A strain of Candida tropicalis was isolated from a blood sample of a patient undergoing treatment with micafungin at Gifu University Hospital. Paradoxically, the strain grew in the presence of higher micafungin concentrations than usual. We characterized this strain by several non-clinical experiments, including the response to therapy in animal models of infection, to investigate whether this strain is indeed resistant to micafungin. In the GLSI M27-A2 microdilution assay, growth of this strain was inhibited in the presence of 0.0625 μg/mL or higher concentrations of micafungin at 24 h of incubation. At 48 h, however, slight growth was visible in the range of 8 to 32 μg/mL. The growth was microscopically observed as a grape-like aggregation. This morphology was quite different from that of the untreated control fungus, which was observed as scattered yeast-like cells. When antibiotic medium 3 was used as the test medium, the strain was killed at the MIG or higher, and the paradoxical growth was no longer seen. Micafungin was similarly efficacious against neutropenic murine models of systemic infection caused by both paradoxical effect-positive and-negative strains, with ED₅₀ values of 029 and 0.35 mg/kg, respectively (95% confidence interval; 0.18 to 0.41 and 0.26 to 0.48 mg/kg, respectively). These results suggest that this strain should be considered susceptible to micafungin because the paradoxical effect appears only due to varying osmotic resistivity and does not influence the in vivo effect of micafungin.

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We studied the efficacy, safety and pharmacokinetics of micafungin (MCFG) in pediatric patients with deep mycoses, and conducted a multicenter, non-blinded, uncontrolled study to estimate the pediatric dosage and administration schedule. The results in the 20 cases that were enrolled in this study are as follows:
1. In terms of the overall clinical effect, the study drug was “effective” in 10/14 cases (71.4%) overall, 7/11 cases (63.6%) of candidiasis, and all of the 3 cases of aspergillosis.
2. The percent incidence of adverse drug reactions (accompanying symptoms) was 5%(1/20 cases), and an anaphylactoid reaction occurred in 1 case only. The percent incidence of adverse drug reactions (abnormal laboratory test value changes) was 25.0%(5/20 cases), and the most frequently seen events were liver function disorders, such as increased AST, increased ALT, increased ALP, increased γ-GTP, etc. None of these events were serious, and it was not necessary to discontinue or decrease the dose of the study drug in any of the patients. The adverse drug reactions were not dose-dependent either.
3. Both C_max and G_min showed linearity in the dose range of 1.0 to 6.0 mg/kg/day based on the results of the pharmacokinetics study. The half-life was approximately 13 hours and was generally constant, irrespective of the dose level and age.
Based on the abovementioned results, the efficacy, safety and in vivo pharmacokinetics of micafungin in pediatric patients, including school children, infants, and nursing infants, at doses (1.0 to 6.0 mg/kg/day) calculated with body weight adjustment from the approved adult dosage (50 to 300 mg/day), did not differ widely from those in adult patients, and the drug is expected to become a useful drug for pediatric patients with deep mycoses.

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We investigated the clinical features of 15 cases treated with linezolid (LZD). The patients ranged in age from 0 to 80 years old (mean: 66 years old). Fifteen strains were isolated as pathogens: 11 strains of methicillin-resistant Staphylococcus aureus (MRSA), 3 strains of methicillin-resistant Staphylococcus epidermidis (MRSE), and 1 strain of methicillin-sensitive Staphylococcus aureus (MSSA). The clinical diagnosis was sepsis in 4 cases, infective arthritis in 4, pneumonia in 2, infective endocarditis in 2, osteomyelitis in 2, deep soft tissue and skin infections in 2, mediastinitis in 1, and meningitis in 1 case. The reasons for LZD use were resistance to previous treatment in 10 cases, renal dysfunction in 5, and intolerance to glycopeptides in 4 cases. As for the adverse effects of LZD, anemia in 4 cases, thrombocytepenia in 3, and liver damage in 1 case were recognized. These results suggest that LZD is effective for the complicated infections caused by Grampositive cocci, such as MRSA or methicillin-resistant coagulase negative Staphylococci (MRCNS), and is better tolerance. However, LZD should be given to carefully selected patients, in order to prevent the appearance of LZD-resistant bacteria

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It is well known that carbapem antibiotic induces a low endotoxin release in the bacteriocidal action. In the present study we compared the endotoxin-releasing activity of imipenem (IPM), doripenem (DRPM) and meropenem (MEPM) against Pseudomonas aeruginosa PAO-1. P. aeruginosa PAO-1 was cultured in endotoxinfree fetal calf serum in the presence of the antibiotic. The endotoxin level was determined by an endotoxinspecific limulus assay. No significant endotoxin release was detected in any of the cultures containing IPM, DRPM, MEPM or ceftazidime (CAZ) at 2 MIC although high endotoxin levels were detected in the culture without any antibiotic. DRPM, MEPM and CAZ at 1/2 MIC induced marked endotoxin release, with the endotoxin level being higher than that in the untreated control. IPM at 1/2 MIC, however, induced much less endotoxin release. The endotoxin release was clearly detected at 8 h after the antibiotic treatment. IPM at 1/2 MIC converted the rod-shaped bacteria into spherical ones, whereas DRPM and MEPM at 1/2 MIC induced the formation of filaments. CAZ also induced long-filament formation in P. aeruginosa. It was suggested that the high endotoxin release induced by DRPM and MEPM at 1/2 MIC was closely associated with the filament formation.

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