Treatment Outcomes Among Patients With a Positive Candida Culture Close to Randomization Receiving Rezafungin or Caspofungin in the ReSTORE Study.

BACKGROUND: Rezafungin, a novel, once-weekly echinocandin for the treatment of candidemia and/or invasive candidiasis (IC) was noninferior to caspofungin for day 30 all-cause mortality (ACM) and day 14 global cure in the phase 3 ReSTORE trial (NCT03667690). We conducted preplanned subgroup analyses for patients with a positive culture close to randomization in ReSTORE. METHODS: ReSTORE was a multicenter, double-blind, double-dummy, randomized trial in patients aged ≥18 years with candidemia and/or IC treated with once-weekly intravenous rezafungin (400 mg/200 mg) or once-daily intravenous caspofungin (70 mg/50 mg). This analysis comprised patients with a positive blood culture drawn between 12 hours before and 72 hours after randomization or a positive culture from another normally sterile site sampled between 48 hours before and 72 hours after randomization. Efficacy endpoints included day 30 ACM, day 14 global cure rate, and day 5 and 14 mycological response. Adverse events were evaluated. RESULTS: This analysis included 38 patients randomized to rezafungin and 46 to caspofungin. In the rezafungin and caspofungin groups, respectively, day 30 ACM was 26.3% and 21.7% (between-group difference [95% confidence interval], 4.6% [-13.7%, 23.5%]), day 14 global response was 55.3% and 50.0% (between-group difference, 5.3% [-16.1%, 26.0%]), and day 5 mycological eradication was 71.1% and 50.0% (between-group difference, 21.1% [-0.2%, 40.2%]). Safety was comparable between treatments. CONCLUSIONS: These findings support the efficacy and safety of rezafungin compared with caspofungin for the treatment of candidemia and/or IC in patients with a positive culture close to randomization, with potential early treatment benefits for rezafungin.

Safety and efficacy of non-reduced use of caspofungin in patients with Child-Pugh B or C cirrhosis: a real-world study.

BACKGROUND AND PURPOSE: The need for dose adjustment of caspofungin in patients with hepatic impairment is controversial, especially for those with Child-Pugh B or C cirrhosis. The purpose of this study was to investigate the safety and efficacy of standard-dose caspofungin administration in Child-Pugh B and C cirrhotic patients in a real-world clinical setting. PATIENTS AND METHODS: The electronic medical records of 258 cirrhotic patients, including 67 Child-Pugh B patients and 191 Child-Pugh C patients, who were treated with standard-dose of caspofungin at the Second Affiliated Hospital of Chongqing Medical University, China, from March 2018 to June 2023 were reviewed retrospectively. The white blood cells (WBC), hepatic, renal and coagulation function results before administration and post administration on days 7, 14 and 21 were collected, and the efficacy was assessed in all patients at the end of caspofungin therapy. RESULTS: Favorable responses were achieved in 137 (53.1%) patients while 34 (13.2%) patients died. We observed that some patients experienced an increase of prothrombin time (PT) or international normalized ratio (INR), or a decrease of WBC, but no exacerbation of hepatic or renal dysfunction were identified and no patient required dose interruption or adjustment because of an adverse drug reaction during treatment with caspofungin. CONCLUSIONS: Standard-dose of caspofungin can be safely and effectively used in patients with Child-Pugh B or C cirrhosis, and we appealed to re-assess the most suitable dosing regimen in this population to avoid a potential subtherapeutic exposure.

A regimen based on the combination of trimethoprim/sulfamethoxazole with caspofungin and corticosteroids as a first-line therapy for patients with severe non-HIV-related pneumocystis jirovecii pneumonia: a retrospective study in a tertiary hospital.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is a life-threatening and severe disease in immunocompromised hosts. A synergistic regimen based on the combination of sulfamethoxazole-trimethoprim (SMX-TMP) with caspofungin and glucocorticosteroids (GCSs) may be a potential first-line therapy for PJP. Therefore, it is important to explore the efficacy and safety of this synergistic therapy for treating non-HIV-related PJP patients. METHODS: We retrospectively analysed the data of 38 patients with non-HIV-related PJP at the First Affiliated Hospital of Xi'an Jiaotong University. Patients were divided into two groups: the synergistic therapy group (ST group, n = 20) and the monotherapy group (MT group, n = 18). All patients were from the ICU and were diagnosed with severe PJP. In the ST group, all patients were treated with SMX-TMP (TMP 15-20 mg/kg per day) combined with caspofungin (70 mg as the loading dose and 50 mg/day as the maintenance dose) and a GCS (methylprednisolone 40-80 mg/day). Patients in the MT group were treated only with SMX-TMP (TMP 15-20 mg/kg per day). The clinical response, adverse events and mortality were compared between the two groups. RESULTS: The percentage of patients with a positive clinical response in the ST group was significantly greater than that in the MT group (100.00% vs. 66.70%, P = 0.005). The incidence of adverse events in the MT group was greater than that in the ST group (50.00% vs. 15.00%, P = 0.022). Furthermore, the dose of TMP and duration of fever in the ST group were markedly lower than those in the MT group (15.71 mg/kg/day vs. 18.35 mg/kg/day (P = 0.001) and 7.00 days vs. 11.50 days (P = 0.029), respectively). However, there were no significant differences in all-cause mortality or duration of hospital stay between the MT group and the ST group. CONCLUSIONS: Compared with SMZ/TMP monotherapy, synergistic therapy (SMZ-TMP combined with caspofungin and a GCS) for the treatment of non-HIV-related PJP can increase the clinical response rate, decrease the incidence of adverse events and shorten the duration of fever. These results indicate that synergistic therapy is effective and safe for treating severe non-HIV-related PJP.

Coagulation dysfunction events associated with echinocandins: a real-world study from FDA adverse event reporting system (FAERS) database.

BACKGROUND: Echinocandins belong to the fourth generation of antifungals, and there are no systematic studies on their risk in coagulation dysfunction; this study will predict the risk of coagulation dysfunction of echinocandins using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHOD: Data from January 2004 to March 2024 were obtained from FAERS. We examined the clinical characteristics of the coagulation dysfunction events and conducted disproportionality analysis by using reporting odds ratios (ROR) to compare echinocandins with the full database. RESULTS: There were 313 reports of coagulation dysfunction related to echinocandins as the primary suspect (PS) drug. The median time to incident for coagulation dysfunction was 3 (interquartile range [IQR] 1-9) days. Compared to triazoles and polyenes, echinocandins have a stronger signal (ROR 3.18, 95%CI 2.81-3.51, p < 0.01) of coagulation dysfunction. Compared to caspofungin and micafungin, anidulafungin has a stronger signal (ROR 6.84, 95%CI 4.83-9.70, p < 0.01). The strongest signal corresponding to disseminated intravascular coagulation (DIC), platelet count decreased, thrombocytopenia, gastrointestinal haemorrhage, cerebral haemorrhage, pulmonary haemorrhage and thrombotic thrombocytopenic purpura (TTP) is micafungin (ROR 27.19, 95%CI 18.49-39.98), micafungin (ROR 3.50, 95%CI 2.36-5.19), anidulafungin (ROR 9.75, 95%CI 5.22-18.19), micafungin (ROR 3.17, 95%CI 2.02-4.97), micafungin (ROR 4.95, 95%CI 2.81-8.72), caspofungin (ROR 20.76, 95%CI 11.77-36.59), micafungin (ROR 20.43, 95%CI 8.49-49.14), respectively. CONCLUSIONS: For coagulation dysfunction, we found stronger signals for echinocandins than triazoles and polyenes, and stronger signals for anidulafungin than micafungin and caspofungin. Coagulation parameters should be closely monitored while using the respective drugs.

Trimethoprim-sulfamethoxazole combined with echinocandins versus trimethoprim-sulfamethoxazole alone for Pneumocystis pneumonia in patients without human immunodeficiency virus infection: A nationwide retrospective cohort study.

BACKGROUND: Although combination therapy of echinocandins with trimethoprim-sulfamethoxazole (TMP-SMX) has been reported for patients with Pneumocystis jirovecii pneumonia (PCP), the effectiveness of this combination therapy in patients with PCP without human immunodeficiency virus (HIV) infection remains unknown. METHODS: Data from the Japanese Diagnosis Procedure Combination inpatient database was used to identify non-HIV patients who underwent their first hospitalisation for PCP between April 2012 and March 2022. The patients were divided into those treated with TMP-SMX alone and those treated with TMP-SMX combined with echinocandins. We performed propensity-score overlap-weighting analysis to estimate in-hospital mortality. RESULTS: Among the 1324 eligible patients, 122 received TMP-SMX plus echinocandins, while 1202 received TMP-SMX alone. The propensity-score overlap-weighting analysis showed that the combination therapy was not associated with reduced in-hospital mortality in comparison with TMP-SMX alone (22.2 % vs. 26.9 %; risk difference, 4.6 %; 95 % confidence interval, -6.1 %-15.3 %; P = 0.398). CONCLUSIONS: Echinocandins combined with TMP-SMX may not improve in-hospital mortality due to PCP in patients without HIV infection.

Comparative Analysis of the Aspergillus fumigatus Cell Wall Modification and Ensuing Human Dendritic Cell Responses by ß-(1,3)-Glucan Synthase Inhibitors-Caspofungin and Enfumafungin.

Caspofungin, a lipopeptide, is an antifungal drug that belong to the class of echinocandin. It inhibits fungal cell wall ß-(1,3)-glucan synthase activity and is the second-line of drug for invasive aspergillosis, a fatal infection caused mainly by Aspergillus fumigatus. On the other hand, Enfumafungin is a natural triterpene glycoside also with a ß-(1,3)-glucan synthase inhibitory activity and reported to have antifungal potential. In the present study, we compared the growth as well as modifications in the A. fumigatus cell wall upon treatment with Caspofungin or Enfumafungin, consequentially their immunomodulatory capacity on human dendritic cells. Caspofungin initially inhibited the growth of A. fumigatus, but the effect was lost over time. By contrast, Enfumafungin inhibited this fungal growth for the duration investigated. Both Caspofungin and Enfumafungin caused a decrease in the cell wall ß-(1,3)-glucan content with a compensatory increase in the chitin, and to a minor extent they also affected cell wall galactose content. Treatment with these two antifungals did not result in the exposure of ß-(1,3)-glucan on A. fumigatus mycelial surface. Enzymatic digestion suggested a modification of ß-(1,3)-glucan structure, specifically its branching, upon Enfumafungin treatment. While there was no difference in the immunostimulatory capacity of antifungal treated A. fumigatus conidia, alkali soluble-fractions from Caspofungin treated mycelia weakly stimulated the dendritic cells, possibly due to an increased content of immunosuppressive polysaccharide galactosaminogalactan. Overall, we demonstrate a novel mechanism that Enfumafungin not only inhibits ß-(1,3)-glucan synthase activity, but also causes modifications in the structure of ß-(1,3)-glucan in the A. fumigatus cell wall.

Caspofungin formulations for buccal and sublingual mucosae anti-fungal infections: physicochemical characterization, rheological analysis, release and ex vivo permeability profiles.

AIM: Oral candidiasis is often challenging due to limited effectiveness of topical treatments. This study aimed to develop novel caspofungin formulations for administration onto the oral mucosa to enhance drug retention and efficacy. METHOD: Five caspofungin (2%, w/v) formulations were developed to assess their permeability, retention and mucoadhesiveness. Ex vivo permeability assays were performed on buccal and sublingual mucosae, and histological analyses conducted to evaluate tissue tolerance. RESULTS: Formulation composed of chitosan demonstrated the highest retention in both buccal (5183.24 ± 587.32 µg/cm2) and sublingual (1090.72 ± 110.26 µg/cm2) mucosae. Other formulations exhibited significantly lower retention, ranging from 7.53 ± 0.81 to 1852.10 ± 193.24 µg/cm2 in buccal mucosa and 1.64 ± 0.14 to 317.74 ± 31.78 µg/cm2 in sublingual mucosa. Chitosan-based formulation exhibited the highest mucoadhesive strength, with values of 5179.05 ± 31.99 mN/cm2 for buccal and 7026.10 ± 123.41 mN/cm2 for sublingual mucosae, and also superior extensibility, which facilitates application in the oral cavity. All formulations showed antifungal activity against Candida spp., and histological analyses revealed minor epithelial alterations. CONCLUSION: The developed formulations offer distinct advantages for treating oral candidiasis, with chitosan formulation emerging as the most promising due to its superior retention, mucoadhesion force, and spreadability, making it a potential candidate for further clinical investigation.

The SET-domain protein CgSet4 negatively regulates antifungal drug resistance via the ergosterol biosynthesis transcriptional regulator CgUpc2a.

Invasive fungal infections, which pose a serious threat to human health, are increasingly associated with a high mortality rate and elevated health care costs, owing to rising resistance to current antifungals and emergence of multidrug-resistant fungal species. Candida glabrata is the second to fourth common cause of Candida bloodstream infections. Its high propensity to acquire resistance toward two mainstream drugs, azoles (inhibit ergosterol biosynthesis) and echinocandins (target cell wall), in clinical settings, and its inherent low azole susceptibility render antifungal therapy unsuccessful in many cases. Here, we demonstrate a pivotal role for the SET {suppressor of variegation 3 to 9 [Su(var)3-9], enhancer of zeste [E(z)], and trithorax (Trx)} domain-containing protein, CgSet4, in azole and echinocandin resistance via negative regulation of multidrug transporter-encoding and ergosterol biosynthesis (ERG) genes through the master transcriptional factors CgPdr1 and CgUpc2A, respectively. RNA-Seq analysis revealed that C. glabrata responds to caspofungin (CSP; echinocandin antifungal) stress by downregulation and upregulation of ERG and cell wall organization genes, respectively. Although CgSet4 acts as a repressor of the ergosterol biosynthesis pathway via CgUPC2A transcriptional downregulation, the CSP-induced ERG gene repression is not dependent on CgSet4, as CgSet4 showed diminished abundance on the CgUPC2A promoter in CSP-treated cells. Furthermore, we show a role for the last three enzymes of the ergosterol biosynthesis pathway, CgErg3, CgErg5, and CgErg4, in antifungal susceptibility and virulence in C. glabrata. Altogether, our results unveil the link between ergosterol biosynthesis and echinocandin resistance and have implications for combination antifungal therapy.

Novel Non-Hot Spot Modification in Fks1 of Candida auris Confers Echinocandin Resistance.

We determined the echinocandin susceptibility and FKS1 genotypes of 13 clinical isolates of Candida auris that were recovered from 4 patients at a tertiary care center in Salvador, Brazil. Three isolates were categorized as echinocandin-resistant, and they harbored a novel FKS1 mutation that led to an amino acid change W691L located downstream from hot spot 1. When introduced to echinocandin-susceptible C. auris strains by CRISPR/Cas9, Fks1 W691L induced elevated MIC values to all echinocandins (anidulafungin, 16 to 32×; caspofungin, >64×; micafungin, >64×).

Crosstalk between the calcineurin and cell wall integrity pathways prevents chitin overexpression in Candida albicans.

Echinocandins such as caspofungin are frontline antifungal drugs that compromise ß-1,3 glucan synthesis in the cell wall. Recent reports have shown that fungal cells can resist killing by caspofungin by upregulation of chitin synthesis, thereby sustaining cell wall integrity (CWI). When echinocandins are removed, the chitin content of cells quickly returns to basal levels, suggesting that there is a fitness cost associated with having elevated levels of chitin in the cell wall. We show here that simultaneous activation of the calcineurin and CWI pathways generates a subpopulation of Candida albicans yeast cells that have supra-normal chitin levels interspersed throughout the inner and outer cell wall, and that these cells are non-viable, perhaps due to loss of wall elasticity required for cell expansion and growth. Mutations in the Ca2+-calcineurin pathway prevented the formation of these non-viable supra-high chitin cells by negatively regulating chitin synthesis driven by the CWI pathway. The Ca2+-calcineurin pathway may therefore act as an attenuator that prevents the overproduction of chitin by coordinating both chitin upregulation and negative regulation of the CWI signaling pathway. This article has an associated First Person interview with the first author of the paper.

Efficacy of initial caspofungin plus trimethoprim/sulfamethoxazole for severe PCP in patients without human immunodeficiency virus infection.

BACKGROUND: The number of pneumocystis pneumonia (PCP) cases is increasing in immunocompromised patients without human immunodeficiency virus infection (HIV), causing serious morbidity with high mortality. Trimethoprim/sulfamethoxazole (TMP/SMZ) monotherapy has limited effectiveness in the treatment of PCP. Clinical data on whether initial caspofungin plus TMP/SMZ for this disease is superior to monotherapy in non-HIV-infected patients are limited. We aimed to compare the clinical effectiveness of these regimens for severe PCP in non-HIV patients. METHODS: A retrospective study reviewed 104 non-HIV-infected patients with confirmed PCP in the intensive care unit between January 2016 and December 2021. Eleven patients were excluded from the study because TMP/SMZ could not be used due to severe hematologic disorders or clinical data were missing. All enrolled patients were divided into three groups according to different treatment strategies: Group 1 received TMP/SMZ monotherapy, Group 2 received caspofungin combined with TMP/SMZ as first-line therapy, and Group 3 initially received TMP/SMZ monotherapy and later received caspofungin as salvage therapy. The clinical characteristics and outcomes were compared among the groups. RESULTS: A total of 93 patients met the criteria. The overall positive response rate of anti-PCP treatment was 58.06%, and the overall 90-day all-cause mortality rate was 49.46%. The median APACHE II score was 21.44. The concurrent infection rate was 74.19%, among whom 15.05% (n = 14) of those patients had pulmonary aspergillosis, 21.05% (n = 20) had bacteremia, and 23.65% (n = 22) had CMV infections. The patients who received initial caspofungin combination with TMP/SMZ had the best positive response rate (76.74%) compared to others (p = 0.001). Furthermore, the group that received initial caspofungin combined with TMP/SMZ had a 90-day all-cause mortality rate (39.53%) that was significantly different from that of the shift group (65.51%, p = 0.024), but this rate showed no statistically significant difference compared with that in the monotherapy group (48.62%, p = 0.322). None of the patients had serious adverse events from caspofungin therapy. CONCLUSIONS: For non-HIV-infected patients with severe PCP, initial combination therapy with caspofungin and TMP/SMZ is a promising first-line treatment option compared with TMP/SMZ monotherapy and combination therapy as salvage therapy.

Caspofungin Suppresses Brain Cell Necroptosis in Ischemic Stroke Rats via Up-Regulation of Pellino3.

PURPOSE: Pellino3, an ubiquitin E3 ligase, prevents the formation of the death-induced signaling complex in response to TNF-α by targeting receptor-interacting protein kinase 1 (RIPK1), and bioinformatics analysis predicted an interaction between Pellino3 and caspofungin, a common antifungal drug used in clinics. This study aimed to explore the effect of caspofungin on brain injury in ischemic stroke and the underlying mechanisms. METHODS: Ischemic stroke injury was induced in Sprague Dawley rats by occlusion of the middle cerebral artery (MCA) for 2 h, followed by 24 h reperfusion. PC12 cells were deprived of both oxygen and glucose for 8 h and then were cultured for 24 h with oxygen and glucose to mimic an ischemic stroke in vitro. RESULTS: Animal experiments showed brain injury (increase in neurological deficit score and infarct volume) concomitant with a downregulation of Pellino3, a decreased ubiquitination of RIPK1, and an up-regulation of necroptosis-associated proteins [RIPK1, RIPK3, mixed lineage kinase domain-like protein (MLKL), p-RIPK1, p-RIPK3, and p-MLKL]. Administration of caspofungin (6 mg/kg, i.m.) at 1 h and 6 h after ischemia significantly improved neurological function, reduced infarct volume, up-regulated Pellino3 levels, increased RIPK1 ubiquitination, and down-regulated protein levels of RIPK1, p-RIPK1, p-RIPK3, and p-MLKL. PC12 cells deprived of oxygen/glucose developed signs of cellular injury (LDH release and necroptosis) concomitant with downregulation of Pellino3, decreased ubiquitination of RIPK1, and elevated necroptosis-associated proteins. These changes were reversed by overexpression of Pellino3. CONCLUSION: We conclude that Pellino3 has an important role in counteracting necroptosis via ubiquitination of RIPK1 and caspofungin can suppress the brain cell necroptosis in ischemic stroke through upregulation of Pellino3.

In vivo evolution to echinocandin resistance and increasing clonal heterogeneity in Candida auris during a difficult-to-control hospital outbreak, Italy, 2019 to 2022.

A difficult-to-control outbreak of Candida auris is ongoing in a large tertiary care hospital in Liguria, Italy, where it first emerged in 2019. In a retrospective analysis, 503 cases of C. auris carriage or infection were observed between July 2019 and December 2022. Genomic surveillance identified putative cases that no longer occurred as part of one defined outbreak and the emergence of echinocandin (pandrug) resistance following independent selection of FKS1S639F and FKS1F635Y mutants upon prolonged exposure to caspofungin and/or anidulafungin.

Analysis of the Localization of Schizosaccharomyces pombe Glucan Synthases in the Presence of the Antifungal Agent Caspofungin.

In recent years, invasive fungal infections have emerged as a common source of infections in immunosuppressed patients. All fungal cells are surrounded by a cell wall that is essential for cell integrity and survival. It prevents cell death and lysis resulting from high internal turgor pressure. Since the cell wall is not present in animal cells, it is an ideal target for selective invasive fungal infection treatments. The antifungal family known as echinocandins, which specifically inhibit the synthesis of the cell wall ß(13)glucan, has been established as an alternative treatment for mycoses. To explore the mechanism of action of these antifungals, we analyzed the cell morphology and glucan synthases localization in Schizosaccharomyces pombe cells during the initial times of growth in the presence of the echinocandin drug caspofungin. S. pombe are rod-shaped cells that grow at the poles and divide by a central division septum. The cell wall and septum are formed by different glucans, which are synthesized by four essential glucan synthases: Bgs1, Bgs3, Bgs4, and Ags1. Thus, S. pombe is not only a perfect model for studying the synthesis of the fungal ß(1-3)glucan, but also it is ideal for examining the mechanisms of action and resistance of cell wall antifungals. Herein, we examined the cells in a drug susceptibility test in the presence of either lethal or sublethal concentrations of caspofungin, finding that exposure to the drug for long periods at high concentrations (>10 µg/mL) induced cell growth arrest and the formation of rounded, swollen, and dead cells, whereas low concentrations (<10 µg/mL) permitted cell growth with a mild effect on cell morphology. Interestingly, short-term treatments with either high or low concentrations of the drug induced effects contrary to those observed in the susceptibility tests. Thus, low drug concentrations induced a cell death phenotype that was not observed at high drug concentrations, which caused transient fungistatic cell growth arrest. After 3 h, high concentrations of the drug caused the following: (i) a decrease in the GFP-Bgs1 fluorescence level; (ii) altered locations of Bgs3, Bgs4, and Ags1; and (iii) a simultaneous accumulation of cells with calcofluor-stained incomplete septa, which at longer times resulted in septation uncoupling from plasma membrane ingression. The incomplete septa revealed with calcofluor were found to be complete when observed via the membrane-associated GFP-Bgs or Ags1-GFP. Finally, we found that the accumulation of incomplete septa depended on Pmk1, the last kinase of the cell wall integrity pathway.

Helium Cold Atmospheric Plasma Causes Morphological and Biochemical Alterations in Candida albicans Cells.

(1) Background: Previous studies reported the promising inhibitory effect of cold atmospheric plasma (CAP) on Candida albicans. However, the exact mechanisms of CAP's action on the fungal cell are still poorly understood. This study aims to elucidate the CAP effect on C. albicans cell wall, by evaluating the alterations on its structure and biochemical composition; (2) Methods: C. albicans cells treated with Helium-CAP were analyzed by atomic force microscopy (AFM) and Fourier transform infrared spectroscopy (FTIR) in order to detect morphological, topographic and biochemical changes in the fungal cell wall. Cells treated with caspofungin were also analyzed for comparative purposes; (3) Results: Expressive morphological and topographic changes, such as increased roughness and shape modification, were observed in the cells after CAP exposure. The alterations detected were similar to those observed after the treatment with caspofungin. The main biochemical changes occurred in polysaccharides content, and an overall decrease in glucans and an increase in chitin synthesis were detected; (4) Conclusions: Helium-CAP caused morphological and topographic alterations in C. albicans cells and affected the cell wall polysaccharide content.

Population Pharmacokinetics of Caspofungin and Dose Simulations in Heart Transplant Recipients.

The effect of heart transplantation (HTx) on the pharmacokinetics (PK) of caspofungin is not well-characterized. The aim of this study was to investigate the population PK of caspofungin in HTx and non-HTx patients and to identify covariates that may affect the PK of caspofungin. Seven successive blood samples were collected before administration and at 1, 2, 6, 10, 16, and 24 h after the administration of caspofungin for at least 3 days. This study recruited 27 HTx recipients and 31 non-HTx patients with 414 plasma concentrations in total. A nonlinear mixed-effects model was used to describe the population PK of caspofungin. The PK of caspofungin was best described by a two-compartment model. The clearance (CL) and volume of the central compartment (Vc) of caspofungin were 0.385 liter/h and 4.27 liters, respectively. The intercompartmental clearance (Q) and the volume of the peripheral compartment (Vp) were 2.85 liters/h and 6.01 liters, respectively. In the final model, we found that albumin (ALB) affected the CL of caspofungin with an adjustment factor of -1.01, and no other covariates were identified. In this study, HTx was not found to affect the PK of caspofungin. Based on the simulations, the dose of caspofungin should be proportionately increased in patients with decreased ALB levels.

Pharmacokinetics/Pharmacodynamics of Caspofungin in Plasma and Peritoneal Fluid of Liver Transplant Recipients.

The weaker diffusion of echinocandins in the peritoneal fluid (PF) could promote Candida-resistant isolates. The aim of this study was to analyze the pharmacokinetics (PK)/pharmacodynamics (PD) of caspofungin in plasma and PF samples from liver transplant recipients. Liver transplant patients received caspofungin as postoperative prophylaxis. Caspofungin concentrations were quantified in plasma and PF samples on days 1, 3, and 8. Data were analyzed using nonlinear mixed-effect modeling and Monte Carlo simulations. Area under the curve (AUC) values for plasma and PF were simulated under three dosing regimens. Probabilities of target attainment (PTAs) were calculated using area under the unbound plasma concentration-time curve from 0 to 24 h at steady state (fAUC0-24)/MIC ratios, with MICs ranging from 0.008 to 8 mg/L. All of the patients included were monitored weekly for Candida colonization and for Candida infections. Twenty patients were included. The median daily dose of caspofungin was 0.81 mg/kg. Plasma (n = 395) and PF (n = 50) concentrations at steady state were available. A two-compartment model with first-order absorption and elimination was described. Our two-compartment model with first-order absorption and elimination produced an effective PK/PD relationship in plasma, achieving a PTA of ≥90% with MICs ranging from 0.008 to 0.12 mg/L for Candida albicans and Candida glabrata. In PF, PTAs at D8 were optimal only for a MIC of 0.008 mg/L in patients weighing 60 kg under the three dosing regimens. Among the 16 patients colonized, all MIC values were below the maximal concentration (Cmax) in plasma but not in PF. PF concentrations of caspofungin were low. Simulations showed that the PTAs for Candida spp. in PF were not optimal, which might suggest a potential risk of resistance.

Aspergillus fumigatus FhdA Transcription Factor Is Important for Mitochondrial Activity and Codon Usage Regulation during the Caspofungin Paradoxical Effect.

Aspergillus fumigatus is the main etiological agent of aspergillosis. The antifungal drug caspofungin (CSP) can be used against A. fumigatus, and CSP tolerance is observed. We have previously shown that the transcription factor FhdA is important for mitochondrial activity. Here, we show that FhdA regulates genes transcribed by RNA polymerase II and III. FhdA influences the expression of tRNAs that are important for mitochondrial function upon CSP. Our results show a completely novel mechanism that is impacted by CSP.

Echinocandins Susceptibility Patterns of 2,787 Yeast Isolates: Importance of the Thresholds for the Detection of FKS Mutations.

Since echinocandins are recommended as first line therapy for invasive candidiasis, detection of resistance, mainly due to alteration in FKS protein, is of main interest. EUCAST AFST recommends testing both MIC of anidulafungin and micafungin, and breakpoints (BPs) have been proposed to detect echinocandin-resistant isolates. We analyzed MIC distribution for all three available echinocandins of 2,787 clinical yeast isolates corresponding to 5 common and 16 rare yeast species, using the standardized EUCAST method for anidulafungin and modified for caspofungin and micafungin (AM3-MIC). In our database, 64 isolates of common pathogenic species were resistant to anidulafungin, according to the EUCAST BP, and/or to caspofungin, using our previously published threshold (AM3-MIC ≥ 0.5 mg/L). Among these 64 isolates, 50 exhibited 21 different FKS mutations. We analyzed the capacity of caspofungin AM3-MIC and anidulafungin MIC determination in detecting isolates with FKS mutation. They were always identified using caspofungin AM3-MIC and the local threshold while some isolates were misclassified using anidulafungin MIC and EUCAST threshold. However, both methods misclassified four wild-type C. glabrata as resistant. Based on a large data set from a single center, the use of AM3-MIC testing for caspofungin looks promising in identifying non-wild-type C. albicans, C. tropicalis and P. kudiravzevii isolates, but additional multicenter comparison is mandatory to conclude on the possible superiority of AM3-MIC testing compared to the EUCAST method.

Pharmacodynamics of Moxifloxacin, Meropenem, Caspofungin, and Their Combinations against In Vitro Polymicrobial Interkingdom Biofilms.

Biofilms colonize medical devices and are often recalcitrant to antibiotics. Interkingdom biofilms, where at least a bacterium and a fungus are present, increase the likelihood of therapeutic failures. In this work, a three-species in vitro biofilm model including Staphylococcus aureus, Escherichia coli, and Candida albicans was used to study the activity of the antibiotics moxifloxacin and meropenem, the antifungal caspofungin, and combinations of them against interkingdom biofilms. The culturable cells and total biomass were evaluated to determine the pharmacodynamic parameters of the drug response for the incubation with the drugs alone. The synergic or antagonistic effects (increased/decreased effects) of the combination of drugs were analyzed with the highest-single-agent method. Biofilms were imaged in confocal microscopy after live/dead staining. The drugs had limited activity when used alone against single-, dual-, and three-species biofilms. When used in combination, additive effects against single- and dual-species biofilms and increased effects (synergy) against biomass of three-species biofilms were observed. In addition, the two antibiotics showed different patterns, moxifloxacin being more active when targeting S. aureus and meropenem when targeting E. coli. All these observations were confirmed by confocal microscopy images. Our findings highlight the interest in combining caspofungin with antibiotics against interkingdom biofilms.