Practical Therapeutics Drugs 9: 364-372 (1975)
Drug Treatment of Pulmonary Tuberculosis Sister Mary Aquinas Medical Superintendent, Ruttonjee Sanatorium, Hong Kong
1. Introduction
When a patient is discovered to have active pulmonary tuberculosis, it is assumed that an antituberculosis drug regimen will forthwith be prescribed that will hopefully kill the bacilli and cure the patient. However, despite the fact that, in theory, drugs are capable of curing almost 100 % of cases, it is found in practice, that for a variety of reasons, the results often fall short of this ideal. This article highlights the points of importance in the management of patients needing chemotherapy for tuberculosis.
2. The Availability ofDrugs
There are now about 12 drugs on the market with proven antituberculosis activity, but for economic reasons, all are not available to everybody treating patients. According to a WHO report dealing with countries of the Western Pacific Region (WHO, 1972), the proportion of the national health budget allocated to tuberculosis control varies from 1 to 15 %. There is, therefore, a great difference in the specific facilities available to an organisation or to a clinician treating tuberculosis in these areas. Generally, it is the country with the greatest tuberculosis problem that has the least money designated for the control of the disease. There is moreover, a wide difference in the cost of these drugs, making the use of them, at least on a large scale, quite prohibitive even in the most affluent society. Again, not all the answers have yet been worked out concerning the precise methods of application of some of the more recent drugs, or indeed of all the older ones. However, enough working formulae are available to render almost all patients non-infectious, provided the rules of chemotherapy are followed.
Drug Treatment of Pulmonary Tuberculosis
365
3. The A vailability ofPersonnel
In spite of the rapid scientific advances made in our own time in the chemotherapy of tuberculosis, it is a fact that only a small proportion of the world's estimated 20 million infectious cases is really in a position to benefit from them. It is also unfortunate that we are now witnessing a negligible interest among the younger members of the medical profession in this challenging situation. It would seem that the title 'specialist' in tuberculosis will have disappeared long before the job has been completed. Luckily, this is compensated for, in part, by the fact that the management of the disease is now becoming a standard technology that can be applied readily by non specialist clinicians. Indeed, in many areas of the world the bulk of the work must necessarily be undertaken by auxiliary health personnel. This all means that a greater number of people will need to have a better working knowledge of tuberculosis and its management. It is not enough to have the correct chemotherapy unless it is inexpensive, palatable and capable of administration by relatively unskilled staff. While it is easy to become familiar with the principles of chemotherapy, it is much more painstaking on the part of clinicians, nurses, the family and the patient himself to follow the course of treatment through to the end. This frequently results in inadequate control of the disease and the breeding of strains resistant to the drugs. Thereafter, this man-made complication calls for enormous inroads on whatever budgetary reserves there may be, in an attempt to rescue the patient. It therefore behoves whoever undertakes to treat tuberculosis, not only to apply the knowledge that is readily available concerning the drugs that he is going to use, but also to consider as a major factor the acquiring and maintaining of the close co-operation of the patient. The principal cause of failure in regimens that are otherwise supposed to be 100 % effective is the failure on the part of the treatment service to obtain full co-operation of the patient (Fox, 1972).
4. TheDrugs Table I lists the commonly accepted drugs, the average dose recommended when used on a daily basis and the principal side-effects attributed to them.
4.1 Standard Drug Regimens The management of tuberculosis would be relatively simple if it could be treated with only one drug. Unfortunately, however, one of the basic require-
Drug Treatment of Pulmonary Tuberculosis
366
Table L Doses and side-effects of commonly accepted antituberculosis drugs Drug
Conventional daily dose
Chief side-effects
Streptomycin
0.75 to 1 g
Dizziness. Tinnitus and vertigo due eighth nerve damage. Fever and skin rashes
Sodium PAS
109
Nausea, vomiting, diarrhoea, abdominal discomfort. Fever, skin rashes and hepatitis
Isoniazid
300 to 400 mg
Peripheral neuropathy; mental changes, uncommon. Fever and skin rashes
Pyrazinamide
30 to 40 mg/kg
'Arthropathy', hepatic toxicity Skin rashes - uncommon
Ethionamide
0.5 to 1 g
Nausea, vomiting, abdominal discomfort, hepatitis. Skin rashes uncommon
Cycloserine
0.5 to 0.75 g
Personality changes, mental disturbances. Can be serious
Ethambutol
25 mg/kg x 2 months, then 15 mg/kg
Visual disturbances, retrobulbar neuritis. Uncommon if dosage schedule is followed
Rifampicin
450 to 600 mg
Hepatitis, purpura. Uncommon
ments for success is that a combination of drugs must be used. This is so because mutants resistant to one drug which are present at the beginning of treatment will multiply as soon as the organisms sensitive to that drug have been killed. A second drug is necessary to prevent these mutants from multiplying. There is now much evidence that in the initial stages of treatment when the bacillary population is large, three drugs are even better than two. The regimen that has stood the test of time and that is still most generally accepted is streptomycin, PAS and isoniazid. Treatment is conveniently divided into two phases, the 'intensive phase' and the 'continuation phase'.
Drug Treatment of Pulmonary Tuberculosis
367
4.1.1 The Intensive Phase The optimum duration of treatment of the initial intensive phase of three drugs is still not finalised. It has been known for a long time that when this regimen has been given daily for 6 months, and then followed by PAS and isoniazid daily for a further period of 18 months, the results were virtually 100 % (IUAT, 1966). In a recent study in Hong Kong (HKTTS/MRC, 1972), it was shown that an initial intensive phase with the same regimen gave as good results when used for 3 months as when used for 6 months. It is now standard practice to use this regimen - streptomycin/pAS/isoniazid in the dosage given in table I for 3 months in the initial intensive phase in Hong Kong.
4.1.2 Continuation Phase At the present time the average case of tuberculosis is treated for a total period of about 18 to 24 months. Even though the continuation phase is less intensive, it is nevertheless very important in order to ensure that the disease is adequately controlled. It is assumed that during the phase of intensive chemotherapy, the bacterial population will be greatly reduced and the chances of resistant mutants multiplying will be small, and therefore it will not be necessary to maintain the same intensity of treatment all through the programme. In practice, this means continuing the treatment with two drugs and the trend now is to do this with streptomycin 1 g and isoniazid 750 mg on a twice weekly basis. In our experience, the majority of patients can tolerate this regimen in the continuation phase. For the elderly or others who cannot tolerate streptomycin, PAS 10 g and isoniazid 300 g is continued on a daily basis for about 18 months.
4.2 Other Regimens Used in the Initial Treatment In spite of the reported 100 % efficacy of the standard regimen streptomycin/PAS/isoniazid when properly used, some disadvantages are associated with it. Many patients find attending a clinic for injections for a prolonged period of time to be troublesome and to interfere with their regular daily employment. PAS has never been all that popular either with doctors or patients. Substitutes for it have therefore been sought for the past 20 years. Thiacetazone, small in tablet size and very inexpensive, has been reassessed and efforts have been made to find a place for it in the chemotherapy programme. Except for a few areas, however, its use has been abandoned on grounds of toxicity. Among Chinese patients in Hong Kong, thiacetazone resulted in such a high incidence of side-effects that its use could not be recommended (HKTTS/MRC, 1968). Ethambutol has now been studied relatively extensively. It would appear to be about as effective as PAS and it is certainly a much more palatable partner to
Drug Treatment of Pulmonary Tuberculosis
368
have in a regimen (Doster, 1973). Using the recommended dosage of 25 mm/kg daily for 2 months followed by 15 mg/kg daily, the risk of developing eye toxicity is very slight. Streptomycin/isoniazid/ethambutol provides a very satisfactory regimen for individual patients who cannot take PAS, though for economic reasons it could hardly be undertaken as an overall policy measure in areas with restricted financial resources. Rifampicin, the latest arrival and the currently most controversial agent in the treatment of tuberculosis, has been shown by many laboratory experiments and clinical studies to have an efficacy comparable with that of isoniazid. In combination with isoniazid, rifampicin has given results superior to other combinations. At the present time however, cost precludes its widespread use in the treatment of the disease. Where financial considerations are not important, regimens containing rifampicin are now more frequently used in the treatment of fresh cases. Such regimens would consist of isoniazid/streptomycin/rifampicin or isoniazid/ethambutol/rifampicin. It is conceivable that rifampicin might eventually find a place, even for a short period, in the initial intensive phase of treatment in less economically privileged areas. In daily use regimens, toxicity is not a big problem, but may be serious in nature especially if purpura develops.
4.3 Reserve Regimens It should be the aim of every clinician to cure the patient with the drug regimen that he decides to use when he treats his patient in the first instance. This implies prescribing an adequate regimen and making sure that the patient takes it to the end of the course. Any drug not used in the initial treatment becomes a 'reserve' or a 'second-line' drug. Ideally, it should not be necessary to have to resort to these reserve drugs. Some patients do fail however, on the initial treatment - the sputum remains positive and the sensitivity tests show that the organisms are resistant to the drugs being used. Other regimens should then be considered. For patients who become treatment failures on the standard regimen of streptomycin/PAS/ isoniazid, an alternative regimen that has been in use for many years is pyrazinamide/ethionamide/cycloserine. This was about the best available until the advent of rifampicin and ethambutol. However, pyrazinamide/ethionamide/ cycloserine was never really considered a choice regimen and in practice about half the patients develop side-effects to one or more of the drugs. It has nevertheless resulted in a satisfactory response in about 80 % of failure cases. A more popular regimen for failure cases would now appear to be rifampicin/ethambutol/ethionamide. As in the initial treatment of tuberculosis, there would also be an 'intensive phase' in the management of failure or retreatment cases to be followed by a 'continuation phase'.
Drug Treatment of Pulmonary Tuberculosis
369
4.4 Intermittent Supervised Chemotherapy It was largely as a result of efforts to overcome the irregularities and deficiencies of self administered long-term daily chemotherapy that the concept of intermittent medication evolved. The most hidden threat to the success of any drug regimen is the difficulty of impressing on the patient the importance of taking the oral medicaments regularly for many months. This is especially so when the patient has no symptoms - he feels well and so he easily forgets, or is just too lazy, to take his drugs. The clinician all too often hears this tale in the course of his management of the patient. With intermittent treatment the patient attends the clinic or office 2 or 3 times a week. His injection is given and he can be seen to swallow the tablets. If he fails to attend, it is known immediately that he has missed his scheduled treatment and appropriate action can be taken. The efficacy of this method is now well established by controlled clinical trials. When streptomycin/PASt isoniazid are given daily for 3 months and followed by streptomycin/isoniazid twice weekly the results are virtually 100 %. On intermittent therapy, the dosage of the drugs must be increased from that used in a daily regimen and both drugs must be given on an intermittent basis. Intermittent treatment was used in the 1950's but the results were poor, largely because the dosage was inadequate. Not all antituberculosis drugs are suitable to have the dosage increased because of toxicity or intolerance. Streptomycin dosage can be increased only slightly, but isoniazid can be tolerated in a relatively high dose. Rifampicin and ethambutol are also being used on an intermittent basis and studies are currently exploring the most effective dosages and sequences of administration.
4.5 Side-Effects One of the most disappointing events in the management of a case which otherwise seems to be quite straightforward is the occurrence of side-effects, due to one or more of the drugs. These reactions may be very minimal and require little or no interruption of treatment, or they may be severe enough to warrant complete withdrawal of the offending chemotherapeutic agent such as some change in personality or temperament in a patient receiving cycloserine. In the case of hypersensitivity reactions, however, the general idea is to try to identify the drug responsible for the side-effect by testing each drug separately, usually in a small dose. Once this information was obtained the patient should be desensitised to that drug by gradually increasing the dose until the full dose is reached. The total time involved in this procedure is important, as if it takes several weeks it may result in the emergence of drug resistant
Drug Treatment of Pulmonary Tuberculosis
370
Table II. A summary of the principles of drug treatment of active pulmonary tuberculosis 1)
Active pulmonary tuberculosis can now be treated effectively by any medical practitioner
2)
Success depends on: a) Providing a drug regimen that is adequate for the disease and acceptable to the patient b) Gaining the long-term co-operation of the patient - which means communicating with him so that he understands enough about the programme to ensure that he takes his medication as prescribed
3)
The approach to treatment: a) A combination of drugs must be used b) Intensive phase for 3 months followed by the very important continuation phase for 15-18 months c) Aim of initial treatment is to cure patient with originally selected drug regimen d) Reserve drug regimens used in cases of initial treatment failure or retreatment cases
4)
Assessment of treatment progress a) Examination of bacterial content of sputum b) X-ray at 3- or 6-monthly intervals generally adequate
strains, and so to inadequate control of the disease. For example, if a patient with acute and extensive tuberculosis develops a severe hypersensitivity reaction while he is receiving streptomycin/PAS/isoniazid it would be advisable not only to abandon the regimen forthwith, but also when the reaction subsides to consider an alternative regimen. Such a regimen would depend on available resources but should be calculated to be reasonably safe - for example, ethambutol/ethionamide/pyrazinamide or ethambutol/ethionamide/rifampicin. As streptomycin and PAS are usually the main offenders in hypersensitivity reactions, it is to be hoped that efforts would be made to reintroduce isoniazid to the new regimen and perhaps to eliminate one of the others. When the new regimen is underway it might be possible to proceed with the desensitising to streptomycin or PAS if this were deemed advisable.
5. Assessment of Treatment Progress
As all antituberculosis drugs are either bactericidal or bacteriostatic, the chief criteria of success lie in the field of bacteriology. From the outset of
Drug Treatment of Pulmonary Tuberculosis
371
effective chemotherapy there is a rapid reduction in the bacterial content of the sputum, as can be judged by repeated direct smear examinations. The vast majority of patients can be expected to be sputum negative by this method after 3 months of treatment, but if the sputum remains positive for 6 months or so, the case should be reviewed. Lesser emphasis is now attached to the value of chest x-rays in the assessment of progress. Usually one is taken at 3 or 6 monthly intervals and this is generally adequate. In the management of patients with minimal disease, who may be diagnosed on an x-ray only and have no symptoms and negative sputum, then the x-ray would assume a more important role in evaluation of progress. The interpretation of the 'activity' of tuberculosis on a single x-ray remains controversial, but the scope of this article is concerned largely with the management of the sputum-positive cases of undoubted activity.
6. The Duration of Chemotherapy
In the early days of tuberculosis chemotherapy, it was customary to treat patients for only 6 months or so, but it was soon discovered that with the drugs and dosages used this was not adequate. Usually only two drugs were used. The result of this dissatisfaction was the prolongation of the average period of treatment to 2 years. It was later still that the use of 3 drugs in the initial phase was shown to be effective in reducing the chances of failure, and the chief factor in failure was, and still is, the emergence of strains resistant to the drugs. In view of the very powerful drug regimens that are available today it is possible to foresee the total period of chemotherapy being much shortened. Studies along these lines are now underway. By using potent drugs from the start, i.e. isoniazid/rifampicin/streptomycin or isoniazid/rifampicin/ethambutol it is hoped that perhaps the disease could be cured in 6 to 9 months. Until more definite evidence of this is available, it is advisable to persevere with the more orthodox methods and regimens.
References Doster, B.; Murray, Fd.; Newman, R. and Woolpert, S.: Ethambutol in the initial treatment of pulmonary tuberculosis. U.S. Public Health Service Tuberculosis Therapy Trials. American Review of Respiratory Diseases 107: 177 (1973).
Fox, W: Selected papers, XXIst International Tuberculosis Conference, Moscow, July 12-16, 1971. Bulletin of the International Union Against Tuberculosis 47: 49 (1972). Hong Kong Tuberculosis Treatment Service/British
Drug Treatment of Pulmonary Tuberculosis Medical Research Council Investigation: A study in Hong Kong to evaluate the role of pretreatment susceptibility tests in the selection of regimens of chemotherapy for pulmonary tuberculosis. American Review of Respiratory Diseases 106: I (1972). Hong Kong Anti-Tuberculosis Association and Government Tuberculosis Service/British Medical Research Council Investigation: A controlled comparison of thiacetazone plus isoniazid with PAS plus isoniazid
372
in Hong Kong. Tubercule 49: 243 (1968). Horsfall. PA.L.: Chemotherapy in pulmonary tuberculosis. Asian Journal of Medicine 8: 316 (1972). International Union Against Tuberculosis: An international investigation of the efficacy of chemotherapy in previously untreated patients with pulmonary tuberculosis. Bulletin of the Union Against Tuberculosis 34: 79 (1966). World Health Organisation: Tuberculosis Control in the Western Pacific Region (WHO,Geneva 1972).
Author's address: Sister Mary Aquinas, Ruttonjee Sanatorium, 266 Queens Road E (Hong Kong).
Drug Treatment of Pulmonary Tuberculosis Sister Mary Aquinas Medical Superintendent, Ruttonjee Sanatorium, Hong Kong
1. Introduction
When a patient is discovered to have active pulmonary tuberculosis, it is assumed that an antituberculosis drug regimen will forthwith be prescribed that will hopefully kill the bacilli and cure the patient. However, despite the fact that, in theory, drugs are capable of curing almost 100 % of cases, it is found in practice, that for a variety of reasons, the results often fall short of this ideal. This article highlights the points of importance in the management of patients needing chemotherapy for tuberculosis.
2. The Availability ofDrugs
There are now about 12 drugs on the market with proven antituberculosis activity, but for economic reasons, all are not available to everybody treating patients. According to a WHO report dealing with countries of the Western Pacific Region (WHO, 1972), the proportion of the national health budget allocated to tuberculosis control varies from 1 to 15 %. There is, therefore, a great difference in the specific facilities available to an organisation or to a clinician treating tuberculosis in these areas. Generally, it is the country with the greatest tuberculosis problem that has the least money designated for the control of the disease. There is moreover, a wide difference in the cost of these drugs, making the use of them, at least on a large scale, quite prohibitive even in the most affluent society. Again, not all the answers have yet been worked out concerning the precise methods of application of some of the more recent drugs, or indeed of all the older ones. However, enough working formulae are available to render almost all patients non-infectious, provided the rules of chemotherapy are followed.
Drug Treatment of Pulmonary Tuberculosis
365
3. The A vailability ofPersonnel
In spite of the rapid scientific advances made in our own time in the chemotherapy of tuberculosis, it is a fact that only a small proportion of the world's estimated 20 million infectious cases is really in a position to benefit from them. It is also unfortunate that we are now witnessing a negligible interest among the younger members of the medical profession in this challenging situation. It would seem that the title 'specialist' in tuberculosis will have disappeared long before the job has been completed. Luckily, this is compensated for, in part, by the fact that the management of the disease is now becoming a standard technology that can be applied readily by non specialist clinicians. Indeed, in many areas of the world the bulk of the work must necessarily be undertaken by auxiliary health personnel. This all means that a greater number of people will need to have a better working knowledge of tuberculosis and its management. It is not enough to have the correct chemotherapy unless it is inexpensive, palatable and capable of administration by relatively unskilled staff. While it is easy to become familiar with the principles of chemotherapy, it is much more painstaking on the part of clinicians, nurses, the family and the patient himself to follow the course of treatment through to the end. This frequently results in inadequate control of the disease and the breeding of strains resistant to the drugs. Thereafter, this man-made complication calls for enormous inroads on whatever budgetary reserves there may be, in an attempt to rescue the patient. It therefore behoves whoever undertakes to treat tuberculosis, not only to apply the knowledge that is readily available concerning the drugs that he is going to use, but also to consider as a major factor the acquiring and maintaining of the close co-operation of the patient. The principal cause of failure in regimens that are otherwise supposed to be 100 % effective is the failure on the part of the treatment service to obtain full co-operation of the patient (Fox, 1972).
4. TheDrugs Table I lists the commonly accepted drugs, the average dose recommended when used on a daily basis and the principal side-effects attributed to them.
4.1 Standard Drug Regimens The management of tuberculosis would be relatively simple if it could be treated with only one drug. Unfortunately, however, one of the basic require-
Drug Treatment of Pulmonary Tuberculosis
366
Table L Doses and side-effects of commonly accepted antituberculosis drugs Drug
Conventional daily dose
Chief side-effects
Streptomycin
0.75 to 1 g
Dizziness. Tinnitus and vertigo due eighth nerve damage. Fever and skin rashes
Sodium PAS
109
Nausea, vomiting, diarrhoea, abdominal discomfort. Fever, skin rashes and hepatitis
Isoniazid
300 to 400 mg
Peripheral neuropathy; mental changes, uncommon. Fever and skin rashes
Pyrazinamide
30 to 40 mg/kg
'Arthropathy', hepatic toxicity Skin rashes - uncommon
Ethionamide
0.5 to 1 g
Nausea, vomiting, abdominal discomfort, hepatitis. Skin rashes uncommon
Cycloserine
0.5 to 0.75 g
Personality changes, mental disturbances. Can be serious
Ethambutol
25 mg/kg x 2 months, then 15 mg/kg
Visual disturbances, retrobulbar neuritis. Uncommon if dosage schedule is followed
Rifampicin
450 to 600 mg
Hepatitis, purpura. Uncommon
ments for success is that a combination of drugs must be used. This is so because mutants resistant to one drug which are present at the beginning of treatment will multiply as soon as the organisms sensitive to that drug have been killed. A second drug is necessary to prevent these mutants from multiplying. There is now much evidence that in the initial stages of treatment when the bacillary population is large, three drugs are even better than two. The regimen that has stood the test of time and that is still most generally accepted is streptomycin, PAS and isoniazid. Treatment is conveniently divided into two phases, the 'intensive phase' and the 'continuation phase'.
Drug Treatment of Pulmonary Tuberculosis
367
4.1.1 The Intensive Phase The optimum duration of treatment of the initial intensive phase of three drugs is still not finalised. It has been known for a long time that when this regimen has been given daily for 6 months, and then followed by PAS and isoniazid daily for a further period of 18 months, the results were virtually 100 % (IUAT, 1966). In a recent study in Hong Kong (HKTTS/MRC, 1972), it was shown that an initial intensive phase with the same regimen gave as good results when used for 3 months as when used for 6 months. It is now standard practice to use this regimen - streptomycin/pAS/isoniazid in the dosage given in table I for 3 months in the initial intensive phase in Hong Kong.
4.1.2 Continuation Phase At the present time the average case of tuberculosis is treated for a total period of about 18 to 24 months. Even though the continuation phase is less intensive, it is nevertheless very important in order to ensure that the disease is adequately controlled. It is assumed that during the phase of intensive chemotherapy, the bacterial population will be greatly reduced and the chances of resistant mutants multiplying will be small, and therefore it will not be necessary to maintain the same intensity of treatment all through the programme. In practice, this means continuing the treatment with two drugs and the trend now is to do this with streptomycin 1 g and isoniazid 750 mg on a twice weekly basis. In our experience, the majority of patients can tolerate this regimen in the continuation phase. For the elderly or others who cannot tolerate streptomycin, PAS 10 g and isoniazid 300 g is continued on a daily basis for about 18 months.
4.2 Other Regimens Used in the Initial Treatment In spite of the reported 100 % efficacy of the standard regimen streptomycin/PAS/isoniazid when properly used, some disadvantages are associated with it. Many patients find attending a clinic for injections for a prolonged period of time to be troublesome and to interfere with their regular daily employment. PAS has never been all that popular either with doctors or patients. Substitutes for it have therefore been sought for the past 20 years. Thiacetazone, small in tablet size and very inexpensive, has been reassessed and efforts have been made to find a place for it in the chemotherapy programme. Except for a few areas, however, its use has been abandoned on grounds of toxicity. Among Chinese patients in Hong Kong, thiacetazone resulted in such a high incidence of side-effects that its use could not be recommended (HKTTS/MRC, 1968). Ethambutol has now been studied relatively extensively. It would appear to be about as effective as PAS and it is certainly a much more palatable partner to
Drug Treatment of Pulmonary Tuberculosis
368
have in a regimen (Doster, 1973). Using the recommended dosage of 25 mm/kg daily for 2 months followed by 15 mg/kg daily, the risk of developing eye toxicity is very slight. Streptomycin/isoniazid/ethambutol provides a very satisfactory regimen for individual patients who cannot take PAS, though for economic reasons it could hardly be undertaken as an overall policy measure in areas with restricted financial resources. Rifampicin, the latest arrival and the currently most controversial agent in the treatment of tuberculosis, has been shown by many laboratory experiments and clinical studies to have an efficacy comparable with that of isoniazid. In combination with isoniazid, rifampicin has given results superior to other combinations. At the present time however, cost precludes its widespread use in the treatment of the disease. Where financial considerations are not important, regimens containing rifampicin are now more frequently used in the treatment of fresh cases. Such regimens would consist of isoniazid/streptomycin/rifampicin or isoniazid/ethambutol/rifampicin. It is conceivable that rifampicin might eventually find a place, even for a short period, in the initial intensive phase of treatment in less economically privileged areas. In daily use regimens, toxicity is not a big problem, but may be serious in nature especially if purpura develops.
4.3 Reserve Regimens It should be the aim of every clinician to cure the patient with the drug regimen that he decides to use when he treats his patient in the first instance. This implies prescribing an adequate regimen and making sure that the patient takes it to the end of the course. Any drug not used in the initial treatment becomes a 'reserve' or a 'second-line' drug. Ideally, it should not be necessary to have to resort to these reserve drugs. Some patients do fail however, on the initial treatment - the sputum remains positive and the sensitivity tests show that the organisms are resistant to the drugs being used. Other regimens should then be considered. For patients who become treatment failures on the standard regimen of streptomycin/PAS/ isoniazid, an alternative regimen that has been in use for many years is pyrazinamide/ethionamide/cycloserine. This was about the best available until the advent of rifampicin and ethambutol. However, pyrazinamide/ethionamide/ cycloserine was never really considered a choice regimen and in practice about half the patients develop side-effects to one or more of the drugs. It has nevertheless resulted in a satisfactory response in about 80 % of failure cases. A more popular regimen for failure cases would now appear to be rifampicin/ethambutol/ethionamide. As in the initial treatment of tuberculosis, there would also be an 'intensive phase' in the management of failure or retreatment cases to be followed by a 'continuation phase'.
Drug Treatment of Pulmonary Tuberculosis
369
4.4 Intermittent Supervised Chemotherapy It was largely as a result of efforts to overcome the irregularities and deficiencies of self administered long-term daily chemotherapy that the concept of intermittent medication evolved. The most hidden threat to the success of any drug regimen is the difficulty of impressing on the patient the importance of taking the oral medicaments regularly for many months. This is especially so when the patient has no symptoms - he feels well and so he easily forgets, or is just too lazy, to take his drugs. The clinician all too often hears this tale in the course of his management of the patient. With intermittent treatment the patient attends the clinic or office 2 or 3 times a week. His injection is given and he can be seen to swallow the tablets. If he fails to attend, it is known immediately that he has missed his scheduled treatment and appropriate action can be taken. The efficacy of this method is now well established by controlled clinical trials. When streptomycin/PASt isoniazid are given daily for 3 months and followed by streptomycin/isoniazid twice weekly the results are virtually 100 %. On intermittent therapy, the dosage of the drugs must be increased from that used in a daily regimen and both drugs must be given on an intermittent basis. Intermittent treatment was used in the 1950's but the results were poor, largely because the dosage was inadequate. Not all antituberculosis drugs are suitable to have the dosage increased because of toxicity or intolerance. Streptomycin dosage can be increased only slightly, but isoniazid can be tolerated in a relatively high dose. Rifampicin and ethambutol are also being used on an intermittent basis and studies are currently exploring the most effective dosages and sequences of administration.
4.5 Side-Effects One of the most disappointing events in the management of a case which otherwise seems to be quite straightforward is the occurrence of side-effects, due to one or more of the drugs. These reactions may be very minimal and require little or no interruption of treatment, or they may be severe enough to warrant complete withdrawal of the offending chemotherapeutic agent such as some change in personality or temperament in a patient receiving cycloserine. In the case of hypersensitivity reactions, however, the general idea is to try to identify the drug responsible for the side-effect by testing each drug separately, usually in a small dose. Once this information was obtained the patient should be desensitised to that drug by gradually increasing the dose until the full dose is reached. The total time involved in this procedure is important, as if it takes several weeks it may result in the emergence of drug resistant
Drug Treatment of Pulmonary Tuberculosis
370
Table II. A summary of the principles of drug treatment of active pulmonary tuberculosis 1)
Active pulmonary tuberculosis can now be treated effectively by any medical practitioner
2)
Success depends on: a) Providing a drug regimen that is adequate for the disease and acceptable to the patient b) Gaining the long-term co-operation of the patient - which means communicating with him so that he understands enough about the programme to ensure that he takes his medication as prescribed
3)
The approach to treatment: a) A combination of drugs must be used b) Intensive phase for 3 months followed by the very important continuation phase for 15-18 months c) Aim of initial treatment is to cure patient with originally selected drug regimen d) Reserve drug regimens used in cases of initial treatment failure or retreatment cases
4)
Assessment of treatment progress a) Examination of bacterial content of sputum b) X-ray at 3- or 6-monthly intervals generally adequate
strains, and so to inadequate control of the disease. For example, if a patient with acute and extensive tuberculosis develops a severe hypersensitivity reaction while he is receiving streptomycin/PAS/isoniazid it would be advisable not only to abandon the regimen forthwith, but also when the reaction subsides to consider an alternative regimen. Such a regimen would depend on available resources but should be calculated to be reasonably safe - for example, ethambutol/ethionamide/pyrazinamide or ethambutol/ethionamide/rifampicin. As streptomycin and PAS are usually the main offenders in hypersensitivity reactions, it is to be hoped that efforts would be made to reintroduce isoniazid to the new regimen and perhaps to eliminate one of the others. When the new regimen is underway it might be possible to proceed with the desensitising to streptomycin or PAS if this were deemed advisable.
5. Assessment of Treatment Progress
As all antituberculosis drugs are either bactericidal or bacteriostatic, the chief criteria of success lie in the field of bacteriology. From the outset of
Drug Treatment of Pulmonary Tuberculosis
371
effective chemotherapy there is a rapid reduction in the bacterial content of the sputum, as can be judged by repeated direct smear examinations. The vast majority of patients can be expected to be sputum negative by this method after 3 months of treatment, but if the sputum remains positive for 6 months or so, the case should be reviewed. Lesser emphasis is now attached to the value of chest x-rays in the assessment of progress. Usually one is taken at 3 or 6 monthly intervals and this is generally adequate. In the management of patients with minimal disease, who may be diagnosed on an x-ray only and have no symptoms and negative sputum, then the x-ray would assume a more important role in evaluation of progress. The interpretation of the 'activity' of tuberculosis on a single x-ray remains controversial, but the scope of this article is concerned largely with the management of the sputum-positive cases of undoubted activity.
6. The Duration of Chemotherapy
In the early days of tuberculosis chemotherapy, it was customary to treat patients for only 6 months or so, but it was soon discovered that with the drugs and dosages used this was not adequate. Usually only two drugs were used. The result of this dissatisfaction was the prolongation of the average period of treatment to 2 years. It was later still that the use of 3 drugs in the initial phase was shown to be effective in reducing the chances of failure, and the chief factor in failure was, and still is, the emergence of strains resistant to the drugs. In view of the very powerful drug regimens that are available today it is possible to foresee the total period of chemotherapy being much shortened. Studies along these lines are now underway. By using potent drugs from the start, i.e. isoniazid/rifampicin/streptomycin or isoniazid/rifampicin/ethambutol it is hoped that perhaps the disease could be cured in 6 to 9 months. Until more definite evidence of this is available, it is advisable to persevere with the more orthodox methods and regimens.
References Doster, B.; Murray, Fd.; Newman, R. and Woolpert, S.: Ethambutol in the initial treatment of pulmonary tuberculosis. U.S. Public Health Service Tuberculosis Therapy Trials. American Review of Respiratory Diseases 107: 177 (1973).
Fox, W: Selected papers, XXIst International Tuberculosis Conference, Moscow, July 12-16, 1971. Bulletin of the International Union Against Tuberculosis 47: 49 (1972). Hong Kong Tuberculosis Treatment Service/British
Drug Treatment of Pulmonary Tuberculosis Medical Research Council Investigation: A study in Hong Kong to evaluate the role of pretreatment susceptibility tests in the selection of regimens of chemotherapy for pulmonary tuberculosis. American Review of Respiratory Diseases 106: I (1972). Hong Kong Anti-Tuberculosis Association and Government Tuberculosis Service/British Medical Research Council Investigation: A controlled comparison of thiacetazone plus isoniazid with PAS plus isoniazid
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Author's address: Sister Mary Aquinas, Ruttonjee Sanatorium, 266 Queens Road E (Hong Kong).
