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1.
J Infect Chemother ; 28(8): 1203-1207, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1821356

ABSTRACT

After lung transplantation, itraconazole (ITCZ) is used as a prophylaxis for aspergillosis. ITCZ is a weak base with high lipophilicity, and the dissolution and absorption of ITCZ tablets and capsules are pH dependent. Therefore, ITCZ may not achieve sufficient serum concentrations in patients with higher gastric pH because of its poor bioavailability. We report a case of a woman in fifties with post-COVID-19 respiratory failure who successfully underwent lung transplantation, followed by improved bioavailability of ITCZ tablets when given with acidic lemon beverages. The patient was initially administered ITCZ oral solution; this was discontinued because of its unpleasant taste, nausea, and vomiting. The ITCZ oral solution was replaced with ITCZ tablets 78 days after transplantation; however, serum concentrations of ITCZ and hydroxy-ITCZ were below the detection limit (100 ng/mL). We co-administered ITCZ tablets with commercially available lemon beverages. Subsequently, serum concentrations of ITCZ and hydroxy-ITCZ increased to 341 and 673 ng/mL, respectively, on the 125th day after transplantation. Infection with fungi, including Aspergillus spp., was not observed in this case. The patient had no adverse events such as gastric ulcer or hyperglycemia. These results suggest that the co-administration of lemon beverages and ITCZ tablets may help achieve better absorption of ITCZ in patients taking acid suppressants.


Subject(s)
COVID-19 , Lung Transplantation , Antifungal Agents , Beverages , Female , Humans , Itraconazole/therapeutic use , Lung , Tablets , Transplant Recipients
2.
Biomed Res Int ; 2022: 5904261, 2022.
Article in English | MEDLINE | ID: covidwho-1799190

ABSTRACT

The manuscript mainly aimed at providing clues on improving the innate immunity of coronavirus patients and safeguarding them from both new mutant strains and black fungus infections. Coronavirus is readily mutating from one variant to another. Among the several variants, we selected SARS-CoV-2 B.1.1.7 in this study. Upon infection of any virus, ideally, the phagocytic cells of the host engulf and destroy the virus by a mechanism called phagocytosis. However, compromised immunity impairs phagocytosis, and thus, restoring the immune system is crucial for a speedy recovery of infected patients. The autophagy and activation of Toll-like receptor-4 are the only ways to restore innate immunity. Recently, immunocompromised COVID-19 patients have been suffering from the coinfection of black fungus. Rhizomucor, a black fungus species, causes more than 75% of cases of mucormycosis. Here, we present the results of molecular docking studies of sixty approved antiviral drugs targeting receptors associated with the SARS-CoV-2 B 1.1.7 variant (PDB id: 7NEH), activating the innate immune system (PDB id: 5YEC and 5IJC). We also studied the twenty approved antifungal drugs with Rhizomucor miehei lipase propeptide (PDB id: 6QPR) to identify the possible combination therapy for patients coinfected with coronavirus and black fungus. The ledipasvir showed excellent docking interactions with the 7NEH, 5YEC, and 5IJC, indicating that it is a perfect candidate for the treatment of COVID-19 patients. Itraconazole showed significant interaction with 6QPR of Rhizomucor miehei, suggesting that itraconazole can treat black fungus infections. In conclusion, the combination therapy of ledipasvir and itraconazole can be a better alternative for treating COVID-19 patients coinfected with black fungus.


Subject(s)
COVID-19 , Coinfection , Benzimidazoles , COVID-19/drug therapy , Coinfection/drug therapy , Fluorenes , Humans , Itraconazole/therapeutic use , Molecular Docking Simulation , Rhizomucor , SARS-CoV-2
3.
Rev Argent Microbiol ; 54(3): 209-214, 2022.
Article in English | MEDLINE | ID: covidwho-1635074

ABSTRACT

We report a case of disseminated histoplasmosis and COVID-19 infection in a renal transplant recipient in Argentina. The patient exhibited respiratory symptoms, and a chest computed tomography scan (CT) showed multiple bilateral centrilobular opacities with a tree-in-bud pattern in both lobes. The patient was initially treated as having bacterial community-acquired pneumonia, and then tuberculosis. A month later, histoplasmosis was diagnosed, and Histoplasma capsulatum LAmB clade was isolated from sputum, skin and oral lesions. The patient was hospitalized and treatment was started with intravenous liposomal amphotericin B. During the course of the antifungal therapy the respiratory symptoms worsened, a new chest CT showed a unilateral lesion with a ground glass appearance and SARS-CoV-2 was detected in a new nasopharyngeal sample. In addition, plasma therapy was administered, and the immunosuppressive regimen was adjusted (everolimus was interrupted, mycophenolate mofetil reduced, and meprednisone increased). Finally, the patient's progress was favorable and was discharged after five days on oral itraconazole treatment for histoplasmosis.


Subject(s)
COVID-19 , Histoplasmosis , Kidney Transplantation , Amphotericin B/therapeutic use , Antifungal Agents/therapeutic use , COVID-19/complications , Everolimus , Histoplasma , Histoplasmosis/complications , Histoplasmosis/drug therapy , Itraconazole/therapeutic use , Kidney Transplantation/adverse effects , Mycophenolic Acid , SARS-CoV-2
4.
EBioMedicine ; 66: 103288, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1141720

ABSTRACT

BACKGROUND: The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 in Vero and human Caco-2 cells. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19. METHODS: Due to the initial absence of preclinical models, the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized COVID-19 patients were randomly assigned to standard of care with or without itraconazole. Primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated. FINDINGS: In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and because an interim analysis showed no signal for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19) for itraconazole vs standard of care. INTERPRETATION: Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. This prompted the premature termination of the proof-of-concept clinical study. FUNDING: KU Leuven, Research Foundation - Flanders (FWO), Horizon 2020, Bill and Melinda Gates Foundation.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Itraconazole/pharmacology , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , COVID-19/etiology , COVID-19/transmission , Chlorocebus aethiops , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Humans , Itraconazole/administration & dosage , Itraconazole/pharmacokinetics , Itraconazole/therapeutic use , Male , Mesocricetus , Middle Aged , Pneumonia, Viral/drug therapy , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Proof of Concept Study , SARS-CoV-2/drug effects , Treatment Outcome , Vero Cells
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