Hideo Ikemoto

A Multicenter, Open-Label Clinical Study of Micafungin (FK463) in the Treatment of Deep-seated Mycosis in Japan

The efficacy and safety of micafungin (FK463), which is a new lipopeptide antifungal agent of the echinocandin class and is active against both Aspergillus and Candida species, were investigated in patients with deep-seated mycosis in this study. 70 patients were treated with micafungin 12.5–150 mg/d intravenously for up to 56 d. The overall clinical response rates were 60% (6/10) in invasive pulmonary aspergillosis, 67% (6/9) in chronic necrotizing pulmonary aspergillosis, 55% (12/22) in pulmonary aspergilloma, 100% (6/6) in candidemia, and 71% (5/7) in esophageal candidiasis. The response rates for patients with prior antifungal treatment which was considered ineffective or toxic, were similar to rates for patients without prior treatment. Mycological eradication was observed in patients infected with Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Aspergillus niger, Candida albicans, Candida glabrata, or Candida krusei. Adverse events related to micafungin were reported in 21 patients (30%), and there was no dose-related occurrence of any adverse event. It is concluded that treatment with micafungin as monotherapy seems to be effective and safe in patients with deep-seated mycosis.

A clinical study of fluconazole for the treatment of deep mycoses

A multicenter clinical study of fluconazole was conducted at 41 hospital sites in Japan. Fluconazole was administered orally or intravenously at daily doses of 50 to 400 mg to 199 patients with deep-seated mycoses. Clinical efficacy was evaluable in 125 of these patients. Most cases were complicated with serious underlying diseases such as cancer, leukemia, or AIDS. Clinical cures were achieved in 56 (87.5%) of 64 cases of candidiasis, in 11 (68.8%) of 16 cases of cryptococcosis, in 19 (44.2%) of 43 cases of aspergillosis, and in one case each (100%) of mucormycosis and fungemia due to an unspecified yeast. Eradication rates of causative fungi were 87.9% in Candida spp., 62.5% in Cryptococcus neoformans, and 52.2% in Aspergillus spp. Side effects were observed in 13 cases, with an incidence rate of 6.5%. In most cases fluconazole was well tolerated. Changes in laboratory test values due to the drug were reported in 35 patients with an incidence rate of 17.6%. The changes were minor and transient; primarily increases in liver enzyme. Fluconazole is a useful antifungal agent for the treatment of systemic deep-seated mycoses.

Antimicrobial susceptibility of pathogens isolated from more than 10 000 patients with infectious respiratory diseases: a 25-year longitudinal study

The Study Group on Antimicrobial Susceptibility of Pathogens Isolated from Respiratory Infections was established in 1981 in Japan to elucidate trends in such susceptibilities in patients with infectious respiratory diseases; the Group has conducted nationwide research in collaboration with 21 medical institutions. Examination of more than 10 000 patients by 2005 allowed a summary of study findings. Streptococcus pneumoniae started to become resistant to penicillin G in the 1990s, and the isolation rate of penicillin-intermediate and penicillin-resistant S. pneumoniae (PISP + PRSP) reached almost 60% in 2001. The proportion of PRSP also increased, reaching 19.4%. Thereafter, the rate of PISP + PRSP decreased somewhat to the mid-30% range. Macrolide resistance was also observed; in 2005, the prevalence of strains highly susceptible to erythromycin with MICs ≦ 0.06 µg/ml had decreased to 15.5%, whereas the proportion of highly resistant strains with MICs ≧ 128 µg/ml exceeded 40%. Among Staphylococcus aureus isolates, the proportion of methicillin-resistant S. aureus (MRSA) strains began to increase rapidly in 1986 and constituted around 60% of all S. aureus strains identified in 1990 and in the following years. In 1993, the prevalence of ampicillin-resistant isolates of Haemophilus influenzae had increased remarkably, presumably related to the outbreak of β-lactamase-negative ampicillin-resistant (BLNAR) H. influenzae strains, and the proportion of these strains among the isolates surpassed 30% in 2002 and thereafter. For Klebsiella pneumoniae, the antimicrobial activity of first- to fourth-generation cephems improved with each generation. The MIC distribution patterns of Pseudomonas aeruginosa shifted towards higher MICs when compared with the MICs for other pathogens. Broad patterns with no distinct peaks reflected the difficulty in treating P. aeruginosa infection. Regarding Moraxella catarrhalis, β-lactamase-producing strains already constituted a majority of the isolates in 1990, and the proportion of strains highly susceptible to ampicillin, with MICs ≦ 0.06 µg/ml, was less than 10% at that time.

Fluconazole monotherapy for cryptococcosis in non-AIDS patients

Treatment with 200 to 400 mg/day fluconazole was evaluated in 44 patients without AIDS who had cryptococcosis (19 with cryptococcal meningitis, 22 with pulmonary cryptococcosis, 3 with other cryptococcal infections). For all patients, the clinical response rate was 89% (48% were clinically cured and 41 % clinically improved). Of the patients with cryptococcal meningitis, 89% were mycologically cured. These rates are comparable to those obtained in the treatment of AIDS patients with cryptococcal disease. In the group of patients with cryptococcal meningitis, there was a high rate of agreement between the mycological response to therapy and cryptococcal antigen test results. The use of cryptococcal antigen testing is recommended in all patients with cryptococcosis.

Endobronchial miconazole for pulmonary aspergilloma.

Excerpt To the editor: We report a patient with pulmonary aspergilloma accompanied by underlying diseases who was incurable by surgical treatment was successfully treated with intracavitary infusio...

Indirect haemagglutination in pulmonary aspergilloma diagnosis

The indirect haemagglutination test was both sensitive and specific for detecting antibodies to Aspergillus fumigatus. Application of the test to sera from 10 cases of pulmonary aspergilloma revealed indirect haemagglutination titers of 1:1024 to 1:4096. Results of the test showed close agreement with those obtained by the agar double diffusion test.

Comparison between 5-Fluorocytosine, Amphotericin B and the Combined Administration of these Agents in the Therapeutic Effectiveness for Cryptococcal Meningitis

Therapeutic effectiveness of 5-fluorocytosine (5-FC), amphotericin B (Am B) and both in combined administration were retrospectively assessed and compared with one another in 28 patients with cryptococcal meningitis. Combined administration was significantly superior to Am B alone and to 5-FC alone, and these agents were suggested to afford a synergetic effect in combined administration. Adverse reactions associated with combined administration did not essentially differ from those with Am B or 5-FC alone. Combined administration was able to decrease the incidence and severity of adverse reactions by employing lower doses of Am B, and this combined administration reduced the duration of treatment. An appropriate dose for each agent in combined administration was deemed to be about 0.350 mg/kg/day Am B i.v. and 150 mg/kg/day 5-FC p. o. based on the results of this study.

Clinical Efficacy of Itraconazole for Systemic Aspergillosis: Multicentre Study in Japan

A multicentre clinical trial of itraconazole for systemic mycoses was carried out in 25 hospitals in Japan. The clinical efficacy and safety of itraconazole in 41 cases of systemic aspergillosis are reported here. Of the patients, 9 were diagnosed as having bronchopulmonary aspergillosis, 30 had pulmonary aspergilloma, 1 had chronic necrotizing pulmonary aspergillosis and 1 had pleural aspergillosis. The diagnosis was established by microscopy, culture, histology, serology, biopsy, radiography and/or endoscopy. The mean age of the patients was 59.0 ± 14.5 years (range, 11-88 years). Itraconazole, 50-200 mg/day, was given for a mean of 150.5 days. Eradication of the fungus was observed in 17 patients out of the 22 cases examined mycologically. The overall clinical efficacy (cure or improvement) was 88.9% (8/9) in bronchopulmonary aspergillosis and 83.3% (25/30) in pulmonary aspergilloma, determined by clinical symptoms, mycological effects and radiographic observation. Radiographic evidence of the disappearance or improvement in size of the fungal ball was observed in 10 patients (33.3%) with aspergilloma. Itraconazole was clinically well tolerated; only 1 patient had pruritus, 1 had constipation, and in 1 elevation of serum aspartate aminotransferase, serum alanine aminotransferase and serum alkaline phosphatase was observed. The minimum inhibitory concentration (MIC) of itraconazole for isolates of Aspergillus from 9/13 cases was below 0.08 µg/ml. As only a few antifungal agents show any activity against Aspergillus spp., itraconazole was considered to be a useful oral agent for treatment of systemic aspergillosis, including pulmonary aspergilloma.

Treatment of Deep-Seated Candidosis with Itraconazole: Multicentre Study in Japan

A multicentre clinical trial of itraconazole for deep-seated mycoses was carried out in 25 hospitals in Japan. The clinical efficacy and safety of itraconazole administered to 31 patients with candidosis are reported here. The diagnosis was confirmed by microscopy, culture, histology, serology, biopsy, radiology and/or endoscopy. Of the patients, 7 had candidaemia, 4 had pulmonary candidosis, 13 had oesophageal candidosis and 7 had urinary tract candidosis. The mean age of the patients was 57.8 years (range, 18-87 years). They had underlying diseases, such as haematological malignancy, acquired immune deficiency syndrome (AIDS) and cancer, leading to immunocompromise. The patients received itraconazole, 50-200 mg/day for 4-60 days (mean, 18.8 days). The overall clinical efficacy of itraconazole was 90% (27/30); in candidaemia it was 83.3% effective (5/6); in pulmonary candidosis, 100% (4/4); in oesophageal candidosis, 84.6% (11 /13); and in urinary tract candidosis, 100% (7/7). Eradication of Candida spp. was observed in 24 of the 31 patients. Itraconazole was well tolerated; eosinophilia and elevation of serum alanine aminotransferase and Γ-glutamyl transferase were each observed in 1 patient. Determination of the serum levels of itraconazole confirmed that effective concentrations were reached. In conclusion, oral administration of itraconazole once or twice a day was well tolerated by all the patients, and satisfactory responses were obtained.