To assess the appropriate intravenous infusion rate of tobramycin (TOB), four methods of administering 1mg/kg of TOB injection and continuous iv infusion over 60, 30 and 15 min, were compared in 4 healthy male adults volunteers by crossover design.
Serum concentrations of TOB after iv infusion over 30 and 60 min were analyzed with a two-compartment model and pharmacokinetic parameters were calculated. Using these parameters, serum concentrations after iv infusion over various periods were simulated, and the calculated peak levels after iv infusion over 2, 5, 15, 30, 60, 120 and 360 min were 7.6, 7.4, 6.6, 5.7, 4.6, 3.3 and 1.7μg/ml, respectively. Observed serum concentrations of TOB after iv infusion over a 15-min period agreed well with the corresponding simulation curve, thus confirming the validity of this pharmacokinetic model.
After iv infusion of 1mg/kg TOB over 15-120min, peak concentrations were 6.6-3.3μg/ml, and concentrations above 2μg/ml were persisted for above 100min. Serum levels 6 hr after the start of infusion were about 0.5μg/ml. Peak serum concentrations after im injection were similar to those after iv infusion over 30-60 min.

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A double-blind controlled trial was carried out using piromidic acid (PA) as a reference drug in order to examine the therapeutic effect of pipemidic acid (PPA) on enteritis including bacillary dysentery and Vibrio parahaemolyticus enteritis, and the influence of PPA on bacterial flora in feces. The results obtained were as follows.
1. Efficacy was evaluated in 27 PPA-and 24 PA-treated cases fulfilling test conditions among total 67 medicated cases. There were no significant differences between these medicationgroups on the background factors analyzed.
2. According to the unified evaluation, the rates of “excellent response plus good response” were 85.2% with PPA and 75% with PA. There was no significant difference between both the drugs, while there was CL tendency that PPA was superior to PA with respect to the efficacy in the cases with bloody stool.
3. From fecal samples taken premedication, pathogens such as Shigella sp., Salmonella sp., Vibrio parahaemolyticus and Klebsiella oxytoca were detected in 8 PPA-and 7 PA-treated cases, but there were no significant differences between both the medication groups on bacteriological effects.
4. Fccal bacterial flora was observed in all fecal samples taken before, during and after medication, Before medication, the numbers of organisms were large in anaerobes, Escherichia coli, Klebsiella sp, Citrobacter sp., Enterobacter sp. and Streptococcus sp. During medication with PPA or PA, the gramnegative organisms were markedly reduced or disappeared, while anaerobes and gram-positive organisms did not change significantly. After medication with PPA, the gram-negative organisms recovered in number to the same degree as before medication, while anaerobes and Streptococcus sp. were increased. Similar results were obtained with the PA-treated cases. A difference was that the degree of reduction in the number of organisms in feces was more marked in PPA-treated cases than in PAtreated cases.
5. The drug-sensitivity of the organisms was determined by the agar-dilution method. The peak minimal inhibitory concentrations of PPA and PA were 0.78-3.13μg/ml and 12.5-25μg/ml respectively for gram-negative organisms, and 12.5μg/ml and 100μg/ml for Pseudomonas sp. The gram-negative organisms resistant to PPA or PA were none or rare, while those resistant to ampicillin, chloramphenicol and tetracycline had a large part of the isolates, and tiwy were greatly reduced by medication with PPA or PA. Those results indicate that PPA as well as PA is a useful drug for enteritis.

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(1) When used alone, MIC of PIPC was found most frequently at 6.25, ug/m1 and that of TIPC at 50 jug/ml. Thus it was found that the antipseudomonal activity of PIPC was almost 3 times as strong as that of TIPC.
(2) Synergistic inhibitory effects of PIPC plus. DKB (FIC index≤0.5) were observed on 26 strains (74.3%) and those of TIPC plus DKB on 23 strains (65.7%). Thus synergistic growth-inhibitory effects by combination of PIPC and DKB were found to be somewhat superior to those of TIPC DKB.
(3) Synergistic potentiation of bactericidal activity (FBC index 50.5) of PIPC plus DKB was found against 23 strains (65.7%), while that of TIPC plus DKB against 18 strains (51.4%). Thus, PIPC was found to show more remarkable effects than TIPC when combined with DKB.
(4) Test strains in this experiment were divided into the following two groups: in group I, MIC of PIPC and TIPC respectively was 6.25, μg/ml and below, and in group II, 12.5, μg/ml and above.
Combined effects of PIPC plus DKB and those TIPC of DKB respectively were compared between group I and group II.
As shown by FIC-and FBC-indices, the combined effects were more evident in group II than in group I.
These results indicated the advantage of combinding β-lactam antibiotics with DKB, as evidenced by enhanced synergistic growth-inhibitory effects on the strains that are not very sensitive to 3-lactams.
MIC of PIPC and TIPC respectively was decreased by addition of a small amount of DKB. When used alone, MIC of 6.25 μg/ml and below was found for PIPC in 19 strains (54.3%) and for TIPC in 2 strains (5.7%) respectively.
In the presence of 0.2 μg/ml of DKB, on the other hand, MIC of 6.25 μg/ml and below was found for PIPC in 33 strains (94.3%) and for TIPC in 23 strains (65.7%) respectively. Similarly, MBC (without partner drug) of 6.25 μg/ml and below was found for PIPC in 15 strains (42.9%) and for TIPC in 2 strains (5.7%) respectively. When combined with 0.2 μg/ml of DKB, MBC of 6.23 μg/ml and below was found for PIPC in 29 strains (82.9%) and for TIPC in 16 strains (45.7%) respectively.

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The effects of coinjection of cephalosporine (CEPs) on renal tissue distribution and toxicity of aminoglycosides (AGs) in the rat were investigated after multiple i. m. administrations and following results were obtained.
1) Following daily administration of cephalothin (CET) and gentamicin (GM), a significant reduction in renal tissue concentration of GM associated with maintenance of endogenous creatinine clearance was observed. However, serum concentration of the latter was not affected.
2) After combined administration of GM and furosemide, renal tissue concentration of GM increaced. Furthermore, additional administration of CET suppressed this change significantly.
From these observations, it was concluded that coinjection of CET may ameliorate the renal impairment due to AG and this may be attributable to reduction of renal tissue accumulation of the latter.
3) Following 24 hrs in vitro incubation of AG with CEP in phosphate buffer solution or terum, in case above 10 fold concentration of CET that of AG, a marked reduction of AG activity was observed. Same results were also obtained from the thin layer chromatographic study. But these were not shown in supernatant of murine renal tissue emulsion. These results seems to be due to the different affinities of protein binding of CEPs.
After all, AG, may combine with CEP and forms new products. Activity of the former may be reduced by such a mechanism.
4) As a model experiment for renal failure, rats were ligated their renal hili and GM was injected with CET. No influence on serum level of GM was shown.

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In order to get some information on pharmacokinetics of antibiotics in liver diseases, hepatic clearance and other pharmacokinetic parameter of cephalothin (CET) and its major metabolite, desacetyl cephalothin (DA-CET), were examined in guinea pigs with or without acute liver impairment produced by treatment with carbon tetrachloride. In acute liver impairment, the CET hepatic clearance was markedly decreased. Accordingly, transport of CET in the hepatocyte may be damaged as well as metabolism of CET into DA-CET. The CET hepatic clearance should be evaluated in 45 minutes after intravenous injection. Hepatic clearance seems to be a good index to evaluate hepatic transport of antibiotics, particularly in patients with liver diseases e. g. hepatic and biliary tract infections. On the other hand the values of k_e1 and T_1/2 showed no significant difference between the control and acutely impaired guinea pigs. The total excretion of CET from the body into bile and urine was not at all diminished.
The hepatic clearance (C_η) was calculated from the following formula;
C_η=B^0→t_X/AUC^0→t_X (ml/t min/kg body wt)
B^t→0_X: cumulated recovery of x in bile in t minutes
AUC^t→0_X: area under the serum level curve of X in t minutes (μg·t min/ml)

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The aminoglycoside antibiotic dibekacin was clinically applied to 15 patients with the various infections in the field of otorhinolaryngology.
Dibekacin was administered by 1 hr. intravenous infusion at a daily dose of 100mg (a. i. d.) in general and the total dose ranged from 700 to 7, 800mg.
Clinical response was favorable and 73.3% of efficacy rate was obtained. As to safety evaluation, no evidence occurred for the dysfunction of kidney, liver and auditory acuity.
In terms of the assessment of efficacy and safety, newly developed enzyme immuno-assay method was thought to be useful for rapid determination of dibekacin serum level which fluctuats by patients, especially by their creatinine clearance.

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Combination therapy with a large dose of antibiotics, ticarcillin either cefazolin or/and aminoglycosides or/and fosfomycin, on 17 episodes in febrile neutropenic patients was studied.
Therapy with intravenously administered ticarcillin (20g/m²/day) and/or cefazolin and/or gentamicin or amikacin was started as soon as a presumptive diagnosis of sepsis had been made, without waiting for the isolation and identification of microorganism.
If no clinical improvement occurred in initial combination of antibiotics, fosfomycin was added to combination therapy.
Among seventeen episodes of presumed sepsis, the excellent and good response was observed in 13 (76.4%) and 14 (82.3%), respectively.
Bone marrow recovery during antibiotic therapy, was observed in patients, and they recovered from the presumed generalized infection.
Toxic effects were not seen markedly, judging from BUN and GPT level.

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In vitro displacing effects of cefotaxime (CTX) and desacetyl-CTX on bilirubin bound to human serum albumin were compared with timsc of other cephalosporins, cefazoiin (CEZ) and cefmetazole (CMZ).
Any of the four compounds at 20-640μg/mi exerted no bilirubin-displacing effect at the normal level of human serum albumin.
At the albumin level approximately 1/5 times lower than the normal, CEZ and CMZ exhibited bilirubindisplacing effects, which were directly proportional to albumin binding affinities of the antibiotics. On the other hand, CTX and desacetyl-CTX displaced bilirubin from albumin to a much lesser extent than CEZ and CMZ.

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The concentrations of a ampicillin in serum and the tonsil after administration were investigated in order to study the definit per oral dosis of ampicillin against tonsillitis. Eight patients underwent tonsillectomy and four healthy adult volunteers were submitted to this study. A dosis of 30mg/kg of ampicillin was given intravenously in the five out of eight patients and the concentrations in serum and the tonsil were measured as a function of time after injection. Fitting curve were computed from measured concentrations of ampicillin in serum and the tonsil. The regression equation is as follows:
Serum concentrations=163.73×(0.9745) ⁴
Tonsil concentrations=30×(0.9732) ^t (t: time)
Average serum concentration of ampicillin after oral administration of 10mg/kg were also studied on four healthy volunteers. The data on the serum concentrations of ampicillin after oral administration were substituted for the regression equations, and concentrations in the tonsil in the internal use were calculated. These results indicated that ampicillin concentration in the tonsil over 0.1μg/g was maintained for about 43/4 hrs, 0.2μg/g was 4 hrs, 0.3μg/g was 3 hrs and 4.0μg/g was 21/4 hrs. Basekon these results, we propose the standard of dosis of ampicillin for internal use against tonsillitis.

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