Dr Sarah Mungall TB Lead Physician

1. Multidrug Resistant Tuberculosis Registrar training day 2.3.18 Dr Sarah Mungall TB Lead Physician Respiratory Department BRI

2. What is MDRTB? • An isolate of M. tuberculosis that is resistant to at least isoniazid and rifampicin and possibly additional agents.” • These 2 drugs have formed the backbone of standard TB treatment for the past few decades. • Standard pulmonary TB treatment is 2 months of rifampicin, isoniazid, pyrazinamide and ethambutol followed by 4 months of rifampicin and isoniazid.

3. What is XDRTB? • XDR-TB (extensively drug resistant): resistant to at least isoniazid, rifampicin, and fluoroquinolones as well as either aminoglycosides (amikacin, kanamycin) or capreomycin or both.

4. Why is it important? • No more infectious than sensitive MTB • Implications of infection much greater in view of treatment regimen – length and toxicity

5. Why is it important? • 2014: estimated 480,000 MDRTB cases worldwide • 52 cases in UK (1.4% of total cases) • Treatment completion within 2 years only 54%

6. Why is risk assessment important? • Isolation (infection control) • Initial treatment regimen • Microbiological testing (ask for PCR for mutations for rifampicin and isoniazid resistance) • Explanation to patient (likely to need 3-6 months in hospital)

7. Risk factors for MDRTB • Known contact with MDR-TB • History of failed treatment (especially abroad) • Country of birth • History of relapse after treatment • HIV infection

8. Most frequent countries of birth of non-UK born TB cases with drug resistance, UK, 2013 • * The table shows the top ten countries of birth for the number of isoniazid resistant cases and MDR-TB cases in 2013. For these countries, the total number of cases and proportions with resistance are shown. • **Culture confirmed cases with DST results for at least isoniazid and rifampicin • Source: Enhance Tuberculosis Surveillance (ETS), Enhanced Surveillance of Mycobacterial Infections (ESMI) • Data as at: May 2014. Prepared by: TB Section, Centre for Infectious Disease Surveillance and Control, Public Health England • Tuberculosis in the UK: 2014 report

9. Proportion of TB cases with isoniazid resistance or MDR-TB, UK, 2004-2013 • Source: Enhance Tuberculosis Surveillance (ETS), Enhanced Surveillance of Mycobacterial Infections (ESMI) • Data as at: May 2014. Prepared by: TB Section, Centre for Infectious Disease Surveillance and Control, Public Health England • Tuberculosis in the UK: 2014 report

10. How to you get MDRTB • Acquired resistance • Infection with MDRTB strain

11. Acquired drug resistance • Wright et al 2009

12. How is it diagnosed? • Molecular testing ( for drug resistance) • Culture confirmation • Whole genome sequencing • Molecular testing for drug resistance should be routine if previous TB, Known MDRTB contact, from country with incidence of MDRTB >5%

13. How is it treated? • There is no good evidence • Expert opinion required: • MDR-TB service • MDR-TB advisory panel

14. What does an MDRTB Service look like? • Negative pressure rooms • Caseload of at least 50 • Links with HIV and paediatric services • Links with thoracic surgery • Access to rapid molecular diagnostics • Outreach and DOT • Multidisciplinary team

15. Multidisciplinary Team • Medical consultant • Medical Microbiologist • Ward (nursing) manager • Lead Control of Infection nurse • TB specialist nurse (responsible for any advice and education to the ward’s nursing team, ongoing contact tracing work, and support around appropriate discharge planning) • PHE representation • Pharmacy input

16. MDRTB Service • Accepts regional referrals • Links in with MDRTB advisory service • Access to bedaquiline and delamanid

17. Before transfer to Bristol • The source hospital is responsible for ensuring the patient is fully aware of the following (interpretation services MUST be used if the patient is non-English speaking): • The nature of their illness. • The reason why transfer out-of-area is essential. • The minimum length of stay they can anticipate. • The name, address, name of ward, and phone contact details of the hospital to which they are being transferred. This must be given in writing to the patient (and their family with the patient’s consent) • Transport during transfer • The source hospital is responsible for arranging safe transport for the patient to the Bristol hospital by ambulance (the ambulance teams are responsible for control of infection during the journey).

18. Before transfer to Bristol • Dependents’ / other social needs • The source hospital is responsible for identifying a person who is accountable for identifying whether the patient has dependents who will need care or support, or other social needs (such as maintenance of a tenancy) and liaising appropriately to ensure these needs are addressed. This person’s name and contact details should be transferred to the receiving hospital, so that nurses have a point of contact for later concerns and queries. • Contact tracing • The source hospital’s TB team or associated TB nurse must identify what contact tracing has been done, and what contact-tracing issues are outstanding. These must be communicated to PHE (phe.agwphechpt@nhs.net), and the receiving TB nurses (bristoltbnurse@nhs.net).

19. Treatment • No good evidence but: • November 2016 MDRTB statement from the British Thoracic Society including summary of: • WHO update June 2016, more practical grouping of drugs including newer drugs • Banglasdeshi short course regimen – at 9/12 cure of 90% vs 20/12 cure of 78%. • Surgery – very limited evidence, consider only if minimal disease

20. Treatment • Based on molecular and drug susceptibility testing results • Short course regimen • Or • Pyrazinamide and four core second line TB medicines ( plus consider high dose isoniazid and ethambutol)

21. Treatment • Bedaquiline : • Time to culture conversion reduced. No mortality benefit – black box warning and informed consent because of increased mortality. (STREAM trial awaited for long term benefit) • Delamanid: • Time to culture conversion reduced. Also showed mortality benefit. • Side effects – prolonged QTc

23. Classes of drugs (WHO 2016)

24. Practical Measures • Strict infection control procedures • Improve inpatient environment • Weekly sputum samples • Directly observed therapy

25. Other things to consider • Develop a treatment-partnership with the patient, and support patient education and self-management: address language barriers early on, contract, DOTS • Physical aspects: exercise bike, exercise programme, fresh air. • Psychological: focus on the patient’s concerns and priorities • Social/ financial: • Spiritual: • Discharge planning:

26. Other things to consider • Contract: • Part 2A orders: • Discharge plans

27. Before discharge • Three sputum samples to be smear and culture negative • Agreement from PHE, microbiology and clinicians that discharge arrangements are suitable • Arrangements for directly observed therapy to be in place • Agreement on arrangements for follow up/treatment decisions • Clear information on previous treatment regimen/monitoring and length of treatment • Consider short inpatient stay in local hospital prior to discharge • Good practice to do monthly letters as inpatient for referring team

28. Top Tips • Think MDRTB • Find out your local lab policies on 1st and 2nd line testing and whole genome sequencing • Information to patient – 3-6 months in hospital • Communication with patient – “contract” • Communication with labs, PHE, nurses, experts • Carrots and sticks • Directly observed therapy • Repatriation (for out of area cases)