Clinical value of microchip technology in determination of drug resistance of Mycobacterium tuberculosis

The patients with multiresistant tuberculosis were divided into 2 groups: the sensitivity of Mycobacteria tuberculosis to antituberculous drugs was evaluated in Group 1 by the methods of absolute concentrations and in Group 2 by biological microchips determining mutations in the rpo3 gene responsible for rifampicin resistance. The results of the drug sensitivity test were obtained after 3 months of treatment in Group 1 and several days prior treatment in Group 2. By taking into account the test results, reserve drugs was used in Group 2 patients. Subsequently, the results of the drug sensitivity tests carried out by the bacteriological method in Group 2 patients showed that isoniazid resistance was simultaneously noted if there were mutations in the rpo-B gene. Timely treatment with reserve drugs exhibited higher efficiency of treatment with its shorter duration in Group 2 than in Group 1.     

结核分枝杆菌异烟肼耐药性——一个不容忽视的问题

异烟肼是控制结核病的主要药物之一。2018年WHO报告的结核病初治病人中利福平敏感的异烟肼耐药率明显高于2017年的耐多药/利福平耐药率。我国结核病人的异烟肼总耐药率明显高于利福平总耐药率。异烟肼耐药容易导致治疗失败或复发。异烟肼耐药机制复杂,多个基因的突变均与异烟肼耐药有关,然而这些基因突变与表型的关系尚未完全清楚,直接影响了分子药敏快速诊断方法的建立。基因组学数据证明异烟肼耐药相关基因突变先于利福平耐药性相关基因突变发生。异烟肼耐药结核分枝杆菌容易诱发菌株获得额外耐药性,其机制可能与外排泵以及氧化应激机制有关。总之,结核分枝杆菌异烟肼耐药问题不容忽视,因此应该加强异烟肼作用机制、耐药机制、协同作用机制等方面的研究。     

结核分枝杆菌中利福平和异烟肼耐药相关基因突变与耐药水平的相关性研究

目的 探究结核分枝杆菌中利福平和异烟肼耐药基因突变谱的分布,为研发更为精准的耐药分子诊断技术和临床决策提供依据。方法 收集国家耐药监测点新疆维吾尔自治区柯坪县、岳普湖县和疏勒县193株和湖南省怀化市、永顺县、祁东县、桃江县和耒阳市592株结核分枝杆菌。采用微孔板法测定菌株的最小抑菌浓度(minimum inhibitory concentration,MIC)。根据药物敏感性试验(简称“药敏试验”)结果选取利福平和异烟肼耐药菌株,经CTAB/NaCl法提取核酸后进行全基因组测序(whole genome sequencing,WGS),将所得基因组原始序列过滤后上传至TBprofiler分析工具以确定耐药基因型。结果 785株结核分枝杆菌中,124株(15.80%)为利福平和(或)异烟肼耐药,包括利福平耐药74株,异烟肼耐药111株,耐多药61株(7.77%)。97.22%(70/72)利福平耐药菌株检测出rpoB基因位点突变,其中98.57%(69/70)的突变位于利福平耐药决定区(RRDR),1株检测出RRDR区以外的与利福平耐药相关的罕见突变I491F。利福平耐药突变主要位于rpoB 450、rpoB 445及rpoB 435密码子,占81.43%(57/70),其中rpoB S450L突变出现的频率最高(45.71%,32/70), rpoB 450位点突变对应高浓度利福平耐药(MIC≥16μg/ml),rpoB 452 位点突变主要对应低浓度利福平耐药(MIC=2μg/ml)。93.58%(102/109)的异烟肼耐药菌株存在耐药相关基因突变,85.29%(87/102)的异烟肼突变位于katG 315及fabG1启动子区,katG S315T为最常见的耐药突变(57.84%,59/102),主要对应高浓度异烟肼耐药(MIC≥2μg/ml),其次为fabG1(C15T)(16.67%,17/102),主要对应低浓度异烟肼耐药(MIC=0.25~1.00μg/ml)。结论 不同耐药基因突变导致的结核分枝杆菌耐药水平不同。对于利福平,rpoB 452位点突变对应低浓度耐药,rpoB 445和450位点突变对应高浓度耐药;对于异烟肼,发病fabG1-15突变对应低浓度耐药,katG 315突变对应高浓度耐药。     

Drug resistance pattern and mutation pattern in pediatric tuberculosis: Study from north India

BackgroundThe emergence of multidrug-resistant MDR-TB and extensively drug-resistant XDR-TB are serious threats to global TB control. Molecular tests like GenoType MTBDRplus has revolutionized MDR-TB diagnosis by rapid detection of resistance, leading to early and appropriate management of DR-TB. Information about common mutations imparting resistance to RIF and INH, helps in understanding the disease epidemiology in various regions. The study was conducted to determine the genetic mutation in drug resistant tuberculosis in children less than 12 years with pulmonary or extrapulmonary tuberculosis.Materials/methodsRetrospective analysis was done over a period of 54 months from January 2015 to June 2019 to study the resistance pattern and mutations present in DR-TB in children less than 12 years with suspected pulmonary or extrapulmonary tuberculosis using Hain's GenoType MTBDRplus VER 2.0.ResultsOver a period of 54 months, samples from 3461 patients with suspected TB were received for MGIT culture, out of which, 347 were positive for Mycobacterium tuberculosis. 250 of these 347 isolated were tested for drug resistance by Hain's GenoType MTBDRplus VER 2.0.61.1% were sensitive to isoniazid and rifampicin while 15.2% were DR-TB (38 out of 250). Out of these 38, 22 were MDR TB, 13 were isoniazid monoresistant (34.2%) and 3 were rifampicin monoresistant. The most common genotypic resistance for rifampicin was absence of rpoB WT8 band and presence of rpoB MUT 3 band (88%). 84.6% of the INH monoresistant isolates showed high level isoniazid resistant. All these isolates showed presence of katG MUT 1 band. On comparing Hain's GenoType MTBDRplus VER 2.0 with Xpert MTB/Rif Assay, most common mutation for rifampicin resistance at S531L which can be detected by Xpert MTB/Rif Assay (probe E). However, two cases with rifampicin resistance had mutation in codon region 509–513 and 513–519 which could be missed by Xpert MTB/Rif Assay.ConclusionsWe cannot solely rely on Xpert MTB/Rif Assay for detection of drug resistance due to the risk of missing the isoniazid monoresistance. GenoType MTBDRplus has revolutionized MDR-TB diagnosis by substantially reducing turn around time and leading to early management of DR-TB cases.     

Antimicrobial therapy of tuberculosis: justification for currently recommended treatment regimens

Prevention of drug resistance became the most important aim following the first clinical trial on streptomycin with a randomized intake in 1948. The occurrence of resistance was reduced by combined therapy with streptomycin and p-aminosalicylic acid and prevented by an initial phase with three drugs. Following the Madras comparison of domiciliary and sanatorium therapy, chemotherapy for the whole world became available, but there remained the problem of compliance during 1 year of treatment. Solutions were sought by the use of intermittently supervised drug administration, and in 1970, by the inclusion of the two major sterilizing drugs rifampicin and pyrazinamide, in regimens lasting only 6 months. The next 15 years were devoted to defining modern regimens, the first with a four-drug initial phase and rifampicin throughout (2EHRZ/4RH), and the second with a continuation phase of ethambutol and isoniazid (2EHRZ/6EH). Considering individual drugs, rifampicin and pyrazinamide provide almost all of the bactericidal activity, whereas isoniazid is bactericidal only during the first 2 days and thereafter prevents the emergence of drug resistance. Although models in vitro and in the mouse suggest that drug efficacy is related to area under the concentration-time curve/minimal inhibitory concentration (AUC/MIC), clinical trials with intermittent regimens indicate that this relationship is not present during human therapy.     

Study of drug resistance in previously treated tuberculosis patients in Gujarat, India.

SETTING: Department of Tuberculosis and Chest Diseases and State Tuberculosis Diagnosis and Training Centre (STDTC), a DOTS centre in Ahmedabad, Gujarat State, India. The study was carried out by retrospectively reviewing patient data between January 2000 and August 2001. OBJECTIVE: To evaluate the pattern of drug resistance among previously treated tuberculosis patients who remained symptomatic or smear-positive despite receiving anti-tuberculosis drugs under DOTS for a minimum of 5 months. DESIGN: A total of 1472 pulmonary tuberculosis patients who had taken anti-tuberculosis treatment were evaluated retrospectively with respect to their drug resistance pattern by sputum culture for acid-fast bacilli (AFB) and sensitivity testing with isoniazid, rifampicin, streptomycin and ethambutol (E). RESULT: Of the 1472 patients evaluated, 804 (54.6%) were treatment failure cases and 668 (45.4%) were relapse cases; 822 patients (373 failure and 449 relapse) were culture-positive. Of these 822 patients, 482 (58.64%, 261 failure and 221 relapse) were resistant to one or more drugs. Resistance to one drug was observed in 86 patients (10.46%), to two drugs in 149 (18.13%), to three drugs in 122 (14.84%) and to four drugs in 125 (15.21%). Single drug resistance was most commonly seen with isoniazid (62 patients, 7.5%), followed by streptomycin (12 patients, 1.4%), rifampicin (eight patients, 0.97%) and ethambutol (four patients, 0.4%). Resistance to isoniazid plus rifampicin alone was seen in 76 patients (9.2%). CONCLUSION: Drug resistance is a major problem in the treatment of pulmonary tuberculosis. Detection of drug resistance patterns and treatment with second-line anti-tuberculosis drugs in appropriate regimens are necessary in the treatment of failure and relapse cases in order to reduce the emergence of multidrug-resistant tuberculosis.     

Resistance to antituberculosis drugs in treated patients in Lagos, Nigeria.

The extent and pattern of drug resistance among previously treated tuberculosis patients was investigated. Ninety-six patients with a total treatment duration of between 6 and 18 months and still smear and culture positive were examined. Treatment was either continuous or in intermittent blocks. Drug susceptibility tests on strains of tubercle bacilli isolated from the patients were performed against isoniazid, streptomycin, p-aminosalicylic acid, ethambutol and rifampicin by the proportion method using LJ medium without potato starch. A total of 56% of the strains were resistant to one or more of the drugs tested. Resistance to isoniazid (38%) and streptomycin (29%) was most common. A significant finding in the study was the low level of resistance to rifampicin (2%) and ethambutol (3%). A relationship between the incidence of drug resistance and the nature and duration of previous treatment appeared likely since susceptible strains were isolated more often from patients with continuous treatment than from patients on intermittent blocks of long-course regimens. It is therefore suggested that the introduction of better supervision of drug taking and the adoption of continuous short-course regimens on a nationwide level will contribute immensely towards the reduction of the drug resistance problems in Nigeria as well as in other developing countries.     

The prevalence of Mycobacterium tuberculosis drug resistance in New Caledonia, 1995-1996.

SETTING: Study of the susceptibility to anti-tuberculosis drugs of Mycobacterium tuberculosis strains isolated in New Caledonia, a French South Pacific Territory, where tuberculosis continues to be a public health problem. OBJECTIVE: To assess the stability of this susceptibility in order to justify both non-systematic susceptibility testing and the implementation of simplified chemotherapy regimens. METHODS: Over a period of nearly 2 years (1995-1996), every new case of tuberculosis confirmed by the laboratory was included in the study. A total of 105 strains were tested against five anti-tuberculosis drugs: isoniazid, rifampicin, ethambutol, pyrazinamide and streptomycin. RESULTS: No primary drug resistance was detected for the main drugs. One strain with acquired resistance to isoniazid and streptomycin was isolated from one of the 12 patients suffering a relapse of the disease. CONCLUSIONS: The results of this exhaustive study justify the non-systematic approach to susceptibility testing for new patients. However, for strains isolated from patients suffering from relapse or therapeutic failure, or who belong to a high risk population, drug susceptibility testing should be performed. This kind of management will aid in the detection of possible isoniazid and streptomycin resistance, thus avoiding the selection and possible emergence of strains resistant to rifampicin. The results of the study argue for the use of a fixed dose regimen using triple combination tablets of isoniazid, rifampicin and pyrazinamide (HRZ) for 2 months, followed by dual drug therapy (HR) for 4 months.     

High initial drug resistance in pulmonary tuberculosis in Ghana

Between July 1985 and March 1987, initial sensitivity to anti-tuberculosis drugs was studied in patients presenting at the Chest Clinic of Agogo Hospital in the forest area of Ghana. Culture and sensitivity test results were obtained in 99 out of 123 consecutive patients with pulmonary tuberculosis who claim not to have received previous treatment. Isoniazid resistance was alarmingly high in the isolates of M. tuberculosis: 21 out of 57 (37%), and thiacetazone resistance was very high in the M. africanum isolates: 20 out of 42 (47%). Overall resistance was high: 27% to isoniazid, 23% to streptomycin, 29% to thiacetazone, 16% to both streptomycin and isoniazid, and 5% to all of these three drugs. Only 45% of the isolates were sensitive to all three drugs. Primary drug resistance to rifampicin, pyrazinamide or ethambutol was not observed. Besides the standard treatment of isoniazid, streptomycin and thiacetazone, rifampicin and pyrazinamide were usually added for the first two months of treatment. Of 13 patients who received standard treatment only, 4 of the 5 patients with resistant organisms who could be followed up failed to respond, whereas there were no failures to respond in the 5 corresponding patients with initially sensitive organisms; 3 patients could not be assessed because they defaulted.     

荧光PCR探针熔解曲线技术检测结核分枝杆菌对五种抗结核药物耐药性的研究

目的运用荧光PCR探针熔解曲线技术检测结核分枝杆菌(MTB)对利福平、异烟肼、乙胺丁醇、链霉素、氟喹诺酮类共5种抗结核药物的耐药性,并评价其临床应用价值。方法收集2018年1—8月分离自抚顺市第四人民医院门诊患者的153株MTB临床分离株,采用荧光PCR探针熔解曲线法检测MTB对利福平、异烟肼、乙胺丁醇、链霉素和氟喹诺酮类药物的耐药性。以比例法药物敏感性试验(简称"药敏试验")为金标准,评价荧光PCR探针熔解曲线法的敏感度、特异度和一致率。结果以比例法药敏试验为金标准,荧光PCR探针熔解曲线法检测MTB对利福平耐药性的敏感度为95.56%(43/45),特异度为94.44%(102/108),一致率为94.77%(145/153),Kappa值为0.88;对异烟肼耐药性的敏感度为90. 57%(48/53),特异度为96.00%(96/100),一致率为94.12%(144/153),Kappa值为0.87;对乙胺丁醇耐药性的敏感度为85.71%(18/21),特异度为92.42%(122/132),一致率为91. 50%(140/153),Kappa值为0. 69;对链霉素耐药性的敏感度为89. 66%(26/29),特异度为92.74%(115/124),一致率为92.16%(141/153),Kappa值为0.76;对氟喹诺酮类药物耐药性的敏感度为93. 75%(15/16),特异度为96. 35%(132/137),一致率为96. 08%(147/153),Kappa值为0. 81。结论荧光PCR探针熔解曲线法检测MTB对利福平、异烟肼、乙胺丁醇、链霉素和氟喹诺酮类药物的耐药性具有良好的效能,可为医生制定用药方案提供重要依据。     

Role of individual drugs in the chemotherapy of tuberculosis.

During the course of chemotherapy, certain drugs are predominant in their bactericidal activities. Isoniazid is responsible for an initial kill of about 95% of organisms during the first 2 days of treatment. Its bactericidal role is then replaced by rifampicin and pyrazinamide during the intensive phase. In the continuation phase with an isoniazid/rifampicin regimen, rifampicin is the only effective drug against persisters, as shown by the similarity of response by patients with initially isoniazid-resistant or sensitive strains. If the continuation phase regimen does not contain rifampicin but does contain isoniazid, the dominant bactericidal drug is isoniazid. In this case, the response of patients with initial isoniazid resistance is appreciably less good than in those with sensitive organisms. The review suggests exploration in randomised control trials of a continuation phase of rifampicin (or rifapentine) alone. It also suggests the importance of the dose size of rifampicin and the need for exploring a higher dose. Finally, it emphasises the importance of finding drugs that act on persisting organisms that are phenotypically but not genetically resistant to rifampicin.     

Resistance to antituberculosis drugs in Riyadh, Saudi Arabia

The prevalence of resistance to antituberculosis drugs in Riyadh was found to be 21.3%, while the rate of primary drug resistance was 11.5%. Resistance to isoniazid was the most common (19.4%) followed by rifampicin and streptomycin. The prevalence of primary and acquired rifampicin resistance was 3 and 33.7% respectively. The majority of isolates from patients with acquired resistance to rifampicin were resistant also to isoniazid.     

Progressive rise of Mycobacterium tuberculosis resistance to rifampicin and streptomycin in Riyadh, Saudi Arabia

OBJECTIVE: The aim of this study was to investigate, for the first time, the factors associated with resistance to antituberculous drugs in Saudi Arabia, and to follow the long-term trends in drug resistance. METHODOLOGY: A retrospective study of patients with positive Mycobacterium tuberculosis recorded at the Riyadh Tuberculosis Center in 1990 was undertaken. The resistance figures from the same centre for the period July 1996 to June 1997 were reviewed for comparison. RESULTS: Resistance was significantly higher in those previously treated (71%) than in those who denied previous treatment (34%). There was a trend towards association of resistance with cavitatory, multilobar, and acid fast bacilli-positive cases. Nationality (Saudis, Yemenis, others) had no significant effect on resistance. The Riyadh Region now has the same high prevalence of rifampicin resistance as previously reported in the Western Region of the Kingdom. The figures on resistance for the years 1986-88, 1990, and 1996-97 were: isoniazid 19.5/13.8/11.1%, rifampicin 10/20.7/24.6%, streptomycin 5/22/27.4%, ethambutol 3.7/3.9/1.8%, respectively. The reduction in isoniazid and ethambutol resistance coincided with a rise in resistance to rifampicin and streptomycin. We speculate that this resulted from the fact that isoniazid and ethambutol are restricted only to the treatment of tuberculosis and cannot, by law, be dispensed by general practitioners or private pharmacies. Rifampicin and streptomycin, however, are widely used for brucellosis; an endemic disease in Saudi Arabia where up to 12 weeks of rifampicin therapy is recommended. CONCLUSIONS: There has been a significant increase in rifampicin and streptomycin resistance in Saudi Arabia over the last 10 years. Possible causes include poor compliance and wide use of these two drugs for non-tuberculosis conditions. These findings could jeopardize the benefits of the directly observed therapy short course policy which is being implemented in Saudi Arabia. Consideration should be given to prohibiting the routine use of rifampicin for the treatment of brucellosis.     

Molecular characterization of rifampicin- and isoniazid-resistant Mycobacterium tuberculosis strains isolated in Kazakhstan

Kazakhstan is one of the 14 countries with a high rate of morbidity due to multidrug-resistant tuberculosis (MDR TB) in WHO European region. The aim of our study was to characterize mutations associated with drug resistance to rifampicin and isoniazid in Mycobacterium tuberculosis isolates from Kazakhstan. M. tuberculosis strains were isolated from TB patients in different regions of Kazakhstan. A drug susceptibility test was performed on Lowenstein-Jensen medium using the absolute concentration method. Sequencing analysis was performed of the rpoB rifampicin resistance-determining region and the katG gene, the oxyR-ahpC intergenic region, and the inhA promoter region in 259 MDR M. tuberculosis isolates, in 51 isoniazid-resistant isolates, and in 13 rifampicin-resistant isolates. The mutational analysis revealed that the most frequent mutations associated with rifampicin and isoniazid resistance in M. tuberculosis are the substitutions at codons 531 (82.7%) and 315 (98.4%) in the rpoB and katG genes, respectively. In addition, we have found mutations with lower frequency at codon 526 (8.4%), 533 (1.5%), and 516 (1.1%) in the rpoB gene. In 6.2% of the isolates, no mutations were found in the rpoB gene. The findings of this study provide useful data for a better understanding of the mutation spectrum of isoniazid and rifampicin resistance among strains isolated from patients in Kazakhstan. Our results are also useful for the development of diagnostic tests of MDR M. tuberculosis.     

Effect of antituberculosis drug resistance on response to treatment and outcome in adults with tuberculous meningitis

BACKGROUND: Tuberculous meningitis (TBM) caused by Mycobacterium tuberculosis resistant to 1 or more antituberculosis drugs is an increasingly common clinical problem, although the impact on outcome is uncertain. METHODS: We performed a prospective study of 180 Vietnamese adults admitted consecutively for TBM. M. tuberculosis was cultured from the cerebrospinal fluid (CSF) of all patients and was tested for susceptibility to first-line antituberculosis drugs. Presenting clinical features, time to CSF bacterial clearance, clinical response to treatment, and 9-month morbidity and mortality were compared between adults infected with susceptible and those infected with drug-resistant organisms. RESULTS: Of 180 isolates, 72 (40.0%) were resistant to at least 1 antituberculosis drug, and 10 (5.6%) were resistant to at least isoniazid and rifampicin. Isoniazid and/or streptomycin resistance was associated with slower CSF bacterial clearance but not with any differences in clinical response or outcome. Combined isoniazid and rifampicin resistance was strongly predictive of death (relative risk of death, 11.63 [95% confidence interval, 5.21-26.32]) and was independently associated with human immunodeficiency virus infection. CONCLUSIONS: Isoniazid and/or streptomycin resistance probably has no detrimental effect on the outcome of TBM when patients are treated with first-line antituberculosis drugs, but combined isoniazid and rifampicin resistance is strongly predictive of death.     

Drug-resistant tuberculosis in South African gold miners: incidence and associated factors.

SETTING: A gold mining company in the Free State Province of South Africa. OBJECTIVE: To document the incidence of and factors associated with drug-resistant tuberculosis (TB) in South African gold miners. DESIGN: Review of Mycobacterium tuberculosis drug susceptibility records for the period from 1 July 1993 to 30 June 1997. RESULTS: Over the study period, 2241 miners had culture-positive M. tuberculosis pulmonary disease where isolates were tested for drug susceptibility to the four primary anti-tuberculosis drugs. The proportions of primary and acquired drug resistance were respectively 7.3% and 14.3% for isoniazid and 1.0% and 2.8% for resistance to at least isoniazid and rifampicin (multidrug resistance). Resistance to streptomycin and ethambutol was uncommon, and rifampicin monoresistance was rare. No significant factors for primary drug resistance were identified. Patients with retreatment pulmonary TB who failed primary TB treatment (versus cure) were significantly more likely to have TB with resistance to any TB drug or MDR (odds ratios respectively 9.82, 95%CI 2.97-33.5, and 18.74, 95%CI 1.76-475). Human immunodeficiency virus (HIV) infection was not significantly associated with primary or acquired drug resistance, and there was no trend of increasing resistance over time. CONCLUSION: Anti-tuberculosis drug resistance has remained stable despite the HIV epidemic and increasing TB rates. Directly observed therapy may have contributed to containing the level of drug resistance. Adherence to and completion of treatment are essential to prevent drug resistance and treatment failure, including in situations with high HIV prevalence.     

Prospective comparative study of ofloxacin or ethambutol for the treatment of pulmonary tuberculosis.

The efficacy of ofloxacin, rifampicin and isoniazid was prospectively compared with the regimen of ethambutol, rifampicin and isoniazid for the primary treatment of pulmonary tuberculosis in 124 patients. All drugs were given orally daily for nine months. Culture conversion rates three months after starting treatment were 98 percent in the ofloxacin group and 94 percent in the ethambutol group; by six months all patients in both groups were culture-negative. Significant radiological improvement of pulmonary infiltrates was observed in 83 percent of the ofloxacin group and 85 percent of the ethambutol group one year after starting treatment. No relapse in either group was observed during a two-year follow-up period after the cessation of chemotherapy. Ofloxacin appears to be as useful as ethambutol in the treatment of pulmonary tuberculosis when either drug is combined with isoniazid and rifampicin.     

Safety of an ofloxacin-based antitubercular regimen for the treatment of tuberculosis in patients with underlying chronic liver disease: a preliminary report

BACKGROUND AND AIMS: Hepatotoxicity is a major side-effect of antitubercular drugs (ATD). As these drugs are metabolized in the liver, there is a theoretical risk of increased hepatotoxicity in patients with underlying chronic liver disease (CLD). Ofloxacin has antitubercular activity and has exclusive renal clearance. The aim was to study the efficacy and safety of an ofloxacin-based antitubercular regimen for treating tuberculosis in patients with underlying CLD. METHODS: Thirty-one cases were randomly assigned to two drug regimens using WHO dosage schedules: (i) regimen A (n = 15): isoniazid, rifampicin and ethambutol for 2 months, followed by isoniazid and rifampicin for a further 7 months; and (ii) regimen B (n = 16): isoniazid, pyrazinamide, ethambutol and ofloxacin for 2 months, followed by isoniazid, ethambutol and ofloxacin for a further 10 months. Hepatotoxicity was diagnosed if alanine aminotransferase/aspartate aminotransferase increased > fivefold from the baseline or to > 400 IU/L, or if bilirubin increased by > 2.5 mg/dL from the baseline. RESULTS: The response to ATD was achieved in all the patients who completed the therapy. Four (26.6%) patients on regimen A developed hepatotoxicity as compared to none on regimen B (P = 0.043). None of these patients could be restarted on ATD using the same regimen A because of the persistently deranged liver functions. CONCLUSIONS: In patients with tuberculosis who have underlying CLD: (i) an ofloxacin-based antitubercular regimen without rifampicin is as effective as a rifampicin-based regimen; and (ii) a combination of isoniazid with rifampicin is more hepatotoxic than a combination with ofloxacin and pyrazinamide.