Principles of chemotherapy for tuberculosis in national tuberculosis programmes of low- and middle-income countries.

National tuberculosis programmes (NTPs) should aim for achieving a very high proportion of cure of all tuberculosis (TB) cases. Ineffective chemotherapy of TB that keeps a substantial proportion of patients alive without cure may amplify resistance during treatment and promote transmission of TB. In 2017, the World Health Organization (WHO) recommended that in patients who require TB retreatment, the retreatment regimen that comprised 8 months of isoniazid, rifampicin and ethambutol supplemented by streptomycin for the initial 2 months, and pyrazinamide for the initial 3 months (2SHRZE/HRZE/5HRE) should no longer be prescribed and drug susceptibility testing (DST) should be conducted to inform the choice of treatment regimen. While GeneXpert MTB/RIF assay may detect rifampicin resistance, it does not detect isoniazid resistance. A 6-month regimen consisting of rifampicin, isoniazid, pyrazinamide and ethambutol may be used for the treatment of previously treated cases in whom rifampicin resistance has been excluded but DST of isoniazid is not available. WHO recommended to treat isoniazid-resistant, rifampicin-susceptible TB (Hr-TB) with rifampicin, ethambutol, pyrazinamide and levofloxacin for a duration of 6 months. In several low- and middle-income countries, the majority of Hr-TB cases are detected after the initiation of treatment with first-line regimens. If patients have an unsatisfactory response to first-line treatment with persistent positive sputum, modification of regimens needs to be done very carefully. Adding a fluoroquinolone in cases with undetected rifampicin resistance runs the risk of acquired fluoroquinolone resistance. Recently, WHO advises NTPs to phase out the injectable-containing short regimen for multidrug-resistant and rifampicin-resistant TB (MDR-/RR-TB) and recommends that the preferred treatment option is a shorter, all-oral, bedaquiline-containing regimen. WHO emphasizes that access to rapid DST, especially for ruling out fluoroquinolone resistance, is required before starting the bedaquiline-containing shorter regimen. The problem is that access to rapid DST for ruling out fluoroquinolone resistance is limited in low- and middle-income countries. The use of WHO-recommended bedaquiline-containing regimens in the treatment of MDR-/RR-TB patients with undetected resistance to fluoroquinolones runs a high risk of acquired bedaquiline resistance, especially in settings with a high prevalence of fluoroquinolone resistance. It is crucial to mitigate the risks of both primary and acquired resistance of rifampicin, fluoroquinolone and bedaquiline by rational design of regimens and effective management of TB patients.