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Frontiers in Cellular and Infection... 2023Opportunistic fungal infections by species arise among cancer patients due to the weakened immune system following extensive chemotherapy. Prophylaxis with antifungal...
OBJECTIVE
Opportunistic fungal infections by species arise among cancer patients due to the weakened immune system following extensive chemotherapy. Prophylaxis with antifungal agents have developed the resistance of spp. to antifungals. Accurate identification of yeasts and susceptibility patterns are main concerns that can directly effect on the treatment of patients.
METHODS
Over a period of three years, 325 cancer patients suspected to infections were included in the current investigation. The clinical isolates were molecularly identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). All strains, were examined for susceptibility to the amphotericin B, itraconazole, fluconazole, and anidulafungin according to the CLSI M27 document.
RESULTS
Seventy-four cancer patients had infections (22.7%). was the most common species (83.8%). Antifungal susceptibility results indicated that 100% of the isolates were sensitive to amphotericin B; however, 17.6%, 9.4%, and 5.4% of clinical isolates were resistant to anidulafungin, fluconazole, and itraconazole, respectively.
CONCLUSION
The findings of the present work shows a warning increase in resistance to echinocandins. Since all fluconazole resistance isolates were obtained from candidemia, we recommend amphotericin B as the first line therapy for this potentially fatal infection.
Topics: Humans; Antifungal Agents; Fluconazole; Amphotericin B; Itraconazole; Anidulafungin; Microbial Sensitivity Tests; Candidiasis; Candida; Candidemia; Neoplasms; Drug Resistance, Fungal
PubMed: 37249981
DOI: 10.3389/fcimb.2023.1152552 -
The Journal of Antimicrobial... Oct 2020We conducted a prospective study in ICU patients of two tertiary hospitals in order to determine basic pharmacokinetic (PK) parameters, associated variation and target...
BACKGROUND
We conducted a prospective study in ICU patients of two tertiary hospitals in order to determine basic pharmacokinetic (PK) parameters, associated variation and target attainment rates for anidulafungin, micafungin and caspofungin.
METHODS
Serum samples from patients treated for 7 days with the standard doses of anidulafungin (N = 13), micafungin (N = 14) or caspofungin (N = 7) were analysed by validated chromatographic methods. PK parameters determined with non-compartmental analysis were correlated with demographic, laboratory and disease severity characteristics. The percentages of patients attaining drug exposures described in the summary of product characteristics (SmPC) documents and preclinical PK/PD targets for stasis were estimated.
RESULTS
The median (range) AUC24 was 101.46 (54.95-274.15) mg·h/L for anidulafungin, 79.35 (28.00-149.30) mg·h/L for micafungin and 48.46 (19.44-103.69) mg·h/L for caspofungin. The interindividual variability of anidulafungin, micafungin and caspofungin AUC24 was 46%-58%, attributed mainly to variability in volume of distribution (V), clearance (CL) and in both V and CL, respectively. Significant correlations were found between anidulafungin AUC24 and BMI (rs = -0.670, P = 0.012) and liver enzymes (rs = 0.572-0.665, P = 0.013-0.041) and between caspofungin Cmin and transaminase levels (rs = -0.775 to -0.786, P = 0.036-0.041). Less than 50% of our patients attained the corresponding SmPC median AUC24s and none of the patients attained the PK/PD targets for Candida albicans and Candida parapsilosis.
CONCLUSIONS
Anidulafungin exposure in ICU patients was comparable with that reported in non-ICU patients and in healthy volunteers. Micafungin exposure was comparable to that of other patients but ∼30% lower than that in healthy volunteers, whereas caspofungin exposure was rather low (∼50% lower than in healthy volunteers). Larger interindividual variability (50%-60%) was recorded in ICU patients compared with other groups for all three echinocandins.
Topics: Anidulafungin; Antifungal Agents; Echinocandins; Humans; Intensive Care Units; Lipopeptides; Microbial Sensitivity Tests; Prospective Studies
PubMed: 32696036
DOI: 10.1093/jac/dkaa265 -
Mycopathologia Jun 2023Aspergillus species are important causes of invasive fungal disease, particularly among those with an impaired immune system. Increasing reports have revealed a rising...
BACKGROUND
Aspergillus species are important causes of invasive fungal disease, particularly among those with an impaired immune system. Increasing reports have revealed a rising incidence of antifungal drug resistance among Aspergillus spp., particularly among cryptic species. Understanding local antifungal susceptibility patterns is paramount to delivering optimal clinical care.
METHODS
Aspergillus spp. recovered from clinical specimens between 2000 and 2021 from Pathology Queensland were collected. Aspergillus spp. were identified routinely morphologically, and where there was ambiguity or a lack of sporulation, by sequencing of the internal transcribed spacer (ITS) region. All Aspergillus spp. that underwent antifungal susceptibility testing according to the CLSI M38-A3 method and were recorded and included in the study. Amphotericin B, voriconazole, posaconazole, isavuconazole, micafungin, caspofungin, and anidulafungin were tested. Pathology Queensland services all public healthcare facilities in Queensland, Australia.
RESULTS
236 Aspergillus spp. were identified from clinical specimens during the study period. The most frequent species identified were Aspergillus section Fumigati (n = 119), Aspergillus section Flavi (n = 35), Aspergillus terreus (n = 32) and Aspergillus niger (n = 29). Overall, MIC values for voriconazole, posaconazole, itraconazole, and isavuconazole were 0.25/1, 0.25/0.5, 0.25/0.5, and 0.5/2 mg/L respectively. Echinocandins demonstrated low MIC values overall with micafungin and anidulafungin both having an MIC of 0.015/0.03 mg/L. A total of 15 cryptic species were identified; high triazole MIC values were observed with a voriconazole MIC of 2/8 mg/L. From 2017 to 2021 we observed an increase in incidence of isolates with high voriconazole MIC values. There was no difference in voriconazole MIC values between Aspergillus spp. acquired in North Queensland when compared to Southeast Queensland, Australia.
CONCLUSION
Increasing reports of antifungal resistance among Aspergillus spp. is concerning and warrants further investigation both locally and worldwide. Active surveillance of both the emergence of different Aspergillus spp. and changes in antifungal susceptibility patterns over time is crucial to informing clinicians and treatment guidelines.
Topics: Humans; Antifungal Agents; Voriconazole; Anidulafungin; Micafungin; Queensland; Aspergillus; Mycoses; Microbial Sensitivity Tests; Drug Resistance, Fungal
PubMed: 37067664
DOI: 10.1007/s11046-023-00713-5 -
Journal of Fungi (Basel, Switzerland) Sep 2020Animal model systems are a critical component of the process of discovery and development of new antifungal agents for treatment and prevention of invasive... (Review)
Review
Animal model systems are a critical component of the process of discovery and development of new antifungal agents for treatment and prevention of invasive aspergillosis. The persistently neutropenic rabbit model of invasive pulmonary aspergillosis (IPA) has been a highly predictive system in identifying new antifungal agents for treatment and prevention of this frequently lethal infection. Since its initial development, the persistently neutropenic rabbit model of IPA has established a strong preclinical foundation for dosages, drug disposition, pharmacokinetics, safety, tolerability, and efficacy for deoxycholate amphotericin B, liposomal amphotericin B, amphotericin B lipid complex, amphotericin B colloidal dispersion, caspofungin, micafungin, anidulafungin, voriconazole, posaconazole, isavuconazole, and ibrexafungerp in treatment of patients with invasive aspergillosis. The findings of combination therapy with a mould-active triazole and an echinocandin in this rabbit model also predicted the outcome of the clinical trial for voriconazole plus anidulafungin for treatment of IPA. The plasma pharmacokinetic parameters and tissue disposition for most antifungal agents approximate those of humans in persistently neutropenic rabbits. Safety, particularly nephrotoxicity, has also been highly predictive in the rabbit model, as exemplified by the differential glomerular filtration rates observed in animals treated with deoxycholate amphotericin B, liposomal amphotericin B, amphotericin B lipid complex, and amphotericin B colloidal dispersion. A panel of validated outcome variables measures therapeutic outcome in the rabbit model: residual fungal burden, markers of organism-mediated pulmonary injury (lung weights and infarct scores), survival, and serum biomarkers. In selected antifungal studies, thoracic computerized tomography (CT) is also used with diagnostic imaging algorithms to measure therapeutic response of pulmonary infiltrates, which exhibit characteristic radiographic patterns, including nodules and halo signs. Further strengthening the predictive properties of the model, therapeutic response to successfully developed antifungal agents for treatment of IPA has been demonstrated over the past two decades by biomarkers of serum galactomannan and (1→3)-β-D-glucan with patterns of resolution, that closely mirror those documented responses in patients with IPA. The decision to move from laboratory to clinical trials should be predicated upon a portfolio of complementary and mutually validating preclinical laboratory animal models studies. Other model systems, including those in mice, rats, and guinea pigs, are also valuable tools in developing clinical protocols. Meticulous preclinical investigation of a candidate antifungal compound in a robust series of complementary laboratory animal models will optimize study design, de-risk clinical trials, and ensure tangible benefit to our most vulnerable immunocompromised patients with invasive aspergillosis.
PubMed: 33007839
DOI: 10.3390/jof6040198 -
British Journal of Clinical Pharmacology Mar 2021The population pharmacokinetics (PK) of anidulafungin in critically ill patients hospitalized in intensive care units (ICUs) was explored with the intention of...
AIMS
The population pharmacokinetics (PK) of anidulafungin in critically ill patients hospitalized in intensive care units (ICUs) was explored with the intention of evaluating and optimizing dosing regimens.
METHODS
A PK study was conducted in a cohort of 13 patients treated with anidulafungin using intensive sampling during multiple periods per patient and the high-performance liquid chromatography method for drug quantification. A population PK model was developed to describe the concentration-time course of anidulafungin and the inter-individual (IIV) and interoccasion variability (IOV) of the PK parameters. Model-based PK simulations have been performed to estimate the probability of target attainment (PTA), given the pharmacokinetic/pharmacodynamic target of free 24-hour area under the free drug concentration-time curve over minimum inhibitory concentration for several dosing regimens.
RESULTS
A two-compartment PK model, with first-order elimination, best described the data with population clearance (CL) and central/peripheral volume of distribution (V1/V2) of 0.778 L/h and 10.2/21.1 L, respectively, and a mean ± s.d. AUC of 119.97 ± 46.23 mg·h/L. Pronounced IIV and IOV variability was found for CL (38% and 31%) and V1 (47% and 30%), respectively. Sequential Organ Failure Assessment (SOFA) and Body Mass Index (BMI) were found to be covariates on CL and V1, respectively. Low PTA values were calculated for borderline Clinical & Laboratory Standards Institute (CLSI)-susceptible Candida strains.
CONCLUSIONS
Although anidulafungin exposure was found comparable to that in healthy volunteers, elevated interindividual and significant interoccasion variability was found in critically ill ICU patients, which resulted in reduced PTA values in these patients.
Topics: Anidulafungin; Anti-Bacterial Agents; Cohort Studies; Critical Illness; Humans; Intensive Care Units; Microbial Sensitivity Tests
PubMed: 32633039
DOI: 10.1111/bcp.14457 -
Rapid automated antifungal susceptibility testing system for yeasts based on growth characteristics.Frontiers in Cellular and Infection... 2023Fungal pathogens are a major threat to public health, as they are becoming increasingly common and resistant to treatment, with only four classes of antifungal medicines...
Fungal pathogens are a major threat to public health, as they are becoming increasingly common and resistant to treatment, with only four classes of antifungal medicines currently available and few candidates in the clinical development pipeline. Most fungal pathogens lack rapid and sensitive diagnostic techniques, and those that exist are not widely available or affordable. In this study, we introduce a novel automated antifungal susceptibility testing system, Droplet 48, which detects the fluorescence of microdilution wells in real time and fits growth characteristics using fluorescence intensity over time. We concluded that all reportable ranges of Droplet 48 were appropriate for clinical fungal isolates in China. Reproducibility within ±2 two-fold dilutions was 100%. Considering the Sensititre YeastOne Colorimetric Broth method as a comparator method, eight antifungal agents (fluconazole, itraconazole, voriconazole, caspofungin, micafungin, anidulafungin, amphotericin B, and 5-flucytosine) showed an essential agreement of >90%, except for posaconazole (86.62%). Category agreement of four antifungal agents (fluconazole, caspofungin, micafungin, and anidulafungin) was >90%, except for voriconazole (87.93% agreement). Two isolates and anidulafungin showed a major discrepancy (MD) (2.60%), and no other MD or very MD agents were found. Therefore, Droplet 48 can be considered as an optional method that is more automated and can obtain results and interpretations faster than previous methods. However, the optimization of the detection performance of posaconazole and voriconazole and promotion of Droplet 48 in clinical microbiology laboratories still require further research involving more clinical isolates in the future.
Topics: Antifungal Agents; Caspofungin; Micafungin; Anidulafungin; Voriconazole; Fluconazole; Reproducibility of Results; Candida; Microbial Sensitivity Tests; Yeasts
PubMed: 37201120
DOI: 10.3389/fcimb.2023.1153544 -
Journal de Mycologie Medicale Dec 2021The present study was conducted to determine the candidate genes involved in caspofungin (CAS) resistance in clinical isolates of Aspergillus flavus (A. flavus).
INTRODUCTION AND AIMS
The present study was conducted to determine the candidate genes involved in caspofungin (CAS) resistance in clinical isolates of Aspergillus flavus (A. flavus).
MATERIALS AND METHODS
The antifungal susceptibility assay of the CAS was performed on 14 clinical isolates of A. flavus using the CLSI-M-38-A2 broth micro-dilution protocol. Since CAS had various potencies, the minimum effective concentration (MEC) of anidulafungin (AND) was also evaluated in the present study. The FKS1 gene sequencing was conducted to assess whether mutations occurred in the whole FKS1 gene as well as hot spot regions of the FKS1 gene of the two resistant isolates. A complementary DNA-amplified fragment length polymorphism (CDNA-AFLP) method was performed to investigate differential gene expression between the two resistant and two sensitive clinical isolates in the presence of CAS. Furthermore, quantitative real-time PCR (QRT-PCR) was utilized to determine the relative expression levels of the identified genes.
RESULTS
No mutations were observed in the whole FKS1 gene hot spot regions of the FKS1 genes in the resistant isolates. A subset of two genes with known biological functions and four genes with unknown biological functions were identified in the CAS-resistant isolates using the CDNA-AFLP. The QRT-PCR revealed the down-regulation of the P-type ATPase and ubiquinone biosynthesis methyltransferase COQ5 in the CAS-resistant isolates, compared to the susceptible isolates.
CONCLUSION
The findings showed that P-type ATPase and ubiquinone biosynthesis methyltransferase COQ5 might be involved in the CAS-resistance A. flavus clinical isolates. Moreover, a subset of genes was differentially expressed to enhance fungi survival in CAS exposure. Further studies are recommended to highlight the gene overexpression and knock-out experiments in A. flavus or surrogate organisms to confirm that these mentioned genes confer the CAS resistant A. flavus.
Topics: Amplified Fragment Length Polymorphism Analysis; Antifungal Agents; Aspergillus flavus; Caspofungin; Echinocandins; Microbial Sensitivity Tests
PubMed: 34293598
DOI: 10.1016/j.mycmed.2021.101166 -
Infection and Drug Resistance 2022spp. infection in immunocompromised patients results in increasing morbidity and mortality. This study investigated clinical and microbiological characteristics of...
BACKGROUND
spp. infection in immunocompromised patients results in increasing morbidity and mortality. This study investigated clinical and microbiological characteristics of aspergillosis in a Chinese tertiary teaching hospital.
METHODS
A total of 114 patients with aspergillosis were included over a 5-year period at Ruijin Hospital. In sum, 114 strains were isolated and identified at species level using matrix-assisted laser desorption ionization time-of-flight mass spectrometry, confirmed by ITS gene region and β-tubulin () gene sequencing. Sensititre YeastOne was used in vitro to test susceptibility to antifungal drugs: amphotericin B, itraconazole, voriconazole, posaconazole, isavuconazole, micafungin, anidulafungin, and caspofungin.
RESULTS
The median age of the patients was 61 (19) years, men accounted for 53.5% (n=61) of the sample, about 64% were immunocompromised, and 36% had underlying diseases. Pulmonary diseases accounted for 27.2%. isolates were mainly isolated from sputum (n=42, 36.8%). Antifungal therapy was administered to 106 (93.0%) patients and voriconazole (n=76, 66.7%) was the most frequently used as empirical therapy. (n=69, 60.5%) was the most common species. There was a 73.7% concordance between MALDI-TOF MS and molecular identification. All isolates showed good susceptibility to anidulafungin and caspofungin.
CONCLUSION
Immunocompromised patients are an at-risk population for aspergillosis, and voriconazole was used as empirical therapy in Ruijin Hospital, China. was the predominant species causing aspergillosis, and - as non species are increasing - the second-leading cause of aspergillosis. Anidulafungin and caspofungin were the most active in vitro against the isolates tested. The MALDI-TOF MS method showed good accuracy for identification of common spp. In vitro antifungal-susceptibility testing is crucially important for decisions on effective therapy with aspergillosis.
PubMed: 36533254
DOI: 10.2147/IDR.S391069 -
The Journal of Antimicrobial... Aug 2019Candida auris is an emerging MDR pathogen. It shows reduced susceptibility to azole drugs and, in some strains, high amphotericin B MICs have been described. For these...
BACKGROUND
Candida auris is an emerging MDR pathogen. It shows reduced susceptibility to azole drugs and, in some strains, high amphotericin B MICs have been described. For these reasons, echinocandins were proposed as first-line treatment for C. auris infections. However, information on how echinocandins and amphotericin B act against this species is lacking.
OBJECTIVES
Our aim was to establish the killing kinetics of anidulafungin, caspofungin and amphotericin B against C. auris by time-kill methodology and to determine if these antifungals behave as fungicidal or fungistatic agents against this species.
METHODS
The susceptibility of 50 C. auris strains was studied. Nine strains were selected (based on echinocandin MICs) to be further studied. Minimal fungicidal concentrations, in vitro dose-response and time-kill patterns were determined.
RESULTS
Echinocandins showed lower MIC values than amphotericin B (geometric mean of 0.12 and 0.94 mg/L, respectively). Anidulafungin and caspofungin showed no fungicidal activity at any concentration (maximum log decreases in cfu/mL between 1.34 and 2.22). On the other hand, amphotericin B showed fungicidal activity, but at high concentrations (≥2.00 mg/L). In addition, the tested polyene was faster than echinocandins at killing 50% of the initial inoculum (0.92 versus >8.00 h, respectively).
CONCLUSIONS
Amphotericin B was the only agent regarded as fungicidal against C. auris. Moreover, C. auris should be considered tolerant to caspofungin and anidulafungin considering that their MFC:MIC ratios were mostly ≥32 and that after 6 h of incubation the starting inoculum was not reduced in >90%.
Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Candida; Caspofungin; Microbial Sensitivity Tests; Microbial Viability; Time Factors
PubMed: 31081031
DOI: 10.1093/jac/dkz178 -
Antimicrobial Agents and Chemotherapy Jun 2023We determined the echinocandin susceptibility and genotypes of 13 clinical isolates of Candida auris that were recovered from 4 patients at a tertiary care center in...
We determined the echinocandin susceptibility and 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 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×).
Topics: Humans; Antifungal Agents; Candida auris; Fungal Proteins; Echinocandins; Caspofungin; Microbial Sensitivity Tests; Drug Resistance, Fungal
PubMed: 37222585
DOI: 10.1128/aac.00423-23