Tuberculosis: Drug resistance in Canada - 2006

Reported susceptibility results of the Canadian Tuberculosis Laboratory Surveillance System

Mission :
To promote and protect the health of Canadians through leadership, partnership, innovation and action in public health.

Table Of Contents

• Introduction
• Methods
• Results
• Discussion
• Limitations
• Conclusions
• References

Figures
	Figure 1.	Reported TB drug resistance in Canada by province/territory - 2006
	Figure 2.	Reported Mycobacterium tuberculosis isolates in Canada by province/territory - 2006
	Figure 3.	Overall pattern of reported TB drug resistance in Canada - 2006
	Figure 4.	Reported TB drug resistance in Canada by type of drug - 2006
	Figure 5.	Any resistance by type of drug in Canada - 1998-2006
	Figure 6.	Any resistance by type of drug in Canada as a proportion of the number of isolates tested - 1998-2006.
	Figure 7.	Overall pattern of reported TB drug resistance in Canada - 1998-2006
	Figure 8.	Overall pattern of reported TB drug resistance in Canada as a proportion of isolates tested - 1998-2006.
Tables
	Table 1.	Overall pattern of reported TB drug resistance in Canada - 1998-2006
	Table 2.	Reported Mycobacterium tuberculosis isolates by "reporting" and "originating" province/territory, Canada - 2006
	Table 3.	Reported MDR-TB isolates by province/territory, Canada - 2006
	Table 4.	Reported TB drug resistance by gender and age group, Canada - 2006
	Table 5.	Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Alberta - 1998-2006
	Table 6.	Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, British Columbia - 1998-2006
	Table 7.	Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Manitoba - 1998-2006
	Table 8.	Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, New Brunswick - 1998-2006
	Table 9.	Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Newfoundland and Labrador - 1998-2006
	Table 10.	Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Northwest Territories - 1998-2006
	Table 11.	Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Nova Scotia - 1998-2006
	Table 12.	Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Nunavut - 1998-2006
	Table 13.	Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Ontario - 1998-2006
	Table 14.	Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Prince Edward Island - 1998-2006
	Table 15.	Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Quebec - 1998-2006
	Table 16.	Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Saskatchewan - 1998-2006
	Table 17.	Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Yukon - 1998-2006
Appendices
	Appendix 1 -	Participating Laboratories of the Canadian Tuberculosis Laboratory Surveillance System (CTBLSS)
	Appendix 2 -	M. tuberculosis Complex Antimicrobial Susceptibility Reporting Form
	Appendix 3 -	Proficiency panel results for anti-microbial susceptibility testing of Mycobacterium tuberculosis 2006

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Introduction

Tuberculosis Prevention and Control (TBPC) at the Centre for Infectious Disease Prevention and Control, Public Health Agency of Canada, in collaboration with the Canadian Tuberculosis Laboratory Technical Network and participating laboratories (representing all provinces and territories) in the Canadian Tuberculosis Laboratory Surveillance System (CTBLSS) (Appendix 1), established a laboratory-based national surveillance system in 1998 to monitor tuberculosis (TB) drug resistance patterns in Canada.

Every year laboratories report to TBPC the results of anti-tuberculosis drug susceptibility testing for every patient for whom a specimen or an isolate is received within the previous calendar year. TBPC subsequently produces this annual report.

Methods

The Canadian Tuberculosis Committee defines a laboratory confirmed case of tuberculosis as any individual with Mycobacterium tuberculosis complex demonstrated on culture, specifically M. tuberculosis, M. africanum, M. canetti, M. caprae, M. microti, M. pinnipedii or M. bovis [excluding M. bovis BCG strain]. Thus, to align the drug susceptibility report with the case report, the CTBLSS contains drug susceptibility test results of Mycobacterium tuberculosis (MTB) and other tuberculosis 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/territory where the tests were performed, and drug susceptibility results. TBPC, in collaboration with the provinces/territories, makes every effort to eliminate duplicate specimens. Only the most recent susceptibility results for a given patient in the reporting year are included for analysis.

This report presents drug susceptibility data for TB isolates tested in 2006. As well, results from the retesting of all multidrug-resistant TB isolates (MDR-TB, isolates showing resistance to at least isoniazid and rifampicin, the two most powerful anti-TB drugs) for the years 2003 through 2006 in an effort to identify any extensively drugresistant TB (XDR-TB) are also presented. XDR-TB is currently defined as resistance to at least rifampin and isoniazid (MDR-TB) with additional resistance to any fluoroquinolone, and to at least one of three injectable second-line drugs (capreomycin, kanamycin, and amikacin).

The historic record is reviewed annually and adjustments are made to ensure duplicate removal and account for late reporting and the availability of new/updated information. The information in this report is current to March 1, 2007.

Some provinces perform drug testing for other provinces/territories. 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 test only their own isolates.

Laboratories perform routine susceptibility testing of MTB or MTBC to first-line anti-TB drugs using either the radiometric proportion method BACTEC® 460 or MGIT® 960. New Brunswick, Nova Scotia and Ontario usedMGIT® 960; Saskatchewan, and Newfoundland and Labrador use a combination of both. All other provinces/territories used BACTEC® 460. Table A lists the first-line and second-line anti-TB drugs and the critical concentrations in mg/L used by the participating laboratories.

Historically, the CTBLSS collected susceptibility results for first-line drugs only. More recently results for second-line drug testing were also submitted to TBPC from some jurisdictions. Starting with this report, a more comprehensive reporting of susceptibility testing results for second-line anti-TB drugs has been carried out for those isolates that were reported as MDR-TB. Streptomycin (SM) was reclassified in 2005 as a second-line anti-TB drug in Canada. This reclassification has resulted in discontinuation of routine testing for resistance to SM in some jurisdictions. Thus, the number of isolates tested against SM will show a decrease in 2006 compared to previous years.

Four laboratories currently perform second-line drug resistance: the National Reference Centre for Mycobacteriology (NRCM), National Microbiology Laboratory (NML) in Manitoba as well as the provincial laboratories in Alberta, Ontario and Quebec. Secondline testing in Alberta is currently done by agar proportion. NRCM, Ontario and Quebec use BACTEC® 460.

This report presents data on various combinations of resistance patterns. Resistance to first-line drugs includes: a) mono-resistance which is resistance to one of the first-line drugs (isoniazid, rifampin, ethambutol or pyrazinamide); b) poly resistance, resistance to 2 or more first-line drugs; and c) MDR-TB, a special instance of poly resistance. In March of 2006, the World Health Organization (WHO) and the United States Centers for Disease Control and Prevention (CDC) reported a new form of resistance, extensively drug-resistant TB (XDR-TB).

In order to determine the incidence of XDR-TB in Canada, laboratories were asked to submit second-line drug susceptibility results for all MDR-TB isolates detected during the period 2003-2006. For this report, the number of isolates tested in the calendar year that met the definition of XDR-TB is reported at the national level only due to the small numbers. All XDR-TB cases are included in the MDR-TB counts and then reported as a subset of MDR-TB.

For the isolates tested for susceptibility to second-line drugs, not all were tested for all the drugs used in the WHO definition for XDR-TB. Certain assumptions were made in reviewing the results of second-line sensitivity. Resistance or sensitivity to either of the aminoglycosides (amikacin or kanamycin) was used in determining an XDR-TB diagnosis; drug sensitivity was considered equivalent so that a resistant result for amikacin would indicate resistance to kanamycin and vice versa. For some second-line drugs there is a lack of accepted standards for drug testing and the clinical interpretation of test results. Until such standards are in place, results should be interpreted cautiously.

As not all isolates were tested for resistance to all drugs, the proportion of isolates showing monoresistance is expressed as the number of isolates resistant to the drug over the total number of isolates tested for sensitivity to that particular drug. An adjustment based on this method has been made to all data starting from 1998. These proportions for 1998 through 2006 are reported in Table 1, and Tables 5-17.

Table A:  Concentrations for testing of anti-tuberculosis drugs 

First-line Anti-Tuberculosis Drugs
Anti-TB 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, tests are repeated with INH 0.4mg/L to determine the level of resistance.
Rifampin (RMP)	2.0		1.0
Ethambutol (EMB)	2.5		5.0	British Columbia uses a critical concentration of 2.5 mg/L.
Pyrazinamide (PZA)	100.0		100.0	Routine testing is not performed for isolates from British Columbia, Saskatchewan and the Yukon Territory.
Second-line Anti-Tuberculosis Drugs
Anti-TB drugs	Critical Concentrations* (mg/L)			Comments
Streptomycin (SM)	2.0	1.0		There is also a high concentration for SM which is 6.0 in BACTEC 460.
	Concentrations Tested‡ (mg/L)
	BACTEC 460†		Agar Proportion
Amikacin (AM)	1.0		_
Kanamycin (KM)	5.0		5.0
Capreomycin (CM)	1.25		10.0
Ethionamide (ETA)	1.25		5.0
Rifabutin (RBT)	0.5		0.5
Ofloxacin (OFL)	2.0		2.0
*Critical concentrations: the lowest concentration of drug that will inhibit 95% (90% for PZA) 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. † Concentrations are pending approval from the Clinical and Laboratory Standards Institute (CLSI). ‡Most second-line drugs were not used at the time of development of the Proportion Method and definition of the critical concentrations.  Therefore, for the current report, we are reporting the "concentrations tested" and suggest caution be exercised when interpreting results.

In 2006, a total of 10 laboratories participated in the proficiency for anti-microbial susceptibility testing of M. tuberculosis to isoniazid (INH), rifampin (RMP), ethambutol (EMB), pyrazinamide (PZA) and streptomycin (SM) conducted by the NRCM. Participant results are presented in Appendix 3.

Results

Of the 1,389 isolates in 2006 included for analysis, 140 (10.1%) were resistant to at least one of the antituberculosis drugs tested: INH, RMP, EMB, PZA or SM. INH resistance was present in 7.3% of isolates tested. Sixteen isolates (1.2%) were MDR-TB. One isolate (0.1%) was classified as XDR-TB according to the current definition. Fourteen isolates demonstrated resistance to three or more of the five anti-TB drugs tested.

MDR-TB isolates were reported from Alberta, British Columbia, Ontario and Quebec. Manitoba and Saskatchewan reported monoresistance but no MDR-TB. New Brunswick, Newfoundland, Northwest Territories, Nova Scotia, Nunavut, and Yukon Territory, reportedthat all isolates tested were susceptible to all the anti-TB drugs.

Between 2003 and 2006, there were a total of 5,511 isolates evaluated for drug susceptibility. Of these, 71 (1.3%) were classified as MDR-TB and of these, two (2.8%) isolates were XDR-TB, one in 2003 and the aforementioned one in 2006.

Demographic information on the individual patients from whom the isolates originated is limited in this laboratory-based surveillance system. Of the 1,375 isolates for which age at time of testing and/or sex of the patient was known, 33% were between the ages 25 and 44, males accounted for 56% of all the isolates and 59% of the drug resistant isolates.

Discussion 

Susceptibility results were reported for 1,389 isolates in 2006. The percentage of isolates demonstrating any type of drug resistance was 10.1%, which is a decrease from previous years. The proportion of isolates that were monoresistant has remained stable but other polyresistant patterns have decreased. One reason for this is the reclassification of SM as a second-line drug in Canada and the resultant discontinuation of testing for SM resistance in some jurisdictions.

The proportion (1.2%) of isolates classified as MDR-TB in 2006 was within the range (0.9-1.6%) observed from 1998 through 2005.

Seventy-five percent of the reported TB isolates in Canada in 2006 originated from three provinces: British Columbia, Ontario and Quebec. These provinces have consistently reported the majority of isolates and MDR-TB in the nine years of data collection. Since the initiation of this laboratory-based surveillance system the Atlantic Provinces, Northwest Territories, Saskatchewan, and Yukon have not reported any MDR-TB isolates.

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), the median prevalence of TB drug resistance among the participating countries was 10.5% (Range 0.0 - 57.1%) for new cases and 22.7% (Range 0.0 - 82.1%) for previously treated cases (as compared with 10.1% overall in Canada). The median prevalence of MDR-TB was 1.2% (Range 0.0 - 14.2%) for new cases and 7.6% (Range 0.0 - 58.3%) for previously treated cases (as compared with 1.2% overall in Canada)*¹.

XDR-TB is a growing international concern with 28 countries reporting XDR-TB cases as of March 1, 2007. In an early assessment of the frequency and distribution of XDR-TB cases, the CDC and the WHO surveyed an international network of TB laboratories. It was determined that between 2000—2004, of 17,690 TB isolates, 20% were MDR and 2% were XDR. In addition, population-based data on drug susceptibility of TB isolates were obtained from the United States (for 1993—2004), Latvia (for 2000-2002), and South Korea (for 2004), where 4%, 19%, and 15% of MDR TB cases, respectively, were XDR. While the incidence of XDR-TB in Canada from 2003 to 2006 was very low, (one case in 2003 and one in 2006), testing of all future MDR-TB isolates in Canada for XDR will be needed to monitor incidence.

Limitations

Sensitivity testing for first-line anti-TB drugs is not uniform across the country. Therefore, there are limitations in interpreting the data, particularly the percentage of isolates that are resistant to SM and PZA.

More epidemiological information on the TB cases from which the isolates were submitted would be 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 case. As well, no differentiation can be made between primary and secondary/acquired drug resistance from the data. The annual Tuberculosis in Canada reportincludes additional epidemiological data for the drug resistance TB cases.

Conclusions

With growing worldwide concern regarding TB drug resistance and with the emergence of XDR-TB, 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 similar to the global average.

References

1. The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance. Anti-TB drug resistance in the world History, Coverage, Issues, Future. Joint Working GroupMeeting. France 16, October 2005.
2. Centers for Disease Control and Prevention. Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs-worldwide, 2000-2004.MMWR. 2006; 55:301-305.

* Unlike IULTD that provides the prevalence of TB drug resistance for both new and retreated cases, TBPC only reports prevalence overall as isolates are not separated into new and retreated.

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Reported susceptibility results of the Canadian Tuberculosis Laboratory Surveillance System

35 pages (379 KB) in PDF Format

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How To Reach Us

For more information, copies of this report or other reports, please contact: 

Tuberculosis Prevention and Control
Centre for Infectious Disease Prevention and Control
Public Health Agency of Canada
100 Eglantine Driveway, Health Canada Building
A.L. 0603B, Tunney's Pasture
Ottawa, ON K1A 0K9

Internal Postal Address: 0603B
Telephone:    (613) 941-0238
Facsimile:    (613) 946-3902
EMAIL: TB_1@ phac-aspc.gc.ca

The following text, figures and tables were prepared by: 

Edward Ellis, MD, MPH, FRCPC Manager Tuberculosis Prevention and Control	Melissa Phypers, MSc Senior Epidemiologist Tuberculosis Prevention and Control
Derek Scholten, MSc Epidemiologist Tuberculosis Prevention and Control	Victor Gallant, MA Tuberculosis Database Manager Tuberculosis Prevention and Control

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© Her Majesty the Queen in Right of Canada, 2007.

Cat. HP37-4/2006 ISBN 978-0-662-49834-6

Cat. HP37-4/2006E-PDF ISBN 978-0-662-45075-7

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Acknowledgments
Tuberculosis Prevention and Control would like to acknowledge the members of the Canadian Tuberculosis Laboratory Technical Network and their teams for their contribution to and their participation in the Canadian Tuberculosis Laboratory Surveillance System (CTBLSS).