In vitro activity of micafungin (FK-463) against Candida spp.: microdilution,time-kill,and postantifungal-effect studies

We evaluated the in vitro activity of the new echinocandin antifungal micafungin against Candida spp. using microdilution and time-kill methods. Additionally, we examined the postantifungal effect (PAFE) of micafungin. Finally, we evaluated the effect of the addition of serum and plasma on the MIC of micafungin. Four Candida albicans isolates and two isolates of each Candida glabrata, Candida krusei, and Candida tropicalis were selected for testing. The MICs of micafungin were determined in RPMI 1640 medium buffered with morpholinepropanesulfonic acid alone and with the addition of 10, 20, and 50% human serum and plasma. MICs were determined by using two endpoints: a prominent reduction in growth (the MIC at which 80% of isolates are inhibited [MIC(80)]) and complete visual inhibition of growth (MIC(100)). The minimum fungicidal concentration (MFC) of micafungin for each isolate was also determined. Time-kill curves were determined for each isolate in RPMI 1640 medium with micafungin at concentrations ranging from 0.125 to 16 times the MIC(80) to assess the correlation between MIC(80) and fungicidal activity. PAFE studies were conducted with each isolate by using concentrations ranging between 0.25 and 4 times the MIC(80). The MIC(80)s for the test isolates ranged from 0.0039 to 0.25 micro g/ml. Overall, the addition of serum or plasma increased the MIC 6 to 7 doubling dilutions for C. albicans and 3 to 4 doubling dilutions for C. krusei and C. tropicalis. Micafungin time-kill studies demonstrated fungicidal activity at concentrations ranging from 4 to 16 times the MIC(80). Micafungin is very potent agent against a variety of Candida spp., producing fungicidal activity against 7 of 10 isolates tested. A PAFE was observed against all isolates. The PAFE was influenced by the drug concentration, with the highest concentration resulting in the longest observed PAFE in each case. The highest concentration tested, four times the MIC, resulted in a PAFE of more than 9.8 h for 5 of 10 isolates tested (range, 0.9 to > or =20.1 h).     

Compartmental Pharmacokinetics and Tissue Distribution of the Antifungal Echinocandin Lipopeptide Micafungin (FK463) in Rabbits

The plasma pharmacokinetics and tissue distribution of the novel antifungal echinocandin-like lipopeptide micafungin (FK463) were investigated in healthy rabbits. Cohorts of three animals each received micafungin at 0.5, 1, and 2 mg/kg of body weight intravenously once daily for a total of 8 days. Serial plasma samples were collected on days 1 and 7, and tissue samples were obtained 30 min after the eighth dose. Drug concentrations were determined by validated high-performance liquid chromatographic methods. Plasma drug concentration data were fit to a two-compartment pharmacokinetic model, and pharmacokinetic parameters were estimated using weighted nonlinear least-square regression analysis. Micafungin demonstrated linear plasma pharmacokinetics without changes in total clearance and dose-normalized area under the concentration-time curve from 0 h to infinity. After administration of single doses to the rabbits, mean peak plasma drug concentrations ranged from 7.62 microg/ml at 0.5 mg/kg to 16.8 microg/ml at 2 mg/kg, the area under the concentration-time curve from 0 to 24 h ranged from 5.66 to 21.79 microg x h/ml, the apparent volume of distribution at steady state ranged from 0.296 to 0.343 liter/kg, and the elimination half-life ranged from 2.97 to 3.20 h, respectively. No significant changes in pharmacokinetic parameters and no accumulation was noted after multiple dosing. Mean tissue micafungin concentrations 30 min after the last of eight daily doses were highest in the lung (2.26 to 11.76 microg/g), liver (2.05 to 8.82 microg/g), spleen (1.87 to 9.05 microg/g), and kidney (1.40 to 6.12 microg/g). While micafungin was not detectable in cerebrospinal fluid, the concentration in brain tissue ranged from 0.08 to 0.18 microg/g. These findings indicate linear disposition of micafungin at dosages of 0.5 to 2 mg/kg and achievement of potentially therapeutic drug concentrations in plasma and tissues that are common sites of invasive fungal infections.     

Efficacy of micafungin against deep-seated candidiasis in cyclophosphamide-induced immunosuppressed mice

OBJECTIVES: We investigated the effects of fluconazole and micafungin for the therapy of deep-seated candidiasis in a cyclophosphamide-induced immunosuppressed mouse model. METHODS: We used the experimental model of intraperitoneal fungal abscess caused by Candida albicans, as described previously. RESULTS AND CONCLUSIONS: Micafungin efficacy was equal to that of fluconazole in one-tenth dosage even in peritonitis. We also assessed the short-term (24 h) and long-term (8 days) therapeutic effects after the end of therapy. Although the therapeutic effect of fluconazole was similar to that of micafungin at 24 h after the end of therapy, the effect of micafungin was superior to that of fluconazole at 8 days after the end of therapy.     

Altered Micafungin Pharmacokinetics in Intensive Care Unit Patients

Micafungin is considered an important agent for the treatment of invasive fungal infections in the intensive care unit (ICU). Little is known on the pharmacokinetics of micafungin. We investigated micafungin pharmacokinetics (PK) in ICU patients and set out to explore the parameters that influence micafungin plasma concentrations. ICU patients receiving 100 mg of intravenous micafungin once daily for suspected or proven fungal infection or as prophylaxis were eligible. Daily trough concentrations and PK curves (days 3 and 7) were collected. Pharmacokinetic analysis was performed using a standard two-stage approach. Twenty patients from the ICUs of four hospitals were evaluated. On day 3 (n = 20), the median (interquartile range [IQR]) area under the concentration-time curve from 0 to 24 h (AUC_0–24) was 78.6 (65.3 to 94.1) mg · h/liter, the maximum concentration of drug in serum (C_max) was 7.2 (5.4 to 9.2) mg/liter, the concentration 24 h after dosing (C₂₄) was 1.55 (1.4 to 3.1) mg/liter, the volume of distribution (V) was 25.6 (21.3 to 29.1) liters, the clearance (CL) was 1.3 (1.1 to 1.5) liters/h, and the elimination half-life (t_1/2) was 13.7 (12.2 to 15.5) h. The pharmacokinetic parameters on day 7 (n = 12) were not significantly different from those on day 3. Daily trough concentrations (day 3 to the end of therapy) showed moderate interindividual (57.9%) and limited intraindividual variability (12.9%). No covariates of the influence on micafungin exposure were identified. Micafungin was considered safe and well tolerated. We performed the first PK study with very intensive sampling on multiple occasions in ICU patients, which aided in resolving micafungin PK. Strikingly, micafungin exposure in our cohort of ICU patients was lower than that in healthy volunteers but not significantly different from that of other reference populations. The clinical consequence of these findings must be investigated in a pharmacokinetic-pharmacodynamic (PK-PD) study incorporating outcome in a larger cohort. (This study is registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01783379","term_id":"NCT01783379"}}NCT01783379.)     

Endotoxin does not alter the pharmacokinetics of micafungin,but it impairs biliary excretion of micafungin via multidrug resistance-associated protein 2 (ABCC2/Mrp2) in rats

Micafungin, a newly developed echinocandin-type antifungal agent, is widely used for the treatment of deep-seated fungal infections including those of Candida species and Aspergillus species. In the present study, the possible alterations in the pharmacokinetics and biliary excretion of micafungin were investigated in endotoxemic rats induced by Klebsiella pneumoniae endotoxin. Endotoxin (2 mg/kg) was injected intraperitoneally 24 h before an intravenous injection of micafungin (1 mg/kg). No significant differences in the plasma concentration–time curves and pharmacokinetic parameters of micafungin were observed between endotoxin-treated and endotoxin-untreated rats. When endotoxin-treated rats received a constant-rate infusion of micafungin, the biliary clearance of micafungin was significantly decreased, whereas the steady-state plasma concentration did not change. By protein immunoblot analysis, a significant decrease in the expression of hepatic multidrug resistance-associated protein 2 (ABCC2/Mrp2), which is an efflux protein for micafungin, was observed in endotoxin-treated rats. These results suggest that endotoxin-induced decrease in the hepatobiliary excretion of micafungin is caused, at least in part, by the reduction of Mrp2-mediated hepatobiliary transport ability. The present study may provide information suggesting that micafungin can be used for patients with endotoxemia without the need for dosage adjustment.     

Differential in vivo activities of anidulafungin, caspofungin, and micafungin against Candida glabrata isolates with and without FKS resistance mutations

We recently observed that the micafungin MICs for some Candida glabrata fks hot spot mutant isolates are less elevated than those for the other echinocandins, suggesting that the efficacy of micafungin may be differentially dependent on such mutations. Three clinical C. glabrata isolates with or without (S3) fks hot spot mutations R83 (Fks2p-S663F) and RR24 (Fks1p-S629P) and low, medium, and high echinocandin MICs, respectively, were evaluated to assess the in vivo efficacy in an immunocompetent mouse model using three doses of each echinocandin. Drug concentrations were determined in plasma and kidneys by high-performance liquid chromatography (HPLC). A pharmacokinetic-pharmacodynamic mathematical model was used to define the area under the concentration-time curve (AUC) that produced half- and near-maximal activity. Micafungin was equally efficacious against the S3 and R83 isolates. The estimates for the AUCs of each echinocandin that induced half-maximal effect (E(50)s) were 194.2 and 53.99 mg · h/liter, respectively. In contrast, the maximum effect (E(max)) for caspofungin was higher against S3 than R83, but the estimates for E(50) were similar (187.1 and 203.5 mg · h/liter, respectively). Anidulafungin failed to induce a ≥1-log reduction for any of the isolates (AUC range, 139 to 557 mg · h/liter). None of the echinocandins were efficacious in mice challenged with the RR24 isolate despite lower virulence (reduced maximal growth, prolonged lag phase, and lower kidney burden). The AUC associated with half-maximal effect was higher than the average human exposure for all drug-dose-bug combinations except micafungin and the R83 isolate. In conclusion, differences in micafungin MICs are associated with differential antifungal activities in the animal model. This study may have implications for clinical practice and echinocandin breakpoint determination, and further studies are warranted.     

In vivo activity of micafungin in a persistently neutropenic murine model of disseminated infection caused by Candida tropicalis

Micafungin is a new echinocandin with broad-spectrum in vitro and in vivo antifungal activity against both Aspergillus and Candida species. We compared the activity of micafungin with that of amphotericin B and fluconazole in a persistently immunocompromised murine model of disseminated candidiasis against a strain of Candida tropicalis that was resistant to amphotericin B and fluconazole in vitro. Mice were rendered persistently neutropenic with multiple doses of cyclophosphamide and infected intravenously with C. tropicalis. Mice were treated with either intraperitoneal amphotericin B (0.5-5 mg/kg per dose), oral fluconazole (50 mg/kg twice a day), intravenous micafungin (1-10 mg/kg per dose) or solvent control for 7 days. Mice were killed at 11 days post-infection and kidneys, lungs, brain and liver removed for quantitative culture. Overall mortality in the model was low, with rates varying between 10% and 25% in treatment groups. Micafungin at doses between 2 and 10 mg/kg were the only regimes able to reduce cfu below the level of detection of tissues infected with C. tropicalis. Micafungin was well tolerated by the mice and was much more effective than amphotericin B or fluconazole against an amphotericin B- and fluconazole-resistant C. tropicalis.     

Relationship between the initial dose of micafungin and its efficacy in patients with candidemia

Micafungin, the first licensed echinocandin in Japan, has shown excellent in vitro and in vivo activity against all Candida species. However, the appropriate dose for the initial treatment of candidemia remains to be determined. In this study, we retrospectively examined the relationship between the clinical outcome of candidemia and the initial dose of micafungin. Patients were divided into two groups according to the initial dose of micafungin administered: group I (<2.25 mg/kg/day) and group II (≥2.25 mg/kg/day). Micafungin produced an excellent 30-day clinical response in patients with candidemia, including Candida parapsilosis; the overall 30-day clinical response was 86%. The administration of higher doses of micafungin accelerated the clinical response and duration until the clinical response in group II was significantly shorter than that in group I (P = 0.021). However, no significant differences were observed in the 30-day mortality attributable to the fungal infection between the two groups. Considering these results, we recommend the administration of 2.25 mg/kg/day or more of micafungin in the initial treatment of patients with candidemia. Y. Ota, K. Tatsuno and S. Okugawa equally contributed to the study.     

Effect of 50% human serum on the killing activity of micafungin against eight Candida species using time-kill methodology

Micafungin activity was determined against 24 wild-type clinical isolates and 5 American Type Culture Collection strains belonging to 8 Candida species in RPMI-1640 with and without 50% serum using broth microdilution and time-kill methodology. MIC values increased from 4- to 128-folds in 50% serum for all Candida species. Micafungin was not fungicidal against C. albicans, C. tropicalis, and against 2 of 3 C. metapsilosis at ≥0.25, 1, and 1 μg/mL, respectively, after 48 h with 50% serum, showing good fungistatic activity. Fungicidal activity at ≥2, 4, and 32 μg/mL was noticed against C. glabrata, C. inconspicua, and C. krusei isolates, respectively. Micafungin at 8-32 μg/mL showed fungistatic activity against C. parapsilosis and C. orthopsilosis. Serum decreased the in vitro activity of micafungin. With serum binding of echinocandins taken into account, safely fungistatic or fungicidal concentrations seem to require elevated doses against some Candida species, including C. parapsilosis, C. orthopsilosis, and C. krusei.     

Safety, tolerability, and pharmacokinetics of Micafungin (FK463) in febrile neutropenic pediatric patients

Micafungin (FK463) is a new parenteral echinocandin. A multicenter, phase I, open-label, sequential-group dose escalation study was conducted to assess the safety, tolerability, and pharmacokinetics of micafungin in neutropenic pediatric patients. A total of 77 patients stratified by age (2 to 12 and 13 to 17 years) received micafungin. Therapy was initiated at 0.5 mg/kg per day and escalated to higher dose levels of 1.0, 1.5, 2.0, 3.0, and 4.0 mg/kg per day. Micafungin was administered within 24 h of initiating broad-spectrum antibacterial antibiotics for the new onset of fever and neutropenia. The most common overall adverse events in the study population were diarrhea (19.5%), epistaxis (18.2%), abdominal pain (16.9%), and headache (16.9%). Nine patients (12%) experienced adverse events considered by the investigator to be possibly related to the study drug. The most common related events were diarrhea, vomiting, and headache, all occurring in two patients each. There was no evidence of a dose-limiting toxicity as defined within the prespecified criteria of this clinical protocol. There was one death during the study due to septic shock. The pharmacokinetic profiles for micafungin over the 0.5- to 4.0-mg/kg dose range demonstrated dose linearity. Clearance, volume of distribution, and half-life remained relatively constant over the dose range and did not change with repeated administration. The overall plasma pharmacokinetic profile was similar to that observed in adults. However, there was an inverse relation between age and clearance. For patients 2 to 8 years old, clearance was approximately 1.35 times that of patients >/=9 years of age. In summary, micafungin over a dosage range between 0.5 and 4.0 mg/kg/day in 77 febrile neutropenic pediatric patients displayed linear pharmacokinetics and increased clearance as a function of decreasing age.     

In vitro antifungal activity of Micafungin (FK463) against dimorphic fungi: comparison of yeast-like and mycelial forms

The characteristics of in vitro micafungin (FK463) antifungal activity against six species of dimorphic fungi were investigated in accordance with the NCCLS M27-A microdilution methods. MICs of micafungin, amphotericin B, itraconazole, and fluconazole for Histoplasma capsulatum var. capsulatum, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Penicillium marneffei, and Sporothrix schenckii were determined both for the yeast-like form and mycelial form. Coccidioides immitis was tested only in its mycelial form. We have clearly demonstrated that the in vitro activity of micafungin depends considerably on the growth form of dimorphic fungi. Micafungin exhibited potent activity against the mycelial forms of H. capsulatum, B. dermatitidis, and C. immitis (MIC range, 0.0078 to 0.0625 micro g/ml), while it was very weakly active against their yeast-like forms (MIC range, 32 to >64 micro g/ml). Micafungin was also more active against the mycelial forms than the yeast-like forms of Paracoccidioides brasiliensis, Penicillium marneffei, and S. schenckii. The MICs of amphotericin B were 2 to 5 dilutions lower for the mycelial forms than for the yeast-like forms of B. dermatitidis and Paracoccidioides brasiliensis. There was no apparent difference in the activity of itraconazole between the two forms. The MICs of fluconazole for the yeast-like forms were generally lower than those for the mycelial forms, and considerably so for B. dermatitidis. These results suggest that the growth form employed in antifungal susceptibility testing of dimorphic fungi can considerably influence the interpretation of results. At present, it cannot be judged whether micafungin has clinical usefulness for dimorphic fungus infections, since for most fungi it remains uncertain which growth form correlates better with therapeutic outcome. However, the results of this study warrant further investigations of micafungin as a therapeutic agent for infections caused by dimorphic fungi.     

Effect of the growth medium on the in vitro antifungal activity of micafungin (FK-463) against clinical isolates of Candida dubliniensis.

Micafungin (FK-463), a member of the new candin family of antifungal agents, was highly active against clinical isolates of Candida albicans and Candida dubliniensis. The in vitro activity of micafungin suggested that it was more potent than fluconazole, flucytosine, amphotericin B or voriconazole against C. albicans, and comparable or moderately less effective against C. dubliniensis isolates when high-resolution medium (HR) was used. Lower MICs of micafungin were recorded when RPMI 2% or AM3 2% media were used, indicating an influence of the growth medium on the MIC.     

Micafungin

OBJECTIVE: To review the pharmacology, mycology, chemistry, in vitro susceptibility, pharmacokinetics, clinical efficacy, safety, tolerability, dosage, and administration of micafungin, an echinocandin antifungal agent. DATA SOURCES: A MEDLINE search, restricted to English language, was conducted from 1978 to November 2003. Supplementary sources included program abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy and the Infectious Diseases Society of America from 1996 to 2003 and information available through the manufacturer's Web site. STUDY SELECTION AND DATA EXTRACTION: In vitro and preclinical studies, as well as Phase II and III clinical trials, were evaluated to summarize the clinical efficacy and safety of micafungin. All published and unpublished trials and abstracts citing micafungin were selected. DATA SYNTHESIS: Micafungin has shown in vitro activity against many yeasts and a variety of molds. Micafungin can be administered only parenterally. Efficacy has been illustrated in open noncomparative studies of esophageal candidiasis in HIV-infected patients and in comparative trials as antifungal prophylaxis in patients undergoing hematopoietic stem-cell transplantation. Adverse events appear mild and limited; the most commonly reported adverse events include hyperbilirubinemia, nausea, and diarrhea. CONCLUSIONS: Micafungin has activity against Aspergillus spp. and a variety of Candida spp., including azole-resistant strains. Micafungin demonstrates efficacy in the treatment of esophageal candidiasis in HIV-infected patients and appears superior to fluconazole as antifungal prophylaxis in patients undergoing hematopoietic stem-cell transplantation. Based on case reports and in vitro efficacy, micafungin may prove to be a clinically useful agent in the treatment of other fungal diseases; however, these indications await the results of clinical trials.     

Role of plasma proteins in pharmacokinetics of micafungin, an antifungal antibiotic, in analbuminemic rats

There were no significant differences in the pharmacokinetics of micafungin and expression of hepatic multidrug resistance-associated protein 2 (ABCC2/Mrp2) between analbuminemic and Sprague-Dawley rats. Micafungin bound strongly to high-density lipoprotein (HDL) and moderately to gamma globulin. These results suggest that HDL and gamma globulin contribute to the pharmacokinetics of micafungin.     

Comparative effects of micafungin, caspofungin, and anidulafungin against a difficult-to-treat fungal opportunistic pathogen, Candida glabrata

The aim of this study was to compare the in vitro and in vivo activities of micafungin, caspofungin, and anidulafungin against Candida glabrata. The MICs against 28 clinical isolates showed that the overall susceptibilities to caspofungin and to micafungin were not statistically different in the absence of human serum, whereas the isolates were less susceptible to micafungin than to caspofungin in its presence. Minimum fungicidal concentrations, as well as time-kill experiments, showed that caspofungin was more active than anidulafungin, while micafungin was superior to either caspofungin or anidulafungin without serum; its addition rendered caspofungin and micafungin equally effective. A murine model of systemic candidiasis against a C. glabrata-susceptible isolate was performed to study the effects of all three echinocandins, and kidney burden counts showed that caspofungin, micafungin, and anidulafungin were active starting from 0.25, 1, and 5 mg/kg of body weight/day, respectively. Two echinocandin-resistant strains of C. glabrata were selected: C. glabrata 30, a laboratory strain harboring the mutation Fks2p-P667T, and C. glabrata 51, a clinical isolate harboring the mutation Fks2p-D666G. Micafungin activity was shown to be as effective as or more effective than that of caspofungin or anidulafungin in terms of MICs. In vivo studies against these resistant strains showed that micafungin was active starting from 1 mg/kg/day, while caspofungin was effective only when administrated at higher doses of 5 or 10 mg/kg/day. Although a trend toward colony reduction was observed with the highest doses of anidulafungin, a significant statistical difference was never reached.     

Micafungin enhances neutrophil fungicidal functions against Candida pseudohyphae

We evaluated the effect of the combination of micafungin and polymorphonuclear leukocytes (PMN) against hyphae of Candida albicans and Candida dubliniensis. Micafungin enhanced the PMN oxidative burst dose dependently. The combination was synergistic (C. albicans) or additive (C. dubliniensis); when PMN were pretreated with granulocyte-macrophage colony-stimulating factor, the combination was more effective.     

Elevated hyaluronan blood concentrations in severely burned patients.

Hyaluronan (HYA) is a polysaccharide found in the interstitial matrix in most tissues. HYA is removed by lymphatic drainage and degraded in local lymph nodes and in the liver. Its normal concentration in human plasma is very low (10-100 micrograms l-1). Following major burn injury in sheep plasma HYA can increase to levels tenfold greater than normal. In the present study, serum HYA concentrations were determined in 10 severely burned patients (burn size: 28 +/- 5% of body surface area (mean +/- SEM)). Serum HYA concentration was 206 +/- 71 micrograms l-1 at 24 h post-injury, twice the upper normal HYA concentration, and remained moderately elevated for the first week post-injury. It appears that mobilization and transport of HYA from the tissues is increased after thermal injury. Increased systemic concentrations of an interstitial matrix component have not previously been reported in burn patients. Possibly, plasma concentrations of connective tissue components might serve as indicators of the severity and extent of burn injuries.     

Micafungin: a therapeutic review

In recent decades, the incidence of aspergillosis, candidiasis and clinically important deep mycoses has been increasing, with advances in transplantation medicine and anticancer chemotherapy. Micafungin (FK463, Fujisawa Healthcare) has been developed as a novel type of antifungal agent, which inhibits 1,3-beta-D-glucan synthase in the fungal cell wall. Micafungin, one of the echinocandins, exhibits extremely high antifungal activity against Aspergillus spp. and Candida spp. in vitro. It is also characterized by a linear pharmacokinetic profile and a much lower prevalence of adverse reactions than amphotericin B. Micafungin is quite useful in the treatment of deep mycoses. In clinical studies in Japan, micafungin was found to be highly effective against aspergillosis (57.1% overall efficacy rate) and candidiasis (78.6%). Micafungin is expected to increase the efficacy rate of treatment in patients with severe aspergillosis or candidiasis when used in combination with amphotericin B or mold azoles.     

Intrapulmonary Pharmacokinetics and Pharmacodynamics of Micafungin in Adult Lung Transplant Patients

Invasive pulmonary aspergillosis is a life-threatening infection in lung transplant recipients; however, no studies of the pharmacokinetics and pharmacodynamics (PKPD) of echinocandins in transplanted lungs have been reported. We conducted a single-dose prospective study of the intrapulmonary and plasma PKPD of 150 mg of micafungin administered intravenously in 20 adult lung transplant recipients. Epithelial lining fluid (ELF) and alveolar cell (AC) samples were obtained via bronchoalveolar lavage performed 3, 5, 8, 18, or 24 h after initiation of infusion. Micafungin concentrations in plasma, ELF, and ACs were determined using high-pressure liquid chromatography. Noncompartmental methods, population analysis, and multiple-dose simulations were used to calculate PKPD parameters. C_max in plasma, ELF, and ACs was 4.93, 1.38, and 17.41 μg/ml, respectively. The elimination half-life in plasma was 12.1 h. Elevated concentrations in ELF and ACs were sustained during the 24-h sampling period, indicating prolonged compartmental half-lives. The mean micafungin concentration exceeded the MIC₉₀ of Aspergillus fumigatus (0.0156 μg/ml) in plasma (total and free), ELF, and ACs throughout the dosing interval. The area under the time-concentration curve from 0 to 24 h (AUC_0-24)/MIC₉₀ ratios in plasma, ELF, and ACs were 5,077, 923.1, and 13,340, respectively. Multiple-dose simulations demonstrated that ELF and AC concentrations of micafungin would continue to increase during 14 days of administration. We conclude that a single 150-mg intravenous dose of micafungin resulted in plasma, ELF, and AC concentrations that exceeded the MIC₉₀ of A. fumigatus for 24 h and that these concentrations would continue to increase during 14 days of administration, supporting its potential activity for prevention and early treatment of pulmonary aspergillosis.Postoperative invasive pulmonary aspergillosis is a frequent clinical problem among patients who have undergone lung transplantation (13, 23, 38-42). Strategies for management of invasive pulmonary aspergillosis in lung transplant recipients are not well defined. While voriconazole is indicated for the primary treatment of invasive aspergillosis, not all patients are able to tolerate this triazole, and drug interactions may be complicated. The role of echinocandins in treatment and prevention of invasive aspergillosis in lung transplant recipients is unknown. Although most lung transplant centers administer some form of antifungal prophylaxis, these regimens vary widely from center to center, and the optimal strategy for prophylaxis is unknown. Aerosolized amphotericin B, either alone or with systemically administered antifungal agents, may be used for prevention of invasive aspergillosis in lung transplant recipients (13).Micafungin, a member of the echinocandin class of antifungal agents, has in vitro as well as in vivo activities against Candida spp. and Aspergillus spp. in treatment of experimental disseminated candidiasis (3, 5, 6, 33-35) and invasive pulmonary aspergillosis (33). Micafungin is licensed for the treatment of patients with esophageal candidiasis and candidemia (5, 12, 15, 30, 32, 36, 49). Micafungin also is approved for prevention of candidemia in neutropenic hematopoietic stem cell transplant recipients (44). Micafungin has been studied alone or in combination with other antifungal agents for treatment of invasive aspergillosis in hematopoietic stem cell transplant recipients (22). Although studies of micafungin for treatment and prevention of invasive pulmonary aspergillosis in animal models and in patients have demonstrated activity against this serious infection (8, 26, 33, 45), little is known about its intrapulmonary pharmacokinetics in patients at risk for invasive aspergillosis (28). We therefore studied the simultaneous intrapulmonary and plasma pharmacokinetics and pharmacodynamics of micafungin in adult lung transplant recipients.     

Micafungin: a therapeutic review

In recent decades, the incidence of aspergillosis, candidiasis and clinically important deep mycoses has been increasing, with advances in transplantation medicine and anticancer chemotherapy. Micafungin (FK463, Fujisawa Healthcare) has been developed as a novel type of antifungal agent, which inhibits 1,3-β-D-glucan synthase in the fungal cell wall. Micafungin, one of the echinocandins, exhibits extremely high antifungal activity against Aspergillus spp. and Candida spp. in vitro. It is also characterized by a linear pharmacokinetic profile and a much lower prevalence of adverse reactions than amphotericin B. Micafungin is quite useful in the treatment of deep mycoses. In clinical studies in Japan, micafungin was found to be highly effective against aspergillosis (57.1% overall efficacy rate) and candidiasis (78.6%). Micafungin is expected to increase the efficacy rate of treatment in patients with severe aspergillosis or candidiasis when used in combination with amphotericin B or mold azoles.