Operational Handbooks

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).

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.