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Rifampin plus Isoniazid in Initial Therapy of Pulmonary Tuberculosis and Rifampin and Ethambutol in Retreatment Cases
Rifampin plus Isoniazid in Initial Therapy of Pulmonary Tuberculosis and Rifampin and Ethambutol in Retreatment Cases* A. W. Lees, AI.D., F.C.C.P.; G. W. Allan, M.B., Ch.B.; ]. Smith, M.B., Ch.B.; Tyrrell, M.B., Ch.B.; and R. ]. Fallon, M.D.
w. F.
88 patients with organisms initially susceptible to rifampin and isoniazid completed six months' therapy; 22 did not. Seventeen of the 22 patients failing to complete the six month period did so for reasons unconnected with treabnent; five were uncooperative; three died of cardiovascular disease; three died of concurren t carcinoma; four had no tubercle bacilli in the sputum and two were transferred elsewhere. Five of the 110 patients failed to complete six months' treatment because of drug side effects.
preliminary clinical investigations of rifampin;':" a recently introduced oral antituberculosis drug, have indicated that it is highly effective. Moreover, it has been regarded as remarkably free from side effects, -I although hepatotoxicity has been reported. n.s In order to evaluate the place of rifampin in antituberculosis therapy, it was combined with isoniazid in the initial treabnent of patients with pulmonary tuberculosis and with ethambutol in retreatment cases. MATERIALS AND METIIOD
Clinical and Radiologic Progress
Patients admitted to the hospital with previously untreated pulmonary tuberculosis were given rifampin 600 mg daily plus isoniazid 300 mg daily. Retreabnent patients were given rifampin 600 mg daily plus ethambutol 25 mg per kilo body weight reducing to 15 mg per kilo after two months. The drugs were given in one prebreakfast dose. The patients were all under hospital treatment for a minimum period of three months. Examination of the urine for albumin, blood, sugar, and bile was carried out weekly; hepatic function tests (SCOT, SCPT, serum bilirubin, serum alkaline phosphatase, thymol turbidity, and total serum protein) were done weekly and chest films and cultures of sputum or bronchial lavage specimens were done monthly. Serum electrolytes and urea were estimated before treatment began and subsequently if clinically indicated. Erythrocyte sedimentation rate (ESR), hemoglobin, PCV, ~1CHC, white blood cell count and differential were assessed before treatment commenced, and hemoglobin, white blood cell count and ESR were subsequently routinely determined monthly. Drug susceptibility tests to rifampin, isoniazid and ethambutol were carried out using the method of estimating resistance ratios described by Cruikshank." Before treatment with rifampin plus ethambutol commenced, visual acuity was tested by the consultant ophthalmologist at first routinely every month, but later only if clinically indicated.
Clinical and radiologic progress was satisfactory in all 88 patients who completed the six-month period of therapy. Of these 88 patients, 23 had six lung zones affected by disease at the beginning of the study; nine, five zones; nine, four zones; 13, three zones; 20, t\VO zones; and 14, one zone. After six months, four had six lung zones affected by disease; six, five zones; nine, four zones; 11, three zones; 22, two zones; 31, one zone; and five had no apparent disease. Cavitation was present in 62 of the 88 patients. These 62 patients had 129 cavities: 101 of these cavities were less than 2.5 cm in diameter; 22, between 2.5 and 5 em in diameter; and six were more than 5 em in diameter. After six months, cavitation was still present in 15 patients. These 15 patients had 16 cavities; 12 of these cavities were less than 2.5 em in diameter; and four were between 2.5 and 5 cm in diameter. Bacteriologic Progress
In every case, tubercle bacilli susceptible to isoniazid and rifampin were cultured from respiratory secretions before therapy commenced. Bacteriologic "conversion" was defined as a monthly culture negative for tubercle bacilli followed by at least one subsequent monthly culture for tubercle bacilli and no further positive results during the period of observation. Of the 88 patients, 47 converted after one month; 18 after two months; 16 after three months; six after four months; and one after five months. No evidence of emergent bacterial resistance to isoniazid or rifampin was noted in any of the patients.
RESULTS
Rifampin and isoniazid
Of 110 patients treated with rifampin and isoniazid, o From
the Chest and Lahoratory Services Departments, Ruchill Hospital, Glasgow, Scotland. Authors' additional degrees are: Dr. Lees-F.R.C.P. (Ed. and Clas ): Dr. Allan-~f.R.C.P. Ed.; Dr. Smith-D.P.H.; Dr. Tyrrell-D.P.H.; Dr. Fallon-M.R.C. Path. Reprint requests: Dr. Lees, Ruchill Hospital, Glasgow G20 9NB, Scotland.
Side Effects Two patients had to be withdrawn from the trial
579
580 because of a violent shock-like illness with fall in blood pressure and elevation of serum transaminase and serum bilirubin. In one patient, when recovery had occurred after discontinuation of treatment, further administration of rifampin and isoniazid provoked- within two hours a recurrence of the shock-like syndrome, indicating that the condition was a generalized drug hypersensitivity phenomenon. Drug rechallenge was not attempted in the other case. Disturbance of liver function was frequently noted. Including the two cases of generalized drug hypersensitivity, transient elevation of serum transaminases was noted in 21 (23 percent) and elevation of serum transaminases plus elevation of serum bilirubin in ten (11 percent) of the patients. Some disturbance of liver function was therefore noted in 31 (33 percent) patients. Apart from the two patients with the generalized drug hypersensitivity reaction, elevation of serum transaminases and serum bilirubin was noted in eight patients, but in none of these was there any significant constitutional disturbance. Treatment was continued in two of these eight patients and liver function tests returned to normal; in three, treatment was stopped, but later restarted with only a transient rise in transaminase; in two, rechallenge with the drugs provoked elevation of transaminase and serum bilirubin levels and treatment was" abandoned; and in one treatment was abandoned, perhaps unnecessarily, since rechaIlenge with the drugs five months later provoked only a transient rise in transaminase levels. All together, therefore, five patients failed to complete six months' therapy because of drug side effects: two because of a generalized drug hypersensitivity reaction, and three because of disturbance of liver function. These side effects occurred in the first two months of treatment. In addition, three patients had mild transient skin rashes.
Hi/ampin and Ethambutol Of 76 patients treated and observed for a period of six months to two years, 66 with organisms initially susceptible to rifampin and ethambutol completed six months' therapy and ten did not. Nine of the ten patients failed to complete the six months for reasons unconnected with treatment: three were uncooperative; two died of coronary disease; two of concurrent bronchial carcinoma; and two were transferred elsewhere. One of the ten patients failed to complete six months of treatment because of drug side effects.
Clinical and Radiologic Progress Clinical and radiologic progress was satisfactory in all 66 patients who completed the six-month period of therapy. Of these 66 patients, 12 had six lung zones affected by disease at the beginning of the study; 14, five zones; nine, four zones; 12, three zones; 14, two zones; and five, one zone. After six months, four had six zones affected by disease; 11, five zones; 14, four zones; nine, three zones; 15, two zones; and 13, one zone. Cavitation was present in 45 of the 66 patients. These
LEES ET AL 45 patients had 119 cavities: 84 of these cavities were less than 2.5 em in diameter; 23 between 2.5 and 5 cm in diameter; and 12 more than 5 em in diameter. After six months, cavitation was still present in 12 patients. These 12 patients had 29 cavities: 20 of these cavities were less than 2.5 cm in diameter; four were between 2.5 and 5 em in diameter; and five were more than 5 em in diameter.
Bacteriologic Progress In every case, tubercle bacilli to be subjected to rifampin and ethambutol were cultured from respiratory secretions obtained before therapy commenced. Of the 66 patients, 40 converted after one month; seven after two months; 11 after three months; six after four months; one after five months; and one patient had stiII not converted at the end of the six month period. No evidence of emergent bacterial resistance to rifampin or ethambutol was noted in any of the patients.
Side Effects Disturbance of liver function was noted in seven (10 percent) of the patients. There was slight transient elevation of transaminase in six (9 percent) and elevation of transaminase together with elevation of serum bilirubin in one (1.5 percent) . Liver function returned to normal in all cases as treatment continued. Skin rash occurred in two (3 percent) of the patients. In one patient, the rash disappeared although treatment was continued; in the other, after treatment had been stopped, it recurred on re-challenge with rifampin and treatment was altered to ethambutol and other drugs. DISCUSSION
Results of this investigation indicate that rifampin plus isoniazid is a highly effective antituberculosis drug combination. Bacteriologic conversion was achieved in all 88 patients who completed the six-month period of treatment and in 81 (92 percent) after three months. The results are in keeping with those of other investigations. Gyselen et al' reported that in 29 patients with initial disease treated with the same rifampin-isoniazid combination, bacteriologic conversion was achieved in all by the 14th week and Constans et al/ using a daily combination of rifampin 900 mg plus isoniazid 10 rng per kilo bodyweight, reported bacteriologic· conversion in three months in alI 54 patients with initial treatment. In retreatment cases, a rifampin-ethambutol drug combination also proved extremely effective and acceptable. By three months, conversion of respiratory secretions had occurred in 58 (88 percen t) of the 66 patients. Only one patient failed to convert by the end of the six-month period. No evidence of emergent bacterial resistance was noted. These results are again in keeping with those of other workers. Hetrick and associates" reported a conversion rate of 96.4 percent after four months' treatment in patients retreated with rifampin plus ethambutol. Raleigh" found that 84 percent of 22
CHEST, VOL. 61, NO.6, JUNE 1972
RIFAMPIN IN INITIAL THERAPY AND RETREATMENT retreatment patients became culture-negative at 12 weeks with rifampin-ethambutol treatment; one patient failed to respond and a second showed bacteriologic relapse. Nitti and associates- in retreatment cases reported 100 percent conversion at four months in 26 patients treated with rifampin-ethambutol. Similarly, Meissner!" found that of 12 patients retreated with rifampin-ethambutol, all had converted by three months. The only severe drug side-effects noted in the present investigation were the two cases of generalized drug hypersensitivity with a shock-like reaction and elevation of serum transaminase and bilirubin in patients treated with rifampin-isoniazid. Lucchesi and ROSSPI encountered three similar cases after a few days of rifampin therapy. This violent hypersensitivity effect was not noted in patients treated with rifampin plus ethambutol; so an isoniazid-rifampin combination may be more liable to produce it. Disturbance of liver function was noticeably more frequent in patients treated with rifampin plus isoniazid than it was in patients treated with rifampin plus ethambutol. Whereas in the rifampin plus isoniazid patients 23 percent had raised transaminase and 11 percent had elevated serum bilirubin in addition; in the rifampin plus ethambutol patients only 9 percent had raised transaminase levels (and then all of minimal degree) and only one patient (1.5 percent) had in addition elevated serum bilirubin levels (and these returned to normal despite continuation of treatment) . Cons tans et al" noted elevation of serum transaminase or alkaline phosphatase in 24 of their patients accompanied by a rise of serum bilirubin in three, but they attributed the disturbance of liver function to the high rifampin dosage and the poor condition of their patients. However, Lesobre et al,5 Lees et al 6 and Hollins and Simmons'" have also reported hepatotoxicity with rifampin in conventional dosage. None of the patients in the present series had any known factor predisposing to hepatotoxicity and all had initially normal liver function tests. Scharer and Smith'> noted elevation of serum transaminases in 10 percent of patients treated solely with 300 mg isoniazid daily. However, at this hospital, in a series of 94 patients treated for at least six months with an isoniazid-ethambutol combination simultaneously with patients receiving isoniazid and rifampin in the present investigation, no significant disturbance of liver function was observed. Nevertheless, the much higher incidence of hepatotoxicity in the rifampin-isoniazid patients as compared with the rifampin-ethambutol patients in the present investigation indicates that isoniazid enhances the toxic effect of rifampin on the liver as we have previously suggested.w-v This is supported by the fact that in this series it was found that patients with eleva ted serum bilirubin levels were almost invariably slow inactivators of isoniazid (see page 587, this issue). It should be emphasized that apart from the two instances in which disturbance of liver function was associated with generalized drug hypersensitivity, constitutional upset was slight or absent, and the condition
CHEST, VOL. 61, NO.6, JUNE 1972
581
might often have been missed but for close supervision including routine liver function testing. Judged by the results of the present investigation, the potential hepatotoxicity of rifampin is, fortunately, in general so mild that it should not preclude the use of this highly active and acceptable agent in first-line antituberculosis treatment. However, close supervision with respect to liver function is indicated in the 6rst two to three months of treatment when rifampin is combined with isoniazid and the experience of Lesobre et al 5 indicates that it should be used with caution in patients with pre-existing liver damage. Side effects in the patients treated with rifampinethambutol were negligible. A troublesome skin rash due to rifampin necessitated change of treatment in one case. The effectiveness, acceptability, and paucity of side effects strongly commend a rifampin-ethambutol combination for the retreatment of patients with pulmonary tuberculosis. SUMMARY
Eighty-eight patients with previously untreated, baceriologically-positive pulmonary tuberculosis were given rifampin 600 mg daily and isoniazid 300 mg daily. Bacteriologic conversion was achieved in 81 (92 percent) in three months and in all 88 patients in six months. Sixty-six patients with previously treated bacteriologically-positive pulmonary tuberculosis were given rifampin 600 mg daily and ethambutol 25/15 mg per kilo bodyweight daily. Bacteriologic conversion was achieved in 58 (88 percent) in three months and in all but one of the 66 patients in six months. Rifampin side effects were negligible when it was combined with ethambutol. When combined with isoniazid, two severe hypersensitivity reactions were observed and disturbance of liver function was fairly frequent, though never severe. Isoniazid, therefore, appears to increase the tendency of rifampin to cause hepatotoxicity. Nevertheless, rifampin would seem indicated in first line treatment of pulmonary tuberculosis, as well as in the management of cases previously treated. REFERENCES
2
3
4 5
Gyselen A, Verbist L, Cosemans J, et al: A cooperative study on rifampicin in original treatment of advanced pulmonary tuberculosis. Acta Tuberc Pneumol Belg 60: 563, 1969 Nitti V, Delli Veneri F, Marra A: La rifampicine dans Ie traitement des tuberculoses chroniques a bacilles resistant aux medications standard. Acta Tuberc Pneumol Belg 60:455, 1969 Raleigh JW: Rifampicin and ethambutol therapy for retreatment of pulmonary tuberculosis. Preliminary results of the pilot trial. 28th Veterans AdministrationArmed Forces Pulmonary Disease Research Conference, Cleveland, p 67, 1969 New drugs against tuberculosis. Lancet 1: 1081, 1969 Lesobre R, Ruffino J, Teyssier L, et al: Les icteres au cours du traitement par la rifampicine (12 observations).
SPECIAL ISSUE
582 Rev Tuberc Pneumonol33:393, 1969 6 Lees AW, Asgher B, Hashem MA, et a1: Jaundice after rifampicin. Br J Dis Chest 64:90, 1970 7 Cruikshank R: Medical Microbiology (11th 00). Edinburgh and London, Livingstone, 1968, p 903 8 Cons tans P, Morin Y, Coury C, et al: Le traitement de la tuberculose pulmonaire recente par l'association rifampicine-isoniazide. Acta Tuberc Pneumol Belg 60:545, 1969 9 Hetrick C, Ras R, Turri M: Rifampicin-ethambutol in treatment of resistant pulmonary tuberculosis. Dtsch moo Wschr 95:1830,1970 10 Meissner G: Rifampicin in chronic polyresistant cases of pulmonary tuberculosis. Acta Tuberc Pneumol Belg 60: 482, 1969
LEES ET AL 11 Lucchesi M, Rossi P: The clinical use of rifampicin against pulmonary tuberculosis in the adult. Riv Tuberc 16:260, 1968 12 Hollins PJ, Simmons AV: Jaundice associated with rifampicin. Tubercle 51 :328, 1970 13 Scharer L, Smith JP: Serum transaminase elevations and other hepatic abnormalities in patients receiving isoniazid. Ann Intern Moo 71:1113,1969 14 Lees AW: Rifampicin toxicity. Report of meeting British Thoracic and Tuberculosis Association. Tubercle 51 :217, 1970 15 Lees AW, Allan GW, Smith J, et aI: Toxicity from rifampicin plus isoniazid and rifampicin plus ethambutol therapy. Tubercle 52:182, 1971
CHEST, VOL. 61, NO.6, JUNE ] 972
w. F.
88 patients with organisms initially susceptible to rifampin and isoniazid completed six months' therapy; 22 did not. Seventeen of the 22 patients failing to complete the six month period did so for reasons unconnected with treabnent; five were uncooperative; three died of cardiovascular disease; three died of concurren t carcinoma; four had no tubercle bacilli in the sputum and two were transferred elsewhere. Five of the 110 patients failed to complete six months' treatment because of drug side effects.
preliminary clinical investigations of rifampin;':" a recently introduced oral antituberculosis drug, have indicated that it is highly effective. Moreover, it has been regarded as remarkably free from side effects, -I although hepatotoxicity has been reported. n.s In order to evaluate the place of rifampin in antituberculosis therapy, it was combined with isoniazid in the initial treabnent of patients with pulmonary tuberculosis and with ethambutol in retreatment cases. MATERIALS AND METIIOD
Clinical and Radiologic Progress
Patients admitted to the hospital with previously untreated pulmonary tuberculosis were given rifampin 600 mg daily plus isoniazid 300 mg daily. Retreabnent patients were given rifampin 600 mg daily plus ethambutol 25 mg per kilo body weight reducing to 15 mg per kilo after two months. The drugs were given in one prebreakfast dose. The patients were all under hospital treatment for a minimum period of three months. Examination of the urine for albumin, blood, sugar, and bile was carried out weekly; hepatic function tests (SCOT, SCPT, serum bilirubin, serum alkaline phosphatase, thymol turbidity, and total serum protein) were done weekly and chest films and cultures of sputum or bronchial lavage specimens were done monthly. Serum electrolytes and urea were estimated before treatment began and subsequently if clinically indicated. Erythrocyte sedimentation rate (ESR), hemoglobin, PCV, ~1CHC, white blood cell count and differential were assessed before treatment commenced, and hemoglobin, white blood cell count and ESR were subsequently routinely determined monthly. Drug susceptibility tests to rifampin, isoniazid and ethambutol were carried out using the method of estimating resistance ratios described by Cruikshank." Before treatment with rifampin plus ethambutol commenced, visual acuity was tested by the consultant ophthalmologist at first routinely every month, but later only if clinically indicated.
Clinical and radiologic progress was satisfactory in all 88 patients who completed the six-month period of therapy. Of these 88 patients, 23 had six lung zones affected by disease at the beginning of the study; nine, five zones; nine, four zones; 13, three zones; 20, t\VO zones; and 14, one zone. After six months, four had six lung zones affected by disease; six, five zones; nine, four zones; 11, three zones; 22, two zones; 31, one zone; and five had no apparent disease. Cavitation was present in 62 of the 88 patients. These 62 patients had 129 cavities: 101 of these cavities were less than 2.5 cm in diameter; 22, between 2.5 and 5 em in diameter; and six were more than 5 em in diameter. After six months, cavitation was still present in 15 patients. These 15 patients had 16 cavities; 12 of these cavities were less than 2.5 em in diameter; and four were between 2.5 and 5 cm in diameter. Bacteriologic Progress
In every case, tubercle bacilli susceptible to isoniazid and rifampin were cultured from respiratory secretions before therapy commenced. Bacteriologic "conversion" was defined as a monthly culture negative for tubercle bacilli followed by at least one subsequent monthly culture for tubercle bacilli and no further positive results during the period of observation. Of the 88 patients, 47 converted after one month; 18 after two months; 16 after three months; six after four months; and one after five months. No evidence of emergent bacterial resistance to isoniazid or rifampin was noted in any of the patients.
RESULTS
Rifampin and isoniazid
Of 110 patients treated with rifampin and isoniazid, o From
the Chest and Lahoratory Services Departments, Ruchill Hospital, Glasgow, Scotland. Authors' additional degrees are: Dr. Lees-F.R.C.P. (Ed. and Clas ): Dr. Allan-~f.R.C.P. Ed.; Dr. Smith-D.P.H.; Dr. Tyrrell-D.P.H.; Dr. Fallon-M.R.C. Path. Reprint requests: Dr. Lees, Ruchill Hospital, Glasgow G20 9NB, Scotland.
Side Effects Two patients had to be withdrawn from the trial
579
580 because of a violent shock-like illness with fall in blood pressure and elevation of serum transaminase and serum bilirubin. In one patient, when recovery had occurred after discontinuation of treatment, further administration of rifampin and isoniazid provoked- within two hours a recurrence of the shock-like syndrome, indicating that the condition was a generalized drug hypersensitivity phenomenon. Drug rechallenge was not attempted in the other case. Disturbance of liver function was frequently noted. Including the two cases of generalized drug hypersensitivity, transient elevation of serum transaminases was noted in 21 (23 percent) and elevation of serum transaminases plus elevation of serum bilirubin in ten (11 percent) of the patients. Some disturbance of liver function was therefore noted in 31 (33 percent) patients. Apart from the two patients with the generalized drug hypersensitivity reaction, elevation of serum transaminases and serum bilirubin was noted in eight patients, but in none of these was there any significant constitutional disturbance. Treatment was continued in two of these eight patients and liver function tests returned to normal; in three, treatment was stopped, but later restarted with only a transient rise in transaminase; in two, rechallenge with the drugs provoked elevation of transaminase and serum bilirubin levels and treatment was" abandoned; and in one treatment was abandoned, perhaps unnecessarily, since rechaIlenge with the drugs five months later provoked only a transient rise in transaminase levels. All together, therefore, five patients failed to complete six months' therapy because of drug side effects: two because of a generalized drug hypersensitivity reaction, and three because of disturbance of liver function. These side effects occurred in the first two months of treatment. In addition, three patients had mild transient skin rashes.
Hi/ampin and Ethambutol Of 76 patients treated and observed for a period of six months to two years, 66 with organisms initially susceptible to rifampin and ethambutol completed six months' therapy and ten did not. Nine of the ten patients failed to complete the six months for reasons unconnected with treatment: three were uncooperative; two died of coronary disease; two of concurrent bronchial carcinoma; and two were transferred elsewhere. One of the ten patients failed to complete six months of treatment because of drug side effects.
Clinical and Radiologic Progress Clinical and radiologic progress was satisfactory in all 66 patients who completed the six-month period of therapy. Of these 66 patients, 12 had six lung zones affected by disease at the beginning of the study; 14, five zones; nine, four zones; 12, three zones; 14, two zones; and five, one zone. After six months, four had six zones affected by disease; 11, five zones; 14, four zones; nine, three zones; 15, two zones; and 13, one zone. Cavitation was present in 45 of the 66 patients. These
LEES ET AL 45 patients had 119 cavities: 84 of these cavities were less than 2.5 em in diameter; 23 between 2.5 and 5 cm in diameter; and 12 more than 5 em in diameter. After six months, cavitation was still present in 12 patients. These 12 patients had 29 cavities: 20 of these cavities were less than 2.5 cm in diameter; four were between 2.5 and 5 em in diameter; and five were more than 5 em in diameter.
Bacteriologic Progress In every case, tubercle bacilli to be subjected to rifampin and ethambutol were cultured from respiratory secretions obtained before therapy commenced. Of the 66 patients, 40 converted after one month; seven after two months; 11 after three months; six after four months; one after five months; and one patient had stiII not converted at the end of the six month period. No evidence of emergent bacterial resistance to rifampin or ethambutol was noted in any of the patients.
Side Effects Disturbance of liver function was noted in seven (10 percent) of the patients. There was slight transient elevation of transaminase in six (9 percent) and elevation of transaminase together with elevation of serum bilirubin in one (1.5 percent) . Liver function returned to normal in all cases as treatment continued. Skin rash occurred in two (3 percent) of the patients. In one patient, the rash disappeared although treatment was continued; in the other, after treatment had been stopped, it recurred on re-challenge with rifampin and treatment was altered to ethambutol and other drugs. DISCUSSION
Results of this investigation indicate that rifampin plus isoniazid is a highly effective antituberculosis drug combination. Bacteriologic conversion was achieved in all 88 patients who completed the six-month period of treatment and in 81 (92 percent) after three months. The results are in keeping with those of other investigations. Gyselen et al' reported that in 29 patients with initial disease treated with the same rifampin-isoniazid combination, bacteriologic conversion was achieved in all by the 14th week and Constans et al/ using a daily combination of rifampin 900 mg plus isoniazid 10 rng per kilo bodyweight, reported bacteriologic· conversion in three months in alI 54 patients with initial treatment. In retreatment cases, a rifampin-ethambutol drug combination also proved extremely effective and acceptable. By three months, conversion of respiratory secretions had occurred in 58 (88 percen t) of the 66 patients. Only one patient failed to convert by the end of the six-month period. No evidence of emergent bacterial resistance was noted. These results are again in keeping with those of other workers. Hetrick and associates" reported a conversion rate of 96.4 percent after four months' treatment in patients retreated with rifampin plus ethambutol. Raleigh" found that 84 percent of 22
CHEST, VOL. 61, NO.6, JUNE 1972
RIFAMPIN IN INITIAL THERAPY AND RETREATMENT retreatment patients became culture-negative at 12 weeks with rifampin-ethambutol treatment; one patient failed to respond and a second showed bacteriologic relapse. Nitti and associates- in retreatment cases reported 100 percent conversion at four months in 26 patients treated with rifampin-ethambutol. Similarly, Meissner!" found that of 12 patients retreated with rifampin-ethambutol, all had converted by three months. The only severe drug side-effects noted in the present investigation were the two cases of generalized drug hypersensitivity with a shock-like reaction and elevation of serum transaminase and bilirubin in patients treated with rifampin-isoniazid. Lucchesi and ROSSPI encountered three similar cases after a few days of rifampin therapy. This violent hypersensitivity effect was not noted in patients treated with rifampin plus ethambutol; so an isoniazid-rifampin combination may be more liable to produce it. Disturbance of liver function was noticeably more frequent in patients treated with rifampin plus isoniazid than it was in patients treated with rifampin plus ethambutol. Whereas in the rifampin plus isoniazid patients 23 percent had raised transaminase and 11 percent had elevated serum bilirubin in addition; in the rifampin plus ethambutol patients only 9 percent had raised transaminase levels (and then all of minimal degree) and only one patient (1.5 percent) had in addition elevated serum bilirubin levels (and these returned to normal despite continuation of treatment) . Cons tans et al" noted elevation of serum transaminase or alkaline phosphatase in 24 of their patients accompanied by a rise of serum bilirubin in three, but they attributed the disturbance of liver function to the high rifampin dosage and the poor condition of their patients. However, Lesobre et al,5 Lees et al 6 and Hollins and Simmons'" have also reported hepatotoxicity with rifampin in conventional dosage. None of the patients in the present series had any known factor predisposing to hepatotoxicity and all had initially normal liver function tests. Scharer and Smith'> noted elevation of serum transaminases in 10 percent of patients treated solely with 300 mg isoniazid daily. However, at this hospital, in a series of 94 patients treated for at least six months with an isoniazid-ethambutol combination simultaneously with patients receiving isoniazid and rifampin in the present investigation, no significant disturbance of liver function was observed. Nevertheless, the much higher incidence of hepatotoxicity in the rifampin-isoniazid patients as compared with the rifampin-ethambutol patients in the present investigation indicates that isoniazid enhances the toxic effect of rifampin on the liver as we have previously suggested.w-v This is supported by the fact that in this series it was found that patients with eleva ted serum bilirubin levels were almost invariably slow inactivators of isoniazid (see page 587, this issue). It should be emphasized that apart from the two instances in which disturbance of liver function was associated with generalized drug hypersensitivity, constitutional upset was slight or absent, and the condition
CHEST, VOL. 61, NO.6, JUNE 1972
581
might often have been missed but for close supervision including routine liver function testing. Judged by the results of the present investigation, the potential hepatotoxicity of rifampin is, fortunately, in general so mild that it should not preclude the use of this highly active and acceptable agent in first-line antituberculosis treatment. However, close supervision with respect to liver function is indicated in the 6rst two to three months of treatment when rifampin is combined with isoniazid and the experience of Lesobre et al 5 indicates that it should be used with caution in patients with pre-existing liver damage. Side effects in the patients treated with rifampinethambutol were negligible. A troublesome skin rash due to rifampin necessitated change of treatment in one case. The effectiveness, acceptability, and paucity of side effects strongly commend a rifampin-ethambutol combination for the retreatment of patients with pulmonary tuberculosis. SUMMARY
Eighty-eight patients with previously untreated, baceriologically-positive pulmonary tuberculosis were given rifampin 600 mg daily and isoniazid 300 mg daily. Bacteriologic conversion was achieved in 81 (92 percent) in three months and in all 88 patients in six months. Sixty-six patients with previously treated bacteriologically-positive pulmonary tuberculosis were given rifampin 600 mg daily and ethambutol 25/15 mg per kilo bodyweight daily. Bacteriologic conversion was achieved in 58 (88 percent) in three months and in all but one of the 66 patients in six months. Rifampin side effects were negligible when it was combined with ethambutol. When combined with isoniazid, two severe hypersensitivity reactions were observed and disturbance of liver function was fairly frequent, though never severe. Isoniazid, therefore, appears to increase the tendency of rifampin to cause hepatotoxicity. Nevertheless, rifampin would seem indicated in first line treatment of pulmonary tuberculosis, as well as in the management of cases previously treated. REFERENCES
2
3
4 5
Gyselen A, Verbist L, Cosemans J, et al: A cooperative study on rifampicin in original treatment of advanced pulmonary tuberculosis. Acta Tuberc Pneumol Belg 60: 563, 1969 Nitti V, Delli Veneri F, Marra A: La rifampicine dans Ie traitement des tuberculoses chroniques a bacilles resistant aux medications standard. Acta Tuberc Pneumol Belg 60:455, 1969 Raleigh JW: Rifampicin and ethambutol therapy for retreatment of pulmonary tuberculosis. Preliminary results of the pilot trial. 28th Veterans AdministrationArmed Forces Pulmonary Disease Research Conference, Cleveland, p 67, 1969 New drugs against tuberculosis. Lancet 1: 1081, 1969 Lesobre R, Ruffino J, Teyssier L, et al: Les icteres au cours du traitement par la rifampicine (12 observations).
SPECIAL ISSUE
582 Rev Tuberc Pneumonol33:393, 1969 6 Lees AW, Asgher B, Hashem MA, et a1: Jaundice after rifampicin. Br J Dis Chest 64:90, 1970 7 Cruikshank R: Medical Microbiology (11th 00). Edinburgh and London, Livingstone, 1968, p 903 8 Cons tans P, Morin Y, Coury C, et al: Le traitement de la tuberculose pulmonaire recente par l'association rifampicine-isoniazide. Acta Tuberc Pneumol Belg 60:545, 1969 9 Hetrick C, Ras R, Turri M: Rifampicin-ethambutol in treatment of resistant pulmonary tuberculosis. Dtsch moo Wschr 95:1830,1970 10 Meissner G: Rifampicin in chronic polyresistant cases of pulmonary tuberculosis. Acta Tuberc Pneumol Belg 60: 482, 1969
LEES ET AL 11 Lucchesi M, Rossi P: The clinical use of rifampicin against pulmonary tuberculosis in the adult. Riv Tuberc 16:260, 1968 12 Hollins PJ, Simmons AV: Jaundice associated with rifampicin. Tubercle 51 :328, 1970 13 Scharer L, Smith JP: Serum transaminase elevations and other hepatic abnormalities in patients receiving isoniazid. Ann Intern Moo 71:1113,1969 14 Lees AW: Rifampicin toxicity. Report of meeting British Thoracic and Tuberculosis Association. Tubercle 51 :217, 1970 15 Lees AW, Allan GW, Smith J, et aI: Toxicity from rifampicin plus isoniazid and rifampicin plus ethambutol therapy. Tubercle 52:182, 1971
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