This experiment was designed to study the combination effect and optical dosing regimen of vancomycin (VCM) and β-lactam against methicillin-resistant Staphylococcus aureus (MRSA) in vitro. Checkerboard studies of VCM and, β-lactam (cefotiam: CTM, cefmetazole: CMZ, flomoxef: FMOX, or imipenem: IPM) against 55 clinically isolated MRSA strains revealed synergistic or additive effects. At constant drug concentrations, the combination effect of VCM and β-lactam, determined by bactericidal activity and postantibiotic effect (PAE), was potentiated when the concentration of β-lactam was increased. On the other hand, it was unchanged or weakened when the VCM concentration was increased. Furthermore, when VCM exposure preceded β-lactam exposure, the combination effect was weakened, as compared with exposing the organism to the β-lactam first. At simulated human serum concentrations of VCM and FMOX, the combination effect, determined by max. kill. down, recovery time, and suppressive, area, showed results similar to those described above in term of dose and order. These findings suggest that in applying combination therapy with VCM and β-lactam to MRSA infections, effectiveness may be diminished if the VCM dose is increased or VCM is administered before the β-lactam.

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The susceptibility of five species of pathogenic Nocardia including 91 strains to erythromycin (EM) and acetylspiramycin (A-SPM) was studied. Inactivation of EM and A-SPM by these pathogenic Nocardia was also tested. Among these Nocardia species, Nocardia nova was found to belong to the most sensitive group, and Nocardia brasiliensis was resistant to both EM and A-SPM. The susceptibility of Nocardia asteroides varied depending on the strain. Nocardia farcinica and Nocardia otitidicaviarum were resistant, but both species are more sensitive to EM than A-SPM. All N. brasiliensis tested inactivated EM as well as A-SPM, and the possible structure of the inactivated product is discussed. No inactivation products were obtained from N. nova.

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1) The effect of a new quinolinecarbonic acid compound, ofloxacin (OFLX), was studied in isolated rabbit thoracic aorta and isolated iris sphincter muscle. The findings obtained with ofloxacin in aorta were compared with those of the Ca antagonist, diltiazem.
2) OFLX attenuated the contractile responses to electrical transmural stimulation and tyramine in aorta. The attenuation of these responses was dose-dependent. In iris sphincter muscle, OFLX did not affect the contractile response to electrical transmural stimulation.
3) OFLX non-competitively shifted the phenylephrine-induced dose-response curve to the right, whereas the compound failed to affect the responses to potassium and Ca²⁺-induced contraction in a Ca²⁺-free medium in the presence of KCl (40 mM).
4) Diltiazem had very weak effect on the response to phenylephrine, but markedly attenuated the KCl and Ca²⁺-induced contractile responses.
5) In a Ca²⁺-free medium, phenylephrine 10^-6 M caused phasic contraction, and subsequent application of Ca²⁺ (2.5 mM) caused tonic contraction. Both contractions were inhibited by OFLX10^-4M.
6) These results suggest that OFLX has a selective inhibitoty action against the adrenergic contractile mechanism, and that the action may be related to the release of intracellular Ca²⁺ and to Ca²⁺-entry through receptor-operated Ca channels.

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The uptake of ceftazidime (CAZ) by lung and bronchial tissues was studied in 37 patients who underwent operation for lung cancer (43-79 years old). CAZ (1g) was administered by intravenous drip infusion for 1 hour before the operation, and the CAZ concentration was determined in lung and bronchial tissues sampled during the operation. Pharmacokinetic analysis was carried out, and the relationships between tissue uptake of the drug and age (70 years or above vs. less than 70years) and pulmonary function (% VC, FFV_1.0, FFV_1.0%) were evaluated.
1. Changes in CAZ concentration were similar in lung and bronchial tissues. At both sites, the peak concentration was observed about 15 minutes after the end of drip infusion, and the mean concentration was estimated to be 30-35 μg/g. The AUC of the CAZ concentration in the lung tissue was 48.0%, and that in the bronchial tissue was 37.2%, the AUC of the serum CAZ concentration.
2. There was no difference in lung and bronchial tissue uptake of the drug between those aged 70 years of above and those aged less than 70 years.
3. Correlations between tissue concentrations of the drug and parameters of pulmonary function were analyzed. A slight association was observed between bronchial tissue concentration and both FFV_1.0 and FFV_1.0%(0.10> P> 0.05), but no correlations were noted between the bronchial tissue concentration or bronchial-lung tissue concentration ratio and % VC, FFV_1.0, or FFV_1.0%.
From these findings, CAZ in considered to be efficiently taken up by ling and bronchial tissues regardless of the age or the pulmonary function of the patient, and it should there fore be effective for various respiratory infections, including those in compromised hosts, because of its wide antibacterial spectrum.

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We investigated the effect of probenecid and the influence of a meal on the pharmacokinetics of zidovudine (AZT) in HIV-1 positive patients and obtained the following results.
1. The meal load had a large influence on the pharmacokinetics of zidovudine, but the effect was almost non-existent when the drug was administered 1 h before the meal.
2. Probenecid administered not only ‘before’ but also ‘with’ AZT was the most effective.
3. The maximum concentration, area under the curve and T-half of AZT and AZT's metabolite, glucuronide-conjugated AZT (GAZT) increased with the co-administration of probenecid, but the urinary excretion of GAZT was decreased.
4. Repeated dosing of AZT with probenecid co-administration seemed to cause an increase in theserum AZT level.
The above results suggest that AZT administered 1 h before a meal would be appropriate and probenecid co-administration would reduce the dosage of AZT.

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A study of ceftazidime (CAZ) in burn-induced infections was conducted to examine its clinical and biological efficacy. Fifteen patients with bacteria in their wound were recruited. The degree of burn was categorized as Superficial Dermal Burn (SDB) in 2 cases, and Deep Dermal Burn (DDB) or Deep Burn (DB) in 13 cases. The burned surface area ranged between 3% and 48%, being below 10% in 4 cases, between 10 and 20% in 5 cases and 30% or above in 6 cases. CAZ was administered intravenously at 1-2g/day for 5-9 days. The total dosage was 6-18 g. The clinical efficacy was measured by body temperature and the rate of improvement in subjective/objective symptoms as shown below, and was assessed as: Markedly improved in 1 case, Moderately improved in 10 cases, Slightly improved in 3 cases. Unchanged in 1 case. Thus the efficacy rate was 73.3%(11/15). In bacteria taken from the wound there are 10 strains of Pseudomonas aeruginosa and 3 strains each of Enterobacter cloacae and Acinetobacter calcoaceticus. The eradication rate of bacteria was 58.3%(14/24). With regard to adverse effects, mild abnormalities (raised GOT and GPT) were observed in two patients, based on clinical laboratory data. The study demonstrated that CAZ is useful for the treatment of burn wound infections in terms of its safety profile as well as its clinical and bacteriological efficacy.

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Four clinical isolates from the blood of granulocytopenic patients (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli and Staphylococcus aureus) were used to determine the 50% effective dose (ED₅₀) of experimental infections in mice, as well as the 6 hours minimal lethal concentration (6-hour-MLC). In all cases, the ED₅₀ in the mice with cycloposphamide (CY)-induced granulocytopenia was markedly increased as compared with normal mice. Concening the DE₅₀ of the granulocytopenic mice, tobramycin (TOB) showed much better results than β-lactam antibiotics [imipenem (IPM), ceftazidime (CAZ)]. In combined administration, TOB+CAZ showed synergistic effects against all gram-negative bacteria. TOB +IPM showed synergistic effects against P. aeruginosa. Concerning 6-hour-MLC, higher doses of antibiotics were required to sterilize gram-negative bacteria than to sterilize S. aureus. TOB showed much better results in sterilizing bacteria during a short period of time than did IPM or CAZ. When granulocyte colony-stimulating factor (G-CSF) was administered prior to infection in the granulocytopenic mice, the ED₅₀ was less than in the mice receiving only CY (administration). When G-CSF was administered after onset of infection in the granulocytopenic mice, the ED₅₀ of the mice did not significantly decrease compared to the mice receiving only CY. These findings suggest that in infected granulocytopenic patients, G-CSF administration after onset of infection would be less effective than administration prior to infection.

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An effectiveness of an administration of the liver extract, Adelavin, was evaluated in terms of the frequency of liver dysfunctions emerged in the course of a combination chemotherapy with a monobactam, aztreonam (AZT), and piperacillin (PIPC), in respiratory or urinary tract infections.
1. There was no significant difference between a control group (82 cases) and an Adelavin one (79 cases) in terms of age and sex or infectious disease they had, the mean age being 60.8±1.9 in the control (including 44 males and 38 females) or 63.5±1.9 in the Adelavin group (including 46 males and 33 females), where the control group included 64 cases of respiratory infections, 17 cases of urinary tract infections and one cases of another one, and the Adelavin group included 58 cases of respiratory infections, 16 cases of the urinary tract infections and 5 ceses of other infections.
2. The rate of effectiveness of the therapy was 74.7 and 78.2% in the control and the Adelavin group respectively. Though the rate was higher in the Adelavin group, there were no significant difference between the two.
3. The frequency of the elevation of s-GOT was s-GPT was 11.4% in the Adelavin group and in 25.6% the control one, indicating the effectiveness of the administration of Adelavin (p<0.05)
4. In the control group, other abnormal data and adverse reactions observed were, exanthem, anorexia and nausea, eosinophilia, and leukopenia respectively in one case. While in the Adelavin group, they were exanthem, an increase in BUN level respectively in one case. They were not serious ones and disappeared during or after the treatment.
The study showed that Adelavin administered to patients with respiratory or urinary tract infections reduced the frequency of the liver dysfunctions in the combination chemotherapy with AZT and PIPC. All the adverse reactions were mild, and there was no problem in the clinical use of Adelavin.

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