The ototoxic injuries of the inner ears in guinea pigs received tobramycin (TOB) were investigated. by differential frequency pinna reflex test in frequency range from 20 kHz to 0.5kHz and histopathologic examination of the whole extent of cochlear duct and vestibular organs.
The following results were obtained :
1) In the intramuscular administration of TOB at the dose of 3mg/kg/day and 6 mg/kg/day, respectively for 90days, there was neither pinna reflex loss in any frequencies tested nor hair cell loss both in spiral and vestibular organ. However, in the 3 guinea pigs received TOB 6 mg/kg/day for 90 days primary decrease in number of spiral ganglion cells and their dendrites always occurred in the posterior portion of the 4 th turn of the cochlea. Regional spiral organs consisted of normal inner and outer hair cells. These results suggest that administration of TOB at dose of 3 mg/kg/day (equivalent to expected clinical dose of TOB) for 90 days was much safer.
2) In the intramuscular administration of TOB at the dose of 50 mg/kg/day or 100 mg/kg/day for 4 weeks in gestation period, the ototoxic injuries of the inner ears of mother guinea pigs administered at the later half period of gestation were much more severe than those administered at the early half period of gestation.
In the mother guinea pigs received TOB (100mg/kg/day) for 4 weeks in gestation period, hair cell loss occurred more frequently both in the cristae ampullares and maculae. The result indicates that administration of TOB at the dose of 100 mg/kg/day for 4 weeks in a period of gestation can cause ototoxicosis in the vestibular organs in association with the cochlea damage.
3) Newborn guinea pigs from the remaining pregnant guinea pigs received TOB did not show pinna reflex loss in the frequencies tested, and a few animals showed histopathological outer hair cell loss confined to the basal end of the unilateral cochlea.
These results indicate that TOB did not induce ototoxic effect on the inner ears in the newborn guinea pigs even at such toxic dose to the pregnant guinea pigs.
4) In the intramuscular administration of TOB at the dose of 50 mg/kg/day for 4 weeks to non-pregnant guinea pigs, the ototoxic injuries of the inner ears occurred only at the slight degree of impairment. At the dose of 100 mg/kg/day for 4 weeks, the injuries remained at only slight impairment by the second week of administration, but they progressed to moderate or severe impairment after the third week of administration.
These results indicate that administration of TOB at the dose of 100 mg/kg/day is less ototoxic by the second week of administration, but more ototoxic after the third week of administration.

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The Second Department of Internal Medicine, School of Medicine, Hokkaido University Tissue concentrations of tobramycin in rats were determined after multiple intramuscular administrations of 10 and 30mg/kg for 10 days. Remarkable accumulation of tobramycin after multiple administrations was observed in the kidney. The elimination of tobramycin from the kidney was rather slow and the half-life was very long. On the other hand, no significant accumulation of tobramycin was observed in other organs such as lung, liver and spleen. Especially, accumulation of tobramycin in serum was not detected in spite of multiple administrations, and the half life was constantly about 1.hour after each repeated administrations.

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Intravenous doxycycline (abbreviated as DOTC (I.V.)) in ampule form prepared for intravenous use containing 100mg of DOTC in 5ml of solvent, was given to 91 surgical patients (52 males and 39 females), ranging from 14 to 84 years of age, the average being 49. 6 years. As a slow direct intravenous injection, 100 mg of DOTC (I. V.), mixed in 20 ml of 20% glucose, were administered. On the first day, DOTC (I. V.) was administered as 2 intravenous injections of 100mg at intervals of 6 hours, and on the next day 12, 15 or 18 hours after the second injection the third intravenous administration of 100 mg was performed. And on subsequent days 100 mg of DOTC (I. V.) were given daily. The average duration of intravenous therapy was 5. 64 days (ranging from 3 to 13 days).
DOTC (I. C.) was clinically effective both in all of 4 cases of pyogenic acute infection and in one of 4 cases of chronic infection. And for the purpose of prevention of postoperative infection it was effective in 75 cases. No side effects were recognized.
Excepting the cases with pre-existing hepatorenal injuries, there were observed no abnormal findings in the post-administrative laboratory investigation of peripheral blood and hepatorenal function.
The DOTC sensitivity of clinically isolated organisms, both from cases of this study and from patients in our hospital in the same period to the former, revealed that, on bacteriologic basis, DOTC was effective on Staphyloc. aureus, Strept. hemolyt., Klebsiella and E. coli in this order, but not so effective on Pseudomonas and Proteus.
Serum level of DOTC in peripheral blood was measured. After the intravenous administration of 100 mg of DOTC, the peak level was 7.3±2.0μg/ml, ranging from 4.7 to 11.4μg/ml, 30 minutes after injection, and the valley level was 2.4±0.9μg/ml, ranging from 1.2 to 3.6μg/ml, 24 hours after injection.

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1) Ninety-five strains were isolated from oto-rhino-laryngological field, cultured overnight and diluted 1, 000 fold by saline water, and MIC of DOTC was tested by the way of agar plate dilution method.
Thirty-one strains of Staphylococcus aureus were all suppressed the growth up to 3.12μg/ml.
2) Tissue concentration of intravenously administered PT-122 M was determined, especially in palatine tonsils and maxillary sinus mucous membrane.
Drug concentration, from 30 minutes to 1 hour after intravenously administered, of palatine tonsil (mean of 5 cases) was 1.59 μg and of maxillary sinus mucous membrane (mean of 7 cases) was 1.26μg, and synchronously tested blood-level (mean of 12 cases) was 1. 26μg/ml.
3) Thirty-nine patients of oto-rhino-laryngological field were clinically investigated with PT-122 M.
Twenty-two cases were excellent, 8 cases were good, 1 case was fair and 5 cases were poor in treatment. Three cases were unassessable.
Effective rate of PT-122 M with 36 cases was 83.3%.
Undesirable side effect was observed in 3 cases; nausea, vomiting and rapid heart rate.
Because of our effective rate, 83.3%, PT-122 M will be useful in treatment of oto-rhino-laryngological infectious diseases.

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The interaction of penicillins-carbenicillin and sulbenicillin-and various aminoglycoside antibiotics was studied in vitro. The mixture of each penicillin and an aminoglycoside drug was incubated at 37°C for up to 48 hours and tested quantitatively by thin layer cup method. In this procedure these penicillins and some aminoglycosides-gentamicin, 3', 4'-dideoxykanamycin B, tobramycin, kanamycin and aminodeoxykanamycin-lowered their antimicrobial activities. The pairing of the penicillin and amikacin, lividomycin or ribostamycin did not show biologically remarkable change. The inactivation of gentamicin or tobramycin by sulbenicillin was slower than by carbenicillin.
Clinically, the inactivation of tobramycin by carbenicillin was observed in 2 patients with renal failure requiring hemodialysis. Therefore the inactivation of aminoglycosides such as gentamicin, 3', 4'-dideoxykanamycin B, tobramycin, kanamycin and aminodeoxykanamycin by carbenicillin or sulbenicillin may be observed in a patient with severe renal failure.

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The interaction of penicillins-carbenicillin and sulbenicillin-and various aminoglycoside antibiotics was studied in vitro. The mixture of each penicillin and an aminoglycoside drug was incubated at37°C for up to 48 hours and tested qualitatively by thin layer chromatography. In this precedure these penicillins and some aminoglycosides?gentamicin, 3', 4'-dideoxykanamycin B, tobramycin, kanamycin and aminodeoxykanamycin-were chemically changed. The pairing of the penicillin and amikacin, lividomycin, ribostamycin or streptomycin did not show chemically remarkable change.
Since the change of each penicillin-carbenicillin, sulbenicillin, penicillin G, ampicillin or cloxacillin-by 3', 4'-dideoxykanamycin B is remarkable, the interaction of these penicillins and aminoglycosides such as gentamicin, 3', 4'-dideoxykanamycin B, tobramycin, kanamycin and aminodeoxykanamycin would be similarly significant.
The mechanism of the interaction of penicillin and aminoglycoside is speculated that β-lactam ring would react slowly to amino group, and penicillin-aminoglycoside complex would be formed with falling of antimicrobial activity. Some molecules of penicillin would turn to penicilloic acid. The degree of interaction may depend on various structures of antibiotic molecules.

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The in vitro sensitivities of bacteria to the antimicrobial agents, even if measured by the standard method recommended by Japan Society of Chemotherapy, fluctuate depending upon the used test strain and the sort of test antibiotic.
This experimental report with cephalexin (CEX), ampicillin (ABPC) and cyclacillin (ACPC), based on the studies on the factors that may cause the fluctuation in MICs, confirms that the size of inoculum was most responsible for the fluctuation of MIC. The comparison of the standard streak method with the stamp method proved that, if inoculated bacterial counts were less than 10⁶ cells per 1 cm² of culture plate, either of the methods produced no different result in the determined MIC values.
Among the three antimicrobial agents, the fluctuation of MIC by the sizes of inocula was most remarkable with CEX, and it was evidenced that this was mainly caused by the morphologic change of the bacterial cell induced by the drug action. In the bacillus in particular, the range of the drug concentration to allow a filament formation was widest with CEX as compared with the other two antibiotics, clearly demonstrating the relation to the fluctuation of MIC.

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It was already reported in the previous study that in the sensitivity tests on ampicillin, cephalexin and cyclacillin, the MICs were fluctuated by the size of inocula and that those fluctuations were classified into three types of sensitivities, i. e., Se-Se type, Re-Re type and Re-Se type.
In this investigation, the correlation between those types of sensitivities and protecting effects was studied in mice infections with S. aureus or E. coli through intraperitoneal challenge by varying challenge doses.
The organisms were proved to have shown three types of sensitivities to three antibiotics respectively. Single oral dose of the above antibiotics was given to infected mice at certain intervals after the challenge.
It was noted that the protecting effects were fluctuated by the challenge dose. The protecting effects correlated with the type of sensitivities were recognized only when 10⁷ viable cell per mouse was challenged to mice.
No protecting effects were noted, however, when the challenge dose more than 10⁸ viable cell per mouse was injected, irrespective of the type of sensitivities.
The protecting effects were shown in all types of sensitivities when both challenge doses 10⁵ and 10⁶ viable cell per mouse were injected in experimental E. coli infection, and no significant difference was noted in the protecting effects between two different challenge doses.
Both cephalexin and cyclacillin had shown higher protecting effects when they were given to mice one hour after the challenge than when given immediately thereafter. In ampicillin, no difference was noted, however, between the two different intervals for administration.

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Relation of postoperative infections to preoperative antibiotic bowel preparation was studied in 53 cases of colon surgery, and the significance of Bacteroides was discussed.
The preoperative bowel preparation with antibiotic agents reduced the occurrence of postoperative infections until as low as 18.6% as compared with 40% in unprepared cases. Postoperative infection rates in KM and KM combined with LCM or EM groups were 16.7 and 23.1% respectively, but the difference was not statistically significant.
Bacteroides was the most predominant population in samples obtained from infected cases both in unprepared and KM prepared patients. This result suggested that Bacteroides might play a significant role in postoperative infections after colon surgery and had the pathogenicity to surgical patients.
Sensitivities to antibiotics of Bacteroides obtained from infected wounds coincided closely with those from other clinical infections : sensitive to LCM, CLDM, EM, TC and CP, resistant to cephalosporins, broad-spectrum synthetic penicillins and aminoglycosides.
Although preoperative bowel preparation with KM combined with LCM or EM revealed the prophylactic effect on postoperative Bacteroides infections in colon surgery, Pseudomonas aeruginosa was proved to be a important causative organism in infected cases among those prepared patients.

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The 168 clinical isolates of K. pneumoniae were tested on biochemical property and antibiotic-susceptibility. On the basis of the indole reaction, 30 isolates (18%) were indole-positive and 138 isolates (82%) were indole-negative. A significant difference in antibiotic-susceptibility was found in each of the two isolates. Of indole-negative isolates, 84.1% was susceptible to CEZ at 6. 25 μg/ml or lower, while indole-positive isolates showed variable susceptibility to CEZ; 30%-susceptible, 53%-moderately resistant and 17%-highly resistant. All of the indole-positive isolates were susceptible to CP and TC, but the indole-negative isolates were varied in susceptibility to CP and TC. There was no relationship between the indole production and the susceptibilities to CER and CET in K. pneumoniae studied.
It appears that the indole reaction is directly related to the susceptibility of K. pneumoniae to CEZ, CP and TC.

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Antibacterial activity of cephalexin and other cephalosporin antibiotics against anaerobic bacteria isolated from various clinical specimens was studied by agar plate dilution technique. In addition, treatment of cephalexin to experimental subcutaneous abscess of mice caused by Fusobacterium necrophorum was examined.
Sixty-five strains (80%) of Peptococcus and 32 strains (70%) of Peptostreptococcus were susceptible to a concentration of 12.5μ/ml of cephalexin. However, 9 strains (45%) of Eubacterium and Propionibacterium were resistant to a concentration of 100μg/ml or more of this drug.
Antimicrobial activity of the drug against 30 strains (50%) of Bacteroides was so strong that they were unable to grow on the plate including 7.8μg/ml. Whereas there were 20 strains of Bacteroides that grew on the plate including 62.5 to 500μg/ml. In Fusobacterium, 35 strains were sensitive to 15.6μg/ml but 17 strains resistant to 125μg/ml.
Among cephalosporin antibiotics used in this study, cephalexin has antibacterial activity against anaerobic bacteria more than cephaloglycin, less than cephaloridine, cephazolin and cephalothin.
In vivo, this drug was effective to subcutaneous abscess caused by F. necrophorum susceptible to the drug in vitro.

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