The combined effects of cefasolin and gentamicin on the fatal murine pneumonia due to Klebsiella pneumoniae have been studied, utilizing the method for quantitating both intrapulmonary viable bacteria and drug concentrations, and revealed the synergistic action small dose of gentamicin with cefazolin.
Before the in vivo experiments, in vitro synergistic effect of cefazolin and gentamicin on the growth curve of Klebsiella pneumoniae B-54 (MIC of cefasolin 1.56 μg/ml; gentamicin 0.39 μg/ml) was examined, using Biophotorecorder TN-112 D [Toyo Kagaku Co.]. This study revealed that 1/50 MIC (0.008 μg/ml) of gentamicin clearly strengthened the suppressing effect of cefazolin on the bacterial growth.
As reported in our previous papers [Chemotherapy 27: 109-115 & 801-806, 1979], in each experment, 150 mice infected with 500 LD₅₀ of Kiebsiella pneumoniae B-54 (LD₅₀; 9.7×10 C. F. U./lung) were treated by subcutaneous injections of cefazolin and/or gentamicin, begun at 12 hours after infection. The curative action of repeated injections of cefazolin 50mg/kg plus either gentamicin 1mg/kg, 0.1mg/kg or 0.01mg/kg was superior to that of cefazolin alone. Furthermore, even the injections of 0.01 mg/kg of gentamicin q. 6h. clearly increased the curative effect of the injections of cefazolin 50 mg/kg q. 1 1/2h. The single injection of cefazolin 50mg/kg plus gentamicin 0.01mg/kg suppressed the bacterial growth in the murine lung during more than 3 hours, while the single injection of cefazolin 50 mg/kg alone suppressed during only one hour.

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Studies on the assay procedure for the concentration of HCFU and its metabolites in organs were carried out using Staphylococcus aureus 209 P as the test organism.
Concentrations of HCFU and its metabolites in organs can be determined essentially by the procedure described previously. With several organs, such as stomach, small intestine and liver, however, it had been difficult to determine 5-FU concentration below 0.4 μg/g organ microbiologically because of an inhibitory effect of some organ-specific factor (factors) on formation of inhibition zone by 5-FU on the lawn of indicator bacteria.
This undesirable effect was eliminated by reextracting the aqueous phase containing 5-FU, with a mixture of propanol and ether.
Thus, we could determine 5-FU concentration in those organs with a lower limit of 0.05μg/g organ.

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Combined regimens on empirical basis have occasionally been employed because of the difficulty of the identification of causative organisms in respiratory infections. The combined regimen of penicillin and aminoglycoside has been proved useful from both bacteriological and clinical view points in cases of infections caused by P. aeruginosa. This report deals with the in vitro evaluation of the effectiveness of the combination of CBPC plus DKB or AMK against various species of or ganisms isolated from patients, and the clinical evaluation of the effectiveness of the combined regimen of CBPC and aminoglycoside in cases of extremely severe respiratory infections.
Results of in vitro experiments: S. pneumoniae, S. pyogenes and alpha hemolyticus were sensitive to CBPC, and the combination of CBPC and DKB showed synergistic or additive effects. H. influenzae was sensitive to both CBPC and DKB, and the combination of the two durgs showed synergistic or additive effects. S. aureus was sensitive to DKB, and the combination of CBPC and DKB showed additive effects. P. aeruginosa and Serratia were sensitive to CBPC and DKB, and the combination of CBPC and DKB showed synergistic effects. E. coli, K. pneumoniae and E. cloacae were resistant to CBPC, and the antagonism between CBPC and DKB was observed on several strains.
The combination of CBPC and AMK showed synergistic effects against most of the organisms studied.
The MIC of DKB against S. aureus, P. aeruginosa or Serratia was lower than that of AMK and the combination of CBPC and DKB was more effective than that of CBPC and AMK. The MIC of AMK was lower than that of DKB against resistant strains of S. aureus or E. coli and the combination of CBPC and AMK was more effective than that of CBPC and DKB.
Results of clinical application: In cases of severe respiratory infections, which could be treated only with difficulty, 10 to 20mg of CBPC were administered (IV drip) in combination with aminoglycoside (IM). The causative organisms of the respiratory infections were eradicated in 11 of 19 cases (57.9%).
The over-all therapeutic effects of the combined regimen of CBPC and aminoglycoside in respiratory infections were good in 11 of 19 cases (57.9%), fair in 2 of 19 cases (10.5%) and poor in 6 of 19 cases (31.6%).

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Apalcillin (APPC), piperacillin (PIPC) and PC-455 developed in Japan as the derivatives of ampicillin or amoxicillin have an acid-amide combined substituent at the 3-position (α position) in the chemical structure. Possible influence of the substituent on the antibacterial action of these agents was studied using carbenicillin (CBPC) as the control drug and Pseudomonas aeruginosa as the test organism, and the following results were obtained.
1. The mode of antibacterial action of the test compounds was studied. APPC, PIPC and PC-455 were more liable to the influence by the inoculum size compared with CBPC. When these compounds acted with the inoculum size of 5×10⁷ cells/ml, CBPC had a marked bactericidal action on the test organism, but APPC, PIPC and PC-455 had a bacteriostatic action.
2. Possible influence of the test compounds on formation of spheroplasts was studied and it was found that CBPC formed spheroplasts at a high percentage but APPC, PIPC and PC-455 scarcely produced spheroplasts.
3. Synergism produced when each of the test compounds was used in combination with lysozyme or an aminoglycoside antibiotic was investigated and it was found that there was marked synergism when CBPC was combined with lysozyme or an aminoglycoside antibiotic, but synergism produced when APPC, PIPC or PC-455 was combined with lysozyme or an aminoglycoside antibiotic was less pronou nced.
4. The components of the bacterial cells treated with each of the test compounds were quantitatively determined. In the bacterial cells treated with APPC, PIPC or PC-455, accumulation of RNA fraction was found but such phenomenon was detected in the bacterial cells treated with CBPC.

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A dialysis cell unit was used in conjunction with our previously described kinetic model for simulating antibiotic concentrations in exudates and tissues.
The bactericidal efficacy of cefazol in in the dialysis cell was investigated in the model simulating the serum levels in the flow cell after i. v. dosing with 0.25 to 2g. In this experiment, the activity of cefazolin was dose-dependent in the range of the drug concentrations used. When 5 strains of E. coli (MIC:3.13-50μg/ml) were used as the test organism, the bactericidal eficacy of cefazolin correlated well with the drug concentrations in the dialysis cell.

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The penetration of FK749 to the outer membrane was compared with those of the five other new cephalosporins: cefotiam, cefuroxime, cefotaxime, cefmetazole and cefoxitin, using a clinical isolate of Enterobacler cloacae as a test strain. The estimation of the permeability was performed by the method utilizing the inhibiting activities of the cephalosporins against the β-lactamase which is localized in the periplasm. Of the cephalosporins tested, FK749 as well as cefmetazole gave the remarkably high concentrations in the periplasm, several times higher than those of cefotaxime and cefoxitin and ten to several tens times higher than those of cefuroxime and cefotiam. The approximate permeability coefficient of FK749 was several times superior to those of cefotiam and cefmetazole and several tens times superior to those of cefoxitin, cefuroxime and cefotaxime.

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