We compared the pharmacokinetics of eight synthetic antimicrobial quinolone derivatives available in Japan, two of which were already used in clinics. The average time course of serum concentrations after a single oral dose of each drug (normalized to 200mg) varied considerably from agent to agent. The area under the serum concentration curve (AUC) and the maximum serum concentration (C_max) showed 10-and 6-fold differences among the drugs, of which fleroxacin had the largest AUC and highest C_max. The time required to reach the maximum serum concentration ranged from 1 to 4 h. The cumulative urinary recovery of unchanged drug showed also a 10-fold difference among the drugs, of which ofloxacin had the highest (84% of the dose). The time for which the serum concentration of each derivative exceeded the MIC₅₀ or MIC₉₀ of representative strains of clinically isolated bacteria, such as Staphylococcus aureus and Escherichia coli, was also examined. Although tosufloxacin had the lowest serum concentration, levels, this was above the MIC₅₀ for more than 3 h against all strains of bacteria tested. Notably, the in vitro antimicrobial activity of tosufloxacin was from one to thirty times greater than those of the other derivatives. Although lomefloxacin showed a serum level about 4 times higher than that of tosufloxacin, and the calculated duration above the MICs for lomefloxacin was shorter than that of tosufloxacin, the former was nevertheless more effective than the latter. This upholds the importance of detailed pharmacokinetic considerations and in vivo pharmacodynamics in order to estimate clinical efficacy.

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We investigated serum and urinary concentrations of ceftazidime and azthreonam in three healthy male volunteers after a single 1.0g intravenous administration, and evaluated their antimicrobial activity in urine against clinical isolates of three Pseudomonas aeruginosa with different MICs, Serratia marcescens and Escherichia coli.The peak serum level of ceftazidime was 94.2μg/ml (HPLC) and that of aztreonam was 103.4μg/ml (HPLC).
The cumulative urinary recovery rate of ceftazidime at 12 hours after intravenous administration was 90.6%(HPLC) and that of aztreonam was 65.1%(HPLC).
Antimicrobial activity of ceftazidime and aztreonam in urine was calculated by the dilution ratio. That of ceftazidime was higher against two of the three isolates of P. aeruginosa, but against S. marcescens and E. coli there was only a slight difference.

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Amphotericin B was incorporated into lipid emulsion using the method of K_IRSH R et al. Shortly 20mg of sodium deoxycholate were dissolved in 1.0 ml of dimethylacetamide. This solution was used to solubilize the amphotericin B at various concentrations, and then Intralipos 20%^® was added.
The LD₅₀ of amphotericin B lipoid emulsion was more than 5.0 mg/kg in normal BALB/C mice, compared with 1.2 mg/kg for conventional amphotericin B (Fungizoneu^®).
In a study of experimental murine disseminated candidiasis, the survival rate of mice given conventional amphotericin B at a dose of 8.0 mg/kg (the maximal tolerated dose without acute lethality) was 20%, whereas the animals treated with amphotericin B in lipid emulsion all were alive 42 days after inoculation (p<0.01).
In the case of experimental murine cryptococcosis, amphotericin B in emulsion also produced higher survival rates than commercial amphotericin B.

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An experimental infection model which was induced in a carboxymethyl cellulose (CMC) pouch on the back of rat was newly designed and compared with the croton oil-induced granuloma pouch method. The results were as follows:
1) Staphylococcus aureus, Eseherichia coli, Pseudomonas aeruginosa and Bacteroides fragilis which had been injected into each type of pouch rapidly increased to complete an infection.
2) The number of white blood cells, complement units and amounts of exudated protein in the two types of pouch were almost the same at 24 h after bacterial injection, though different from each other at the time of injection. The composition of exudated protein did not differ between the two types.
3) In the pathological investigations, an inflammatory pattern characterized by a remarkable infiltration of neutrophils in the subcutis of the CMC pouch and a granuloma in the croton oil pouch were observed.
4) Penetration of, β-lactam antibiotics into the CMC pouch was better than that into the granuloma pouch.
Our results strongly suggest that the experimental infection model in the CMC pouch was useful in evaluating various antibacterial agents and that the model had the merits of being easy to operate and quick to prepare.

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Miconazole was administered by intravenous infusion in 400mg doses two to four times daily to 103 patients with deep-seated fungal infections associated with hematological diseases. The mean duration of administration was 18.3±13.1 days. The data of 87 of these cases were used for analysis. The results were as follows.
1. Out of 87, marked efficacy was seen in 10 cases and efficacy in 45. The overall efficacy rate was 63 %, the efficacy rate in the group administered up to 800mg/day of miconazole was 50 %, and that in the group receiving more than 1, 200mg/day was 69 %.
2. The fungus was eliminated in 8 and reduced in 4 of the 23 cases in which mycological examination was done before and after treatment with miconazole.
3. In chest X-ray films of 42 cases, shadows disappeared in 2 and improved in 18.
4. Side effects occurred in 9 (8.7 %) of 103 cases, none of them being serious.
We consider miconazole a potent antifungal agent for treatment of deep-seated fungal infections associated with hematological diseases.

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A pharmacokinetic study of cefuzonam (CZON), one of the new third-generation cephems, was performed in four hemodialyzed patients on days with and without regular hemodialysis (HD) treatment (cross-over method). All subjects had normal liver function.
CZON (1.0g) was administered by a single i. v. injection for 5 min, and blood samples were collected at selected time intervals. Serum concentrations of the drug were measured by highperformance liquid chromatography.
The pharmacokinetic parameters of CZON were calculated from the average serum concentrations, according to both one-compartment model (dialysis session time, 1-6 h afterinjection) and two-compartment model (whole time, 1-24 h after injection). Overall T_1/2 was 2.419 ±0.619 h on the HD day, and 2.794± 0.316 h on the off-HD day. The T_1/2 of the dialysis session time was 1.916±0.434 on the HD day and 2.145±0.793 on the off-HD day. The T_1/2 in hemodialyzed patients was about 2 times longer than normal subjects. For T_1/2, no significant difference was found between the on-HD and off-HD day. Similarly, For both AUC and Clt, there was no significant difference.
Assuming that 1.0g of CZON was given by i. v. injection once a day for 1 week to hemodialyzed patients, we calculated the changes in serum concentration. On such a schedule CZON was revealed to be non-cumulative in patients with HD treatment thrice a week.
We conclude that the T_1/2 of CZON in hemodialyzed patients is longer than in normal subjects but that there is little dialysis effect on the serum concentration of CZON. We suspect, however, that extra-renal or extra-dialysis elimination is increased.

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Ceftazidime (CAZ) monotherapy in severe infections was performed on 25 patients with hematological diseases: 7 with acute leukemia, 3 with aplastic anemia, 7 with myelodysplastic syndrome, 3 with multiple myeloma, 3 with malignant lymphoma, amd 2 with idiopathic thrombocytopenic purpura.
The details of the severe infections were: 6 sepsis, 10 suspected sepsis, 7 pulmonary diseases, such as pneumonia, and 2 others.
Two grams of CAZ were administered by 1 hour intravenous drip infusion 2 to 4 times a day.
Twenty-one of 25 patients were evaluated for efficacy. Clinical efficacy was markedly effective in 7 cases, effective in 4, fairly effective in 5, and ineffective in 5. The overall efficacy ratio was 52.3%.
The efficacy ratio of CAZ was 58.3% in the patients with granulocyte counts more than 500/μl, while it was 44.4% in those with less than 500/μl prior to the therapy.
No side effects or abnormal laboratory findings were observed.
We consider CAZ a useful drug in empiric therapy for fever in granulocytopenic patients.

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We performed basic and clinical studies on ciprofloxacin (CPFX), a new pyridone carboxylic acid derivative.
Concentrations of CPFX in skin tissue and mammary gland were measured in patients with breast disease after a single oral administration of 200mg CPFX. The ratio of tissue to plasma levels of CPFX at 48-180 minutes after administration ranged from 0.33 to 1.51, and was on average 0.81 (n=20).
Eighty patients with secondary infections (due to wounds, burns or surgical operations), mastitis, areolitis and periproctal abscess were enrolled in this clinical study, and given CPFX orally at a daily dose of 200mg b. i. d. or t. i. d. Clinical efficacy assessed by the doctors in charge was excellent in 33 cases, good in 27, fair in 10 and poor in 10, with an overall rate of 75.0%. Clinical efficacy assessed according to the “Evaluation Criteria” was excellent in 26 cases, good in 36, fair in 12 and poor in 6, with an overall rate of 77.5%.
As to bacteriological response, 62 of the 66 clinical isolates were eradicated, and the eradication rate was 93.9%.
No adverse reactions were observed. Abnormal laboratory findings were noted in two cases: leukocytopenia and thrombocytopenia in one, and elevated S-GOT and S-GPT in another.

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