Treatment

Infection control is vital to both inpatient and outpatient management of MDR/RR-TB patients and for the community. Within facilities, adequate ventilation, upper-room germicidal ultraviolet light systems and appropriate respirators for staff should be considered (i.e. N95 masks). Ventilation is also important at home, and education about personal safety and practices related to cough hygiene should be provided for patients and families (34). Most TB patients are likely to become noninfectious within weeks of commencing an effective treatment (35).

Contact tracing is critical to identify further cases of MDR/RR-TB, prevent ongoing transmission and ultimately work towards the global endTB strategy. Assessment should be offered for household contacts where feasible, especially for children aged below 5 years. Measures available for screening should include symptom assessment, chest X-ray and sputum testing (preferably using WHO-recommended molecular tests) (33).

In the ZeNix trial, all medications were administered with food throughout, because the bioavailability of bedaquiline (and pretomanid) increases when taken with food. The BPaLM/BPaL regimen should be administered with food and adequate water intake. Because calcium can bind the fluoroquinolones and make them ineffective, it is recommended to avoid taking dairy products, calcium supplements or calcium-containing antacids for 2 hours before and 2 hours after taking BPaLM.

Patients with extrapulmonary TB were excluded from the ZeNix trial; however, in the TB-PRACTECAL trial, only those with TB involving the CNS, osteomyelitis and arthritis were excluded. WHO recommends the BPaLM/BPaL for all forms of extrapulmonary TB except TB involving the CNS, osteoarticular TB and disseminated (miliary) TB. The longer MDR-TB regimens apply to such patients.

Pulmonary TB patients with radiological evidence of bilateral disease or radiological evidence of cavitation were included in the Nix-TB, ZeNix and TB-PRACTECAL studies. As such, patients with extensive pulmonary disease can be started on the BPaLM/BPaL regimen; however, close microbiological and clinical monitoring for culture conversion and clinical response should be maintained. In patients on the BPaL regimen, where there is a lack of culture conversion or clinical response between months 4 and 6, the regimen can be extended to 9 months (39 weeks) total duration.

People with HIV represented 19.5% of those enrolled in the ZeNix trial, 51% of those enrolled in the Nix-TB study and 26.7% of those enrolled in the TB-PRACTECAL trial. People with HIV were eligible to enrol in the ZeNix trial if they had a CD4 count of more than 100 cells/uL, and in TB-PRACTECAL regardless of CD4 count. Thus, patients can be enrolled in the BPaLM/BPaL regimen irrespective of the CD4 count; however, care should be taken when CD4 counts are below 100 cells/mm³.

Children were excluded from the Nix-TB, ZeNix (0–13 years) and TB-PRACTECAL (0–14 years) studies; therefore, no analysis specific to this subgroup of patients could have been performed. Although bedaquiline, linezolid and fluoroquinolones have been used to treat MDR/RR-TB in children, there are no data about the use of pretomanid in children, and further study is required to expand the use of BPaLM/BPaL to children. It is recommended that children aged below 14 years with pulmonary MDR/RR-TB be given consideration for the 9-month treatment regimen.

The BPaLM/BPaL regimen may need to be discontinued in some patients. In such cases, patients need to be evaluated and treatment switched to an individualized longer regimen, based on the WHO guidelines for regimen design using priority grouping of medicines. The most common situations in which the regimen may be discontinued are treatment failure, inability to use linezolid for enough time owing to adverse effects (discussed above) or pregnancy that occurs during treatment.

The only experience using these new regimens stems from two clinical trials; it is therefore suggested that the programmatic implementation be aligned with this experience. Safe management of adverse events may warrant dose reduction or discontinuation of the component drugs. However, the BPaLM/ BPaL regimen has been studied as a standardized course of treatment. Modification of the regimen through early discontinuation or replacement of any of the component drugs may result in poor treatment outcomes.

Linezolid is by far the most toxic drug in the BPaLM and BPaL regimens; it requires significant monitoring and at times a mitigation strategy to reduce adverse effects. Although it is preferred to continue linezolid at the full dose for the entire duration, the dose of linezolid can be reduced to 300 mg or discontinued (and restarted when possible) if there is significant toxicity. In general, action should be taken in the following manner for the common toxicities associated with linezolid: