Treatment

The ethionamide variation involves the initiation of bedaquiline, levofloxacin/moxifloxacin, clofazimine, ethionamide, ethambutol, isoniazid (high dose) and pyrazinamide. All seven drugs are given for 4 months, with the possibility of extending to 6 months if the patient’s sputum remains bacteriologically positive at the end of the fourth month on treatment. Ethionamide and high-dose isoniazid are dropped after 4 or 6 months, depending on the decision to extend treatment based on smear status at month 4 of treatment.

Due to the risk of myelosuppression associated with even relatively short exposures to linezolid, pretreatment assessment of haemoglobin, neutrophils and platelets is crucial in patients considering treatment with a linezolid-containing regimen. Severe anaemia in patients with TB is a significant risk factor for poor treatment outcomes (48), and patients with a low baseline haemoglobin may be at risk of severe linezolid-induced haematological toxicity.

The 9-month all-oral regimen is not adequate for the treatment of patients with pre-XDR-TB or XDR-TB; it is also not adequate to treat MDR/RR-TB that has both inhA and katG mutations. It is recommended that samples be submitted for susceptibility testing to at least fluoroquinolones before the start of this regimen. In settings without access to the Xpert MTB-XDR cartridge, a line probe assay (LPA: MTBDRplus) can be used to detect the two most common mutations that confer resistance to isoniazid.

The extent of a patient’s TB disease is important in determining appropriate regimen options, in addition to the drug susceptibility of the M. tuberculosis and other considerations mentioned above. Patients with extensive disease are not eligible for the 9-month all-oral regimen with either linezolid or ethionamide.

For patients who become pregnant during treatment, it will be necessary to discontinue the BPaLM/ BPaL regimen and prescribe another regimen.

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.