1.2.1. First-line drug therapy
Drug therapy for TB disease is given in 2 phases: the intensive phase and continuation phase. In the intensive phase, 3 or 4 effective drugs are used in combination to rapidly kill TB organisms and prevent the selection of drug-resistant organisms. In treatment of drug-susceptible disease, the intensive phase should last 2 months; during this time, TB drugs should be dosed daily (Table 1).1,2 In the continuation phase, a minimum of 2 effective drugs are used, and treatment duration varies depending on the drug regimen, adherence and risk of relapse. In this second phase, there is an option for intermittent (thrice weekly) therapy in select circumstances under directly observed therapy, or DOT (defined here as the direct observation of a person ingesting TB medications) ((Table 1), but daily dosing is preferred when possible.2–4
1.2.2. Rationale for multidrug therapy
Patients with TB disease are infected with a large number of TB bacilli, with up to 1010 bacilli in people with cavitary pulmonary disease.5,6 Mutations conferring resistance to any particular drug appear to occur spontaneously at a very low but constant rate. The rate of spontaneous resistance to isoniazid (INH) and rifampin is estimated to be 4 × 10−6 and 3 × 10−8, respectively, with the rate of spontaneous mutation to both drugs estimated to be as low as 1 × 10−15.6,7 In people with drug-susceptible TB disease, particularly those with a high bacillary burden, the presence of small numbers of TB bacilli with spontaneously occurring resistance to each first line drug is likely, while simultaneous resistance to 2 drugs is less likely and 3 drugs is highly unlikely.5,6
Based on the aforementioned reasoning and extensive randomized controlled trial experience, it is recommended that at least 2 effective drugs be used at all times in treatment of TB disease.6,8 A drug is considered effective when susceptibility of the Mycobacterium tuberculosis (M. tuberculosis) strain has been confirmed by drug susceptibility testing (DST). If DST results are pending, then more drugs are required to ensure receipt of at least 2 drugs that are likely to be effective. This reinforces the importance of microbiologic confirmation of TB disease and the use of DST to guide treatment.
Table 1. Recommended drug doses for daily and intermittent therapy in adolescents and adults.
|By weight||Maximum a||By weight||Maximum a|
|Isoniazid||5mg/kg||300 mg||15 mg/kg||900mg|
|Rifampin||10mg/kg||no maxb||10 mg/kg||no maxb|
|Pyrazinamide||25mg/kg||2000 mg||30-40 mg/kg||4000 mg|
|Ethambutol||15mg/kg||1600 mg||25-40 mg/kg||2400 mg|
Abbreviations: TB, tuberculosis .
a Dosing based on body weight for people with body mass index (BMI) 18.5-30. In people with BMI >30 or <18.5 consider dosing based on ideal body weight and consider therapeutic drug monitoring if available. 1
b This represents a change from previous Canadian TB Standard dosing recommendations, based on an evidence review performed by the WHO Pharmacokinetics and Pharmacodynamics Task Force. 2 , 27
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