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PubMed2004

Combined action of micafungin, a new echinocandin, and human phagocytes for antifungal activity against Aspergillus fumigatus.

Micafungin, a new echinocandin, inhibits fungal cell wall beta-glucan synthesis. We postulated micafungin and host phagocytic cells could act together in damaging fungi. Using the metabolic XTT assay, micafungin alone (0.01 and 0.10 microg/ml) inhibited Aspergillus fumigatus germlings by 48% and 61%, respectively. Polymorphonuclear neutrophils (PMNs) inhibited germlings by 53%. Micafungin at 0.01 or 0.10 microg/ml and PMNs resulted in additive inhibition, 82% and 99%, respectively. Monocyte-derived macrophage (MDM) monolayers inhibited germling growth by 66%; micafungin (0.01 or 0.10 microg/ml) alone inhibited by 32% and 42%, respectively. MDMs and micafungin (0.01 or 0.10 microg/ml) caused an additive inhibition of growth, 85% and 95%, respectively. Hyphae were generated by incubation of conidia for 24 h with or without micafungin. PMNs alone, added to hyphae, inhibited growth by 19% in the subsequent 20 h. Hyphae generated in the presence of micafungin (0.10 microg/ml) and subsequently cultured with micafungin for 24 h inhibited growth by 64%. PMNs plus micafungin resulted in 82% inhibition. Monocytes alone inhibited hyphal growth by only 5%. Hyphae produced in the presence of micafungin (0.01 microg/ml) and incubated again with micafungin for 24 h inhibited growth by 47%; combination with monocytes resulted in 62% inhibition. These data indicate that micafungin inhibits growth of tissue forms of A. fumigatus, and phagocytes and micafungin together have an additive effect. These findings support the thesis that the greater efficacy of micafungin in vivo compared with in vitro could be due to combined effect of phagocytic cells and micafungin.

Antifungal Agents↗
PubMed2002

Comparative antifungal activities and plasma pharmacokinetics of micafungin (FK463) against disseminated candidiasis and invasive pulmonary aspergillosis in persistently neutropenic rabbits.

Micafungin (FK463) is an echinocandin that demonstrates potent in vitro antifungal activities against Candida and Aspergillus species. However, little is known about its comparative antifungal activities in persistently neutropenic hosts. We therefore investigated the plasma micafungin pharmacokinetics and antifungal activities of micafungin against experimental disseminated candidiasis and invasive pulmonary aspergillosis in persistently neutropenic rabbits. The groups with disseminated candidiasis studied consisted of untreated controls (UCs); rabbits treated with desoxycholate amphotericin B (DAMB) at 1 mg/kg of body weight/day; or rabbits treated with micafungin at 0.25, 0.5, 1, and 2 mg/kg/day intravenously. Compared with the UCs, rabbits treated with micafungin or DAMB showed significant dosage-dependent clearance of Candida albicans from the liver, spleen, kidney, brain, eye, lung, and vena cava. These in vivo findings correlated with the results of in vitro time-kill assays that demonstrated that micafungin has concentration-dependent fungicidal activity. The groups with invasive pulmonary aspergillosis studied consisted of UCs; rabbits treated with DAMB; rabbits treated with liposomal amphotericin B (LAMB) at 5 mg/kg/day; and rabbits treated with micafungin at 0.5, 1, and 2 mg/kg/day. In comparison to the significant micafungin dosage-dependent reduction of the residual burden (in log CFU per gram) of C. albicans in tissue, micafungin-treated rabbits with invasive pulmonary aspergillosis had no reduction in the concentration of Aspergillus fumigatus in tissue. DAMB and LAMB significantly reduced the burdens of C. albicans and A. fumigatus in tissues (P < 0.01). Persistent galactomannan antigenemia in micafungin-treated rabbits correlated with the presence of an elevated burden of A. fumigatus in pulmonary tissue. By comparison, DAMB- and LAMB-treated animals had significantly reduced circulating galactomannan antigen levels. Despite a lack of clearance of A. fumigatus from the lungs, there was a significant improvement in the rate of survival (P < 0.001) and a reduction in the level of pulmonary infarction (P < 0.05) in micafungin-treated rabbits. In summary, micafungin demonstrated concentration-dependent and dosage-dependent clearance of C. albicans from persistently neutropenic rabbits with disseminated candidiasis but not of A. fumigatus from persistently neutropenic rabbits with invasive pulmonary aspergillosis.

Animals↗
PubMed2004

Optimal prophylactic dosage and disposition of micafungin in living donor liver recipients.

Micafungin, a new candin antifungal drug, has a good safety profile and a significant therapeutic effect against Candida and Aspergillus. Little is known, however, about the optimal prophylactic dosage and the disposition of micafungin in liver transplant recipients, or about the effect of continuous venovenous hemodialysis (CVVH) on the pharmacokinetics of micafungin. Six living donor liver transplant patients were enrolled in this study. The mean C(max) and C(min) (trough) values of micafungin in plasma were 6.31 +/- 1.08 and 1.65 +/- 0.54 microg/mL, respectively. The mean elimination half-life (t(1/2)) and mean area under the curve up to 12 h post-dosing (AUC 0-12 h) were 13.63 +/- 2.77 h and 50.04 +/- 6.48 microg.h/mL, respectively. The concentrations of micafungin at the inlet and outlet of the dialyzer were very similar. The mean (+/-SD) ratio of micafungin concentrations at the inlet and outlet of the dialyzer (coutlet/cinlet) and the clearance of micafungin were 0.96 +/- 0.04 and 0.054 +/- 0.04 mL/min/kg, respectively. The amount in the ultrafiltrate was 1.0 mg. Micafungin effectively prevents systemic fungal infection in patients who have undergone liver transplantation. No significant differences were observed in the disposition of micafungin in recipients, and the therapeutic drug level can be achieved by administration of micafungin at a dosage of 40-50 mg/d. The CVVH had little effect on micafungin kinetics, and no dose adjustment or modification of dosing interval was needed during CVVH.

Child↗
PubMed2004

Micafungin.

Micafungin, an echinocandin antifungal agent with a novel mechanism of action, inhibits beta-(1,3)-D-glucan synthase interfering with fungal cell wall synthesis. It shows excellent antifungal activity against a broad range of Candida spp., including azole-resistant strains, and Aspergillus spp. in in vitro and animal studies. In HIV-positive patients, intravenous micafungin 50-150 mg/day dose-dependently eradicated endoscopically confirmed oesophageal candidiasis, with micafungin 100 and 150 mg/day being more effective than micafungin 50 mg/day and as effective as fluconazole 200 mg/day in a double-blind trial. In nonblind trials, micafungin (monotherapy or combination therapy) was effective against invasive aspergillosis, candidiasis and candidaemia in paediatric and adult patients with newly diagnosed or refractory infections. Micafungin 50 mg/day provided significantly better antifungal prophylaxis than fluconazole 400 mg/day in 882 haematopoietic stem cell transplant recipients in a randomised, double-blind trial. Respective overall success rates were 80% and 73.5%. Micafungin is generally well tolerated. Adverse events were not dose- or infusion-related with micafungin 12.5-900 mg/day; no histamine-like reactions occurred. Micafungin was as well tolerated as fluconazole, with numerically fewer micafungin recipients discontinuing treatment (4.2% vs 7.2%).

Animals↗
PubMed2006

Breakthrough trichosporonosis in patients with hematologic malignancies receiving micafungin.

BACKGROUND: Micafungin is a newly approved antifungal agent in the echinocandin class that is active against Candida species and Aspergillus species. However, this agent has limited activity against a number of fungi, including Trichosporon species. We describe 4 patients who developed disseminated trichosporonosis during the use of micafungin. No cases of trichosporonosis had been seen in the 2 years prior to January 2003, when micafungin became available in our hospital. METHODS: We reviewed microbiological records of patients at Kameda General Hospital (Kamogawa City, Chiba, Japan) from 1 January 2002 to 31 July 2005, and identified 4 patients whose blood culture results were positive for Trichosporon species. RESULTS: Since January 2003, four patients--3 with acute myelocytic leukemia and 1 with myelodysplastic syndrome--developed disseminated trichosporonosis while receiving treatment with micafungin with or without amphotericin B. The initial 2 isolates were identified as Trichosporon beigelii, and the later 2 isolates were identified as Trichosporon asahii. All 4 patients received micafungin, and 2 also received amphotericin B concomitantly. Minimal inhibitory concentrations of micafungin were >16 microg/mL for the 2 isolates available for susceptibility testing. One patient with hematologic recovery (neutrophils >500 cells/mm3) showed elimination of the fungus after receiving treatment with voriconazole. However, the 3 other patients without hematologic or immunological recovery died of disseminated infection. CONCLUSIONS: The rarity of trichosporonosis in our hospital and its emergence after the introduction of micafungin therapy support the idea that micafungin may exert a significant, selective pressure toward resistant fungi, such as Trichosporon species. Therefore, care should be taken regarding the possibility of trichosporonosis in patients receiving micafungin with or without amphotericin B.

Amphotericin B↗
PubMed2005

Pharmacokinetic and maximum tolerated dose study of micafungin in combination with fluconazole versus fluconazole alone for prophylaxis of fungal infections in adult patients undergoing a bone marrow or peripheral stem cell transplant.

In this dose escalation study, 74 adult cancer patients undergoing bone marrow or peripheral blood stem cell transplantation received fluconazole (400 mg/day) and either normal saline (control) (12 subjects) or micafungin (12.5 to 200 mg/day) (62 subjects) for up to 4 weeks. The maximum tolerated dose (MTD) of micafungin was not reached, based on the development of Southwest Oncology Group criteria for grade 3 toxicity; drug-related toxicities were rare. Commonly occurring adverse events considered related to micafungin were headache (6.8%), arthralgia (6.8%), hypophosphatemia (4.1%), insomnia (4.1%), maculopapular rash (4.1%), and rash (4.1%). Pharmacokinetic profiles for micafungin on days 1 and 7 were similar. The mean half-life was approximately 13 h, with little variance after repeated or increasing doses. Mean maximum concentrations of the drug in serum and areas under the concentration-time curve from 0 to 24 h were approximately proportional to dose. There was no clinical or kinetic evidence of interaction between micafungin and fluconazole. Five of 12 patients (42%) in the control group and 14 of 62 (23%) in the micafungin-plus-fluconazole groups had a suspected fungal infection during treatment which resulted in empirical treatment with amphotericin B. The combination of micafungin and fluconazole was found to be safe in this high-risk patient population. The MTD of micafungin was not reached even at doses up to 200 mg/day for 4 weeks. The pharmacokinetic profile of micafungin in adult cancer patients with blood or marrow transplants is consistent with the profile in healthy volunteers, and the area under the curve is proportional to dose.

Adolescent↗
PubMed2006

Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis.

BACKGROUND: Micafungin (FK463) is a new lipopeptide compound (echinocandin) with activity against Aspergillus and Candida species. This study evaluated the safety and efficacy of micafungin in patients with proven or probable invasive aspergillosis (IA). METHODS: A multinational, non-comparative study was conducted to examine proven or probable (pulmonary only) Aspergillus species infection in a wide variety of patient populations. The study employed an open-label design utilizing micafungin alone or in combination with another systemic antifungal agent. Criteria for IA and therapeutic responses were judged by an independent panel. RESULTS: Of the 331 patients enrolled, only 225 met diagnostic criteria for IA as determined by the independent panel and received at least one dose of micafungin. Patients included 98/225 who had undergone hematopoietic stem cell transplantation (HSCT) (88/98 allogeneic), 48 with graft versus host disease (GVHD), and 83/225 who had received chemotherapy for hematologic malignancy. A favorable response rate at the end of therapy was seen in 35.6% (80/225) of patients. Of those only treated with micafungin, favorable responses were seen in 6/12 (50%) of the primary and 9/22 (40.9%) of the salvage therapy group, with corresponding numbers in the combination treatment groups of 5/17 (29.4%) and 60/174 (34.5%) of the primary and salvage treatment groups, respectively. Of the 326 micafungin-treated patients, 183 (56.1%) died during therapy or in the 6-week follow-up phase; 107 (58.5%) deaths were attributable to IA. CONCLUSIONS: Micafungin as primary or salvage therapy proved efficacious and safe in high-risk patients with IA, although patient numbers are small in the micafungin-only groups.

Acute Disease↗
PubMed2004

A randomized, double-blind, parallel-group, dose-response study of micafungin compared with fluconazole for the treatment of esophageal candidiasis in HIV-positive patients.

BACKGROUND: Severely immunocompromised individuals are highly susceptible to Candida infection of the esophagus. This randomized, double-blind study assessed the dose-response relationship of the new echinocandin antifungal, micafungin, compared with that of standard fluconazole treatment. METHODS: A total of 245 patients (age, > or =18 years) with a prior diagnosis of acquired immunodeficiency syndrome/human immunodeficiency virus (HIV) infection and esophageal candidiasis, confirmed by endoscopy and culture, were randomized to receive micafungin (50, 100, or 150 mg per day) or fluconazole (200 mg per day). Both agents were administered once per day by a 1-h intravenous infusion for 14-21 days. The primary efficacy end point was endoscopic cure rate, defined as endoscopy grade of 0 at the end of therapy. RESULTS: The endoscopic cure rate (grade 0) was dose-dependent with 50, 100, and 150 mg of micafungin per day at 68.8%, 77.4%, and 89.8%, respectively. Symptoms improved or resolved rapidly (3-7 days of treatment in the majority of patients). The endoscopic cure rate for 100 and 150 mg of micafungin per day (83.5%) was comparable to that for 200 mg of fluconazole per day (86.7%; 95% confidence interval for the difference in endoscopic cure rate, -14.0% to 7.7%). The overall safety and tolerability was acceptable, with no important differences between micafungin (all doses) and fluconazole. CONCLUSIONS: The dose-response findings demonstrate a greater efficacy with micafungin at 100 and 150 mg per day than at 50 mg per day. This study also indicates that the efficacy of micafungin (at dosages of 100 and 150 mg per day) was comparable to that of fluconazole, suggesting that micafungin represents a valuable new treatment option for esophageal candidiasis in HIV-positive patients.

AIDS-Related Opportunistic Infections↗
PubMed2005

Toxicological evaluation of micafungin ophthalmic solution in rabbit eyes.

There have been no reports of the topical application of micafungin to the eye. The aim of this study was to evaluate the safety of topical instillation of 0.1% micafungin ophthalmic solution in rabbit eyes. In New Zealand white rabbits (n = 6), 50 microL of 0.1% micafungin solution was topically instilled to 1 eye, and 50 microL of sterile saline was applied to the other eye. Both eyedrops were administered hourly from 7 A.M. for 7 days. Measurements were conducted on corneal thickness, intraocular pressure, endothelial cell density, and lactate dehydrogenase (LDH) activity of tear samples. The eyes were examined slit-lamp biomicroscopically and histopathologically. Topical micafungin application for 1 week did not induce any changes in intraocular pressure, endothelial cell density, and tear LDH. Corneal thickness after instillation was slightly, but significantly, smaller in the micafungin group than in the control group (P = 0.0156, paired t test), but this difference disappeared within 24 hours after the final instillation. Biomicroscopy and histopathology revealed no significant toxic influence of micafungin application on the cornea. Topical instillation of micafungin solution had no apparent toxicity to the cornea. These results warrant future studies on the efficacy of micafungin ophthalmic solution against corneal fungal infection.

Animals↗
PubMed2005

A randomized, double blind, comparative trial of micafungin (FK463) vs. fluconazole for the treatment of oesophageal candidiasis.

AIM: To determine efficacy and safety of intravenous micafungin vs. intravenous fluconazole in the treatment of oesophageal candidiasis. METHODS: A total of 523 patients > or =16 years with documented oesophageal candidiasis were randomized (1:1) in this controlled, non-inferiority study to receive either micafungin (150 mg/day) or fluconazole (200 mg/day). Response was evaluated clinically and endoscopically. Post-treatment assessments were performed at 2 and 4 weeks after discontinuation of therapy. RESULTS: Median duration of therapy was 14 days. For the primary end-point of endoscopic cure, treatment difference was -0.3% (micafungin 87.7%, fluconazole 88.0%). Documented persistent invasive disease at the end of therapy was reported in 2.7% and 3.9% of patients, respectively. Both 84.8% of micafungin and 88.7% of fluconazole patients remained recurrence free at 4-weeks post-treatment. The overall therapeutic response rate was 87.3% for micafungin and 87.2% for fluconazole. The incidence of drug-related adverse events was 27.7% for micafungin and 21.3% for fluconazole. Six (2.3%) micafungin- and two (0.8%) fluconazole-treated patients discontinued therapy; rash was the most common event leading to discontinuation. CONCLUSION: Intravenous micafungin (150 mg daily) is well tolerated and as efficacious as intravenous fluconazole (200 mg daily) in the primary treatment of oesophageal candidiasis, achieving high rates of clinical and endoscopic cure.

Adolescent↗
PubMed2002

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).

Candida↗
PubMed2006

Activities of micafungin against 315 invasive clinical isolates of fluconazole-resistant Candida spp.

Micafungin is a new echinocandin exhibiting broad-spectrum activity against Candida spp. The activity of the echinocandins against Candida species known to express intrinsic or acquired resistance to fluconazole is of interest. We determined the MICs of micafungin and caspofungin against 315 invasive clinical (bloodstream and other sterile-site) isolates of fluconazole-resistant Candida species obtained from geographically diverse medical centers between 2001 and 2004. MICs were determined using broth microdilution according to the CLSI reference method M27-A2. RPMI 1640 was used as the test medium, and we used the MIC endpoint of prominent growth reduction at 24 h. Among the 315 fluconazole-resistant Candida isolates, 146 (46%) were C. krusei, 110 (35%) were C. glabrata, 41 (13%) were C. albicans, and 18 (6%) were less frequently isolated species. Micafungin had good in vitro activity against all fluconazole-resistant Candida spp. tested; the MICs at which 50% (MIC(50)) and 90% (MIC(90)) of isolates were inhibited were 0.03 microg/ml and 0.06 microg/ml, respectively. All the fluconazole-resistant Candida spp. were inhibited at a micafungin MIC that was </=1 microg/ml. Among the most common fluconazole-resistant Candida spp. tested in the collection, C. glabrata exhibited the lowest micafungin MICs (MIC(90), </=0.015 microg/ml), followed by C. albicans (MIC(90), 0.03 microg/ml) and C. krusei (MIC(90), 0.06 microg/ml). The new echinocandin micafungin has excellent in vitro activity against 315 invasive clinical isolates of fluconazole-resistant Candida, which represents the largest collection to date of fluconazole-resistant Candida isolates tested against micafungin. Micafungin may prove useful in the treatment of infections due to azole-resistant Candida.

Antifungal Agents↗
PubMed2004

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.

Antifungal Agents↗
PubMed2006

Once-weekly micafungin therapy is as effective as daily therapy for disseminated candidiasis in mice with persistent neutropenia.

The effect of micafungin dose scheduling on the treatment of candidemia is unknown. Neutropenic mice with disseminated Candida glabrata infection were treated with single intraperitoneal micafungin doses of 0 to 100 mg/kg of body weight and sacrificed 7 days later. The maximal decline in kidney fungal burden was 5.8 log(10) CFU/g. A 1-week pharmacokinetic-pharmacodynamic study revealed a micafungin serum half-life of 6.13 h. In mice treated with > or =50 mg/kg, there was maximal fungal decline without regrowth during the 1-week dosing interval. Next, doses associated with 34% (34% effective dose [ED(34)]) and 50% (ED(50)) of maximal kill were administered at one of three dose schedules: a single dose at t = 0, two equal doses at t = 0 and t = 3.5 days, and 7 equal doses daily. Some mice received a single dose of 100 mg/kg. Fungal burden was examined on days 1, 5, and 7. In mice treated with the ED(34), microbial kill with the daily therapy initially lagged behind the intermittent doses but exceeded it by day 7. In mice treated with the ED(50), daily and intermittent doses had equivalent day 7 effects. In mice treated with 100 mg/kg, there was no regrowth. The relative likelihoods that the area under the concentration-time curve/MIC ratio was linked to microbial kill versus peak concentration/MIC ratio or time above the MIC was 10.3 and 10,161.2, respectively. In all the experiments, no paradoxical increase in fungal burden was observed with high micafungin doses. However, only a single Candida isolate was tested. Regimens that simulated micafungin concentration-time profiles in patients treated with a single micafungin dose of 1,400 mg once a week demonstrated maximal fungal decline. Once-weekly micafungin therapy is as efficacious as daily therapy in a murine model of disseminated candidiasis.

Animals↗
PubMed2003

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.

Antifungal Agents↗
PubMed2005

Concomitant tacrolimus and micafungin pharmacokinetics in healthy volunteers.

Tacrolimus is an approved immunosuppressive agent and a known substrate for CYP3A. Micafungin is an echinocandin antifungal agent and a mild inhibitor of CYP3A metabolism in vitro. The objectives of this study were to evaluate the pharmacokinetics of tacrolimus (5 mg oral) and micafungin (100 mg intravenous) alone and with concomitant administration (n=26). Tacrolimus area under the concentration-time curve was 298+/-135 microg*h/L when tacrolimus was administered alone, 305+/-129 microg*h/L (P=.8; confidence interval 89%, 118%) when tacrolimus was given with single-dose micafungin, and 282+/-138 microg*h/L (P=.4; confidence interval 82%, 107%) when tacrolimus was given with steady-state micafungin. Despite the mild inhibition of CYP3A in vitro by micafungin, there does not appear to be a drug interaction with tacrolimus and micafungin either with single-dose or steady-state micafungin administration.

Adult↗
PubMed2006

Comparative study of disc diffusion and microdilution methods in susceptibility testing of micafungin against Candida species.

OBJECTIVES: To compare the Clinical Laboratory Standards Institute CLSI M44-A disc diffusion (DD) and M27-A2 broth microdilution (MD) methods for determining the susceptibility of Candida spp. to micafungin (FK463). PATIENTS AND METHODS: A total of 355 clinical yeast isolates including 270 Candida albicans, 45 Candida glabrata, 24 Candida krusei, 11 Candida tropicalis and 5 Candida parapsilosis were studied. The MIC of micafungin was determined by following the CLSI M27-A2 guidelines (MD). Endpoints were defined as the lowest concentration of micafungin resulting in partial inhibition (IC(50)) of visual growth after 24/48 h of incubation at 35 degrees C. Final concentrations were 0.008-4 mg/L of micafungin. DD testing was performed using a CLSI M44-A document with 2.5 mug micafungin discs. Zone diameter endpoints were read after 24/48 h of incubation at 35 degrees C. Arbitrary breakpoints were 4 mg/L for MD and 15 mm for DD. RESULTS: The best correlation was observed when we read MD 48 h/DD 24 and 48 h (97%). When the reading was MD 24 h/DD 24 and 48 h the percentage of correlation was 95.2%. CONCLUSIONS: The DD method performs well for testing the susceptibility of Candida spp. to micafungin. More studies involving more Candida strains with elevated MIC values are needed.

AIDS-Related Opportunistic Infections↗
PubMed2006

The pharmacokinetics and safety of micafungin, a novel echinocandin, in premature infants.

BACKGROUND: : Candidal fungal infection rates in neonates are increasing and are a significant cause of mortality, especially in low birth weight infants. Micafungin is an echinocandin that works by inhibiting 1,3-beta-D-glucan synthase, an enzyme responsible for fungal cell wall synthesis. The objective of this study was to determine the safety and pharmacokinetics of micafungin in premature infants. METHODS: : This was a phase I, single-dose, multicenter, open-label, sequential-dose trial of intravenous micafungin investigating 3 doses (0.75 mg/kg, 1.5 mg/kg and 3.0 mg/kg) in 18 premature infants weighing >1000 g (n = 6 in each dosage group). A further 5 infants (500-1000 g) were enrolled in the 0.75 mg/kg dosage group only. RESULTS: : The mean +/- standard deviation gestational age in the >1000 g dosage group was 26.4 +/- 2.4 weeks and, on entry, patients had one or more of a variety of underlying conditions, including sepsis, pneumonia and other infections caused by Candida or other species. Micafungin pharmacokinetics in preterm infants appears linear. However, premature infants >1000 g on average displayed a shorter half-life (8 hours) and a more rapid rate of clearance (approximately 39 mL/h per kg) compared with published data in older children and adults. All doses of micafungin were well tolerated and no serious drug-related adverse events were observed. CONCLUSIONS: : Single doses of micafungin, ranging up to 3.0 mg/kg, appear well tolerated in premature infants weighing >1000 g. The drug's elimination half-life and total plasma clearance in preterm infants appear dissimilar to published values for these parameters in older children and adults. The reason(s) for this apparent difference remain to be investigated.

Antifungal Agents↗