Optimal doses of caspofungin during continuous venovenous hemodiafiltration in critically ill patients (original) (raw)
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International journal of antimicrobial agents, 2017
The objective of this study was to evaluate the efficacy of different dosages of caspofungin in the treatment of invasive candidiasis and aspergillosis, in relation to the probability of pharmacokinetic/pharmacodynamic target attainment, using modelling and Monte Carlo simulations in critically ill adult patients on continuous haemodiafltration. Critically ill adult patients on continuous venovenous haemodiafiltration treated with caspofungin were analysed. A population pharmacokinetic model was developed. Four caspofungin dosing regimens were simulated: the licensed regimen, 70 mg/day, 100 mg/day or 200 mg/day. A pharmacokinetic/pharmacodynamic target was defined as the ratio between the area under caspofungin concentration-time curve over 24 hours and the minimal inhibitory concentration (AUC/MIC) for candidiasis or the minimal effective concentrations (AUC/MEC) for Aspergillus spp. Target attainment based on preclinical target for Candida and Aspergillus was assessed for differen...
Journal of Antimicrobial Chemotherapy, 2014
To explore the pharmacokinetics (PK) and pharmacodynamics (PD) of micafungin in patients undergoing continuous venovenous haemofiltration (CVVH). Patients and methods: Ten patients receiving CVVH treated with 100 mg/day micafungin were included (April-December 2012). CVVH was performed using polyethersulphone or polysulphone haemofilters. Dialysis membranes were not changed on sampling days. On Days 1 and 2, blood samples from arterial pre-filter and venous post-filter ports and ultrafiltrate samples were collected at the start and end of the infusion and at 3, 5, 8, 18 and 24 h. Concentrations were determined using HPLC. Values for the area under the concentration-time curve (AUC 0-24) were calculated. Monte Carlo simulations were performed using pre-filter and post-filter AUC 0-24 / MIC ratios on Days 1 and 2. The probability of target attainment (PTA) was calculated using AUC 0-24 /MIC cutoffs: 285 (C. parapsilosis), 3000 (all Candida spp.) and 5000 (non-parapsilosis Candida spp.). Cumulative fraction responses (CFRs) were calculated using EUCAST MIC distributions. Results: Mean post-filter AUC 0-24 (mg. h/L) values were higher than pre-filter values on Day 1 (83.31+15.87 versus 71.31+14.24; P¼ 0.008) and Day 2 (119.01+27.20 versus 104.54+21.23; P ¼ 0.005). PTAs were ≥90% for MICs of 0.125 mg/L (cut-off ¼ 285), 0.016 mg/L (cut-off ¼ 3000) and 0.008 mg/L (cut-off ¼5000) on Day 1, and for MICs of 0.25 mg/L (cut-off ¼ 285) and 0.016 mg/L (cut-off¼ 3000 and 5000) on Day 2, without differences between pre-and post-filter values. On Day 2, CFRs .90% were obtained for C. albicans (cut-off ¼ 3000 and 5000) and C. glabrata (cut-off ¼ 3000), but not for C. parapsilosis. Conclusions: There was no removal of micafungin by CVVH or need for dose adjustment, and there was optimal PK/PD coverage for non-parapsilosis Candida and equivalence of pre-and post-filter PD.
Antimicrobial Agents and Chemotherapy, 2005
Pharmacokinetic and pharmacodynamic studies were conducted in a murine model of systemic candidiasis to determine the pharmacodynamic parameter linked with caspofungin efficacy. Additional studies defined the importance of persistent tissue drug concentrations to treatment outcome. The pharmacokinetics of caspofungin were determined in the serum and kidneys of infected mice over 96 h. Population pharmacokinetic analysis demonstrated a serum terminal half-life ( t 1/2 ) for caspofungin of 20.2 h when only serum concentrations were considered, but the terminal t 1/2 increased to 59.2 h when serum and kidney concentration-time data were comodeled. In dose-range studies, the dose-response effect was well described by an inhibitory sigmoid curve for the exposure-effect killing caused by the drug ( r 2 > 0.96; P ≪ 0.001). In dose-fractionation studies, fungal counts in kidneys were not statistically different for total doses given as one, two, or four equally divided doses over 96 h, i...
Journal of Medical Microbiology, 2014
Killing rates (K) of 1-32 mg ml "1 caspofungin were determined in RPMI-1640 and in 50 % serum using time-kill methodology against three Candida krusei (MICs of all three isolates 0.25 mg ml "1 in RPMI-1640 and 2 mg ml "1 in serum) and three Candida inconspicua clinical isolates (MIC ranges 0.06-0.12 mg ml "1 in RPMI-1640 and 0.25-0.5 mg ml "1 in serum), against C. krusei ATCC 6258 and against one C. krusei isolate that was resistant to echinocandins (MIC 8 mg ml "1 in RPMI-1640 and 32 mg ml "1 in serum). In RPMI-1640, the highest mean K values were observed at 4 ("1.05 h "1 ) and 16 ("0.27 h "1 ) mg ml "1 caspofungin for C. krusei and C. inconspicua clinical isolates, respectively. In 50 % serum, mean K value ranges at 1-32 and 4-32 mg ml "1 concentrations for C. inconspicua and C. krusei were "1.12 to "1.44 and "0.42 to "0.57 h "1 , respectively. While K values against C. krusei in RPMI-1640 and 50 % serum were comparable, serum significantly increased the killing rate against C. inconspicua (P,0.0003 for all tested concentrations). In a neutropenic murine model, daily caspofungin at 1, 2, 3, 5 and 15 mg kg "1 significantly decreased the fungal tissue burden of C. inconspicua in the kidneys (P,0.05-0.001). Against C. krusei, doses of 3, 5 and 15 mg kg "1 caspofungin were effective (P,0.05-0.01). All effective doses were comparably efficacious for both species. Only the highest 15 mg kg "1 caspofungin dose was effective even against the echinocandin-resistant C. krusei isolate. In 50 % serum, killing was concentration independent at effective concentrations (¢4 and ¢1 mg ml "1 for C. krusei and C. inconspicua, respectively), suggesting that the efficacy of dose escalation is questionable. These in vitro results were also supported by the murine model.
Mycopathologia, 2014
It was previously demonstrated that brief (≤1 h) exposures to echinocandins are as effective to kill Candida albicans cells as continuous 24-h exposure. However, killing rates after continuous and short (1 h) echinocandin exposures to C. albicans have not yet been evaluated in RPMI-1640 with and without 50 % serum. We evaluated four echinocandin susceptible C. albicans bloodstream isolates, ATCC 10231 type strain and an echinocandin-resistant isolate (DPL20, FKS F645P). Caspofungin MICs, time-kill and postantifungal effect (PAFE) tests were performed in RPMI-1640 with and without 50 % serum. Killing rates (k values) in time-kill and PAFE experiments were determined for each strain and concentration. In time-kill experiments, colony count decreases were isolate- and concentration-dependent at 0.25, 1, 4, 8, 16 and 32 mg/L in RPMI-1640, but concentration-independent at 1, 4, 8, 16 and 32 mg/L in 50 % serum. One-hour caspofungin exposure at 4, 16 and 32 mg/L resulted in CFU decreases c...
European Journal of Clinical Microbiology & Infectious Diseases, 2012
The safety and efficacy profile of caspofungin and micafungin in Japanese patients with fungal infections were directly compared in this prospective, randomized, double-blind study. The proportion of patients who developed significant drug-related adverse event(s) (defined as a serious drug-related adverse event or a drug-related adverse event leading to study therapy discontinuation) was compared in 120 patients [caspofungin 50 mg, or 50 mg following a 70-mg loading dose on Day 1 (hereinafter, 70/50 mg) group: 60 patients; micafungin 150 mg: 60 patients]. The overall response rate was primarily evaluated in the perprotocol set (PPS) population. The proportion of patients who developed significant drug-related adverse events was 5.0 % (3/60) in the caspofungin group and 10.0 % (6/60) in the micafungin group [95 % confidence interval (CI) for the difference: −15.9 %, 5.2 %]. The favorable overall response in the PPS population for patients with esophageal candidiasis, invasive candidiasis, and chronic pulmonary aspergillosis including aspergilloma was 100.0 % (6/6), 100.0 % (3/ 3), and 46.7 % (14/30) in the caspofungin group, and 83.3 % (5/6), 100.0 % (1/1), and 42.4 % (14/33) in the micafungin group, respectively. In Japanese patients with Candida or Aspergillus infections, there was no statistical difference in the safety between caspofungin and micafungin. Consistent with other data on these two agents, the efficacy of caspofungin and micafungin was similar.
Clinical Infectious Diseases, 2009
Background. The standard caspofungin treatment regimen (50 mg/day after a 70-mg dose on day 1) is effective and well tolerated for the treatment of invasive candidiasis, but experience with higher doses of caspofungin is limited. We evaluated the safety and efficacy of caspofungin at 3 times the standard dosing regimen. Methods. Patients with proven invasive candidiasis were randomized to receive a standard or high-dose (150 mg/day) caspofungin treatment regimen. Safety was assessed in all patients as treated. Efficacy was assessed as a secondary objective in a full-analysis-set population. A favorable overall response was defined as symptom resolution and microbiological clearance at the end of caspofungin therapy. Results. A total of 204 patients were included in the safety analysis (104 received the standard regimen, and 100 received the high-dose regimen), and 197 were included in the efficacy analysis (102 and 95 in the standard and high-dose treatment groups, respectively). Patient demographic characteristics, neutropenia status (6.7% and 8.0% had neutropenia, respectively), and Acute Physiology and Chronic Health Evaluation II scores (mean, 16.5 and 17, respectively) were similar between treatment groups. Significant drug-related adverse events occurred in 1.9% of patients receiving the standard regimen and 3.0% of patients receiving the high-dose regimen (difference, 1.1%; 95% confidence interval, Ϫ4.1% to 6.8%). The most-common drug-related adverse events in the standard and high-dose treatment groups were phlebitis (3.8% and 2.0%, respectively), increased alkaline phosphatase level (6.9% and 2.0%, respectively), and increased aspartate transaminase level (4.0% and 2.0%, respectively). Overall, 71.6% of patients who received the standard regimen and 77.9% of patients who received the high-dose regimen had favorable overall responses (difference, 6.3%; 95% confidence interval, Ϫ5.9% to 18.4%; not statistically significant). Mortality at 8 weeks after therapy was similar between groups. Conclusions. Both caspofungin dosing regimens were effective and well tolerated in patients with invasive candidiasis. No safety concerns were found for caspofungin at a dosage of 150 mg/day. The incidence and clinical importance of serious Candida infections have increased dramatically during the
Dose escalation studies with caspofungin against Candida glabrata
Journal of Medical Microbiology, 2015
Echinocandins are recommended as first-line agents against invasive fungal infections caused by Candida glabrata, which still carry a high mortality rate. Dose escalation of echinocandins has been suggested to improve the clinical outcome against C. glabrata. To address this possibility, we performed in vitro and in vivo experiments with caspofungin against four WT C. glabrata clinical isolates, a drug-susceptible ATCC 90030 reference strain and two echinocandinresistant strains with known FKS mutations. MIC values for the clinical isolates in RPMI 1640 were #0.03 mg l 21 but increased to 0.125-0.25 mg l 21 in RPMI 1640+50 % serum. In RPMI 1640+50 % serum, the replication of C. glabrata was weaker than in RPMI 1640.Caspofungin in RPMI 1640 at 1 and 4 mg l 21 showed a fungicidal effect within 7 h against three of the four clinical isolates but was only fungistatic at 16 and 32 mg l 21 (paradoxically decreased killing activity). In RPMI 1640+50 % serum, caspofungin at ¢1 mg l 21 was rapidly fungicidal (within 3.31 h) against three of the four isolates. In a profoundly neutropenic murine model, all caspofungin doses (1, 2, 3, 5 and 20 mg kg 21 daily) decreased the fungal tissue burdens significantly (P,0.05-0.001) without statistical differences between doses, but the mean fungal tissue burdens never fell below 10 5 cells (g tissue) 21 .The echinocandin-resistant strains were highly virulent in animal models and all doses were ineffective. These results confirm the clinical experience that caspofungin dose escalation does not improve efficacy.
Journal of Microbiology, Immunology and Infection, 2014
Background: Although echinocandins have high in vitro antifungal efficacy according to prior reports, comparative studies on the clinical cure rates of anidulafungin, caspofungin, and micafungin in systemic candida infections have not yet been reported. Methods: Interpretation of clinical and microbiological responses to anidulafungin, caspofungin, and micafungin in 109 cases of candidemia was done according to the published criteria. The clinical cure rates between patients treated with echinocandins and patients treated with fluconazole were also compared. The minimal inhibitory concentrations (MICs) of anidulafungin, caspofungin, micafungin, and fluconazole for these 109 blood isolates of candida were determined with the Clinical and Laboratory Standards Institute M27-A reference microdilution method. Logistic regression with forward selection was used to determine the important factors of prognosis with variables such as age, underlying diseases, acute physiology and chronic health evaluation (APACHE) III score, persistent candidemia, and antimicrobial therapy. Results: Among the 109 cases of candidemia, 70 were treated with echinocandins, azoles, or amphotericin B for !7 days. The clinical cure rate of cases treated with antifungal agents adequately (!7 days) and inadequately (<7 days) were 44/70 (62.9%) and 4/39 (10.2%),