Public Health Agency of Canada
www.publichealth.gc.ca
Tuberculosis - Drug resistance in Canada 2010
Introduction
Drug-resistant strains of tuberculosis (TB) pose a serious threat to TB prevention and control efforts. Although drug-resistant TB has not yet been identified as a major problem in Canada, the potential exists due to the increase and ease of international travel. In response, the Centre for Communicable Diseases and Infection Control (CCDIC), Tuberculosis Prevention and Control (TBPC) at the Public Health Agency of Canada in collaboration with the Canadian Tuberculosis Laboratory Technical Network (CTLTN) (see Appendix 1) and participating laboratories (representing all provinces and territories) established the Canadian Tuberculosis Laboratory Surveillance System (CTBLSS) to monitor TB drug resistance patterns in Canada.
Each year laboratories report to CCDIC-TBPC the results of anti-tuberculosis drug susceptibility testing for every patient for whom a culture grows or a bacterial isolate is received from another laboratory, within the previous calendar year. CCDIC-TBPC subsequently produces this annual report.
Methods
CCDIC-TBPC maintains the CTBLSS which contains drug susceptibility test results of Mycobacterium tuberculosis (MTB) and other TB species (M. africanum, M. canetti, M. caprae, M. microti, M. pinnipedii and M. bovis). It also contains MTB complex (MTBC) isolates as laboratories report identification of isolates either at the complex level (MTBC) or at the species level. Isolates identified as Mycobacterium bovis BCG are included in the CTBLSS but are excluded from this report. M. bovis BCG is intrinsically resistant to pyrazinamide (PZA) and the identity of the majority of these isolates can be inferred from the history of recent vaccination.
Data are collected either through manual completion of a standard reporting form (Appendix 2) or by electronic transmission. Information collected includes sex, year of birth, province/territory from which the specimen originated (province/territory of residence of patient), province/territory where the laboratory tests were conducted, and susceptibility results. Some provinces perform drug testing for other provinces/territories. For first-line susceptibility testing, British Columbia tests British Columbia and Yukon isolates; Alberta tests Alberta, Northwest Territories and Nunavut isolates, and Nova Scotia tests isolates for Nova Scotia and Prince Edward Island. All other provinces report susceptibility results for isolates originating in their province only. Four provinces conduct second-line testing: Alberta, Ontario, Quebec and the National Reference Centre for Mycobacteriology (NRCM) in Manitoba.
Every effort is made to eliminate duplicate specimen results or results from two specimens taken from the same person. In the event that a duplicate record is found and confirmed, only the most recent susceptibility result is included for analysis.
All isolates are routinely tested for resistance against first-line anti-tuberculosis drugs. Results in this report present resistance patterns to first-line drugs routinely tested for resistance, typically isoniazid (INH), rifampin (RMP), pyrazinamide (PZA) and ethambutol (EMB). However, not all isolates are tested for resistance to all drugs. For example some provinces do not routinely test for PZA. Therefore, the percentage of isolates showing resistance to a particular drug is expressed as the number of isolates resistant to the drug over the total number of isolates tested for sensitivity to that particular drug.Resistance patterns that are described in this report include: a) mono-resistance - defined as resistance to one of the first-line drugs (INH, RMP, EMB or PZA); b) poly-resistance - defined as resistance to two or more first-line drugs not including the isoniazid and rifampin combination; c) multidrug-resistant tuberculosis (MDR-TB) - defined as TB that is resistant to at least the two best first-line anti-tuberculosis drugs, isoniazid and rifampin, but which does not meet the definition of extensively drug-resistant TB (XDR-TB); and finally d) extensively drug-resistant TB (XDR-TB) - defined as TB that is resistant to at least the two best first-line anti-tuberculosis drugs, isoniazid and rifampin, plus resistant to second-line drugs including any fluoroquinolone, and to at least one of three injectable second-line anti-tuberculosis drugs (amikacin, capreomycin and kanamycin).
All provinces/territories are asked to submit second-line testing results for all isolates showing resistance to both INH and RMP. Second-line drug testing varies between jurisdictions, but typically testing is done for amikacin (AK) or kanamycin (KM), capreomycin (CM), clofazimine (CF), ethionamide (ETH), ofloxacin (OFL), para-amino salicylic acid (PAS) and rifabutin (RBT).
Prior to 2007, all specimens received in the laboratories between January 1 and December 31, were included in the annual report. However, this resulted in delayed reporting of results for specimens that were received in the laboratory in late December but only grew MTB in January or early February. Thus, starting in 2007, any culture that grows MTB in a given year is included in the statistics for that calendar year; otherwise the result will be recorded in the subsequent year’s set. For example, if a specimen was received on December 20, 2008 and the culture grew MTB only in January 2009, it would be counted in 2009.
All laboratories are now performing routine susceptibility testing of MTB or MTBC to first-line anti-tuberculosis drugs using fluorometric proportion method BACTEC® 960. In 2010, four of the laboratories conducted second-line anti-tuberculosis drug testing. Table A lists the first-line and second-line anti-tuberculosis drugs and the critical concentrations in mg/L used by the participating laboratories.
| *Critical concentrations: the lowest concentration of drug that will inhibit 95% of wild strains of MTB that have never been exposed to drugs while at the same time not inhibiting strains of MTB that have been isolated from patients who are not responding to therapy and that are considered resistant. † Antimicrobial testing methodology with the new technology (BACTEC® 960) has been standardized and validated by multiple studies in reference laboratories and will be reflected in the new Clinical and Laboratory Standards Institute (CLSI) (publication anticipated in 2011) |
|||
| First-Line Anti-Tuberculosis Drug | |||
|---|---|---|---|
| Anti-tuberculosis drugs | Critical Concentrations* (mg/L) | Comments | |
| BACTEC® 460 | BACTEC® 960† | ||
| Isoniazid (INH) | 0.1 | 0.1 | When resistance to INH is found to 0.1 mg/L, tests are repeated with INH 0.4mg/L to determine the level of resistance. Regardless, the isolate will be reported as resistant using the 0.1 mg/L cut off level. |
| Rifampin (RMP) | 2.0 | 1.0 | |
| Ethambutol (EMB) | 2.5 | 5.0 | |
| Pyrazinamide (PZA) | 100.0 | 100.0 | Routine testing is not performed for isolates from British Columbia and Saskatchewan. |
| Second-Line Anti-Tuberculosis Drugs | |||
| Anti-tuberculosis drugs | Critical concentration (μg/ml) BACTEC® 960† | Comments | |
| Amikacin (AK) | 1 | ||
| Capreomycin (CM) | 2.5 | ||
| Ethionamide (ETH) | 5 | ||
| Kanamycin (KM) | 2.5 | ||
| Linezolid (INN) | 1 | ||
| Moxifloxacin (MOX) | 0.25 | ||
| Ofloxacin (OFL) | 2 | ||
| Para-amino salicylic acid (PAS) | 4 | ||
| Rifabutin (RBT) | 0.5 | ||
| Streptomycin (SM) | 1 | ||
All members of the CTLTN participate in the NRCM proficiency testing program. In addition to this national initiative, a number of laboratories also participate in other select external proficiency programs such as the College of American Pathologists, Quality Management Program - Laboratory Services, the United States Centers for Disease Control and Prevention Drug Susceptibility Testing or the New York State Department of Health. All testing methods, including drug selection and concentrations, are done in compliance with the recommended laboratory standards detailed in the CLSI document.1 The information presented in this report represents the most up to date information available as of February 2011. The historic record is reviewed annually and adjustments are made to the tables as new/updated information becomes available.
Results
For 2010, drug sensitivity results for 1,290 isolates were reported to CCDIC-TBPC. Of these, 14 were Mycobacterium bovis (BCG) and were excluded from the analysis. For this report the results for 1,276 isolates were analysed. This represents a 4.1% decline from the number of isolates reported in 2009. Apart from testing all the isolates from Alberta, the Northwest Territories and Nunavut, Alberta also tested and reported on one isolate from British Columbia. Similarly, Ontario tested three isolates from Quebec and one from Nunavut. Manitoba also tested one isolate from Nunavut (Table 1). Figure 1 provides a breakdown of the number of isolates reported by the province of origin. Figure 2 provides an overview of the patterns of drug resistance across Canada for 2010.
Of the 1,276 isolates included for analysis, 112 (8.8%) were resistant to at least one of the first-line anti-tuberculosis drugs tested: INH, RMP, EMB or PZA. Eighty-eight (6.9%) of the isolates were monoresistant and of those 77 (87.5%) were resistant to INH. Please refer to figures 3 and 4 for a detailed breakdown of the different patterns of reported resistance for 2010.
Table 2 reports on the historical trends in drug resistance patterns between 2000 and 2010 and there has been little variation in the proportion of isolates showing resistance. Over the past 11 years, on average, 9.3% of isolates tested were resistant to at least one of the first-line drugs with a range from 8.0% in 2001 to 10.5% in 2003. The average annual percentage of reported MDR-TB was 1.2% and ranged from a low of 0.8% in 2007 to a high of 1.6% in 2005. For a full review of the 11-year trends see table 2 and figures 5 and 6.
For 2010, 18 isolates coming from six provinces (Alberta, British Columbia, Manitoba, Ontario, Quebec and Saskatchewan) were resistant to both INH and RMP. To rule out XDR-TB, these isolates were subsequently tested for resistance to second-line drugs. Of particular interest was the resistance shown to the three injectables (amikacin, capreomycin, and kanamycin) and ofloxocin, the fluoroquinolone routinely reported to CCDIC-TBPC by the four laboratories doing second-line testing. Resistance to one of the injectables and the fluoroquinolone would identify the isolate as XDR-TB. The results of second-line testing identified 17 MDR-TB isolates and one XDR-TB isolate. Table 3 lists the complete resistance profile for these isolates.
In Canada, since TB drug resistance surveillance started in 1998, 216 isolates have been classified as MDR-TB, representing 1.2% of all isolates tested during that period. A review of all the data in the CTBLSS identified five XDR-TB cases reported between 1998 and 2010. Table B provides a summary of the isolates that were tested and of those, the number and the percentage that were identified as MDR-TB and XDR-TB.
| Year | Total number of Isolates | MDR-TB (%) | XDR-TB (%) |
|---|---|---|---|
| 1998 | 1,461 | 18 (1.2) | 0(–) |
| 1999 | 1,415 | 18 (1.3) | 0(–) |
| 2000 | 1,490 | 15 (1.0) | 0(–) |
| 2001 | 1,475 | 15 (1.0) | 0(–) |
| 2002 | 1,419 | 20 (1.4) | 1 (0.07) |
| 2003 | 1,407 | 20 (1.4) | 1 (0.07) |
| 2004 | 1,378 | 12 (0.9) | 0(–) |
| 2005 | 1,336 | 22 (1.7) | 0(–) |
| 2006 | 1,389 | 15 (1.1) | 1 (0.07) |
| 2007 | 1,267 | 11 (0.9) | 0(–) |
| 2008 | 1,356 | 15 (1.1) | 1 (0.07) |
| 2009 | 1,331 | 18 (1.4) | 0(–) |
| 2010 | 1,276 | 17 (1.3) | 1 (0.08) |
| Total | 18,000 | 216 (1.2) | 5 (0.03) |
Since data collection began in 1998, the majority of the MDR-TB isolates have originated from British Columbia, Ontario and Quebec. Table C presents the provincial/territorial distribution of these cases.
*Province/Territory of origin for the isolate. | |||
| Province/Territories* | Total number of Isolates | MDR-TB isolates | XDR-TB isolates |
|---|---|---|---|
| Alberta | 1,458 | 14 (6.5) | 0 (–) |
| British Columbia | 3,306 | 38 (17.6) | 0 (–) |
| Manitoba | 1,407 | 10 (4.6) | 2 (40.0) |
| New Brunswick | 111 | 0 (–) | 0 (–) |
| Newfoundland and Labrador | 101 | 0 (–) | 0 (–) |
| Northwest Territories | 127 | 0 (–) | 0 (–) |
| Nova Scotia | 92 | 0 (–) | 0 (–) |
| Nunavut | 379 | 1 (0.5) | 0 (–) |
| Ontario | 7,303 | 128 (59.3) | 3 (60.0) |
| Prince Edward Island | 16 | 0 (–) | 0 (–) |
| Quebec | 2,909 | 23 (10.6) | 0 (–) |
| Saskatchewan | 761 | 2 (0.9) | 0 (–) |
| Yukon | 30 | 0 (–) | 0 (–) |
| Total | 18,000 | 216 (100.0) | 5 (100.0) |
Demographic information on individual patients from whom the isolates originated is limited in this laboratory-based surveillance system with only information on age and sex available. Age was known for 1,274 of the isolates tested, with 35% of isolates from individuals between the ages of 25 and 44. For isolates showing any resistance, 46% were from individuals between the ages of 25 and 44; 47% of the MDR-TB isolates were from individuals between the ages of 15 and 24. Sex was reported for 1,264 of the isolates with 57% being males. Of the isolates for which sex was reported, 58% of those isolates showing any resistance originated from males; 60% of the MDR-TB originated from males (Table 4).
For a complete review of the resistance patterns for all the isolates originating from each province/territory refer to tables 5 through 17. All isolates reported from Newfoundland and Labrador, Prince Edward Island, and Yukon, were susceptible to all first-line drugs tested. For the remaining provinces/territories some resistance was reported.
Discussion
Susceptibility results were reported for 1,276 isolates in 2010. The proportion of the total number of isolates tested which demonstrated any type of drug resistance was 8.8%. The proportion of isolates classified as MDR-TB was 1.3%. Over the past 11 years, this proportion has remained stable at around 1.2% of isolates tested. As of February 2011, the CTBLSS has reported five XDR-TB cases, one in each of 2002, 2003, 2006, 2008 and 2010. Additionally, a journal article identified a sixth Canadian case diagnosed in 1997 with a highly drug-resistant strain of M. bovis, which met the criteria for XDR-TB2 .
Seventy percent of the reported laboratory TB isolates in Canada in 2010 originated from British Columbia, Ontario and Quebec which have consistently reported the majority of isolates and MDR-TB in the 13 years of data collection. Since the initiation of this laboratory-based surveillance system, the Atlantic Provinces, Northwest Territories and Yukon have not reported any MDR-TB isolates.
Extensively drug-resistant tuberculosis is a growing international concern. Because XDR-TB isolates are resistant to the best first- and some of the best second-line drugs, treatment options are seriously limited. In order to continue surveillance of XDR-TB in Canada, all isolates resistant to both INH and RMP should be routinely tested for resistance to second-line antibiotics.
Compared with international reports, results observed to date in this surveillance system show that, for Canada, the rates of drug-resistant TB are relatively low. In the latest report of the global TB drug resistance surveillance project jointly conducted by the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease (IUATLD),3 the global population weighted percentage was 17% for any resistance among new cases, 35% for previously treated cases and 20% for all cases combined.
The number of incident MDR-TB cases reported for 2006 in the WHO/IUALTD drug resistance report was 4.8% (95% CLs, 4.6% – 6.0%) of the total number of estimated incident TB cases in 2006 in 185 countries3.
Limitations
Typically, only isolates with MDR-TB or other extensive resistance patterns will receive drug sensitivity testing to select second-line drugs. Other isolates may be resistant to a fluoroquinolone, because of widespread use for respiratory infections, but not be MDR-TB. This limits the understanding of the emergence of second-line resistance within Canada.
More epidemiological information on the TB cases from which the isolates were submitted is desirable to examine more critically the drug resistance patterns in Canada. However, this information is difficult to collect as isolates are often submitted to the laboratories with only the sex and year of birth of the individual. As well, no differentiation can be made between primary and secondary/acquired drug resistance from the data. The annual Tuberculosis in Canada reports (http://www.phac-aspc.gc.ca/tbpc-latb/surv-eng.php) include additional drug resistance data for each reported TB case.
Conclusions
With growing worldwide concern regarding resistance and with the emergence of extensively drug-resistant tuberculosis, the Canadian Tuberculosis Laboratory Surveillance System is vital in providing important input into tuberculosis control and prevention strategies for the management of TB drug resistance in Canada. The surveillance data collected to date indicates that the presence of TB drug resistance in this country is below the global average.
References
- Clinical and Laboratory Standards Institute.(CLSI) Susceptibility Testing of Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard, M24-A. Clinical and Laboratory Standards Institute, 2003.
- Long R, Nobert E, Chomyc S, van Embden J, McNamee C, Rey Duran R, Talbot J, Fanning A. Transcontinental spread of multidrug-resistant Mycobacterium bovis. American Journal of Respiratory and Critical Care Medicine 1999;159: 2014–2017.
- The WHO/IUALTD Global Project on Anti-tuberculosis drug Resistance Surveillance 2002-2007. Anti-Tuberculosis Drug Resistance in the World: Fourth Global Report (WHO/HTM/TB/2008.394)
Geneva: World Health Organization, 2008.
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