1. Drug resistant tuberculosis
Professor Peter D.O. Davies,
Tuberculosis Research and Resources Unit, Liverpool.

2. Warning will kill one person in three
A new plague is sweeping across the planet
Soon multidrug resistant tuberculosis
will kill one person in three
The Constant Gardener November 2005

3. Definitions Multidrug-resistant tuberculosis (MDRTB)
Resistance to Isoniazid and Rifampicin
Extensively (extremely) drug-resistant (XDR-TB)
MDR-TB plus resistance to a second line injectable drug such as amykacin plus a quinolone.

7. The extent of MDR-TB, 2004. Zignol M, et al. Global incidence of MDR-TB. JID 2006:194:479-485.
of all cases.
181,000 (95%CI 135, ,000) 43% previously treated.
China, India, Russian Fed: 62% of global burden.

10. An unfortunate case Date Smear result Treatment Resistance
Jan HRZ
March HR
April H resistant
April HRE
Sept HRE resistant
Oct HRZE
Dec SHRE resistant
Jan

11. An unfortunate case Date Smear result Treatment Resistance
Jan HRZ
March HR
April H resistant
April HRE
Sept HRE resistant
Oct HRZE
Dec SHRE resistant
Jan

12. A near miss Indian male aged 28 with extensive hilar gland enlargement
HRZE HR resistant and partial E resistant
Action Stop HR
Increase E and add S and Cipro
ZESCip
Danger Already E and Z resistant .
May have resistance to S too.
Result SHRZECipro resistant
Actual responding to Z Cipro Prothionamide Cyc

13. Table of drugs used for the treatment of tuberculosis.
First line drugs
Second line drugs
Essential
Other
Old
New
Isoniazid  Rifampicin   
Pyrazinamide
Ethambutol Streptomycin
Ethionamide Cycloserine Capreomycin Amikacyn  Kanamycin PAS Thiocetazone
Quinolones
ofloxacin ciprofloxacin moxifloxacin
Macrolides
clarithromycin
Clofazimine Amoxycillin & Clavulanic acid
New rifamycins    Rifabutin    Rifapentine
Linezolid

14. Currently recommended treatment of fully sensitive tuberculosis
Isoniazid
Rifampicin
Pyrazinamide
Ethambutol/Streptomycin
For 2 months or until sensitivities available
Then
Isoniazid and Rifampicin for 4 months
10 months for CNS TB
Use FDCs where possible

16. Drug resistance - risk factors
A. Previous treatment especially if prolonged
B. Contact with drug resistant patient
C. Country of origin East Europe
Former USSR
Middle East
South and SE Asia
Latin America
Africa
D. Age (In MDR area, commoner in children)
E. HIV (Where MDR common)
F. Substance abuse and homelessness

17. Management of the potentially drug resistant patient
1. History – assess risk factors.
a. No previous history HRZE
b. Previous history : HR plus four drugs not taken before.
Eg: HRZ: HRE Amik Cipro Eth
Eg: SHRZE: HR Amik Cipro Eth Cyclo
2. Rifampicin resistance gene
3. Fast track bacteriology
4. Never add a single drug at a time.

18. Drug resistant Genes in M.tuberculosis
Drug Gene
Rifampicin rpoB
Streptomycin rpsL
Isoniazid No: base pairs
katG
inhA

20. Possible regimens according to patterns of drug resistance
Suggested regimen
Length
Comments
Isoniazid and PZI
Amik,
RIF,E,Mox
9 months to a year
Anticipate good response
Isoniazid and E
Amik,RIF,
PZI,Mox.
9-12/12
Isoniazid and RIF
Amik,PZI,
E,Mox.
At least 18/12
Consider surgery

21. Possible regimens according to patterns of drug resistance
Suggested regimen
Length
Comments
INH,RIF,
PZI
Amik,E,
Mox,Eth,Cy
18-24/12
After cul-ve
Consider surgery
PZI,E
Amik,Mox.Eth,Cy,Clar
As above
Assume
To Strep
Unless
Sensitivity

22. Other forms of therapy Cytokines IL-2 Gamma-interferon
Immunomodulators
Mycobacterium vaccae

24. Infection Control issues
Careful
Evidence free
Negative pressure rooms
Special face masks
Care over transfer of patients
Nursing issues

25. Management of MDRTB
DON’T

26. Estonia Very high rates of MDRTB Manageable numbers (75-100)
Small country
Single controller
Several treatment supervisors
Monthly progress meetings

27. England Low rate Manageable number (75-100)
Central sensitivity testing
Undesignated experts
No co-ordination of therapy
No central assessment

28. Proposal for the management of drug resistant tuberculosis at national level
All MDRTB specimens identified by reference lab.
Clinician managing patient informed
Central management co-ordinator informed
Clinician contacted and regimen suggested
Monthly clinical updates from clinician to co-ordinator.
Regular monitoring of bacteriological results
Regular input from central co-ordinator.
Regular meetings convened by co-ordinator

29. National MDR-TB co-ordination centre
Voluntary
Patient data and progress
Outcomes: bacteriological and clinical.
Availability of advice re: management
Development of expert committee.
Headed MDRTB

30. MDRTB Useful references
The WHO/IUATLD Global project on Anti-tuberculosis Drug Resistance Surveillance, Antituberculosis drug resistance in the world. Report n. 2. Prevalence and trends. Geneva:World Health organisation. WHO/CDS/TB/
Iseman M. Treatment of multi-drug resistant tuberculosis. NEJM 1993;329:
Yew WW. Chemotherapy of tuberculosis:present,future and beyond. in Clinical Tuberculosis, Edit: PDODavies, Arnold 2003,pp And other chapters.
Davies PDO. Multi-drug resistant tuberculosis. In Tuberculosis, Edit: M Monir Madkour, Springer 2004, pp
ATS The treatment of tuberculosis MMWR 2003;52:RR 1-77
Zignol M, et al. Global incidence of MDR-TB. JID 2006:194:

31. Estimated % of new TB cases with MDR, 2000
7 or more
No estimate
Source: Dye et al. J.Infect.Dis. 185 (8): , 2002
The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.
© WHO 2002

32. Drug resistance in the UK 2003 HPA DATA http://www. hpa. org
Mono
resistance
With or Without
Other
Isoniazid
273
5.5%
361
7.3%
Rifamp: 23
0.5%
100
2.0%
Any
314
6.3%
404
8.2%
MDR 77
1.6%