5.2.5 Regimen modifications

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:

  • Bedaquiline is usually given for 6 months but may be extended to 9 months if the initial phase of the regimen is extended from 4 to 6 months because of positive sputum smears at month 4 of treatment.
  • Linezolid is only given for 2 months (instead of 4–6 months of ethionamide). If occasional doses of linezolid are missed during that time, the missed doses can be added on to the end of the 2-month period if the patient is tolerating the drug well; however, once fluoroquinolone resistance has been definitively ruled out, it may not be strictly necessary to make up the missed doses. The linezolid dose should not be reduced to less than the recommended dose to reduce the severity of adverse effects. If the full dose of linezolid (600 mg in adults) is not tolerated for the first full 2 months of treatment (apart from occasionally missed doses, which can be added to the end of the 2-month period), then the patient must either switch to an ethionamide-containing 9-month regimen (provided fluoroquinolone susceptibility is confirmed and the patient is not pregnant) or to an individualized longer regimen without linezolid. In selected cases where the risk of undetected resistance to fluoroquinolones and other second-line TB drugs is very low and the patient is unable to tolerate linezolid but would greatly benefit from a shorter regimen (e.g. migrant populations and children), the treating clinician may, after weighing up the risks and benefits, choose to stop linezolid before 2 months and continue the 9-month all-oral regimen, with close monitoring for relapse or recurrence.
  • Prothionamide may be used instead of ethionamide.
  • Moxifloxacin may be used instead of levofloxacin, provided close ECG monitoring is feasible (should this be required).
  • If, for any reason, a patient is unable to tolerate pyrazinamide or ethambutol within the 9-month regimen, then one (but only one) of these drugs may be dropped during the continuation phase without necessitating a switch to a longer regimen. If two or more of these drugs are not tolerated within the 9-month regimen, the treatment will have to switch to a longer regimen. If any of the other drugs within the 9-month regimen (bedaquiline, levofloxacin/moxifloxacin, linezolid/ ethionamide or clofazimine) are stopped early because of toxicity or intolerance then the patient will also have to switch to a new regimen. Patients switching to a new regimen due to toxicity or intolerance need to be reported as “treatment failed” (Chapter 10).
  • At the fourth month of treatment on the 9-month regimen, the decision to extend the initial phase from 4 to 6 months is based on the bacteriological sputum smear status of the patient’s sputum specimen. If the specimen is smear negative at month 4 (regardless of smear status at the start of treatment), the patient may move to the continuation phase of treatment. If the specimen is smear positive at month 4, the initial phase is prolonged to 6 months. The duration of the continuation phase remains fixed at 5 months.
  • At the sixth month of treatment, the culture result from the specimen taken at month 4 and possibly month 5 should be available, as well as the smear results from the specimens taken at months 5 and 6. If the culture from the 4-month specimen is positive for M. tuberculosis, the clinician should undertake a full work-up to assess for treatment failure – this involves a comprehensive clinical assessment, review of treatment adherence to address specific challenges, radiological assessment and collection of another respiratory sample for bacteriological assessment, as well as repeat DST of the most recent positive culture to test for emerging resistance to second-line TB drugs. Similarly, if the month 5 and 6 culture results remain persistently positive, treatment failure should be suspected, particularly if the patient has had suboptimal adherence to treatment or shows other signs of poor clinical or radiological response to treatment.

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