It is important to consider drug-resistant TB early on, as TB treatment recommendations are based on the assumption that the pattern of drug resistance will not change between the time the specimen was collected and the time the phenotypic DST results are reported. Unfortunately, this gap can last several weeks, during which the patient is receiving standard or empiric therapy. If the initial isolate of the TB bacterium turns out to be polydrug-resistant or MDR, then the standard or empiric regimen may have not only been inadequate in the number and strength of drugs necessary for cure, but also may have induced resistance to other drugs included in the initial regimen (“amplified” resistance).
There are really only two ways to avoid the aforementioned scenario: (i) make certain (within reason) that the empiric regimen is strong enough to cover the possibility that the pretreatment isolate is resistant; or (ii) use one of the newer molecular DST methods that target resistance-conferring mutations and provide an indication, early on, of the existence of resistance to INH and/or RMP (see the following section). Ideally, rapid molecular tests to predict RMP resistance (and, ideally, INH resistance) should be performed for every patient newly diagnosed with TB disease (based upon a positive nucleic acid amplification test or a positive culture), with results used to guide treatment. In locations that do not perform rapid molecular DST on all new positive samples/cultures, rapid molecular tests to detect rifampin resistance (and, ideally, INH resistance) should be performed for patients with risk factors for drug-resistant TB. See the Diagnostic Considerations section, Section 3.1, for additional guidance.
The aforementioned comments pertain to the consideration of resistance at the time of initial diagnosis and treatment initiation. During the course of treatment, certain factors should make clinicians consider the possibility that drug resistance has been acquired (among patients with initially susceptible TB) or amplified (in patients starting with a form of drug-resistant TB). Progressive clinical and/or radiographic deterioration, failure of smears or cultures to convert in a timely fashion or reversion of smears or cultures from negative to positive should lead to suspicion of TB treatment failure (defined in Canada and the United States as continued or recurrent positive cultures after 4 or more months of treatment),55 which should trigger a review of prior DST results and performance of repeat DST on the most recently collected, on-treatment, culture-positive sample. Self-administered treatment, if used, should be abandoned in favor of directly observed therapy (DOT) and, in the event of possible drug malabsorption, serum drug concentrations should be measured.55 Depending upon the circumstances, consideration should be given to a change or expansion of the treatment regimen. If a decision is made to expand the regimen, then a minimum of two new drugs is suggested — it is inadvisable to add a single drug to a failing regimen. It is also advisable for the new drugs to be chosen from those to which the organism is known to be susceptible and/or those that the patient has never received.56
Good practice statements
Prior to choosing an initial TB treatment regimen, clinicians should assess all patients for risk factors for drug-resistant TB.
While awaiting rapid molecular drug susceptibility testing (DST) results, an empiric 4-drug (first-line) regimen can be initiated, with the regimen modified when rapid molecular DST results return (typically <48 hours later). If rapid molecular DST cannot be performed or will be delayed, and conventional culture-based DST results are not expected imminently, consultation with a drug-resistant TB expert is advised regarding the optimal empiric regimen in patients considered at high risk for drug-resistant TB.
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