Results and Randomized Original Treatment in Cases of Pulmonary Tuberculosis with Isoniazid-Streptomycin versus Isoniazid-Thiocarlide

Results and Randomized Original Treatment in Cases of Pulmonary Tuberculosis with Isoniazid-Streptomycin versus Isoniazid-Thiocarlide* Gerard Eaoez, M.D., F.G.G.P.,·· Jean-Daniel Gonin, M.D., Etienne Guberan, M.D., Jean-Pierre de KalbermaUen, M.D., Pierre Yulliemoz, M.D., and Glaude Willa, M.D.

The antituberculosis properties of the association isoniazid-tbiocarlide (INHTC) have been compared, in a controlled study, with the assodation isoniazidstreptomycin (INH-SM) in the treatment of 113 original cases of infectious pulmonary tuberculosis. It has been possible to retain 83 of the total cases for the final assessment made after a period of observation from 5 to 7th years. In the course of the hospital care. the development of resistance to isoniazid was observed in one case in the INH-SM group, and in two cases of the INHTC group. During the follow-up period, one relapse with bacilli sensitive to INH occurred in the INH-SM group, and four relapses with INH resistant bacM in the INH-TC group. The association INH-TC is not adequate for the treatment in two pbases of cavitary lung tuberculosis: ie, a massive initial bactericidal ejfect foUowed by the Iong-tenn destruction of the persistent bacUIL As the resistance to INH was disclosed late, on occasion of the relapse in four patients who had eliminated sensitive organisms until bacterial conversion took place, it is suggested that, in a controUed study, the evaluation of a new bacteriostatic agent in association with a bactericidal one, and compared to the ej(ect of two known bactericidal agents, requires at least five years.

The tuberculostatic properties of thiocarlide, ie, 4-4' diisoamyloxythiocarbanilid (TC) were demonstrated in vitro l-4 and in vivo.l\-9 Resorption of the drug provides serum levels in excess of the minimal inhibitory concentration (MIC) .10.11 Gubler and co-workers!" showed that a daily dose of 6 gm inhibits the growth of H37Rv cultures on Tarshis blood agar up to 24 hours'after administration. On the other hand, clinical trials yielded contradictory results, which were the object of a critical leading article. III Olejnicek and associates'< in particular reported the emergence of INH-resistance in nine patients out of 13 treated with the combination INH-TC; Moodie and colleagues'" noted resistance to INH in 50 percent of cases similarly treated, against only 18 percent in a group of patients receiving INH-PAS. The observations made by various authors with thiocarIide

in single-drug therapy are worth examining. A summary of these is given in Table 1. The bacteriostatic activity of thiocarlide in man may thus be assumed; however, present lack of a proper perspective makes the interpretation of clinical results difficult. MATERIAL AND METIIOD

One hundred and thirteen patients suffering from infectious pulmonary tuberculosis, not having undergone any previous treatment, received 600 mg of isoniazid daily together with 30 mg of pyridoxine. The series was formed of two randomized groups. Group 1 received 1 gm of streptomycin by the intramuscular route every day for two months followed by 3 gm weekly. Group 2 received 6 gm of thiocarlide by the oral route daily in a single dose. All these preparations were administered before breakfast. The clinical study lasted from January, 1962 to September. 1964. After their dismissal from the clinic, the patients of group 1 received 300 mg of INH, 15 mg of pyridoxine and 6 gm of calcium-benzoyl-PAS for 18 to 24 months. All three substances were administered orally in the form of six tablets. Each tablet contained 50 mg of INH, 2.5 mg of pyridoxine, and 1 gm of B-PAS. The patients of group

·Clinique Sylvana, Tuberculosis Unit, Department of Medicine (Prof. A. Vannotti, head), University of Lausanne Medical School, Epalinges, Switzerland. e e Associate professor.

234

235

INH·STREPTOMYCIN VS INH·THIOCARLIDE IN PULMONARY TUBERCULOSIS

Table I-Summarized Results of Single Drug Regimen with Thiocarlide in Tuberculosis According to Five Different Trials. No. Patients

Type of Tuberculosis

Daddi and others 16

39

14 original cases 25 chronic cases

Titscher-?

20

Chronic and multiple 1 yr. drug resistant cases

10

Urbancik18

16

Heidelbach and others!ll

19

Authors

Brouet and others 2O

Duration of Monotherapy 1 to 3 mo.

43 40

18% obtained in ItA! mo.

grn/ day

4

2~

2 conversions after 4 mo.: 2 after 3 mo; 2 after 5 mo.

Chronic and multiple 4 to 6 mo. drug resistant cases mostly

6 and 8 gm/day

4

25%

Original cases

6 gm/day 15

46~

11

32.3~

6 to 8 wk.

13

Original cases

10 to 18 wk.

34

Original cases

2 to 3 mo.

Males Females 30 25

6 gm/day

13 15

Commentary

36~

Table 2-Distribution of the Cases According to Sex and Age Groups.

INH-SM INH-TC

Conversions ,-No. i---, 14

2 continued treatment with 300 mg of INH, 15 mg of pyridoxine, and 3 gm of thiocarlide in separate tablets administered once daily. The patients were dismissed from the hospital as soon as the conversion of the cultures was obtained in three samples and Iaminagraphy revealed closure of any cavity. On admission, a complete clinical examination of the patient was made together with laminagraphs of the thorax, bronchoscopy, lung function tests, bacteriologic investigation performed on four samples-! ie, two samples of sputum or gastric lavage, bronchial lavage and sputum collected during 24 hours after the bronchoscopy. The following tests were made on admission and repeated every month: blood count, urea and glucose in the blood, dehydrogenase of sorbitol, SePT and SCOT, bromsulfalein test, as well as the usual urinalysis. Every two months the bromsulfalein test and the determination of direct total bilirubin in the blood were made. Laminagraphs were performed at the end of the second month following hospitalization, and monthly thereafter. Cultures of sputum or gastric lavage with a sensitivity test were made every month on three samples 72 hours after the interruption of the antituberculosis medication. Roentgenologic and bacteriologic check-ups were made for five years after dismissal of the last case and seven and one-half years after the first dismissal in the patients of both groups. The final assessment made in July 1969, comprises 83 patients, whose age groups and data are reported in Table 2. The data for 16 patients of group 1 (INH-SM) were discarded: four of these patients underwent pulmonary resection during their hospitalization, two revealed a primary resistance to isoniazid, and ten were lost to followlip (they left the country or refused the check-lips). The data for 14 patients of group 2 (INH-TC) were discarded: six of these patients underwent pulmonary resection during their hospitalization, six were lost to follow-up (for the same reasons as those of group 1), and two showed primary resistance to INH (Table 3).

Drug regimens

Dosage

15 to 40yr 23 19

41 to Above 60 yr 60yr 16 14

CHEST, VOL. 57, NO.3, MARCH 1970

4 7

6 grn/day

10 after 6 to 8 wk. 5 between 10 and 18 wk.

original course of chemotherapy 3 mo.

REsuLTS In the course of the first six months, conversion of the cultures was achieved in 42 out of 43 patients (98 percent) in group INH-SM and 39 out of 40 patients (98 percent) in group INH-TC. The results of these conversions are shown in Table 4, according to the size of the cavities (total of the largest diameters of the cavities measured on admission). During hospital care, resistance to INH developed in one patient of group INH-SM and in two patients of group INH-TC. The results are indicated in Table 5, according to the size of the cavities on admission. Radiologically revealed closure of the cavities was achieved in 67 percent of the patients in group INH-SM and 67 percent of the patients in group INH-TC during the first four months. After six months, the corresponding percentages were 72 and 77. The results are indicated in Table 6. Relapse took place in one patient of group INHSM, two years and nine months after dismissal, and the strain was found to be still sensitive to INH. In the INH- TC group, four relapses were Table 3-No. of Patients in the Beginning of the Controlled Study and at the Final A88e88ment.

Infectious patients admitted to the controlled study Primary resistance to INH Lobectomy and/or segmentectomy Lost of view during the follow up Patients taken in account for the final assessment

Croup 1 INH-SM

Group 2 INH-TC

Total

59 2

54

113

2

4

4

6

10

10

6

16

43

40

83

236

FAVEZ ET AL Table 4-Bacteriologic ReBfllts for the First Six Months of Treatment According to the Drug Regimen and the Size of the Cavities in 43 Patients of the INH-SM group and 40 Patients of the INH-TC Group.

Drug Regimen

INH-TC

INH-SM

A

A

Cavity Diameter No. of cavitary cases No. of infectious patients Conversion after 2 months 3 months 4 months 6 months Positive culture at the end of the 6th month

Noncavitary Cases

<2cm

2to4cm >4cm

Total

Noncavitary Cases

<2cm

2to4cm

>4cm

Total

16

17

7

40

12

25

6

43

8

8

21

6

43

8

11

14

7

40

8

5

15 2 3

3

31 2 9

8

6 4 1

10 2

6 1

30

3

3

1

observed after 12 and 15 months, and after two and one-half and four years. The strains had become resistant to INH in all four cases. The results are shown in Table 7, according to the diameters of the cavities on admission. When accumulating the number of resistances against INH during hospital care and the follow-up since dismissal, ie, after five and seven and one-half years, one case occurred in the 43 patients of group INH-SM (2.3 percent), and six cases in the 40 patients of group INH-TC (15 percent). This result is statistically confirmed by p = 0.047. During observation in the hospital no drug allergy or hepatic, renal or hematopoietic disorders were found in one or the other of the two groups. Thiocarlide was well tolerated. Streptomycin caused slight vestibular disturbances in eight patients (two of them in the third month, two in the fourth, and four in the fifth). DISCUSSION

The patients who underwent pulmonary resection were not taken into account because, as the site of the main mycobacterial population had been suppressed, it was not possible to compare these cases with those where residual organisms remained in the lesions. INH-SM was chosen as the point of reference

1

1

1

1

7 1 1

because it was the most effective one known at the time the clinical study was made. Although the difference in number of cases of resistance observed in the groups INH-SM and INH-TC is statistically confirmed, there still exists some doubt as to the validity of the comparison. It is not certain that the patients who submitted to regular check-Ups during the posthospitalization period are truly representative of the total group studied in the beginning. The proportion of minimal and moderately advanced cases (87 percent in group INH-SM and 83 percent in group INH-TC) does not exclude the possibility that conversion of the cultures could have been achieved in several of the patients with INH alone, which was administered at the dosage level of 600 mg per day. It is known that single-drug therapy with INH is capable of obtaining more bacteriologic conversions at high dosages than at low ones.22 However, bacteriologic conversion was obtained during the period of observation without relapses and without development of resistance to INH in seven far advanced cases of group INH-TC. The daily dose of 600 mg of INH corresponds to an average of 8.6 mgtkgt body weight. On the one hand, in the Madras study (treatment with INH alone},23 the mean daily dose of INH was 8.7 mgt

Table 5-Resistance to INH as Noted during the Hospital Stay in Relation to Drug Regimen and Cavity Diameter. --~---

Drug Regimen

---==~===

INH-SM ~

Cavity diameter Resistance to INH noted dming hospital stay

<2cm

INH-TC

A~

2 to 4 em

,

A

~

>4cm

Total

<2cm

2to4cm

1

1

1

1

>4cm

Total

2

CHEST, VOL. 57, NO.3, MARCH 1970

237

INH-STREPTOMYCIN VS INH·THIOCARLIDE IN PULMONARY TUBERCULOSIS

Table 6-Closu,e of the Cavities in Relation to Drug Regimen and Cavity Diameter in the Course of the First Six Montha. Drug Regimen

INH-SM

INH-TC

A

Cavity diameter Number of cases Cavity closure at the end of the 2nd month 3rd month 4th month 6th month Cavities present at the end of the 6th month

A

<2 em

2to4em

>4cm

Total

<2 em

2to4em

>4 em

Total

12

25

6

43

16

17

7

40

6 2

7 7

10 1

3

3

1

1

13 9 7 2

8 1 1 1

1 2 1

6 4

6

3

9

1

5

7

kg in a total of 70 patients, 90 percent of whom were minimal or moderately advanced cases. INHresistant strains were found in all the patients who were still infectious after six months. On the other hand, the mean numher of bacilli in an average-size cavity (less than 4 cm ) amounts to at least I X lOR Individuals>' and the proportion of INH resistant mutants in a wild strain is ahout I X 10- 5 to I X 10-6.25.26 Accordingly, it may be considered that thiocarlide was instrumental in inhibiting the multiplication of INH-resistant mutants in the wild strain in seven patients. Nevertheless, the association INH-TC proved to be, on the whole, definitely inferior to the association of INH-SM. This difference can presumably be explained by the three following reasons. First, a bacteriostatic agent possesses a lesser antimicrobial activity than a bactericidal one. 2i Second, the contradiction between the favorable result obtained in seven far advanced cases and the failure observed in six lesser cases may be attributable to an insufficient penetration of thiocarlide into certain cavities. Third, the fluctuations of the plasma levels are compatible with an excellent action of streptomycin, whereas they are presumably detrimental to those of thiocarlide. The intermittent effect of a bactericidal agent achieving a

3

2

12

18

3

peak of plasma concentration once in 24 hours or even three times a week is sufficient to diminish considerably the number of survivals." On the contrary, the plasma levels of a bacteriostatic should be maintained permanently above the MIC, which is difficult to carry out in practice. The proportion of streptomycin-resistant mutants in a wild strain is about I X 10-6.25.26 The association INH-SM, consisting of two bactericidal drugs,28 produces the inhibition of the entire wild strain. On the contrary, the association INH-TC consists of a bactericidal and an essentially bacteriostatic drug. Thus the bactericidal effect of the INH-resistant mutants is particularly slight and is only due to the natural defence mechanism of the patient." The information available so far does not support the hypothesis that a bacteriostatic drug has not the capability of preventing the transduction of the episome or the plasmid from an INH-resistant cell to a contemporary sensitive one. CONCLUSIONS

The bacteriologic results observed suggest that the association isoniazid-thiocarlide is inadequate to ensure a rational therapy of cavitary lung tuberculosis in two phases: the initial massive bactericidal effect followed by the long-term destruction

Table 7-Number of Relapses and Sensitivity of the Strain to INH at the Time of the Relapse in Relation to Drug Regimen and Cavity Diameter at the Admission. Results Collected up to July 1969 (After 5 to 7V2 Years of Obseroation.) Drug Regimen

INH-SM

INH-TC

A

Cavity diameter Number of relapses in the course of the observation Resistance to INH at the time of the relapse

<2 em

2to4em

A

>4 em

Total

1

CHEST, VOL. 57, NO.3, MARCH 1970

o

<2 em

2to4em

>4em

Total

3

4

3

4

238

FAVEZ ET AL

of the persistent bacilli. 29~'l1 The spacing of the bacteriologic data in the course of the hospital care and throughout the ensuing follow-up, revealed a phenomenon worth retaining. Each of the four patients in group INHTC, who had INH-resistant bacilli at the moment of the relapse, had a strain sensitive to INH until conversion of the culture. At the time of their dismissal, the previous cavitary lesions must, therefore, have harbored INH-resistant bacilli. The comparatively high dosage of INH administered (600 mg per day) may have killed the sensitive organisms before the INH-resistant bacilli had multiplied sufficiently to create local conditions leading to their elimination. Therefore, it may be justified to assume that the results of observations for four to six months, generally proposed in controlled trials for the antituberculosis properties of a new drug to be evaluated, can prove inaccurate in the long run, at least as concerns the treatment with an association comprising a bacteriostatic and a hactericidal agent.

13 14

15

16

17 18 19

20

REFERENCES

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21 22 23

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25

carlid beim Menschen, Beitr. Klin. Tuberk., 133:126, 1966. Isoxyl, Tubercle, 46:298, 1965, (Leading article). OLEJNICEK, M., WEBEROVA, M., NOVAK, M., AND JANCIK, E.: A controlled trial of isoniazid and 4-4' Diisoamyloxythiosemicarbanilide compared with isoniazid and PAS and isoniazid, streptomycin and PAS, Tubercle, 46:188, 1965. MOODIE, A.S., ACQUINAS, M., AND FOORD, R.D.: Controlled clinical trial of 4-4' diisoamyloxythiocarbanilide in the treatment of pulmonary tuberculosis, Tubercle, 45:192, 1964. DADDI, G., GRASSI, C., AND FADDA, A.: Ricerche sperimentali e cIiniche sulla attivita antitubercolare della 4-4' diisoamilossitiocarbanilide, G. ital. Chimioter., 11:100, 1964. TITSCHER, R.: Monotherapie mit Isoxyl/Da'I', Praa. Pneumol., 20:202, 1966. URBANCIK, B.: A clinical trial of Thiocarlide (4-4' Diisoarnyloxythio-Carbanilide), Tubercle, 47:283, 1966. HEIDELBACH, H., KAMPELMANN, F., MEISSNER, G., OHM, W., RAUCH, H.W., SCHMELZER, K.H., AND SCHMIDT, P.G.: Zur Isoxyl-Behandlung, Prax. Pneumol., 20:410, 1966. BROUET, G., MEENS-BITH, J., PARIENTE, R., AND NEVOT, P.: Etude c1inique et bacterlologique du 4-4'-di-isoamyloxy-thio-carbanilide dans la tuberculose pulmonaire de I'adulte, Rev. Tuberc., Paris, 30:1249, 1966. WHO Expert Committee on antibiotics, WHO Techn. Rep. Ser., 210:3, 1961. East African British Medical Research Council: Isoniazid investigation, Tubercle, 40:1, 1959. Tuberculosis Chemotherapy Centre, Madras: A concurrent comparison of Isoniazid plus PAS with three regimens of isoniazid alone in the domiciliary treatment of pulmonary tuberculosis in South India, Bull. WHO, 23:535, 1960. CANETTI, G.: Host factors and chemotherapy of tuberculosis, in Chematherapy of Tuberculosis, Butterworths, London, 1964, p. 175. CANETTI, G., AND GROSSET, J.: Teneur des souches sauvages de Mycobacterium tuberculosis en variants resistants I'isoniazide et en variants resistants la streptomycine sur milieu de Lowenstein-jensen, Ann. Inst. Pasteur, 101:28, 1961. KREIS, B.: Resistance et survivance du bacille tuberculeux aux medications antihacillaires, Masson, Paris, 1966. 1 vol., p 163 et seq. MITCffiSON, D.A.: Chemotherapy of tuberculosis: a bacteriologist's viewpoint, Brit. t. Med., 1933, 1965/1. MITCHISON, D.A., AND SELXON, J.B.: The bactericidal activities of antituberculous drugs, Amer. Rev. Tuberc., 74 (supp!.):I09, 1956. KASS, 1., RUSSEL, W.F., HEATON, A., MIYAMOTO, T., MIDDLEBROOK, G., AND DRESSLER, S.M.: Changing concepts in the treatment of pulmonary tuberculosis, Ann. Intern. Med., 47:744, 1957. CANETTI, G.: Present aspects of bacterial resistance in tuberculosis, Amer. Rev. Resp. Dis., 92:687, 1965. Fox, W.: Changing concepts in the chemotherapy of pulmonary tuberculosis, Amer. Rev. Resp. Dis., 97:767, 1968.

a

26

27 28

29

30 31

a

Reprint requests: Dr. Favez, Clinique Sylvana, 1066 Epalinges, Switzerland.

CHEST, VOL. 57, NO.3, MARCH 1970