Micafungin in the treatment of invasive candidiasis and invasive aspergillosis

Micafungin is an echinocandin antifungal agent available for clinical use in Japan, Europe, and the United States. Through inhibition of β-1,3-glucan production, an essential component of the fungal cell wall, micafungin exhibits potent antifungal activity against key pathogenic fungi, including Candida and Aspergillus species, while contributing minimal toxicity to mammalian cells. This activity is maintained against polyene and azole-resistant isolates. Pharmacokinetic and pharmacodynamic studies have demonstrated linear kinetics both in adults and children with concentration-dependent activity observed both in vitro and in vivo. Dosage escalation studies have also demonstrated that doses much higher than those currently recommended may be administered without serious adverse effects. Clinically, micafungin has been shown to be efficacious for the treatment of invasive candidiasis and invasive aspergillosis. Furthermore, the clinical effectiveness of micafungin against these infections occurs without the drug interactions that occur with the azoles and the nephrotoxicity observed with amphotericin B formulations. This review will focus on the pharmacology, clinical microbiology, mechanisms of resistance, safety, and clinical efficacy of micafungin in the treatment of invasive candidiasis and invasive aspergillosis

Critically Ill Recipients of Weight-Based Fluconazole Meeting Drug-Induced Liver Injury Network Criteria

Background: Fluconazole-associated liver injury is estimated to occur in <10% of patients; however, effect of weight-based fluconazole dosing on liver injury is unknown. Furthermore, no studies have systematically applied the Drug-Induced Liver Injury Network (DILIN) Criteria to identify patients who may have drug-induced liver injury in an intensive care unit (ICU) setting. Objective: This study evaluated how often patients met DILIN criteria when receiving fluconazole daily doses of <6 mg/kg versus ⩾6 mg/kg. Methods: This dual-center, retrospective cohort study was performed in hospitalized critically ill fluconazole recipients. We compared liver function tests (LFTs) upon fluconazole initiation to peak LFTs within 2 weeks after discontinuation using DILIN criteria. The primary objective was to evaluate the number of patients meeting DILIN criteria when receiving fluconazole daily doses of <6 mg/kg versus ⩾6 mg/kg. Secondary objectives were to evaluate incidence of patients meeting DILIN criteria in patients with renal dysfunction, cirrhosis, septic shock, or those receiving a loading dose. Results: Of 248 patients included, 90% had a documented fungal infection or received empiric therapy for suspected invasive candidiasis. In patients receiving <6 mg/kg of fluconazole, 55% (110/199) met DILIN criteria versus 46.9% (23/49) in the ⩾6 mg/kg cohort (P = .20). Only 14.5% of patients meeting DILIN criteria also met the definition for hepatocellular damage. Weight-based fluconazole dose and creatinine clearance <50 mL/min were not independent risk factors for meeting DILIN criteria. However, 77.3% of patients with cirrhosis met DILIN criteria (OR 4.84 [95% confidence interval, CI, 2.61-9.28]) and 76.3% with septic shock met DILIN criteria (OR 4.56 [95% CI, 2.44-8.88]). Conclusion: Weight-based fluconazole dosing did not affect the number of critically ill recipients who met DILIN criteria. However, DILIN criteria may overestimate the incidence of fluconazole-associated liver injury in critically ill patients

Critically-Ill Recipients of Weight-Based Fluconazole Meeting Drug-Induced Liver Injury Network (DILIN) criteria.

Purpose: Fluconazole-associated liver injury is estimated to occur in <10% of patients; however, the effect of weight-based fluconazole dosing on liver injury has not been assessed. This study evaluated how often patients met Drug Induced Liver Injury Network (DILIN) criteria when receiving fluconazole daily doses of <6mg/kg versus ≥6mg/kg. Methods: This multi-center, retrospective cohort study was performed in critically-ill fluconazole recipients hospitalized from January 2009 to December 2012. It included patients who received ≥3 fluconazole doses with ≥1 dose administered in the intensive care unit. Patients were excluded if they were pregnant, presented with acetaminophen toxicity, received fluconazole within 1 week of liver transplantation, or missed >1 fluconazole dose during therapy. We compared liver function tests (LFTs) upon fluconazole initiation to peak LFTs within 2 weeks after fluconazole discontinuation using DILIN criteria. The Fisher’s exact test was used to detect differences in the primary outcome of patients meeting DILIN criteria by weight-based dosing as well as in subgroups of patients with kidney dysfunction, liver disease, septic shock, and those receiving a loading dose. Results: Two-hundred and forty-eight of 767 patients met inclusion criteria; 90% had a documented fungal infection or received empiric therapy for suspected invasive candidiasis. Of the 199 patients receiving <6 mg/kg of fluconazole, 55% met DILIN criteria versus 46.9% of the 49 patients in the ≥6 mg/kg cohort (p=0.20). Only 14.5% of patients meeting DILIN criteria also met the definition for hepatocellular damage. In analysis of subgroups, 77.3% of patients with cirrhosis and 76.3% with septic shock met DILIN criteria (p<0.001 for both compared to those without these conditions). Conclusions: Weight-based fluconazole dosing did not affect the number of critically-ill recipients who met DILIN criteria. However, DILIN criteria may overestimate the incidence of fluconazole-associated liver injury in critically-ill patients

Critically-Ill Recipients of Weight-Based Fluconazole Meeting Drug-Induced Liver Injury Network (DILIN) criteria.

Purpose: Fluconazole-associated liver injury is estimated to occur in <10% of patients; however, the effect of weight-based fluconazole dosing on liver injury has not been assessed. This study evaluated how often patients met Drug Induced Liver Injury Network (DILIN) criteria when receiving fluconazole daily doses of <6mg/kg versus ≥6mg/kg. Methods: This multi-center, retrospective cohort study was performed in critically-ill fluconazole recipients hospitalized from January 2009 to December 2012. It included patients who received ≥3 fluconazole doses with ≥1 dose administered in the intensive care unit. Patients were excluded if they were pregnant, presented with acetaminophen toxicity, received fluconazole within 1 week of liver transplantation, or missed >1 fluconazole dose during therapy. We compared liver function tests (LFTs) upon fluconazole initiation to peak LFTs within 2 weeks after fluconazole discontinuation using DILIN criteria. The Fisher’s exact test was used to detect differences in the primary outcome of patients meeting DILIN criteria by weight-based dosing as well as in subgroups of patients with kidney dysfunction, liver disease, septic shock, and those receiving a loading dose. Results: Two-hundred and forty-eight of 767 patients met inclusion criteria; 90% had a documented fungal infection or received empiric therapy for suspected invasive candidiasis. Of the 199 patients receiving <6 mg/kg of fluconazole, 55% met DILIN criteria versus 46.9% of the 49 patients in the ≥6 mg/kg cohort (p=0.20). Only 14.5% of patients meeting DILIN criteria also met the definition for hepatocellular damage. In analysis of subgroups, 77.3% of patients with cirrhosis and 76.3% with septic shock met DILIN criteria (p<0.001 for both compared to those without these conditions). Conclusions: Weight-based fluconazole dosing did not affect the number of critically-ill recipients who met DILIN criteria. However, DILIN criteria may overestimate the incidence of fluconazole-associated liver injury in critically-ill patients

Compensatory response of the cell wall integrity pathway and chitin to caspofungin exposure in Candida glabrata

Background: Studies in Saccharomyces cerevisiae and Candida albicans have reported an up-regulation of the cell wall integrity pathway and an increase in cell wall chitin following caspofungin exposure. This study sought to examine the genetic and phenotypic response of the emerging fungal pathogen Candida glabrata to caspofungininduced cell wall damage. Methods: Antifungal susceptibility testing was performed using Saccharomyces cerevisiae deletion strains to identify genes affecting caspofungin activity. Bioinformatics (tBLASTn) searches were used to identify homologs of these sequences in C. glabrata. The XTT colorimetric viability assay and time-kill studies were used to assess the phenotypic response of wild-type C. glabrata ATCC 200989 and the corresponding (Delta symbol)slt2 gene knockout strain to caspofungin. Following caspofungin challenge, relative gene expression of SLT2 (a mitogen-activated protein kinase of the cell wall integrity pathway), CHS3 (chitin synthase III), and SKT5 (activator of chitin synthase III) was determined in triplicate using reverse-transcriptase real-time PCR. Chitin was quantified in triplicate using a colorimetric assay. Results: SLT2, CHS3 and SKT5 deletion in S. cerevisiae resulted in enhanced caspofungin activity. Each of these genes was found to have a homologous region within the C. glabrata genome. Fungal viability of wild-type C. glabrata ATCC 200989 did not fall below 16.3% viability following any caspofungin concentration. In contrast, no viable cells were present in the C. glabrata (Delta symbol)slt2 mutant strain at caspofungin concentrations (Greater than or equal to)0.25 mcg/mL. Similarly, time-kill results demonstrated that caspofungin was only fungicidal against the C. glabrata (Delta symbol)slt2 strain at concentrations of 1 and 16 mcg/mL. Relative gene expression of SLT2, CHS3 and SKT5 increased 2- to 4-fold following caspofungin exposure in wildtype C. glabrata. In addition, chitin content increased 3- to 4.5-fold in wild-type C. glabrata following all caspofungin concentrations tested. In the C. glabrata (Delta symbol)slt2 strain, CHS3 expression and chitin content did not increase following caspofungin challenge. Conclusions: Caspofungin was not fungicidal against the wild-type C. glabrata strain and gene expression of SLT2, CHS3 and SKT5 increased in response to caspofungininduced cell wall damage. Additionally, chitin content was elevated following caspofungin exposure in wild-type C. glabrata. In the corresponding C. glabrata strain with a deletion in SLT2 (a key component of the cell wall integrity pathway) caspofungin activity was significantly enhanced. Also, gene expression of CHS3 and chitin content were not elevated with increasing caspofungin concentrations. This suggests a link between the cell wall integrity pathway, increased chitin concentrations and the decreased caspofungin potency in C. glabrata.Pharmac

Long time no flower: RAV genes from A to A / Genetic mapping of important agronomic and phytochemical traits in cannabis

Trabajo presentado en el Internal Seminar del Centre de Recerca Agrigenómica (CRAG), celebrado el 15 de octubre de 2021.Peer reviewe

In Vitro Pharmacodynamics of Anidulafungin and Caspofungin against Candida glabrata Isolates, Including Strains with Decreased Caspofungin Susceptibility

The activities of anidulafungin and caspofungin against Candida glabrata were evaluated. MICs, 50% inhibitory concentrations (IC(50) values), and IC(90) values for anidulafungin were lower than those for caspofungin for 16 of 18 strains tested. Anidulafungin has potent in vitro activity against C. glabrata that is maintained against isolates with elevated caspofungin MICs