10.1 Design of therapeutic regimens in MDR-TB

The following are the basic principles involved in MDR-TB regimen design1:

– The intensive phase includes at least four core Group 2 to 4 anti-TB drugs likely to be effective, including an injectable agent − plus pyrazinamide (Z).

– In the case of unclear evidence about the effectiveness of a certain drug, it can be part of the regimen but it should not be counted as one of the four core second-line anti-TB drugs.

– An anti-TB drug is considered “likely to be effective” when:
1 - The drug has not been used in a regimen that failed for the individual patient;
2 - Drug susceptibility testing (DST) performed on the patient’s strain indicates that the strain is susceptible. Only DST for isoniazid, rifampicin, Group 2 and 3 drugs is considered reliable;
3 - No known resistance to drugs with high cross-resistance;
4 - No known close contacts with a patient infected with a strain resistant to the drug;
5 - In the absence of DST or for drugs in which individual DST is not reliable, a drug resistance survey demonstrates that resistance to the drug is rare in patients with similar TB history.

– It is not always possible that all five criteria can be ascertained and clinical judgment is often necessary on whether to count a drug as “likely effective”.

– An important pitfall in designing MDR-TB regimens is due to the turnaround time necessary for DST, the patient may have already received months of a treatment by the time DST results become available from the laboratory. The possibility of further acquired resistance during this time must be considered. If there is a high probability of acquired resistance to a drug after the specimen for DST was collected, this drug should not be counted as one of the four second-line anti-TB drugs in the core regimen, but can be included as an adjunctive agent.

– The most effective regimens for MDR-TB include at least a fluoroquinolone (preferably a third-generation), an injectable agent, ethionamide (or prothionamide), either cycloserine or para-aminosalicylic acid, and pyrazinamide.

– There are conditions when more than five drugs may be started, as is the case if the susceptibility pattern is unknown or the effectiveness is questionable for a drug(s).

– A drug should not be used when patient is known to have a major contraindication of usage (e.g. known major drug-drug interactions, history of allergic reaction, pregnancy).

– Each dose is given under directly observed therapy (DOT) throughout the treatment. A treatment card is marked for each observed dose. DOT can be performed either facilitybased or home-based (often referred to as community-based). See Chapter 13.

– Treatment is given six or seven days a week. Six days a week is chosen for those patients managed in outpatient settings where DOT cannot be done everyday.