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The treatment of chronic cavitating pulmonary tuberculosis by long-term chemotherapy
Tubercle, Lond., (1961),42,438
438
THE TREATMENT OF CHRONIC CAVITATING PULMONARY TUBERCULOSIS BY LONG-TERM CHEMOTHERAPY By D. H.
BLAKE
from the Lelcestershire Chest Service, Markfield Hospital, Leicester SUMMARY
A series of 50 patients with chronic cavitating pulmonary tuberculosis not amenable to surgical treatment, but whose cultures were sensitive to 2 or more of the 3 standard drugs were treated by long-term chemotherapy. Initial sputum conversion was achieved in 46. Out of 4S patients followed up for 3 years, 40 were still sputum negative at the end of this period. Twenty four of the patients have been followed up for a period of 5 years and 22 are still sputum negative. Before the introduction of long-term chemotherapy in pulmonary tuberculosis there was a group of patients attending chest clinics who were sometimes called 'chronic sputum-positive cases.' The radiographic appearances were those of multiple thick-walled cavities, often with complete excavation of part of the lungs, and with evidence of fibrosis in the form of mediastinal displacement, contraction of interlobar fissures, or compensatory basal emphysema. Many of these patients had been under clinic supervision long before the advent of chemotherapy; they may have been considered at the time unsuitable for chemotherapy; or they may have been given short courses of drug treatment with either no benefit or only very temporary sputum conversion. Even when long-term effective chemotherapy became possible treatment of this type of case tended to be withheld in the belief that it could not materially affect the x-ray appearances, and could not therefore be expected to be of any therapeutic value; indeed by producing drug-resistant organisms it might even be disadvantageous. From time to time patients with similar x-ray appearances and a positive sputum are picked-up at chest clinics as 'new cases'. Because of age, extent of disease, or respiratory insufficiency they are unsuitable for surgical treatment. They may be described as cases of chronic cavitating pulmonary tuberculosis not amenable to surgical treatment; and they are the type of case with which this paper is concerned. The paper sets out to answer the following questions. First, is it possible to render these patients non-infectious by chemotherapy? Secondly, is it possible to keep them sputum negative by long-term chemotherapy? As early as 1952 Clarke advocated the use of streptomycin in the management of the chronic tuberculous patient. Douglas and Horne (1956) published encouraging results from treatment by long-term chemotherapy of 6 cases of 'advanced pulmonary tuberculosis with persistent cavitation', but only 1 patient was followed up for as long as 36 months. Methods When this work was started in 1955 the clinic records contained 36 cases of the type. A further 14 consecutive new cases were added, thus making a series of 50 cases. These 50 patients were treated by long-term chemotherapy and the investigation was continued until 24 of them had been
LONG-TERM CHEMOTHERAPY
439
followed up for 5 years . Sputum tests, or, in the absence of sputum, examinations of laryngeal swabs were carried out in every case during the period of study at 3 monthly interval s. The criterion for sp ut um negativity was a negative sputum test both on direct smear and after 6 weeks culture or 2 negative laryngeal swabs after culture for 6 weeks. Sensitivity tests to the 3 standard antituberculosis drugs streptomycin, isoniazid, and PAS, were carried out prior to the commencement of treatment, and in all cases where the sputum remained positive or where laryngeal swabs were po sitive for tubercle bacilli .
Sensitivity Tests The following techniques were used in carrying alit the sensiti vity tests. The drugs were incorporated into Lowenstein-Jensen media. Three strengths of each drug were used, viz. 100 units, 10 units, and 3 units of streptomycin per ml. of the medium ; 2 flog., I flog., and 0'2 flog. of isoniazid per ml, of the medium; and 10 flog., 1 (-Lg., and 0·1 flog. of PAS per mI. of the medium. LowensteinJensen slopes were prepared by the introduction of 10 ml. of the medium into 2 oz. bottles, and sterilization and inspissation at 80aC. for 1 hour. The inoculum was prepared by taking a loopful of growth from a culture on Lowenstein-Jensen medium , and shaking up with 0.3 ml. of distilled water in a half ounce bottle containing 2 sterile glass beads for 3 mins, to form an emulsion. One standard loopful of the prepared inoculum was used to inoculate each of the media . Two controls were used in each series of sensitivity tests carried out:1. Inoculation of a Lowenstein-Jensen slope containing no drug. 2. Inoculation of the prepared media with the standard sensitive strain of Mycobacterium tuberculosis H37Rv. Interpretation of the results depends upon a comparison of the growth of the standard sensitive H37Rv strain and the test strain. Growth of the H37Rv st rain should not occur on any of the test slopes. Strains under test which failed to grow in the presence of all 3 concentrations of streptomycin , isoniazid and PAS were considered to be fully sensitive to these drugs. Test strains which grew in the presence of the two lowest concentrations of the drug and not in the highest concentrations were interpreted as being of partial resistance, whilst those growing in the presence of the highest concentration of the drug were taken to be fully resistant. Pre-treatment Condition The patients were divided into 2 groups : Group I, consisting of patients who had had previous chemotherapy ; and Group II, consisting of patients who had had no previous chemotherapy. There were 28 patients in Group I, and 22 patients in Group 11,8 of whom had been under previous clinic supervision and 14 of whom were treated as new cases. Of the 28 patients in Group I, only 3 had become sputum negative as a result of their previous chemotherapy, and these had quickly reverted to sputum positive again when chemotherapy was discontinued. In Group I there were 2 patients whose cultures were initially resistant to streptomycin, and 1 patient who had resistant cultures to isoniazid. The tubercle bacilli of all the remaining 25 patients in Group I, and all the patients in Group II were fully sensitive to streptomycin, isoniazid and PAS . The ages of the patients ranged from 22-70 years, 76 % being between the ages of 40 and 65 years . There were 43 males and 7 females. (T able I). Nature of Chemotherapy 16 patients in Group 1, including the 2 with cultures resistant to streptomycin, and 5 in Group II were treated by a combination of PAS and isoniazid. 11 patients in Group I and the remaining 17 in Group II were treated with an initial course of streptomycin and isoniazid followed by a combination of PAS and isoniazid. The dosage of streptomycin and isoniazid was that recommended E
440
TUBERCLE TABLE I.-THE AGE, SEX, PREVIOUS TREATMENT AND SENSITIVITY TESTS. --- .,-
Pre-treatment sensitivity tests.
No. of patients
Group INo previous chemothrapy Group IIPrevious chemotherapy Total
Age
-- - -- - ----S. INH PAS S. INH PAS Range (yrs) - - - - -- - - - -
28
26
27
28
22
22
22
22
50
2 0 1-
48
49
Sex
Resistant
Sensitive
50
2
40-65 yrs.
M.
1
0
22- 65
21
24
0
0
35-70
17
19
1
0
22-70
38
43
--
-F.
4
-
3 7
by the Medical Research Council (1955), viz. 1 g. of streptomycin daily and 100 mg. isoniazid twice daily; and the dosage of PAS and isoniazid was 10-12 g. of PAS and 200-300 mg. of isoniazid daily. The one patient in Group I who had tubercle bacilli initially resistant to isoniazid was treated by streptomycin 1 g. and 18 g. of PAS daily followed by PAS 18 g. daily and tetracycline 250 mg. four times daily. Results
The patients in Group 1 were divided into 3 sub-groups:Group fa :-previous chemotherapy, sensitive to all three standard drugs, treated with streptomycin and isoniazid followed by PAS and isoniazid. Group lb :-previous chemotherapy, sensitive to all three standard drugs, treated with PAS and isoniazid. Group fc:-previous chemotherapy, resistant to one of the three standard drugs . . The patients in Group II were divided into 2 sub-groups:Group Ila :-no previous chemotherapy, sensitive to all three standard drugs, treated with streptomycin, and isoniazid followed by PAS and isoniazid. Group IIb:-no previous chemotherapy, sensitive to all three standard drugs, treated with PAS and isoniazid. The results are summarized in Tables II to VI. Initial sputum conversion by chemotherapy was achieved in 46 of the 50 cases i.e. 92 %. At the end of 3 years 45 patients had been followed up and 40 (89 %) of them were still sputum negative. Of the 24 patients who were followed up for 5 years, 22 were still sputum negative. Bacterial Resistance The cultures became drug resistant in 6 patients. One of these patients died; 4 have been treated by alternative chemotherapy and are still sputum positive, and 1 remains sputum positive having had no further chemotherapy. One patient in group IIb who remained sputum positive is shown in Table VI as not developing drug-resistant organisms until the fourth year of treatment: this is due to the fact that previously the laboratory had been unable to culture the bacillus satisfactorily and therefore were unable to obtain results for drug sensitivities. Toxic Manifestations Twenty nine patients received streptomycin as a part of their chemotherapeutic regime, and in 7 of these the drug had to be discontinued because of the development of vertigo. Treatment with PAS and isoniazid had to be discontinued in only 1 patient because of the development of gastrointestinal upset due to the PAS. Discussion
The results of this investigation suggest that those patients whose treatment included streptomycin did better than those whose treatment did not. To be balanced against this is the fact that
TABLE IJ.-GROUP IA: PREVIOUS CHEMOTHERAPY; SENSITIVE TO ALL 3 STANDARD DRUGS; TREATED WITH STREP10MYCIN AND ISONIAZID, FOLLOWED BY PAS AND ISONIAZID
Completed period of observation (years)
Total No. of patients at start ofperiod
Resistance Chemo-
Died
therapy
changed
Remaining Chemo'in therapy experience' continues
Sputum positive
Chemo-
therapy stopped
Streptomycin
-------PAS
Isoniazid I
Partial Complete Partial Complete Partial Complete
0 I 2 3
11
4
10
5
7
II 11 11
-
-
-
-
-
II II
-
10 9
11
-
9
8 5
-
7
3
-
-
1
11 2 0 I 0 0
I 2 3
4 4
-
-
I
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
r
o Z
Q , -i tTl :>:l
;;:;
o
:r:
rn
;;:;
o
-i
TABLE III.-GROUP IB: PREVIOUS CHEMOTHERAPY; SENSITIVE TO ALL
3
:r: rn
STANDARD DRUGS; TREATED WITH PAS AND ISONIAZfD
:>:l
> Completed period of observation (years)
Total No. ofpatients at start ofperiod
-e
Resistance Died
Chemotherapy changed
Remaining Chemo'in therapy experience' continues
Chemotherapy stopped
Sputum positive
-<
PAS
Isoniazid
Partial Complete Partial Complete 0 1 2 3 4 5
14 14 14 12 11 7
-
-
-
-
14 12 11 11
I
1 1
-
-
-
1
-
6
13
8 8 4 3
-
1
8
3 7 3
14 2 4 2 1 1
-
-
2 -
-
-
-
-
-
3 2 1 1
-
1 3
-
1
-
-
1 1
.l>-
-*""
TABLE IV.-GROUP
-
Ie:
PREVIOUS CHEMOTHERAPY; RESISTANT TO
1 OF THE 3 STANDARD
~
DRUGS
~
N
Completed period of observation (years)
Resistance
Total No. ofpatients at start ofperiod
Died
Chemotherapy changed
Remaining Chemo'in therapy experience' continues
Chemotherapy stopped
Sputum positive
Streptomycin
Isoniazid
PAS
Partial Complete Partial Complete Partial Complete
0 1 2
3
3
3
4
2 2
5
3 3
TABLE V.-GROUP IIA:
Completed period of observation (years)
-
-
-
Total No. ofpatients at start ofperiod
-
-
2
3
-
-
No
-
-
-
1
-
3
3
2 2
2 2
2
2
-
3 1 0 0 0 0
I I 1 0
-
-
-
-
0
2 I 1 1
-
-
-
-
-
1 I 1 1
-
-
-
1
-
-
-
-
-
-
1
PREVIOUS CHEMOTHERAPY; SENSITIVE TO ALL 3 STANDARD DRUGS; TREATED WITH STREPYOMYCIN AND ISONIAZID, FOLLOWED BY PAS AND ISONIAZID
Resistance Died
Chemotherapy changed
Remaining Chemo'in therapy experience' continues
Chemotherapy stopped
Sputum positive
Streptomycin
Isoniazid
...,
PAS
c::
Partial Complete Partial Complete Partial Complete 0
17
I 2
17 17
3 4 5
17 9 4
-
-
-
-
1 -
-
-
-
-
-
17 17
17 16 10 4
16 9 4
-
I
-
17
0 1
-
0 0 0 0
5 5 3
-
-
0
-
-
-
-
-
-
-
-
Completed period of observation (years)
Total No. ofpatients at start ofperiod
0
5 5 5 5 5 5
No
PREVIOUS CHEMOTHERAPY; SENSITIVE TO ALL
3
-
-
-
-
-
rn
-
-
-
-
-
-
-
-
-
.....
_-~
STANDARD DRUGS; TREATED WITH PAS AND ISONIAZID
Resistance Died
Chemotherapy changed
Remaining
Chemoherapy experience' continues 'in
Chemotherapy stopped
Sputum positive
Streptomycin
Isoniazid
PAS
Partial Complete Partial Complete I
2 3 4
5
-
-
-
-
-
-
5 5
5 5
0 0
5 5
-
5
5 3 2
0
-
2 3
5 I I I I
1
!
-
-
-
-
-
-
-
tTl
;0
o
..,.-"...... TABLE Vr.-GROUP lIB:
til
-
-
-
-
-
-
-
I 1
1
-
r
LONG-TERM CHEMOTHERAPY
443
of those who were given streptomycin the drug had to be discontinued, because of the development of vertigo, in a quarter. The patients were predominantly in the 40-65 years age range and it is already well known that patients over the age of 40 years are particularly susceptible to the development of vertigo as a manifestation of toxicity to streptomycin. On the other hand patients were able to tolerate a combination of 10-12 g of PAS and 200-300 mg. of isoniazid for long periods of time. Although the numbers are relatively small it would appear that patients who had had previous chemotherapy did practically as well as those who had had no previous chemotherapy. It is suggested that where possible a regime which includes initial treatment with streptomycin followed by long-term chemotherapy with PAS and isoniazid is the method of choice in the treatment of the patient with chronic cavitating pulmonary tuberculosis who is unsuitable for ultimate surgical treatment. This study has shown that it is possible to obtain sputum conversion in at least 90 %of patients with chronic cavitating pulmonary tuberculosis not amenable to surgical treatment, but whose tubercle bacilli are sensitive to 2 or more of the 3 standard drugs and that sputum conversion can be maintained by long-term chemotherapy. This work has been carried out with the approval of the Clinical Research Subcommittee of the Sheffield Regional Hospital Board. I wish to express my thanks to the Medical Director, Dr. Mair, and the Staff of the Medical Research Council's Public Health Laboratory, Leicester, for carrying out the numerous bacteriological examinations and drug sensitivity tests. My thanks are also due to my colleagues Dr. H. Selby, Dr. M. C. Brough, and Dr. T. A. Adkins for permission to treat and have access to some of their patients. REFERENCES CLARKE, O. (1952). Brit. med. J., ii, 644. DOUGLAS, A. C., & HORNE, N. W. (1956). MEDICAL RESEARCH COUNCIL (1955), Brit.
Brit. med, J., i, 375.
med. J., i, 435.
438
THE TREATMENT OF CHRONIC CAVITATING PULMONARY TUBERCULOSIS BY LONG-TERM CHEMOTHERAPY By D. H.
BLAKE
from the Lelcestershire Chest Service, Markfield Hospital, Leicester SUMMARY
A series of 50 patients with chronic cavitating pulmonary tuberculosis not amenable to surgical treatment, but whose cultures were sensitive to 2 or more of the 3 standard drugs were treated by long-term chemotherapy. Initial sputum conversion was achieved in 46. Out of 4S patients followed up for 3 years, 40 were still sputum negative at the end of this period. Twenty four of the patients have been followed up for a period of 5 years and 22 are still sputum negative. Before the introduction of long-term chemotherapy in pulmonary tuberculosis there was a group of patients attending chest clinics who were sometimes called 'chronic sputum-positive cases.' The radiographic appearances were those of multiple thick-walled cavities, often with complete excavation of part of the lungs, and with evidence of fibrosis in the form of mediastinal displacement, contraction of interlobar fissures, or compensatory basal emphysema. Many of these patients had been under clinic supervision long before the advent of chemotherapy; they may have been considered at the time unsuitable for chemotherapy; or they may have been given short courses of drug treatment with either no benefit or only very temporary sputum conversion. Even when long-term effective chemotherapy became possible treatment of this type of case tended to be withheld in the belief that it could not materially affect the x-ray appearances, and could not therefore be expected to be of any therapeutic value; indeed by producing drug-resistant organisms it might even be disadvantageous. From time to time patients with similar x-ray appearances and a positive sputum are picked-up at chest clinics as 'new cases'. Because of age, extent of disease, or respiratory insufficiency they are unsuitable for surgical treatment. They may be described as cases of chronic cavitating pulmonary tuberculosis not amenable to surgical treatment; and they are the type of case with which this paper is concerned. The paper sets out to answer the following questions. First, is it possible to render these patients non-infectious by chemotherapy? Secondly, is it possible to keep them sputum negative by long-term chemotherapy? As early as 1952 Clarke advocated the use of streptomycin in the management of the chronic tuberculous patient. Douglas and Horne (1956) published encouraging results from treatment by long-term chemotherapy of 6 cases of 'advanced pulmonary tuberculosis with persistent cavitation', but only 1 patient was followed up for as long as 36 months. Methods When this work was started in 1955 the clinic records contained 36 cases of the type. A further 14 consecutive new cases were added, thus making a series of 50 cases. These 50 patients were treated by long-term chemotherapy and the investigation was continued until 24 of them had been
LONG-TERM CHEMOTHERAPY
439
followed up for 5 years . Sputum tests, or, in the absence of sputum, examinations of laryngeal swabs were carried out in every case during the period of study at 3 monthly interval s. The criterion for sp ut um negativity was a negative sputum test both on direct smear and after 6 weeks culture or 2 negative laryngeal swabs after culture for 6 weeks. Sensitivity tests to the 3 standard antituberculosis drugs streptomycin, isoniazid, and PAS, were carried out prior to the commencement of treatment, and in all cases where the sputum remained positive or where laryngeal swabs were po sitive for tubercle bacilli .
Sensitivity Tests The following techniques were used in carrying alit the sensiti vity tests. The drugs were incorporated into Lowenstein-Jensen media. Three strengths of each drug were used, viz. 100 units, 10 units, and 3 units of streptomycin per ml. of the medium ; 2 flog., I flog., and 0'2 flog. of isoniazid per ml, of the medium; and 10 flog., 1 (-Lg., and 0·1 flog. of PAS per mI. of the medium. LowensteinJensen slopes were prepared by the introduction of 10 ml. of the medium into 2 oz. bottles, and sterilization and inspissation at 80aC. for 1 hour. The inoculum was prepared by taking a loopful of growth from a culture on Lowenstein-Jensen medium , and shaking up with 0.3 ml. of distilled water in a half ounce bottle containing 2 sterile glass beads for 3 mins, to form an emulsion. One standard loopful of the prepared inoculum was used to inoculate each of the media . Two controls were used in each series of sensitivity tests carried out:1. Inoculation of a Lowenstein-Jensen slope containing no drug. 2. Inoculation of the prepared media with the standard sensitive strain of Mycobacterium tuberculosis H37Rv. Interpretation of the results depends upon a comparison of the growth of the standard sensitive H37Rv strain and the test strain. Growth of the H37Rv st rain should not occur on any of the test slopes. Strains under test which failed to grow in the presence of all 3 concentrations of streptomycin , isoniazid and PAS were considered to be fully sensitive to these drugs. Test strains which grew in the presence of the two lowest concentrations of the drug and not in the highest concentrations were interpreted as being of partial resistance, whilst those growing in the presence of the highest concentration of the drug were taken to be fully resistant. Pre-treatment Condition The patients were divided into 2 groups : Group I, consisting of patients who had had previous chemotherapy ; and Group II, consisting of patients who had had no previous chemotherapy. There were 28 patients in Group I, and 22 patients in Group 11,8 of whom had been under previous clinic supervision and 14 of whom were treated as new cases. Of the 28 patients in Group I, only 3 had become sputum negative as a result of their previous chemotherapy, and these had quickly reverted to sputum positive again when chemotherapy was discontinued. In Group I there were 2 patients whose cultures were initially resistant to streptomycin, and 1 patient who had resistant cultures to isoniazid. The tubercle bacilli of all the remaining 25 patients in Group I, and all the patients in Group II were fully sensitive to streptomycin, isoniazid and PAS . The ages of the patients ranged from 22-70 years, 76 % being between the ages of 40 and 65 years . There were 43 males and 7 females. (T able I). Nature of Chemotherapy 16 patients in Group 1, including the 2 with cultures resistant to streptomycin, and 5 in Group II were treated by a combination of PAS and isoniazid. 11 patients in Group I and the remaining 17 in Group II were treated with an initial course of streptomycin and isoniazid followed by a combination of PAS and isoniazid. The dosage of streptomycin and isoniazid was that recommended E
440
TUBERCLE TABLE I.-THE AGE, SEX, PREVIOUS TREATMENT AND SENSITIVITY TESTS. --- .,-
Pre-treatment sensitivity tests.
No. of patients
Group INo previous chemothrapy Group IIPrevious chemotherapy Total
Age
-- - -- - ----S. INH PAS S. INH PAS Range (yrs) - - - - -- - - - -
28
26
27
28
22
22
22
22
50
2 0 1-
48
49
Sex
Resistant
Sensitive
50
2
40-65 yrs.
M.
1
0
22- 65
21
24
0
0
35-70
17
19
1
0
22-70
38
43
--
-F.
4
-
3 7
by the Medical Research Council (1955), viz. 1 g. of streptomycin daily and 100 mg. isoniazid twice daily; and the dosage of PAS and isoniazid was 10-12 g. of PAS and 200-300 mg. of isoniazid daily. The one patient in Group I who had tubercle bacilli initially resistant to isoniazid was treated by streptomycin 1 g. and 18 g. of PAS daily followed by PAS 18 g. daily and tetracycline 250 mg. four times daily. Results
The patients in Group 1 were divided into 3 sub-groups:Group fa :-previous chemotherapy, sensitive to all three standard drugs, treated with streptomycin and isoniazid followed by PAS and isoniazid. Group lb :-previous chemotherapy, sensitive to all three standard drugs, treated with PAS and isoniazid. Group fc:-previous chemotherapy, resistant to one of the three standard drugs . . The patients in Group II were divided into 2 sub-groups:Group Ila :-no previous chemotherapy, sensitive to all three standard drugs, treated with streptomycin, and isoniazid followed by PAS and isoniazid. Group IIb:-no previous chemotherapy, sensitive to all three standard drugs, treated with PAS and isoniazid. The results are summarized in Tables II to VI. Initial sputum conversion by chemotherapy was achieved in 46 of the 50 cases i.e. 92 %. At the end of 3 years 45 patients had been followed up and 40 (89 %) of them were still sputum negative. Of the 24 patients who were followed up for 5 years, 22 were still sputum negative. Bacterial Resistance The cultures became drug resistant in 6 patients. One of these patients died; 4 have been treated by alternative chemotherapy and are still sputum positive, and 1 remains sputum positive having had no further chemotherapy. One patient in group IIb who remained sputum positive is shown in Table VI as not developing drug-resistant organisms until the fourth year of treatment: this is due to the fact that previously the laboratory had been unable to culture the bacillus satisfactorily and therefore were unable to obtain results for drug sensitivities. Toxic Manifestations Twenty nine patients received streptomycin as a part of their chemotherapeutic regime, and in 7 of these the drug had to be discontinued because of the development of vertigo. Treatment with PAS and isoniazid had to be discontinued in only 1 patient because of the development of gastrointestinal upset due to the PAS. Discussion
The results of this investigation suggest that those patients whose treatment included streptomycin did better than those whose treatment did not. To be balanced against this is the fact that
TABLE IJ.-GROUP IA: PREVIOUS CHEMOTHERAPY; SENSITIVE TO ALL 3 STANDARD DRUGS; TREATED WITH STREP10MYCIN AND ISONIAZID, FOLLOWED BY PAS AND ISONIAZID
Completed period of observation (years)
Total No. of patients at start ofperiod
Resistance Chemo-
Died
therapy
changed
Remaining Chemo'in therapy experience' continues
Sputum positive
Chemo-
therapy stopped
Streptomycin
-------PAS
Isoniazid I
Partial Complete Partial Complete Partial Complete
0 I 2 3
11
4
10
5
7
II 11 11
-
-
-
-
-
II II
-
10 9
11
-
9
8 5
-
7
3
-
-
1
11 2 0 I 0 0
I 2 3
4 4
-
-
I
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
r
o Z
Q , -i tTl :>:l
;;:;
o
:r:
rn
;;:;
o
-i
TABLE III.-GROUP IB: PREVIOUS CHEMOTHERAPY; SENSITIVE TO ALL
3
:r: rn
STANDARD DRUGS; TREATED WITH PAS AND ISONIAZfD
:>:l
> Completed period of observation (years)
Total No. ofpatients at start ofperiod
-e
Resistance Died
Chemotherapy changed
Remaining Chemo'in therapy experience' continues
Chemotherapy stopped
Sputum positive
-<
PAS
Isoniazid
Partial Complete Partial Complete 0 1 2 3 4 5
14 14 14 12 11 7
-
-
-
-
14 12 11 11
I
1 1
-
-
-
1
-
6
13
8 8 4 3
-
1
8
3 7 3
14 2 4 2 1 1
-
-
2 -
-
-
-
-
-
3 2 1 1
-
1 3
-
1
-
-
1 1
.l>-
-*""
TABLE IV.-GROUP
-
Ie:
PREVIOUS CHEMOTHERAPY; RESISTANT TO
1 OF THE 3 STANDARD
~
DRUGS
~
N
Completed period of observation (years)
Resistance
Total No. ofpatients at start ofperiod
Died
Chemotherapy changed
Remaining Chemo'in therapy experience' continues
Chemotherapy stopped
Sputum positive
Streptomycin
Isoniazid
PAS
Partial Complete Partial Complete Partial Complete
0 1 2
3
3
3
4
2 2
5
3 3
TABLE V.-GROUP IIA:
Completed period of observation (years)
-
-
-
Total No. ofpatients at start ofperiod
-
-
2
3
-
-
No
-
-
-
1
-
3
3
2 2
2 2
2
2
-
3 1 0 0 0 0
I I 1 0
-
-
-
-
0
2 I 1 1
-
-
-
-
-
1 I 1 1
-
-
-
1
-
-
-
-
-
-
1
PREVIOUS CHEMOTHERAPY; SENSITIVE TO ALL 3 STANDARD DRUGS; TREATED WITH STREPYOMYCIN AND ISONIAZID, FOLLOWED BY PAS AND ISONIAZID
Resistance Died
Chemotherapy changed
Remaining Chemo'in therapy experience' continues
Chemotherapy stopped
Sputum positive
Streptomycin
Isoniazid
...,
PAS
c::
Partial Complete Partial Complete Partial Complete 0
17
I 2
17 17
3 4 5
17 9 4
-
-
-
-
1 -
-
-
-
-
-
17 17
17 16 10 4
16 9 4
-
I
-
17
0 1
-
0 0 0 0
5 5 3
-
-
0
-
-
-
-
-
-
-
-
Completed period of observation (years)
Total No. ofpatients at start ofperiod
0
5 5 5 5 5 5
No
PREVIOUS CHEMOTHERAPY; SENSITIVE TO ALL
3
-
-
-
-
-
rn
-
-
-
-
-
-
-
-
-
.....
_-~
STANDARD DRUGS; TREATED WITH PAS AND ISONIAZID
Resistance Died
Chemotherapy changed
Remaining
Chemoherapy experience' continues 'in
Chemotherapy stopped
Sputum positive
Streptomycin
Isoniazid
PAS
Partial Complete Partial Complete I
2 3 4
5
-
-
-
-
-
-
5 5
5 5
0 0
5 5
-
5
5 3 2
0
-
2 3
5 I I I I
1
!
-
-
-
-
-
-
-
tTl
;0
o
..,.-"...... TABLE Vr.-GROUP lIB:
til
-
-
-
-
-
-
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of those who were given streptomycin the drug had to be discontinued, because of the development of vertigo, in a quarter. The patients were predominantly in the 40-65 years age range and it is already well known that patients over the age of 40 years are particularly susceptible to the development of vertigo as a manifestation of toxicity to streptomycin. On the other hand patients were able to tolerate a combination of 10-12 g of PAS and 200-300 mg. of isoniazid for long periods of time. Although the numbers are relatively small it would appear that patients who had had previous chemotherapy did practically as well as those who had had no previous chemotherapy. It is suggested that where possible a regime which includes initial treatment with streptomycin followed by long-term chemotherapy with PAS and isoniazid is the method of choice in the treatment of the patient with chronic cavitating pulmonary tuberculosis who is unsuitable for ultimate surgical treatment. This study has shown that it is possible to obtain sputum conversion in at least 90 %of patients with chronic cavitating pulmonary tuberculosis not amenable to surgical treatment, but whose tubercle bacilli are sensitive to 2 or more of the 3 standard drugs and that sputum conversion can be maintained by long-term chemotherapy. This work has been carried out with the approval of the Clinical Research Subcommittee of the Sheffield Regional Hospital Board. I wish to express my thanks to the Medical Director, Dr. Mair, and the Staff of the Medical Research Council's Public Health Laboratory, Leicester, for carrying out the numerous bacteriological examinations and drug sensitivity tests. My thanks are also due to my colleagues Dr. H. Selby, Dr. M. C. Brough, and Dr. T. A. Adkins for permission to treat and have access to some of their patients. REFERENCES CLARKE, O. (1952). Brit. med. J., ii, 644. DOUGLAS, A. C., & HORNE, N. W. (1956). MEDICAL RESEARCH COUNCIL (1955), Brit.
Brit. med, J., i, 375.
med. J., i, 435.