To stimulate the growth of dysgonic bovine strains of mycobacteria, the effect of theaddition of Tween 80 to M-Y RP medium was investigated, which contained glucose and Napyruvate as main carbon sources and was regarded as the best medium among those tested inthe foregoing experiments. In any of the media, which contained only one of the abovementioned three carbon sources, i. e. glucose, Na pyruvate and Tween 80, independently, nofavorable growth was observed. However, in the media, which contained Na pyruvate andTween 80, obviously better growth was obtained in most of the strains examined than in M-YRP medium. On the other hand, the growth was stimulated obviously by the addition of Napyruvate to the medium, which contained glucose and Tween 80 but did not enhance thegrowth of organisms favorably. Therefore, for the better utilization of Na pyruvate andTween 80 as carbon sources, it seemed better to remove or reduce the amount of glucose toless than 0.5%. The semi-synthetic agar medium of the following prescription seemed to beadequate, at present, to stimulate the growth of dysgonic bovine strains of mycobacteria:
KH₂PO₄ 2.0, Na₂HPO₄.12 1120 1.5, Asparagine 6.0, Na. citrate 2.0, CaCl₂ 0.0025, MgSO₄.7 H₂O 0.02, Glucose 5.0, Na. pyruvate 2.0, Tween 80 0.1ml, BSA Fraction V 5.0, Yeast RNA100μg, Agar-agar 15.0, Aq. 1, 000 ml.

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In order to investigate the prognosis of open negative cavity, 34 cases of pulmonarytuberculosis were followed up for 5 to 14 years, average 9.7 years, after open negativecavity was attained. The open negative cavity (O. N. C.) was defined as follows: At thebeginning of treatment, cavity was observed on chest radiogram and tubercle bacilli wereconfirmed in sputum, and during chemotherapy, the cavity remained while bacilli becamecontinuously negative both on smear and culture for 12 months by monthly examinations.
Of 34 cases, 13 had an unilocular cavity and 21 had a multilocular cavity, and they werefollowed up on the average 10.2 and 9.1 years, respectively.
Bacteriological relapse was observed in only 2 cases or 5.9%. Radiological worsening wasobserved in 2 of 14 unilocular cavities and in 4 of 23 multilocular cavities. The worsening wasconfirmed to be tuberculous in one unilocular cavity and 2 multilocular cavities, while in theother 2 multilocular cavities, the worsening was due to the other infection (fungus infection, etc.), and in another one unilocular cavity, changes were judged as worsened as the shadowbecame larger through atelectasis formation in the segment where a cavity existed 8 yearsafter O. N. C. was attained. O. N. C. was classified by Iwasaki according to the thickness of cavity wall on radiograminto A, B, C, D, E, F, G, H and I, and the details are presented in notes of Table 6. Accordingto this classification, types B and D were dominant in unilocular cavities and types C, F, Gand H were dominant in multilocular cavities when O. N. C. was attained. Five years later, complete disappearance of cavity, inspissation into a small shadow or changes into type Cwere most frequently seen in unilocular cavities, while multilocular cavities showed types C, H, I and D and solid atelectatic shadow. Accordingly, the type of cavity showed changesduring 5 years' period after O. N. C. was attained. If the effective chemotherapy is properlycontinued, the cavity wall became thinner and changed into types A, C or D, and thereaftersome of the cavities showed complete disappearance or contraction or the contraction of cavitary area. The former might be an essential change of tuberculous cavity and the latter issecondary change probably due to protection mechanism of the host. In the case of cavities with thicker wall, the prognosis was in general unfavourable if the thickness of cavity showedno changes.
The duration of chemotherapy was about 3 years in cases with unilocular cavity and 5 to 6 years in cases with multilocular cavity after O. N. C. was attained. Regimen of chemotherapywas changed to previously unused drugs among cases showing no changes in thickness ofcavity wall, and 2 cases of multilocular cavity showed diminution in thickness of cavity wallafter changing the regimen.
It can be concluded as follows from the above results: Pulmonary tuberculosis patientswith open negative cavity should be treated with the effective chemotherapy for at least 4to 5 years after O. N. C. is attained until the cavity wall becomes thin.

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In the first study, the Tuberculosis Research Committee, Rytiken (Japan), reported theresults of therapeutic effect of rifampicin (RFP) on re-treatment cases of pulmonary tuberculosis (Kekkaku, Vol.45. p.227), in which the combination of RFP with ethambutol (EB) showed an excellent therapeutic effect, and no difference in the effect was observed betweenthe regimen with daily administration of both drugs and that of rifampicin twice weeklycombined with ethambutol daily.
The second report presents the results of the therapeutic effect of combination regimen ofRFP with EB and pyrazinamide (PZA) on re-treatment cases of pulmonary tuberculosis.
Patients whose cultures had failed to convert to negative in spite of long-term treatment with primary and secondary anti-tuberculous drugs, other than RFP, EB and PZA, and whose sputahad been positive at least for three consecutive months were assigned to the following fiveregimens randomly.The five regimens are shown in Table 1.
The dose of drugs was determined according to body weight and mode of administration, daily or intermittent (Table 2). The drugs were given in a single daily dose before breakfast.
Among 196 cases submitted to the study, 46 were excluded from the analysis because ofnegative culture before study or of drop-out within six months, etc. The number of casesexcluded and reason for exclusion are shown in Table 3, and the patients discontinued medication because of the side-effects of the drugs were included in the study. The backgroundfactors of the patients sex, body weight, bacteriological findings, NTA classification, X-rayfindings etc are shown in Table 4. The duration of the study was twelve months.
The results are summarized as follows: Bacteriological findings and interruption of the assigned regimen because of side-effectsduring six-month treatment were analysed in 30, 29, 31, 31 and 29 cases in each regimen asshown in Table 5 and Figure 1. The rate of negative culture and the cumulative rate of dropout cases because of side-effects within six months did not differ markedly among the threecombined regimens of RFP, EB and PZA twice weekly or daily; the rates of negative culturewere 70 to 74% and the rates of drop-out cases due to side-effects were 14 to 20%. Theregimen of RFP daily with EB twice weekly (Regimen V) achieved, however, 79% ofnegative conversion rate at 6 th month and 3.4% of drop-out rate due to side-effects withinsix months. In the Regimen IV, drop-out cases due to side-effects were none, but the rateof negative culture was 61% at 6 th month of the therapy.
The rate of favourable cases (consecutively negative cultures at 4th, 5th and 6 th months) after six-month treatment was 65 to 70% in the regimens I, II and III, and 48% in theregimen IV, 76% in the regimen V (Figure 2). The rate of unfavourable cases after sixmonth treatment (including drop-out cases due to side-effects) was highest in the regimen IVand lowest in the regimen V. Among unfavourable cases, nearly half of the cases was thedrop-out cases because of side-effects in the regimens I, II and III in which PZA werecombined with.
The rate of bacteriological relapse among favourable cases at 6 th month was low in thefollowing six months (Table 6).

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This study was undertaken in an attempt to compare the clinical results and side effectsof daily and twice weekly intermittent administration of rifampicin (RFP) in re-treatment of pulmonary tuberculosis.
The subjects were 203 re-treatment cases of pulmonary tuberculosis with cavity resistantto multiple drugs who had not received RFP and pyrazynamide (PZA). They were dividedinto three groups; the first group consisting of 67 cases was given RFP 450mg daily incombination with PZA, the second group consisting of 67 cases, RFP 450mg twice weekly incombination with PZA, and the third group consisting of 69 cases, RFP 900mg twice weeklyin combination with PZA, and the treatment was continued for six months in all the groups.RFP was given orally in a single dose 30 minutes before breakfast and PZA orally in adaily dose of 1.5g divided into three doses after each meal.
The background factors in these three groups are shown in Table 1. There was nodistinct difference between groups.As shown in Table 2, negative conversion rate reached to a peak at the second month oftreatment in each group and negative conversion rate by culture at the sixth month was 63per cent in the group given RFP 450mg daily and 65 per cent in the group given RFP 900mg twice weekly, while in the group given RFP 450mg twice weekly it was as low as 47 per Changes of the basic lesions in the chest X-ray films are shown in Table 3. The rate ofimprovement including slight ones at the sixth month of treatment was 20 per cent in thegroup given RFP 450 mg daily, and it was slightly higher than 13 per cent in the group given RFP 450 mg twice weekly and 10 per cent in the group given RFP 900 mg twice weekly. Asshown in Table 4, the rate of improvement of slerotic-walled cavity was low in all thegroups.For sensitivity tests against RFP, Kirchner semisolid agar medium was used, and it wasregarded as resistant when the bacilli showed resistance to more than 5 mcg/ml of RFP. Asshown in Table 5, emergence of RFP resistant tubercle bacilli was frequently observed afterfour months of treatment, when RFP administration did not succeed in negative conversion ofbacilli, and at the sixth month it was over 60 per cent in all the groups.
Side effects due to RFP are shown in Table 6. Of 67 cases in the group given RFP 450mgdaily, RFP was discontinued in one case due to gastrointestinal disturbances, while there wasno case in which RFP was discontinued due to allergy-like symptoms. On the other hand, of67 cases in the group given RFP 450mg twice weekly, fever which was likely an allergicsymptom was observed in 6 cases, and among them 5 had to discontinue treatment. In addition, the treatment was discontinued in one case due to purpuric subcutaneous hemorrhage.Of 69 cases in the group given RFP 900 mg twice weekly, fever was observed in 7 cases, and 6 had to discontinue RFP. It is worth while to note that there was practically no caseshowing fever which was likely an allergic symptom in the group given RFP daily, while itwas frequently observed in groups given RFP intermittently.

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1. The investigation on the distribution of Rifampicin (RFP) resistant tubercle bacilliisolated from patients previously untreated with RFP.
Out of 120 strains tested on Kirchner's semi-solid media, resistance to 0.5 mcg/ml RFP wasseen in 4 percent and 96 percent of strains was inhibited their growth on 0.5 mcg/ml RFP.
The grade of resistant to RFP of 136 strains tested on Ogawa's media was as follows; 92.6 percent were sensitive, 5.2 percent incompletely resistant and 1.5 percent completely resistantto 10mcg/ml RFP. Only 1 strain (0.7%) was resistant to 25mcg/ml RFP.
The susceptibility to RFP of 66 strains of atypical mycobacteria was tested on Ogawa'smedia, and 16 strains were sensitive to 10mcg/ml RFP and 44 strains showed resistance tomore than 50mcg/ml RFP.
2. The emergence of bacterial resistance to RFP in clinical observation.
The resistance to RFP elevated to higher degree rapidly. Among cases considered to be RFP monotherapy because of the resistance to the other combined drugs, the rate of emergenceof resistance (more than 10mcg/ml RFP in Kirchner's semi-solid media) by month was asfollows; 2 nd month 54.5 percent; 4 th month 77.7 percent; 6th month 100 percent. Amongcases given RFP together with PZA or other sensitive drugs, appearance of RFP resistancewas as follows; 2nd month 31.5 percent; 4 th month 68.9 percent; 6th month 80.7 percent.
In these resistant cases there were no clinical effects of RFP, and in all patients showingbacterial relapse during and after RFP treatment the appearance of resistance more than 10mcg/ml RFP on Kirchner's semi-solid media and more than 50 mcg/ml RFP on Ogawa's mediawere observed.
As a controlled trial of RFP and PZA combined therapy, RFP was administered in thefollowing way; RFP 450 mg daily, RFP 450 mg twice weekly and 900mg twice weekly. Nosignificant difference was seen among three regimens in the time and rate of emergence of RFP resistance.

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