Critical concentration for defining rifampicin resistance of tubercle bacilli in sputa of patients was studied in the Ogawa egg medium.
The critical concentration should be determined by considering two points; (i) distribution of the degree of resistance in patients previously untreated with the agent, excluding presence of cross-resistance with a drug previously used and of natural resistance and (ii) pattern of resistance development. Critical concentration should be higher than the upper limit of distribution of resistance degrees in patients previously untreated, and should be higher than a low level of resistance, that is, be selective for low-resistant mutants, which are shown by tubercle bacilli after administration of drug.

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Ethambutol (EB), an anti-tuberculous drug, was released into the market in February, 1967 in Japan by Lederle (Japan), Ltd. and by Kaken Chemical Co., Ltd. under the trade name of ESANBUTOL and EBUTOL respectively.
In order to find out the status of visual disturbances caused by EB and to prevent them as far as possible, we, Lederle (Japan), Ltd. and Kaken Chemical Co., Ltd., have made follow up studies on the visual disturbances in the patients who were treated with EB.
During the period from February, 1967 to January, 1968, 171 cases of possibly EB-related side effects and adverse reactions were reported to us by doctors. Out of 171 cases, 131 complained visual disorder and the others complained paralysis of lower extremities, exanthema, gastrointestinal upsets, mental disturbances, etc. We visited the doctors who treated these cases to check the daily dose, total amount of EB administered till the adverse reaction occurred, the grade of visual disturbances and its prognosis, etc. Ninty-three cases with visual disturbances which coincided with one of the two categories were selected out of 131 cases. They are; 1) the case with visual acuity reduced by more than three lines of the internationally used Snellen chart when the visual disorder was only decrease in visual acuity, and 2) the case with visual acuity reduced by less than 3 lines of the Snellen chart when the visual disorder was complicated by any of central and peripheral scotomas and abnormal color vision. The follow-up studies were made on the course of recovery from the disturbances up to Feb., 1970. The results of studies are summarized in the following.
1) Visual disturbances due to EB were highly significant in the patients who were over fifty years old (X2 test, = 0.01). The average age was 51.3 years old.
2) The significant relation was observed between the visual disturbances and the body weight of the patients. The disturbances were observed more frequently in the patients whose body weights were below 50 kg (X2 test, =0.05). The average body weight was 46.5 kg.
3) The total dosage of EB administered before the emergence of visual disturbances was 148.3 g in average. No corelation was observed between the total dosage and emergence of disturbances.
4) Seventy-five out of 93 cases have recovered their visual acuity after 5.8 months in average.
5) In 13 out of 93 cases, visual disturbances were not recovered by the end of June, 1968. Visual acuities of these 13 patients were not recovered to the levels or close to the levels which they had before the treatment with EB. Of 13 cases, 5 recovered the visual acuity by February, 1970, but 4 did not. Out of the rest 4 cases, 2 died and 2 could not be followed up by doctors. Four cases who did not recover by Feb. 1970, had been with visual distur bances for more than 2 years. Two out of 4 cases are still suffering from the disturbance in the central and peripheral visual field but they are gradually getting better. The other 2 cases are not showing any improvement, requiring further follow-up survey.
6) Of 75 cases who recovered from the visual disturbances, EB was readministered to 14 cases. No adverse reaction were reported in these cases when the survey was conducted.
7) For the treatment of the visual disturbances, hydroxocobalamine and activated thiamine derivatives were mainly used.

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The virulence of rifampicinresistant tubercle bacilli for guinea pig and mouse was reported.
The rifampicinresistant strain was prepared by repeated cultivation of Kurono strain (freeze-dried and stored tubercle bacilli) on Dubos Tween Albumin media containing increasing concentration of rifampicin.
For the evaluation of virulence in guinea pig, index of macroscopic findings, root spleen index and number of viable bacilli in spleen were used a in mouse, specific lung weight and number of viable bacilli in lung were used.
The methods and results of examination were summarized as follows:
Experiment : The virulence of tubercle bacilli resistant to 10 mcg rifampicin (RFP) for guinea pig and mouse.
The strain resistant to 10 mcg RFP was prepared by cultivation of freeze-dried Kurono strain on Dubos media containing increasing concentration of rifampicin. The concentrations of rifampicin in Dubos media for making the rifampicin resistant strain were, (1) 0.02mcg→(2) 0.1 mcg→(3) 1mcg→ (4) 2.5 mcg→(5) 10 mcg. The same subculture in Dubos media not containing rifampicin was performed for original strain as the control strain.
The vilurence of strain resistant to 10 mcg rifampicin attenuated markedly for guinea pig but not for mouse (Table 1, Figure 1 and Table 2, Figure 2).
To elucidate the relationship of degree of rifampicin resistance and virulence for guinea pig, the following experiments were performed.
Experiments 2 and 3: The virulence of tubercle bacilli resistant to 0. 1 and 1 mcg rifam picin for guinea pig.
The strains resistant to 0.1 and 1 mcg rifampicin were made by cultivation of freeze-dried Kurono strain on Dubos media containing increasing concentration of rifampicin. The concen tration of rifampicin for making the rifampicin resistant strain were, (1) 0.01 mcg→(2) 0.02 mcg→(3) 0.04 mcg→(4) 0.05 mcg→ (5) 0.1 mcg (Inoculated for guinea pig)→(6) 0.4 mcg→(7) 1 mcg (Inoculated for guinea pig)→(8) 2.5 mcg→(9) 5 mcg(Inoculated for guinea pig) (10) 10 mcg.
The virulence of strain resistant to 0.1 mcg rifampicin attenuated markedly comparing with the original strain which was performed the same number of subculture in Dubos media not containing rifampicin (Table 3, Figure 3 and 4).
The strain resistant to 1 mcg rifampicin also showed the decreased virulence for guinea pig (Table 4, Figure 5 and 6).
In conclusion, rifampicin-resistant tubercle bacilli showed markedly attenuated virulence for guinea pig.

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The experimental researches on antituberculous activity of a new antibiotics, Lividomycin (LVM) were carried out and the following results were obtained.
1. The minimal inhibitory concentration of LVM against Mycobacterium tuberculosis was 0.5mcg/ml in Dubos' liquid medium and 25-50 mcg/ml in Ogawa's egg medium, which were almost as same as the MIC of KM. Tubercle bacilli resistant to SM, INH, PAS and RFP were susceptible to LVM. There was cross resistance between LVM and KM, but LVM was more susceptible than KM to KM resistant strains.
2. Atypical Mycobacteria were usually not so susceptible to LVM, but a few strains were inhibited their growth by 1mcg/ml of LVM in Dubos' liquid medium.
3. Following intramuscular injection of 500 mg LVM given to man, maximum serum concentration of 23.5-37.8 mcg/ml were obtained after 1 hour.
4. Evaluating by the survival days, in experimental tuberculosis of mice, LVM was equally effective as KM and SM.

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Three hundred seventy four retreatment cases of pulmonary tuberculosis with positive culture and previously untreated with ethambutol and ethionamide were allocated at random to the following three regimens;
1.1321 TH 0.5g daily+E-EB 1.0g daily
2. 1321 TH 0.5 g daily+RFP 0.45g daily
3. EB 1.0 g daily+RFP 0.45g daily
Out of 374 cases, 91 were excluded due to various reasons shown in Table 2, and 41 cases dropped out before the end of 2nd month. Thus, the remaining 242 cases were subjected to the analysis of clinical results.
After 6 months treatment with the above regimens, the treatment was continued with RFP twice weekly combined with other drugs for cases who converted to negative by the regimens 2 and 3 and for cases who failed to convert by the regimen

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