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Journal of Biomolecular Structure &... 2022COVID-19, for which no confirmed therapeutic agents are available, has claimed over 48,14,000 lives globally. A feasible and quicker method to resolve this problem may...
COVID-19, for which no confirmed therapeutic agents are available, has claimed over 48,14,000 lives globally. A feasible and quicker method to resolve this problem may be 'drug repositioning'. We investigated selected FDA and WHO-EML approved drugs based on their previously promising potential as antivirals, antibacterials or antifungals. These drugs were docked onto the nsp12 protein, which reigns the RNA-dependent RNA polymerase activity of SARS-CoV-2, a key therapeutic target for coronaviruses. Docked complexes were reevaluated using MM-GBSA analysis and the top three inhibitor-protein complexes were subjected to 100 ns long molecular dynamics simulation followed by another round of MM-GBSA analysis. The RMSF plots, binding energies and the mode of physicochemical interaction of the active site of the protein with the drugs were evaluated. Suramin, Penciclovir, and Anidulafungin were found to bind to nsp12 with similar binding energies as that of Remdesivir, which has been used as a therapy for COVID-19. In addition, recent experimental evidences indicate that these drugs exhibit antiviral efficacy against SARS-CoV-2. Such evidence, along with the significant and varied physical interactions of these drugs with the key viral enzyme outlined in this investigation, indicates that they might have a prospective therapeutic potential in the treatment of COVID-19 as monotherapy or combination therapy with Remdesivir.
Topics: Humans; SARS-CoV-2; COVID-19; Anidulafungin; Suramin; Molecular Docking Simulation; Antiviral Agents
PubMed: 34784490
DOI: 10.1080/07391102.2021.2000498 -
Revista Iberoamericana de Micologia Jun 2008The fungal cell wall is a structure with a high plasticity that protects the cell from different types of environmental stresses including changes in osmotic pressure.... (Review)
Review
The fungal cell wall is a structure with a high plasticity that protects the cell from different types of environmental stresses including changes in osmotic pressure. In addition to that, the cell wall allows the fungal cell to interact with its environment, since some of its proteins are adhesins and receptors. Some of its components are highly immunogenic. The structure of the fungal cell wall is unique to the fungi, and it is composed of glucan, chitin and glycoproteins. Since humans lack the components present in the cell walls of fungi, this structure is an excellent target for the development of antifungal drugs. Anidulafungin, like the rest of echinocandins acts on beta-1,3-D-glucan synthase inhibiting the formation of beta-1,3-D-glucan and causing, depending on the type of fungus, a fungicidal or either a fungistatic effect.
Topics: Anidulafungin; Antifungal Agents; Cell Wall; Echinocandins; Fungi
PubMed: 18473501
DOI: 10.1016/s1130-1406(08)70024-x -
Enfermedades Infecciosas Y... Dec 2008The most frequent invasive fungal infections in critically ill patients are invasive candidiasis, among which is candidemia. In the last few years, these infections have... (Review)
Review
The most frequent invasive fungal infections in critically ill patients are invasive candidiasis, among which is candidemia. In the last few years, these infections have become more common in intensive care units (ICU), including those produced by species other than Candida albicans. This phenomenon may lead to the development of species resistant to antifungal agents. To start the most appropriate treatment, early diagnosis of the infection is essential, which would reduce empirical antibiotic treatment and increase the proportion of advanced or directed antibiotic therapy. Given the poor reliability of the available diagnostic techniques, new strategies are currently being employed in the ICU, such as the use of scores to evaluate the presence of fungal infections. The therapeutic arsenal against these infections has been increased and the introduction of anidulafungin represents the addition of a highly appropriate drug for the treatment of invasive candidiasis in immunocompetent critically ill patients.
Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Candidiasis; Clinical Trials as Topic; Critical Illness; Cross Infection; Drug Therapy, Combination; Echinocandins; Fluconazole; Fungemia; Humans; Immunocompetence; Intensive Care Units; Itraconazole; Practice Guidelines as Topic
PubMed: 19572433
DOI: 10.1016/s0213-005x(08)76591-1 -
Antimicrobial Agents and Chemotherapy Nov 2006Candidemia is often fatal, especially in patients with persistent neutropenia. New therapies are needed. We performed 24-h pharmacodynamic studies to compare the...
Candidemia is often fatal, especially in patients with persistent neutropenia. New therapies are needed. We performed 24-h pharmacodynamic studies to compare the efficacies of anidulafungin, fluconazole, and amphotericin B in neutropenic mice with disseminated candidiasis caused by one of three strains of Candida glabrata. Anidulafungin produced a maximal fungal kill (E(max)) of 1.4 to 1.9 log(10) CFU/g in kidneys and was not influenced by resistance to either fluconazole or amphotericin B. Fluconazole produced an E(max) of 1.3 log(10) CFU/g in mice infected with fluconazole-susceptible C. glabrata, but the E(max) was 0 for mice infected with a C. glabrata strain that had a fluconazole MIC of >/=32 mg/liter. Amphotericin B achieved an E(max) of 4.2 log(10) CFU/g in mice infected with amphotericin B-susceptible C. glabrata, but the E(max) was 0 for mice infected with a C. glabrata strain with an amphotericin B MIC of 2 mg/liter. In all instances, anidulafungin's maximal microbial kill was superior to that of fluconazole. Next, we performed a 96-h anidulafungin pharmacokinetic-pharmacodynamic study. Anidulafungin exhibited delayed peak concentrations in kidneys compared to those in serum, after which the concentrations declined, with a serum terminal half-life of 21.6 (+/-4.6) h. This was accompanied by a persistent 96-h decrease in the kidney fungal burden after treatment with a single anidulafungin dose of >/=8 mg/kg of body weight. This pharmacokinetic-pharmacodynamic picture of anidulafungin persistence in tissues and the resultant persistent fungal decline should be exploited to improve the efficacy of anidulafungin therapy for candidemia.
Topics: Algorithms; Amphotericin B; Anidulafungin; Animals; Antifungal Agents; Area Under Curve; Candida glabrata; Candidiasis; Colony Count, Microbial; Dose-Response Relationship, Drug; Echinocandins; Female; Fluconazole; Mice; Microbial Sensitivity Tests; Neutropenia; Peptides, Cyclic
PubMed: 16954319
DOI: 10.1128/AAC.00507-06 -
Antimicrobial Agents and Chemotherapy Aug 2012
Topics: Aged; Anemia, Hemolytic, Autoimmune; Anidulafungin; Antifungal Agents; Candida glabrata; Candidiasis; Echinocandins; Endocarditis; Female; Hepatitis C; Humans; Liver Cirrhosis; Pancytopenia; Thrombocytopenia; Tricuspid Valve
PubMed: 22644027
DOI: 10.1128/AAC.00515-12 -
Clinical Pharmacology and Therapeutics Aug 2020In a pooled population analysis, we investigated the pharmacokinetics of i.v. anidulafungin in four studies across a full range of adult and pediatric ages in patients...
In a pooled population analysis, we investigated the pharmacokinetics of i.v. anidulafungin in four studies across a full range of adult and pediatric ages in patients with confirmed, suspected, or at high risk of invasive candidiasis (IC). Relationships between anidulafungin exposure and key efficacy end points (global response of success and all-cause mortality) and safety end points (all-cause hepatic or gastrointestinal adverse events) in all patients and separately in pediatric patients and the appropriate dosing regimen for IC treatment in pediatric patients were evaluated. Pediatric patients received a 3.0 mg/kg (maximum 200 mg) i.v. loading dose and 1.5 mg/kg (maximum 100 mg) daily thereafter. Adults received a 200 mg i.v. loading dose and 100 mg daily thereafter. Estimated systemic anidulafungin exposures were similar across age groups (neonates to adults) at the weight-based doses studied in pediatric patients. No clear associations were identified between anidulafungin exposure and efficacy or safety end points.
Topics: Administration, Intravenous; Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Anidulafungin; Antifungal Agents; Candidiasis, Invasive; Child; Child, Preschool; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Dosage Calculations; Drug Monitoring; Humans; Infant; Infant, Newborn; Male; Middle Aged; Models, Biological; Treatment Outcome; Young Adult
PubMed: 32189334
DOI: 10.1002/cpt.1831 -
Transplant Infectious Disease : An... Aug 2021Invasive candidiasis (IC) is a substantial cause of morbidity and mortality among lung transplant recipients (LTRs). Postoperative factors include prolonged hospital...
BACKGROUND
Invasive candidiasis (IC) is a substantial cause of morbidity and mortality among lung transplant recipients (LTRs). Postoperative factors include prolonged hospital stay, central lines, delayed chest closure, and dehiscence increase IC risk. Correspondingly, current guidelines propose targeted IC coverage early posttransplant with fluconazole or an echinocandin.
METHODS
This retrospective analysis was performed on LTRs from January 2016 to January 2020 and evaluated effectiveness of a recent protocol utilizing perioperative anidulafungin for early IC prevention in addition to long-term triazole antifungal prophylaxis. Prior to this protocol, patients were primarily established on itraconazole prophylaxis alone. The primary endpoint was proven or probable IC within 90 days after transplant. Multivariable logistic regression modeling was used to assess risk factors for invasive fungal infection (IFI).
RESULTS
Among 144 LTRs, there was a numerically lower incidence of IC in the protocol group, although not statistically significant (6% vs. 13%, p = 0.16). Incidence of proven or probable IFI was 7.5% in the protocol cohort and 19.5% in the pre-protocol cohort (p = 0.038). In multivariable analysis, when controlling for lung allocation score (OR 1.04, 95% CI 1.01-1.08), donor perioperative culture with fungal growth (OR 2.92, 95% CI 1.02-8.92), and dehiscence (OR 3.54, 95% CI 1.14-10.85), protocol cohort was not significantly associated with IFI (OR 0.41, 95% CI 0.12-1.23).
CONCLUSIONS
To our knowledge, this is the first study investigating combination triazole/echinocandin use in the early post-lung transplant period. These findings demonstrate that in-hospital anidulafungin offers unclear benefit for early IC prevention when used in combination with triazole prophylaxis.
Topics: Anidulafungin; Candidiasis, Invasive; Humans; Lung; Retrospective Studies; Transplant Recipients; Triazoles
PubMed: 34270137
DOI: 10.1111/tid.13692 -
Critical Care (London, England) Mar 2014
Topics: Albumins; Anidulafungin; Antifungal Agents; Candidiasis, Invasive; Echinocandins; Humans; Renal Dialysis
PubMed: 25028805
DOI: 10.1186/cc13805 -
European Journal of Clinical... Oct 2019The incidence of nosocomial invasive fungal infections involving Candida spp. has increased markedly in recent years in patients undergoing abdominal surgery. This post...
The incidence of nosocomial invasive fungal infections involving Candida spp. has increased markedly in recent years in patients undergoing abdominal surgery. This post hoc analysis aimed to determine the efficacy and safety of anidulafungin treatment in patients with intra-abdominal candidiasis (IAC) from five prospective studies (one comparative and four open-label) of adult surgical patients with microbiologically confirmed Candida intra-abdominal infection. Patients received an intravenous (IV) loading dose of anidulafungin 200 mg, followed by a daily 100-mg maintenance dose. Per study protocols, some patients could be switched to an oral azole after ≥ 5 or ≥ 10 days of IV treatment. Antifungal treatment was maintained for ≥ 14 days after the last positive Candida culture and resolution of symptoms. The global response rate (GRR) at the end of IV treatment (EOIVT) was the primary endpoint. GRR at the end of therapy (EOT), all-cause mortality at days 14 and 28, and safety was also evaluated. Seventy-nine patients had IAC from peritoneal fluid or hepatobiliary tract. C. albicans (72.2%) and C. glabrata (32.9%) were the most common pathogens. Overall GRR was 73.4% and 67.1% at EOIVT and EOT, respectively. All-cause mortality was 17.7% at day 14 and 24.1% at day 28 in the modified intent-to-treat population. Anidulafungin was well tolerated in this population, with most adverse events mild or moderate in severity. In these patients with IAC, anidulafungin showed a GRR at EOIVT similar to the anidulafungin registrational trial, and the results of our analysis confirmed the known safety profile of anidulafungin. ClinicalTrials.gov registration number NCT00496197, registered July 3, 2007, https://clinicaltrials.gov/ct2/show/study/NCT00496197 ; ClinicalTrials.gov registration number NCT00548262, registered October 19, 2007, https://clinicaltrials.gov/ct2/show/record/NCT00548262 ; ClinicalTrials.gov registration number NCT00537329, registered September 25, 2007, https://clinicaltrials.gov/ct2/show/record/NCT00537329 ; ClinicalTrials.gov registration number NCT00689338, registered May 29, 2008, https://clinicaltrials.gov/ct2/show/study/NCT00689338 ; ClinicalTrials.gov registration number NCT00805740, registered November 26, 2008, https://clinicaltrials.gov/ct2/show/NCT00805740.
Topics: Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Anidulafungin; Antifungal Agents; Candida; Candidiasis; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Incidence; Intraabdominal Infections; Male; Middle Aged; Prospective Studies; Surgical Wound Infection; Treatment Outcome; Young Adult
PubMed: 31280481
DOI: 10.1007/s10096-019-03617-9 -
Liver Transplantation : Official... Jun 2012The aim of this study was the evaluation of the safety of anidulafungin in adult solid organ transplantation (SOT) recipients. During the study period (14 months), we...
The aim of this study was the evaluation of the safety of anidulafungin in adult solid organ transplantation (SOT) recipients. During the study period (14 months), we included all consecutive SOT recipients from 14 centers who received anidulafungin for at least 48 hours for the treatment of invasive fungal infections (IFIs) or as prophylaxis. Relevant clinical and analytical information on clinical charts was reviewed. Clinical side effects, liver function tests, and serum creatinine levels were assessed at least weekly. The need for the modification of immunosuppressive drugs was also recorded by the investigators. All patients were followed for at least 1 week after the end of treatment (EOT) or until death. Eighty-six SOT recipients were evaluated (56 transplant recipients, 20 lung transplant recipients, 8 kidney transplant recipients, and 2 heart transplant recipients). Sixty-two patients (72%) received anidulafungin for prophylaxis, and 24 (28%) received anidulafungin for the treatment of IFIs [candidemia/invasive candidiasis (16) or invasive aspergillosis (8)]. At the baseline, only 5% of the patients were neutropenic (<500 neutrophils/mL). There was no need for the modification of immunosuppressive drug doses because of anidulafungin therapy. No patient discontinued anidulafungin because of severe adverse effects. While receiving anidulafungin, 1 patient developed mild liver toxicity, but the liver function normalized without the discontinuation of anidulafungin. At EOT, the median serum creatinine, aspartate aminotransferase, and alanine aminotransferase levels were significantly lower than the baseline levels, even in liver transplant recipients and patients who had higher baseline levels of serum creatinine. In conclusion, these results show that anidulafungin is a well-tolerated drug in SOT recipients.
Topics: Adult; Aged; Anidulafungin; Antifungal Agents; Echinocandins; Female; Follow-Up Studies; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Lung Transplantation; Male; Middle Aged; Mycoses; Organ Transplantation; Postoperative Complications; Retrospective Studies; Young Adult
PubMed: 22328277
DOI: 10.1002/lt.23410