HomeConventional, culture-based (phenotypic) DST, while still considered the gold standard, takes weeks before a result is reported. Rapid molecular DST assays detect mutations in mycobacterial DNA that are associated with resistance to specific drugs. These assays can be performed on patient samples or on positive cultures, with results available within hours to days. Current molecular DST assays are reviewed in Chapter 3: Diagnosis of Tuberculosis Disease and Drug-resistant Tuberculosis.
Rapid molecular tests to predict rifampin resistance (and, ideally, INH resistance) should be performed for every patient newly diagnosed with TB disease. In locations that do not perform rapid molecular DST on all new positive samples/cultures, rapid molecular testing for rifampin resistance should be requested by clinicians at the time of TB diagnosis in patients considered at increased risk for MDR/rifampin resistant TB, including patients who have been treated for TB in the past, patients who have lived for at least one year in a country with a high primary MDR-TB prevalence (≥2%) or moderate total TB incidence (≥20/100,000), patients who have a history of contact with a person with infectious drug-resistant TB and patients with HIV infection.57 Clinicians should communicate with their laboratory to request this testing and ensure that the laboratory has the specimens needed; generally, multiple samples from potentially involved organs should be collected, in order to increase the likelihood of obtaining good samples/isolates for molecular and phenotypic DST.
Use of rapid molecular DST also reduces the delay to the start of appropriate second-line therapy.58,59 It is assumed that this will, in turn, benefit the patient by increasing cure, decreasing mortality, reducing development of additional resistance and reducing the likelihood of failure and relapse, although data supporting benefits in these patient-important outcomes are limited to lower-resource settings.58 Additional assumed benefits of early initiation of appropriate therapy include reduced risk of transmission and shorted duration of airborne isolation.
It is important to note that the positive predictive value of rapid molecular DST for the detection of rifampin resistance is low in populations with a very low prevalence of drug resistance (for example, most Canadian-born TB patients). Clinicians should consider the possibility of a false positive result in patients with a low risk for rifampin resistance, and liaise with the laboratory regarding confirmatory testing (sequencing-based methods, or conventional DST). While awaiting confirmatory testing when a rapid molecular test demonstrates rifampin resistance, the patient’s individual risk for rifampin resistance should be considered before deciding on the initial treatment regimen. Patients considered at increased risk for rifampin resistance should be initiated on an MDR-TB treatment regimen. However, patients considered at low risk for rifampin resistance could receive the standard first-line regimen plus additional second-line drugs. Consultation with a drug-resistant TB expert is strongly advised in these circumstances.
Use of rapid tests does not eliminate the need for culture and phenotypic DST. These are important to confirm the molecular results, and for susceptibility testing for other first- and second-line drugs. Individual patient data meta-analyses have demonstrated worse outcomes in the treatment of MDR-TB when drugs are used despite demonstrated in vitro resistance.60 Currently (2021), phenotypic drug susceptibility testing is available in Canada for all first-line drugs, but only some second-line drugs. Importantly, at the time of writing, phenotypic DST for 2 key drugs now recommended for first-line treatment of MDR-TB (bedaquiline, clofazimine) are not available anywhere in Canada, even though lab standards have been established for these drugs.61 Until testing for bedaquiline and clofazimine susceptibility becomes available in Canada, isolates should be sent to reference laboratories in the United States for this testing.
Cross-resistance occurs among certain anti-TB drugs; this should be considered when constructing a treatment regimen.
Cross-resistance among anti-TB drugs
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Resistance to amikacin induces cross-resistance to kanamycin and vice versa.62
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Resistance to streptomycin does not induce cross-resistance with amikacin-kanamycin, or capreomycin.62
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Isolates acquiring resistance to capreomycin are usually susceptible to kanamycin and amikacin.62
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Isolates acquiring resistance to amikacin and kanamycin may or may not be resistant to capreomycin.62
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Resistance to one fluoroquinolone induces class-effect cross-resistance to all other fluoroquinolones, though data suggest that this cross-resistance may not be complete. Some isolates resistant to ofloxacin may be susceptible to moxifloxacin.56,63,64
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Most isolates resistant to rifampin (approximately 80%) are also resistant to rifabutin.62 Resistance to rifapentine is universal in rifampin-resistant isolates.
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Cross-resistance to ethionamide may occur when there is low-level resistance to INH.56
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There have been a few reports of cross-resistance between bedaquiline and clofazimine.65,66
Recommendation
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We strongly recommend that isolates from all TB patients diagnosed with rifampin resistance/multidrug resistance undergo phenotypic drug susceptibility testing for all anti-TB medicines currently recommended to treat MDR-TB (good evidence).
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