micafungin and Candidemia

Invasive candidiasis is the most common fungal infection in patients attending health services and is associated with high mortality rates and prolonged hospital stay. The aim of this review was to evaluate and compare efficacy and safety of antifungal agents for the treatment of candidemia.. A systematic review with network meta-analysis (NMA), surface under the cumulative ranking analysis (SUCRA) and stochastic multicriteria acceptability analyses (SMAA) was performed (PROSPERO-CRD42020149264). Searches were conducted in PubMed and Scopus (Nov-2021). Randomised controlled trials evaluating the effect of oral antifungals (any dose or regimen) on mycological cure, discontinuation rates and adverse events were included.. Overall, 13 trials (n=3632) were analysed. There were no significant differences between therapies for the efficacy outcomes; however, caspofungin (50-150 mg), rezafungin (200-400 mg) and micafungin (100-150 mg) had higher rates of clinical and mycological responses (SUCRA overall response >60%) and were considered the most promising therapies. Fluconazole (400 mg) rated worst for overall response (17%). Rezafungin (200-400 mg) and micafungin (100 mg) were associated with lower discontinuation rates (<40%). Conventional amphotericin B (0.6-0.7 mg/kg) was more likely to be discontinued (odds ratio [OR] 0.08; 95% credibility interval [CrI] 0.00-0.95 vs. caspofungin 150 mg) and may impair liver function (87%).. Echinocandins are recommended as first-line treatments for invasive candidiasis following a priority order of caspofungin then micafungin. Rezafungin, an echinocandin under development, represents a potential option that should be further investigated. Azoles and liposomal amphotericin B can be used as second-line treatments in cases of fungal resistance or hypersensitivity.

Topics: Antifungal Agents; Candidemia; Candidiasis, Invasive; Caspofungin; Echinocandins; Humans; Lipopeptides; Micafungin; Network Meta-Analysis

Infection due to species other than Candida albicans is increasing among solid organ transplant recipients. Candida utilis, commonly used in the food industry, is considered as a low-virulence yeast. We report the first case of C. utilis fungaemia involving a solid organ transplant recipient. The infection was triggered by the withdrawal of a ureteral stent and was successfully treated with intravenous micafungin. We also propose a review of all reported cases of infection caused by C. utilis.

Topics: Administration, Intravenous; Antifungal Agents; Candida; Candidemia; Echinocandins; Female; Humans; Kidney Transplantation; Lipopeptides; Micafungin; Middle Aged; Stents; Transplant Recipients; Treatment Outcome; Ureter

The infection rate of arteriovenous (AV) grafts is high, but fungal etiology is rare. Only five cases of graft infection due to Candida albicans (C. albicans) or C. tropicalis have been described in the literature. Herein, we report the first case of AV graft infection caused by C. glabrata. A 60-year-old woman on maintenance hemodialysis for end-stage renal disease was admitted because of intermittent fever, for 10 days. Upon physical examination, tenderness over the AV graft site was noticed. Blood culture yielded C. glabrata and her clinical symptoms improved after she was treated with micafungin for 1 month. However, C. glabrata candidemia reoccurred 5 weeks later. Cure was achieved after removal of the AV graft and anidulafungin treatment. Pus was observed in the removed graft, from which C. glabrata was isolated. The outcome of our case and patients from the literature review suggest that removal of the infected graft is important for treatment success of AV graft Candida infection.

Topics: Antifungal Agents; Blood; Candida glabrata; Candidemia; Debridement; Echinocandins; Female; Humans; Lipopeptides; Micafungin; Middle Aged; Organ Transplantation; Transplants; Treatment Outcome

In the Asia-Pacific region, Candida albicans is the predominant Candida species causing invasive candidiasis/candidemia in Australia, Japan, Korea, Hong Kong, Malaysia, Singapore and Thailand whereas C. tropicalis is the most frequently encountered Candida species in Pakistan and India. Invasive isolates of C. albicans, C. parapsilosis complex and C. tropicalis remain highly susceptible to fluconazole (>90% susceptible). Fluconazole resistance (6.8-15%), isolates with the non-wild-type phenotype for itraconazole susceptibility (3.9-10%) and voriconazole (5-17.8%), and echinocandin resistance (2.1-2.2% in anidulafungin and 2.2% in micafungin) among invasive C. glabrata complex isolates are increasing in prevalence. Moreover, not all isolates of C. tropicalis have been shown to be susceptible to fluconazole (nonsusceptible rate, 5.7-11.6% in China) or voriconazole (nonsusceptible rate, 5.7-9.6% in China).

Topics: Anidulafungin; Antifungal Agents; Asia; Azoles; Candida; Candida albicans; Candida glabrata; Candida tropicalis; Candidemia; Candidiasis; Candidiasis, Invasive; Drug Resistance, Fungal; Echinocandins; Fluconazole; Humans; Incidence; Itraconazole; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Phenotype; Prevalence; Voriconazole

Neutropenia is linked to the development of invasive candidiasis/candidaemia, for which micafungin has demonstrated efficacy, but evidence in patients with neutropenia is limited. The aim of this study was to evaluate the efficacy of micafungin for the treatment of invasive candidiasis/candidaemia in patients with neutropenia (<500 neutrophils/μL) and without neutropenia. This pooled, post hoc analysis of 2 Phase 3 trials compared micafungin 100 mg/d (adults) and 2 mg/kg/d (paediatrics) with L-AmB 3 mg/kg/d (NCT00106288) and micafungin 100 mg/d and 150 mg/d with caspofungin 70 mg/d followed by 50 mg/d (adults) (NCT00105144); treatment duration 2-4 weeks (≤8 weeks for chronic disseminated candidiasis). Effects of neutropenia duration and Candida spp. on efficacy outcomes (treatment success, clinical and mycological response) were examined. Of 685 patients, 77 had neutropenia. The most common infection in patients with/without neutropenia was due to C. tropicalis (31/77) and C. albicans (295/608) respectively. Overall success was numerically lower in patients with vs without neutropenia (63.6% vs 72.9%). Clinical and mycological response was similar between groups. Neutropenia duration or Candida spp. did not impact micafungin's overall success rate. This analysis supports evidence that micafungin is effective against invasive candidiasis/candidaemia in patients with neutropenia, irrespective of neutropenia duration or Candida spp., although overall success may be lower than in patients without neutropenia.

Topics: Adolescent; Adult; Antifungal Agents; Candida; Candida albicans; Candida tropicalis; Candidemia; Candidiasis; Candidiasis, Invasive; Caspofungin; Echinocandins; Female; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Neutropenia; Treatment Outcome; Young Adult

To identify the factors associated with the interindividual pharmacokinetic (PK) variability of micafungin and to evaluate the probability of reaching the previously determined PK/pharmacodynamic efficacy thresholds (AUC/MIC >5000 for non-parapsilosis Candida sp. and ≥285 for Candida parapsilosis) with the recommended 100 mg daily dose in ICU patients with sepsis and mechanical ventilation.. One hundred patients were included and 436 concentrations were available for PK analysis performed with NONMEM software. PTA was determined by Monte Carlo simulations.. Micafungin obeyed a two-compartment model with first-order elimination from the central compartment. Mean parameter estimates (percentage interindividual variability) were 1.34 L/h (34%) for clearance (CL), 11.80 L (38%) and 7.68 L (39%) for central (Vc) and peripheral (Vp) distribution volumes, respectively, and 4.67 L/h (37%) for distribution clearance. CL, Vc and Vp increased by 14% when the albumin level was ≤25 g/L and CL decreased by 25% when SOFA score was ≥10. Body weight was related to CL, Vc and Vp by allometric models. PTA was ≥90% in Candida albicans and Candida glabrata infections, except when the MIC was ≥0.015 mg/L, and ranged between 0% and 40% for C. parapsilosis infections with MIC ≥0.5 mg/L.. A possible increase in the dose should be evaluated for infections due to C. parapsilosis and for infections due to C. albicans and C. glabrata with MICs ≥0.015 mg/L.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Candida; Candidemia; Echinocandins; Female; Humans; Intensive Care Units; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Monte Carlo Method; Respiration, Artificial

Micafungin demonstrated non-inferiority to caspofungin as definitive therapy for candidaemia and invasive candidiasis (IC) in a major randomised clinical trial.. The aim of this study was to investigate if micafungin is a cost-saving option compared with caspofungin for treating candidaemia and IC.. A decision analytical model was constructed to capture downstream consequences of using either agent as initial therapy for candidaemia and IC. The main outcomes were treatment success and treatment failure (i.e. death, mycological persistence, emergent infection, clinical failure but microbiological success). Outcome probabilities and treatment pathways were derived from the literature. Cost inputs were from the latest Australian resources, and resource use was estimated by expert panel. The analysis was from the Australian hospital perspective. Sensitivity analyses using Monte Carlo simulation were conducted.. Micafungin (AU$52 816) was associated with a lower total cost than caspofungin (AU$52 976), with a net cost-saving of $160 per patient. This was primarily due to the lower cost associated with alternative antifungal treatment in the micafungin arm. Hospitalisation was the main cost-driver for both arms. The model outcome was most sensitive to the proportion of treatment success in the micafungin arm. Uncertainty analysis demonstrated that micafungin had a 58% chance of being cost-saving compared with caspofungin.. Micafungin was cost-equivalent to caspofungin in treating candidaemia and IC, with variation in drug acquisition cost the critical factor.

Topics: Antifungal Agents; Candidemia; Candidiasis, Invasive; Caspofungin; Cost-Benefit Analysis; Echinocandins; Humans; Lipopeptides; Micafungin; Models, Economic; Treatment Outcome

The potential interest of antifungal treatment of non-immunocompromized patients with sepsis, extra-digestive Candida colonization and multiple organ failure is unknown. It represents three-quarters of antifungals prescribed in Intensive Care Units. It may allow early treatment of invasive fungal infection in the incubation phase but expose patients to unnecessary antifungal treatments with subsequent cost and fungal selection pressure. As early diagnostic tests for invasive candidiasis are still considered to be insufficient, the potential interest in this strategy needs to be demonstrated.. This prospective multicenter, double blind, randomized-controlled trial is conducted in 23 French Intensive Care Units. All adult patients, mechanically ventilated for more than four days with sepsis of unknown origin and with at least one extradigestive fungal colonization site and multiple organ failure are eligible for randomization. Patients with proven invasive candidiasis are not included. After a complete mycological screening, patients are allocated to receive micafungin 100 mg intravenously once a day or placebo for 14 days. We plan to enroll 260 patients. The main objective is to demonstrate that micafungin increases survival of patients without invasive candidiasis at day 28 as compared to placebo. Other outcomes include day 28 and 90 survival and organ failure evolution. Additionally, pharmacokinetics of micafungin in enrolled patients will be measured and evolution of fungal biomarkers and susceptibility profiles of infecting fungi will also be followed.. This study will help to provide guidelines for treating non-immunocompromized patients with fungal colonization multiple organ failure and sepsis of unknown origin.. Clinicaltrials.gov number NCT01773876.

Topics: Antifungal Agents; Candidemia; Clinical Protocols; Cross Infection; Double-Blind Method; Echinocandins; Humans; Intensive Care Units; Lipopeptides; Micafungin; Multiple Organ Failure; Prospective Studies

Echinocandins are guideline-preferred therapies for invasive candidiasis (IC). Fixed dosing of echinocandins is commonly used despite variations in body mass index and echinocandin susceptibility. The purpose of this study was to evaluate clinical outcomes of micafungin based on population-predicted pharmacokinetic/pharmacodynamic (PK/PD) factors and susceptibility.. Candida isolate results were screened from bloodstream or intraabdominal cultures of hospitalized patients admitted to a quaternary-care teaching hospital. Patients with a first episode of IC who received micafungin for at least 48 h were included. Patients with mixed cultures or Candida species with no minimum inhibitory concentration (MIC) differences were excluded. Breakpoints for micafungin MIC and area under the curve (AUC)/MIC ratio were calculated using classification and regression tree (CART) analysis and related to clinical outcomes. Primary efficacy outcome was candida-contributable mortality, defined as mortality within 28 days of positive culture with concomitant micafungin treatment failure; secondary outcome was micafungin treatment failure within 28 days, MAIN RESULTS: Seventy-two patients were included of whom 15 (21%) had Candida-contributable mortality and 34 (47%) experienced micafungin treatment failure. C. albicans and C. tropicalis did not have differing MICs and these patients were excluded from the study. Mortality using a CART-derived MIC breakpoint of ≥1.0 mg/L was 38% compared to 9% in patients infected with lower MIC strains (p = 0.003). Patients with a CART-derived AUC/MIC value >138.5 had a mortality rate of 9% compared to 41% for patients with AUC/MIC values below the breakpoint (p = 0.0013). Results were similar for treatment failure rates, and both were confirmed using multivariable models.. CART-derived micafungin MIC and AUC/MIC breakpoints predicted patient mortality and treatment failure for certain Candida species. These results support the need for further PK/PD studies to optimize echinocandin dosing and improve patient outcomes.

Topics: Antifungal Agents; Candida; Candidemia; Echinocandins; Humans; Lipopeptides; Micafungin

We investigated the neutralization performance of various automated blood culture systems for antifungal agents with regard to the most commonly isolated Candida species.. In this study, we evaluated the time to detection (TTD) of simulated candidemia for 6 Candida spp. (C. albicans, C. auris, C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis) in 3 automated blood culture systems (BACTEC™ FX, BACT/ALERT® 3D, and BACT/ALERT® VIRTUO®), with or without trough and peak levels of eight antifungal agents (amphotericin B, anidulafungin, caspofungin, fluconazole, itraconazole, micafungin, posaconazole, and voriconazole).. Caspofungin and micafungin significantly prolonged the TTDs for most of the tested strains in the 3 blood culture instruments, especially at peak concentrations.. Peak concentrations of caspofungin and micafungin influence the performance of blood culture detection systems. Therefore, one should be careful about the possibility of prolonged TTDs for candidemia when using the abovementioned antifungal agents.

Topics: Antifungal Agents; Candida; Candida albicans; Candida glabrata; Candida parapsilosis; Candida tropicalis; Candidemia; Caspofungin; Fluconazole; Humans; Micafungin; Microbial Sensitivity Tests

The increasing incidence of candidemia and the emergence of drug-resistant Candida species are major concerns worldwide. Therefore, long-term surveillance studies are required. Here, we provide one of the largest longitudinal overviews of the trends in the prevalence of Candida species using national data of 57 001 candidemia isolates obtained from > 2000 hospitals for the 2010-2019 period in the Japan Nosocomial Infections Surveillance database. The proportion of Candida species, except Candida krusei and Candida guilliermondii, was almost the same during the study period. The proportion of C. guilliermondii surpassed that of C. krusei in 2014. The incidence of candidemia due to C. albicans (P < 0.0001), C. parapsilosis (P = 0.0002), and C. tropicalis (P < 0.0001) have decreased significantly over this period. Azole susceptibility of C. tropicalis was low, with 17.8% of isolates resistant to fluconazole and 13.5% resistant to voriconazole. The micafungin susceptibility of C. glabrata was low, with 8.0% of isolates showing resistance. The resistance rate of C. krusei toward amphotericin B fluctuated considerably (between 3.2% and 35.7%) over this period. The incidence rate of candidemia caused by C. parapsilosis and C. guilliermondii in hospitals responsible for bone marrow transplantation was significantly higher than that in other hospitals. Overall, our study suggests that in Japan, the species distribution of Candida was almost the same in this period and similar to that reported in North America and Europe. A relatively high resistance to azoles and micafungin was observed in C. glabrata, C. tropicalis, and C. krusei isolates, which require continued surveillance.. This study verifies that the proportion of Candida species in Japan was almost the same from 2010–2019. A relatively higher resistance to azoles and micafungin was observed for C. glabrata, C. tropicalis, and C. krusei isolates.

Topics: Amphotericin B; Antifungal Agents; Azoles; Candida; Candida albicans; Candida glabrata; Candida parapsilosis; Candida tropicalis; Candidemia; Drug Resistance, Fungal; Fluconazole; Humans; Japan; Micafungin; Microbial Sensitivity Tests; Voriconazole

We aimed to detect possible changes in Candida species distribution over time and to know the antifungal susceptibility profile of isolates obtained from patients with bloodstream infection (BSI) due to this pathogen. Risk factors associated with 30-day mortality were also assessed. We conducted a retrospective cohort study of patients diagnosed with Candida BSI at a Japanese university hospital from 2013 to 2021. The change in the distribution pattern of the Candida spp. isolated was examined by considering three successive sub-periods of 3 years each. Risk factors for 30-day mortality were determined using Cox regression analysis. In the entire study period, Candida albicans was the most frequent species (46.7%), followed by Candida glabrata (21.5%) and Candida parapsilosis (18.7%). There was no change in Candida species distribution comparing the three sub-periods analyzed. All isolates were susceptible to micafungin, and most were susceptible to fluconazole, except for C. glabrata. No isolates were resistant to amphotericin B or voriconazole. The overall 30-day mortality was 40.2%. Univariate analysis revealed an association between 30-day mortality and central venous catheter (CVC) removal at any time, high Pitt bacteremia score (PBS), and high Charlson comorbidity index (CCI). Multivariate Cox analysis found that high PBS was the only independent predictor of 30-day mortality; subsequent multivariate Cox regression demonstrated that early CVC removal significantly reduced 30-day mortality. Candida species distribution and antifungal susceptibility profile in our hospital remained similar from 2013 to 2021. Early CVC removal may improve candidemia outcomes.

Topics: Amphotericin B; Antifungal Agents; Candida; Candida glabrata; Candidemia; Candidiasis; Drug Resistance, Fungal; Fluconazole; Hospitals, University; Humans; Japan; Longitudinal Studies; Micafungin; Microbial Sensitivity Tests; Retrospective Studies; Voriconazole

Studies have demonstrated that ECMO leads to pharmacokinetic changes, with alterations in volume of distribution, clearance and drug sequestration by the circuit. We describe a successful dosing approach for daptomycin and micafungin for the treatment of VRE faecium bacteremia and C. glabrata fungemia in a patient receiving veno-venous ECMO and CRRT.. We report a case of a patient with ARDS on veno-venous ECMO complicated by VRE faecium bacteremia and C. glabrata fungemia. The patient was treated with daptomycin 10 mg/kg every 24 h and micafungin 150 mg every 24 h for 14 days. Key observations included the documented bacteremia and fungemia clearance without the need for ECMO circuit exchange.. This case report demonstrates successful bacteremia and fungemia clearance in an adult without the need for ECMO circuit exchange. It also highlights the need for more research to identify optimal antimicrobial dosing strategies in similar scenarios.

Topics: Aged; Anti-Infective Agents; Bacteremia; Candida glabrata; Candidemia; Continuous Renal Replacement Therapy; Daptomycin; Dose-Response Relationship, Drug; Enterococcus faecium; Extracorporeal Membrane Oxygenation; Humans; Male; Micafungin; Vancomycin-Resistant Enterococci

Topics: Adolescent; Antifungal Agents; Candidemia; Child; Echinocandins; Female; Humans; Micafungin; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Candida glabrata; Candidemia; Caspofungin; Cross-Sectional Studies; Drug Resistance, Fungal; Fluconazole; Humans; Micafungin; Pakistan; Retrospective Studies; Tertiary Care Centers

Bacterial and fungal infections in Coronavirus Disease-19 (COVID-19) patients have been inadequately investigated and reported thus far. The safety profile of tocilizumab (TCZ) administration in candidemia patient still debatable.. A 54 year-old woman presenting with weakness on the left side of her body was diagnosed with COVID-19. After 7 days of admission, her condition worsened and developed respiratory distress and was having respiratory distress despite standard treatment.. Acute respiratory distress syndrome (ARDS) in COVID 19 was diagnoses based on real time-PCR swab, deterioration of PaO2/FiO2 and increased of acute phase reactants.. Anti Interleukin-6 (IL-6) was considered to tackle her inflammatory condition. Prior to TCZ administration, blood culture was performed and the result came with Candida tropicalis in the absence of bacterial growth.. No major complications associated with intravenous antifungal or TCZ occurred. After 40 days of hospitalization, the patient's clinical condition improved and was finally discharged.. This case underscores the safety profile of giving TCZ in candidemia as a secondary infection in severe COVID-19 patient.

Topics: Antibodies, Monoclonal, Humanized; Antifungal Agents; Candida tropicalis; Candidemia; Coinfection; COVID-19; COVID-19 Drug Treatment; Female; Humans; Interleukin-6; Micafungin; Middle Aged; SARS-CoV-2

Candida auris, a multidrug-resistant species, has the propensity of nosocomial transmission despite normal decontamination procedures. Here, we describe the isolation of C auris from patients in various hospitals in Kuwait during 2014-2018. Susceptibility to antifungal drugs and molecular basis of resistance to fluconazole, voriconazole and micafungin were also studied.. Candida auris (n = 314) obtained from 126 patients in eight hospitals were studied. All isolates were identified by PCR amplification and/or PCR-sequencing of ribosomal DNA (rDNA). Antifungal susceptibility was determined by Etest. Molecular basis of resistance to fluconazole and micafungin was studied by PCR-sequencing of ERG11 and FKS1 genes, respectively.. Bloodstream (n = 58), urine (n = 124), respiratory (n = 98) and other (n = 34) specimens yielded 314 C auris isolates. The proportion of bloodstream C auris among all yeast isolates was higher (42 of 307, 13.7%) in 2018 as compared to 2014-2017 (16 of 964, 1.7%) (P = .001). More bloodstream isolates (42 of 139) were cultured in 2018 than during 2014-2017 (16 of 175) (P = .001). Resistance to amphotericin B, fluconazole, voriconazole and micafungin was detected in 27.1%, 100%, 41.1% and 1.7% isolates, respectively. Fluconazole-resistant isolates contained either Y132F or K143R mutation in ERG11. Isolates with K143R mutation were additionally resistant to voriconazole. Micafungin-resistant isolates contained S639F mutation in hot spot 1 of FKS1.. Our study highlights spreading of C auris in major hospitals across Kuwait and its increasing role as a bloodstream pathogen in 2018. Cross-resistance to voriconazole was also seen in isolates with K143R mutation in ERG11, while micafungin-resistant isolates harboured S639F mutation in hot spot 1 of FKS1.

Topics: Antifungal Agents; Candida; Candidemia; Candidiasis; Cross Infection; Drug Resistance, Fungal; Fluconazole; Genes, Fungal; Humans; Kuwait; Micafungin; Microbial Sensitivity Tests; Pathology, Molecular; Voriconazole

Topics: Academic Medical Centers; Candida; Candidemia; Humans; Micafungin; Retrospective Studies

Candida glabrata readily develops resistance to echinocandins. Identification, antifungal susceptibility testing (AST) and resistance mechanism to echinocandins among C. glabrata was determined in Kuwait. C. glabrata isolates (n = 75) were tested by Vitek2, multiplex PCR and/or PCR-sequencing of rDNA. AST to fluconazole, caspofungin, micafungin and amphotericin B was determined by Etest and to micafungin by broth microdilution (BMD). Mutations in hotspot-1/hotspot-2 of FKS1/FKS2 and ERG11 were detected by PCR-sequencing. All isolates were identified as C. glabrata sensu stricto. Seventy isolates were susceptible and five were resistant to micafungin by Etest and BMD (essential agreement, 93%; categorical agreement, 100%). Three micafungin-resistant isolates were resistant and two were susceptible dose-dependent to caspofungin. Four and one micafungin-resistant isolate contained S663P and ∆659 F mutation, respectively, in hotspot-1 of FKS2. Micafungin-resistant isolates were genotypically distinct strains. Only one of 36 fluconazole-resistant isolate contained nonsynonymous ERG11 mutations. Thirty-four of 36 fluconazole-resistant isolates were genotypically distinct strains. Our data show that micafungin susceptibility reliably identifies echinocandin-resistant isolates and may serve as a surrogate marker for predicting susceptibility/resistance of C. glabrata to caspofungin. All micafungin-resistant isolates also harbored a nonsynonymous/deletion mutation in hotspot-1 of FKS2. Fingerprinting data showed that echinocandin/fluconazole resistance development in C. glabrata is not clonal.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Candida glabrata; Candidemia; Drug Resistance, Fungal; Echinocandins; Female; Fluconazole; Fungal Proteins; Glucosyltransferases; Humans; Kuwait; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Molecular Epidemiology; Phylogeny; Sequence Deletion

Candida sp. osteoarticular infection is rare and most often due to hematogenous seeding during an episode of candidemia in immunocompromised patients. However, the diagnosis can be delayed in patients with subtle symptoms and signs of joint infection without a concurrent episode of candidemia.. A 75-year-old woman presented with a three-year history of pain and swelling of the left knee. Candida pelliculosa was detected from the intraoperative tissue when the patient had undergone left total knee arthroplasty 32 months ago, but no antifungal treatment was performed. One year after the total knee arthroplasty, C. pelliculosa was repeatedly isolated from the left knee synovial fluid and antifungal treatment comprising amphotericin B deoxycholate and fluconazole was administered. However, joint infection had extended to the adjacent bone and led to progressive joint destruction. The patient underwent surgery for prosthesis removal and received prolonged antifungal treatment with micafungin and fluconazole.. This case shows that C. pelliculosa, an extremely rare non-Candida albicans sp., can cause fungal arthritis and lead to irreversible joint destruction owing to delayed diagnosis and treatment.

Topics: Aged; Amphotericin B; Antifungal Agents; Arthritis, Infectious; Arthroplasty, Replacement, Knee; Candida; Candidemia; Candidiasis; Deoxycholic Acid; Device Removal; Drug Combinations; Female; Fluconazole; Humans; Intraoperative Care; Joint Prosthesis; Knee; Micafungin; Osteomyelitis

Echinocandins are recommended for the treatment of invasive candidiasis and candidemia. However, there are few studies comparing anidulafungin and micafungin in terms of efficacy and safety. The objective of this study was to evaluate the clinical efficacy and safety between anidulafungin and micafungin treatment for adult patients with candidemia.. This retrospective cohort study performed on adult candidemia patients diagnosed from January 2006 through December 2018 at a tertiary medical center. The study subjects included adult patients ≥ 19 years with candidemia who were only treated with anidulafungin or micafungin for ≥ 3 days. Clinical characteristics were collected and analyzed. Hepatotoxicity was assessed according to the Common Terminology Criteria for Adverse Events Version 5.0.. A total of 98 patients with candidemia were treated with anidulafungin (n = 52, 53.1%) or micafungin (n = 46, 46.9%). There were no significant differences in age, sex, source of candidemia, and comorbidities between the anidulafungin and micafungin groups. Although there were more patients with abnormal baseline liver function test (LFT) in the anidulafungin group, the rate of clinical response (51.9% vs. 46.7%), mycological response (76.9% vs. 67.4%), and mortality (30-day mortality 26.9% vs. 21.7% and 90-day mortality 78.8% vs. 73.9%) was similar between the anidulafungin and micafungin groups. Also, there was no significant difference in terms of hepatotoxicity, even among the patients with abnormal baseline LFT between the two groups.. Our results suggest that clinical efficacy and safety may be similar between anidulafungin and micafungin treatment for adult patients with candidemia.

Topics: Aged; Anidulafungin; Antifungal Agents; Candidemia; Echinocandins; Female; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Retrospective Studies

Invasive infections with Candida krusei are uncommon and rarely complicated by spondylitis. Previous described cases were solely treated with antimycotic therapy, despite guidelines recommending surgical interventions.. We describe a case of C. krusei spondylitis in a patient treated with chemotherapy for acute myeloid leukemia. After induction chemotherapy, the patient developed a candidemia, which was treated with micafungin. One month after the candidemia, the patient was admitted with severe lumbar pain. Spondylitis of the L4 and L5 vertebra was diagnosed on MR-imaging, with signs suggesting an atypical infection. The patient was treated with anidulafungin combined with voriconazole. Despite maximal conservative management symptoms gradually worsened eventually requiring surgical intervention.. In contrast to previous case reports, antimycotic treatment alone could be insufficient in treating C. krusei spondylitis.

Topics: Aged; Anidulafungin; Antifungal Agents; Candida; Candidemia; Candidiasis; Humans; Immunocompromised Host; Induction Chemotherapy; Male; Micafungin; Spondylitis; Treatment Outcome; Voriconazole

In cases where catheter-related candidemia (CRC) must be managed without catheter withdrawal, antifungal lock therapy using highly active anti-biofilm (HAAB) agents is combined with systemic treatment. However, the activity of HAAB agents has never been studied in in vivo models using bioluminescence. We assessed the efficacy of micafungin using a bioluminescent Candida albicans SKCA23-ACTgLuc strain in an animal model of CRC. We divided 33 female Wistar rats into five groups: sham (A), infected nontreated (B), treated with lock therapy (0.16 mg/ml) (C), systemically treated only (1 mg/kg) (D), and systemically treated+lock (E). Catheters were colonized 24 h before insertion into the femoral vein (day 0). Treatment started on day 1 and lasted 7 days, followed by 7 days of surveillance. Bioluminescence assays were carried out on days 1, 3, 5, and 14, together with daily monitoring of clinical variables. Postmortem microbiological cultures from the catheter and several tissue samples were also obtained. Overall, 28 rats (84.8%) completed the study. Group B animals showed significant weight loss at days 2, 4, and 5 compared with groups C and D (P < .05). In group B, no animals survived after day 7, 75% had CRC, and bioluminescence remained constant 5 days after catheter implantation. Positive catheter culture rates in groups C, D, and E were, respectively, 83.3%, 62.5%, and 25.0% (P = .15). Micafungin proved to be a HAAB agent when administered both systemically and in lock therapy in an animal model of CRC, although the bioluminescence signal persists after treatment. This persistence should be further analyzed.

Topics: Animal Structures; Animals; Antifungal Agents; Biofilms; Candida albicans; Candidemia; Catheter-Related Infections; Catheters; Disease Models, Animal; Female; Luminescent Measurements; Micafungin; Rats, Wistar; Survival Analysis; Treatment Outcome

Candida albicans is the most frequently isolated fungal species in hospital settings worldwide. However, non-albicans Candida species with decreased susceptibility to antifungals have emerged as an important cause of fungemia. The aims of this study were to determine the species distribution of fungi isolated from the blood samples of patients at a Swedish University Hospital and to define the in vitro susceptibilities of these isolates to nine antifungal agents. In total, 233 yeast isolates from 143 patients were included in this study. Antifungal susceptibility testing was performed using broth dilution Sensititre YeastOne panels, which comprised amphotericin B, 5-flucytosine, fluconazole, itraconazole, voriconazole, posaconazole, anidulafungin, micafungin, and caspofungin. The most common species in all age groups was C. albicans (n = 93, 65%), followed by C. glabrata (n = 27, 19%) and C. parapsilosis (n = 15, 10%). C. glabrata was mostly found in elderly individuals, while C. parapsilosis was found mainly in young children (p = 0.008). Antifungal resistance was low in the Candida species, except for reduced susceptibility to fluconazole among C. glabrata strains. C. albicans is the most frequent colonizer of Swedish patients. In general antifungal resistance is uncommon in Candida species. Nevertheless, reduced susceptibilities to fluconazole and echinocandins were found in C. glabrata and C. parapsilosis, respectively.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Anidulafungin; Antifungal Agents; Candida; Candida albicans; Candida glabrata; Candida parapsilosis; Candidemia; Caspofungin; Child; Child, Preschool; Female; Fluconazole; Flucytosine; Humans; Itraconazole; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Triazoles; Voriconazole; Young Adult

Micafungin was shown to be as efficacious as caspofungin in treating patients with candidaemia and invasive candidiasis (IC). However, it remains unknown if micafungin or caspofungin is a cost-effective definitive therapy for candidaemia and IC in Turkey. The present study aimed to determine the economic impact of using micafungin versus caspofungin for treatment of candidaemia and IC in the Turkish setting. A decision analytic model was constructed and was populated with data (i.e. transition probabilities, duration of initial antifungal treatment, reasons for treatment failure, percentage of patients who stepped down to oral fluconazole, and duration on oral fluconazole) obtained from a published randomised clinical trial. Cost inputs were derived from the latest Turkish resources while data that were not readily available in the literature were estimated by expert panels. One-way sensitivity analyses, threshold analyses, scenario analyses and probabilistic sensitivity analyses were conducted. Caspofungin (€2693) incurred a lower total cost than micafungin (€4422), with a net cost saving of €1729 per treated patient. Drug acquisition cost was the main cost driver for both study arms. The model outcome was robust over wide variations (of ±100.0% from the base case value) for all input parameters except for micafungin drug cost and the duration of initial treatment with micafungin. Caspofungin appears to be a cost-saving option in treating candidaemia and IC from the Turkish hospital perspective.

Topics: Antifungal Agents; Candidemia; Candidiasis, Invasive; Caspofungin; Cost-Benefit Analysis; Databases, Factual; Echinocandins; Humans; Lipopeptides; Micafungin; Models, Economic; Treatment Outcome; Turkey

Guidelines on treating invasive candidiasis recommend initial treatment with a broad-spectrum echinocandin (e.g. micafungin), then switching to fluconazole if isolates prove sensitive (de-escalation strategy). This study aimed to evaluate the cost-effectiveness of de-escalation from micafungin vs escalation from fluconazole from a Chinese public payers perspective.. Cost-effectiveness was estimated using a decision analytic model, in which patients begin treatment with fluconazole 400 mg/day (escalation) or micafungin 100 mg/day (de-escalation). From Day 3, when susceptibility results are available, patients are treated with either fluconazole (if isolates are fluconazole-sensitive/dose-dependent) or micafungin (if isolates are resistant). The total duration of (appropriate) treatment is 14 days. Model inputs are early (Day 3) and end-of-treatment mortality rates, treatment success rates, and health resource utilization. Model outputs are costs of health resource utilization over 42 days, incremental cost per life-year, and incremental cost per quality-adjusted life-year (QALY) over a lifetime horizon.. In the base-case analysis, the de-escalation strategy was associated with longer survival and higher treatment success rates compared with escalation, at a lower overall cost (-¥1,154; -175 United States Dollars). Life-years and QALYs were also better with de-escalation. Thus, this strategy dominated the escalation strategy for all outcomes. In a probabilistic sensitivity analysis, 99% of 10,000 simulations were below the very cost-effective threshold (1 × gross domestic product).. The main limitation of the study was the lack of real-world input data for clinical outcomes on treatment with micafungin in China; data from other countries were included in the model.. A de-escalation strategy is cost-saving from the Chinese public health payer perspective compared with escalation. It improves outcomes and reduces costs to the health system by reducing hospitalization, due to an increase in the proportion of patients receiving appropriate treatment.

Topics: Antifungal Agents; Candidemia; Candidiasis, Invasive; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Echinocandins; Fluconazole; Humans; Lipopeptides; Micafungin; Survival

To identify the frequency of micafungin resistance among clinically significant isolates of Candida stored at our institution from 2005 to 2015. Chart review of patients with resistant isolates then informed the clinical setting and outcomes associated with these infections.. Clinical Candida isolates had been stored at -80°C in Brucella broth with 20% glycerol from 2005. Isolates were tested using broth microdilution to determine micafungin MICs. All Candida glabrata isolates and all isolates demonstrating decreased susceptibility to micafungin were screened for FKS mutations using a Luminex assay.. In total, 3876 Candida isolates were tested for micafungin resistance, including 832 C. glabrata isolates. Of those, 33 isolates from 31 patients were found to have either decreased susceptibility to micafungin and/or an FKS mutation. C. glabrata accounted for the majority of these isolates. While bloodstream infections were found to have a very high mortality rate, isolates from other sites were uncommonly associated with 30-day mortality. Overall resistance rates were very low.. Echinocandin resistance in C. glabrata has been increasingly reported but rates at our institution remain very low. We hypothesize that a focus on antifungal stewardship may have led to these observations. Knowledge of local resistance patterns is key to appropriate empirical treatment strategies.

Topics: Academic Medical Centers; Adult; Antifungal Agents; Candida; Candida glabrata; Candidemia; Candidiasis; Caspofungin; Drug Resistance, Fungal; Echinocandins; Female; Fungal Proteins; Humans; Male; Micafungin; Microbial Sensitivity Tests; Mutation

We identified 8 pediatric patients on micafungin (MCFG; ≥3 doses) at our institution who had breakthrough candidemia (BC). The causative strains of the BC were Candida parapsilosis in 7 patients. The minimum inhibitory concentration of MCFG was ≤1 µg/mL (susceptible) in all 8 isolates. Immunocompromised patients may develop BC caused by MCFG-susceptible strains.

Topics: Adolescent; Antifungal Agents; Candida; Candidemia; Child; Child, Preschool; Drug Resistance, Fungal; Female; Humans; Male; Micafungin; Microbial Sensitivity Tests; Retrospective Studies

Delay in treatment of candidaemia and invasive candidiasis remains a cause of significant morbidity and mortality in high-risk patients. Widespread empirical utilization of antifungal therapy often occurs in an effort to minimize this risk.. This study assessed the impact of the T2Candida Panel in a multi-hospital community health system on time to initiation of antifungal therapy in candidaemic patients as well as the utilization of micafungin.. Outcomes were compared between those patients with candidaemia prior to T2Candida implementation and those after implementation. Micafungin utilization for patients with suspected candidaemia/invasive candidiasis was compared with that for patients with a negative T2Candida Panel post-implementation.. There was a significant decrease in time to appropriate therapy in the post-T2Candida group (34 versus 6 h, P = 0.0147). Empirical antifungal therapy was avoided in 58.4% of T2Candida-negative patients.. These results support the implementation of T2Candida to improve time to appropriate therapy for candidaemic patients while simultaneously expanding antimicrobial stewardship efforts to appropriately utilize antifungals.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Antimicrobial Stewardship; Candida; Candidemia; Candidiasis, Invasive; Community Health Centers; Female; Humans; Male; Micafungin; Middle Aged; Retrospective Studies

Micafungin was reported to be non-inferior to liposomal amphotericin B (LAmB) in treating patients with candidaemia and invasive candidiasis (IC). The current study aimed to evaluate the economic impact of using micafungin versus LAmB for treatment of candidaemia and IC in Turkey. A decision analytic model, which depicted economic consequences upon administration of micafungin or LAmB for treating patients with candidaemia and IC in the Turkish hospitals, was constructed. Patients were switched to an alternative antifungal agent if initial treatment failed due to mycological persistence. All patients were followed up until treatment success or death. Outcome probabilities were obtained from published literature and cost inputs were derived from the latest Turkish resources. Expert panels were used to estimate data that were not available in the literature. Cost per patient treated for each intervention was then calculated. Sensitivity analyses including Monte Carlo simulation were performed. For treatment of candidaemia and IC, micafungin (€4809) was associated with higher total cost than LAmB (€4467), with an additional cost of €341 per treated patient. Cost of initial antifungal treatment was the major cost driver for both comparators. The model outcome was robust over a wide variation in input variables except for drug acquisition cost and duration of initial antifungal treatment with micafungin or LAmB. LAmB is cost-saving relative to micafungin for the treatment of candidaemia and IC from the Turkish hospital perspective, with variation in drug acquisition cost of the critical factor affecting the model outcome.

Topics: Amphotericin B; Antifungal Agents; Candidemia; Candidiasis, Invasive; Cost-Benefit Analysis; Decision Support Techniques; Humans; Micafungin; Treatment Outcome; Turkey

Rapid identification of Candida species facilitates pathogen-directed therapy with either fluconazole or an echinocandin.. We applied Sepsityper matrix-assisted laser desorption ionisation time of flight mass spectrometry (MALDI-TOF-MS) technology on positive blood culture broths for rapid species identification.. Of the 74 patients with candidaemia, 25 had the species identified on the day of the positive blood culture directly from the broth (rapid identification group) while the remaining 49 had the species identified from culture (conventional identification group). Three (13.6%) out of 22 treated patients in the rapid identification group received echinocandin compared to 20/45 (44.4%) in the conventional identification group. The appropriateness of therapy was 90.9% in the rapid identification group and 62.2% in the conventional identification group (p = 0.01). Cost savings were more than £10,000 in the first three days of treatment.. Sepsityper-MALDI-TOF-MS is a useful tool in supporting antifungal stewardship programmes.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Blood Culture; Candida; Candidemia; Cost Savings; Female; Fluconazole; Humans; Male; Micafungin; Middle Aged; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Time Factors

We determined micafungin, caspofungin and amphotericin B (AMB) minimum inhibitory concentration (MICs) and killing rates in RPMI-1640 and in RPMI-1640 with 50% serum against three Candida krusei bloodstream isolates. MIC ranges in RPMI-1640 were 0.125-0.25, 0.25 and 0.125-0.5 mg/L, in RPMI-1640 with 50% serum, MICs were 64-128-, 8- and 4-16-fold higher, respectively. In RPMI-1640 micafungin and caspofungin at 1, 4, 16 and 32 mg/L as well as AMB at 2 mg/L were fungicidal against all isolates in ≤3.96, ≤4.42 and 14.96 h, respectively. In RPMI-1640 with 50% serum, caspofungin was fungicidal for all isolates only at 32 mg/L, micafungin and AMB were fungistatic. In neutropenic mice, 5 mg/kg caspofungin and 1 mg/kg AMB were ineffective against two of the three isolates. Thus, in vivo efficacy of echinocandins and AMB is weak or absent against C. krusei. Prescribers treating C. krusei infections with echinocandins should watch out for clinical resistance and therapeutic failure.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida; Candidemia; Caspofungin; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Micafungin; Microbial Sensitivity Tests

Topics: Amphotericin B; Antifungal Agents; Aortic Valve; Burns; Candida tropicalis; Candidemia; Echocardiography; Endocarditis; Heart Valve Prosthesis Implantation; Hospitalization; Humans; Invasive Fungal Infections; Male; Micafungin; Middle Aged; Mitral Valve

Knowledge of contemporary epidemiology of candidaemia is essential. We aimed to identify changes since 2004 in incidence, species epidemiology and antifungal susceptibilities of Candida spp. causing candidaemia in Australia.. These data were collected from nationwide active laboratory-based surveillance for candidaemia over 1 year (within 2014-2015). Isolate identification was by MALDI-TOF MS supplemented by DNA sequencing. Antifungal susceptibility testing was performed using Sensititre YeastOne™.. A total of 527 candidaemia episodes (yielding 548 isolates) were evaluable. The mean annual incidence was 2.41/105 population. The median patient age was 63 years (56% of cases occurred in males). Of 498 isolates with confirmed species identity, Candida albicans was the most common (44.4%) followed by Candida glabrata complex (26.7%) and Candida parapsilosis complex (16.5%). Uncommon Candida species comprised 25 (5%) isolates. Overall, C. albicans (>99%) and C. parapsilosis (98.8%) were fluconazole susceptible. However, 16.7% (4 of 24) of Candida tropicalis were fluconazole- and voriconazole-resistant and were non-WT to posaconazole. Of C. glabrata isolates, 6.8% were resistant/non-WT to azoles; only one isolate was classed as resistant to caspofungin (MIC of 0.5 mg/L) by CLSI criteria, but was micafungin and anidulafungin susceptible. There was no azole/echinocandin co-resistance.. We report an almost 1.7-fold proportional increase in C. glabrata candidaemia (26.7% versus 16% in 2004) in Australia. Antifungal resistance was generally uncommon, but azole resistance (16.7% of isolates) amongst C. tropicalis may be emerging.

Topics: Anidulafungin; Antifungal Agents; Australia; Azoles; Candida; Candida glabrata; Candida tropicalis; Candidemia; Caspofungin; Drug Resistance, Fungal; Echinocandins; Female; Fluconazole; Humans; Incidence; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Sequence Analysis, DNA; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Triazoles; Voriconazole

Cost-effectiveness studies of echinocandins for the treatment of invasive candidiasis, including candidemia, are rare in Asia. No study has determined whether echinocandins are cost-effective for both Candida albicans and non-albicans Candida species. There have been no economic evaluations that compare non-echinocandins with the three available echinocandins. This study was aimed to assess the cost-effectiveness of individual echinocandins, namely caspofungin, micafungin, and anidulafungin, versus non-echinocandins for C. albicans and non-albicans Candida species, respectively.. A decision tree model was constructed to assess the cost-effectiveness of echinocandins and non-echinocandins for invasive candidiasis. The probability of treatment success, mortality rate, and adverse drug events were extracted from published clinical trials. The cost variables (i.e., drug acquisition) were based on Taiwan's healthcare system from the perspective of a medical payer. One-way sensitivity analyses and probability sensitivity analyses were conducted.. For treating invasive candidiasis (all species), as compared to fluconazole, micafungin and caspofungin are dominated (less effective, more expensive), whereas anidulafungin is cost-effective (more effective, more expensive), costing US$3666.09 for each life-year gained, which was below the implicit threshold of the incremental cost-effectiveness ratio in Taiwan. For C. albicans, echinocandins are cost-saving as compared to non-echinocandins. For non-albicans Candida species, echinocandins are cost-effective as compared to non-echinocandins, costing US$652 for each life-year gained. The results were robust over a wide range of sensitivity analyses and were most sensitive to the clinical efficacy of antifungal treatment.. Echinocandins, especially anidulafungin, appear to be cost-effective for invasive candidiasis caused by C. albicans and non-albicans Candida species in Taiwan.

Topics: Anidulafungin; Antifungal Agents; Candida; Candida albicans; Candidemia; Candidiasis, Invasive; Caspofungin; Cost-Benefit Analysis; Echinocandins; Economics, Pharmaceutical; Fluconazole; Humans; Lipopeptides; Micafungin; Taiwan; Treatment Outcome

We report data on the frequency of the paradoxical effect of echinocandins against Candida spp. (n = 602 incident isolates) using the EUCAST definitive document EDef 7.2 procedure. The paradoxical effect for one or more echinocandins was observed in 16% of the isolates. However, differences between species were found, and the paradoxical effect was more common in Candida tropicalis (P < 0.001). Caspofungin was the drug in which the paradoxical effect was most common, followed by anidulafungin and micafungin (P < 0.001).

Topics: Anidulafungin; Antifungal Agents; Candida; Candida tropicalis; Candidemia; Candidiasis; Caspofungin; Echinocandins; Lipopeptides; Micafungin; Microbial Sensitivity Tests

The prophylactic use of antifungal drugs in allogeneic hematopoietic cell transplant recipients has revealed that the rate of non-albicans candidemia has increased. We herein report the case of a patient with adult T-cell leukemia who developed candidemia due to Candida fermentati during micafungin treatment after cord blood transplantation. The isolate was identified on day 47 by sequencing of the internal transcribed spacer region of the ribosomal RNA gene. The sequencing of the hot spot region of fks1p of isolate revealed naturally occurring amino acid substitutions, which conferred reduced echinocandin susceptibility. This case highlights that breakthrough candidemia due to C. fermentati occurred in a patient receiving micafungin treatment.

Topics: Aged; Antibiotic Prophylaxis; Antifungal Agents; Candida; Candidemia; Central Venous Catheters; Cord Blood Stem Cell Transplantation; DNA, Fungal; Drug Resistance, Fungal; Echinocandins; Fungal Proteins; Graft vs Host Disease; Humans; Leukemia-Lymphoma, Adult T-Cell; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Mutation; Sequence Analysis, DNA; Transplant Recipients; Transplantation Conditioning

Micafungin is more active against biofilms with high metabolic activity; however, it is unknown whether this observation applies to caspofungin and anidulafungin and whether it is also dependent on the biomass production. We compare the antifungal activity of anidulafungin, caspofungin, and micafungin against preformed Candida albicans biofilms with different degrees of metabolic activity and biomass production from 301 isolates causing fungemia in patients admitted to Gregorio Marañon Hospital (January 2007 to September 2014). Biofilms were classified as having low, moderate, or high metabolic activity according XTT reduction assay or having low, moderate, or high biomass according to crystal violet assay. Echinocandin MICs for planktonic and sessile cells were measured using the EUCAST E.Def 7.2 procedure and XTT reduction assay, respectively. Micafungin showed the highest activity against biofilms classified according to the metabolic activity and biomass production (P < .001). The activity of caspofungin and anidulafungin was not dependent on the metabolic activity of the biofilm or the biomass production. These observations were confirmed by scanning electron microscopy. None of the echinocandins produced major changes in the structure of biofilms with low metabolic activity and biomass production when compared with the untreated biofilms. However, biofilm with high metabolic activity or high biomass production was considerably more susceptible to micafungin; this effect was not shown by caspofungin or anidulafungin.

Topics: Anidulafungin; Antifungal Agents; Biofilms; Biomass; Candida albicans; Candidemia; Caspofungin; Echinocandins; Gentian Violet; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Microscopy, Electron, Scanning; Oxidation-Reduction; Portugal; Staining and Labeling; Tetrazolium Salts

The in vitro activities of caspofungin and micafungin were determined with and without farnesol against Candida parapsilosis biofilms. Drug interactions were examined using the XTT colorimetric assay-based broth microdilution chequerboard method. Drug-drug interactions were assessed utilising the FICI, Bliss independence models and time-kill experiments. Median sessile MICs of five C. parapsilosis clinical isolates ranged between 32-256 mg/L, 16-512 mg/L and >300 μM for caspofungin, micafungin and farnesol, respectively. Median MICs for caspofungin and micafungin in combination with farnesol showed 8-64- and 4-64-fold decreases, respectively. Paradoxical growth noticed with both echinocandins was eliminated by farnesol. Based on FICIs for sessile clinical isolates, synergism was observed for caspofungin (range of median FICIs, 0.155-0.5) and micafungin (range of median FICIs, 0.093-0.5). Concordantly, MacSynergy analysis and global fitting of non-linear regression based on a Bliss independence models also showed synergism for caspofungin and micafungin. In line with FICI findings and the Bliss independence model, synergistic interactions were confirmed by time-kill experiments. The metabolic activity of fungal cells was significantly inhibited by caspofungin+farnesol at all three tested combinations (4 mg/L+75 μM, 8 mg/L+75 μM and 16 mg/L+75 μM) between 3 and 24 h compared with the control (P<0.05-0.001). Significant inhibition was observed for micafungin+farnesol between 3 and 12h (P<0.001) but not at 24 h. Despite the favourable effect of farnesol in combination with echinocandins, further in vivo studies are needed to confirm its therapeutic advantage in catheter-associated infections caused by C. parapsilosis.

Topics: Antifungal Agents; Biofilms; Candida; Candidemia; Caspofungin; Colorimetry; Drug Interactions; Echinocandins; Farnesol; Formazans; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests

Candida tropicalis is the fourth most common cause of candidaemia in hospitalized patients and associated mortality is high. C. tropicalis frequently causes biofilm-related infections. Echinocandins and amphotericin B show potent in vitro activity against C. albicans biofilms, but their activity against C. tropicalis biofilms has received little attention.. We studied production of biofilm by 54 C. tropicalis isolates from blood and the antifungal susceptibility of these isolates to micafungin, amphotericin B and liposomal amphotericin B. Biofilm production was measured using the crystal violet assay to determine biomass and the XTT reduction assay to determine metabolic activity. The antifungal susceptibility of planktonic and sessile cells was measured using the EUCAST EDef 7.2 procedure and XTT reduction assay, respectively. The sessile MIC endpoint of SMIC80 was defined as an 80% reduction in the metabolic activity of the biofilm treated with the antifungal compared with the control well.. The three drugs were very active against the isolates in planktonic form, with micafungin showing the highest activity (P < 0.001). Micafungin was the most active agent against C. tropicalis biofilms (P < 0.001). In contrast, liposomal amphotericin B showed poor antifungal activity.. Micafungin was the most active drug against C. tropicalis biofilm. Although the echinocandins and liposomal amphotericin B are considered very active against Candida spp. biofilms, this is not true for C. tropicalis, as liposomal amphotericin B showed poor antifungal activity against biofilms.

Topics: Amphotericin B; Antifungal Agents; Biofilms; Biomass; Candida tropicalis; Candidemia; Echinocandins; Formazans; Gentian Violet; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Staining and Labeling; Tetrazolium Salts

Direct treatment costs caused by candidemia in German intensive care unit (ICU) patients are currently unknown. We analyzed treatment costs and the impact of antifungal drug choice. Comprehensive data of patients who had at least one episode of candidemia while staying in the ICU between 01/2005 and 12/2010 were documented in a database using the technology of the Cologne Cohort of Neutropenic Patients (CoCoNut). A detailed analysis of all disease-associated treatment costs was performed. Patients treated with echinocandins (i.e., anidulafungin, caspofungin, micafungin) or fluconazole were analyzed separately and compared. Forty-one and 64 patients received echinocandins and fluconazole, respectively. The mean Acute Physiology and Chronic Health Evaluation (APACHE) IV score was 114 (95 % confidence interval [CI]: 106-122) vs. 95 (95 % CI: 90-101, p = <0.001). Twenty-three (56 %) and 33 (52 %, p = 0.448) patients survived hospitalization, while 17 (41 %) and 22 (34 %, p = 0.574) survived one year after diagnosis. In the echinocandin and fluconazole groups, the mean costs per patient of ICU treatment were 20,338 (95 % CI: 12,893-27,883) vs. 11,932 (95 % CI: 8,016-15,849, p = 0.110), and the total direct treatment costs per patient were 37,995 (95 % CI: 26,614-49,376) vs. 22,305 (95 % CI: 16,817-27,793, p = 0.012), resulting in daily costs per patient of 1,158 (95 % CI: 1,036-1,280) vs. 927 (95 % CI: 828-1,026, p = 0.001). Our health economic analysis shows the high treatment costs of patients with candidemia in the ICU. Sicker patients had a prolonged hospitalization and were more likely to receive echinocandins, leading to higher treatment costs. Outcomes were comparable to those achieved in less sick patients with fluconazole.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anidulafungin; Antifungal Agents; Candidemia; Caspofungin; Child; Child, Preschool; Echinocandins; Female; Fluconazole; Health Care Costs; Hospitalization; Humans; Infant; Intensive Care Units; Lipopeptides; Male; Micafungin; Middle Aged; Treatment Outcome; Young Adult

The direct or indirect interactions that antifungals have with the host immune response may play a significant role in defining their activity in vivo. However, the impact that acquired antifungal resistance has on the immunopharmacologic activity of antifungals is not well described. We assessed the immunopharmacologic activity of caspofungin, micafungin, and voriconazole among isolates of Candida glabrata with or without FKS-mediated echinocandin resistance. Clinical bloodstream isolates of C. glabrata from patients who did (n = 5) or did not (n = 3) develop persistent candidemia and who did (n = 2) or did not (n = 11) harbor FKS gene mutations were included. A cell-based assay was used to compare differences in macrophage activation among isolates when grown in the presence or absence of subinhibitory concentrations of caspofungin, micafungin, or voriconazole. In the absence of antifungals, macrophage activation was significantly lower for index C. glabrata isolates obtained from persistent candidemia patients than for those from nonpersistent patients (33% versus 79% increase over negative controls, respectively; P < 0.01). Growth of isolates possessing wild-type FKS genes in subinhibitory concentrations of micafungin or caspofungin, but not voriconazole, significantly increased macrophage inflammatory responses compared to untreated controls (1.25- to 2.75-fold increase, P < 0.01). For isolates harboring the FKS2 hot spot 1 (HS1) S663P mutation, however, a significant increase was observed only with micafungin treatment (1.75-fold increase versus negative control, P < 0.01). Macrophage activation correlated with the level of unmasking of β-glucan in the cell wall. The diminished macrophage inflammatory response to isolates that caused persistent candidemia and differential immunopharmacologic activity of echinocandins among FKS mutants suggest that certain strains of C. glabrata may have a higher propensity for immunoevasion and development of antifungal resistance during treatment.

Topics: Animals; Antifungal Agents; beta-Glucans; Candida glabrata; Candidemia; Caspofungin; Cell Line; Echinocandins; Fungal Proteins; Humans; Immunity, Innate; Lipopeptides; Micafungin; Mice; Microbial Sensitivity Tests; Mutation; Voriconazole

Candidaemia and other forms of invasive candidiasis (C/IC) in the intensive care unit are challenging conditions that are associated with high rates of mortality. New guidelines from the European Society for Clinical Microbiology and Infectious Diseases strongly recommend echinocandins for the first-line treatment of C/IC. Here, a cost-effectiveness model was developed from the United Kingdom perspective to examine the costs and outcomes of antifungal treatment for C/IC based on the European Society for Clinical Microbiology and Infectious Diseases guidelines.. Costs and treatment outcomes with the echinocandin anidulafungin were compared with those for caspofungin, micafungin and fluconazole. The model included non-neutropenic patients aged ≥16 years with confirmed C/IC who were receiving intravenous first-line treatment. Patients were categorised as either a clinical success or failure (patients with persistent/breakthrough infection); successfully treated patients switched to oral therapy, while patients categorised as clinical failures switched to a different antifungal class. Other inputs were all-cause mortality at 6 weeks, costs of treatment-related adverse events and other medical resource utilisation costs. Resource use was derived from the published literature and from discussion with clinical experts. Drug-acquisition/administration costs were taken from standard United Kingdom costing sources.. The model indicated that first-line anidulafungin could be considered cost-effective versus fluconazole (incremental cost-effectiveness ratio £813 per life-year gained) for the treatment of C/IC. Anidulafungin was cost-saving versus caspofungin and micafungin due to lower total costs and a higher rate of survival combined with a higher probability of clinical success.. European Society for Clinical Microbiology and Infectious Diseases guidelines recommend echinocandins for the first-line treatment of C/IC; our model indicated that anidulafungin marries clinical effectiveness and cost-effectiveness.. From the United Kingdom perspective, anidulafungin was cost-effective compared with fluconazole for the treatment of C/IC and was cost-saving versus the other echinocandins.

Topics: Anidulafungin; Antifungal Agents; Candidemia; Candidiasis, Invasive; Caspofungin; Cost-Benefit Analysis; Drug Costs; Echinocandins; Fluconazole; Humans; Intensive Care Units; Length of Stay; Lipopeptides; Micafungin; Models, Economic; Treatment Outcome; United Kingdom

Echinocandins are N-acyl-substituted cyclic hexapeptides with potent in vitro and in vivo activity against Candida species that are used for primary treatment and prevention of candidemia and invasive candidiasis. Recent progress in the translational research of echinocandins has led to new approaches for treatment of central venous catheter Candida biofilms. Other studies have laid the experimental and clinical foundation for use of extended dosing intervals for administration of echinocandins in treatment and prevention of candidemia and invasive candidiasis.

Topics: Antifungal Agents; Biofilms; Candida; Candidemia; Candidiasis; Candidiasis, Invasive; Caspofungin; Catheter-Related Infections; Echinocandins; Humans; Lipopeptides; Micafungin; Translational Research, Biomedical

The incidence of invasive candidiasis caused by non-albicans Candida (NAC) spp. is increasing. The aim of this analysis was to evaluate the efficacy of micafungin, caspofungin and liposomal amphotericin B in patients with invasive candidiasis and candidaemia caused by different Candida spp. This post hoc analysis used data obtained from two randomised phase III trials was conducted to evaluate the efficacy and safety of micafungin vs. caspofungin and micafungin vs. liposomal amphotericin B. Treatment success, clinical response, mycological response and mortality were evaluated in patients infected with C. albicans and NAC spp. Treatment success rates in patients with either C. albicans or NAC infections were similar. Outcomes were similar for micafungin, caspofungin and liposomal amphotericin B. Candida albicans was the most prevalent pathogen recovered (41.0%), followed by C. tropicalis (17.9%), C. parapsilosis (14.4%), C. glabrata (10.4%), multiple Candida spp. (7.3%) and C. krusei (3.2%). Age, primary diagnosis (i.e. candidaemia or invasive candidiasis), previous corticosteroid therapy and Acute Physiology and Chronic Health Evaluation II score were identified as potential predictors of treatment success and mortality. Micafungin, caspofungin and liposomal amphotericin B exhibit favourable treatment response rates that are comparable for patients infected with different Candida spp.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Candida; Candidemia; Candidiasis, Invasive; Caspofungin; Clinical Trials, Phase III as Topic; Echinocandins; Female; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Survival Analysis; Treatment Outcome; Young Adult

We identified a case of breakthrough candidemia in a 25-year-old patient receiving micafungin prophylaxis (50 mg/day). Five Candida glabrata isolates were obtained from blood cultures and were classified as multidrug-resistant isolates, since all of them exhibited high MICs for echinocandin and azole drugs. A mutation (S663F) in hot spot 1 of the FKS2 gene was found in all five isolates. This mutation yielded a 1,3-β-D-glucan synthase enzyme with highly reduced sensitivities to echinocandin drugs.

Topics: Adult; Amphotericin B; Antifungal Agents; Azoles; Candida glabrata; Candidemia; Drug Resistance, Fungal; Echinocandins; Fungal Proteins; Humans; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation

The Guidelines for Management of Deep-seated Mycoses 2007 recommend the use of micafungin as a first-line agent for the treatment of candidemia. On the package insert, the recommended dose of micafungin is 50 mg/d. However, the Guidelines recommend a micafungin dose of 100-150 mg/d. In the present study, we evaluated the relationship between the effectiveness and dose of micafungin in 42 patients with candidemia who underwent treatment with micafungin. We found that the efficacy rate of micafungin at a dose of 50 mg/d was 40%, whereas that at ≥100 mg/d was 87.5%. Moreover, the treatment was more effective in patients who received ≥100 mg/d of micafungin as compared to those who received 50 mg/d of micafungin. Furthermore, we assessed the efficacy of micafungin according to the Candida species. Among all patients, the efficacy rate of micafungin was found to be lower in patients infected by Candida parapsilosis as compared to those infected by other Candida species. However, among the patients who received ≥100 mg/d of micafungin, the efficacy rate in patients infected by Candida parapsilosis was equivalent to that of patients who were infected by other Candida species. Thus, based on the results of the present study, the optimal micafungin dose for the treatment of candidemia appears to range from 100 to 150 mg/d, as recommended by the Guidelines.

Topics: Aged; Antifungal Agents; Candida; Candidemia; Dose-Response Relationship, Drug; Echinocandins; Female; Humans; Lipopeptides; Male; Micafungin

So-called lock therapy, consisting of high concentrations of antimicrobials instilled into the lumen of the catheter, has been suggested avoid central venous catheter removal during fungal infection. We report a baby who developed catheter-related candidemia. Systemic antifungal treatment did not resolve the candidemia. Lock therapy with 0.3 mL of ethanol 70% and micafungin sodium 5 mg/L was added to the therapy, and blood cultures became sterile.

Topics: Antifungal Agents; Candida albicans; Candidemia; Catheter-Related Infections; Central Venous Catheters; Critical Illness; Echinocandins; Ethanol; Failure to Thrive; Humans; Infant; Lipopeptides; Male; Micafungin; Parenteral Nutrition

The response rate among 58 patients with cancer and candidemia or deep-seated candidiasis treated with micafungin monotherapy was 81%. Intensive care unit (ICU) stay, concomitant nonfungal infections, and acute kidney injury were significantly associated with the 30-day crude mortality rate. Severe neutropenia was an independent predictor of micafungin failure. The efficacy and safety of micafungin in cancer patients with invasive candidiasis were comparable to those reported for patients without malignancy and for cancer patients treated with caspofungin.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Candidemia; Candidiasis; Candidiasis, Invasive; Echinocandins; Female; Humans; Intensive Care Units; Lipopeptides; Male; Micafungin; Middle Aged; Neoplasms; Neutropenia; Young Adult

Species distribution and antifungal susceptibility of Candida isolates at one institution were evaluated. Detection rates of fungi were examined for 5 years between 2007 and 2011. Sensitivities of fungi to amphotericin B, flucytosine, fluconazole, micafungin, itraconazole, and voriconazole were evaluated in blood culture-positive patients. A total of 3,832 fungal isolates were detected, including Candida albicans 66.5%, Candida glabrata 20.3%, Candida parapsilosis 6.2%, Candida tropicalis 5.5%, and others 1.5%. Candidemia was diagnosed in 131 patients, and C. albicans, C. parapsilosis, C. glabrata, C. tropicalis, and others were present in 42.0%, 27.5%, 16.0%, 8.4%, and 6.1% of these patients, respectively. Voriconazole had the lowest MIC90s against C. albicans and C. parapsilosis (0.015 and 0.25). Micafungin had a low MIC90 against C. glabrata and C. tropicalis. C. albicans was the most common fungus in patients with candidemia. Voriconazole and micafungin were effective against C. albicans. Amphotericin B was effective for C. parapsilosis, and micafungin showed good efficacy against C. glabrata and C. tropicalis.

Topics: Amphotericin B; Antifungal Agents; Candida; Candida albicans; Candida glabrata; Candida tropicalis; Candidemia; Drug Resistance, Fungal; Echinocandins; Fluconazole; Flucytosine; Health Facilities; Humans; Itraconazole; Japan; Lipopeptides; Micafungin; Time Factors; Voriconazole

Candida glabrata strains sequentially isolated from blood developed resistance to micafungin (MICs from <0.015 to 4 μg/ml). A novel mutation identified in micafungin-resistant strains at bp 262 of FKS2 (containing a deletion of F659 [F659del]) was inserted into the homologous region in FKS1.

Topics: Aged, 80 and over; Antifungal Agents; Base Sequence; Candida glabrata; Candidemia; Echinocandins; Fungal Proteins; Gene Conversion; Humans; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Molecular Sequence Data; Mutagenesis, Insertional; Sequence Deletion

Empiric antifungal coverage is indicated in patients with graft-versus-host disease (GVHD) following a stem cell transplant (SCT) who are febrile and neutropenic for extended periods of time. Empiric antifungal coverage is indicated for patients with hematologic malignancies who have persistent fever and neutropenia as well as patients who have GVHD following SCT. Although the prophylactic use of antifungals is a cornerstone of the care for such patients, the selection of the particular antifungal is at the discretion of the clinician. We report a patient case whose surveillance blood cultures obtained 14 days after the switch from voriconazole to micafungin were positive for the growth of Candida albicans. Clinicians prescribing echinocandin therapy for antifungal prophylaxis must be aware of the risks of echinocandin resistance and possible breakthrough candidemia with C. albicans.

Topics: Antifungal Agents; Candida albicans; Candidemia; Drug Resistance, Fungal; Echinocandins; Fatal Outcome; Female; Humans; Leukemia, Myeloid, Acute; Lipopeptides; Micafungin; Middle Aged; Stem Cell Transplantation; Transplantation, Homologous; Voriconazole

Echinocandins are recommended for Candia glabrata candidemia. Mutations in the FKS1 and FKS2 genes are associated with echinocandin resistance. Few studies have assessed risk factors for FKS mutant isolates and outcomes in patients receiving micafungin treatment.. Patients with C. glabrata bloodstream infection admitted to a large, tertiary care hospital between 2009 and 2012 were included in this study. For each isolate, FKS1 and FKS2 genes were sequenced to identify mutations. Risk factors for FKS mutations and treatment outcomes in patients receiving an echinocandin were assessed using multivariate logistic regression.. Seventy-two patients were included in the study of which 13 (18%) had an FKS mutant isolate. The only significant predictor for FKS mutations was prior echinocandin exposure (odds ratio [OR], 19.9; 95% confidence interval [CI], 4.7-84.7; P ≤ .01). Treatment failure occurred in 17 (30%) of 57 patients who received an echinocandin and was more common in patients with FKS mutants (6 of 10; 60%) compared with non-FKS mutants (11 of 47; 23%). Underlying gastrointestinal disorder (OR, 4.7; 95% CI, 1.1-20.9; P = .04) and prior echinocandin exposure (OR, 8.3; 95% CI, 1.7-40.4; P ≤ .01) were independent predictors of echinocandin treatment failure. Treatment response and echinocandin minimum inhibitory concentrations varied among specific FKS mutations.. FKS mutations were identified in 18% of 72 patients with C. glabrata candidemia. Common risk factors for FKS mutant isolates included previous echinocandin exposure, which also influenced response rates.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Candida glabrata; Candidemia; Candidiasis; Caspofungin; Drug Resistance, Fungal; Echinocandins; Female; Fungal Proteins; Humans; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Mutation; Patient Outcome Assessment; Prognosis; Risk Factors; Treatment Failure; Treatment Outcome; Young Adult

Candida glabrata is the second leading cause of candidemia in U.S. hospitals. Current guidelines suggest that an echinocandin be used as the primary therapy for the treatment of C. glabrata disease due to the high rate of resistance to fluconazole. Recent case reports indicate that C. glabrata resistance to echinocandins may be increasing. We performed susceptibility testing on 1,380 isolates of C. glabrata collected between 2008 and 2013 from four U.S. cities, Atlanta, Baltimore, Knoxville, and Portland. Our analysis showed that 3.1%, 3.3%, and 3.6% of the isolates were resistant to anidulafungin, caspofungin, and micafungin, respectively. We screened 1,032 of these isolates, including all 77 that had either a resistant or intermediate MIC value with respect to at least one echinocandin, for mutations in the hot spot regions of FKS1 and FKS2, the major mechanism of echinocandin resistance. Fifty-one isolates were identified with hot spot mutations, 16 in FKS1 and 35 in FKS2. All of the isolates with an FKS mutation except one were resistant to at least one echinocandin by susceptibility testing. Of the isolates resistant to at least one echinocandin, 36% were also resistant to fluconazole. Echinocandin resistance among U.S. C. glabrata isolates is a concern, especially in light of the fact that one-third of those isolates may be multidrug resistant. Further monitoring of U.S. C. glabrata isolates for echinocandin resistance is warranted.

Topics: Anidulafungin; Antifungal Agents; Candida glabrata; Candidemia; Caspofungin; Drug Resistance, Multiple, Fungal; Echinocandins; Fluconazole; Fungal Proteins; Glucosyltransferases; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Mutation; United States

The ability to form biofilm enables Candida spp. to cause catheter-related candidaemia. The use of agents with in vitro activity against Candida albicans biofilms, such as micafungin, could obviate catheter removal. The metabolic activity of C. albicans biofilms is strain-dependent, and cell wall formation is thought to be more prominent in biofilms showing high metabolic activity.. We studied the antifungal activity of micafungin against 265 C. albicans isolates with different degrees of metabolic activity causing fungaemia in 246 patients admitted to Gregorio Marañón Hospital (January 2007 to June 2013). All strains were classified according to the metabolic activity of their biofilm, which was classified as low, moderate and high using XTT. Micafungin MICs for planktonic and sessile cells were assessed using the EUCAST E.Def 7.2 procedure and XTT reduction assay, respectively. The MIC was defined as a 50% and 80% reduction in metabolic activity compared with the control well.. Micafungin was uniformly more active against planktonic cells than against sessile cells (MIC50 ≤ 0.015 versus 8 mg/L), although it was not consistently active against all C. albicans biofilms. Isolates with low metabolic activity biofilms showed the lowest susceptibility to micafungin, followed by moderate and high metabolic activity biofilms (P < 0.001).. Our study suggests that the metabolic activity of biofilm may have a role in future evaluations of micafungin for the eradication of C. albicans biofilms (e.g. the lock therapy approach).

Topics: Antifungal Agents; Biofilms; Candida albicans; Candidemia; Echinocandins; Humans; Lipopeptides; Micafungin

Topics: Aged, 80 and over; Antifungal Agents; Candida glabrata; Candidemia; Drug Resistance, Fungal; Echinocandins; Genes, Fungal; Humans; Lipopeptides; Male; Micafungin; Mutation

Inappropriate initial therapy for Candida-related septic shock is common and associated with a high mortality rate. This before-after pilot study was conducted to determine the feasibility of using empiric therapy for reducing the time to appropriate antifungal therapy in patients with Candida-related septic shock.. Patients aged 18-99 years with septic shock presenting to Barnes-Jewish Hospital, St. Louis, Missouri, in 2012-2013 were assigned to 1 of 2 groups. Patients presenting between January 1, 2012, and December 31, 2012, were managed according to local standard of care for patients with septic shock, to include antifungal therapy at the discretion of the treating physician (standard therapy group). Patients presenting between January 1, 2013, and December 31, 2013, received empiric antifungal therapy (primarily micafungin 100 mg/d or fluconazole 800 mg on day 1, followed by 400 mg/d), facilitated by a clinical pharmacist in the medical intensive care unit, until microbiologic cultures were available to determine the cause of septic shock (empiric therapy group). The primary outcome was time to appropriate therapy after shock onset.. A total of 28 patients were enrolled (mean age, 56.3 [15.1] years [range, 30-92 years]; 16 [57.1%] men). The time to appropriate therapy after shock onset was statistically shorter with empiric therapy (n = 13) compared with standard therapy (n = 15) (10.6 [15.8] vs 40.5 [26.0] hours; P = 0.001). Patients receiving empiric therapy were more likely to have received appropriate therapy within 12 hours (69.2% vs 6.7%; P = 0.001) and within 24 hours (76.9% vs 40.0%; P = NS) of shock onset. In an analysis to determine the number of septic shock patients needed to be treated with empiric antifungal therapy for 1 patient with Candida-related septic shock to receive appropriate treatment, 256 patients without Candida infection received a total of 687 doses of empiric antifungal therapy (mean, 2.7 doses per patient) compared with 136 patients who received 382 doses of standard antifungal therapy (mean, 2.8 doses per patient); the number needed to treat was 19.6.. The present pilot study demonstrated that the use of empiric antifungal therapy for Candida-related septic shock was associated with a statistically shorter time to administration of appropriate treatment. ClinicalTrials.gov identifier.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Candidemia; Colony Count, Microbial; Controlled Before-After Studies; Echinocandins; Female; Fluconazole; Humans; Intensive Care Units; Lipopeptides; Male; Micafungin; Middle Aged; Numbers Needed To Treat; Pilot Projects; Retrospective Studies; Shock, Septic; Time Factors

Micafungin was non-inferior to liposomal amphotericin B (LAmB) for the treatment of candidaemia and invasive candidiasis (IC) in a major clinical trial. The present study investigated the economic impact of micafungin vs. LAmB in treating candidaemia and IC. A decision analytical model was constructed to capture downstream consequences of using micafungin or LAmB as primary definitive therapy. The main outcomes were treatment success and treatment failure due to mycological persistence, or death. Outcome probabilities were derived from key published sources. Resource used was estimated by an expert panel and cost inputs were from the latest Australian resources. The analysis was from an Australian hospital perspective. Sensitivity analyses using Monte Carlo simulation were conducted. Micafungin (AU$61 426) had a lower total cost than LAmB (AU$72 382), with a total net cost-saving of AU$10 957 per patient. This was primarily due to the lower cost associated with initial antifungal treatment and shorter length of stay for patients in the micafungin arm. Hospitalisation was the main cost driver for both arms. Results were robust over a wide range of variables. The uncertainty analysis demonstrated that micafungin had a 99.9% chance of being cost-saving compared with LAmB. Micafungin was associated with cost-saving relative to LAmB in the treatment of candidaemia and IC in Australia.

Topics: Amphotericin B; Antifungal Agents; Australia; Candidemia; Candidiasis, Invasive; Echinocandins; Health Care Costs; Humans; Lipopeptides; Micafungin; Treatment Outcome

Candida species other than Candida albicans are increasingly recognized as causes of biofilm-associated infections. This is a comprehensive study that compared the in vitro activities of all three echinocandins against biofilms formed by different common and infrequently identified Candida isolates. We determined the activities of anidulafungin (ANID), caspofungin (CAS), and micafungin (MFG) against planktonic cells and biofilms of bloodstream isolates of C. albicans (15 strains), Candida parapsilosis (6 strains), Candida lusitaniae (16 strains), Candida guilliermondii (5 strains), and Candida krusei (12 strains) by XTT [2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide] assay. Planktonic and biofilm MICs were defined as ≥ 50% fungal damage. Planktonic cells of all Candida species were susceptible to the three echinocandins, with MICs of ≤ 1 mg/liter. By comparison, differences in the MIC profiles of biofilms in response to echinocandins existed among the Candida species. Thus, C. lusitaniae and C. guilliermondii biofilms were highly recalcitrant to all echinocandins, with MICs of ≥ 32 mg/liter. In contrast, the MICs of all three echinocandins for C. albicans and C. krusei biofilms were relatively low (MICs ≤ 1 mg/liter). While echinocandins exhibited generally high MICs against C. parapsilosis biofilms, MFG exhibited the lowest MICs against these isolates (4 mg/liter). A paradoxical growth effect was observed with CAS concentrations ranging from 8 to 64 mg/liter against C. albicans and C. parapsilosis biofilms but not against C. krusei, C. lusitaniae, or C. guilliermondii. While non-albicans Candida planktonic cells were susceptible to all echinocandins, there were drug- and species-specific differences in susceptibility among biofilms of the various Candida species, with C. lusitaniae and C. guilliermondii exhibiting profiles of high MICs of the three echinocandins.

Topics: Anidulafungin; Antifungal Agents; Biofilms; Candida; Candida albicans; Candidemia; Caspofungin; Echinocandins; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Plankton; Species Specificity

We herein report the case of an 85-year-old woman presenting with right internal jugular vein candidal thrombophlebitis associated with central venous catheters (CTCVC). The infecting agent was Candida albicans, which caused recurrent candidemia five times in total. Micafungin (MCFG) alone was ineffective; however, the combination of MCFG with fosfluconazole (F-FLCZ) successfully treated the patient without a need for any anticoagulant or surgical therapies. To the extent of our knowledge, this is the first report of CTCVC being successfully treated with a combination of F-FLCZ and MCFG. These new antifungal agents have better efficacy, tolerability and bioavailability; therefore, they can be useful alternatives to classical combination therapies such as amphotericin-B and 5-fluorocytosine.

Topics: Aged, 80 and over; Antifungal Agents; Candidemia; Catheter-Related Infections; Central Venous Catheters; Drug Therapy, Combination; Echinocandins; Female; Fluconazole; Humans; Jugular Veins; Lipopeptides; Micafungin; Organophosphates; Recurrence; Thrombophlebitis; Tomography, X-Ray Computed; Ultrasonography, Doppler, Color

Although micafungin pharmacokinetic values were comparable between younger (<5 years) and older children (≥5 years) with candidemia and invasive candidiasis, younger children had a lower peak plasma micafungin concentration, lower micafungin exposure and larger micafungin clearance. Half-life remained unchanged with repeated dosing. Metabolite plasma concentrations remained low in older children; however, metabolite M-5 concentrations were higher in younger children.

Topics: Adolescent; Age Factors; Antifungal Agents; Candidemia; Candidiasis, Invasive; Child; Child, Preschool; Echinocandins; Female; Humans; Infant; Lipopeptides; Male; Metabolic Clearance Rate; Micafungin

Topics: Antifungal Agents; Candidemia; Candidiasis, Invasive; Echinocandins; Female; Humans; Lipopeptides; Male; Micafungin

To determine the prevalence of C. parapsilosis sensu stricto, C. orthopsilosis and C. metapsilosis among candidemia at Nantes University Hospital and to evaluate the in vitro susceptibility of the isolates against three echinocandin drugs (caspofungin, micafungin and anidulafungin).. Retrospective study (march 2004 to july 2009) of 178 cases of candidemia corresponding to 183 Candida spp. strains identified by means of routine phenotypical methods. Re-identification of C. parapsilosis sensu lato isolates was performed by ITS rDNA sequencing analysis. Minimal inhibitory concentrations (MIC) were determined by E-test(®). All echinocandin non-susceptible isolates (MIC>2 μg/mL) were analyzed for the presence/absence of FKS1 mutations associated with resistance.. During this period, C. parapsilosis sensu lato was responsible for 27 candidemia, ranging at the second most common Candida species after C. albicans (n=99, 54.1%). Neither isolates belong to C. orthopsilosis nor C. metapsilosis. According to the literature, all the isolates displayed high MICs against the three echinocandin drugs. All the isolates displayed both susceptibility (MIC ≤ 2 μg/mL) and a good agreement between MICs read at 24h and 48 h for caspofungin and micafungin (MIC(50)=0.75 μg/mL, MIC(90)=1.5 μg/mL). Surprisingly, whereas most of the strains were susceptible to anidulafungin at 24h (MIC(50)=1 μg/mL, MIC(90)=1.5 μg/mL), 14 (52 %) displayed non-susceptibility, despite the lack of mutation associated with resistance on FKS1, when reading was performed at 48 h (MIC(50)=3 μg/mL, MIC(90)=12 μg/mL).. Prevalence of C. orthopsilosis and C. metapsilosis in patients with candidemia is low at Nantes University Hospital. The difficulty encountered with MIC reading by E-test(®) are discussed.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anidulafungin; Antifungal Agents; Candida; Candidemia; Caspofungin; Child; Child, Preschool; Drug Resistance, Fungal; Echinocandins; Female; France; Fungal Proteins; Glycosyltransferases; Hospitals, University; Humans; In Vitro Techniques; Infant; Infant, Newborn; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Prevalence; Retrospective Studies; Ribotyping; Species Specificity; Young Adult

Echinocandins have become a first-line therapy for invasive candidiasis (IC). Using phase 3 trial data for patients with IC, pharmacokinetic-pharmacodynamic (PK-PD) relationships for efficacy for micafungin were examined. Micafungin exposures were estimated using a population pharmacokinetic model, and univariable and multivariable logistic regressions were used to identify factors associated with outcome, including the micafungin area under the concentration-time curve (AUC)/MIC ratio. Monte Carlo simulation was used to evaluate the probability of achieving AUC/MIC ratios associated with efficacy. Mycological and clinical success rates for evaluable cases were 89.4 and 90.9, respectively. MIC50s and MIC90s for Candida species inhibition were 0.008 and 0.5 mg/liter, respectively. The median AUC/MIC ratio was 15,511 (range, 41.28 to 98,716). Univariable analyses revealed a significant relationship between the AUC/MIC ratio and mycological response, with the worst response being among patients with lower (≤3,000) AUC/MIC ratios (P=0.005). For patients with Candida parapsilosis, AUC/MIC ratios of ≥285 were predictive of a higher mycological response (P=0.11). Multivariable logistic regression demonstrated the AUC/MIC ratio, APACHE II score, and history of corticosteroid use to be significant independent predictors of a favorable response. PK-PD target attainment analyses suggested that 76.7% and 100% of patients would achieve an AUC/MIC ratio of ≥3,000 for an MIC of 0.03 mg/liter and an AUC/MIC ratio of ≥285 for an MIC of <0.5 mg/liter, respectively. The identification of a lower AUC/MIC ratio target for C. parapsilosis than other Candida species suggests consideration of species-specific echinocandin susceptibility breakpoints and values that are lower than those currently approved by regulatory agencies.

Topics: Antifungal Agents; Candidemia; Candidiasis; Clinical Trials, Phase III as Topic; Echinocandins; Female; Humans; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Monte Carlo Method; Randomized Controlled Trials as Topic

We report the appearance of Candida glabrata strains with reduced sensitivity during treatment with the echinocandin drug micafungin (MCF). Four C. glabrata strains were isolated from sputum, gastric juice, and blood taken from a patient during hospitalization. Two of these strains, one of which was obtained after treatment with MCF for suspected Candida pneumonia and the other of which was obtained during MCF treatment for candidemia, were isolated from blood and found to have a reduced susceptibility to MCF. These two clinical isolates showed a high minimum inhibitory concentration (MIC) for MCF, with this change in MIC being unique for MCF among established antifungal drugs. To further investigate the mechanism underlying this reduced sensitivity, an in vivo mouse infection model and in vitro enzymatic analysis were performed. MCF had little effect in the mouse disseminated infection model and enzymatic analysis showed the low affinity of MCF to the 1,3-Beta-D-glucan synthase of the clinical isolates, although the enzymes of both clinical isolates and control strain were noncompetitively inhibited by MCF. Taken together, this low affinity of MCF for the enzymes is likely to cause the reduced sensitivities. These data further indicate that MCF could induce acquired MCF-resistant strains during clinical use.

Topics: Aged; Animals; Antifungal Agents; Body Temperature; Candida glabrata; Candidemia; Disease Models, Animal; Echinocandins; Fatal Outcome; Female; Glucosyltransferases; Humans; Kinetics; Lipopeptides; Male; Micafungin; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests