Drug-resistant tuberculosis treatment

Addition of isoniazid. There was no clear evidence that the addition of isoniazid affects patients (i.e. 
adding benefit or harm). For patient convenience and ease of administration, the four-drug HREZ 
FDCs
23
may be used to deliver the Hr-TB treatment regimen alongside
levofloxacin.
The use of high-dose isoniazid (10–15 mg/kg per day in adults) was not evaluated in this review because 
there was insufficient data. However, the GDG discussed the effect of increasing isoniazid dosing beyond 
that provided in weight-banded FDCs, depending on the type of molecular mutations identified. In vitro 
evidence suggests that when specific inhA mutations are detected (and when katG mutations are absent), 
increasing the dose of isoniazid is likely to be effective; thus, additional isoniazid up to a maximum dose 
of 15 mg/kg per day could be considered. In the case of katG mutations, which usually confer a higher 
level resistance, the use of isoniazid even at a higher dose is less likely to be effective (37).
24
Dosage. Although the IPD analysis did not provide evidence to address the frequency of dosing, it is 
best to avoid intermittent or divided dosing of the 6(H)REZ–levofloxacin regimen (29, 38, 39). In the 
absence of full information about optimal drug doses, a weight-band dosing scheme for levofloxacin 
is recommended.
25
Drug–drug interactions. Levofloxacin may interfere with lamivudine clearance (increasing the levels 
of lamivudine) but it is not contraindicated with other antiretroviral agents, and no drug dosing 
adjustments are needed (36). Co-administration of levofloxacin with oral divalent cation-containing 
compounds (e.g. antacids) may impair its absorption and should be avoided (9). Restriction of 
concomitant use of milk products is not
necessary.
Treatment prolongation beyond 6 months. This may be considered for patients with extensive 
disease or in those slow to convert to smear or culture negative. In the latter, acquisition of additional 
resistance to rifampicin must be ruled out, as must resistance to fluoroquinolones and pyrazinamide, 
if possible. Such patients require careful monitoring and follow-up.
22 
Baseline-corrected QT. Prolongation of the QT interval and isolated cases of torsade de pointes have been reported. Avoid use in patients 
with known prolongation, those with hypokalaemia, and with other drugs that prolong the QT
interval.
23 
Although most countries currently procure the four-drug FDC via the Stop TB Partnership’s Global Drug Facility (GDF), in settings where 
only the three-drug combination FDC (i.e. HRZ) is available, ethambutol has to be administered
separately.
24 
An isolated katG or inhA mutation can correspond to variable minimum inhibitory concentration (MIC) levels. This implies that inhA 
mutations do not always indicate low-level isoniazid resistance, or that katG mutations are not necessarily correlated with high-level 
isoniazid resistance. The presence of both mutations is usually an indication of high-level resistance (37).
25 
Studies included in this IPD analysis involved the use of regimens containing levofloxacin (usually at a dose of 750–1000 mg/day), 
moxifloxacin (400 mg/day) or gatifloxacin (400 mg/day), as well as early generation fluoroquinolones (ciprofloxacin and ofloxacin), which 
are no longer recommended for the treatment of drug-resistant TB. Gatifloxacin is currently unavailable in quality-assured formulations, 
and ciprofloxacin and ofloxacin are no longer recommended for use in drug-resistant TB
care.

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WHO consolidated 
guidelines 
on
tuberculosis: 
drug-resistant tuberculosis treatment
11