibility and the emergence of echinocandin resistance samples bearing mutations in FKS1 in comparison with pre-COVID-19 pandemic samples. One sample (CAS109) was resistant to three classes of antifungal drugs with a unique premature stop codon in ERG3 and novel mutations in CDR2, which may be associated with elevated amphotericin B and azole resistance.
DISCUSSION
Candida auris isolates from patients with COVID-19 and from most patient samples without COVID-19 in Qatar were highly clonal. The data demonstrated the emergence of multidrug-resistant strains that carry novel mutations linked to enhanced resistance to azoles, echinocandins, and amphotericin B. Understanding the epidemiology and drug resistance will inform the infection control strategy and drug therapy.
Topics: Humans; Antifungal Agents; Candida auris; Amphotericin B; Pandemics; Qatar; Candidiasis; Candida; COVID-19; Echinocandins; Azoles; Drug Resistance, Fungal; Microbial Sensitivity Tests
PubMed: 37116861
DOI: 10.1016/j.cmi.2023.04.025 -
PLoS Neglected Tropical Diseases Sep 2022Amphotericin B is increasingly used in treatment of leishmaniasis. Here, fourteen independent lines of Leishmania mexicana and one L. infantum line were selected for...
Amphotericin B is increasingly used in treatment of leishmaniasis. Here, fourteen independent lines of Leishmania mexicana and one L. infantum line were selected for resistance to either amphotericin B or the related polyene antimicrobial, nystatin. Sterol profiling revealed that, in each resistant line, the predominant wild-type sterol, ergosta-5,7,24-trienol, was replaced by other sterol intermediates. Broadly, two different profiles emerged among the resistant lines. Whole genome sequencing then showed that these distinct profiles were due either to mutations in the sterol methyl transferase (C24SMT) gene locus or the sterol C5 desaturase (C5DS) gene. In three lines an additional deletion of the miltefosine transporter gene was found. Differences in sensitivity to amphotericin B were apparent, depending on whether cells were grown in HOMEM, supplemented with foetal bovine serum, or a serum free defined medium (DM). Metabolomic analysis after exposure to AmB showed that a large increase in glucose flux via the pentose phosphate pathway preceded cell death in cells sustained in HOMEM but not DM, indicating the oxidative stress was more significantly induced under HOMEM conditions. Several of the lines were tested for their ability to infect macrophages and replicate as amastigote forms, alongside their ability to establish infections in mice. While several AmB resistant lines showed reduced virulence, at least two lines displayed heightened virulence in mice whilst retaining their resistance phenotype, emphasising the risks of resistance emerging to this critical drug.
Topics: Mice; Animals; Amphotericin B; Leishmania mexicana; Nystatin; Serum Albumin, Bovine; Sterols; Oxidative Stress; Polyenes; Transferases; Glucose; Fatty Acid Desaturases; Antiprotozoal Agents
PubMed: 36170238
DOI: 10.1371/journal.pntd.0010779