Richard Long, MD, FRCPC, FCCP
Monica Avendano, MD, FRCPC
Dennis Kunimoto, MD, FRCPC
People with TB are said to have drug-resistant disease if their strain of Mycobacterium tuberculosis is resistant to one or more first-line drugs: isoniazid (INH), rifampin (RMP), pyrazinamide (PZA) and ethambutol (EMB). The impact of drug resistance on the outcome of TB treatment varies according to which drug, or combination of drugs, is resistant and reflects the different but complementary role each drug plays in the treatment of TBFootnote 1.
Globally, the improper prescription of anti-TB drugs, their proper prescription but unavailability, inadequate supervision or, uncommonly, the malabsorption of these drugs has increased the prevalence of drug-resistant TB. In low- to middle-income countries the resource-driven use of standardized regimens that do not take into account pre-treatment DST results may have inadvertently amplified the problem of drug-resistant TB. In a systematic review and meta-analysis of initial drug resistance and TB treatment outcomes the cumulative incidence of acquired drug resistance with initially pan-sensitive strains was 0.8% (95% confidence interval [CI] 0.5% to 1.0%) compared with 6% (CI 4% to 8%) with initially single drug-resistant strains and 14% (CI 9% to 20%) with initially polydrug-resistant strainsFootnote 2.
The fourth global report on Anti-tuberculosis drug resistance in the world, produced by the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease, describes resistance patterns in 81 countries and 2 special administrative regions of China from 2002 to 2006.3 The population-weighted mean of resistance to any of INH, RMP, EMB or streptomycin (SM) was 17.0% (95% CI 13.6% to 20.4%) in new cases, 35.0% (CI 24.1% to 45.8%) in previously treated cases and 20% (CI 16.1% to 23.9%) in all TB cases. The global weighted mean of MDR-TB, defined as resistance to at least INH and RMP, the two most important anti-TB drugs, was 2.9% (CI 2.2% to 3.6%) in new cases, 15.3% (CI 9.6% to 21.0%) in previously treated cases and 5.3% (CI 3.9% to 6.7%) in all TB cases. In 2008, an estimated 440,000 cases of MDR-TB emerged globally, India and China accounting for almost 50% of the world’s total cases.4 In the 46 countries that reported continuous surveillance or representative surveys of second-line drug resistance in MDR-TB cases, 5.4% were found to have extensively drug-resistant (XDR) TB, defined as resistance to INH and RMP as well as any fluoroquinolone (FQN) and any one of the second-line injectable agents, amikacin, kanamycin or capreomycinFootnote 3 Footnote 4.
In Canada, two systems are used to track drug-resistant TB.
Provincial and territorial TB control programs participate in the CTBRS national surveillance system by reporting to the Centre for Communicable Diseases and Infection Control, Public Health Agency of Canada (PHAC), all new and re-treatment cases of active TB. Between 2006 and 2010, drug-resistant TB was reported most commonly in people with a past history of TB ("re-treatment cases") and in foreign-born people (refer to Table 1)Footnote A.
Of 5,807 new active cases of TB, 5.3% had an INH-resistant/RMP-sensitive strain and 0.7% had an MDR strain. Of 427 cases of re-treatment TB, 7.5% had an INH-resistant/RMP-sensitive strain and 2.3% had an MDR-TB strainFootnote 5. Between 2006 and 2010, foreign-born people with TB were 1.9 times more likely to have INH-resistant/RMP-sensitive TB and almost 13 times more likely to have MDR-TB than Canadian-born people. Higher rates of drug resistance among foreign-born people correspond to higher rates of drug resistance in their country or region of birth. Countries in which the majority of the population has access to the DOTS strategy (directly observed treatment, short course; refer to Chapter 5, Treatment of Tuberculosis Disease) have lower rates of drug resistanceFootnote 6. In Alberta the prevalence of MDR-TB was higher among immigrants who arrived in the decade ending in 2011 than in the decades ending in 1991 or 2001 (Figure 1)Footnote 7. In Canada, drug-resistant TB cases present earlier after arrival than drug-susceptible TB cases (Figure 2)Footnote 8. Immigrants to Canada from the Western Pacific may be at higher risk of MDR-TB due to Beijing/W strains of M. tuberculosisFootnote 9. Most TB cases (71.0%) and most MDR-TB cases (84.0%) in Canada were reported in three provinces: BC, Ontario and QuebecFootnote 10.
|Country of Birth|
|Resistance Pattern||Disease type||Canadian-born||Foreign-born||Unknown||Total|
|Susceptible to INH and RMP||New active||1,733||84.4||3,600||84.7||89||78.8||5,422||84.5|
|Resistant to INH, susceptible to RMP||New active||66||3.2||268||6.3||3||2.7||337||5.3|
|Resistant to RMP, susceptible to INH||New active||2||0.1||4||0.1||0||0.0||6||0.1|
|Resistant to INH and RMP (MDR-TB)||New active||1||0.0||41||1.0||0||0.0||42||0.7|
Figure 1. Number of foreign-born people with MDR-TB diagnosed in Alberta by year of arrival. The number of cases is represented by the solid line and the trend in MDR-TB case counts by the dashed lineFootnote 7.
Figure 2. Time from arrival in Canada to diagnosis of foreign-born, culture-positive tuberculosis cases by drug susceptibility pattern of incident case isolate (1997-2008)Footnote 8
Time from arrival to diagnosis was calculated by subtracting year of arrival from year of diagnosis. Year of arrival was known for 6,928 of the 10,589 foreign born cases. Cases with time since arrival between 0 and 55 years displayed.
Bar graph represents the absolute number of cases diagnosed, and line graph represents the cumulative proportion of foreign-born TB cases diagnosed since their time of arrival in Canada.
This national laboratory-based surveillance system was established in 1998 to collect timely data on TB drug resistance across Canada. Participating laboratories include members of the Canadian Tuberculosis Laboratory Technical Network (covering all provinces and territories). Refer to Table 2 for the overall pattern of TB drug resistance in Canada, 2006 to 2010, as reported by this system. For additional reports, refer to the annual Tuberculosis Drug Resistance in Canada reports.Footnote 10
Drug resistance is detected by the performance of in-vitro DST on pure cultures of M. tuberculosis complex grown from clinical specimens collected from patients (refer to Chapter 3, Diagnosis of Active Tuberculosis and Drug Resistance). Prompt turnaround times for laboratory results are of paramount importance in rapid diagnosis and appropriate treatment of drug-resistant TB. Recent advances in molecular biology have allowed identification of the genetic loci and biologic mechanisms of resistance to each of the first-line and selected second-line drugs.
|Any first-line drug resistanceFootnote B|
|Any resistance to INH||101||7.3||110||8.7||102||7.5||113||8.5||101||7.9||527||8.0|
|Any resistance to RMP||24||1.7||13||1||19||1.4||21||1.6||18||1.4||95||1.4|
|Any resistance to EMB||12||0.9||23||1.8||13||1||17||1.3||10||0.8||75||1.1|
|Any resistance to PZA||16||1.2||27||2.1||22||1.6||18||1.4||25||2||108||1.6|
|Resistant to ≥1 first line drug||126||9.1||133||10.5||116||8.6||127||9.5||112||8.8||614||9.3|
Traditionally, drug resistance in TB has been classified into three typesFootnote 11.
1. 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 travelled abroad to a country with a high prevalence of anti-TB drug resistance.
2. Acquired drug resistance:
When patients who initially have drug-susceptible TB bacteria later become drug-resistant as a result of inadequate, inappropriate or irregular treatment or, more importantly, because of nonadherence in drug taking. Acquired drug resistance is uncommon in Canadian-born people, perhaps because directly observed therapy (DOT) is frequently used to promote treatment adherenceFootnote 12.
3. Initial drug resistance:
When drug resistance occurs in patients who deny previous treatment but whose history of prior drug use cannot be verified. In reality it consists of true primary resistance and an unknown amount of undisclosed acquired resistance. It may be best to classify drug resistance in the foreign-born who deny previous drug use as initial rather than primary, unless their prior drug use can be verified. The following theory relates to acquired drug resistanceFootnote B.
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 mutantsFootnote 13 Footnote 14. Random mutations that confer resistance to each of the major anti-TB drugs occur at predictable frequencies in nontreated populations of TB bacteria (Table 3). A 2 cm diameter TB cavity harbouring 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, etc. 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 drugFootnote 13 Footnote 15 Footnote 16. When 1% or more of a bacterial population is resistant to a given drug, clinical success with a regimen that is dependent upon that drug is less likelyFootnote 13 Footnote 15 Footnote 16.
|Drug||Mutation rate||Average mutant frequencies|
|INH (0.2 µg/mL)||1.84 x 10-8||3.5 x 10-6|
|RMP (1.0 µg/mL)||2.2 x 10-10||1.2 x 10-8|
|EMB (5.0 g/mL)||1.0 x 10-7||3.1 x 10-5|
|SM (2.0 µg/mL)||2.9 x 10-8||3.8 x 10-6|
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:17 "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." Because PZA accelerates bacterial killing in the initial phase and shortens the duration of treatment, and because bacterial loads may occasionally be very large, PZA is usually added to INH and RMP; to prevent acquired resistance to RMP in the event the initial isolate of M. tuberculosis (MTB) is resistant to INH, EMB is usually added to INH, RMP and PZAFootnote 1 Footnote 18. Thus, the standard short-course therapy recommended includes four drugs: INH, RMP, PZA and EMB. If the initial isolate is determined to be fully drug-susceptible, EMB may be discontinued (refer to Chapter 5, Treatment of Tuberculosis Disease).
If infection (latent TB infection or LTBI) and not disease is present, then it is reasonably safe to assume the bacterial load is small, and treatment need only include a single drug, usually INHFootnote 18.
The emergence of drug resistance is due to the selection of pre-existing resistant mutants in the original bacterial population by "drug pressure." Footnote 15 Footnote 17 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 and 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 to the armamentarium. 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 yearsFootnote 19. If RMP alone is now added to the regimen, then by the same mechanism an MDR strain (i.e. resistant to both INH and RMP) 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 RMPFootnote 15 Footnote 17.
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 circumstancesFootnote 15 Footnote 20 Footnote 21. 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 favouring 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.
The possibility of drug-resistant TB should be considered at the time of selection of the initial treatment regimen. Failure to consider the possibility of drug-resistant TB until DST results become available weeks later can result in unnecessarily inadequate treatment regimens.
In patients who have not yet started their anti-TB drugs the most important predictors of drug-resistant TB are the following:
1. Previous treatment of TB disease
Drug-resistant TB should be suspected if the patient was previously treated for smear-positive or cavitary pulmonary TB; or if the treatment regimen was inadequate or self-administered; or if the patient was nonadherent. Conversely, if the patient is reported to have been lost to follow-up when taking multidrug DOT (i.e. stops all medications at the same time) or has relapsed after completion of a directly observed standardized regimen, then theoretically the likelihood of the isolate being drug-resistant is lowerFootnote 23.
To quote the Francis J. Curry National Tuberculosis Center:Footnote 22 "the soliciting of a history of previous TB treatment requires a great deal of patience and attention to detail. In a culturally sensitive and confidential setting one must allow plenty of time, utilize an accurate and unbiased interpreter (if necessary), and be willing to repeat or rephrase a question to obtain the information. One must give the patient encouragement to review accurate information by asking and responding in a nonjudgmental manner. One must ask the patient if he/she has any written information regarding his or her treatment, any old radiographs, etc." Patients born in Canada may have records of previous treatment at the level of the provincial/territorial TB program. Foreign-born people who have been referred for medical surveillance by Citizenship and Immigration Canada (CIC) because of inactive pulmonary TB, history of TB or another condition that puts them at high risk of active TB may have overseas records of previous treatment that CIC can retrieve (refer to Chapter 13, Tuberculosis Surveillance and Screening in Selected High-risk Populations).
If active TB disease is not adequately excluded beforehand, treatment of LTBI, even if only for a month, can result in drug resistance.
2. Origin from, history of residence in, or frequent or extended (1 month or more) travel to a country/region with high rates of drug resistance
Although drug-resistant TB is more common in the foreign-born than in other population groups in Canada, transmission of drug-resistant TB from the foreign-born to the Canadian-born is relatively uncommonFootnote 12 Footnote 24.
3. Exposure to an individual with infectious drug-resistant TB, including exposure in facilities where drug resistance has occurred, e.g. correctional facilities, homeless shelters or other congregate settings
While some data suggest that drug-resistant bacteria are less transmissible or less pathogenic once transmitted than drug-susceptible bacteria,Footnote 25-34 other data indicate that this may not be so and the transmission risk is offset by longer periods of infectiousness in drug-resistant casesFootnote 34 Footnote 35 or compensatory mutations in drug-resistant bacteriaFootnote 36. Clinical evidence of the transmissibility of drug-resistant strains is compellingFootnote 37-40. For practical purposes, i.e. for the ordering of treatment regimens or for contact tracing, drug-resistant bacteria should be considered just as transmissible and just as pathogenic as drug-susceptible bacteria.
4. Exposure to a person with active TB who has had prior treatment for TB resulting in treatment failure or relapse and whose DST results are not known
Depending upon the circumstances of the individual case (e.g. likelihood of resistance to more than one first-line drug, severity of disease) an expanded, empiric treatment regimen may be indicated from the outset. Although few countries report drug resistance data disaggregated by HIV status, the two with the most robust data (Latvia and Donetsk Oblast, Ukraine) both showed a significant association between HIV and MDR-TBFootnote 3. This association may have more to do with environmental factors, such as transmission in congregate settings, than biological factorsFootnote 41.
A drug-susceptible strain of TB may become drug-resistant, or a monoresistant strain may become polydrug-resistant (refer below) during treatment. This is more likely to occur under the following circumstances:
Rare instances of mixed infection, with selection of a drug-resistant subpopulation during treatment with first-line drugs of a dominant drug-susceptible population, have been reportedFootnote 44 Footnote 45. Also reported have been instances of reinfection with a drug-resistant strain during treatment of disease that is due to a drug-susceptible strainFootnote 46.
Among patients with drug-susceptible pulmonary TB who are treated with standard four-drug therapy, approximately 80% will have negative sputum cultures after 2 months of treatmentFootnote 47. Progressive clinical and/or radiographic deterioration or failure of smears or cultures to convert in a timely fashion should lead to suspicion of treatment failure (defined as: [i] sputum smears positive after 5 months or more of treatment or [ii] continued or recurrent positive cultures after 4 or more months of treatment in patients in whom medication ingestion was confirmed) and acquired drug resistanceFootnote 47 Footnote 48. Prior DST results should be reviewed and repeat DST performed. Self-administered treatment, if used, should be abandoned in favour of DOT and, in the event of possible drug malabsorption, serum drug concentrations should be measuredFootnote 47. 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 recommended – it is inadvisable to add a single drug to a failing regimen. It is 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 receivedFootnote 22.
For the optimal management of drug-resistant TB, particularly MDR-TB, the following is recommended: the performance of state-of-the-art DST, an uninterrupted supply of first- and second-line anti-TB drugs (refer below), the capacity to provide DOT, and access to a physician and team experienced in the management of drug-resistant TB. Steps to ensure that there is an uninterrupted supply of drugs should begin 6 months or more in advance of anticipated need, and drug needs should be estimated as accurately as possibleFootnote 49.
The WHO "gold standard" method for M. tuberculosis DST for first-line drugs uses an automated liquid culture system and an indirect or direct testFootnote 50. Such phenotypic testing systems are most accurate for INH and RMP and less reliable (the extent to which a test result remains consistent when repeated under identical conditions) and reproducible (the ability of a test to be accurately reproduced or replicated under independent conditions) for PZA, EMB and SM. Liquid culture DST for aminoglycosides, polypeptides and FQNs has been shown to have relatively good reliability and reproducibilityFootnote 50. The Clinical and Laboratory Standards Institute, which offers practical operating guidelines that lead to consistent laboratory practices, precision and efficient use of resources, recommends that after having been tested for first-line anti-TB drugs, isolates found to be monoresistant to RMP or to demonstrate resistance to any two of the first-line anti-TB drugs should be tested against a panel of second-line drugsFootnote 51. When FQNs may be added to therapy for cases showing monoresistance to INH (refer below), it is also recommended that second-line anti-TB drug testing should be performedFootnote 51. In anticipation of possible INH resistance/intolerance many laboratories are now including routine FQN DST at the time of first-line DST. In Canada in 2011, four laboratories conducted second-line anti-TB drug susceptibility testing: the provincial laboratories in Alberta, Ontario and Quebec, and the National Reference Centre for Mycobacteriology in ManitobaFootnote 10 Footnote 52.
Among patients with the various patterns of drug resistance, definitive, randomized trials of treatment have not been performed. Recommendations for treatment are based upon less than ideal evidence. With few exceptions the treatment regimens for drug-resistant nonrespiratory TB are the same as those for respiratory TBFootnote 49. Generally, the regimens assume that the pattern of drug resistance has not changed between the time the specimen was collected and the time the phenotypic DST results were reported. Unfortunately, this gap can include several weeks during which the patient is receiving standard or empiric therapy. If the initial isolate of MTB 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 have induced resistance to other drugs included in the initial regimen ("amplified" resistance).
There are really only three ways to avoid this scenario: (i) delay treatment altogether until the DST results on the initial isolate are available – rarely an acceptable option, (ii) make certain (within reason) that the empiric regimen is strong enough to cover the possibility that the pre-treatment isolate is highly resistant or (iii) use one of the newer genotypic DST methods that target resistance-conferring mutations and provide an indication, early on, of the existence of resistance to INH and/or RMP (refer below)Footnote 7.
In Canada, RMP resistance strongly suggests (85% or more of the time) the presence of MDR-TB (refer to Table 1). Two new WHO-approved molecular tests rapidly detect RMP resistance and by doing so signal the likely presence of MDR-TB: the line probe assays (LPAs) and the Xpert MTB/RIF testFootnote 50. LPAs use a polymerase chain reaction (PCR) hybridization technique to identify members of the MTB complex while simultaneously identifying drug-resistant strains through detection of the most common single nucleotide polymorphisms associated with resistance. The major advantage of LPAs is that they can be performed directly on smear-positive sputum samples, giving rapid (approximately 5 hour) drug susceptibility results without the need for culture. The disadvantages of LPAs are that they are labour intensive and require highly trained personnel, and dedicated laboratory space and equipment. The Xpert MTB/RIF test is a fully automated, closed system that performs both sample preparation and real-time PCR, producing results (detecting MTB complex while simultaneously detecting RMP resistance [targeting the rifampin resistance-determining region of the rpoB gene]) in less than 2 hours. The sensitivity and specificity of these two systems for detecting RMP resistance are in the order of 97%-100%Footnote 50 Footnote 53.
The WHO currently recommends rapid DST of INH or RMP alone over conventional testing or no testing at the time of diagnosis of TB, subject to available resourcesFootnote 54. The basic assumption is that rapid DST will reduce the delay to the start of appropriate second-line therapy and thus provide benefit to the patient by increasing cure, decreasing mortality, reducing development of additional resistance and reducing the likelihood of failure and relapse. Studies supporting this assumption are just beginning to emergeFootnote 55-57. With the use of decision analysis modelingFootnote 58, it was found that rapid testing for both INH and RMP at diagnosis rather than later during treatment was the most cost-effective DST strategy available, starting from an MDR-TB prevalence greater than 1% and an INH resistance (other than MDR-TB) greater than 2%, both of which apply to foreign-born TB patients in Canada (Table 1)Footnote 8. Origin from, history of residence in or frequent travel to one of the 27 countriesFootnote C with a high MDR-TB burden, especially if residence or travel occurred within recent years, should prompt consideration of rapid testingFootnote 4.
Other patients to consider for rapid testing include those with a history of previous treatment, those who are contacts of MDR-TB cases and those who are HIV coinfectedFootnote 4 Footnote 7. Most Canadian-born TB patients would not be good candidates for rapid testing, given the low positive predictive value of these tests in patient groups in which RMP resistance is rare. It is recommended that use of rapid tests not obviate the need for culture and phenotypic DST. The current status of second-line DST methodology, consensus on reliability and reproducibility, and critical concentrations for different methodologies can be found in a WHO policy document on the rational use of second-line DSTFootnote 59. Susceptibility testing to all second-line drugs (cycloserine excepted) is available in CanadaFootnote 10 Footnote 52.
In Canada, INH resistance is the most common pattern of first-line drug resistance (refer to Table 1 and Table 2). Resistance to INH is usually due to a mutation in either the katG or INHA geneFootnote 60 Footnote 61. Less commonly it is due to one or more mutations in other genes, such as the ahpC geneFootnote 15.
INH is a prodrug that must be activated by catalase-peroxidase, an enzyme that is regulated by the katG gene, in order to be effective against MTB. Mutation of the katG gene results in high level resistance to INH (resistance concentration 1.0 µg/mL using solid media [agar proportion method], 0.4 µg/mL using liquid media [indirect proportion method])Footnote 15 Footnote 62. When the katG gene is not mutated, activated INH acts on several M. tuberculosis genes, of which those in the INHA promoter region are the most importantFootnote 62. Mutations in the INHA gene or INHA promoter region result in low-level resistance to INH (0.2 µg/mL using solid media, 0.1 µg/mL using liquid media). Isolates that have high-level resistance to INH are usually susceptible to ethionamide; isolates that have low-level resistance to INH are usually resistant to ethionamide but susceptible to high dose (15 mg/kg or 900 mg thrice weekly) INH (refer below)Footnote 62.
In general, on the basis of the research, it is recommended that patients suspected of having INH-resistant TB (with or without SM resistance) should, at a minimum, be started on all four first-line drugs while DST results are pending. An initial four-drug regimen is also advisable whenever the prevailing rate of INH resistance among those in whom there is no history of anti-TB drug use is 4% or more (refer to Table 1 and Table 2)Footnote 63.
Recommended regimens for the treatment of INH-resistant TB are listed in Table 4Footnote 64 Footnote 65. The presence of SM resistance does not affect the efficacy of these regimens. Ideally, each regimen should be regarded as the minimum effective therapy, and consideration should be given to administering the regimen as DOT (refer to Chapter 5, Treatment of Tuberculosis Disease).
Direct observation of treatment is especially important in patients with smear-positive pulmonary disease or HIV coinfection. Given that a randomized controlled trial showed moxifloxacin, a fourth-generation FQN, to be equivalent to INH in the initial phase of treatment of smear-positive pulmonary TB, it is assumed that moxifloxacin or, by inference, levofloxacin (a third-generation FQN) would be equally efficacious and therefore could be interchangeable with INH in the treatment of INH-resistant TBFootnote 66
(Strong recommendation, based on moderate evidence)
Still unresolved is the question of whether an FQN can be used in an intermittent regimen; in theory a thrice weekly regimen of levofloxacin and RMP could be effective as the half-lives of these two drugs tend to be similar. A thrice weekly regimen of moxifloxacin and RMP is not considered advisable, as the half-life of moxifloxacin is longer than that of RMP, resulting in conditions of moxifloxacin monotherapyFootnote 65.
|Initial phase||Continuation phase|
|2 months daily (INH) RMP/PZA/EMBFootnote A||4-7 months daily or thrice weekly RMP/PZA/EMBFootnote 64|
|2 months daily (INH) RMP/PZA/EMB||10 months daily or thrice weekly RMP/EMBFootnote 22|
|2 months daily (INH) FQN/RMP/PZA/EMBFootnote B||4-7 months daily or thrice weekly FQN/RMP/EMBFootnote 66|
Resistance to RMP is due to point mutations in the rpo gene in the beta subunit of DNA-dependent RNA polymerase in 95% of casesFootnote 67. Resistance to RMP results in cross-resistance to rifabutin (RBT) in most (~80%) and to rifapentine (RPT) in all (100%) cases. With one exception, i.e. the occurrence of acquired RMP resistance in HIV-infected patients, RMP monoresistance is uncommon. It has been described in AIDS patients taking RBT as prophylaxis against M. avium complex and in HIV-coinfected TB patients, in whom the consistent associations are advanced HIV disease (CD4 counts in cases of acquired rifamycin resistance have all been <200 cells × 106/L and usually <50 cells × 106/L) and the use of an intermittent regimen during the initial phase of treatmentFootnote 68-74. In general, for HIV-coinfected TB patients it is recommended that intermittent treatment should be avoided altogether in the initial phase and used selectively in HIV sero-negative patients (refer to Chapter 5, Treatment of Tuberculosis Disease). Treatment options for patients determined to be RMP-monoresistant are given in Table 5Footnote 22 Footnote 47 Footnote 75-78.
|Initial phase||Continuation phase|
|2 months daily (INH) RMP/PZA/EMBFootnote A||10-16 months daily or thrice weekly INH/EMB/FQNFootnote 22 Footnote 47 Footnote 75|
|2 months daily (INH) RMP/PZA/EMB
(or other aminoglycoside/polypeptide daily or thrice weekly)
|7 months daily or thrice weekly INH/PZA/SMFootnote 76|
|2 months daily (INH) FQN/RMP/PZA/EMBFootnote B||16 months daily or thrice weekly INH/EMBFootnote 77|
Isolated resistance to PZA or EMB is rare. Isolated PZA resistance occurs genotypically in M. bovisFootnote 15. In 2003, PZA monoresistance was reported in isolates of M. tuberculosis from QuebecFootnote 79. Patients with these strains had worse clinical outcomes than those with fully susceptible strainsFootnote 80. In patients with disease due to PZA-resistant isolates, the total duration of treatment should be 9 months or more. EMB monoresistance will not change the efficacy or duration of treatment with standard regimensFootnote 22 Footnote 47.
Polydrug-resistant TB is uncommon in Canada (refer to Table 2); the range of possible resistance patterns and treatment options are outlined in Table 6Footnote 22 Footnote 47 Footnote 49. It is recommended that patients with polydrug-resistant TB be treated with daily DOT in the initial phase and daily or thrice weekly DOT in the continuation phase.
|Pattern of drug resistance||Suggested regimen||Minimum duration of treatment||Comments|
|INH and PZA||RMP, EMB, FQN||9-12 mo||A longer duration of treatment should be used for patients with extensive disease.|
|INH and EMB||RMP, PZA, FQN||9-12 mo||A longer duration of treatment should be used for patients with extensive disease.|
|RMP and EMB||INH, PZA, FQN plus an injectable agent for at least the first 2-3 months||18 mo||A longer course (6 months) of the injectable agent may strengthen the regimen for patients with extensive disease.|
|RMP and PZA||INH, EMB, FQN plus an injectable agent for at least the first 2-3 months||18 mo||A longer course (6 months) of the injectable agent may strengthen the regimen for patients with extensive disease.|
|INH, EMB, PZA||RMP, FQN plus an oral second-line agent, plus an injectable agent for the first 2-3 months||18 mo||A longer course (6 months) of the injectable agent may strengthen the regimen for patients with extensive disease.|
MDR-TB, and especially MDR-TB that is XDR, represents a grave threat to TB prevention and careFootnote 81 Footnote 82 Footnote D. It is recommended that people with MDR or XDR TB be treated with second-line drugs, here listed as the aminoglycosides (streptomycin, amikacin, kanamycin), polypeptides (capreomycin), the FQNs, ethionamide, cycloserine and para-aminosalicylic acid, which on balance are weaker, more toxic and more costly than first-line drugs (refer to Table 7)Footnote 22 Footnote 47 Footnote 49 Footnote 84-87. Furthermore, the duration of MDR or XDR TB treatment is longer, on average 20-24 months. Four MDR-TB case series have been reported in CanadaFootnote 7 Footnote 8 Footnote 88-90. In all of them, a high proportion of cases were foreign-born (83.3%-95.2%) and undergoing re-treatment (32.9%-67.7%); of those who were HIV tested few were HIV coinfected (0.0%-27.7%). (Refer to Table 8). MDR-TB has also been reported in HIV-seronegative Tibetan refugees in OntarioFootnote 91 . Longitudinal data from Alberta suggest that MDR-TB cases that report having arrived in Canada in the near past are more likely to have primary drug resistance than those reporting having arrived in the remote pastFootnote 7.
|DRUGFootnote A||Usual adult daily dosage (pediatric doses)||Peak serum concentration, µg/mL||Recommended regular monitoring||Adverse reactions|
(20-40 mg/kg daily)
(MAX 1 gm)
|35-45||Vestibular function, audiometry, creatinine, electrolytes, magnesium and calcium||Auditory, vestibular and renal toxicity. If possible, avoid in pregnancy.|
(15-30 mg/kg par jour)
(max. : 1 g)
BID or TID
(15-20 mg/kg daily divided BID)
(MAX 1 gm)
|1-5||Hepatic enzymes, glucose, TSH||GI disturbance, hepatotoxicity, endocrine effects, neurotoxicity. Avoid in pregnancy.|
|Para-amino salicylic acid||4 g
BID or TID
(200-300 mg/kg daily in 2-4 divided doses)
(MAX 10 gm)
|20-60||Hepatic enzymes, electrolytes, TSH||GI disturbance, hepatic dysfunction, hypothyroidism. Avoid if allergic to aspirin.|
BID or TID
(10-15 mg/kg daily divided BID)
(MAX 1 gm)
|20-35||Mental status, pharmocokinetics of cycloserine||Avoid in patients with epilepsy, mental illness or alcoholism.|
|Levofloxacin||500-1000 mg OD
(< 5 yrs, 15-20 mg/kg daily divided BID)
(> 5 yrs, 10 mg/kg OD)
(MAX 500 mg)
|8-12||GI disturbance, headache, anxiety, tremulousness, prolonged Q-T interval. Avoid in pregnant women or growing children.|
|Moxifloxacin||400-600 mg OD
(10 mg/kg daily OD)
(MAX 400 mg)
|Rifabutin||300 mg OD||Hepatic enzymes, complete blood count, vision screening||Hepatotoxicity, uveitis thrombocytopenia, neutropenia, drug interactions|
|Clofazimine||100-300 mg OD||0.5-2.0||Macular pigmentary changes, symptoms||Skin, conjunctiva, cornea, body fluid discoloration, GI intolerance, photosensitivity|
|No. of cases||No. (%) foreign-born||No. (%) re-treatment||No. (%) HIV coinfected||Mean no. of first-line drugs to which the isolate was resistantFootnote A|
|Footnote 88 Footnote 89||AB & BC
(January 1989 to June 1998)
|24||20 (83.3)Footnote B||16 (66.7)||1/17 (5.9)||3.25|
(January 1986 to June 1999)
|40||38 (95.0)||26 (65.0)||6/46 (13.0)Footnote C||3.20|
(January 1997 to December 2008)
|177||163 (92.1)||55/167 (32.9)||9/38 (23.7)||NA|
|Footnote 7 Footnote D||AB
(January 1982 to December 2011)
|31||27 (87.1)||12 (38.7)||0/22 (0.0)||3.35|
Prior to the availability of DST results, MDR-TB should be suspected in the following:
In a recent study from California, independent predictors of acquired MDR-TB were initial INH resistance, initial RMP resistance, HIV infection and cavitary disease in the absence of DOT throughout therapyFootnote 92. As outlined earlier, the suspicion of drug-resistant TB, and in particular MDR-TB, should precede the introduction of any anti-TB drugs. It should follow meticulous history-taking and the assembly of all available information concerning previous treatment and DST. Patients may recognize drugs as having been taken in the past when they are shown pictures of the drugs or the drugs themselves. Previous treatment with second-line drugs is a strong, consistent risk factor for resistance to these drugsFootnote 93. As informed a prediction as possible should be made about precisely which drugs are likely to be effective in the individual. Great care should be taken to avoid a circumstance whereby an empiric regimen inadequate in the number or effectiveness of drugs allows the emergence of further drug resistance. Once DST results are available for the current episode, it is recommended that any unnecessary drugs prescribed in an initial surfeit regimen be stopped. Generally, drugs to which there is known in-vitro resistance are not recommended. Exceptions to this may be the use of high dose INH in the presence of low-level INH resistance or the use of a fourth-generation FQN in the presence of second-generation FQN (ofloxacin) resistanceFootnote 94-98. Previous use of a drug may be associated with reduced clinical response, despite apparent in-vitro susceptibilityFootnote 19 Footnote 99.
In a Canadian study, people with MDR-TB were more likely than those with resistant non MDR-TB, and people with resistant non MDR-TB were more likely than those with drug-susceptible TB, to be re-treatment casesFootnote 8. Unless they were infected with a drug-resistant isolate from the outset (primary resistance), it is presumed that some combination of physician error and patient nonadherence to treatment turned fully susceptible organisms, or those with less complex resistance patterns, into MDR-TBFootnote 100. In this regard it is noteworthy that among patients with MDR-TB referred to the National Jewish Medical and Research Center (Denver, Colorado) there were an average of 3.9 physician treatment errors per caseFootnote 100. The most common errors were addition of a single drug to a failing regimen, failure to identify pre-existing or acquired resistance, and administration of an initial regimen inadequate in number of drugs or duration of therapy, or both. MDR-TB patients without a history of previous treatment have a better response to treatment than do patients with a history of previous treatmentFootnote 101-103.
MDR-TB has been associated with reduced rates of cure and treatment adherence and increased rates of fatality and relapseFootnote 104 Footnote 105. MDR-TB patients who have XDR TB are yet more difficult to manage, their outcomes yet worseFootnote 106.
The following recommendations are based on evidence consisting of multiple observational studies, an individual patient data meta-analysis and expert opinion. As such, all recommendations below should be considered conditional, based on weak to very weak evidence. They may change as new and stronger evidence is published. The major sources for the recommendations are the WHO,Footnote 54 Footnote 107 the Francis J. Curry National Tuberculosis Centre,Footnote 22an individual patient data meta-analysisFootnote 108 and the Centers for Disease Control and Prevention in AtlantaFootnote 47 Footnote 109.
When extensive resistance to first- and second-line drugs (XDR-TB) has been documented, better outcomes have been reported in those who received more than five drugsFootnote 131. In these patients or in others, such as MDR-TB patients intolerant of second-line drugs, consideration may need to be given to surgery (refer below). Several new anti-TB drugs, for example, bedaquiline (TMC207), delamanid (OPC67683), SQ109, PA824, AZD5847 and PNU100480, have entered human trials and may be available for clinical use within the next few yearsFootnote 79. Results of Phase II trials of bedaquiline and delamanid have been published; outcomes of treatment when these drugs were added to an optimal background regimen were better than with placeboFootnote 132 Footnote 133. Compassionate use of and expanded access to new drugs are being explored internationallyFootnote 134.
It is recommended to make it clear to patients, families and staff from the outset that meticulous adherence to the prescribed regimen is critical to cure. Patients should be counseled to accept minor side effects in order to achieve cure and agree to remain under direct observation with each dose supervised; as well, it is recommended that patients receive in their own language clear and complete instructions before treatment begins, in addition to consistent psychological support during treatment. Traditional roles and responsibilities within families may need to be examined, and social support may need to be provided to secure adherence. Strategies for reducing treatment default in drug-resistant TB have recently been reviewedFootnote 135.
Pregnancy may complicate the management of MDR-TB, and experience with the issues involved is necessary. The teratogenic risks of second-line drugs, the use of holding regimens, the timing of treatment initiation, the risks of vertical and lateral transmission and the role of BCG vaccination in infants have recently been reviewedFootnote 22 Footnote 49 Footnote 136 Footnote 137.
Canadian Thoracic Society recommended criteria for specialized centres for the management of MDR-TB patients
The option of resecting diseased lung tissue becomes more attractive as the number of drugs to which the patient’s isolate is resistant increases and the likelihood of a pharmacologic cure decreases. Unfortunately for many patients the extent of disease and/or the severity of the underlying lung function abnormality preclude a surgical option. At the National Jewish Medical and Research Center patients were selected for surgery on the basis of extensive drug resistance, poor response to medical therapy and disease sufficiently localized to permit resection of the bulk of involved lung with enough remaining functioning lung to predict recovery without respiratory insufficiencyFootnote 138 Footnote 139.
The selection of surgical candidates and the timing of adjunctive surgery should be performed on a case-by-case basis. It is recommended that only those patients whose organisms demonstrate drug resistance patterns that predict a high probability of treatment failure should be considered for resection. The goal of surgery should be to remove as much diseased lung as possible, particularly cavities, while avoiding crippling respiratory impairmentFootnote 15. The optimal timing of surgical intervention is after 3 to 4 months of therapy and sputum culture conversion, though the latter may not always be possibleFootnote 15. Engaging a surgeon experienced in the performance of lung resection in TB patients is recommended. The anticipated site of the surgical stump should be evaluated bronchoscopically before surgery to establish the absence of endobronchial TB, which, if present, is associated with poor healing and a persistent broncho-pleural fistulaFootnote 112 Footnote 140 Surgical outcomes are generally goodFootnote 139 Footnote 141-144. Anti-TB drug treatment should be continued for 18 to 24 months after surgeryFootnote 117 Footnote 139.
It is recommended that the monitoring of patients with MDR-TB include a systematic, organized approach, such as that outlined in detail by the Francis J. Curry National Tuberculosis CenterFootnote 22. Elements of such monitoring should include drug administration, weight and nutrition, drug absorption and drug interactions, substance abuse and mental health, respiratory and systemic symptoms, symptoms of drug toxicity, blood tests, visual screens, audiology and vestibular testing, bacteriology, therapeutic drug monitoring and radiology. Although the exact role of therapeutic drug monitoring in the management of MDR-TB has not been extensively studied, there are a few situations in which drug concentrations are routinely measured: aminoglycoside concentrations, especially in patients who have known renal dysfunction, cycloserine concentrations to help predict and minimize central nervous system adverse reactions and prevent seizure activity, and EMB concentrations in patient with reduced renal functionFootnote 22.
With respect to mycobacteriology, the use of sputum smear and culture results, rather than sputum smear alone, is recommended for the monitoring of patients with MDR-TB during treatment. Hospitalized patients with smear- and/or culture-positive pulmonary disease should have sputum submitted at least weekly and remain in airborne isolation until three consecutive sputum samples are culture-negative after 6 weeks of incubation in broth or 8 weeks in solid media. Otherwise, WHO criteria for culture conversion are recommended: two consecutive negative smears and cultures taken at least 30 days apart. Time to conversion is calculated as the interval between the date of MDR-TB treatment initiation and the date of sputum collection of the first of the two consecutive negative culturesFootnote 49. Even after culture conversion specimens should be submitted at least monthly to document the stability of the mycobacteriologic response. An MDR-TB patient is not considered cured until he or she has completed treatment according to the regimen and has at least five consecutive negative cultures from samples collected at least 30 days apart in the final 12 months of treatmentFootnote 49 Footnote 145. An MDR-TB patient is considered to have failed treatment if two or more of the five cultures recorded in the final 12 months are positive, or if any one of the final three cultures is positiveFootnote 145.
Patients who have completed treatment of MDR-TB or XDR-TB should undergo clinical, radiologic and mycobacteriologic follow-up at 6-monthly intervals for a minimum of 2 years.
Contacts of patients with MDR-TB should be rapidly identified and evaluated, especially when the index case has smear-positive pulmonary TB or laryngeal TBFootnote 49. In settings with a high HIV prevalence, the incidence of MDR-TB among household contacts has been found to be extremely high, most secondary cases occurring shortly after the diagnosis of the source caseFootnote 146. Close contacts of an infectious case, especially those who are under the age of 5 years or are immunocompromised, are especially important to screen. After active TB has been excluded, contacts who have a tuberculin skin test (TST) result of 5 mm or more of induration or TST-negative contacts who are under the age of 5 years or are immunocompromised should be evaluated for therapy of latent TB infection (LTBI) (also, refer to Chapter 6, Treatment of Latent Tuberculosis Infection).
There are no randomized controlled trials that have assessed the effectiveness of treatment of LTBI in people exposed to MDR-TBFootnote 147. In a systematic review of the literature on people treated and not treated for LTBI after exposure to MDR-TB there were only two observational studies that met the inclusion criteriaFootnote 148. A prospective cohort study found individualized treatment, tailored to DST, was effective in preventing active TB in childrenFootnote 149, and a retrospective cohort study found INH not to be effectiveFootnote 150. Since then another observational study has found that individualized treatment was effective