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November 1985, Volume 35, Issue 11

Editorial

THERAPY IN TUBERCULOSIS

Salim uddin Aziz  ( PMRC Research Centre, Jinnah Post Graduate Medical Centre, Karachi. )

Developments in the last few years have greatly changed the therapy of tuberculosis. Primary drugs are highly effective, relatively simple to take, and are well tolerated, parenteral treatment is not necessary, nor is the long protracted treatment in the sanatorium. New cases can safely be treated at home without any risk to the family, there is little risk of being infected after chemotherapy has begun1-4 If cases have to be admitted for diagnosis or complications they can be managed in the chest ward of a general hospital.
Effective drug therapy for pulmonary tuberculosis depends upon appropriate drugs, in adequate doses for adequate period. There are over 10 drugs available (table).


Primary drugs i.e. Isoniazid and Rifampicin are most effective with low toxicity, secondary drugs are more toxic and less effective, while tertiary are least effective and most toxic.
Newly diagnosed cases can be treated with a combination of at least 2 drugs, depending upon the extent of the disease and drug resistance (Primary). Treatment will have to be modified in special medical situations like acquired and primary resistance, pregnancy, renal and hepatic insufficiency. There is a practice of using 3 drugs also, but there are indications that Isoniazid, Rifampicin combination produces earlier conversion of sputum than standard 3 drug regimen5. There are many combinations of drugs and different regimens of short and long courses are available. However in special situations selection of a treatment regimen or its successful completion may prove difficult
DRUG RESISTANCE
Treated cases who relapse may be due to drug resistance, though most give a history of non-compliance. In Pakistan resistance has not been investigated fully, some earlier reports regarding standard drugs showed acquired resistance of 41.9% (16.5% to one, 14.8% to two and 1% to three)6 to 38.3%7 increasing to 71% in the same locality8  which was much higher than others reported at that time (Britain 1960 5.1%, East Africa 1960 5.1%, Nigeria 1960 12%). There is no data available for Rifampicin and other newer drugs, though primary resistance of 8% has been suggested (lqbal personal communications). Relapse should ideally be treated according to the drug sensitivities, though cultures take a long time. Methods of rapid testing of drug susceptibility, that measures the incorporation of radioactive label, by multiplying bacteria have recently been described9-10 but have not found general favour. Detailed history of previous treatment should be taken, and drugs not previously used should be prescribed. Under no circumstances should one new drug be added to previously used therapy. The regimen can be re-adjusted once the sensitivities are available.
RENAL DISEASE
With decreased renal function the drugs which are excreted in the urine are the cause of increased blood levels. Among the antituberculosis drugs Ethambutol and Kenamycin are most problematic. Since Ethambutol is almost all excreted in the urine, reduced renal functions will increase the blood levels, and should be avoided in chronic renal failure. If it has to be used the recommended dose is 9mg/kg/day11. Ophthalmic, examination and liver functions should be monitored during the therapy. Even though 50-80% of Isoniazid is excreted in urine with normal renal functions in 24hours, part of it is excreted in unchanged form but mainly as acetylisoniazid and isonicotinic acid plus a small amount of isonicotinic acid congugate as isonicotinoyl hydrazon12. The usual dose of Isoniazid like that of Rifampicin is quite safe in renal disease13. No data is available for pyrazinamide, but renal excretion may be significant and dose should be modified to 12-20mg/Kg/day.
The incidence of tuberculosis is increased 10-12 times greater than the general population10,14 in patients on long term dialysis for end stage renal disease, particularly extra pulmonary disease. It is suggested that impaired cellular immunity associated with Uraemia due to advanced renal failure may predispose to increased incidence. There is limited data about the dosage of antituberculosis drugs for dialysis. Isoniazid, Kenamycin, Ethambutol are all dialyzable. Isoniazid15 and Rifampicin should be given in normal dosage and if Ethambutol must be used it should not exceed 9mg/kg.11 The drugs should be administered immediately after dialysis.
LWER DISEASES
The treatment of patients with liver dysfunction is difficult, since most of the effective drugs are potentially hepatotoxic.
Least toxic regimens like Streptomycin, Ethambutol, and Isoniazid should be prescribed. In severe hepatic failure the drugs should be given in reduced dosage.16
PREGNANCY
The drugs of choice in pregnancy are Ethambutol and Isoniazid, both are well tolerated by mother and17-18 featus. Rifampicin is also relatively safe, but experience with this is more limited and should not be given in first trimester. Streptomycin causes featal ototoxicity19 and is best avoided, Ethionamide is teratogenic.20 Since all drug exposure should be avoided in pregnancy diagnosis must be confirmed before starting ant ituberculosis treatment. Some antituberculo sis drugs i.e. Streptomycin, Isoniazid and Rifampicin are excreted in breast milk21 which should also be taken into consideration during the post­partum stage.
INTERACTIONS
During treatment, with other medications antituberculosis drugs may cause problems. The complete list of drugs apart from antituberculosis being received by the patient should be reviewed, since many antituberculosis drugs interfere with others reducing or potentiating their effects. Isoniazid interferes in the excretion of phenytoin and may cause toxicity in a patient stabiised on a dose,22 the dose will have to be reduced accordingly to maintain the same therapeutic level. Rifampicin, a hepatic mixed-functionoxidase inducer, is likely to interact with other drugs. Since oxidase enzyme system helps in clearance of many drugs, various Rifampicin interactions may be expected. To date it has been implicated in accelerating the metabolism of cumarin type of anticoagulants,23 reducing the effects of oral contraceptives20-24 so patient of antituberculosis should use dthór contraceptive methods. The therapeutic effects of corticosteriods25 Methadone26 oral Hypoglycaemic agents27 and Digoxin20 are also effected by Rifampicin, and dosage will have to be modified accordingly.
Tuberculosis therapy now is so effective that once the patient has completed a full course of drugs faithfully relapse is so infrequent that he should be discharged from supervision with the instructions to seek medical advice for such symptoms as persistant cough, protracted fever, and Haemoptysis.28,29

REFERENCES

1. Andrew, R.W. , Devadatta, S., Fox, W., Radhakrishna, S., and Ramakrishnan, C.V. Prevalance of tuberculosis among close family contacts of tuberculosis patients in South India, and influence of segregation of the patient on the early attack rate. Bull. WHO., 1960; 23: 463.
2. Kamat, S.R., Dawson, JJ.Y., Devadatta, S., Fox, W., Jaaardhañam, B., Radhakirshna, S., Ramakrish nan, C.V., Somasundaram, P.R., Stott, H. and Velu, S.A. Controlled study of the influence of segregation of tuberculous patient for one year on attack rate of tuberculosis in 5-years period in close family contacts in South India, and influence of segregation of the patient on the early attack rate. Bull. WHO., 1966; 34 :517.
3. Brooks, S.M., Lassiter, N.L. and Young, E.C. A pilot study concerning the infection risk of sputum positive tuberculous patients on chemotherapy. Am. Rev. Respir. Dis., 1973; 108 : 799.
4. Gunnels, J.J, Bates, J.H. and Swindoll, H. Infectivity of sputum-positive tuberculosis patients on chemotherapy. Am. Rev. Respir. Dis., 1974; 109 : 323.
5. Nawman, R., Doster, B.E., Murray, F.J. and Woolpert, S.F. Rifampicin in initial treatment of pulmonary tuberculosis; a U.S. public health service tuberculosis therapy trial. Am. Rev. Respir. Dis., 1974;109 :216.
6. Yad. M.I. Drug sensitivity of mycobacterium tuberculosis. Pakistan J. Health, 1963; 13:2.
7. Gilani, S., Khan, A.M. Drug sensitivity patterns of mycobacterium tuberculosis. Pakistan J. Med. Res., 1965;4 : 329.
8. Gilani, S. and Khan, A.M. Drug sensitivity pattern of mycobacterium tuberculosis-Il. Pakistan J. Med. Res., 1967;6: 93.
9. McDaniel, R.E., Abensohn, M.K., Spoon, D.R., Kobayashi, G.S., Medoff, G., and Marr, J.J. A rapid radiometric method for determining the sensitivity of clinical isolates of mycobacterium tuberculosis to several chemotherapeutic agents. J. Lab. Chin. Med, 1977;89:861.
10. Kertcher, J.A., Chen, M.F., Charache, P., et al. Rapid radiometric susceptibility testing of myco­ bacterium tuberculosis. Am. Rev. Respir. Dis., 1978; 117 : 631.
11. Andrew, O.T. , Schoenfeld, P.Y. , Hopewell, P.C. and Humphreys, M.H. Tuberculosis in patients with end stage renal disease. Am. J. Med., 1980; 68 : 59.
12. Hughes, H.B. On the metabolic fate of isoniazid. J. Pharmcol. Exp. Ther., 1953; 109 : 444.
13. Pradhan, R.P., Katz, L.A., Nidus, B.D., Matalon, R. and Eisinger, R.P. Tuberculosis in dialyzed patients. JAMA, 1974; 229 : 798.
14. Lundin, A.P., Adler, A.J., Berlyne, G.M. and Friedman, E.A. Tuberculosis in patients under­going maintainance haemodialysis. Am. J. Med., 1979; 67 : 597.
15. Bowersox, D.W., Winterbauer, R.H., Stewart, G.L., Orme, B. and Barron, E. Isoniazid dossage in patients with renal failure. N. Engi. J. Med., 1973; 289 : 84.
16. Acoceila, G., Bonollo, L., Garimoldi, M., Mainardi, M., Tenconi, L.T. and Niclis, F.B. Kinetics of rifampicin and Isoniazid administered alone and in combination, to normal subjects and patients with liver disease. Gut, 1972; 13 : 47.
17. Schaefer, G., Zervoudakis, l.A., Fuchs, F.F. and David, S. Pregnancy and pulmonary tuberculosis. Obstet. Gynecol., 1975 ;46 : 706.
18. Bobrowitz, D. Ethainbutol in pregnancy. Chest, 1974;66 :20.
19. Crofton, J. and Douglas, A. Respiratory diseases, 3rd ed. Edinburgh, Blackwell, 1981;P. 288.
20. Potworowska, M., Sianozecka, E. and Szufladowicz R. Ethanomide treatment and pregnancy. Pol. Med.J., 1966;5 :1152.
21. O’Brien, T.E. Excretion of drugs in human Milk. Am.J.Hosp.Pharm., 1974;31 :844.
22. Miller, R.R. , Potter, J. and Greenblatt, D.J. Clinical importance of the interpretations of phenytoin and isoniazid. Chest, 1979;75 : 356.
23. O’Relly, R.A. Interaction of chronic daily warfarin therapy and rifampin. Ann. Intern. Med., 1975;83 :506.
24. Bolt, H.M., Kappus, H. and Bolt, M. Rifampicin and oral contraception. Lancet, 1974; 1: 1280.
25. Edwards, O.M., Courtenay-evans, R.J., Gaily, G.M. , Hunter, J. and Tait, A.D. Changes in cortisol metabolism following Rifampicin therapy. Lancet, 1974; 2 : 549.
26. Kreek, M.J. , Garfield, J.W., Gutjahr, C.L. and Giusti, M. Rifampicin-induced methadone with-drawl. N. Eng. J. Med., 1976; 294 : 1104.
27. Syvalahti, E.K.G., Pihlajamaki, K.K. and Lisalo, E.J. Rifampicin and drug metabolism. Lancet, 1974;2 :232.
28. Edsall, J. and Collins, G. Routine followup of inactive tuberculosis, a practice to be abandoned. Am. Rev. Respir. Dis., 1973; 107 : 851.
29. Ad. Hoc. Committee on the discharge of patients from Medical Surveillance. Discharge of tuber culosis patients from Medical Surveillance. Am. Rev. Respir. Dis., 1976;113 :709.

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