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Antimicrobial Agents and Chemotherapy Mar 2021Echinocandins have been used as primary therapy of invasive aspergillosis (IA), with suboptimal results at standard dosing. Here, we explored the efficacy of dose...
Comparative Pharmacodynamics of Echinocandins against Aspergillus fumigatus Using an Pharmacokinetic/Pharmacodynamic Model That Correlates with Clinical Response to Caspofungin Therapy: Is There a Place for Dose Optimization?
Echinocandins have been used as primary therapy of invasive aspergillosis (IA), with suboptimal results at standard dosing. Here, we explored the efficacy of dose escalation in a validated pharmacokinetic/pharmacodynamic (PK/PD) model. Six echinocandin wild-type (WT) and three non-WT isolates were tested in an PK/PD model simulating anidulafungin, caspofungin, and micafungin exposures with a free drug maximum concentration (C) of 0.01 to 16 mg/liter and a half-life () of 8 to 22 h. The relationship between the area under the dosing interval time-free drug concentration curve (AUC)/minimum effective concentration (MEC) and % aberrant mycelium formation was analyzed. PK/PD indices associated with 50 to 99.99% maximal activity (EI to EI) were correlated with the clinical outcome of a 50-mg/day standard dose of caspofungin. The probability of target attainment (PTA) was calculated for different dosing regimens of each echinocandin via Monte Carlo analysis. A sigmoidal PK/PD relationship was found for WT isolates with EI values of 766, 8.8, and 115 AUC/CLSI MEC for anidulafungin, caspofungin, and micafungin, respectively. No aberrant mycelia were observed for non-WT isolates, irrespective of their MEC and drug exposure. The EI, EI, and EI values corresponded to 2-, 3-, and 4-log formation of aberrant mycelia and correlated with survival, favorable, and complete response rates to caspofungin primary therapy in patients with IA. A very low PTA (<13%) was found for the standard doses of all echinocandins, whereas a PTA of ≥90% was found with 100 and 150 mg/day of caspofungin and 1,400 mg/day micafungin against WT isolates. For anidulafungin, the PTA for 1,500 mg/day was 10%. Among the three echinocandins, only caspofungin at 2 or 3 times the licensed dosing was associated with a high PTA. Caspofungin dose escalation might deserve clinical validation.
Topics: Anidulafungin; Antifungal Agents; Aspergillus fumigatus; Caspofungin; Echinocandins; Humans; Lipopeptides; Microbial Sensitivity Tests
PubMed: 33495222
DOI: 10.1128/AAC.01618-20 -
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 -
European Journal of Clinical... Apr 2015Echinocandins and triazoles were proven to be effective antifungal drugs against invasive fungal infections (IFI), which may cause significant morbidity and mortality in... (Comparative Study)
Comparative Study Meta-Analysis Review
Echinocandins and triazoles were proven to be effective antifungal drugs against invasive fungal infections (IFI), which may cause significant morbidity and mortality in immunocompromised patients. The aim of this study was to compare the efficacy and safety between echinocandins and triazoles for the prophylaxis and treatment of fungal infections. PubMed, Embase, and the Cochrane Library were searched to identify relevant randomized controlled trials (RCTs) up to July 2014. The quality of trials was assessed with the Jadad scoring system. The primary outcomes of interest were treatment success, microbiological success, breakthrough infection, drug-related adverse events (AEs), withdrawals due to AEs, and all-cause mortality. Ten RCTs, involving 2,837 patients, were included, as follows: caspofungin versus fluconazole (n = 1), caspofungin versus itraconazole (n = 1), anidulafungin versus fluconazole (n = 1), micafungin versus fluconazole (n = 4), micafungin versus voriconazole (n = 2), and micafungin versus itraconazole (n = 1). Echinocandins and triazoles showed similar effects in terms of favorable treatment success rate [relative risk (RR) = 1.02, 95% confidence interval (CI), 0.97-1.08], microbiological success rate (RR = 0.98, 95% CI, 0.90-1.15), breakthrough infection (RR = 1.09; 95% CI, 0.59-2.01), drug-related AEs (RR = 0.94; 95% CI, 0.71-1.15), and all-cause mortality (RR = 0.85; 95% CI, 0.66-1.10) in the prophylaxis and treatment of fungal infections. Additionally, echinocandins were more effective than triazoles for prophylaxis in patients undergoing hematologic malignancies or those who received hematopoietic stem cell transplantation (HSCT; RR = 1.08; 95% CI, 1.02-1.15). Echinocandins significantly decreased the AE-related withdrawals rate compared with triazoles (RR = 0.47; 95% CI, 0.33-0.67). This meta-analysis revealed that echinocandins are as effective and safe as triazoles for the prophylaxis and treatment of patients with fungal infections.
Topics: Antifungal Agents; Chemoprevention; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Echinocandins; Humans; Mycoses; Randomized Controlled Trials as Topic; Survival Analysis; Treatment Outcome; Triazoles
PubMed: 25502737
DOI: 10.1007/s10096-014-2287-4 -
Journal of Fungi (Basel, Switzerland) Aug 2021Human infectious fungal diseases are increasing, despite improved hygienic conditions. We present a case of gastrointestinal basidiobolomycosis (GIB) in a 20-year-old...
Human infectious fungal diseases are increasing, despite improved hygienic conditions. We present a case of gastrointestinal basidiobolomycosis (GIB) in a 20-year-old male with a history of progressively worsening abdominal pain. The causative agent was identified as a novel species. Validation of its novelty was established by analysis of the partial ribosomal operon of two isolates from different organs. Phylogeny of ITS and LSU rRNA showed that these isolates belonged to the genus positioned closely to and . Morphological and physiological data supported the identity of the species, which was named , with CBS 146281 as the holotype. The strains showed high minimum inhibitory concentrations (MICs) to fluconazole (>64 µg/mL), itraconazole and voriconazole (>16 µg/mL), anidulafungin and micafungin (>16 µg/mL), but had a low MIC to amphotericin B (1 µg/mL). The pathogenic role of in gastrointestinal disease is discussed. We highlight the crucial role of molecular identification of these rarely encountered opportunistic fungi.
PubMed: 34436192
DOI: 10.3390/jof7080653 -
Journal of Fungi (Basel, Switzerland) May 2021The aim of the study was to describe the microbiology and susceptibility profile of candidemia and to identify the risk factors associated with mortality in Colombia. A...
The aim of the study was to describe the microbiology and susceptibility profile of candidemia and to identify the risk factors associated with mortality in Colombia. A cohort of patients was followed for 30 days during 2008 to 2010. Microbiological identification and susceptibility assessments were performed in a reference centre. Demographic, clinical and treatment variables were evaluated for their associations with mortality. A parametric survival regression analysis was used to identify the risk factors associated with mortality. A total of 109 patients with candidemia in four hospitals in Colombia were identified, with a median age of 30 years old. was the most frequently identified microorganism (38.5%); the susceptibility of all isolates was high to fluconazole and anidulafungin, except for isolates. The overall mortality was 35.7%, and the risk factors associated with mortality included lack of antifungal treatment (HR 5.5, 95% CI 3.6-11.4), cancer (HR 3.9, 95% CI 2.3-8.0), diabetes (HR 2.5, 95% CI 1.03-6.4), and age (HR 1.13 per every 10 years, 95% CI 1.02-1.24). Catheter removal was associated with a low mortality rate (HR 0.06, 95% CI 0.00-0.49). Prompt antifungal treatment, better glycemic control and catheter removal should be prioritized in the management of candidemia.
PubMed: 34073125
DOI: 10.3390/jof7060442 -
Infection and Drug Resistance 2018species remains one of the most important causes of opportunistic infections worldwide. Invasive candidiasis (IC) is associated with considerable morbidity and... (Review)
Review
species remains one of the most important causes of opportunistic infections worldwide. Invasive candidiasis (IC) is associated with considerable morbidity and mortality in liver disease (LD) patients if not treated promptly. Echinocandins are often recommended as a first-line empirical treatment for managing IC and can especially play a critical role in managing IC in LD patients. However, advanced LD patients are often immunocompromised and critically ill. Hence altered pharmacokinetics, drug interactions as well as tolerance issues of antifungal treatments are a concern in these patients. This comprehensive review examines the epidemiology, risk factors and diagnosis of IC in patients with LD and evaluates differences between three available echinocandins for treating this group of patients.
PubMed: 29881298
DOI: 10.2147/IDR.S165676 -
Journal of Fungi (Basel, Switzerland) Jun 2023is an emerging fungal pathogen responsible for hospital outbreaks of invasive candidiasis associated with high mortality. The treatment of these mycoses is a clinical...
is an emerging fungal pathogen responsible for hospital outbreaks of invasive candidiasis associated with high mortality. The treatment of these mycoses is a clinical challenge due to the high resistance levels of this species to current antifungal drugs, and alternative therapeutic strategies are needed. In this study, we evaluated the in vitro and in vivo activities of combinations of citral with anidulafungin, amphotericin B or fluconazole against 19 isolates. The antifungal effect of citral was in most cases similar to the effect of the antifungal drugs in monotherapy. The best combination results were obtained with anidulafungin, with synergistic and additive interactions against 7 and 11 of the 19 isolates, respectively. The combination of 0.06 μg/mL anidulafungin and 64 μg/mL citral showed the best results, with a survival rate of 63.2% in infected with UPV 17-279. The combination of fluconazole with citral reduced the MIC of fluconazole from > 64 to 1-4 μg/mL against 12 isolates, and a combination of 2 μg/mL fluconazole and 64 μg/mL citral was also effective in reducing mortality in . Amphotericin B combined with citral, although effective in vitro, did not improve the activity of each compound in vivo.
PubMed: 37367584
DOI: 10.3390/jof9060648 -
Microorganisms Apr 2021is an emerging and frequently multidrug-resistant pathogen against which the echinocandins are the preferred therapeutic option. We compared killing activities of...
Comparison of In Vitro Killing Activity of Rezafungin, Anidulafungin, Caspofungin, and Micafungin against Four Clades in RPMI-1640 in the Absence and Presence of Human Serum.
is an emerging and frequently multidrug-resistant pathogen against which the echinocandins are the preferred therapeutic option. We compared killing activities of anidulafungin, caspofungin, micafungin, and rezafungin against 13 isolates representing four clades (South Asian = 3; East Asian = 3; South African = 3; South American = 4, of which two were of environmental origin). Minimum inhibitory concentration MICs and killing kinetics in RPMI-1640 and RPMI-1640 plus 50% serum (50% serum) were determined. The four echinocandins were never fungicidal and induced large aggregates in RPMI-1640 and, less markedly, in 50% serum. Colony forming unit CFU decreases were found more consistently in 50% serum than in RPMI-1640. Isolates from the East Asian clade were killed at ≥1-≥ 4 mg/L with all echinocandins regardless of media. Anidulafungin and micafungin produced killing at peak drug serum concentration (8 mg/L) against environmental but not clinical isolates from the South American and the South African clades. Micafungin at ≥8 mg/L but not anidulafungin produced CFU decreases against the South Asian clade as well. In 50% serum, rezafungin at ≥1-≥ 8 mg/L produced killing against all four clades. The next generation echinocandin, rezafungin, showed the same or better activity at clinically attainable trough concentration regardless of media, compared with anidulafungin, caspofungin, and micafungin against all four tested clades.
PubMed: 33923783
DOI: 10.3390/microorganisms9040863 -
International Microbiology : the... Jan 2021In spite of evidence that domestic and wild birds may act as carriers of human pathogenic fungi, data on the role of laying hens as reservoirs of drug resistant and...
In spite of evidence that domestic and wild birds may act as carriers of human pathogenic fungi, data on the role of laying hens as reservoirs of drug resistant and virulent yeasts is lacking. Here, we assess several virulence factors (phospholipase and haemolysin activity) and the antifungal susceptibility profiles of 84 Candida albicans and 17 Candida catenulata strains isolated from cloacae (group A), faeces (group B) and eggs (group C) of laying hens. Of these strains, 95% C. albicans and 23% C. catenulata strains displayed phospholipase and haemolytic activities. For C. albicans, the highest values of phospholipase (Pz = 0.62) and haemolytic activities (Hz = 0.49) were recorded among the strains from group C whilst for C. catenulata (Pz = 0.54; Hz = 0.49) among those from group A. High minimum inhibitory concentration (MIC) values for azoles and amphotericin B (AmB) were recorded irrespective of their sources in all C. albicans strains. A total of 22 C. albicans strains were multidrug resistant, displaying resistance to fluconazole, itraconazole (ITZ), voriconazole (VOR) and posaconazole (POS). All C. catenulata strains from group C were resistant to ITZ, POS, micafungin and anidulafungin and susceptible to AmB. In this study, C. albicans and C. catenulata isolated from the cloacae, faeces and eggs of laying hens produced phospholipase and haemolysin and might be multidrug resistant. In the environment (faeces) or in eggs, C. albicans and C. catenulata strains might acquire pathogenic virulence traits and/or show multidrug resistance profiles. Based on these results, breeding and handling of laying hens and/or eggs may have implications for human and animal health.
Topics: Animals; Antifungal Agents; Candida; Candida albicans; Chickens; Drug Resistance, Fungal; Eggs; Feces; Female; Microbial Sensitivity Tests; Virulence
PubMed: 32772220
DOI: 10.1007/s10123-020-00141-1 -
Antimicrobial Agents and Chemotherapy Feb 2018There is currently a small number of classes of antifungal drugs, and these drugs are known to target a very limited set of cellular functions. We derived a set of...
There is currently a small number of classes of antifungal drugs, and these drugs are known to target a very limited set of cellular functions. We derived a set of approximately 900 nonessential, transactivator-defective disruption strains from the tetracycline-regulated GRACE collection of strains of the fungal pathogen This strain set was screened against classic antifungal drugs to identify gene inactivations that conferred either enhanced sensitivity or increased resistance to the compounds. We examined two azoles, fluconazole and posaconazole; two echinocandins, caspofungin and anidulafungin; and a polyene, amphotericin B. Overall, the chemogenomic profiles within drug classes were highly similar, but there was little overlap between classes, suggesting that the different drug classes interacted with discrete networks of genes in We also tested two pyridine amides, designated GPI-LY7 and GPI-C107; these drugs gave very similar profiles that were distinct from those of the echinocandins, azoles, or polyenes, supporting the idea that they target a distinct cellular function. Intriguingly, in cases where these gene sets can be compared to genetic disruptions conferring drug sensitivity in other fungi, we find very little correspondence in genes. Thus, even though the drug targets are the same in the different species, the specific genetic profiles that can lead to drug sensitivity are distinct. This implies that chemogenomic screens of one organism may be poorly predictive of the profiles found in other organisms and that drug sensitivity and resistance profiles can differ significantly among organisms even when the apparent target of the drug is the same.
PubMed: 29203491
DOI: 10.1128/AAC.02365-17