1. Ward 5D Linda Iskandar 1

2. Patient MR From Nepal, has been in Australia for 2 years on a dependent student visa studying nursing. Presenting complaints * Fever every evening * Night sweats * Chest pain * Weight loss * Weakness and dizziness in the last week Diagnosed with extensive drug resistant (XDR) pulmonary Tuberculosis 2

3. Patient background Smoker Lives with friends Partner in Nepal Works in a sushi train restaurant Father has had TB as well as patient when he was 6 years of age. 3

4. Tests/plan PICC Start antibiotic treatment echo Immunodeficiency screening HIV status Liver and renal function tests Visual test 4

5. Tuberculosis TB is a disease caused by a bacteria known as mycobacterium tuberculosis which mainly affects the lungs (23,4,12). Diagnosis Acid Fast Bacili (AFB) microscopy AFB Culture QuantiFERRON-TB Gold Assay Clinical features - Night sweats - dry cough - chest pain - fever - Weakness and dizziness - weight loss 5

6. Risk factors Smoking Gender Exposure to TB Immunocompromised people e.g HIV (3).. 6

7. Drug resistant TB Multi-drug resistant tuberculosis (MDRTB) MDRTB is characterised by a strain of Mycobacterium tuberculosis which exhibits resistance to at least isoniazid (INH) and/or rifampicin (RIF), which are the two key first line drugs in TB treatment (12). Extensively drug-resistant tuberculosis (XDRTB) Is MDRTB with additional resistance to any fluoroquinolone, and to at least one of three injectable second-line anti-TB drugs (capreomycin, kanamycin, and amikacin), which are second line drugs used in MDRTB treatment (12). 7

8. Basic treatment principles 8 Table 1: General principles for designing an empirical regimen to treat MDR-TB (9).

9. Table 2: WHO anti-TB drug classification (12). 9 Classifying drug groups.

10. First line treatment for TB Rifampin (RIF) Isoniazid (INH) Ethambutol (EMB) Pyrazinamide (PZA) Streptomycin (STR) (3,4,7,8) 10

11. 11 Figure 1: Mode of action of first line drugs treatments for TB (4).

12. Resistance with first line treatment of TB INH and RIF resistance is found in 7-10% of mycobacterium tuberculosis isolated in Australia, predominantly in patients born overseas and in those with a history of treated TB (2). 12

13. Second line treatment Para-aminosalicylic acid (PAS) Fluoroquinolones e.g. Moxifloxacin (MOXI) Thioamides e.g. Prothionamide (PRO) Aminoglycosides e.g. amikacin (AMI) Polypeptides e.g. capreomycin (CAP) Cycloserine (7,8) 13

14. 14 Figure 2: Mode of action of second line drugs treatments for TB (4).

15. MDR-TB in the top 15 countries 15 Figu re 3: Prevalence of multi-drug-resistant (MDR) tuberculosis among new cases in the top 15 settings (>6%) with 95% CI. The black bars show the prevalence of MDR tuberculosis (resistance to at least INH and RIF), the white bars the prevalence of MDR tuberculosis cases harboring bacilli with additional resistance to EMB and streptomycin (9).

16. Patient MR: Medications 22/3 Isoniazid (INH) 300mg nocte Moxifloxacin (MOXI) 400mg nocte Ethambutol (EMB) 500mg D Pyrazinamide (PZA) 2g D Prothionamide (PRO) start 250mg D aim is750mg Para-aminosalicylic acid (PAS) start on 2g D aim is 4g BD Amikacin (AMI) 1000mg D IV 25/3 Ondansetron 8mg IV 16

17. Change to current medications 27/4 Pyridoxine 100mg D INH 400mg D EMB 1500mg nocte PZA 2g mane MOXI 400mg mane PRO 750mg nocte AMI 1000mg D IV Sodium bicarbonate 5%+ 2 drops TDS into the glycerol 30% left ear Paracetamol 1g QID Metoclopramide 10mg TDS PO/IV 17

18. Test results 16/5 *MDR TB smear +ve involving right upper lobe, lobectomy to be considered. *Multiple +ve AFB sputum 17/5 * multi-resistant organism as suspected consider starting linezolid, amoxycillin + clavulanic acid, clofazimine and PAS. 01/6 VRE confirmed from a rectal swab collected on the 17/5 18

19. Medications cont.. 1/6 Pyridoxine was decreased to 25mg mane. 6/6 PRO was stopped and the following were added; * PAS 4g BD * linezolid 400mg BD * clofazimine 50mg D * amoxycillin+ clavulanic acid 1 BD 19

20. Patient MR: Medication regimen now Pyridoxine 25mg mane INH 400mg mane EMB 1500mg nocte PZA 2g mane MOXI 400mg mane AMI 1000mg D IV Metoclopramide 10mg TDS PAS 4g TDS linezolid600mg BD clofazimine 100mg D amoxycillin+ clavulanic acid 1 BD Omeprazole 40mg mane Ondansetrone 4mg BD 20

21. Monitoring Sputum should be cultured on a monthly basis until negative on repeated specimens, and then cultured at the end of the treatment (2,7,9). Patients on EMB should have their vision checked monthly particularly if therapy is continued for more then 2 months (2,7,9). Liver function Regular monitoring of liver function tests (LFTs) is recommended, particularly for older patients and for those with abnormal baseline LFTs, pre- existing liver disease, chronic viral hepatitis or high alcohol intake (2,8,12). 21

22. Monitoring Kidney function Will require regular U&E’s to monitor kidney function while on Amikacin (1,2,6,12) FBC and neurology Bone marrow suppression and peripheral neuropathy are sometimes observed with prolonged linezolid therapy (more than 14 days) and regular haematological and neurological monitoring are recommended (6,12) Drug interactions (1,2,6,12) Pharmacokinetic Pharmacodynamic Cumulative toxicity 22

23. Possible Drug Adverse Effect 23 Table 3: Management strategies for adverse neurological reactions due to second-line anti- tuberculosis drugs (12).

24. Monitoring using DOTS Directly Observed treatment short-course (DOTS) is a major plank in the WHO Global plan to stop TB. DOTS focuses on five main points of action; 1. Government commitment to control TB, 2. Diagnosis based on sputum-smear microscopy tests done on patients who actively report TB symptoms, 3. Direct observation short-course chemotherapy treatments, 4. A definite supply of drugs and 5. Standardized reporting and recording of cases and treatment outcomes (13). 24

25. Take home Message Laboratory tests are a necessity to eliminate other underlying disease and to ensure effective progress of treatment. QUM needs to be enforced to eliminate resistance and toxicity. Educate patient about treatment duration, importance of treatment adherence and possible adverse effects to look out for. 25

26. References 1. Australian Medicines Handbook, 2010. Australian Medicines Handbook Pty Ltd. Adelaide, Australia. 2. eTG. Last accessed 23 rd June 2011, available at: http://etg.hcn.net.au.ezproxy1.canberra.edu.au/ 3. Walker R, Edwards C. (2003). Clinical Pharmacy and Therapeutics. Churchill Livingstone 4th edition. 4. NIAID. Last accessed 23 rd Jne 2011, available at: http://www.niaid.nih.gov/topics/tuberculosis/Understanding/WhatIsTB/ScientificIllustrations/Page s/extensivelyDrugResistantIllustration.aspx. 5. Peloquin C, et al. (2004). Aminoglycoside toxicity: daily versus thrice-weekly dosing for treatment of mycobacterial diseases. Clin Infect Dis 38, 1538 44. 6. Chan E, et al. (2003). Pyrazinamide, ethambutol,ethionamide, and aminoglycosides. In: Rom WN, Garay SM (editors), Tuberculosis, 2nd edition. Philadelphia, PA: Lippincott Williams & Wilkins, pp. 773 789. 7. Di Perri, G., and Bonora, S. (2004).Which agents should we use for the treatment of multidrug- resistant Mycobacterium tuberculosis? J Antimicrob Chemother 54, 593 602. 8. Centers for disease control. TB. Last accessed 21 st June 2011, available at: www.cdc.gov/tb 9. Chiang, C., Centis, R.,and Migliori, G.B., et al. (2010). Drug-resistant tuberculosis: Past, present, future. Respirology 15, 413–432. 10. McIlleron H, et al. (2006) Determinants of rifampin, isoniazid, pyrazinamide, and ethambutol pharmacokinetics in a cohort of tuberculosis patients. Antimicrob Agents Chemother 50, 1170 7. 11. Burman W, et al. (2006). Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis. Am J Respir Crit Care Med 174, 331 8. 12. Department of health and aging. Communicable disease intelligence. Last accessed 28 th June 2011, available at: commhttp://www.health.gov.au/internet/main/publishing.nsf/Content/cda- cdi3104i.htm 13. Mendez A.P., Gowda D.K., and Frieden T.R. (2002). Controlling multidrug-resistant tuberculosis and access to expensive drugs: a rational framework. Bulletin of the world health organization 6, 80. 26