micafungin and Aspergillosis--Allergic-Bronchopulmonary

A 56-year-old man with allergic bronchopulmonary aspergillosis (ABPA) was admitted due to the appearance of nodular opacities in the right upper lung field on chest radiography, after discontinuing itraconazole and clarithromycin on the suspicion of possible hepatic adverse effects. Chest CT scans on admission revealed nodular opacities in the right S3 and lingula bronchus, and bilateral bronchiectasis with mucoid impactions. A specimen obtained by transbronchial lung biopsy showed complete replacement of bronchioles by necrotizing granulomatous inflammation, containing the diagnosis of bronchocentric granulomatosis. Treatment with corticosteroids and micafungin sodium resulted in marked resolution of nodular opacities and mucoid impacts. This case suggests that abrupt cessation of antifungal agents and macrolides may provoke acute exacerbation of ABPA and development of bronchocentric granulomatosis.

Topics: Antifungal Agents; Aspergillosis, Allergic Bronchopulmonary; Bronchial Diseases; Clarithromycin; Drug Therapy, Combination; Echinocandins; Granuloma; Humans; Itraconazole; Lipopeptides; Lipoproteins; Macrolides; Male; Methylprednisolone; Micafungin; Middle Aged; Tomography, X-Ray Computed; Treatment Outcome

The safety and concentration-dependent pharmacodynamic characteristics of the echinocandins make them ideal candidates for dosage escalation in the treatment of aspergillosis. However, paradoxical attenuation of antifungal activity with increasing doses has been reported for some echinocandins in experimental models of invasive pulmonary aspergillosis (IPA).. We compared the activity of micafungin and caspofungin administered over a wide dosing range that encompasses clinical exposures (0.25-10 mg/kg) in a neutropenic murine model of IPA.. Both echinocandins exhibited dose-dependent reductions in fungal burden; however, caspofungin displayed a relatively steeper dose-response curve with a modest paradoxical increase in fungal burden that was not seen in micafungin-treated animals. Equivalent activity was observed with both echinocandins at daily doses ranging from 4 to 10 mg/kg.. Both micafungin and caspofungin exhibit dose-dependent pharmacodynamic activity in vivo in the treatment of neutropenic IPA. Both echinocandins were equivalent at dosages > or = 4 mg/kg day.

Topics: Animals; Aspergillosis, Allergic Bronchopulmonary; Caspofungin; Cyclophosphamide; Dose-Response Relationship, Drug; Echinocandins; Female; Immunocompromised Host; Lipopeptides; Lipoproteins; Micafungin; Mice; Mice, Inbred BALB C; Neutropenia

In this report, we describe a patient with X-linked severe combined immunodeficiency (X-SCID) who had high serum IgG, IgA, and IgM levels. The boy did well until 6 months of age, when he developed interstitial pneumonia caused by Aspergillus species, with a white cell count of 12,840/microL and only 10% lymphocytes; IgG, 991 mg/dL; IgA, 65 mg/dL; IgM, 472 mg/dL. Cell markers showed only 6.3% CD3, 2.1% CD4, 0.7% CD8, but 92% CD19 and 0.1% CD16+CD56+ (NK cells). A mutation was detected within exon 2 (C196 A-->C), leading to the substitution of proline for glutamine, which has not been reported previously. The boy was successfully treated with the new antifungal drug, micafangin (MCFG), at 5 mg/kg/day for 89 days. After resolution of the pneumonia, the patient underwent successful hematopoietic stem cell transplantation with completely matched unrelated female cord blood. The CD34 stem cell dose was 3.4 x 10(4) cells/kg. In conclusion, MCFG can be a first line agent for Aspergillus pneumonia in immunocompromised hosts.

Topics: Antifungal Agents; Aspergillosis, Allergic Bronchopulmonary; Cord Blood Stem Cell Transplantation; Echinocandins; Humans; Immunoglobulins; Infant; Lipopeptides; Lipoproteins; Male; Micafungin; Peptides, Cyclic; X-Linked Combined Immunodeficiency Diseases

We performed a scanning and transmission electron microscopic study on the efficacy of micafungin (MCFG) to understand what kind of damage MCFG causes to Aspergillus and to confirm its previously reported in vitro killing activity against Aspergillus in a mouse model of pulmonary aspergillosis. Aspergillus hyphae in MCFG-treated mice displayed hyphal burst, evidenced as either flattened or atrophied appearance and leakage of cellular contents after collapse of the cell wall. Thus, MCFG can induce the destruction of Aspergillus hyphae at the focus of infection. The results of the present study indicate that MCFG improves pulmonary aspergillosis due to lethal damage to Aspergillus hyphae. This action can effectively reduce the invasive ability of Aspergillus even though MCFG does not sterilize the fungal burden.

Topics: Animals; Antifungal Agents; Aspergillosis, Allergic Bronchopulmonary; Aspergillus; Disease Models, Animal; Echinocandins; Lipopeptides; Lipoproteins; Micafungin; Mice; Peptides, Cyclic

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.

Topics: Animals; Antifungal Agents; Aspergillosis, Allergic Bronchopulmonary; Candidiasis; Echinocandins; Galactose; Lipopeptides; Lipoproteins; Lung; Mannans; Micafungin; Neutropenia; Organ Size; Peptides, Cyclic; Rabbits