Thorax 1990;45:403-408 403 Guidelines Thorax: first published as 10.1136/thx.45.5.403 on 1 May 1990. Downloaded from Chemotherapy and management of in the United Kingdom: recommendations of the Joint Tuberculosis Committee of the British Thoracic Society

L P Ormerod for a subcommittee of the Joint Tuberculosis Committee

The number of notified cases of tuberculosis , and for in Britain has fallen over the last 10 years but the initial two months, followed by the disease still causes appreciable morbidity and isoniazid for a further four months, is and mortality.' 2 There have been major chan- recommended standard treatment for adult ges in the staffing of thoracic medicine over pulmonary tuberculosis irrespective of the the same period since the retirement of many bacteriological state of the sputum. There is physicians with long experience of tuber- evidence that the fourth drug (ethambutol) culosis. The treatment of tuberculosis can be omitted in patients with a low risk of depends not only on the correct prescription resistance to isoniazid.9 '° This applies to of effective chemotherapy regimens but also previously untreated patients in Britain. on the patient's compliance with treatment. Several studies have shown that when treat- NON-PULMONARY TUBERCULOSIS ment is not supervised by thoracic physicians Although there have been relatively few con- prescription errors and excessive or trolled clinical trials in non-pulmonary tuber- inadequate treatment occur in an appreciable culosis, the evidence suggests that it can be proportion of patients.5 The patient's com- treated with the same regimens as pulmonary

pliance is a major determinant of the success disease." The duration of chemotherapy for http://thorax.bmj.com/ of drug treatment, and is more likely to be some forms of extrapulmonary tuberculosis achieved if the most effective and shortest (described below*), may need to be longer regimens are prescribed correctly, with treat- than six months. ment monitored, and adjusted if necessary, by an experienced physician. Recent studies have Meningitis* shown problems of compliance and default Isoniazid and pyrazinamide penetrate into the (10O,,) and drug toxicity (10°O) in adult cerebrospinal fluid well'2; rifampicin pen-

patients in England and Wales.6 etrates less well. and etham- on September 29, 2021 by guest. Protected copyright. In view of the development of effective butol do so only in adequate concentrations short course regimens and major changes in when the meninges are inflamed at an early the staffing of the services that provide tuber- stage of treatment. Intrathecal administration culosis treatment, the Joint Tuberculosis of any drug is unnecessary. Experience in Committee of the British Thoracic Society centres treating large numbers of cases sug- believes that it is now opportune to issue gests that rifampicin and isoniazid for 12 guidelines for the management of tuberculosis months supplemented by pyrazinamide for at in the United Kingdom. Guidelines have been least the first two months will give good published recently by the American Thoracic results." Corticosteroids are recommended in Society7 and by the International Union more severe disease (stage II or III"). against Tuberculosis and Lung Diseases.8 The committee considers that treatment of all Lymph nodes* cases of adult pulmonary tuberculosis should The British Thoracic Society trial showed Compiled by a be supervised by physicians in thoracic that a nine month course of rifampicin and subcommittee of the that the treatment of all Joint Tuberculosis medicine, and drug isoniazid is as effective as an 18 month course Committee forms of adult non-pulmonary tuberculosis if combined with ethambutol for the first two comprising should at the very least be supervised in months.'3 If pyrazinamide is given for the first K M Citron conjunction with a thoracic physician. The be J H Darbyshire two months instead of ethambutol, it may L P Ormerod treatment of children should be shared by a possible to reduce the total duration of treat- (coordinator) and paediatrician and a thoracic physician. ment to six months. This is currently under M L Smith (for the British Thoracic British Paediatric investigation in a further Association) Society trial. The course of lymph node dis- Recommended regimens for adults Address for reprint requests: ease is variable; abscesses may form, nodes Dr L P Ornerod, Blackburn PULMONARY TUBERCULOSIS may enlarge, or new nodes may develop dur- Royal Infirmary, Blackburn A six month BB2 3LR. regimen, comprising rifampicin, ing or after treatment, without any evidence of 404 Ormerod

Table 1 Recommended treatment active constrictive pericarditis," and the same has been shown for pericardial effusion."6 Initial phase Continuation phase Other sites, including genitourinary tract Drugs Months Drugs Months Total months The six month regimen for pulmonary disease ADULTS is recommended. If pyrazinamide is omitted Thorax: first published as 10.1136/thx.45.5.403 on 1 May 1990. Downloaded from Pulmonary RHZE 2 RH 4 6 Non-pulmonary or cannot be tolerated treatment should be Meningitis RHZ 2 R H 10 12 extended to a total of nine months. Pericarditis RHZE 2 RH 4 6 As with the committee Lymph node RHZ 2 R H 4 6 pulmonary disease, Bone, joint j strongly recommends that drug treatment Other sites RHZE 2 RH 4 6 or should be determined by a thoracic physician RHE 2 RH 7 9 and preferably also supervised by that CHILDREN physician and supporting services. Pulmonary RHZ 2 R H 4 6 or The recommended drug regimens are sum- RH 2 RH 7 9 marised in table 1. Non-pulmonary (as above) Chemoprophylaxis H 6 6 RH 3 3 Chemotherapy for children It is important that wherever possible a R-rifampicin; H-isoniazid; E-ethambutol; Z-pyrazinamide. paediatrician and thoracic physician should be concerned in the treatment of children. Al- bacteriological reactivation of disease. They though there is very little research on do not therefore in isolation imply failure of chemotherapy in children the same basic prin- treatment. ciples of chemotherapy are considered to apply. Higher dosages (in relation to body weight) of certain drugs have been recommen- Bone andjoints* ded, but there is now evidence that 10 mg/kg The spine is the most common bony site of of both rifampicin and isoniazid are sufficient tuberculosis. Multicentre trials have shown (table 2). Pyrazinamide is used throughout the that ambulatory chemotherapy is highly world in children, and is recommended for effective in disease of the thoracic and lumbar use by the American Thoracic Society7 and spine. Recent studies have confirmed that the International Union against Tuberculosis nine months' treatment with rifampicin and and Lung Diseases.8 Because of the difficul- isoniazid with or without initial streptomycin ties of testing eyesight and of obtaining gives good results." '4 Although these studies reports of visual symptoms in young children, did not include pyrazinamide, the nine month ethambutol should be used only in exceptional regimen with two months' pyrazinamide is circumstances-for example, in the presence likely to give equally good results for tuber- of drug resistance or drug toxicity. Dosages http://thorax.bmj.com/ culosis of bones and joints, and six months' should be rounded up or down to facilitate the treatment might be just as effective. Surgery prescription of easily given volumes of syrup may be required in a few patients with or appropriate strengths of tablet; the dosage evidence of spinal cord compression. may need to be revised with weight gain. For pulmonary disease the six month Pericarditis regimen of rifampicin and isoniazid, sup- A six month regimen of rifampicin and iso- plemented by pyrazinamide for the first two

niazid, supplemented with streptomycin and months, is recommended. No routine on September 29, 2021 by guest. Protected copyright. pyrazinamide for three months, has been pyridoxine supplement is needed if isoniazid shown to be highly effective,'5 and the six is given in standard dosage (table 2). If month regimen recommended for pulmonary pyrazinamide is not given the duration of disease is likely to be equally effective. The treatment should be extended to nine months. same trial also showed clear additional benefit Non-pulmonary disease should be treated by from high dose corticosteroid treatment in the same regimens as in adults (see above).

Table 2 Recommended dosage

Daily dosage Intermittent dosage Adults Adults Children Children Drug (mglkg) Weight Dose (mg/kg) Weight Dose Isoniazid 10 - 300 mg 15 - 15 mg/kg 3 times weekly 3 times weekly Rifampicin 10 <50 kg 450 mg 15 - 600-900 mg > 50 kg 600 mg 3 times weekly Pyrazinamide 35 <50kg 1-5 g 50 <50kg 2-0g > 50 kg 2-0 g 3 times weekly > 50 kg 2-5 g 75 <50kg 30g 2 times weekly > 50 kg 3-5 g Streptomycin* 15-20 < 50 kg 750 mg 15-20 < 50 kg 750 mg >50kg I g 3timesweekly >50kg I g Ethambutol* 25 for 2 months 25 mg/kg for 2 months 30 30 mg/kg then 15 then 15 mg/kg 3 times weekly 3 times weekly or or 15 15 mg/kg 45 45 mg/kg throughout throughout 2 times weekly 2 times weekly *Accurate calculation is required to avoid toxicity-see under "Special precautions." Chemotherapy and management of tuberculosis in the United Kingdom 405

CHEMOPROPHYLAXIS be given in standard dosage in renal failure. If Children (under 16) streptomycin or ethambutol is used, reduced Children who are found to have a strongly dosage is required and serum concentrations positive skin test response but no should be monitored. Dialysis in patients with clinical evidence of disease may need prophy- chronic renal failure has a considerable effect lactic treatment. Chemoprophylaxis is recom- on the clearance of drugs, and requires Thorax: first published as 10.1136/thx.45.5.403 on 1 May 1990. Downloaded from mended if the Heaf test response is positive modification of dosages.22 The dose of any (grades 2-4) in a person without previous BCG corticosteroids should be doubled if rifampicin vaccination, and should be considered if the is used.23 response test is strongly positive (grade 3-4) in someone who has had BCG."7 Many studies AIDS have shown that 12 months' chemoprophylaxis No clinical trial data are available, but it is with isoniazid is effective.'8 Isoniazid pro- recommended that standard treatment with phylaxis for six months is probably as effec- four drugs (isoniazid, rifampicin, pyra- tive.'9 Regimens of rifampicin and isoniazid zinamide, and ethambutol) should be given lasting only three months have been used initially; this may need to continue for longer extensively in clinical practice in some areas of than standard treatment.24 It is also suggested the United Kingdom with good effect and no that isoniazid alone should be continued after increased adverse reactions.20 treatment has been completed. Consideration Treatment with either isoniazid alone for six should be given to isoniazid prophylaxis in months or rifampicin and isoniazid for three HIV positive individuals with a positive months are recommended. tuberculin test response. Non-tuberculous mycobacteria are a common problem in Adults patients with AIDS. If chemoprophylaxis is considered appropriate for adults,'7 the same regimens should be used. Corticosteroids Corticosteroids may be indicated, in addition Neonates to effective antituberculosis treatment, in Newborn babies ofmothers with sputum smear patients with extensive pulmonary disease, positive pulmonary tuberculosis should be tuberculosis affecting the ureter,25 pleural given chemoprophylaxis for three months, fol- effusion,26 pericarditis,'5 and stage II and III lowed by BCG vaccination after the comple- meningitis," and to suppress hypersensitivity tion of chemoprophylaxis, provided that the reactions. mother is no longer infectious. Non-compliant patients Special groups Vagrants, alcoholics, and patients who are Diabetes mentally ill are unlikely to comply with self http://thorax.bmj.com/ Diabetic patients have an increased incidence medication. These, and others found to be non- of tuberculosis, and pulmonary disease is compliant, are best given fully supervised usually more extensive. Standard treatment chemotherapy regimens. Isoniazid, rifampicin, should be given. Rifampicin interacts with and pyrazinamide with streptomycin or etham- some oral hypoglycaemic drugs. butol three times weekly for two months, followed by rifampicin and isoniazid three Liver disease times weekly for four months, are recommen-

Although rifampicin, isoniazid, and pyrazin- ded (for dosages see table 2). on September 29, 2021 by guest. Protected copyright. amide are all potentially hepatotoxic, the addi- tion of pyrazinamide to regimens containing Unconscious patients the other two drugs does not increased mor- Standard treatment should be given to uncons- bidity.2" In patients with pre-existing liver cious patients, but ethambutol should be omit- disease standard treatment should be given, ted as visual acuity cannot be tested. Isoniazid but monitoring of liver function in such and rifampicin can be given as syrup, and patients is advised. crushed pyrazinamide tablets by nasogastric tube (for dosages see table 2). Alternatively, Pregnancy rifampicin (Rifadin infusion) and isoniazid Standard treatment should be given to preg- (Rimifon) can be administered by once daily nant women. Streptomycin and other amino- intravenous infusion. Isoniazid can also be glycosides should be avoided in pregnancy as given by intramuscular injection. Strep- they are ototoxic to the fetus. None of the first tomycin is given intramuscularly. line drugs has been shown to be teratogenic in man, but ethionamide and prothionamide may be. Patients should be told of the reduced Drugs effectiveness of the combined oral contracep- Controlled trials of antituberculosis chemo- tive in regimens containing rifampicin. Should therapy have established a number of highly pregnancy occur in patients taking rifampicin, effective short course regimens in widely however, it is not an indication for termination. varying populations of patients and health Patients can breast feed normally while taking services.27 As a result of trials and parallel in antituberculous drugs. vivo and in vitro laboratory studies the basic mechanisms of action of the major antituber- Renal disease culosis drugs are better understood.2729 Iso- Rifampicin, isoniazid, and pyrazinamide can niazid is the most effective bactericidal drug, 406 Ormerod

but rifampicin is also important. Rifampicin potentiated (phenytoin, ethosuximide, and pyrazinamide are the most important carbamazepine). sterilising drugs and are thought- to act by killing different populations of semidormant Rifampicin organisms (persisters). Isoniazid and rifam- Hepatitis2 picin are the most effective drugs at preventing Rash Thorax: first published as 10.1136/thx.45.5.403 on 1 May 1990. Downloaded from the emergence of resistance to other drugs.27 3 Gastrointestinal upset. Streptomycin and ethambutol have been included in the initial phase of many short With intermittent or irregular treatment a course regimens but are considered to be of "flu like" syndrome with abdominal and lesser importance in patients with fully sen- respiratory symptoms may occur; these sitive organisms. resolve if treatment is given daily. Shock, The efficacy of short course chemotherapy acute renal failure, and thrombocytopenic with a nine month regimen of rifampicin and purpura may occur, usually with intermit- isoniazid supplemented by two months' initial tent treatment; ifso withdraw the drug and streptomycin or ethambutol for pulmonary do not reintroduce. disease in the United Kingdom was shown by Interactions: Induction of microsomal hepatic studies carried out by the British Thoracic and enzymes-reduced serum half life and there- Tuberculosis Association.3 32 Several studies fore efficacy of warfarin, phenytoin, sulpho- have shown that six month regimens were also nylureas, oestrogen oral contraceptives, corti- highly effective provided that pyrazinamide costeroids. Corticosteroid dose should be was added in the initial two month;s of treat- doubled.23 ment.2"335 The need for the fourth drug (streptomycin or ethambutol) in the initial Ethambutol phase of chemotherapy for fully sensitive Dose related optic neuropathy; rare at organisms has been questioned. Trials in 15 mg/kg. Singapore9 and Poland'" have shown no loss of Patients should be warned to stop the drug efficacy if streptomycin is omitted. The same is immediately if any visual symptoms occur probably true of ethambutol, which is a less and report to the physician. Avoid the drug potent antituberculosis drug. In Britain daily whenever possible in patients with re- unsupervised drug treatment is used almost duced renal function and young children, invariably.2' 3' In other parts of the world and in anyone with pre-existing visual regimens that are either partially or wholly impairment. intermittent have been shown to be highly effective. Thus the alternatives of daily treat- Streptomycin ment throughout the six months, daily treat- Giddiness

ment for two months followed by treatment Rash (hypersensitivity) http://thorax.bmj.com/ two or three times weekly for four months,8 9 or Avoid in babies, the elderly, and patients treatment two or three times weekly for six with reduced renal function or pregnancy. months36 have all been shown to be highly effective. The dosages of antituberculosis Pyrazinamide drugs for daily and intermittent use are set out Initial facial flushing in table 2. All drugs should be given in a single Rash daily dose. It should be noted that for some of Nausea

the drugs used in intermittent treatment the Anorexia on September 29, 2021 by guest. Protected copyright. dosages are higher than those for daily use Vomiting (table 2). Arthralgia Raised serum uric acid (may be overcome by intermittent dosage) Adverse reactions Hepatitis.2' All the antituberculosis drugs may occasionally cause adverse reactions. Surveys of the results of antituberculosis treatment given in Special precautions and pretreatment Britain637 have shown that treatment required screening modification for drug toxicity in an appreciable Renal function should be checked before treat- proportion of patients. The most important ment with steptomytin or ethambutol. If pos- adverse reactions and interactions are set out sible the drugs should be avoided in renal below (for full details of all possible adverse failure, but if they are used serum concentra- reactions the appropriate data sheet should be tions should be monitored and substantially consulted). ,reduced dosages given. Because of the possible (but rare) toxic effects of ethambutol on the Isoniazid eye, it is recommended that visual acuity Cutaneous hypersensitivity should be tested by Snellen chart before it is Peripheral neuropathy (preventable by used.38 The drug should be used only in pyridoxine 10 mg; this is advised for those patients who have reasonable visual acuity and at risk of neuropathy-for example, who are able to appreciate and report visual diabetic and alcoholic patients and those symptoms. The notes should record that the with chronic renal failure or malnutrition) patient has been told to report visual symp- Hepatitis-less common.2' toms, and the general practitioner should be Interactions: Anticonvulsant effects may be informed of this. In small children and in those Chemotherapy and management of tuberculosis in the United Kingdom 4i07

with language difficulties ethambutol should non-infectious within two weeks of treatment be avoided where possible. that contains rifampicin and isoniazid.29 Follow Liver function should be checked before up should be at least monthly initially and then treatment. Transient increases in hepatic two monthly, the early follow up being im- transaminases are common after the start of portant to reinforce education of the patient. treatment, and require no action unless the Sputum examination for pulmonary disease Thorax: first published as 10.1136/thx.45.5.403 on 1 May 1990. Downloaded from patient has symptoms of hepatitis or jaundice. should be repeated two months before treat- After the initial measurement liver function ment is due to be stopped if the patient's does not need to be monitored routinely except clinical progress is unsatisfactory or where in alcoholics and those with other liver diseases. compliance is in doubt. A chest radiograph If jaundice or other symptoms of hepatitis should be taken at the end of treatment. Clinic develop, all drugs must be stopped. It is usually nurses or tuberculosis health visitors are possible to restart all drugs after liver function extremely important for monitoring patients' has returned to pretreatment levels. If symp- compliance and the accuracy and continuity of toms recur, however, the drugs should be prescribing, tablet checks and urine tests for introduced individually, once liver function rifampicin being carried out during chemo- has returned to normal, at a lower dose initially therapy. Monitoring ofnon-pulmonary disease together with at least one drug that is unlikely is largely based on clinical assessment and to cause hepatic dysfunction (streptomycin or radiography where appropriate. ethambutol).39 Failure during chemotherapy or a relapse after treatment in patients prescribed effective Combined drug preparations regimens is almost invariably due to poor Some combined preparations are available. compliance (see below). Mynah (Lederle) contains a combination of ethambutol and isoniazid in various dosages; 3 Drug resistance Rifinah (Merrell) and Rimactizid (CIBA) com- Treatment of patients with drug resistant bine isoniazid and rifampicin; and the newer tuberculosis should be carried out only by a Rifater (Merrell) combines isoniazid, rifam- thoracic physician experienced in the man- picin, and pyrazinamide. Combined prepara- agement of such cases. Initial drug resistance tions have the major advantages of aiding is now rare in white patients.4243 It occurs in compliance and preventing monotherapy. 8-130, of Indian, Pakistani, and Bangladeshi Those containing rifampicin provide a useful patients, however, 1100 having organisms re- means of checking compliance as the urine can sistant to stretomycin; but this is not clinically be assessed visually or checked in the labora- important in the UK because streptomycin is tory for the orange/pink discoloration. The now rarely used.37 Six per cent ofpatients from bioavailability of drugs from such combination the Indian subcontinent, however, have resis- tablets is similar to that from the same doses of tance to isoniazid, which is highly relevant as it http://thorax.bmj.com/ drugs given individually,40 and clinical results may require a change in treatment. It is par- are satisfactory.4' The dosages of isoniazid, ticularly important to include ethambutol rifampicin, and pyrazinamide in some studies under these circumstances. of combined preparations" 41 have varied If isoniazid resistance is known before treat- slightly from the dosages in the currently ment is started, a regimen of streptomycin, available Rifater (Merrell) in the UK (50 mg pyrazinamide, rifampicin, and ethambutol for isoniazid, 120 mg rifampicin, and 300 mg two months followed by rifampicin and etham- pyrazinamide per tablet). These minor vari- butol for seven months has been shown to give on September 29, 2021 by guest. Protected copyright. ations are unlikely to be clinically important in good results when fully supervised." Ifdefinite combined preparations with proved bioavail- pretreatment resistance to isoniazid is reported ability. Care must be taken with the writing and after the start of chemotherapy isoniazid may dispensing of prescriptions because of the be stopped, but ethambutol (15 mg/kg) should similarity in the names rifampicin, Rifinah, be given with rifampicin for a minimum of 12 Rimactizid, and Rifater. Similar care must be months, together with two months' initial taken with the calculation ofthe dose ofetham- pyrazinamide, although there is evidence that butol if Mynah is prescribed because of the the regimen may be effective without this.45 range of doses. In cases of multiple drug resistance affecting both rifampicin and isoniazid, treatment should be started with at least three drugs to Clinical management which the organism is sensitive and continued The minimum requirements are: until sputum cultures become negative, after 1 Notification which two drugs should be continued for at Notification of the index case should be made least nine months more. Treatment in such so that appropriate contact tracing can be patients has to be planned on an individual arranged."' basis,30 and may need to include reserve drugs (table 3). Such treatment must be closely 2 Treatment monitored, as full compliance is essential to Most patients do not require admission to prevent the emergence of further drug resis- hospital, and can be treated and supervised as tance. outpatients. If the patient is admitted to hospi- tal and is smear positive for acid fast bacilli, 4 After treatment segregation for reasons of infectivity is re- Relapse is uncommon in the United Kingdom quired for only two weeks; patients become with the recommended regimen (0-3% of 408 Ormerod

Table 3 Reserve drugs: dosages and side effects chemotherapy in patients undergoing radical surgery for tuberculosis of the spine in Hong Kong. Tubercle 1986;67:243-59. Daily dosage 15 Strang JIG, Kakaka HHS, Gibson DG, Girling DJ, Nunn AJ, Fox W. Controlled trial of prednisolone as adjuvant in Adults treatment of tuberculous constrictive pericarditis in Children Transkei. Lancet 1987;ii:1418-22. Druig (mg/kg'v Weight Dose Main side effects 16 Strang JIG, Kakaza HH, Gibson DG, et al. Controlled clinical trial of complete open surgical drainage and of Thorax: first published as 10.1136/thx.45.5.403 on 1 May 1990. Downloaded from T hiacetazone 4 150 mg Gastrointestinal, rash, prednisolone in treatment of tuberculous pericardial vertigo, conjunctivitis effusion in Transkei. Lancet 1988;ii:759-63. Ethionamide* and 15-20 < 50 kg 750 mg Hepatitis, 17 Joint Tuberculosis Committee of the British Thoracic prothionamide 50 kg 10 g gastrointestinal Society. Control and prevention of tuberculosis: an PAS (sodium)* 300 10-15 g Gastrointestinal, updated code ofpractice. 1990. Br Med J 1990;300:995-8. rash, hepatitis 18 Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. A general review. Adv Tuberc Res 1970;17: Divided doses 28-104. Kanamycint 10-15 500 mg-1 g See streptomycin 19 Thomson NJ. Efficacy of various durations of isoniazid 't 15 - 1 g See streptomycin preventive therapy in tuberculosis: 5 years of follow-up in Cvcloserine'± 15 < 50 kg 750 mg Depression, fits the IUAT trial. Bull WHO 1982;60:555-64. >50kg I g 20 McNicol MW, Thompson H, Riordan JF, Forde E, Allen CJ. Antituberculous chemotherapy with isoniazid-rifam- *Not currently available in the UK. picin [abstract]. Thorax 1984;39:223-4. -;Adults only. 21 British Thoracic Association. A controlled trial of 6-months PAS-para-aminosalicylic acid. chemotherapy in pulmonary tuberculosis. First report: results during chemotherapy. Br J Dis Chest 1981;75: cases) if there is good compliance with treat- 141-53. ment.35 If compliance has been good and there 22 Anonymous. Tuberculosis in patients having dialysis [editorial]. Br Med J 1980;i:349. are no residual clinical problems no follow up is 23 Edwards OM, Courtney-Evans RJ, Galley JM, Hunter J, required, but the patient should be advised to Tait AD. Changes in cortisol metabolism following rifampicin therapy. Lancet 1974;ii:549-51. return if symptoms recur. Relapse after recom- 24 Goldman KP. AIDS and tuberculosis. Br Med J 1987; mended chemotherapy when compliance is 295:511-2. 25 Horne NW, Tulloch WS. Conservative management of good is almost always with fully sensitive renal tuberculosis. Br J Urol 1975;47:481-7. organisms and can be treated with the same 26 Horne NW. A critical evaluation of corticosteroids in tuberculosis. Adv Tuberc Res 1966;15:1-54. regimen. If poor compliance is thought to be a 27 Girling DJ. The chemotherapy of tuberculosis. In: Ratledge factor in relapse, a fully supervised regimen C, Stanford J, Grange JM, eds. Biology of mycobacteria- clinical aspects of mycobacteria. Vol 3. London: Academic should be considered. The development of Press, 1989:285-323. acquired drug resistance should be treated as in 28 Mitchison DA. Treatment of tuberculosis. J R Coll Physicians 1980;14:91-9. (3) above. 29 Jindani A, Aber VR, Edwards EA, Mitchison DA. The early The organisational framework for the moni- bactericidal activity of drugs in patients with pulmonary tuberculosis. Am Rev Respir Dis 1980;121:139-48. toring of tuberculosis treatment already exists 30 Anonymous. Chemotherapy of pulmonary tuberculosis in in local thoracic medical clinics with trained Britain. Drug Ther Bull 1988;26:1-4. 31 British Thoracic and Tuberculosis Association. Short- doctors and nurses. Treatment is therefore course chemotherapy in pulmonary tuberculosis. 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Oxford textbook of 8 Committee on Treatment of the International Union against medicine. 2nd ed. Oxford: Oxford Medical Publications, Tuberculosis and Lung Disease. Antituberculosis 1987:295 (section 5). regimens of chemotherapy. Bull IUAT Lung Dis 1988; 40 Ellard GA, Ellard DR, Allen BW, etal. The bioavailability 63(No 2):60-4. of isoniazid, rifampin and pyrazinamide in two commer- 9 Singapore Tuberculosis Service and British Medical cially available combined formulations designed for use in Research Council. Clinical trial of three 6-month the short-course therapy in tuberculosis. Am Rev Respir regimens of chemotherapy given intermittently in the Dis 1986;133:1076-80. continuation phase in the treatment of pulmonary tuber- 41 Geiter LJ, O'Brien RJ, Combs DL, Snider DE. United culosis. Am Rev Respir Dis 1985;132:374-8. States Public Health Service tuberculosis therapy trial 21. 10 Snider DE, Graczyk DE, Bek E, Rogowski J. Supervised Preliminary results of an evaluation of a combination six-months treatment of newly diagnosed pulmonary tablet of isoniazid, rifampin and pyrazinamide. Tubercle tuberculosis using isoniazid, rifampin and pyrazinamide 1 987;68:41-6. with and without Streptomycin. Am Rev Respir Dis 42 Medical Research Council Tuberculosis and Chest Diseases 1984;130:1091-4. Unit. A national survey of tuberculosis notifications in 11 Girling DJ, Darbyshire JH, Humphries MJ, Sister Gabriel England and Wales 1978-9. Br MedIJ1980,281:895-8. O'Mahoney. Extra-pulmonary tuberculosis. Br Med Bull 43 Medical Research Council Tuberculosis and Chest Diseases 1988;44:738-56. Unit. National survey of notifications of tuberculosis in 12 Ellard GA, Humphries MJ, Gabriel M, Tech R. Penetration England and Wales 1983. Br Med J1985;291:658-61. of pyrazinamide into the CSF in . 44 Babu Swai 0, Alnoch JA, Githui WA, et al. Controlled Br Med J 1987;294:284-5. clinical trial ofa regimen of2 durations for the treatment of 13 British Thoracic Society Research Committee. Short course isoniazid resistant tuberculosis. Tubercle 1988;69:5-14. chemotherapy for tuberculosis of lymph nodes; a con- 45 Mitchison DA, Nunn AJ. Influence of initial drug resistance trolled trial. Br Med J 1985;290:1106-8. on the response to short-course chemotherapy in pul- 14 MRC Working Party on Tuberculosis of the Spine. A monary tuberculosis. Am Rev Respir Dis 1986;133: controlled trial of 6-month and 9-month regimens of 423-30.