The pharmacokinetics of ceftazidime, a new parenteral cephem antibiotic, were studied in 7 healthy volunteers and 32 patients with renal insufficiency after the intravenous administration of a single 500-mg dose. Ceftazidime concentrations in plasma and urine were determined by the thin-layer paper disk method, usingProteus mirabilisATCC 21100 as the titration strain and DST agar as the culture medium. Endogenous creatinine clearance (Ccr) was used as an indicator of renal function. The pharmacokinetic parameters for ceftazidime were calculated on the basis of a two-compartment open model. Plasma concentrations during the β-phase increased in parallel with the degree of renal impairment. A prolongation of the plasma half-life during the β-phase from 1.67hr. in the volunteers to 14.37 hr. in the patients with Ccr of less than 10 ml/min was found. There was a linear correlation between the elimination rate constant of ceftazidime and the Ccr. The mean cumulative urinary recovery of ceftazidime during the first 24 hr. was 89.6% of the administered dose in the volunteers and decreased with the lowering of renal function. Ideal schedules for the administration of the drug should be considered in patients with severe renal impairment to avoid excessive blood level of the drug.

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For the purpose of investigation on the availability of cephalosporin antibiotics, ceftizoxime (Epocelin^®, CZX) in the oral and maxillary region, the concentration in serum and bone tissue were examined by bioassay method on experimental animals and operative cases of oral surgery region.
The following results were obtained:
1. After administration of CZX 20 mg/kg (i. p.) in ddy mice (male) the concentration in maxillary bone tissue reached 7.16μg/g in 30 minutes, 4.48 μg/g in 60 minutes, 3.26μg/g in 90 minutes and 0.99μg/g in 120 minutes.
2. In 21 operative cases of oral surgery region CZX levels in serum and maxillary bone tissue were investigated after one shot i. v. injection of 1.0g (11 cases) or 2.0g (10 cases).
In serum the group at a dose of 1.0 g and the group at a dose of 2.0 g nearly correlated to each others and in maxillary bone tissues a similar correlation was displayed.
3. Judging from the concentration in serum and bone tissue, the MIC value against bacteria of various species and diffusion into maxillary bone, availability of CZX to infection of oral and maxillary region was suggested.

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The antibacterial activity of bifonazole, a novel imidazole antimycotic, against aerobic and anaerobic bacteria was examined in comparison with that of clotrimazole and the following results were obtained.
(1) Bifonazole showed a relatively strong antibacterial activity similar to that of clotrimazole against aerobic and anaerobic gram-positive bacteria, irrespective of cocci or rods.
(2) Bifonazole exhibited no antibacterial activity against aerobic and facultative anaerobic gramnegative bacteria, but it had a moderate antibacterial activity against Bacteroides, obligatory anaerobes.
(3) No difference in the antibacterial activity of bifonazole against aerobic and facultative anaerobic bacteria was observed between aerobic and anaerobic culture conditions.

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To clarify the mode of antifungal action of bifonazole, a new imidazole antimycotic, the effects of this drug on lipid metabolism, cell membrane function, etc. were examined using relatively low sensitiveCandida albicansTIMM 0144 (minimum inhibitory concentration 10μg/ml) and highly sensitiveC. PseudotropicalisTIMM 0301 (minimum inhibitory concentration 0.2μg/ml) as the test organisms.
Bifonazole caused a selective inhibition of synthesis of lipid among several major cellular constituents, and it potently inhibited ergosterol synthesis by blocking C 14-demethylation in the pathway of sterol synthesis at drug concentrations as low as 0.1μg/ml in cells of each strain. In addition, bifonazole induced release of K⁺and inorganic phosphate from cells of each strain, and elevation of p H value in a cell suspension of each strain at concentrations of ≥10μg/ml, suggesting that the drug damages the cell membrane function at relatively high concentrations.
BAY n 7133-resistant mutants, which had a reduced ability to synthesize ergosterol, were obtained artificially from both strains ofCandida, and the sensitivity of mutants and the corresponding wild type to bifonazole were comparatively tested. TIMM 0144 mutants showed almost the same sensitivity as that of the wild type, while the sensitivity of TIMM 0301 mutants was much lower than that of the comparable wild type and the sensitivity level was almost equal to the level of TIMM 0144 wild type.
On the basis of all these results, it is suggested that bifonazole has dualistic modes of antifungal action. That is to say, bifonazole exerts the antifungal activity against low-sensitive strains by mainly damaging the cell membrane. Against highly sensitive strains, on the other hand, bifonazole exerts the antifungal activity by primarily inhibiting ergosterol synthesis at the low drug concentration range, although it may exert the antifungal activity by damaging the cell membrane at the high concentration range.
The extent of inhibition by bifonazole of synthesis of bulk lipids and ergosterol in cells of TIMM 0301 was greater than that in cells of TIMM 0144.

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To investigate thein vivoantimycotic activity of bifonazole (BFZ), a new imidazole antimycotic agent, the therapeutic effectiveness of the drug in the topical treatment of experimentalT.mentagrophytesinfection in guinea-pigs was compared with that of clotrimazole (CTZ), a reference drug.
(1) 1% cream, 1% solution or 1% polyethylene glycol solution of BFZ was applied topically at adose of 0.3g/day for 14 or 21 consecutive days, starting on the 3 rd or 5 th day after infection. The treatment resulted in a significant improvement in symptoms and a complete heal as early as 6 to 10 days after initiation of application. After completion of the treatment course, local skin cultures revealed either an elimination of the fungus or a significant decrease in the fungal count.
(2) The therapeutic effectiveness of BFZ in the 21-day treatment course was superior to that in the 14-day course, irrespective of the type of drug preparation used.
(3) Comparison of each BFZ preparation with the corresponding CTZ preparation showed no significant difference in efficacy between the two drugs.S

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Ceftazidime (CAZ), a new cephem antibiotic, was evaluated about the clinical effect to superficial secondary infections.
Fifty-one cases, namely 35 of postoperative wound infection, 9 of burn wound infection, 4 of traumatic wound infection and 3 of others were treated with CAZ either by intravenous bolus injection or by drip infusion, mostly at the daily dose of 2 g for 3 to 17 days.
The clinical efficacy in the 41 assessable cases was excellent in 3 cases, good in 27, fair in 10 and poor in 1 (efficacy rate: 73%). The clinical efficacy was excellent or good in 24 out of 32 cases (75%) in postoperative wound infection and 5 out of 8 cases (63%) in burn wound infection. In 1 case of traumatic wound infection, clinical efficacy was good.
Bacteriological response in the 30 assessable cases was “eradicated” in 16 cases, “decreased” in 9, “unchanged” in 2 and “replaced” in 3 (eradication rate including “replaced” cases: 63%). Twenty strains of gram-positive bacteria (e. g.S. aureus), 22 of gram-negative bacteria (e. g.E. coli) and 14 of anaerobic bacteria (e. g.B. fragilis) were isolated before treatment. The bacteriological responses of these isolates were “eradicated” in 42 strains, “decreased” in 5 and “unchanged” in 9 (eradication rate: 75%).
No clinical side effect was observed in any of the 50 cases excluding a case of combined therapy with other antibiotic. Abnormal laboratory findings were observed in 6 out of 50 cases (10 incidents); eosinophilia (2 incidents), elevation of GOT (3), GPT (2) and Al-P (2), and increase in RBC in urinary sediment (1).
CAZ was considered from these result to be a highly useful drug for the treatment of superficial secondary infections in the field of surgery.

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Ceftazidime was administered in treatment of 15 cases of bacterial prostatitis including 9 of GNB and 6 of GPC infections. The drug was given to each patient at a dose of 2 g daily for 5 to 14 days, by bolus or drip infusion. In treatment on GNB infection group, excellent or good results were achieved in all 9 cases (8E. coliand 1Klebsiellainfections), however in GPC infection group, the response was obtained only in 1 of 6 (17%).
There were no any side reactions or abnormal laboratory findings throughout the treatment in all cases.
From the above results, CAZ was considered to be a highly effective and useful antibacterial drug for the treatment of bacterial prostatitis caused by GNB shown sensitive to CAZ.

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