[Characteristics and treatment outcomes of INH-resistant or RFP-resistant tuberculosis].
BACKGROUND
As an effective regimen for isoniazid-resistant but rifampicin-susceptible tuberculosis (INHr-TB), the use of a 6-month three or four-drug treatment regimen including refampicin (or rifampin) and pyrazinamide has been recommended by many experts of the world. On the other hand, treatment regimen for rifampicin-resistant but isoniazide-susceptible tuberculosis (RFPr-TB) has not been well established because of the small number of such patients. In Japan the standard regimen has not been established even for INHr-TB, and the treatment has been done by each physician on the empirical bases.


OBJECTIVE
To determine the adequate therapy of INH-resistant TB or RFP-resistant TB.


METHODS
Retrospective cohort study. SUBJECTIVES: Hundred and eleven INHr-TB patients (4.9%) and 5 RFPr-TB patients (0.2%) out of 2252 new smear-positive tuberculosis patients who were admitted to our hospital from 1994 to 1998.


RESULTS
Patients with previous tuberculosis history was found in 35 of 111 INHr-TB (31.5%) patients, of which 13 (37.1%) were re-treated within 3 years. On the other hand 146 patients (21.1%) of all new culture-positive tuberculosis patients (N = 690) treated in our hospital from 1997 to 1999 had the previous tuberculosis history of which only 8 patients (5.5%) were retreated within 3 years while 115 patients relapsed more than 10 years after the onset of previous tuberculosis history. The frequency of recurrence within 3 years after the onset of previous tuberculosis history was, significantly higher (p < 0.0001) in cases of INHr-TB (13/111 [11.7%]) than in cases of newly registered ones (8/690 [1.2%]), and the fact indicates that the incidence of tuberculosis recurrence was higher in INHr-TB patients than in pan-sensitive TB patients when the previous treatment was discontinued or insufficiently implemented. The resistance pattern of the INHr-strains were as follows. INH alone 40 (36.0%), SM-resistant 47 (42.3%), TH resistant 19 (17.1%), EB-resistant 18 (16.2%), KM-resistant 6 (5.4%), and others 3 (2.7%). Therefore the mean number (+/- SD) of resistant drugs excluding INH was 1.4 +/- 0.7. Eighteen out of 71 (25.4%) strains with low grade INH-resistance (0.1 microgram/ml complete resistance) had also TH-resistance, while only one out of 40 (2.5%) strains with high grade INH-resistance (1 microgram/ml resistance) was resistant to TH (p = 0.005). Of 111 INHr-TB patients, 9 patients (8.1%) discontinued treatment by themselves, 17 patients (15.3%) admitted to another hospital, and 17 patients (15.3%) died. The patients who died (age [M +/- SD] 66.4 +/- 14.0 yrs) were older than those who were alive (48.7 +/- 17.8, p < 0.001), and were too seriously ill to accept sufficient chemotherapy, and therefore their deaths were not considered to be related to INH resistance. The treatment outcomes of the remaining 68 patients who were followed in our hospital were summarized as follows. 1) Treatment failure occurred in 3 patients, of whom 2 patients could not be treated with full dose rifampicin in the initial phase of treatment because of side effects to liver or accompanying idiopathic thrombocytepenic purpura (ITP). Two out of these 3 patients developed multi-drug resistant tuberculosis (MDR-TB). Success rate of treatment was 65/68 (95.6%). 2) Alterations of regimens after knowing INHr-TB were done in 41 of 65 patients (63.0%) with treatment success in all cases. The susceptible drugs used were 65 (100%) for RFP, 62 (95.4%) for EB, 23 (35.4%) for PZA, 26 (40.0%) for SM, 32 (49.2%) for new quinolone (NQ). 3) The sputum culture conversion rates two months after starting chemotherapy with (N = 16) and without (N = 52) PZA were 13/16 (81.3%) and 31/52 (59.6%), respectively. 4) After the completion of treatment, relapse occurred in 4 patients during follow-up period (1-39 months). The recurrence occurred in 3 out of 20 patients (15%) treated with INH and two susceptible drugs, none out of 13 with three susceptible drugs (0%), 1 out of 20 with INH and three susceptible drugs (5%), and none out of 11 with more than 4 susceptible drugs (0%), and the fact indicates that there was no significant advantage to add INH of usual dose to the regimens. 5) The durations of treatment were not less than 9 months except one case. When 3 or more susceptible drugs were used, the recurrence rate in the group of treatment duration 9-12 months was 0/12 and that in the group of treatment duration more than 12 months was 1/33. Even in the groups without PZA in the initial 2 months of treatment, the recurrence rate in the group of treatment duration 9-12 month was 0/8, and that in the group of treatment duration more than 12 months was 0/22. The fact indicates that 12 months therapy was sufficient irrespective of the use of PZA. 6) One of 5 RFPr-TB patients discontinued treatment by himself. Remaining 4 patients were treated by 4.5 +/- 0.5 susceptible drugs including INH for more than 20 months (21.7 +/- 2.8 months) after sputum culture conversion with the successful result of treatment and no relapses during the followup period for 3-60 months.


CONCLUSIONS
For INHr-TB, even when PZA can't be used because of adverse effects or resistance, 3 or 4 susceptible drugs regimens including RFP for 12 months were effective. For RFPr-TB, the treatment with 4 or more susceptible drugs for 20 months after sputum culture conversion might be adequate.
Saito
Wakana
W
Department of Respiratory Medicine, Tokyo National Hospital, 3-1-1, Takeoka, Kiyoseshi, Tokyo 204-8585, Japan. wakana-s@tokyo.hosp.go.jp
Nagayama
Naohiro
N
Miyamoto
Maki
M
Hara
Hiromichi
H
Suzuki
Junko
J
Masuda
Kimihiko
K
Baba
Motoo
M
Tamura
Atsuhisa
A
Nagai
Hideaki
H
Akagawa
Shinobu
S
Kawabe
Yoshiko
Y
Machida
Kazuko
K
Kurashima
Atsuyuki
A
Yotsumoto
Hideki
H
D000328:Adult; D000368:Aged; D000995:Antitubercular Agents / Q000008:administration & dosage*; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D011718:Pyrazinamide / Q000008:administration & dosage; D012189:Retrospective Studies; D012293:Rifampin / Q000008:administration & dosage*; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*
D000995:Antitubercular Agents; D011718:Pyrazinamide; D007538:Isoniazid; D012293:Rifampin