Journal of Antimicrobial Chemotherapy (1976) 2, 265-270
Lack of association between rifampicin-dependent antibodies and bacteriological response during intermittent rifampicin treatment
In Hong Kong, 146 Chinese patients with sputum culture-positive pulmonary tuberculosis, whose treatment with first-line drugs had failed, were retreated with twice-weekly, once-weekly or daily and then once-weekly rifampicin plus ethambutol. In Singapore, 431 Chinese, Malay and Indian patients with newly diagnosed, culture-positive disease were treated with twice-weekly or once-weekly rifampicin plus isoniazid. At 12 months, on each regimen, the proportion of patients with a favourable bacteriological status and the proportion with an unfavourable status who had rifampicin-dependent antibodies in their serum was similar. There was thus no evidence that the presence of antibodies to rifampicin affected the therapeutic response.
Introduction
Circulating rifampicin-dependent antibodies are liable to develop in patients on intermittent but not on daily rifampicin (Worlledge, 1973). They may be associated with adverse reactions to rifampicin, especially the "flu" syndrome (Aquinas, Allan, Horsfall, Jenkins, Wong, Girling, Tall & Fox, 1972; Hong Kong Tuberculosis Treatment Services/ Brompton Hospital/British Medical Research Council, 1974). Patients may also develop antibodies without any adverse reaction to intermittent rifampicin, particularly those on a low dosage (Singapore Tuberculosis Service/British Medical Research Council, 1975). It could be argued that antibodies to rifampicin might reduce its bioavailability and so its therapeutic efficacy. Alternatively, since the incidence of antibodies depends upon the dose size ofrifampicin(Singapore Tuberculosis Service/British Medical Research Council, 1975) there could be an association in the opposite direction, antibodies being commoner in patients who achieve higher serum concentrations of rifampicin and who are thereby more likely to obtain a good therapeutic response. The present paper investigates whether there is an association between the presence of circulating antibodies and the bacteriological status at 12 months, in 2 studies in Hong Kong (Hong Kong Tuberculosis Treatment Services/Brompton Hospital/British Medical Research Council, 1974; Hong Kong Tuberculosis Treatment Services/British Medical Research Council, 1974a) and a study in Singapore (Singapore Tuberculosis Service/British Medical Reprints may be obtained from the Medical Research Council Tuberculosis and Chest Diseases Unit, Brompton Hospital, Fulham Road, London SW3 6HP, England. 265
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Fransisco on April 25, 2015
Hong Kong Tuberculosis Treatment Services, Singapore Tuberculosis Service, Royal Postgraduate Medical School, Brompton Hospital, British Medical Research Council
266
Rifampicin antibodies and bacteriological response
Research Council, 1975) in which patients with sputum culture-positive pulmonary tuberculosis were treated with intermittent regimens containing rifampicin. Plan and conduct of study
Table I. Rifampicin regimens studied Study
First Hong Kong 1 Rifampicin (mg) — 450 retreatment study plus (1974) ethambutol (mg/kg)— 25 for 2 months; then 15
V Daily J
2 Rifampicin (mg) — 900, 1050, or 1200* plus ethambutol (mg/kg)— 45
"1 V Twice a week J
3 Rifampicin (mg) — 900, 1050 or 1200* plus ethambutol (mg/kg)— 90
~) >Once a week J
4 Rifampicin (mg) — 450; then 900,1050 or plus 1200* ethambutol (mg/kg)— 25; then 90
}
Second Hong 1 Rifampicin (mg) — 900, 1050 or 1200* Kong retreatment plus study (1974a) ethambutol (mg/kg)— 90 plus pyrazinamide (g) — 2 0 , 2-5, 3 0 , 3-5 or 4 0 * Singapore studyf (1975)
Rhythm
Drugs and dosages
1 Rifampicin (mg) plus isoniazid (mg/kg)
— 900
2 Rifampicin (mg) plus isoniazid (mg/kg)
— 600
3 Rifampicin (mg) plus isoniazid (mg/kg) 4 Rifampicin (mg) plus isoniazid (mg/kg)
— 15
— 15 — 900 — 15 — 600 — 15
Daily for 2 months; then once a week
> Once a week Once a week for first 3 months
} }
Twice a week from 3rd week Twice a week from 3rd week
I Once a week from [ 3rd week I Once a week from [ 3rd week
•According to body weight. fAll patients received daily streptomycin plus isoniazid plusrifampicinfor the first 2 weeks.
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Fransisco on April 25, 2015
Patients In Hong Kong, adult Chinese patients with chronic, smear-positive, isoniazid-resistant pulmonary tuberculosis which had failed to respond to standard chemotherapy were admitted to 2 studies of retreatment regimens. In the first (Table I), patients were allocated at random to daily or intermittent rifampicin plus ethambutol or a standard reserve regimen (Hong Kong Tuberculosis Treatment Services/Brompton Hospital/ British Medical Research Council, 1974). In the second study, patients were allocated to once-weekly rifampicin plus ethambutol, with pyrazinamide once a week for the first 3 months (Hong Kong Tuberculosis Treatment Services/British Medical Research
Rifampicin antibodies and bacteriological response
267
Investigation procedures The methods of sputum examination by smear and culture, the identification of mycobacteria and their testing for drug sensitivity have been referred to previously (Hong Kong Tuberculosis Treatment Services/Brompton Hospital/British Medical Research Council, 1974; Hong Kong Tuberculosis Treatment Services/British Medical Research Council, 1974a; Singapore Tuberculosis Service/British Medical Research Council, 1975). Serum was tested for rifampicin-dependent antibodies by the indirect antiglobulin method (Worlledge, 1973). Results The bacteriological status at 12 months was based in the first Hong Kong Study on 3 sputum culture results in the Brompton Hospital laboratory and 3 in the Hong Kong laboratories (mean 5-8) at 10, 11 and 12 months, and in the second study on 6 in the Medical Research Council laboratory and 3 in the Hong Kong laboratories (mean 8-4) at 10, 11 and 12 months. In Singapore it was based on 6 results in the Medical Research Council laboratory and 2 in the Singapore laboratory (mean 7-4) at 10, 11 and 12 months. In all 3 studies, a favourable status was defined as all cultures negative, or no more than 2 positive. Of 13 patients in Hong Kong (Table II) who produced antibodies on the twice-weekly regimen, 85% had a favourable bacteriological status at 12 months, as had 74% of 34 patients without antibodies. The corresponding figures for patients on the once-weekly regimen were 82 and 89% and on the daily followed by once-weekly regimen, 90 and 90%.
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Fransisco on April 25, 2015
Council, 1974a). Serological tests for rifampicin antibodies at 2, 4, 6, 9 and 12 months were introduced in the first study a year after the intake had begun, and were done throughout the second study. There were 146 patients with culture-positive disease treated on the intermittent regimens, with sufficient results available for bacteriological and serological assessment at 12 months; 47 received rifampicin plus ethambutol twice a week; 60 once a week (28 from the first study and 32 from the second) and 39 daily for 2 months and then once a week. The daily rifampicin dosage (Table I) was 450 mg, and the dosages in the two intermittent regimens were 900 mg for patients weighing less than 90 lb (40-9 kg), 1050 mg for patients weighing 90 to 109 lb (40-9 to 49-5 kg) and 1200 mg for heavier patients. The ethambutol dosages were 25 mg/kg body weight daily, 45 mg/kg twice a week and 90 mg/kg once a week. Every dose of each regimen was given under the direct supervision of hospital or clinic staif. In Singapore, adult Chinese, Malay and Indian patients with newly diagnosed, smearpositive disease were allocated at random to 4 intermittent regimens of isoniazid plus rifampicin (Singapore Tuberculosis Service/British Medical Research Council, 1975). A total of 431 patients with culture-positive disease was assessed bacteriologically and serologically at 12 months. All patients received daily streptomycin 1-0 g (0-75 g for patients aged 40 years or more) plus isoniazid 300 mg plus rifampicin 450 mg for an initial 2 weeks. This was followed (Table I) either by isoniazid 15 mg/kg body weight plus rifampicin 900 mg (110 patients) or 600 mg (107 patients) twice a week, or by isoniazid 15 mg/kg plus rifampicin 900 mg (102 patients) or 600 mg (112 patients) once a week. Every dose of each regimen was given under the direct supervision of hospital or clinic staff. Serum samples were tested for rifampicin-dependent antibodies at 1, 2, 4, 6, 8, 10 and 12 months.
Rifampicin antibodies and bacteriological response
268
In Singapore (Table II), 50 of 110 patients on rifampicin 900 mg twice a week and 27 of 107 on 600 mg twice a week had antibodies, and every one of them had a favourable bacteriological status at 12 months. Of 47 patients with antibodies by 12 months on rifampicin 900 mg once a week, 96% had a favourable status at 12 months, as had 98% of 55 without antibodies. The corresponding figures for patients on the lower dosage once a week were 95 % of 37 and 92% of 75. Table n . Rifampicin antibodies and bacteriological status at 12 months
Hong Kong retreatment studies (1974, 1974a)
Singapore primary chemotherapy study (1975)
Knytnm
900-1200
Twice a week
900-1200
Once a week
900-1200 900 600 900 600
Antibodies by 12 months
Patients with a favourable status at 12 months No.
/o
Once a week from 3rd month
Present Absent Present Absent Present Absent
13 34 22 38 10 29
11 25 18 34 9 26
85 74 82 89 90 90
Twice a week from 3rd week Twice a week from 3rd week Once a week from 3rd week Once a week from 3rd week
Present Absent Present Absent Present Absent Present Absent
50 60 27 80 47 55 37 75
50 60 27 80 45 54 35 69
100 100 100 100 96 98 95 92
There was thus no evidence in any of the studies that the presence of antibodies had any effect on the therapeutic results. It is relevant that, in 6 of the 7 regimens studied, the majority of patients who formed antibodies, namely 140 (71 %) of 196, did so by 6 months. The exception was that only 3 of the 10 Hong Kong patients who produced antibodies during once-weekly chemotherapy after an initial 2-month daily phase did so by 6 months. However, 9 of these patients had antibodies detected by 9 months. Discussion If circulating antibodies to rifampicin, or indeed to any antibiotic or chemotherapeutic agent, can reduce its bioavailability and therapeutic efficacy, their effect would only be apparent when the antibiotic dosage schedule was such that therapeutic failures occurred, as was the case in the present studies. Furthermore, if antibodies bind sufficiently strongly to the antibiotic molecule to interfere with its therapeutic action, it should be possible to precipitate the complex by the Farr technique (Farr, 1958). Using this method, Nilsson, Boman & Bullock (1973) and Dukor, Schumann & Dietrich (1973) failed to demonstrate more protein binding of rifampicin in sera containing rifampicin antibodies than in control sera. It is thus unlikely that the rifampicin-dependent antibodies detected by the indirect antiglobulin method (Worlledge, 1973) could have a detrimental therapeutic effect, and this has proved to be the case even in the circumstances of the present studies in which rifampicin was given intermittently and in moderate or low dosages.
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Fransisco on April 25, 2015
Study
Rifampicin dosage (mg)
Rifampicin antibodies and bacteriological response
269
Acknowledgements In Hong Kong, the patients were inpatients in the Ruttonjee Sanatorium, Grantham Hospital, Haven of Hope Sanatorium or Kowloon Hospital, or outpatients attending the Wanchai, the Sai Ying Pun, the Shaukei Wan, the Yaumatei, the Kowloon, the Shek Kip Mei, or the Kwai Chung Chest Clinics. Bacteriological examinations were carried out at the hospital laboratories and at the Government Institute of Pathology. In Singapore, the patients were inpatients in the Tan Tock Seng Hospital or outpatients attending the clinics of the Outpatient Services. Bacteriological examinations were carried out at the Tuberculosis Control Unit. In London, bacteriological examinations were carried out for the first Hong Kong study at the Tuberculosis Laboratory of the Brompton Hospital and for the second Hong Kong study and for the Singapore study at the Medical Research Council Unit for Laboratory Studies of Tuberculosis. The tests for rifampicin-dependent antibodies were carried out in the Blood Transfusion Laboratory of the Royal Postgraduate Medical School. The analysis was undertaken and the report prepared on behalf of the co-operating physicians, whose names have been given in previous reports (Hong Kong Tuberculosis Treatment Services/Brompton Hospital/British Medical Research Council, 1974;
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Fransisco on April 25, 2015
Alternatively, there could be an association between the presence of antibodies and a favourable therapeutic response. Patients on a higher dosage of intermittent rifampicin have a higher incidence of antibodies than those on a lower dosage given in the same rhythm (Singapore Tuberculosis Service/British Medical Research Council, 1975). It could therefore be argued that on any one dosage schedule the patients in whom antibodies developed might be those who attained higher serum rifampicin concentrations and were thus more likely to obtain a successful therapeutic result. Indeed, in two studies in which serum rifampicin concentrations were measured, albeit not concurrently, in the same laboratory (The Medical Research Council Unit for Laboratory Studies of Tuberculosis) it was found that in 11 patients on once-weekly rifampicin who had antibodies, the geometric mean serum rifampicin concentration 4h after a dose was 27-11 ug/ml (Gabriel O'Mahoney & Chew, 1973), whereas in 11 similar patients on the same dosage schedule but without antibodies it was 20-91 ug/ml (Hong Kong Tuberculosis Treatment Services/British Medical Research Council, 1974Z>). However, the difference between these samples was not significant (0-05
Lack of association between rifampicin-dependent antibodies and bacteriological response during intermittent rifampicin treatment
In Hong Kong, 146 Chinese patients with sputum culture-positive pulmonary tuberculosis, whose treatment with first-line drugs had failed, were retreated with twice-weekly, once-weekly or daily and then once-weekly rifampicin plus ethambutol. In Singapore, 431 Chinese, Malay and Indian patients with newly diagnosed, culture-positive disease were treated with twice-weekly or once-weekly rifampicin plus isoniazid. At 12 months, on each regimen, the proportion of patients with a favourable bacteriological status and the proportion with an unfavourable status who had rifampicin-dependent antibodies in their serum was similar. There was thus no evidence that the presence of antibodies to rifampicin affected the therapeutic response.
Introduction
Circulating rifampicin-dependent antibodies are liable to develop in patients on intermittent but not on daily rifampicin (Worlledge, 1973). They may be associated with adverse reactions to rifampicin, especially the "flu" syndrome (Aquinas, Allan, Horsfall, Jenkins, Wong, Girling, Tall & Fox, 1972; Hong Kong Tuberculosis Treatment Services/ Brompton Hospital/British Medical Research Council, 1974). Patients may also develop antibodies without any adverse reaction to intermittent rifampicin, particularly those on a low dosage (Singapore Tuberculosis Service/British Medical Research Council, 1975). It could be argued that antibodies to rifampicin might reduce its bioavailability and so its therapeutic efficacy. Alternatively, since the incidence of antibodies depends upon the dose size ofrifampicin(Singapore Tuberculosis Service/British Medical Research Council, 1975) there could be an association in the opposite direction, antibodies being commoner in patients who achieve higher serum concentrations of rifampicin and who are thereby more likely to obtain a good therapeutic response. The present paper investigates whether there is an association between the presence of circulating antibodies and the bacteriological status at 12 months, in 2 studies in Hong Kong (Hong Kong Tuberculosis Treatment Services/Brompton Hospital/British Medical Research Council, 1974; Hong Kong Tuberculosis Treatment Services/British Medical Research Council, 1974a) and a study in Singapore (Singapore Tuberculosis Service/British Medical Reprints may be obtained from the Medical Research Council Tuberculosis and Chest Diseases Unit, Brompton Hospital, Fulham Road, London SW3 6HP, England. 265
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Fransisco on April 25, 2015
Hong Kong Tuberculosis Treatment Services, Singapore Tuberculosis Service, Royal Postgraduate Medical School, Brompton Hospital, British Medical Research Council
266
Rifampicin antibodies and bacteriological response
Research Council, 1975) in which patients with sputum culture-positive pulmonary tuberculosis were treated with intermittent regimens containing rifampicin. Plan and conduct of study
Table I. Rifampicin regimens studied Study
First Hong Kong 1 Rifampicin (mg) — 450 retreatment study plus (1974) ethambutol (mg/kg)— 25 for 2 months; then 15
V Daily J
2 Rifampicin (mg) — 900, 1050, or 1200* plus ethambutol (mg/kg)— 45
"1 V Twice a week J
3 Rifampicin (mg) — 900, 1050 or 1200* plus ethambutol (mg/kg)— 90
~) >Once a week J
4 Rifampicin (mg) — 450; then 900,1050 or plus 1200* ethambutol (mg/kg)— 25; then 90
}
Second Hong 1 Rifampicin (mg) — 900, 1050 or 1200* Kong retreatment plus study (1974a) ethambutol (mg/kg)— 90 plus pyrazinamide (g) — 2 0 , 2-5, 3 0 , 3-5 or 4 0 * Singapore studyf (1975)
Rhythm
Drugs and dosages
1 Rifampicin (mg) plus isoniazid (mg/kg)
— 900
2 Rifampicin (mg) plus isoniazid (mg/kg)
— 600
3 Rifampicin (mg) plus isoniazid (mg/kg) 4 Rifampicin (mg) plus isoniazid (mg/kg)
— 15
— 15 — 900 — 15 — 600 — 15
Daily for 2 months; then once a week
> Once a week Once a week for first 3 months
} }
Twice a week from 3rd week Twice a week from 3rd week
I Once a week from [ 3rd week I Once a week from [ 3rd week
•According to body weight. fAll patients received daily streptomycin plus isoniazid plusrifampicinfor the first 2 weeks.
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Fransisco on April 25, 2015
Patients In Hong Kong, adult Chinese patients with chronic, smear-positive, isoniazid-resistant pulmonary tuberculosis which had failed to respond to standard chemotherapy were admitted to 2 studies of retreatment regimens. In the first (Table I), patients were allocated at random to daily or intermittent rifampicin plus ethambutol or a standard reserve regimen (Hong Kong Tuberculosis Treatment Services/Brompton Hospital/ British Medical Research Council, 1974). In the second study, patients were allocated to once-weekly rifampicin plus ethambutol, with pyrazinamide once a week for the first 3 months (Hong Kong Tuberculosis Treatment Services/British Medical Research
Rifampicin antibodies and bacteriological response
267
Investigation procedures The methods of sputum examination by smear and culture, the identification of mycobacteria and their testing for drug sensitivity have been referred to previously (Hong Kong Tuberculosis Treatment Services/Brompton Hospital/British Medical Research Council, 1974; Hong Kong Tuberculosis Treatment Services/British Medical Research Council, 1974a; Singapore Tuberculosis Service/British Medical Research Council, 1975). Serum was tested for rifampicin-dependent antibodies by the indirect antiglobulin method (Worlledge, 1973). Results The bacteriological status at 12 months was based in the first Hong Kong Study on 3 sputum culture results in the Brompton Hospital laboratory and 3 in the Hong Kong laboratories (mean 5-8) at 10, 11 and 12 months, and in the second study on 6 in the Medical Research Council laboratory and 3 in the Hong Kong laboratories (mean 8-4) at 10, 11 and 12 months. In Singapore it was based on 6 results in the Medical Research Council laboratory and 2 in the Singapore laboratory (mean 7-4) at 10, 11 and 12 months. In all 3 studies, a favourable status was defined as all cultures negative, or no more than 2 positive. Of 13 patients in Hong Kong (Table II) who produced antibodies on the twice-weekly regimen, 85% had a favourable bacteriological status at 12 months, as had 74% of 34 patients without antibodies. The corresponding figures for patients on the once-weekly regimen were 82 and 89% and on the daily followed by once-weekly regimen, 90 and 90%.
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Fransisco on April 25, 2015
Council, 1974a). Serological tests for rifampicin antibodies at 2, 4, 6, 9 and 12 months were introduced in the first study a year after the intake had begun, and were done throughout the second study. There were 146 patients with culture-positive disease treated on the intermittent regimens, with sufficient results available for bacteriological and serological assessment at 12 months; 47 received rifampicin plus ethambutol twice a week; 60 once a week (28 from the first study and 32 from the second) and 39 daily for 2 months and then once a week. The daily rifampicin dosage (Table I) was 450 mg, and the dosages in the two intermittent regimens were 900 mg for patients weighing less than 90 lb (40-9 kg), 1050 mg for patients weighing 90 to 109 lb (40-9 to 49-5 kg) and 1200 mg for heavier patients. The ethambutol dosages were 25 mg/kg body weight daily, 45 mg/kg twice a week and 90 mg/kg once a week. Every dose of each regimen was given under the direct supervision of hospital or clinic staif. In Singapore, adult Chinese, Malay and Indian patients with newly diagnosed, smearpositive disease were allocated at random to 4 intermittent regimens of isoniazid plus rifampicin (Singapore Tuberculosis Service/British Medical Research Council, 1975). A total of 431 patients with culture-positive disease was assessed bacteriologically and serologically at 12 months. All patients received daily streptomycin 1-0 g (0-75 g for patients aged 40 years or more) plus isoniazid 300 mg plus rifampicin 450 mg for an initial 2 weeks. This was followed (Table I) either by isoniazid 15 mg/kg body weight plus rifampicin 900 mg (110 patients) or 600 mg (107 patients) twice a week, or by isoniazid 15 mg/kg plus rifampicin 900 mg (102 patients) or 600 mg (112 patients) once a week. Every dose of each regimen was given under the direct supervision of hospital or clinic staff. Serum samples were tested for rifampicin-dependent antibodies at 1, 2, 4, 6, 8, 10 and 12 months.
Rifampicin antibodies and bacteriological response
268
In Singapore (Table II), 50 of 110 patients on rifampicin 900 mg twice a week and 27 of 107 on 600 mg twice a week had antibodies, and every one of them had a favourable bacteriological status at 12 months. Of 47 patients with antibodies by 12 months on rifampicin 900 mg once a week, 96% had a favourable status at 12 months, as had 98% of 55 without antibodies. The corresponding figures for patients on the lower dosage once a week were 95 % of 37 and 92% of 75. Table n . Rifampicin antibodies and bacteriological status at 12 months
Hong Kong retreatment studies (1974, 1974a)
Singapore primary chemotherapy study (1975)
Knytnm
900-1200
Twice a week
900-1200
Once a week
900-1200 900 600 900 600
Antibodies by 12 months
Patients with a favourable status at 12 months No.
/o
Once a week from 3rd month
Present Absent Present Absent Present Absent
13 34 22 38 10 29
11 25 18 34 9 26
85 74 82 89 90 90
Twice a week from 3rd week Twice a week from 3rd week Once a week from 3rd week Once a week from 3rd week
Present Absent Present Absent Present Absent Present Absent
50 60 27 80 47 55 37 75
50 60 27 80 45 54 35 69
100 100 100 100 96 98 95 92
There was thus no evidence in any of the studies that the presence of antibodies had any effect on the therapeutic results. It is relevant that, in 6 of the 7 regimens studied, the majority of patients who formed antibodies, namely 140 (71 %) of 196, did so by 6 months. The exception was that only 3 of the 10 Hong Kong patients who produced antibodies during once-weekly chemotherapy after an initial 2-month daily phase did so by 6 months. However, 9 of these patients had antibodies detected by 9 months. Discussion If circulating antibodies to rifampicin, or indeed to any antibiotic or chemotherapeutic agent, can reduce its bioavailability and therapeutic efficacy, their effect would only be apparent when the antibiotic dosage schedule was such that therapeutic failures occurred, as was the case in the present studies. Furthermore, if antibodies bind sufficiently strongly to the antibiotic molecule to interfere with its therapeutic action, it should be possible to precipitate the complex by the Farr technique (Farr, 1958). Using this method, Nilsson, Boman & Bullock (1973) and Dukor, Schumann & Dietrich (1973) failed to demonstrate more protein binding of rifampicin in sera containing rifampicin antibodies than in control sera. It is thus unlikely that the rifampicin-dependent antibodies detected by the indirect antiglobulin method (Worlledge, 1973) could have a detrimental therapeutic effect, and this has proved to be the case even in the circumstances of the present studies in which rifampicin was given intermittently and in moderate or low dosages.
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Fransisco on April 25, 2015
Study
Rifampicin dosage (mg)
Rifampicin antibodies and bacteriological response
269
Acknowledgements In Hong Kong, the patients were inpatients in the Ruttonjee Sanatorium, Grantham Hospital, Haven of Hope Sanatorium or Kowloon Hospital, or outpatients attending the Wanchai, the Sai Ying Pun, the Shaukei Wan, the Yaumatei, the Kowloon, the Shek Kip Mei, or the Kwai Chung Chest Clinics. Bacteriological examinations were carried out at the hospital laboratories and at the Government Institute of Pathology. In Singapore, the patients were inpatients in the Tan Tock Seng Hospital or outpatients attending the clinics of the Outpatient Services. Bacteriological examinations were carried out at the Tuberculosis Control Unit. In London, bacteriological examinations were carried out for the first Hong Kong study at the Tuberculosis Laboratory of the Brompton Hospital and for the second Hong Kong study and for the Singapore study at the Medical Research Council Unit for Laboratory Studies of Tuberculosis. The tests for rifampicin-dependent antibodies were carried out in the Blood Transfusion Laboratory of the Royal Postgraduate Medical School. The analysis was undertaken and the report prepared on behalf of the co-operating physicians, whose names have been given in previous reports (Hong Kong Tuberculosis Treatment Services/Brompton Hospital/British Medical Research Council, 1974;
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Fransisco on April 25, 2015
Alternatively, there could be an association between the presence of antibodies and a favourable therapeutic response. Patients on a higher dosage of intermittent rifampicin have a higher incidence of antibodies than those on a lower dosage given in the same rhythm (Singapore Tuberculosis Service/British Medical Research Council, 1975). It could therefore be argued that on any one dosage schedule the patients in whom antibodies developed might be those who attained higher serum rifampicin concentrations and were thus more likely to obtain a successful therapeutic result. Indeed, in two studies in which serum rifampicin concentrations were measured, albeit not concurrently, in the same laboratory (The Medical Research Council Unit for Laboratory Studies of Tuberculosis) it was found that in 11 patients on once-weekly rifampicin who had antibodies, the geometric mean serum rifampicin concentration 4h after a dose was 27-11 ug/ml (Gabriel O'Mahoney & Chew, 1973), whereas in 11 similar patients on the same dosage schedule but without antibodies it was 20-91 ug/ml (Hong Kong Tuberculosis Treatment Services/British Medical Research Council, 1974Z>). However, the difference between these samples was not significant (0-05
