Treatment

Modified all-oral shorter MDR-TB regimens (i.e. regimens that differ from the recommended 9-month shorter regimens) should only be implemented under “operational research conditions”. The main conditions are:

At present, there is little evidence to support modified all-oral shorter MDR-TB regimens that are designed using the hierarchy of TB medicines (Table 6.1). NTPs that intend to pilot such types of shorter MDR-TB regimens are advised to do so under operational research conditions.

The South African NTP implemented the 9-month all-oral MDR/RR-TB regimen as a standardized course of treatment, with little room for variation. Some changes to the prescribed regimen were considered acceptable in the South African context and may be appropriate in other settings (as described in Section 5.2).

Some patients who start treatment with the 9-month all-oral regimen are unable to continue or complete the course of treatment, and may have to restart or switch to a different regimen; for example, in the following situations:

Extensive (or advanced) TB disease in adults is defined as the presence of bilateral cavitary disease or extensive parenchymal damage on chest radiography. In children aged below 15 years, extensive (or advanced) disease is usually defined by the presence of cavities or bilateral disease on chest radiography (see above regarding severe and nonsevere TB disease in children). This highlights the importance of chest radiography as part of the diagnostic work-up for patients, along with the usual patient–clinician interaction.

Dosing and safety data to support the optimal use of second-line TB medicines during pregnancy are generally sparse. There have been case reports and observational data reporting successful treatment and pregnancy outcomes among women who received treatment (including bedaquiline-containing regimens) for MDR/RR-TB during pregnancy and postpartum, but pregnant and breastfeeding women are usually excluded from clinical drug trials and early access programmes.

Aside from bedaquiline, the medicines that compose the 9-month all-oral regimen have been part of MDR/RR-TB regimens for many years, in similar combinations, for both adults and children. The associated adverse drug reactions have been widely described and the drug dosages established (Annex). Child-friendly formulations are now available for all second-line drugs and should be provided to children whenever possible.

The 9-month all-oral MDR/RR-TB regimen should be implemented as a standardized package. It is not advisable to change the composition of the regimen or the duration of either the initial or continuation phase, with a few exceptions, as follows:

The dosages of all drugs included in both variations of the 9-month all-oral regimen are outlined in the Annex. Most drugs, except for bedaquiline, are administered once a day, 7 days per week. In the 9-month regimen, bedaquiline is initially administered daily, with a higher loading dose for the first 2 weeks, followed by a lower maintenance dose on 3 days a week (with at least 48 hours between doses) thereafter.

In terms of choice of fluoroquinolone, either levofloxacin or moxifloxacin may be used in the 9-month all-oral regimen, because they have shown similar efficacy for treating MDR/RR-TB. Although levofloxacin results in a higher pill burden, it is often preferred because moxifloxacin is associated with a higher risk of QT interval prolongation (49). Clinically significant, severe QT interval prolongation is relatively uncommon among patients treated with the 9-month all-oral regimens. However, the additive effect of co-administration of other QT-prolonging drugs (i.e.

The linezolid variation involves initiation of bedaquiline, linezolid, levofloxacin/moxifloxacin, clofazimine, ethambutol, isoniazid (high dose) and pyrazinamide. Linezolid is only given for the first 2 months of treatment. Clinical and haematological monitoring are crucial to detect early linezolid-associated adverse events, particularly haematological events (sudden or significant drop in haemoglobin, neutrophils or platelets).