1. Page 1 Extreme Drug Resistant TB and the Work Place Dr Jennifer Coetzee Ampath

2. Page 2 Outline The “ABC” of TB drug resistance –Current anti-TB drugs available –What is MDR? –What is XDR? –How does TB drug resistance develop? Epidemiology of XDR TB XDR TB in the work place? Prevention and management of TB transmission in the occupational setting

3. Page 3 Anti TB Drugs Currently Available 1st Line Drugs: INH Rifampicin PZA Ethambutol Streptomycin 2nd Line Drugs Capreomycin Kanamycin Ethionamide PAS Cycloserine Quinolones Thiacetazone

4. Page 4 The ABC of TB Drug Resistance MDR TB: Resistance to INH and Rifampicin XDR TB: MDR TB that is also resistant to quinolones (e.g. ciprofloxacin) and one other of 2 nd line injectable drug Thus Extreme Drug resistance Laboratory diagnosis based on susceptibility testing Cure rate for MDR TB +/- 50% XDR TB 64% more likely to die than if MDR TB

5. Page 5 How does TB drug resistance develop? Spontaneous and random mutations in the bacterial chromosome: –INH - 1 X 10 6 organisms –Rif - 1 x 10 8 –EMB - 1 x 10 6 –Strep - 1 x 10 5 Probability of spontaneous mutants being simulta- neously resistant to 2 or more drugs is product of individual frequencies… INH + Rif = 10 6 + 10 8 = 10 14

6. Page 6 MDR: Global Perspective 50 million people infected worldwide Low prevalence of MDR: –well functioning TBCP with DOTS, low prevalence of TB, resource rich High prevalence of MDR TB: –high TB rates, poor countries, limited medication available MDR rates estimated to be 3 - 4% Primary MDR: 1 - 3% Acquired: 7 - 17%

7. Page 7 Implications of MDR TB 100 X more expensive to treat Duration of Rx up to 24 months –Patient hospitalised for 4 - 6 months Extensive laboratory monitoring required Side effects of 2nd line drugs significant Inconvenient routes of administration >30% default rate Treatment failure > 10% if optimally Mx Mortality rate: –30 - 40% if HIV uninfected –70 - 80% if HIV infected

8. Page 8 XDR TB Hot off the press Term coined in March 2006 Report published in MMWR 24/03/06 350 cases worldwide between 2000 and 2004 Primarily in South Korea, Eastern Europe and western Asia 74 cases in USA

9. Page 9 Current Situation XDR USA: 4% of MDR cases meet criteria for XDR Latvia: 19% of MDR cases considered XDR Australia, Belgium, Canada, France, Germany, Ireland, Portugal, Spain, Britain: –XDR TB increased from 3% of drug resistant cases to 11% (2000 to 2004) Pandemic threat!

10. Page 10 RSA: The Tugela Ferry Event In Tugela Ferry HIV/TB co-infected patients, respon- ding to ARV but not to ATT, were identified early 2005 This prompted culture and susceptibility testing Infection with highly resistant M.tuberculosis

11. Page 11 South African Situation (Tugela Ferry) 1428 Patients with sputum sent 475 (34%) Culture-Positive for M.tb 921 Culture-Negative Lancet 2006, 368:1575-1580 Surveillance at District Hospital:

12. Page 12 475 patients Culture-Positive for M.tb 185 (39%) Resistant to Isoniazid & Rifampin (MDR TB) 290 Susceptible or Resistant but not MDR 30 (6%) Resistant to all tested drugs (XDR TB) Prof. W. Sturm

13. Page 13 Overall Data for the Area 52 of 53 people with XDR TB died 44 were co-infected with HIV Average survival was 16 days after sputum collection 55% of the patients were primary XDR! At least 2 HCWs were infected, died. A further 4 were suspected to have contracted XDR TB Strain resistant to all 7 anti-TB drugs available in SA Impact of 5.5 million people infected with HIV/AIDS

14. Page 14 Susceptibility Pattern Isoniazide R RifampicinR PyrazinamideR Ethambutol R Streptomycin R Kanamycin/amikacinR Ciprofloxacin/ofloxacin R EthionamideS Cycloserine? Capreomycin S PAS ?

15. Page 15 XDR TB and the Work Place Health care workers from KZN only published proven transmission of XDR TB to have occurred to date Recent case of patient with XDR TB on aero- plane in US Outbreaks of MDR TB has been well described No evidence to suggest that MDR or XDR TB is more easily transmitted than drug susceptible TB

16. Page 16 Principles of TB Transmission Inhalation of microscopic, aerosolised particles containing TB bacilli Vast majority: particles elaborated by coughing, sneezing or singing Alveolar deposition thought to be essential –Tiny enough to drift with inspired air rather than impact on mucous membranes Droplet nuclei of 0.5-5 µm usually vectors of infection Patients with extensive pulmonary TB pose greatest risk Study form Alabama, gradient of skin-test reactivity of contacts: –HHCs to smear (+) cases: 46% –Non-HHCs to smear (+) cases: 34% –HHCs to smear (-), culture (+) cases: 28% –Non-HHCs to smear (-), culture (+) cases: 24%

17. Page 17 Environmental Factors That Increase the Risk of Transmission of TB Exposure to TB in small, enclosed spaces Inadequate local or general ventilation that results in insufficient dilution or removal of infectious nuclei Recirculation of air containing infectious droplet nuclei Inadequate cleaning and disinfection of medical equipment Improper procedure for handling specimens

18. Page 18 Risk for Health-Care Associated Transmission of TB Transmission and outbreaks well described Magnitude of risk varies by: –Setting –Occupational group –Prevalence of TB in the community –Patient population –Effectiveness of TB infection-control measures

19. Page 19 Outbreaks in Health-Care Settings Multiple outbreaks involved transmission of MDR TB strains to both patients and HCWs –Majority of patients and HCWs were HIV infected Also outbreaks described in outpatient settings Factors contributing to outbreaks: –Delayed diagnosis of TB disease –Delayed initiation and inadequate airborne precautions –Inadequate precautions for cough-inducing and aerosol- generating procedures –Lack of adequate respiratory protection

20. Page 20 Principles of Management of TB Contacts Earliest possible identification of index cases –Rapid laboratory detection of MDR TB if indicated Duration / time-line of exposure often unknown Baseline CXR, symptom screening Diagnosis of latent TB infection –Role of blood assays, incl. TB Spot, Quantiferon Gold –Skin testing? Counseling, HIV testing imperative –Risk of reactivation disease Treatment of latent TB infection If exposed to MDR/XDR TB, to be referred to infectious disease specialist. Optimal therapy unknown.

21. Page 21 Conclusion “After 25 years working in TB treatment, I’m extremely concerned - we see very little progress, and there seems to be complacency in general about TB” Dr Karin Weyer, August 2006