We studied the in vitro antifungal activity of amphotericin B (AMPH), flucytosine (5-FC), itraconazole (ITZ), miconazole (MCZ) and fluconazole (FCZ) against 50 strains of Cryptococcus neoformans. Among the cryptococci, three isolates were resistant to 5-FC, but no strains resistant to the other antimycotics were observed. As test media for the assay of AMPH and ITZ, yeast morphology agar medium (YMA) and sensitivity test medium (KDA) were found to exhibit higher activity. On the other hand, lower MIC values were confirmed with MCZ in SDA medium. Although the IC₅₀ (50% inhibitory concentration of growth) values of AMPH, ITZ, MCZ and 5-FC were very similar to those of each MIC value, considerable differences between IC₅₀ and MIC values were observed for FCZ. Synergistic effects between azole antimycotics (FCZ, ITZ and MCZ) and an allylamine antimycotic (terbinafine) were confirmed by checkerboard as well as paper disk method. But the combination of AMPH and azole antimycotics, or AMPH and terbinafine, was antagonistic.

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The in vitro bactericidal effect of cefminox (CMNX), a new cephamycin antibiotic, and its in vivo therapeutic efficacy against infection in divided administration were compared with those of the cephamycin antibiotics latamoxef (LMOX), ceftadizime (CAZ), imipenem/cilastatin (IPM/CS), and the aminoglycoside gentamicin (GM). The following results were obtained.
1) Against intraperitoneal infection in mice induced by Klebsiella pneumoniae, CMNX showed outstanding efficacy, second only to GM, but when frequent by administered CAZ had the same results as CMNX.
2) Regarding the relation between pharmacokinetic parameters and efficacy, a correlation with the total dose was noted for GM, CMNX and IPM/CS, while for CAZ and LMOX a tendency towards correlation with duration above the MIC was assumed.
3) CMNX and IPM/CS differ from other β-lactam drugs in their in vitro bactericidal action, in that they display the same outstanding, dose-dependent shortterm bactericidal action as GM.
This is thought to reflect the correlation between total dose and efficacy against infection.

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We investigated β-lactam antibiotic regimens in patients with renal insufficiency using cefminox (CMNX) as a model. Plasma levels of CMNX after a single administration were assayed by HPLC in healthy volunteers and patients with varying degrees of impaired renal function, and pharmacokinetic parameters were determined using a two-compartment model. To plan a regimen, βa was selected as the parameter which varied in accordance with the degree of impaired renal function as measured by creatinine clearance. The applicability of this regimen was confirmed in subsequent high-dose and multiple-dose studies.

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We assessed the clinical response toaztreonam (AZT) in combination withcefmetazole (CMZ) or cefuzonam (CZON) in empiric therapy for febrile, neutropenic children with hemato-oncological diseases. One hundred and nine patients with neutrophil counts less than500/μl and fever up to 38.0°C lasting for more than 24 h were included in this study. Patients were given100-150mg/kg of AZT in combination with 120-150mg/kg of CMZ orCZON by 1-h intravenous drip infusion. In 55 children treated with AZT and CMZ, the overall clinical efficacyrate was 74.5%. The clinical response rate according to type of infection was 83.3% for sepsis, 66.7% for suspected sepsis and pneumonia, and 77.8% for fever of unknown origin (FUO). In 54 children treated with AZT and CZON, the overall clinical efficacy rate was 68.5%: 50% for sepsis, 63.6% for suspected sepsis and 87.5% for FUO. The efficacy rate for AZT with CMZ or CZON was 100% in patients with neutrophil counts more than 101/μl in both groups 68.9% and 64.6% in those with less than100/μl prior to the therapy, while it was 45.4% and 41.7% in those with less than100/μl after the therapy, respectively. Toxicity wass minimal with all the treatment regimens. Skin rash (AZT with CMZ) and mild liver dysfunction (AZT with CZON) were observed during therapy, but these recovered spontaneously after cessation of chemotherapy. We conclude that combination treatment with AZT and CMZ or CZON was useful in empiric therapy for febrile, severely neutropenic children with hematooncological diseases.

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We conducted a clinical study on, a new injectable formulation of clindamycin phosphate, and obtained the following results.
1. Thirty-two patients with pneumonia or bronchitis were given 1, 200 or 2, 400mg day of clindamycin by i.v. drip infusion, b. i. d for 3-16 days. Clinical efficacy assessed by the attendant committee was rated as exellent in 4 cases, good in 20, fair in 1 and poor in 1, with an efficacy rate of 92.3%(24/26). Five cases were unevaluable and one excluded from assessment.
2. Causative organisms were isolated from five cases where assessment of bacteriological efficacy was possible. These organisms were identified as Streptococcus pneumoniae and finally eradicated.
3. As to side effects, moderate eruption was noted in two cases. Abnormal laboratory findings included elevated GOT and GPT and eosinophilla, but all of these were slight.

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This study was undertaken at several major hospitals in lbaraki-ken to clarify the following aspects 1) the prevalence of methicilin-resistant Staphylococcus aureus (MRSA), defined as resistant to 12.5μg/ml of methicillin (DMPPC) in isolates of Staphylococcus aureus: 2) the in vitro susceptibility of clinical isolates of Staphylococcus aureus: and 3) the clinical efficacy of a combination of cefmetazole (CMZ) or cefuzonam (CZON) with fosfomycin (FOM) in patients with significant MRSA infection. The proportion of Staphylococcus aureus in all the isolates ranged from 5% 17% and of MRSA from 51%-82% depending upon the hospital. The in vitro susceptibility (251 strains) of clinical isolates (362 strains) was examined and 52 cases were diagnosed as having significant MRSA infection. The clinically assessable cases (25), treated with a combination of FOM and CZON (7 cases) or CMZ (18 cases), were included in this study for evaluation of therapeutic efficacy. The MRSA infected patients included 18 cases of respiratory infection, 3 of urinary tract infection, 1 of postsurgical wound infection and 3 other infections. The clinical response to FOM and CMZ combination therapy was 88.9% and to FOM and CZON 57.1% showing no statistical differences between the two regimens. Four of 18 cases responded to a combination of FOM and CMZ. although the in vitro susceptibility results showed no enhanced effect as assessed by the fractional inhibitory concentration (FIC) index (over 1.0). In contrast, 3 of 7 cases did not respond to FOM and CZON combination therapy although the FIC index suggested enhanced effects. These observations led us to conclude that the minimum inhibitory concentration (MIC) and blood concentration of each drug in vivo are as important parameters as the FIC index. In vitro analyses assessed by the FIC index of 251 isolates revealed that FOM had an additive or synergistic effect with CMZ in 53.8%, with CZON in 66.9%, with minocycline (MINO) in 43.8%, with cefamandole (CMD) in 61.8%, with cefazolin (CEZ) in 62.9% and with imipenem/cilastatin sodium (IPM/CS) in 68.9% of all isolates. Furthermore, the extent of the therapeutic efficacy was predicted by evaluating the relation between the MIC and the blood levels of each drug at 3 after intravenous administration of the recommended dosage. The cumulative curve of susceptibility to single CMZ and the combination of CMZ and FOM revealed that the blood levels of CMZ at 3 after intravenous administration covered 57% of the isolates when used alone and 82% when in combination with FOM. The blood levels of CZON at 3 covered 5% of the isolates when used alone and 41% when in combination with FOM. The extent of the efficacy was increased from 6% to 42% by CMD, from 12% to 54% by CEZ, from 20% to 58% by IPM/CS and from 78% to 84% by MINO. The combination of CMZ and FOM was found to be most potent in enhancing efficacy against MRSA in vitro.

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We evaluated the validity of determining Plasma (1→3)-β-D-glucan in assisting the cminical diagnosis of systemic fungal infection by reviewing the data obtalned from 10 patlents with microbiologically doculnented ftmgemia and 6 patients with autopsy-verified deep mycosls. The concentration of (1→3)-β-D-glucan was calculated from the difference between the results of Toxicolor (Seikagaku Kogyo, Ltd., Tokyo, Japan), which is sensitive to endotoxin and (1→3)-β-D-glucan, and Endospecy (Seikagaku Kogyo, Ltd., Tokyo, Japan), which ls sensltive only to endotoxin. The calculated plasma (1→3)-β-D-glucan concentration was more than 10μg/ml in all of the 16 patients. Miconazole, an antifungal agent, was administered to 27 febrile patients with clinically suspected systemic fungal infection. The overall response rate was 63.0%(17/27) and side effects were minimal. Of 16 patients with high plasma (1→3)-β-D-glucan concentration (≥10μg/ml), 13 (81.3%) responded, although of 11 patients with low plasma (1→3)-β-D-glucan concentratlon (<10pg/ml), only 4 (36.4%) responded. Miconazole is effective in treating systemic fungal infection and the determination of plasma (1→3)-β-D-glucan concentration provides a good guide for its use.

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We studied adenosine triphosphate (ATP) synthesized by bacteria in tube dilution cultures to devise a rapid antibacterial susceptibility test. The ATP level was determined with a firefly (Photinus pyralis) luciferin/luciferase bioluminescence assay, which allows a direct quantifying of bacteria above 10, 000 CFU/ml. At sub-MIC, total bacterial ATP levels were paralleled by increased viable bacterial counts. At above MIC, however, total bacterial ATP levels remained almost constant or decreased gradually. Large differen in total ATP level were observed between sub-and above-MIC levels in the overnight cultures. These differences were also observed in cultures at 6 h. This method may be utilized for rapid antibiotic susceptibility testing.

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