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Chemotherapy of previously treated patients with pulmonary tuberculosis
Tubercle, Lond., (1964), 45, 202
202
C H E M O T H E R A P Y OF PREVIOUSLY TREATED PATIENTS WITH P U L M O N A R Y TUBERCULOSIS By NENAD GIUNIO*
from Kasindol Hospitalfor Tuberculosis, Yugoslavia
SUMMARY In June 1963 there were 154 patients in Kasindol Hospital who had had cultures resistant to one or more of the 'primary' drugs when they were admitted and who had ah'eady received some chemotherapy. Before the results of sensitivity tests were known, patients with a history of previous chemotherapy had been treated with isoniazid, streptomycin and PAS, together with one, two or three of the 'secondary' drugs, depending on the nature of the previous chemotherapy and the extent of the tuberculosis. After the results were known, treatment had been continued with 3 drugs to which the cultures were sensitive. Seventy-six per cent of 93 who had had more than 3 months sucli treatment had negative cultures. Of 29 in whom the treatment had been continuous 26 (90 %) had negative cultures. Of 64 with interrupted treatment only 45 (70 %) had negative cultures.
Treatment with isoniazid, streptomycin and PAS is the accepted optimum for patients with advanced disease and cultures sensitive to these three drugs. It is reasonable to use a similar tripledrug regimen if the cultures are sensitive to only one or two of these drugs, the 'lost' drugs being replaced by others. But in previously treated patients this cannot be done until the results of sensitivity tests are known. Initially, therefore, we have been treating such patients with the three 'primary' drugs and one, two or three of the 'secondary' ones, according to the probability, from the chemotherapy history, that resistant cultures might be present. This has been our policy since January 1962. To estimate the success of this policy we collected the relevant data on all patients in the hospital on 5th June 1963. Among the 609 patients there were 154 who had had resistant cultures when admitted to the hospital. These 154 patients are described in this report.
Methods On 5th June, 1963 there were 609 patients under treatment in the hospital. Of 232 with completed sensitivity tests on cultures set up on admission, 154 had had resistant cultures and had previously received chemotherapy. Sensitivity Tests Four tests were done on each sputum specimen, two direct and two indirect tests. The indirect test was done by the method described by the International Union against Tuberculosis (1964). In this method, 4 suspensions of the patient's bacilli (and of the standard strain H37Rv) are inoculated onto a series of drug-containing slopes. Approximately 10"z, 10"3, 10-4 and 10-6 nag. * Present address: Pludni odjel, Opca Bolnica, Split, Yugoslavia.
PREVIOUSLY TREATED PATIENTS
203
bacilli are inoculated. The concentrations of isoniazid in the slopes are 0.012, 0.025, 0.05, 0.1, 0.2, 0.4 and l~g./ml., of streptomycin I, 2, 4, 8, I6 and 32 ~g./ml., and of PAS 0.03, 0.06, 0.12, 0.25, 0.5 1 and 2 t~g./ml. The growth of the 10-6 inoculum on two control slopes gives a countable number of colonies (up to I00) from which can be determined how many viable units were inoculated in each of the 4 suspensions. A culture was considered resistant if over I ~ of the population grew on 0.2 ~g./ml. isoniazid, 4 ~g./ml. streptomycin or 0.5 ~.g./ml. PAS. With the same test the result could be expressed as a 'resistance ratio' in comparison with the standard strain H37Rv. A ratio of 4 was reported 'doubtfully resistant', 8 or above 'resistant' and less than 4 'sensitive'. Direct sensitivity tests were done if the sputum was positive on microscopy. If'resistance' was reported by 2 or more of the 4 tests (proportional method, resistance ratio and two direct tests) the specimen was considered resistant. During treatment cultures were set up every two weeks. The results of treatment are expressed entirely interms of the culture results. Treatment The chemotherapy was almost uniform for all patients. If the sputum was positive on microscopy when the patient was admitted and the patient had already had the 'primary' drugs for longer than 2 months, resistance was suspected and one 'secondary' drug given in addition to isoniazid, streptomycin and PAS if the disease was moderately advanced and two 'secondary' drugs if the disease was far advanced. If the history suggested that resistance had probably developed to all 3 'primary' drugs, three 'secondary" drugs were given. If this scheme of treatment was not possible in any case the whole chemotherapy was discontinued until sensitivity test results were available. When the results of sensitivity tests to the three 'primary' drugs became available therapy was continued in all cases with a regimen consisting of 3 drugs to which the cultures were known to be sensitive or in the case of the 'secondary' drugs presumed to be sensitive. The following daily doses were used: streptomycin~l g.; isoniazid~5 mg./kg.; sodium P A S ~ 12 g. ; pyrazinamide~2-3 g., ethionamide~l g. ; cycloserine 1 g. All drugs were administered in the treatment room under the supervision of a nurse. Ethionamide and cycloserine were given in divided do~es, the other drugs in single daily doses. If treatment with one or more of the drugs was stopped for 10 days or longer (because of toxicity or temporary shortage of drugs) the therapy has been recorded as 'interrupted'. The Patients The patients were of similar age range to the whole group of patients in hospital at that time. 75~o were 20-39 years old. The male/female ratio was 3 to 1. There were 80~o with far advanced disease, 19 ~ with moderately advanced disease and only l patient with minimal disease. Almost three quarters (72 ~,,) had sputum positive on microscopy. Drug-resistance Of the 154 patients, 50 (32 ~o) had cultures resistant to one of the three 'primary'drugs (isoniazid ~ 3 5 , streptomycin~13, PAS~2). Tlaere were 49 (32~ resistant to two drugs (isoniazid plus streptomycin--45, isoniazid plus P A S ~ 2 , streptomycin plus PAS~2). The cultures were resistant to all 3 drugs in 55 (35 o/,,) patients. Results Of the 154 patients assessed on 5th June 1963, 103 (67 ~ ) were sputum negative on culture. There were 69 patients who had had no interruption of treatment and 53 (77 ~,,) were negative. But among 85 in whom treatment had been interrupted there were only 50 (59 ~/) negative. Some patients had, of course, been treated for only short periods at the time the assessment was made. In fact, 61 (40 ~ ) had had up to three months treatment" and 93 (60 o/) had had more than 3 months. Of these 93, 71 (76 ~o) were negative on culture. Again there is a difference between those who had had continuous treatment and those in whom treatment was interrupted. There were 29
204
TUBERCLE
with continuous treatment for more than 3 months: only 3 (10%) were still culture-positive and two of these had broncho-pleural fistulae, a form of disease in which sputum conversion might be expected to be slow. In 90 ~o the cultures were negative. Among the 64 with interrupted treatment, on the other hand, there were only 70 % culture negative. Discussion The goal of chemotherapy in previously untreated patients has for long been accepted as persisting sputunl negativity. There is no reason why this should not apply to previously treated patients, provided that tile cultures are sensitive to the drugs used. But there must inevitably be a period of waiting until the results of sensitivity tests become available; and it is on the chemotherapy to be used during this period that there are most differences of opinion. There seems no good reason for merely continuing the same regimen of 'primary' drugs that has failed in the past in these patients. To prescribe triple-drug therapy with 'secondary' drugs in all patients is a possible solution : but it is difficult in practice. Because of toxicity and intolerance, some of the patients would have inadequate chemotherapy during the period: and others would be unnecessarily exposed to toxic risks and difficulties. Almost one third of our patients had cultures sensitive to two of the 'primary" drugs and another third had cultures sensitive to one. In 12 % the cultures were still sensitive to isoniazid. It would be unwise to ignore these conserved sensitivities and to use the 'secondary' drugs only. In some cases the chemotherapy history is such that resistance to all 3 drugs seems probable. In these cases, 3 'secondary' drugs can be given in addition to the three 'primary' ones during the waiting period. In other patients with a less suggestive history, it seems reasonable to give one or two 'secondary' drugs, according to the extent of the pulmonary disease. By doing this, few patients will have less than 3 effective drugs during the waiting period, so that further resistance should not develop during this period and continued triple-drug treatment based on the results of sensitivity tests when tile patient entered hospital should be effective. The essential of success is, of course, continuity of treatment. In our experience only visual supervision of actual drug-taking will ensure such continuity. We insist uncompromisingly on administering the entire therapy during the waiting period or none at all. We do not allow certain drugs to be omitted or others substituted, or the daily doses to be reduced. Such omissions or reductions may not be harmful to one individual patient, but they might be harmful to another; and it is much easier for patients to accept the inevitability of the total regimen in company with other patients than to be disturbed by the possibility of compromise. The success of our policy appears to range between 70 o/.o and 90 70 of sputum conversions after 3 months' treatment. If properly conducted, chemotherapy with 'secondary' drugs can lead to lasting sputum conversion. But there are many obstacles to success. However, the mere fact that we, the physicians, believe in the efficacy of the 'secondary' drugs will help us, as well as the patients, in our efforts to administer c o n t i n u o u s therapy to more and more patients. The larger the number of 'primary' drugs to which the cultures are still sensitive, the easier the planning and administration of continuous therapy.
REFERENCE INTERNATIONALUNIONAGAINSTTUItERCULOSlS(I 964). Bull. int. Un. Tuberc. In press.
202
C H E M O T H E R A P Y OF PREVIOUSLY TREATED PATIENTS WITH P U L M O N A R Y TUBERCULOSIS By NENAD GIUNIO*
from Kasindol Hospitalfor Tuberculosis, Yugoslavia
SUMMARY In June 1963 there were 154 patients in Kasindol Hospital who had had cultures resistant to one or more of the 'primary' drugs when they were admitted and who had ah'eady received some chemotherapy. Before the results of sensitivity tests were known, patients with a history of previous chemotherapy had been treated with isoniazid, streptomycin and PAS, together with one, two or three of the 'secondary' drugs, depending on the nature of the previous chemotherapy and the extent of the tuberculosis. After the results were known, treatment had been continued with 3 drugs to which the cultures were sensitive. Seventy-six per cent of 93 who had had more than 3 months sucli treatment had negative cultures. Of 29 in whom the treatment had been continuous 26 (90 %) had negative cultures. Of 64 with interrupted treatment only 45 (70 %) had negative cultures.
Treatment with isoniazid, streptomycin and PAS is the accepted optimum for patients with advanced disease and cultures sensitive to these three drugs. It is reasonable to use a similar tripledrug regimen if the cultures are sensitive to only one or two of these drugs, the 'lost' drugs being replaced by others. But in previously treated patients this cannot be done until the results of sensitivity tests are known. Initially, therefore, we have been treating such patients with the three 'primary' drugs and one, two or three of the 'secondary' ones, according to the probability, from the chemotherapy history, that resistant cultures might be present. This has been our policy since January 1962. To estimate the success of this policy we collected the relevant data on all patients in the hospital on 5th June 1963. Among the 609 patients there were 154 who had had resistant cultures when admitted to the hospital. These 154 patients are described in this report.
Methods On 5th June, 1963 there were 609 patients under treatment in the hospital. Of 232 with completed sensitivity tests on cultures set up on admission, 154 had had resistant cultures and had previously received chemotherapy. Sensitivity Tests Four tests were done on each sputum specimen, two direct and two indirect tests. The indirect test was done by the method described by the International Union against Tuberculosis (1964). In this method, 4 suspensions of the patient's bacilli (and of the standard strain H37Rv) are inoculated onto a series of drug-containing slopes. Approximately 10"z, 10"3, 10-4 and 10-6 nag. * Present address: Pludni odjel, Opca Bolnica, Split, Yugoslavia.
PREVIOUSLY TREATED PATIENTS
203
bacilli are inoculated. The concentrations of isoniazid in the slopes are 0.012, 0.025, 0.05, 0.1, 0.2, 0.4 and l~g./ml., of streptomycin I, 2, 4, 8, I6 and 32 ~g./ml., and of PAS 0.03, 0.06, 0.12, 0.25, 0.5 1 and 2 t~g./ml. The growth of the 10-6 inoculum on two control slopes gives a countable number of colonies (up to I00) from which can be determined how many viable units were inoculated in each of the 4 suspensions. A culture was considered resistant if over I ~ of the population grew on 0.2 ~g./ml. isoniazid, 4 ~g./ml. streptomycin or 0.5 ~.g./ml. PAS. With the same test the result could be expressed as a 'resistance ratio' in comparison with the standard strain H37Rv. A ratio of 4 was reported 'doubtfully resistant', 8 or above 'resistant' and less than 4 'sensitive'. Direct sensitivity tests were done if the sputum was positive on microscopy. If'resistance' was reported by 2 or more of the 4 tests (proportional method, resistance ratio and two direct tests) the specimen was considered resistant. During treatment cultures were set up every two weeks. The results of treatment are expressed entirely interms of the culture results. Treatment The chemotherapy was almost uniform for all patients. If the sputum was positive on microscopy when the patient was admitted and the patient had already had the 'primary' drugs for longer than 2 months, resistance was suspected and one 'secondary' drug given in addition to isoniazid, streptomycin and PAS if the disease was moderately advanced and two 'secondary' drugs if the disease was far advanced. If the history suggested that resistance had probably developed to all 3 'primary' drugs, three 'secondary" drugs were given. If this scheme of treatment was not possible in any case the whole chemotherapy was discontinued until sensitivity test results were available. When the results of sensitivity tests to the three 'primary' drugs became available therapy was continued in all cases with a regimen consisting of 3 drugs to which the cultures were known to be sensitive or in the case of the 'secondary' drugs presumed to be sensitive. The following daily doses were used: streptomycin~l g.; isoniazid~5 mg./kg.; sodium P A S ~ 12 g. ; pyrazinamide~2-3 g., ethionamide~l g. ; cycloserine 1 g. All drugs were administered in the treatment room under the supervision of a nurse. Ethionamide and cycloserine were given in divided do~es, the other drugs in single daily doses. If treatment with one or more of the drugs was stopped for 10 days or longer (because of toxicity or temporary shortage of drugs) the therapy has been recorded as 'interrupted'. The Patients The patients were of similar age range to the whole group of patients in hospital at that time. 75~o were 20-39 years old. The male/female ratio was 3 to 1. There were 80~o with far advanced disease, 19 ~ with moderately advanced disease and only l patient with minimal disease. Almost three quarters (72 ~,,) had sputum positive on microscopy. Drug-resistance Of the 154 patients, 50 (32 ~o) had cultures resistant to one of the three 'primary'drugs (isoniazid ~ 3 5 , streptomycin~13, PAS~2). Tlaere were 49 (32~ resistant to two drugs (isoniazid plus streptomycin--45, isoniazid plus P A S ~ 2 , streptomycin plus PAS~2). The cultures were resistant to all 3 drugs in 55 (35 o/,,) patients. Results Of the 154 patients assessed on 5th June 1963, 103 (67 ~ ) were sputum negative on culture. There were 69 patients who had had no interruption of treatment and 53 (77 ~,,) were negative. But among 85 in whom treatment had been interrupted there were only 50 (59 ~/) negative. Some patients had, of course, been treated for only short periods at the time the assessment was made. In fact, 61 (40 ~ ) had had up to three months treatment" and 93 (60 o/) had had more than 3 months. Of these 93, 71 (76 ~o) were negative on culture. Again there is a difference between those who had had continuous treatment and those in whom treatment was interrupted. There were 29
204
TUBERCLE
with continuous treatment for more than 3 months: only 3 (10%) were still culture-positive and two of these had broncho-pleural fistulae, a form of disease in which sputum conversion might be expected to be slow. In 90 ~o the cultures were negative. Among the 64 with interrupted treatment, on the other hand, there were only 70 % culture negative. Discussion The goal of chemotherapy in previously untreated patients has for long been accepted as persisting sputunl negativity. There is no reason why this should not apply to previously treated patients, provided that tile cultures are sensitive to the drugs used. But there must inevitably be a period of waiting until the results of sensitivity tests become available; and it is on the chemotherapy to be used during this period that there are most differences of opinion. There seems no good reason for merely continuing the same regimen of 'primary' drugs that has failed in the past in these patients. To prescribe triple-drug therapy with 'secondary' drugs in all patients is a possible solution : but it is difficult in practice. Because of toxicity and intolerance, some of the patients would have inadequate chemotherapy during the period: and others would be unnecessarily exposed to toxic risks and difficulties. Almost one third of our patients had cultures sensitive to two of the 'primary" drugs and another third had cultures sensitive to one. In 12 % the cultures were still sensitive to isoniazid. It would be unwise to ignore these conserved sensitivities and to use the 'secondary' drugs only. In some cases the chemotherapy history is such that resistance to all 3 drugs seems probable. In these cases, 3 'secondary' drugs can be given in addition to the three 'primary' ones during the waiting period. In other patients with a less suggestive history, it seems reasonable to give one or two 'secondary' drugs, according to the extent of the pulmonary disease. By doing this, few patients will have less than 3 effective drugs during the waiting period, so that further resistance should not develop during this period and continued triple-drug treatment based on the results of sensitivity tests when tile patient entered hospital should be effective. The essential of success is, of course, continuity of treatment. In our experience only visual supervision of actual drug-taking will ensure such continuity. We insist uncompromisingly on administering the entire therapy during the waiting period or none at all. We do not allow certain drugs to be omitted or others substituted, or the daily doses to be reduced. Such omissions or reductions may not be harmful to one individual patient, but they might be harmful to another; and it is much easier for patients to accept the inevitability of the total regimen in company with other patients than to be disturbed by the possibility of compromise. The success of our policy appears to range between 70 o/.o and 90 70 of sputum conversions after 3 months' treatment. If properly conducted, chemotherapy with 'secondary' drugs can lead to lasting sputum conversion. But there are many obstacles to success. However, the mere fact that we, the physicians, believe in the efficacy of the 'secondary' drugs will help us, as well as the patients, in our efforts to administer c o n t i n u o u s therapy to more and more patients. The larger the number of 'primary' drugs to which the cultures are still sensitive, the easier the planning and administration of continuous therapy.
REFERENCE INTERNATIONALUNIONAGAINSTTUItERCULOSlS(I 964). Bull. int. Un. Tuberc. In press.