We studied the mode of inhibition of protein synthesis by two major metabolites of clarithromycin (CAM), N-Demethyl CAM (M-1) and (14 R)-14-Hydroxy CAM (M-5). The results are summarized as follows:
1. The degree of inhibition of Escherichia coli cell-free polypeptide synthesis by CAM and its metabolites was in the order CAM=M-5>M-1 in both polyadenylate and MS 2 phage RNA-directed polypeptide synthesis.
2. The degree of inhibition of MS 2 phage RNA-directed cell-free synthesis of coat protein was in the order M-5≥CAM>M-1. They all inhibited the incorporation of the second and third amino acids after the initiation of polypeptide synthesis.
3. Cold CAM and its metabolites competitively inhibited the binding of [¹⁴C] CAM to E. coli ribosomes in the order CAM≥M-5>M-1.
4. The degree of inhibition of the incorporation of [³H] methionine and [³H] thymidine into the protein and DNA fraction of primary cultured rat hepatocytes was in the order CAM≥M-1>M-5.
Our results (1, 2, and 3) demonstrate that these metabolites inhibit polypeptide synthesis by he same mode of action as that of CAM. They also suggest (4) that the toxicity of CAM administered in extremely high doses to rats could be caused by M-1 or by CAM and M-1.

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We have devised a new method for the analysis of the in vitro combined effect of three antimicrobial agents by using the three-dimensional checkerboard method as reported by us previously, in which a new program designed by us for a personal computer system (NEC P-9801, Nihon-Denki Co. Ltd., Japan) was applied. 1.5×10^-4ml of an overnight culture of 87 strains consisting of 10 strains of Staphylococcus aureus, 17 of Escherichia coli and 20 each of Klebsiella pneumoniae, Serratia marcescens and Pseudomonas aeruginosa were inoculated into the microtiter plates containing varying concentrations of piperacillin (PIPC), amikacin (AMK) and minocycline (MINO) which were prepared by the MIC 2000 system based on the three-dimensional checkerboard method. The MIC values were input into the program after 20 hours' incubation at 37°C, and then VUS (volume under the surface) values, VUS index and optimum combinations of three agents were calculated for each strain and species. A VUS index of less than 0.75 was evaluated as “synergism”, one between 0.75 and 1.0 as “partial synergism”. The effect of combination as “indifference” when the VUS index was 1. 0 and as “antagonism” when it was more than 1.0. The combination of the three agents was found to be synergistic against all the species as shown by a mean VUS index of 0.702. The mean VUS index for each species was 0.867 against S. aureus, less than 0.679 against E. coli, 0.578 against K. pneumoniae, 0.726 against S. marcescens and 0.847 against P. aeruginosa. We conclude from the above results that the computer-aided three-dimensional checkerboard method is useful for the analysis of the in vitro combined effect of three antimicrobial agents.

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Fluoroquinolones inhibit bacteria by interacting with the A subunit of DNA gyrase. In comparison with earlier quinolones, the fluoroquinolones have achieved the objectives of higher activity and a broader spectrum. Minimal inhibitory concentrations (MICs) of the fluoroquinolones norfloxacin, ofloxacin, enoxacin and ciprofloxacin are consistent worldwide, with allowances for differences in acquired resistance. The susceptibility of causative organisms (21 species, 859 strains) from respiratory infections and urinary tract infections to four fluoroquinolones (norfloxacin, ofloxacin, enoxacin and ciprofloxacin) was determined. Clinical resistance to fluoroquinolones had increased and occurred most often among respiratory and urinary pathogens, particularly Pseudomonas aeruginosa and Staphylococcus aureus from patients with chronic urinary tract infections. Against streptococci, including enterococci and pneumococci, the drugs activity was moderate or poor. Haemophilus influenzae and Branhamella catarrhalis were, however, very susceptible.
To date overall resistance of bacteria to fluoroquinolones has emerged as a major problem in serious infections in Japan.

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Changes of concentration of antimicrobial agent in prostatic tissue by transurethral operation have not been studied extensively.In 1985, we measured the concentration of cefoperazone in rat prostatic tissues which were steeped in irrigation fluid, cut in pieces and shaken as a model of TUR-simulation, and reported that steeping in irrigation fluid and cutting in pieces reduced the concentration of antimicrobial agent.I have now studied the difference in prostatic tissue level of ampicillin, dibekacin, minocycline and ciprofloxacin.The concentration of antimicrobial agents in prostatic tissue was influenced by the characteristics of the drug tested, namely, pH and water solubility, and this influence was increased by the transurethral operation.

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Recently, a bleeding tendency during the administration of antibiotics has been given attention.
We studied the effects of flomoxef sodium (FMOX), a new class of oxacephem antibiotic, on platelet function and blood coagulation.
The subjects were 12 cases of respiratory tract infections.
FMOX was administered by drip infusion at a dose of 2 g /day for 7 days. And the following parameters were measured before and after the administration: platelet count, bleeding time, platelet adhesiveness, platelet aggregation activity, platelet ATP release activity, prothrombin time, active partial thromboplastin time, serum fibrinogen, fibrin degradation products, thrombo test, hepaplastin test, clotting factors II·VII·IX·X, PIVKA-II
As a result of this study, there was no deterioration in the platelet function and blood coagulation tests. In 2 cases, however, PIVKA-II was positive. We could not prove any vitamin K deficiency in other parameters and the patients had, normal prothrombin values. We thought on this study that the significance of PIVKA-II is a feature issue.
We concluded that FMOX is a safe antibiotic regarding platelet function and blood coagulation at a dose of 2 g /day for 7 days.

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The clinical efficacy and safety of imipenem/cilastatin sodium (IPM/CS) in the treatment of immunocompromised patients suffering from moderate or severe bacterial infections against which other antibiotics had been ineffective was investigated. The infectious diseases treated were sepsis, 5 cases ; suspected sepsis, 5 cases ; pneumonia, 12 cases; pleuritis with pneumonia, 3 cases: idiopathic interstitial pneumonia with bacterial infection, 2 cases; and decubitus infection, 1 case.
Doses of IPM/CS ranging from 0.25-1g were administered one to three times a day by drip infusion for 3-40 days. Because the infections were severe, 16 patients were treated in combination with minocycline, fosfomycin, aminoglycoside, etc.
The clinical effect in 16 patients (57.1%) was good, fair (14.3%), poor (17.9%) and unevaluable (10.7%)
As for bacteriological effects after the treatment, causative organisms were eradicated in 6 patients, decreased in 2, replaced in 2, and persisted in 3.
No clinical adverse effects were noted. As for laboratory findings, slight elevations of GOT, GPT were noted in 2 patients, slight elevation of GOT, GPT and BUN in 1, and eosinophilia in 1.
In conclusion, IPM/CS was a well tolerated and very effective antibiotic even in patients in whom other antibiotics had been ineffective.

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Respiratory infections with Staphylococcus aureus resistant to methicillin (DMPPC) are common particularly in hospital-acquired pneumonia in irnrnuno-compromised patients and in patients with recurrent bronchial infections with chronic bronchitis, diffuse panbronchiolitis or bronchiectasis. We studied the use of β-lactams, aminoglycosides, minocyclines, new-quinolones and fosfomycin or combination therapy with these antibiotics in 53 patients in Kawatana National Hospital with chest infections and underlying obstructive lung diseases. Fourteen of the 15 patients with pneumonia, and 29 of 37 with chronic respiratory infections had methicillin-resistant S. aureus (MRSA) in their sputum. The overall efficacy rate of monotherapy in eleven respiratory infections was 45.5% and the efficacy rate of combination therapy with β-lactarns and minocycline or others was 100%.
Minocycline was found to be effective in the treatment of most instances of MRSA chest infections in patients with pneumonia and chronic respiratory infections.

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