Traditionally, drug resistance in TB has been classified into 3 types.8
Primary drug resistance: When previously untreated patients are found to have drug-resistant organisms, presumably because they have been infected from an outside source of resistant bacteria. Primary drug resistance is uncommon in Canadian-born people unless they have traveled abroad to a country with a high prevalence of drug-resistant TB.
Acquired drug resistance: When patients who initially have drug-susceptible TB bacteria that later become drug-resistant during treatment. Acquired drug resistance is uncommon in Canadian-born people.9
Initial drug resistance: When drug resistance occurs in patients who deny previous treatment but whose lack of prior TB drug use cannot be verified. In reality it consists of true primary resistance and an unknown amount of undisclosed acquired resistance.
An understanding of acquired drug resistance theory is key to the prevention of drug-resistant TB. In any large population of M. tuberculosis bacteria, there will be several naturally occurring drug-resistant mutants.10,11 Random mutations that confer resistance to each of the major anti-TB drugs occur at predictable frequencies in nontreated populations of TB bacteria (Table 2). A 2-cm diameter TB cavity harboring 108 (100 million) bacteria may contain a few (∼100) bacteria resistant to INH, a few (∼10) resistant to RMP, a few (∼10-100) resistant to EMB, and so forth. This does not mean that when a sample of this population of bacteria is cultured in the laboratory, it will be determined to be resistant to these drugs: for resistance to be reported in the laboratory, at least 1% of the bacterial population needs to be resistant to the drug.10,12,13
Table 2. Mutation rates (per bacterium, per generation) and average mutant frequencies (in an unrelated population of bacteria, the proportions of resistant bacilli) for several commonly used drugs. 12
|Drug||Mutation rate||Average mutant frequencies|
|INH (0.2 µg/mL)||1.84 × 10–8||3.5 × 10–6|
|RMP (1.0 µg/mL)||2.20 × 10–10||1.2 × 10–8|
|EMB (5.0 g/mL)||1.00 × 10–7||3.1 × 10–5|
|SM (2.0 µg/mL)||2.90 × 10–8||3.8 × 10–6|
Abbreviations: INH, isoniazid; RMP, rifampin; EMB, ethambutol; SM, streptomycin.
The sites of resistance within the mutants are chromosomally located and are not linked. Accordingly, the likelihood of a bacterium spontaneously developing resistance to two unrelated drugs is the product of probabilities: for example, for INH and RMP resistance, 1 in 108 × 1 in 1010 equals 1 in 1018. Because the total number of bacteria in the body, even with far advanced disease, rarely approaches this number (1018), spontaneous evolution of MDR-TB is very rare. As Iseman and Madsen have enunciated so clearly: “This is the salient principle of modern TB chemotherapy. Because naturally occurring two-drug resistance is very uncommon, therapy with two (or more) drugs prevents the emergence of progressive resistance in the following manner: some organisms in the population will be resistant to drug A, and some others will be resistant to drug B, but none will be simultaneously resistant to both drugs. Thus drug B will kill those organisms resistant to drug A, whereas drug A will kill those resistant to drug B. In principle this means a two-drug regimen should be adequate to treat the usual case of drug-susceptible TB.”14 Because PZA accelerates bacterial killing in the initial phase and shortens the duration of treatment, and because bacterial loads may occasionally be very large, it is usually added to INH and RMP; to prevent acquired resistance to RMP in the event the initial isolate of M. tuberculosis is resistant to INH, EMB is usually added to INH, RMP and PZA.1,15 Thus, the standard short-course therapy recommended includes these 4 drugs. If the initial isolate is determined to be fully drug-susceptible, EMB may be discontinued (see Chapter 5: Treatment of Tuberculosis Disease).
If latent TB infection (LTBI) is present, then it is reasonably safe to assume the bacterial load is small, and treatment need only include a single drug, usually RMP or INH.15
The emergence of drug resistance is due to the selection of preexisting resistant mutants in the original bacterial population by “drug pressure.” For example, if INH alone is prescribed (or is the only first-line drug taken in a multidrug regimen), then it will kill all of the bacteria susceptible to it, including those random mutants resistant to drugs such as RMP or EMB, but it will not kill INH-resistant mutants. These will continue to multiply and will eventually dominate the population because they have a selective advantage in the presence of the drug, and INH will be lost as a tool to the practitioner. The likelihood of this happening is influenced by the duration of such monotherapy: 25% among those receiving INH alone for 2 weeks, 60% for those receiving it for 6 months and 80% for those receiving it for 2 years.16 If RMP alone is now added to the regimen, then by the same mechanism, an MDR strain (ie, resistant to both drugs) will emerge: RMP will kill all bacteria resistant to INH, but it will not kill those few random mutants in the new population that are resistant to both INH and RMP.12,14
This classic theory of drug resistance in TB posits a sequence of events in which the patient effectively receives monotherapy. It does not explain how resistance may emerge solely because of irregularity in drug taking and without monotherapy. Other mechanisms have been proposed to explain resistance under these circumstances.1,12,17 In essence, they require several cycles of killing (when drugs are taken) and regrowth (when drug-taking stops). In each of these cycles, there is selection favoring the resistant mutants relative to the susceptible bacterial population. Regrowth back to the size of the original population may occur with the consequent presence of increasing proportions of resistant bacteria at the start of each cycle.
1.3.1. Acquired drug resistance
A drug-susceptible strain of TB may become drug-resistant, or a mono-resistant strain may become polydrug-resistant, during treatment. This is more likely to occur under the following circumstances:
when there is intermittent or erratic ingestion of the prescribed anti-TB drugs; 12,14
when suboptimal drug doses, or poor-quality drugs are used;2
when the patient is malabsorbing 1 or more of the drugs in the treatment regimen;12
when the patient has cavitary pulmonary TB, with cavities containing large numbers of bacteria with correspondingly large numbers of drug-resistant mutants10, and differential penetration of anti-TB drugs into cavities has been shown; and 18
when the patient’s disease is sequestered, for example, pericardial TB, meningeal TB, or TB empyema, which also may lead to differential drug penetration.19–21
Heteroresistance, either due to infection with a mixture of drug-susceptible and drug-resistant organisms arising from a single strain, or infection with mixed strains, has also been described, and may lead to selection of a drug-resistant subpopulations during treatment.22–26 Instances of infection with a drug-resistant strain during treatment of disease that is due to a drug-susceptible strain have also been reported.27
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