HomeIn Canada, resistance to INH is the most common pattern of first-line drug resistance (see Table 1). Resistance to INH is usually due to a mutation in either the katG or inhA gene.68,69 Less commonly, it is due to one or more mutations in other genes, such as the ahpC gene.13
INH is a prodrug that must be activated by catalase-peroxidase, an enzyme that is regulated by the katG gene, in order to be effective against M. tuberculosis. Mutation of the katG gene results in high-level resistance to INH (resistance concentration 1.0 μg/mL using solid media [agar proportion method], 0.4 μg/mL using liquid media [indirect proportion method]).13 When the katG gene is not mutated, activated INH acts on several M. tuberculosis genes, of which those in the inhA promoter region are the most important.70 Mutations in the inhA gene or inhA promoter region result in low-level resistance to INH (0.2 μg/mL using solid media, 0.1 μg/mL using liquid media).
INH is considered one of the two most effective anti-TB drugs and has particularly potent early bactericidal activity. INH resistance is the most common form of drug-resistant TB, with prevalence among previously untreated patients ranging from 1% to 20% in different countries and averaging approximately 8% globally.30,71 A systematic review and meta-analysis of patients who received standardized regimens of INH, RMP, PZA and EMB, followed by INH and RMP, found that patients with INH mono-resistance had failure, relapse and acquired MDR rates of 11, 10 and 8%, respectively, compared to rates of 1, 5 and 0.3%, respectively, in patients with fully drug-susceptible TB.72 Hence, it is clear that effective therapy is necessary to reduce the risk of failure, relapse and acquired MDR in patients with isolates that are resistant to INH.
In 2017, an individual patient database (IPD) was assembled of 33 datasets. In a meta-analysis of this IPD, 3,923 patients in 33 datasets were analyzed to inform WHO73 and ATS/CDC/ERS/IDSA/ERS/IDSA (American Thoracic Society, Centers for Disease Control and Prevention, European Respiratory Society and the Infectious Diseases Society of America) guidelines.55 Briefly, a fluoroquinolone added for at least 1 month to a regimen of 6 months of RMP, EMB and PZA had significantly improved treatment success compared to 6 months of those 3 drugs alone (adjusted odds ratio (aOR): 2.8; [95% confidence intervals (CI): 1.1 to 7.3]) and significant reduction in acquired drug resistance (aOR 0.1: [0.0 to 1.2]).67 The addition of fluoroquinolone was also associated with lower mortality, but this was not significant (aOR: 0.7 [0.4 to 1.1]). Findings were similar when analyses were restricted to patients who received later-generation fluoroquinolones, such as levofloxacin or moxifloxacin. A subset of 118 patients received only 2 months of PZA together with 6 months or more of a fluoroquinolone plus RMP and EMB. In this subset, 117 had treatment success, a much higher rate than with 6 months of INH, RMP and PZA alone (aOR: 5.2; [0.6 to 47]). The wide confidence intervals reflect the smaller number who received this regimen, and that only 1 person failed or relapsed with the 2-month PZA regimen. In the IPD dataset, almost all studies considered persons whose isolates had “low-level” or “high-level” INH resistance as having INH resistance. Hence, the benefits of adding a fluoroquinolone can be expected for persons with disease due to isolates with either level of resistance. There was insufficient information in the IPD datasets to analyze relative frequency of serious adverse events with the different regimens. Therefore, an important consideration that remains unresolved is the tradeoff between risk of adverse events and improvement of end-of-treatment outcomes with addition of a fluoroquinolone, and/or dropping PZA after 2 months. The preferred fluoroquinolone is Levofloxacin, due to lower hepatotoxicity and less effect on QT interval.
In practice, many patients are started on empiric therapy with INH, RMP, PZA and EMB, and the INH resistance is detected 1-to-2 months later. In these patients, 6 months of fluoroquinoline therapy is counted from the day the fluoroquinolone is added. In other words, the initial therapy of 1-to-2 months empiric regimen is not considered part of the total recommended therapy. RMP, EMB and PZA alone for 6 months (counting as previously outlined) can be an option if there is fluoroquinolone resistance or the fluoroquinolone is not tolerated.
Recommendations
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We strongly recommend, in patients with mono-isoniazid resistance, a treatment regimen including a later-generation fluoroquinolone (levofloxacin is preferred), rifampin, ethambutol and pyrazinamide, given for 6 months (Good evidence).
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We conditionally recommend that, in patients with less extensive disease (eg, noncavitary), and especially if there is increased risk of liver toxicity, pyrazinamide be given for the first 2 months only; in the final 4 months, rifampin, ethambutol and the fluoroquinolone should be given (Poor evidence).
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