Brit. J. Dis. Chest (x965) 59, 028.

ETHIONAMIDE I,OOO mG. AND ISONIAZID 400 mG. IN PREVIOUSLY UNTREATED CASES OF

PULMONARY TUBERCULOSIS BY A. W. LEF.s

Ruchill Hospital, Glasgow, Scotland

SINCE Brouet et al. (I95O) reported their observations on the clinical effective- ness of ethionamide (alpha-ethyl-thioisonicotinamide) it has been widely used in patients with organisms resistant to the standard drugs. Favourable experience of its action in such cases at this hospital prompted a trial of its use with isoniazid in previously untreated cases of pulmonary tuberculosis in order to assess its potential more accurately. Early findings suggested that this com- bination was effective (Lees, 1964), and the results of an extension of this study are now presented.

Material and Methods Newly diagnosed patients with pulmonary tuberculosis were treated with

ethionamide i G. daily (in the form of uncoated tablets) and isoniazid 400 mG. daily. Both drugs were routinely given in four divided doses, although in some patients who suffered upset at particular times of the day the daily dosage was suitably redistributed. The only patients excluded from the trial were patients who on admission had such overwhelming disease that it seemed advisable to give triple drug therapy. Examination of urine for albumin, blood and bile was carried out weekly; liver function tests (serum albumin and globulin, serum bilirubin, thymol turbidity, alkaline phosphatase) monthly; chest X-ray and culture of sputum or bronchial lavage specimens monthly. Specimens of respiratory secretions were concentrated by Petroff's method and cultured on Lowenstein-Jensen medium. Sensitivity tests were carried out by incorporating the drugs in Lowenstein-Jensen medium in the following strengths: isoniazid 0-2, i, 5, and 5 °/~G./ml.; and ethionamide 5, IO, 20, and 4 ° tzG./ml. Sensitivity test media were controlled by means of the standard strain H37 Rv.

Six-Monthly Results Of 52 patients with organisms initially sensitive to ethionamide and

isoniazid, 36 completed 6 months' therapy and 16 failed to do so. Eight failed to complete the 6 months because of drug side-effects, and 8 for reasons un- connected with therapy (in 2 cases because of death from non-tuberculous disease, and in 6 because of lack of co-operation or transfer elsewhere). Thus the failure rate from drug side-effects was 18 per cent. (8 of 44 patients).

(Received for publication, August I965)

ETHIONAMIDE AND ISONIAZID IN PULMONARY TUBERCULOSIS 2~9

Clinical and radiological Clinical and radiological progress were satisfactory in all 36 patients who

completed the 6 months' period. Of these 36 patients, 7 had initially six zones affected by disease; I had five zones; 4 had four zones; 9 had three zones; 8 had two zones; and 7 had one zone. After 6 months 3 had four zones affected by disease; 6 had three zones; I I had two zones; and I6 had one zone,

Cavitation was initially present in 25 of the 36 cases. These 25 cases had altogether 49 cavities, 43 less than i in. in diameter and 6 more than I in. in diameter. After 6 months' therapy cavities had closed in 22 of the 25 patients who originally had them. Three patients still had a single cavity each: follow- up showed that they closed after 7, 8 and 11 months' treatment, respectively. The general condition of the patients improved satisfactorily and all but 2 gained weight.

Bacteriological Bacteriological conversion was defined as a negative monthly culture

followed by at least one subsequent negative monthly culture and no further positives during the period of observation. By this standard respiratory secretions remained unconverted in only i of the 36 cases at the end of the 6 months' period. In 2i cases conversion occurred at I month; in 4 at 2 months; in 5 at 3 months; in 2 at 4 months; in I at 5 months; and in 2 at 6 months. In the solitary case unconverted at 6 months, follow-up showed that conversion occurred at 7 months. The patient died from non-tuberculous disease 2 months later and post-mortem examination showed very satisfactory healing of the originally extensive cavitatory disease.

No evidence of emergent bacterial resistance to ethionamide or isoniazid was noted in any of the cases.

One Year's Resul ts

Twenty-seven of the 36 patients who had 6 months' therapy completed a further 6 months' therapy. Nine failed to complete a year's therapy, in 4 instances because of drug side-effects, and in 5 for reasons unconnected with therapy (death from non-tuberculous disease in 3 cases, lack of co-operation in I and transfer elsewhere in i). Thus the failure rate from drug side-effects was 13 per cent. in the second 6 months of therapy (4 of 31 patients).

Clinical and radiological Clinical and radiological progress were satisfactory in all 27 patients who

completed i year's therapy. Of these 27 patients, 4 had initially six lung zones affected by disease; i had five lung zones; 4 had four lung zones; 7 had three lung zones; 6 had two lung zones; and 5 had one lung zone.

After I year ~ patients had three lung zones affected by disease; 6 had two zones; i8 had one zone; and in I patient disease was no longer visible.

Cavitation was initially present in 19 of the 27 patients. These 19 patients had altogether 35 cavities, 3o less that I in. in diameter, and 5 more than I in.

23 ° LEES

in diameter. After i year's therapy cavities had closed in all but i patient in whom a thin-walled cavity less than I in. in diameter remained. Treatment was given in this case for 2½ years and was then stopped as bacteriology had been negative since the fourth month after diagnosis. The thin-walled cavity remained, and it was assumed that open-cavity healing had occurred; after a further 6 monthS' observation the patient's condition remains satisfactory.

Clinical and radiological progress was also entirely satisfactory in all 9 patients who failed to complete the second 6 months.

Bacteriological Bacteriological conversion as previously defined occurred in 17 cases at i

month; in 3 cases at 2 months; in 3 cases at 3 months; in i case at 4 months; in I case at 5 months; and in 2 cases at 6 months. There was no evidence of emergent bacterial resistance to ethionamide or isoniazid.

Bacteriological results were also satisfactory in the 9 patients who failed to complete the second 6 months.

Further foUow-up Patients completing i year's therapy have now been followed for variable

periods up to a maximum of 3 years from the beginning of therapy. In 18 cases no further treatment was considered necessary after periods varying from I8 months to 2½ years depending on initial extent and character of the disease.

In 7 cases therapy was stopped because of toxic symptoms, but no further treatment was considered necessary in any of these cases because progress had been completely satisfactory. Progress is also entirely satisfactory in the remaining 2 cases still on routine therapy.

Drug toxicity Twelve (23 per cent. ) of the 52 patients starting the trial had initial toxic

side-effects, mostly nausea, but occasionally a metallic taste in the mouth or heart-burn. These side-effects were usually mild and disappeared in a few days; in no case had therapy to be stopped on this account.

Eight patients failed to complete 6 months' therapy because of side-effects; since 36 patients completed the 6 months' period this gives a failure rate from toxicity of z 8 per cent. (8 out of 44)- In 4 cases the side-effect was jaundice; this appeared in a male patient after 2 months' therapy, in a female patient after 4 months' therapy, and in 2 further female patients after 5 months' therapy.

Treatment had to be stopped after 3 months in 2 male patients because of peripheral neuritis which in I case was accompanied by mental depression. In the remaining 2 cases treatment was stopped because of mental disturbance; after 2 weeks a young woman complained of mental depression, and after 6 weeks a young man began to suffer from hallucinations and severe mental depression. The young woman had previously suffered from emotional in- stability and depression, but it seemed reasonably certain that the drug was having an adverse effect on her mental condition.

ETHIONAMIDE AND ISONIAZID IN PULMONARY TUBERCULOSIS 2 31

Minor side-effects not necessitating cessation of treatment were encoun- tered: acne after 2 months in 2 cases, alopecia after 2 months in I case and blurring of vision after 5 months in x case.

Four patients failed to complete a second 6 months' period of therapy because of side-effects; and since 2 7 patients succeeded, the failure rate from toxicity in the second 6 months was 13 per cent. (4 out of 3 I). Treatment was stopped in a male patient after 7 months because of persistent nausea. It was also stopped in 2 male patients after 8 months and Io months, respectively; in z case because of peripheral neuritis accompanied by transient double vision due to weakness of the left internal rectus muscle, and in the other because of peripheral neuritis accompanied by insomnia and double vision. The remaining case was that of a female patient in whom treatment was stopped after i o months because of depression: she was mentally unstable in any case, but it was considered that ethionamide was worsening her depression.

In the 2 7 patients completing i year's therapy minor side-effects not necessitating cessation of treatment were encountered in the second 6 months: occasional nausea in 5 instances; and menorrhagia after I I months in one case.

Patients completing I year's treatment have now been followed for a maxi- mum of 3 years, the total period of routine treatment having varied from I8 months to 21 years.

Treatment was stopped after I year because of side-effects in 6 cases: in the first because of nausea and nervousness (at 13 months); in the second because of lack of concentration and depression (at 14 months) ; in the third and fourth because of nausea (at 15 and 17 months, respectively); in the fifth because of transient diplopia, occasional dizziness and trembling (at I8 months); and in the sixth because of depression probably due to the drug (at i8 months).

D i s c u s s i o n

The results obtained in the present series with ethionamide i G. daily and isoniazid 40o mG. daily have tended to confirm experience in the earlier stages of this study previously reported (Lees, I964). In 36 cases treated for at least 6 months and in 27 treated for at least i year there was not a single therapeutic failure. In all cases cultures of respiratory secretions became negative and remained negative, and clinical and radiological progress was likewise com- pletely satisfactory. Evidence of the development of bacterial resistance to either drug was absent in all these cases. It was never necessary to abandon the ethionamide/isoniazid regimen because of lack of anti-bacterial efficacy, and, in those cases in which treatment was prematurely stopped for some other reason, clinical, radiological, and bacteriological progress was uniformly good for as long as treatment continued (and indeed thereafter). The results in this series therefore indicate that ethionamide I G. daily plus isoniazid 400 mG. daily is an extremely effective antituberculous drug regimen.

Unfortunately, with a daily dosage of ethionamide as high as I G., side- effects, some very serious, were so common that it cannot be recommended for routine use.

~32 LEES

TriMs with a lower dose of ethionamide to find out if this will reduce side- effects without impairing effectiveness are in progress, Reports of clinical trials by Rist et al. (1962) and the Research Committee of the British Tuberculosis Association (I964) , and experimental work in mice by Grumbach (1962) suggest that this may prove to be the case.

Summary Fifty-two patients with previously untreated pulmonary tuberculosis were

given ethionamide I G. daily and isoniazid 40o mG. daily. Thirty-six patients completed 6 months' treatment, and 27 patients completed at least i year's treatment. The observation period ranged from 18 months to 3 years. Clinical and radiologicM progress was satisfactory as far as the tuberculosis was con- cerned, and bacteriological conversion was achieved and maintained in every case. There was no evidence of emergent bacterial resistance to either drug. In this series treatment had never to be abandoned because of lack of effective- ness, and progress was uniformly satisfactory in cases in which treatment had to be stopped for some other reason.

Drug toxicity was common: on this account 18 per cent. of patients failed to complete 6 months' treatment, and 31 per cent. failed to complete I year's treatment. Side-effects necessitating cessation of therapy were: hepatitis with jaundice, peripheral neuritis, and mental depression or other mental disturb- ance. Other side-effects encountered were nausea, visual disturbance, acne, Mopecia, and menorrhagia. Even after a year side-effects serious enough to necessitate withdrawal of therapy occurred: nausea, mental depression, and neurological disturbance.

The results of this trial suggest that while ethionamide I G. daily plus isoniazid 400 mG. daily is an extremely potent antituberculosis drug regimen it cannot be recommended for routine use because of serious side-effects. Further trials to find out whether lowering the dose of ethionamide will reduce the incidence of serious side-effects without sacrifice of effectiveness are indi- cated.

REFERENCES BROUET, G., M.ARCHE, J., Ris% N., Cm~VALLIER, J., & LE MEuR, G. (I95O). Amer. Rev.

Tuberc., 79, 6. GR~BACH, F. (I96I). Reo. Tuberc. (Paris), 25, I365. LEES, A. W. (1963). Amer. Rev. resp. Dis., 88, 347. LEES, A. W. (1964). Dis. Chest, 45, 247. RESEARCH COMMITTEE UP THE BRITISH TUBERCULOSIS ASSOCIATION AND THE TUBERCULOSIS

TREATMENT SERVICES IN HUNG KONO (I964). Tubercle (Edinb.)~ 45, 299. RIST, N. (1962). Rev. Tuberc. (Paris), 26, 74 o.