Tuberculosis: Drug resistance in Canada-2007

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Cat. HP37-4/2007E-PDF ISBN 978-0-662-48037-2

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

Tuberculosis Prevention and Control
Community Acquired Infections Division
Centre for Communicable Diseases and Infection Control
Infectious Disease and Emergency Preparedness Branch
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

This report can also be accessed on the internet at:

http://www.publichealth.gc.ca/tuberculosis

Acknowledgment

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.

Table of Contents

• INTRODUCTION
• METHODS
• RESULTS
• DISCUSSION
• LIMITATIONS
• CONCLUSIONS
• REFERENCES
• FIGURES
  • Figure 1. Reported TB drug resistance in Canada by province/territory – 2007
  • Figure 2. Reported Mycobacterium tuberculosis isolates in Canada by province/territory – 2007.
  • Figure 3. Overall pattern of reported TB drug resistance in Canada – 2007
  • Figure 4. Reported TB drug resistance in Canada by type of drug – 2007
  • Figure 5. Any resistance by type of drug in Canada as a percentage of the number of isolates tested – 1998-2007
  • Figure 6. Overall pattern of reported TB drug resistance in Canada as a percentage of isolates tested – 1998-2007
• TABLES
  • Table 1. Overall pattern of reported TB drug resistance in Canada – 1998-2007
  • Table 2. Reported Mycobacterium tuberculosis isolates by “reporting” and “originating” province/territory, Canada – 2007
  • Table 3. Reported MDR-TB isolates by province/territory, Canada – 2007
  • Table 4. Reported TB drug resistance by sex and age group, Canada – 2007
  • Table 5. Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Alberta – 1998-2007
  • Table 6. Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, British Columbia – 1998-2007
  • Table 7. Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Manitoba – 1998-2007
  • Table 8. Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, New Brunswick – 1998-2007
  • Table 9. Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Newfoundland and Labrador – 1998-2007
  • Table 10. Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Northwest Territories – 1998-2007
  • Table 11. Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Nova Scotia – 1998-2007
  • Table 12. Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Nunavut – 1998-2007
  • Table 13. Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Ontario – 1998-2007
  • Table 14. Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Prince Edward Island – 1998-2007
  • Table 15. Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Quebec – 1998-2007
  • Table 16. Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Saskatchewan – 1998-2007
  • Table 17. Reported results for routine drug susceptibility testing of Mycobacterium tuberculosis isolates, Yukon – 1998-2007
• APPENDICES
  • Appendix 1 – Participating Laboratories of the Canadian Tuberculosis Laboratory Surveillance System (CTBLSS)
  • Appendix 2 – Mycobacterium tuberculosis Complex Antimicrobial Susceptibility Reporting Form

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.

Every year laboratories report to 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 lab, within the previous calendar year. TBPC subsequently produces this annual report.

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/territory where the tests were performed, and susceptibility results. 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 report only their own isolate susceptibility results.

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, only the most recent susceptibility result is included for analysis.

Results presented are for first-line drugs routinely tested for resistance, typically isoniazid (INH), rifampin (RMP), pyrazinamide (PZA) and ethambutol (EMB). Although streptomycin (SM) was reclassified in 2005 as a second-line anti-TB drug in Canada, it will continue to be reported in the same format for provinces/territories that routinely test for SM resistance. As well, 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).

Historically, results for second-line drugs were submitted to TBPC but only from some jurisdictions. Starting with this report, a more comprehensive reporting of susceptibility testing results for second-line anti-tuberculosis drugs has been carried out, but only for those isolates that were identified as MDR-TB. Second-line drug testing varies between jurisdictions, but typically testing is done for amikacin or kanamycin, capreomycin, clofazimine, ethionamide, ofloxacin, para-amino salicylic acid and rifabutin.

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 will be submitted and counted for that calendar year, otherwise the result will be recorded in the next year’s set. For example, if a specimen is received on December 20, 2007 and the culture grows only in January 2008 it would be considered a 2008 isolate. With this approach the majority of results will be ready by January 31 of each subsequent year. Initially, there may be a slightly larger than expected decrease in the number of isolates reported between 2006 and 2007. This difference is expected to reverse by 2008.

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 non-radiometric fluorometric proportion method MGIT® 960. New Brunswick, Newfoundland and Labrador, Nova Scotia, Ontario and Saskatchewan use MGIT® 960. All other provinces/territories used Bactec® 460. Four laboratories conduct second-line testing: Alberta, Ontario, Quebec and the National Reference Centre for Mycobacteriology (NRCM) in Manitoba. Table A lists the first-line and second-line anti-tuberculosis drugs and the critical concentrations in mg/L used by the participating laboratories.

Table A: Critical concentrations for routine testing of anti-tuberculosis drugs

First-Line Anti-Tuberculosis Drug
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. For 2007 approximately 60% of isolates from Manitoba were also tested. There is also a high concentration for SM which is 6.0 mg/L in BACTEC® 460.
	Concentrations Tested*** (mg/L)
Amikacin (AMK)	1.0
Capreomycin (CAP)	1.25
Ethionomide (ETH)	1.25
Kanamyin (KAN)	5.0
Para-amino salicylic acid (PAS)	2.0
Ofloxacin (OFLOX)	2.0
Rifabutin (RIF)	0.5

*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.
**MGIT 960 concentrations are pending approval from the Clinical and Laboratory Standards Institute (CLSI).
***Most of the second-line drugs were not used at the time of the development of the Proportion Method and the definition of the critical concentrations. For the current report we are using the "concentrations tested" and suggest caution to be exercised when interpreting results. Concentrations are for the Bactec 460.

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, 2008. The historic record is reviewed annually and adjustments are made to the tables as new/updated information becomes available.

RESULTS

For 2007, 1,271 reports were received. Of these, five were Mycobacterium bovis (BCG) and were excluded from the analysis. Between 1998 and 2006 the annual rate of decline in the number of isolates submitted was 0.6%. Between 2006 and 2007 the decrease in the number of isolates reported was 9%. This was due in part to the change in methodology, where only those reports with known results as of December 31st of the year are reported as opposed to the results for all samples received in the lab in a given year.

There were no reports received from Prince Edward Island. New Brunswick, Newfoundland and Labrador, Northwest Territories, Nova Scotia, Nunavut and Yukon reported that all isolates tested were susceptible to all first-line anti-tuberculous drugs. For the remaining provinces some resistance was reported.

Of the 1,266 isolates included for analysis, 139 (11.0%) were resistant to at least one of the anti-tuberculosis drugs tested: INH, RMP, EMB, PZA or SM. Of the isolates tested, 8.7% demonstrated INH resistance. Eleven isolates (0.9%) were MDR- TB and were reported from British Columbia, Ontario and Quebec.

Demographic information on individual patients from whom the isolates originated is limited in this laboratory-based surveillance system. The age of the individual was known for 1,230 isolates. Of these, 35% were between the ages of 25 and 44. For 1,213 isolates, the sex of the individual was known, and of these, 55% were male.

Second-line drug testing was done for all MDR-TB isolates to determine the extent of XDR-TB. Resistance to second-line drugs was reported: 14% of those tested for amikacin were resistant, 18% were resistant to capreomycin, 25% were resistant to kanamycin (only 4 isolates tested) and 9% were resistant to ofloxacin. There were no cases that met the accepted definition of XDR-TB. For each of the MDR –TB cases identified, second-line drugs tested and the results of the testing are given in the Table B.

Table B: Second line resistance pattern for MDR-TB cases reported in 2007

A retrospective review of all reported TB isolates tested between 1998 and 2007 identified 170 that were classified as MDR-TB representing 1.2% of all data in the CTBLSS. Table C provides a summary of the isolates that were tested and of those the number and the percentage that were identified as MDR-TB. Table D presents the provincial/territorial distribution of MDR-TB cases.

Table C: Total number of isolates tested and number and percentage identified as MDR-TB: Canada 1998 -2007

Year	Total number of Isolates	Annual percentage change	MDR-TB (%)
1998	1 461		18 (1.2)
1999	1 415	↓ 3.1	18 (1.3)
2000	1 491	↑ 5.4	15 (1.0)
2001	1,476	↓ 1.0	15 (1.0)
2002	1,419	↓ 3.9	22 (1.6)
2003	1,408	↓ 0.8	21 (1.6)
2004	1,379	↓ 2.1	12 (0.9)
2005	1,336	↓ 3.1	22 (1.6)
2006	1,389	↑ 4.0	16 (1.2)
2007	1,266	↓ 8.9	11 (0.9)
TOTAL	14,040		170 (1.2)

 

 

Table D: Provincial/territorial breakdown of identified MDR-TB isolates: 1998- 2007

Province	Count	Percent (%)
Alberta	9	5.3
British Columbia	34	20
Manitoba	10	5.9
Nunavut	1	0.6
Ontario	102	60
Quebec	14	8.2
Total	170	100

Figure A shows, of the 170 MDR-TB isolates identified between 1998 and 2007, the number that had any resistance to the second-line drugs used to define XDR-TB cases, (amikacin, capreomycin, kanamycin and ofloxacin), measured as a percentage of the total number of isolates tested against the drug.  Between 1998 and 2007 there appears to be a greater percentage of the isolates tested that show some resistance to one or more to the second-line drugs; however the numbers are small and any interpretation must be made with caution.  Only 2 of the 170 MDR-TB isolates met the definition of XDR-TB, one case reported in 2003 and the second reported in 2006.  There were no cases reported in 2007.

Figure A:   Trend in drug resistance patterns over time for MDR-TB isolates tested for second-line drug resistance: Canada 1998 – 2007

DISCUSSION

Susceptibility results were reported for 1,266 isolates in 2007.  The percentage of isolates demonstrating any type of drug resistance was 11.0%.  The proportion of isolates classified as MDR-TB decreased slightly from 1.2% in 2006 to 0.9% in 2007.  The average annual percentage of reported MDR-TB since 1998 was 1.2%. There were no XDR-TB cases in 2007.

Seventy-seven percent of the reported laboratory TB isolates in Canada in 2007 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, Saskatchewan and Yukon have not reported any MDR-TB isolates.

Extensively drug-resistant tuberculosis is a growing international concern. As of February 2008, 45 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),2 the global population weighted percentage for any resistance among new cases was  reported as 17%  and for previously treated cases was 35.0%. In Canada* for 2007, the percentage of isolates showing any resistance was 11.0%. 

The global estimated population weighted mean of MDR-TB as reported for 2006 in the WHO/IUALTD drug resistance report is 4.8% (95% CLs, 4.6-6.0).²  In Canada for 2007 the percentage of isolates that were identified as MDR-TB was 0.9%.

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*Unlike the WHO/IUATLD that provide the prevalence of TB drug resistance for both new and retreated cases, this report presents only overall incidence - isolates are not separated into new and retreated cases.

LIMITATIONS 

Sensitivity testing for anti-tuberculosis 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.

Usually 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 MDRTB. 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 report includes 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. 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.