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

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

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.

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 135,000-319,000) 43% previously treated. China, India, Russian Fed: 62% of global burden.

An unfortunate case Date Smear result Treatment Resistance Jan 1998 + HRZ March HR April H resistant April HRE Sept + HRE resistant Oct HRZE Dec SHRE resistant Jan +

An unfortunate case Date Smear result Treatment Resistance Jan 1998 + HRZ March HR April H resistant April HRE Sept + HRE resistant Oct HRZE Dec SHRE resistant Jan +

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

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

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

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

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.

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

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

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

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

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

Management of MDRTB DON’T

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

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

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

National MDR-TB co-ordination centre Voluntary Patient data and progress Outcomes: bacteriological and clinical. Availability of advice re: management Development of expert committee. Pat.Jones@ctc.nhs.uk Headed MDRTB

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/2000.278. http://www.who.int/gtb/publications/drugresistance/infullorpartial.html Iseman M. Treatment of multi-drug resistant tuberculosis. NEJM 1993;329:784-91. Yew WW. Chemotherapy of tuberculosis:present,future and beyond. in Clinical Tuberculosis, Edit: PDODavies, Arnold 2003,pp 191-210. And other chapters. Davies PDO. Multi-drug resistant tuberculosis. In Tuberculosis, Edit: M Monir Madkour, Springer 2004, pp809-838. ATS The treatment of tuberculosis MMWR 2003;52:RR 1-77 http://www.priory.com/cmol/TBMultid.htm Zignol M, et al. Global incidence of MDR-TB. JID 2006:194:479-485.

Estimated % of new TB cases with MDR, 2000 0 - 0.9 1 - 2.9 3 - 4.9 5 - 6.9 7 or more No estimate Source: Dye et al. J.Infect.Dis. 185 (8):1197-1202, 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

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%