Tuber& and Lung Disease (1992) 73.5947 A controlled study of rifabutin and an uncontrolled study of ofloxacin in the retreatment of patients with pulmonary tuberculosis resistant to isoniazid, streptomycin and rifampicin Hong Kong Chest Service/British Medical Research Council S U MMA R Y. A study of rifabutin in the retreatment of patients with chronic pulmonary tuberculosis whose strains of tubercle bacilli were resistant to all three of the drugs isoniazid, streptomycin, and rifampicin, and usually to others as well, was undertaken in 22 Chinese patients in Hong Kong. They were arranged in 11 pairs such that the resistance pattern of the strains for both patients was the same or closely similar. One of each pair was allocated at random to receive rifabutin (B) daily and the other rifampicin (R) daily. The two members of each pair were also prescribed the same or similar companion drugs, selected on the basis of the results of susceptibility tests and of the history of previous antituberculosis chemotherapy. The bacteriological results showed no evidence of a sustained benefit in any patient. A temporary response was seen on sputum smear examination in 14 patients (7B, 7R), of whom 10 (5B, 5R) had a period of smear-negativity, and on sputum culture examination in 10 patients (SB, SR), of whom 3 (2B, 1R) had a period of culture-negativity. The duration of response was longer for the B patient in 5 pairs and for the R patient in 5. Two patients (both B) had rifabutht-susceptible strains on admission to the study; their temporary responses were among the best and were associated with the emergence of rifabutin resistance, suggesting that rifabutin may have contributed to their response. A total of 17 patients, including 7 not in the paired comparison, were subsequently retreated with ofloxacin; 10 showed a response, disease becoming and remaining quiescent in 3. The results suggest that rifabutin does not have a useful role in the retreatment of patients with multidrug-resistant pulmonary tuberculosis, which includes rifampicin resistance, except possibly in a small proportion of patients who have rifabutin-susceptible strains. Ofloxacin appears to be a better drug to use, in combination with any companion drugs still available. R XI? S UM I?. Une etude sur la rifabutin dans le retraitement de malades atteints d’une tuberculose pulmonaire chronique dont les souches de bacilles tuberculeux resistaient a l’ensemble des trois drogues: isonazide, streptomycine et rifampicine - et habituellement a d’autres Cgalement - a Cte entreprise a Hongkong sur 22 malades chmois. Ils ont et6 apparies (11 groupes de deux) en fonction d’une resistance des souches identique ou trb proche. Un des deux patients recevait apres randomisation un traitement quotidien par rifabutin (B), et l’autre par rifampichre (R). Chacun d’eux recevait des medicaments associes, identiques ou similaires et d&ermines selon les rbultats des etudes de sensibilite et la nature de la chhniothdrapie antituberculeuse anterieure. Les r6sultats bacteriologiques n’ont montre aucune evidence d’un benefice stable chez aucun patient. Une reponse temporaire a et6 notee 3r l’examen des frottis de 14 malades (7B, 7R) (dont 10 - 5B, 5R - ont eu une p&Me le bacilloscopie negative), et sur la culture des crachats de 10 malades (5B, 5R) (dont 3 - 2B, 1R - ont eu une p&ode de culture negative). La dur6e de reponse etait plus longue pour le malade B dans 5 paires, et pour le malade R dans 5 paires. 2 malades (tous les deux B) avaient eu des souches sensibles B la rifabutin lors de l’admission dans l’etude; leurs reponses temporaires etaient parmi les meilleures et s’associaient a Wmergence d’une resistance a la rifabutin, ce qui suggere que la rifabutin a pu contribuer 21 cette reponse favorable. Un total de 17 malades, y compris 7 qui ne faisaient pas pat-tie de la comparaison par paires, ont CtC soumis par la suite a un retraitement par l’ofloxacine; 10 ont montre une reponse favorable et Correspondence to: Dr D. J. Girling, MRC Cancer Trials Office, 1 Brooklands Avenue, Cambridge CB2 2BB, UK. Requests for reprints to: Dr 1). J. Girling, MRC Cancer Trials Office, 1 -Brooklands Avenue, Cambridge, CB2 2BB, UK or to Dr S. L. Chan, Wanchai Chest Clinic, Kennedy Road, Wanchai, Hong Kong. 59
Transcript
Tuber& and Lung Disease (1992) 73.5947
A controlled study of rifabutin and an uncontrolled study of ofloxacin in the retreatment of patients with pulmonary tuberculosis resistant to isoniazid, streptomycin and rifampicin
Hong Kong Chest Service/British Medical Research Council
S U MMA R Y. A study of rifabutin in the retreatment of patients with chronic pulmonary tuberculosis whose strains of tubercle bacilli were resistant to all three of the drugs isoniazid, streptomycin, and rifampicin, and usually to others as well, was undertaken in 22 Chinese patients in Hong Kong. They were arranged in 11 pairs such that the resistance pattern of the strains for both patients was the same or closely similar. One of each pair was allocated at random to receive rifabutin (B) daily and the other rifampicin (R) daily. The two members of each pair were also prescribed the same or similar companion drugs, selected on the basis of the results of susceptibility tests and of the history of previous antituberculosis chemotherapy. The bacteriological results showed no evidence of a sustained benefit in any patient. A temporary response was seen on sputum smear examination in 14 patients (7B, 7R), of whom 10 (5B, 5R) had a period of smear-negativity, and on sputum culture examination in 10 patients (SB, SR), of whom 3 (2B, 1R) had a period of culture-negativity. The duration of response was longer for the B patient in 5 pairs and for the R patient in 5. Two patients (both B) had rifabutht-susceptible strains on admission to the study; their temporary responses were among the best and were associated with the emergence of rifabutin resistance, suggesting that rifabutin may have contributed to their response. A total of 17 patients, including 7 not in the paired comparison, were subsequently retreated with ofloxacin; 10 showed a response, disease becoming and remaining quiescent in 3. The results suggest that rifabutin does not have a useful role in the retreatment of patients with multidrug-resistant pulmonary tuberculosis, which includes rifampicin resistance, except possibly in a small proportion of patients who have rifabutin-susceptible strains. Ofloxacin appears to be a better drug to use, in combination with any companion drugs still available.
R XI? S UM I?. Une etude sur la rifabutin dans le retraitement de malades atteints d’une tuberculose pulmonaire chronique dont les souches de bacilles tuberculeux resistaient a l’ensemble des trois drogues: isonazide, streptomycine et rifampicine - et habituellement a d’autres Cgalement - a Cte entreprise a Hongkong sur 22 malades chmois. Ils ont et6 apparies (11 groupes de deux) en fonction d’une resistance des souches identique ou trb proche. Un des deux patients recevait apres randomisation un traitement quotidien par rifabutin (B), et l’autre par rifampichre (R). Chacun d’eux recevait des medicaments associes, identiques ou similaires et d&ermines selon les rbultats des etudes de sensibilite et la nature de la chhniothdrapie antituberculeuse anterieure. Les r6sultats bacteriologiques n’ont montre aucune evidence d’un benefice stable chez aucun patient. Une reponse temporaire a et6 notee 3r l’examen des frottis de 14 malades (7B, 7R) (dont 10 - 5B, 5R - ont eu une p&Me le bacilloscopie negative), et sur la culture des crachats de 10 malades (5B, 5R) (dont 3 - 2B, 1R - ont eu une p&ode de culture negative). La dur6e de reponse etait plus longue pour le malade B dans 5 paires, et pour le malade R dans 5 paires. 2 malades (tous les deux B) avaient eu des souches sensibles B la rifabutin lors de l’admission dans l’etude; leurs reponses temporaires etaient parmi les meilleures et s’associaient a Wmergence d’une resistance a la rifabutin, ce qui suggere que la rifabutin a pu contribuer 21 cette reponse favorable. Un total de 17 malades, y compris 7 qui ne faisaient pas pat-tie de la comparaison par paires, ont CtC soumis par la suite a un retraitement par l’ofloxacine; 10 ont montre une reponse favorable et
Correspondence to: Dr D. J. Girling, MRC Cancer Trials Office, 1 Brooklands Avenue, Cambridge CB2 2BB, UK.
Requests for reprints to: Dr 1). J. Girling, MRC Cancer Trials Office, 1 -Brooklands Avenue, Cambridge, CB2 2BB, UK or to Dr S. L. Chan, Wanchai Chest Clinic, Kennedy Road, Wanchai, Hong Kong.
59
60 Tubercle and Lung Disease
pour 3 d’entre eux la maladie est devenue et est demeurke quiescente. Les rhultats suggkrent que la rifabutin n’a pas de r6le utile dans le retraitement de malades atteints d’une tuberculose pulmonaire multirkistante, incluant une histance h la rifampicine, sauf possiblement dans une proportion 1imitCe de maiades porteurs de soucbelj sensibles h la rifabutin. L’ofloxacine semble une meilleure drogue B utiliser, combinCe avec toute autre drogue associCe encore disponible.
R E S U M E N. En Hong Kong se realiz6 un estudio en 22 pacientes chinos, sobre la eficacia de la rifabutina en el retratamiento de la tuberculosis pulmonar crhica con cepas de bacilos tuberculosos resistentes a 3 medicamentos, la isoniacida, la estreptomicina y la rifampicina, y babitualmente a otras. Fueron agrupados en 11 pares, de manera tal que el patrh de resistencia de las cepas de ambos pacientes fuese el mismo o muy similar. Cada uno de 10s individuos de1 par fue asiguado en forma randomizada a un tratamiento cotidiano ya sea con rifabutina (B) o rifampicina (R). Ambos componentes de1 par recibieron igualmente medicamentos asociados, que podian ser 10s mismos o similares, seleccionado en base a 10s resultados de 10s tests de sensibilidad y a 10s antecedentes de quimioterapia antituberculosa. Los resultados bacteriolhgicos no indican evidencias de un beneficio sostenido en ninguno de 10s pacientes. En 14 pacientes se observ6 una respuesta temporal evaluada en base al examen de 10s frotis de esputo (7B, 7R), de 10s cuales 10 (5B, 5R) tuvieron un period0 de baciloscopia negativa; de 10 pacientes (5B, 5R) en quienes se efectu6 cultivo de esputo, 3 (2B, 1R) presentaron un period0 de cultivos negativos. La duracih de la respuesta fue mL prolongada para el paciente B en 5 pares y para el paciente R en 5. DOS pacientes (ambos B) presentaban cepas sensibles a la rifabutina al ingreso al estudio; sus respuestas temporales se situaban entre las mejores y estaban asociadas con la emergencia de la resistencia a la rifabutina, sugiriendo que la rifabutina puede baber contribuido a su respuesta. Un total de 17 pacientes, incluyendo 7 no comparados en 10s pares, fueron subsecuentemente retratados con ofloxacina; 10 presentaron una respuesta, y en 3 la enfermedad se bizo quiescente y permaneci6 coma tal. Los resultados sugieren que la rifabutina no tiene utilidad en el retratamiento de 10s pacientes con tuberculosis pulmonar multirresistente, lo cual incluye la resistencia a la rifampicina, except0 posiblemente en un pequeiio porcentaje de pacientes que presentan cepas sensibles a la rifabutina. La ofloxacina parece ser un mejor medicamento, y puede utilizarse en combinacih con cualquiera de 10s medicamentos de asociacih todavia disponibles.
INTRODUCTION
Kifabutin (ansamycin, LM427) is a Spiro-piperidyl rifamycin which is highly active against Mycobacterium
tuberculosis. ’ Moreover, some clinical isolates of tubercle bacilli resistant to rifampicin have been found
to be susceptible to rifabutir? 3, and some patients with
rifampicin-resistant pulmonary tuberculosis have shown
a favourable clinical and bacteriological response to the
drug.4 The main aim of this study was to find out whether
rifabutin has a role in the retreatment of patients with
ment both with primary chemotherapy and with standard retreatment regimens has failed, and who are excreting
strains of tubercle bacilli resistant to most if not all of the antituberculosis drugs, including all three of the
drugs isoniazid, streptomycin, and rifampicin. A subsidiary aim was to investigate, in patients no longer responding to rifabutin administration, whether there is a role in retreatment for ofloxacin, one of the 5- fluoroquinolones with the greatest in vitro activity against M. tuberculosis. Ofloxacin has been shown to have bactericidal action against M. tuberculosis in vitro without cross-resistance with other antituberculosis drugs;, 6 and to have in vivo activity as well.’ There is also evidence that it may benefit patients with chronic
pulmonary tuberculosis, and that the risk of adverse
effects is small.8
METHODS
Patients and treatment regimens
The patients in the study were identified from among
patients with chronic pulmonary tuberculosis attending the Hong Kong Government Chest Service whose
treatment both with primary chemotherapy and with
retreatment regimens had failed. At the time of admission, all of them were excreting strains of tubercle bacilli found in the London laboratory to be resistant to
all three of the drugs isoniazid, streptomycin, and rifampicin, and to other drugs as well. All had received long periods of antituberculosis chemotherapy about
which a history was obtained. On the basis of the results of susceptibility tests in the London laboratory to isoniazid, streptomycin, rifampicin, pyrazinamide,
ethambutol, prothionamide/ethionamide, kanamycin, para-aminosalicylic acid (PAS), and capreomycin, the patients were arranged in pairs in the coordinating centre in London such that the resistance pattern of their strains of bacilli was the same or closely similar. One member of each pair was then allocated at random to daily treatment with rifabutin (450mg for patients weighing
Rifabutin and ofloxacin in retreatment of TB 61
less than 50 kg and 600 mg for heavier patients), and the
other to daily treatment with rifampicin (in the same
dosages as for rifabutin). In addition, the two members of each pair were treated with the same or similar
companion drug or drugs, selected on the basis of the results of the London susceptibility tests and the history
of previous antituberculosis chemotherapy. The daily
dosages used were pyrazinamide 1.5 g (2.0 g for patients weighing 50 kg or more), ethambutol 25 mg/kg for 2
months and then 15 mg/kg, prothionamide or ethionarnide 500 mg, kanamycin 750 mg i.m. 5 days per
week, PAS (sodium salt) 10 g, and capreomycin 750 mg i.m. 5 days per week, all given together as a single dose
daily under the direct supervision of hospital or
outpatient clinic staff. The details of every dose were
recorded on a special treatment sheet. The aim was to treat all the patients for at least 12
months, preferably as inpatients for at least the first 3 months. If a patient was responding satisfactorily,
treatment was to be continued for a total of at least 18 months. If a patient allocated to receive rifampicin failed
to respond bacteriologically during a period of at least 6 months, or having responded deteriorated again, the
rifampicin could be replaced by rifabutin. If a patient failed to respond to rifabutin, this could be replaced by
ofloxacin in a single daily dose of 800 mg.
The study protocol was approved by the Ethics Committee of the Hong Kong Medical and Health
Services; informed consent was obtained from all the
patients.
Assessment of progress
For the paired comparison, reports were made on each patient on admission, then every 4 weeks to 24 weeks,
then at 6 months and at every calendar month to 24
months. On admission, the weight, haemoglobin
concentration, plasma bilirubin, alanine aminotransferase (ALT), alkaline phosphatase (AP), urea and creatinine concentrations were recorded, and at each subsequent
assessment to 12 months the plasma bilirubin, ALT, and
AP were recorded. At each assessment, the nature, severity, and management of any adverse effects were
recorded. A posteroanterior chest radiograph was
obtained on admission, at 16 weeks, and at 6 and 12 months. Three sputum specimens were sent to the
London laboratory on admission; 1 specimen was sent every 2 weeks during the first 16 weeks, then 1 speci-
men at every subsequent assessment, except that 2
specimens were sent at 6 and 12 months, and 3
whenever a change in chemotherapy was made. During
the uncontrolled assessments of rifabutin and ofloxacin,
the patients were assessed and sputum specimens
obtained with the same frequency as in the paired
comparisons. All sputum specimens were examined by smear and
culture in the London laboratory. Positive cultures were
identified and 2 cultures from specimens obtained on
admission to the paired comparison were tested for susceptibility to the full range of drugs, and all
subsequent positive cultures to both rifabutin and
rifampicin and to the other drugs being administered at
the time. Before any change in treatment was made,
susceptibility tests were done to both rifabutin and rifampicin, and to any new companion drugs to be
prescribed. The bacteriological methods have been
reported previously.’ The drug concentrations used in the susceptibility tests and the definitions of resistance are shown in Table 1. The definitions of resistance were based on titrations of fully drug-susceptible strains of
Table 1. Drug concentrations used in susceptibility tests and definitions of resistance
Drug* Concentration (mg/I)
Definitions of resistance: minimal inhibitory concentrations Doubtfully Resistant resistant
*Susceptibility tests were set up on Lijwenstein-Jensen (LJ) medium unless otherwise indicated. Rifabutin and rifampicin tests were set up on both L J medium and 7Hll medium. Pyrazinamide tests were set up on acid L J medium.
62 Tubercle and Lung Disease
tubercle bacilli obtained from untreated patients with culture results on admission were all negative. There pulmonary tuberculosis in Hong Kong. remained 11 pairs for comparison.
RESULTS
Patients studied
Between June 1986 and January 1988, 88 patients were screened for possible eligibility for the paired
comparison. Of these, 54 were ineligible, 18 because
their bacilli were susceptible to one or more of the drugs
isoniazid, streptomycin and rifampicin, 13 because all
their cultures were negative or no susceptibility test
results were available, 13 because they died before the
results of the susceptibility tests were known, 6 because they declined to participate and 4 because they were
already receiving ofloxacin. Of the remaining 34 eligible patients who were paired and randomised, 12 were
excluded from analysis, 6 because they missed more than 9 of the first 16 weeks of their allocated regimen, 3
because they were given ofloxacin from the start in
addition to their allocated drugs and 3 because their
Characteristics of the patients on admission
The characteristics on admission of the 11 pairs of
patients are shown in Table 2. As stipulated in the criteria of eligibility, all the patients had bacilli resistant
to isoniazid, streptomycin and rifampicin. Only 2
patients had bacilli susceptible to rifabutin, namely the
first patient in pair 2 and the first patient in pair 10; thus
both were, by chance, allocated to be treated with this
drug. Two patients (pair 3) had bacilli susceptible to pyrazinamide. Among the 7 patients without a
pyrazinamide susceptibility test result available on admis- sion, 3 (6:R, 9:R, 10:R) subsequently had a susceptible
culture. In the remaining 4, no results were available.
Bacteriological results
The bacteriological results showed no evidence of
Table 2. Characteristics of the patents on admission
*B = rifabotin, R = rifampicin, Z = pyrazinamide, M = ethambutol, E = ethionamidc/prothionamide, K = kanamycin, p = PAS, A = capreomycin.
Rifabutin and ofloxacin in retreatment of TR 63
Table 3. Temporary responses in smear and culture results
Pair Test* Rifabutin patients Response Week Duration started (weeks)
Negative Week Duration started (weeks)
Rifampicin patients Response Week Duration started (weeks)
Negative Longer Week Duration response started (weeks)
I S 2 6 _ _ _ _ 20 12
C _ _ _ _ 14 6 _ _ Rifampicin 2 s 6 36 6 24 _ _ _ _
C 10 16 14 12 _ _ _ _ Rifabutin 3 s _ _ _ _ 16 8 _ _
C _ _ _ _ 24 8 _ _ Rifampicin
4 s 2 14 4 10 18 6 18 6 C 2 12 _ _ _ _ _ _ Rifabutin
5 s 4 24 _ IO 8 12 6 C 2 14 _ _ _ _ _ _ Rifabutin
6 s 6 16 _ _ _ 2 24 C _ _ 2 16 2 16 Rifampicin
7 S 12 IO 12 10 6 6 6 6 C 14 8 14 8 _ _ _ Rifabutin
8 S _ _ _ _ 4 14 _ _
C _ _ _ _ 2 6 _ _ Rifampicin 9 S _ _ _ _ _ _ _ _
C _ _ _ _ _ _ Neither 10 S 2 16 2 8 8 14 _ _
C 2 12 _ _ _ _ _ _ Rifabutin 11 S _ _ 6 6 20 24 _ _
C _ _ _ _ 14 8 _ _ Rifampicin
*S = smear; C = culture.
See text for definitions of response.
sustained benefit in any patient. A temporary response
on smear result was defined as a reduction from heavy
or moderate to scanty or negative for 6 or more consecutive weeks, and on culture result from confluent
growth or innumerable colonies to 20+ or less for 6 or
more consecutive weeks. The periods for which temporary responses were obtained in smear and culture results are shown in Table 3, which also shows the
periods (of 6 or more consecutive weeks) for which smears and cultures were negative. On smear results, 14
patients (7B, 7R) showed a response including 10 (5B, 5R) with a 6-week or longer period of negativity. On
culture results, 10 (5B, 5R) showed a response including
3 (2B, IR) with a period of negativity. Within the 11
pairs, the duration of response was longer for the B patient in 5 pairs and for the R patient in 5; in the
remaining pair, neither patient showed a response. Of the 2 patients with rifabutin-susceptible strains (pairs 2 and lo), both of whom were in the B group, 1
responded for 36 weeks on smear (results being negative for 24 weeks) and for 16 weeks on culture
(negative for 12 weeks); the other responded for 16 weeks on smear (negative for 8 weeks) and for 12
weeks on culture. In the first, rifabutin resistance emerged during the first 2 weeks of treatment, and in
the second during the 14th week. Of the 11 R patients, 5 (from pairs 1, 2, 4, 5, 8) were treated with rifabutin once it had become clear that they were not responding or were no longer responding to their rifampicin
regimen. Only 1 (pair 8) showed a temporary response: on smear for 10 weeks and on culture for 6 weeks
without smear or culture negativity. One other patient
excluded from the paired comparison because of
inadequate treatment with rifampicin and prothionamide
was treated with rifabutin without response on either
smear or culture.
The results suggest that rifabutin and rifampicin had little beneficial effect. It is likely that such temporary responses as were obtained resulted mainly from the action of the companion drug or drugs. Nevertheless, the
temporary responses in the 2 patients with rifabutin-
susceptible bacilli were among the best and were associated with the rapid development of rifabutin
resistance, suggesting that the drug contributed to the
response in these 2 patients.
Response to ofloxacin
A total of 17 patients were treated with ofloxacin (Table
4), namely 10 (patients 1, 2, 3, 5, 6, 7, 9, 12, 13, 16) from the paired comparison, 4 (4, 8, 10, 11) who were excluded from the paired comparison, and 3 who were given the drug in addition to their originally allocated
regimen. Ofloxacin MICs were available for 13 patients
before administration of the drug was started, the bacilli being susceptible in 10. The remaining 3 had strains
initially resistant, the MICs being greater than 9.6 mg/l both before and during the early weeks of treatment with ofloxacin. No history of previous treatment with
ofloxacin was obtained from any of the 17 patients. Of the 14 patients with strains susceptible to ofloxacin or in whom susceptibility test results were not available. 10
Patient Regimen* MfC (mgn) Test+ started (weeks) started (weeks)
1 0 2.4
2 0 1.2
3 0 2.4
4 0 >9.6
5 0 1.2
6 OP >9.6
I OP 1.2
8 OM >9.6
9 OA 2.4
10 OB 1.2
11 oz NA
12 OAP 2.4
13 OAP 1.2
14 OEZ NA
15 OKR NA
16 OBE 1.2
17 OBME NA
s _ C _
S _
C _
s C s C S 1 C 1 S _
C _
S 12 C 2 S -
C S 14 C _
S 6 C 6 S 12 C 16 S C 2 S _
C 8 S _
C 22 S _
C 2 S C 2 S -
C _
_ _ _
12 10 _
26 36
14
6 6
33+months 32+months
50 _
20+months _
8 _
16 _
15+months _ _
- _ _ - _ _ _ _ 1 1 _ -
16 - _
20
_ _
16 16
8 8
16 16 _ _
1 8
10 6 _
_ _ _ _ - - - _ 8 8 - -
10 - - -
8 - _ _
32+months 32+months 22 22 18+months 18+months _ _
16 6
14+months lS+months
*0 = ofloxacin; P = PAS; M = ethambuthol; A = capreomycin; B = rifabutin; Z = pyrazinamide; E = ethionamide/prothionamide; K = kanamycin; R = rifampicin.
+S = smear: C = culture
showed a response (defined as in the paired com- parison), 1 to ofloxacin alone. They included 6 of the 10
whose treatment in the paired comparison had failed, and none of the 3 patients with initially ofloxacin-
resistant bacilli. Response was temporary in 7 patients
(5, 7, 9, 10, 12, 14, 15), the duration of response on smear ranging from 6 to 26 weeks, and on culture from 6
to 50 weeks. MICs were available for 5 of the 7 and indicated a high level of resistance (greater than 9.6mg/l) during ofloxacin administration in all 5. In 3
other patients (11, 13, 16), the disease was rendered quiescent, the ofloxacin regimen being given for a total
of 12 months (patient 11) and 18 months (patients 13
and 16). In all 3 cases, their disease is still quiescent, smears and cultures having been negative for between 14 and 32 months without relapse. All 3 remain on follow-up. Two (patients 13 and 16) had been in the paired comparison (B group pair 2, R group pair 6), and the cultures remained ofloxacin-susceptible until conver- sion to negativity in both. The third had been excluded from the paired comparison because of inadequate treat- ment in the B series; no ofloxacin MICs were available.
Adverse reactions reported
The analysis of adverse reactions during rifabutin and rifampicin administration (Table 5) was based on the 15
B patients and 19 R patients who started treatment on their originally allocated regimen. They include the 3 patients (lB, 2R) who were given ofloxacin in addition
to their allocated regimen. Reactions were common in both series, being reported in 12 patients in each group, but many were attributed to companion drugs. Of the 11
patients (7B, 4R) who had the administration of one or more drugs terminated, 1 of 15 had rifabutin withdrawn,
2 of 19 rifampicin, and 11 of the 34 one or more
companion drugs, namely 4 of 18 ethambutol, 4 of 17 prothionamide, 2 of 12 kanamycin, 2 of 14 PAS and 2 of 5 capreomycin. No patient had hepatitis but 2 patients (both B) had chemotherapy interrupted transiently because of raised ALT concentrations, and a further 5 (3B, 2R) had transiently raised ALT concentrations without any modification to chemotherapy. Two patients (1 in each group) had impaired renal function, but it was not considered to have been drug-induced, both patients
Rifabutin and ofloxacin in retreatment of TB 65
Table 5. Adverse reactions reported and modifications to chemotherapy made in their management based on 15 B and 19 R patients
Patients Month of start Modification to chemotherapy
Interruption Drug(s) terminated
Reaction Rifamycin with allocated* reaction 1 2 3 4-6 later Nil ~1 days 27 days Total B/R M E K P A
Any
Nausea, anorexia without vomiting
Vomiting
Cutaneous
Dizziness
Tinnitus
Deafness
Joint pains, bone pains
Fever
Hepatic, no symptoms
Reduced renal function
Impaired vision
Thrombocytopenia
B R
B R
B R
B R
B R
B R
B R
B R
B R
B R
B R
B R
B R
12 12
3 5
5 0
5 3
2 0
1 3
1 2
0
8 1 1 2 0 2(l) 0 3 3 2 2 2 3(l) 2
1 1 0 1 0 l(1) 0 2 0 1 0 2 2 1
5 0 0 0 0 I 0 _
2 1 0 0 2 2[11 0 0 1 1 1 0 0 I 2 0 0 0 0 0 0
_
0 0 0 0 1 0 0 2 1 0 0 0 I 0 0 0 0 0 1 0 0
0 0 0 1 0 l(1) 0
1 0 1 2 0 1 0 0 0 0 1 0 l(1) 0
2 1 0 0 0 1 0 0 1 0 0 1 0 0
1 1 0 0 0 0 1111 - _ - - - _ _
0 0 1 0 0 0 0 0 1 0 0 0 0 0
0 0 1 0 0 0 0
0 0 0 2 0 l(1) 0
1 0 0 0 0 ILlI 0 _ _
3 3
1 1 2 _
3 2
1 _
0 I 0 0 1 0
0 1
1 _
0 0
0 0
0 _
I I
4 2
1 0 1 1
2 0 _
0 - 0 -
I 0 _ _
1 0 1 0
1 0 0 -
2 1 0 _
2 I 1 1
0 _ _ _
1 0 1 1
I 0 1 0 0 _
_
2 3 1 2 I 2 I I 0 1 0 1 0 0 0 0 I 0 0 0 0 2 0 0 0
0 I 0 0 0
0 0 I 0 0 0 0 I 0 0 0 0 1 0 0
0 I 0 0 0
1 0 0 2 0 1 0 0 0 1
0 0 0 0 I I 0 0 0 1
I 0 0 0 0 I 0 0 0 0
*B = rifabutin; R = rifampicin; M = ethambutol; E = ethionamide/prothionamide; K = kanamycin; P = PAS; A = capreomycin.
Figures in round bracket ( ) indicate patients who refused to continue treatment. Figures in square brackets [ ] indicate patients treated with steroids.
Table 6. Adverse reactions reported in 17 patients during ofloxacin administration
Reaction Patients Month of start with reaction I 2 later
being severely ill at the time. The B patient with jaundice developed, the haemoglobin concentration thrombocytopenia was treated with steroids without falling from 12.4 g/d1 to 9.5 g/dl. Rifabutin was with- interruption of the antituberculosis regimen. The drawn, packed red cells were transfused, and signs of thrombocytopenia resolved rapidly and did not recur. haemolysis rapidly resolved and did not recur.
In addition to the above reactions, 1 patient who was initially allocated to treatment with rifampicin, ethambutol, and prothionamide, had this changed to rifabutin alone after only a transitory response to the initial regimen. After 6 months of regular daily treatment with rifabutin, haemolytic anaemia and
Adverse reactions were reported in 6 of the 17
patients during ofloxacin administration (Table 6). Only 2 had the drug terminated, one capreomycin for tinnitus (patient 12 in Table 4), and the other rifabutin for thrombocytopenia (patient 10 in Table 4). In both patients the reaction subsided and did not recur.
66 Tubercle and Lung Disease
Discussion
In vitro studies have shown that the minimal inhibitory concentrations of rifabutin for rifampicin-resistant A4.
tuberculosis are appreciably lower than those of rifampicin, the difference being attributed either to a
different mode of action of the two rifamycins or simply
to higher activity of rifabutin against both susceptible
and resistant strains. lo This finding has suggested that
rifabutin might be effective in the treatment of
rifampicin-resistant tuberculosis, especially when the
strains of Mtuberculosis at the start of treatment had
relatively low minimal inhibitory concentrations of
rifampicin. In our experience, such strains are much less common than are strains with high minimal inhibitory
concentrations, an experience confirmed in the present study. Furthermore, the pharrnacokinetics of rifabutin
differ from those of rifampicin. Rifabutin produces
plasma concentrations that are about 7 times lower, and
concentrations in the tissues and in macrophages that are higher, than those following an equal dose of
rifampicin.‘i-‘3 Since it is difficult to predict how these
differences in pharrnacokinetics might affect the results
of treatment, the present study was conducted to examine the responses of patients with initially rifampicin-
resistant strains to treatment with rifabutin. Although
rifabutin is usually prescribed in a dose size lower than that of rifampicin, equal sized doses of the two
rifamycins were used in order to give rifabutin the best opportunity of producing a therapeutic response.
The patients had chronic pulmonary tuberculosis with strains resistant to at least rifampicin, isoniazid and
streptomycin. They required retreatment with any other
antituberculosis drugs that seemed, from the initial
susceptibility pattern, to be of potential use for them. In order to separate the effects of treatment with rifabutin
from those due to the companion drugs, pairs of patients
with similar drug susceptibility patterns were allocated at random to a rifabutin-containing multidrug regimen or to a similar control regimen in which rifampicin, expected to
have no curative activity, was used in place of rifabutin. It is only by the use of such a control regimen that it is
possible to obtain a valid assessment of the activity of
rifabutin against rifampicin-resistant strains.
In the 22 patients of the study, no sustained responses were obtained. In 18 of the 22, a temporary bacteri-
ological response was observed, but this response lasted longer for the patient receiving rifabutin in 5 pairs and
for the patient receiving rifampicin in 5 pairs, no response occurring in either patient in the remaining pair. It is therefore likely that these temporary responses resulted mainly from the action of the other companion drugs rather than the rifabutin or rifampicin.
There were 2 patients in the study whose strains had low minimal inhibitory concentrations of rifabutin, provisionally classified as susceptible, and who were, by chance, treated with rifabutin. The temporary bacteri-
ological responses in these 2 were among the best and
were associated with the development of rifabutin resistance. This suggests that the rifabutin contributed to
the response in these 2 patients. It is therefore possible that rifabutin could have a minor effect in the retreat-
ment of such patients, but a response is unlikely to be sustained unless one or more of the other anti-
tuberculosis drugs are still available for use in com- bination with it.
17 patients, including 10 from the above paired
comparison once they were no longer responding, were
retreated with ofloxacin. In 5 cases, ofloxacin was given
alone as there were no remaining companion drugs available. Initial resistance to ofloxacin was found in 3
of the 17 patients. Although no history was obtained of previous treatment with ofloxacin, this drug is freely
available and is widely used in Hong Kong for the treatment of other infections. Among the 14 patients
with strains susceptible to ofloxacin or in whom sus-
ceptibility test results were not available, 10 showed a response, 1 to ofloxacin alone; in 7 of the 10 this was
temporary but in the remaining 3 treated with ofloxacin
for 12, 18 and 18 months, respectively, their disease was
rendered quiescent, smears and cultures having remained negative for between 14 and 32 months, all 3 still being
on follow-up. Ofloxacin, together with any other companion drugs still available, is now therefore being
used routinely in the retreatment of the few patients with chronic multidrug-resistant pulmonary tuberculosis in Hong Kong. Rifabutin might be considered in addition
to ofloxacin in the exceptional patients with strains of
tubercle bacilli susceptible to this drug although resistant to rifampicin.
Adverse reactions were common during rifabutin and rifampicin administration. This was expected because
the other drugs given included ethionamide or
prothionamide, kanamycin, PAS, and capreomycin. Thus, although 11 of 34 patients had administration of
one or more drugs terminated because of adverse effects, only 1 had rifabutin terminated and 2 rifampicin, compared with 11 one or more of the drugs ethambutol,
prothionamide, kanarnycin, PAS, and capreomycin. The commonest reactions were gastrointestinal and cuta-
neous. One patient had haemolytic anaemia during treat- ment with rifabutin alone. This rapidly resolved when
rifabutin administration was terminated. During ofloxacin
administration, adverse reactions were reported in 6 of
the 17 patients; 2 had a drug withdrawn, 1 capreomycin for tinnitus and the other rifabutin for thrombocytopenia. When patients with chronic multidrug-resistant
pulmonary tuberculosis are being retreated, it is usually necessary to use potentially toxic drugs which can cause
unpleasant adverse effects. It is important to encourage such patients to persevere with their treatment and to continue taking all their drugs for an adequate period of treatment unless a potentially serious or life-threatening adverse reaction occurs.
Rifabutin and ofloxacin in retreatment of TB 67
Acknowledgements
In Hong Kong, the medical and laboratory staffs, the medical social workers, health visitors, enrolled nurses (Health), and health auxiliaries, and the nursing, radiographic, technical, secretarial, and administrative staffs of Wanchai, Sai Ying Pun, Shau Kei Wan, Yaumati, Kowloon, East Kowloon, Shek Kip Mei, South Kwai Chung, Yung Fung Shee, and Yan Oi Government Chest Clinics, the Gover- nment Pathological Institute, Ruttonjee, Grantbarn, Haven of Hope, Wong Tai Sin, and Kowloon hospitals cooperated in the study.
The London laboratory was the Medical Research Council Unit for Laboratory Studies of Tuberculosis (subsequently the Department of Bacteriology, Royal Postgraduate Medical School) (Professor D. A. Mitchison, Mr B.W. Allen, and Mr V. R. Aber).
In Hong Kong, the study was coordinated by Dr S.L. Chan; the coordinating secretary was Ku Yee Wan. In London, the coordinator was Dr D. .I. Giiling of the Medical Research Council Tuberculosis and Chest Diseases Unit (subsequently the MRC Cancer Trials Office). The report was prepared on behalf of all the collaborators by Dr D.J. Girhng, Professor D. A. Mitchison, Mr A. J. Nunn and Mr V. R. Aber.
All those who cooperated in the study thank the Director of the Medical and Health Services in Hong Kong, Dr K. L. Thong, and then the Director of Health, Dr S. H. Lee, for their interest and encouragement.
The study was supported by research grants from the World Health Organization and from Farmitalia Carlo Erba, who also supplied the rifabutin.
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