Public Health Agency of Canada
www.publichealth.gc.ca
Tuberculosis - Drug resistance in Canada 2009
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, Tuberculosis Prevention and Control (TBPC) 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 TBPC the previous year’s results of anti-tuberculosis drug susceptibility testing for every patient for whom a culture grows or for whom a bacterial isolate is received. TBPC subsequently produces this annual report. This report presents 2009 drug susceptibility data for TB isolates from across Canada as of March, 2010.
Methods
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 or 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 of residence of patient), province/territory where the tests were performed, 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 laboratories 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 no 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 which is 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) is resistance to at least isoniazid and rifampin; and finally d) extensively drug-resistant TB (XDR-TB), defined as resistance to at least rifampin and isoniazid and further resistance to any fluoroquinolone, and to at least one of three injectable second-line drugs (amikacin, capreomycin and kanamycin).
The resistance patterns for all MDR-TB cases are included and resistance patterns for both first and second-line drugs are reported. All provinces/territories are asked to submit all second-line testing results for all isolates showing MDR-TB. Second-line drug testing varies between jurisdictions, but typically testing is done for amikacin (AK) or kanamycin (KM), capreomycin (CM), clofazimine (CF), ethionamide (ETA), ofloxacin (OFL), paraamino salicylic acid (PAS) and rifabutin (RBT).
Prior to 2007, all specimens received in the laboratories between the 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 lab in late December but only grew in January or early February. Thus starting in 2007 any culture that grows or isolate received by a lab as of December 31 is submitted and counted 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 grows only in January 2009 it would be considered a 2009 isolate. With this approach the majority of results will be ready by January 31 of each subsequent year.
Laboratories perform routine susceptibility testing of MTB or MTBC to first-line anti-tuberculous drugs using either the radiometric proportion method Bactec® 460 or the fluorometric proportion method MGIT® 960. Manitoba, New Brunswick, Newfoundland and Labrador, Nova Scotia, Ontario, Quebec and Saskatchewan use MGIT® 960. All other provinces/territories used Bactec® 460. In 2009, for the labs conducting second line testing, Bactec® 460 or agar proportion method was used. Table A lists the first-line and second-line anti-tuberculosis drugs and the critical concentrations in mg/L used by the participating laboratories.
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*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.
|
|||
| First-Line Anti-Tuberculosis Drugs | |||
|---|---|---|---|
|
Anti-tuberculosis drugs |
Critical Concentrations* (mg/L) |
Comments |
|
|
Bactec 460 |
MGIT 960† |
||
|
Isoniazid (INH) |
0.1 |
0.1 |
When resistance to INH is found at the 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, Saskatchewan. |
| Second-Line Anti-Tuberculosis Drugs | |||
|
Anti-tuberculosis drugs |
Critical Concentrations* (mg/L) |
Comments |
|
|
Streptomycin (SM) |
2.0 |
1.0 |
Routine testing is performed for isolates from British Columbia, Alberta and Saskatchewan. There is also a high concentration for SM which is 6.0 mg/L in BACTEC® 460. |
|
|
Concentrations Tested‡
(mg/L) |
|
|
|
Amikacin (AK) |
1.0 |
|
|
|
Capreomycin (CM) |
1.25 |
|
|
|
Ethionomide (ETA) |
2.5 |
|
|
|
Kanamycin (KM) |
5.0 |
|
|
|
Para-amino salicylic acid (PAS) |
2.0 |
|
|
|
Ofloxacin (OFL) |
2.0 |
|
|
|
Rifabutin (RBT) |
0.5 |
|
|
All members of the CTLTN participate in the NRCM (National Microbiology Laboratory) proficiency testing program. In addition to this national initiative, a number of laboratories also participate in other select external proficiency programs such as College of American Pathologists, Quality Management Program - Laboratory Services, United States Centers for Disease Control and Prevention Drug Susceptibility Testing or 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 Clinical and Laboratory Standards Institute document.1
The information presented in this report represents the most up to date information available as of March, 2010, for the years 1999 to 2009. The historic record is reviewed annually and adjustments are made to the tables as new/updated information becomes available. For previous years’ reports please refer to: http://www.phac-aspc.gc.ca/tbpc-latb/surv-eng.php.
Results
For 2009, 1,334 unique reports were received. Of these, thirteen were Mycobacterium bovis (BCG) and were excluded from the analysis. The results for 1,321 isolates are included in the final report. This represents a 2.5% decline from the number of isolates reported on in 2008. Apart from testing all the isolates from Alberta, the Northwest Territories and Nunavut, Alberta also tested and reported the results for one isolate from Ontario and five isolates from Saskatchewan. Likewise, Manitoba tested one isolate from Nunavut along with all of those from Manitoba (Table 1).
Of the 1,321 isolates included for analysis, 125 (9.5%) were resistant to at least one of the first-line anti-tuberculosis drugs tested: INH, RMP, EMB or PZA. Ninety-six (7.3%) of the isolates were monoresistant and of those 83 (86.5%) were resistant to INH. Of all the isolates tested, 112 (8.5%) demonstrated some resistance to INH. Eighteen isolates (1.4%) were MDR- TB. In 2009 there was no XDR-TB identified (Table 2).
All isolates originating from New Brunswick, Newfoundland and Labrador, Nova Scotia, Prince Edward Island, and Yukon were susceptible to all first-line anti-tuberculous drugs. For the remaining provinces some resistance was reported (Table 5 – 17). 2009 was the first time since reporting began that MDR-TB was identified in Saskatchewan.
Demographic information on individual patients from whom the isolates originated is limited in this laboratory-based surveillance system with only the age and sex available. The age was known for 1,316 of the isolates tested with 38% between the ages of 25 and 44. For isolates showing any resistance, 47% were from individuals between the ages of 25 and 44; 50% of the MDR-TB isolates were from individuals between 15 and 24. Sex was reported for 1,288 of the isolates with 58% being male. Of the isolates for which sex was reported, 63% of those isolates showing any resistance were male; 71% of the MDR-TB were male (Table 4).
In Canada, between 1999 and 2009, 181 isolates have been classified as MDR-TB representing 1.2% of all data in the CTBLSS for those years. A retrospective review of all the data in the CTBLSS identified four XDR-TB cases reported between 1998, when DST data collection was started and 2009. 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 between 1999 and 2009.
The majority of the MDR-TB cases that have been reported originate from Ontario and British Columbia which is not surprising given that the majority of the tested isolates originate from these two provinces. Table C presents the provincial/territorial distribution of these cases.
Year |
Total number of Isolates |
MDR-TB (%) |
XDR-TB (%) |
|---|---|---|---|
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 |
1,321 |
18 (1.4) |
0 (-) |
Total |
15,253 |
181 (1.2) |
4 (0.02) |
Province |
MDR-TB (%) |
XDR-TB (%) |
|---|---|---|
Alberta |
10 (5.5) |
0 (-) |
British Columbia |
35 (19.3) |
0 (-) |
Manitoba |
7 (3.9) |
1 (25.0) |
Nunavut |
1 (0.6) |
0 (-) |
Ontario |
107 (59.1) |
3 (75.0) |
Quebec |
20 (11.0) |
0 (-) |
Saskatchewan |
1 (0.6) |
0 (-) |
Total |
181 (100.0) |
4 (100.0) |
Discussion
Susceptibility results were reported for 1,321 isolates in 2009. The percentage of isolates demonstrating any type of drug resistance was 9.5%. The proportion of isolates classified as MDR-TB increased slightly from 1.1 in 2008 to 1.4% in 2009. The average annual percentage of reported MDR-TB since 1998 was 1.2%. As of March 2010, the CTBLSS has reported 4 XDR-TB cases, 1 in each of 2002, 2003, 2006 and 2008. Additionally, a fifth Canadian case was identified, being diagnosed in 1997 with a highly drug-resistant strain of M. bovis, which met the criteria for XDR-TB2
Sixty-eight percent of the reported laboratory TB isolates in Canada in 2009 originated from British Columbia, Ontario and Quebec which have consistently reported the majority of isolates and MDR-TB in the ten 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. As of September 2009, 57 countries, including Canada, have reported the presence of XDR-TB cases. Because XDR-TB is resistant to the best first- and second-line drugs, treatment options are seriously limited. In order to continue surveillance of XDR-TB in Canada, all MDR-TB isolates will be routinely tested for resistance to second-line antibiotics.
The results observed to date in this surveillance system are consistent with international data. 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.
The global estimated number of incident MDR-TB cases as reported for 2006 in the WHO/IUALTD drug resistance report was 4.8% (95% CIs, 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 selected 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 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, this surveillance system is vital in providing the necessary data in a timely fashion to monitor trends in TB drug resistance in Canada. The surveillance data collected to date indicate that the presence of TB drug resistance in this country is below the global average.
References
1. National Committee for Laboratory Standards. Susceptibility testing of mycobacteria, Nocardiae, and other aerobic actinomycetes: approved standard M24-A. Wayne PA, National Committee for Clinical Laboratory
Standards, 2003.
2. 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. merican Journal Of Respiratory And Critical Care Medicine 1999;159: 2014–2017.
3. 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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